VOLUME 60, NUMBER 1 (SUPPL)

VOLUME 60, NUMBER 1 (SUPPL) — OCTOBER 2014

HEPATOLOGY
Official Journal of the American Association for the Study of Liver Diseases
HEPATOLOGY
October 2014 — Pages 1–1266
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AT
TH N
E PA V I L I O
Over 9 year
yearss o
off p
prescribing
rescribing
experience in the US
More than 9 million
prescriptions filled
worldwide1
Indication
BARACLUDE (entecavir) is indicated for the treatment of chronic hepatitis B
virus (HBV) infection in adults with evidence of active viral replication
and either evidence of persistent elevations in serum aminotransferases
(ALT or AST) or histologically active disease. The following points should be
considered when initiating BARACLUDE:
• This indication is based on histologic, virologic, biochemical, and serologic
responses in nucleoside-treatment-naïve and lamivudine-resistant adult
subjects with HBeAg-positive or HBeAg-negative chronic HBV infection
and compensated liver disease.
• Virologic, biochemical, serologic, and safety data are available from
a controlled study in adult subjects with chronic HBV infection
and decompensated liver disease.
• Virologic, biochemical, serologic, and safety data are available for a
limited number of adult subjects with HIV/HBV co-infection who have
received prior lamivudine therapy.

Important Safety Information

WARNINGS: SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS
CO-INFECTED WITH HIV AND HBV, and LACTIC ACIDOSIS AND HEPATOMEGALY
• Severe acute exacerbations of hepatitis B have been reported in patients
who have discontinued anti-hepatitis B therapy, including entecavir.
Hepatic function should be monitored closely with both clinical and
laboratory follow-up for at least several months in patients who
discontinue anti-hepatitis B therapy. If appropriate, initiation of
anti-hepatitis B therapy may be warranted.
• Limited clinical experience suggests there is a potential for the
development of resistance to HIV (human immunodeficiency virus) All individuals depicted are
nucleoside reverse transcriptase inhibitors if BARACLUDE (entecavir) is models and not actual patients.
used to treat chronic HBV infection in patients with HIV infection that is
not being treated. Therapy with BARACLUDE is not recommended for
HIV/HBV co-infected patients who are not also receiving highly active Please see Brief Summary of
antiretroviral therapy (HAART).
Full Prescribing Information,
• Lactic acidosis and severe hepatomegaly with steatosis, including
fatal cases, have been reported with the use of nucleoside analogues, Including Boxed WARNINGS,
alone or in combination with antiretrovirals. following the next pages.
(continued on the following pages)
For nucleoside-naïve chronic hepatitis B (CHB) adults with evidence of active virus and
either evidence of persistent elevations in ALT or AST or histologically active disease

®
BARACLUDE
B AR (entecavir) is a
eco
rrecommended first-line option
nC
iin CHB guidelines in the
US a and around the world 2-8

APASL

US Algorithm European Chinese The Korean Japanese Ministry Asian Pacific

Association for Medical Association of Health, Labour Association
American Association
the Study of the Association for the Study and Welfare Study for the Study
for the Study of Liver
Liver (EASL) of the Liver Group Guideline of the Liver
Diseases (AASLD)
for CHB

Important Safety Information about BARACLUDE® (entecavir) TABLETS:

(continued from previous page)
Warnings and Precautions
• Before initiating BARACLUDE (entecavir)
therapy, HIV antibody testing should be
offered to all patients. BARACLUDE has not
been studied as a treatment for HIV infection
and is not recommended for this use.
• Lactic acidosis with BARACLUDE use has been
reported, often in association with hepatic
decompensation, other serious medical
conditions, or drug exposures. Patients with
decompensated liver disease may be at higher
risk for lactic acidosis. BARACLUDE should
be suspended in any patient who develops
clinical or laboratory findings suggestive of
lactic acidosis or pronounced hepatotoxicity.
Adverse Reactions
• In clinical trials in patients with compensated
liver disease, the most common (≥3%) adverse
reactions of any severity with at least a possible
relation to study drug for BARACLUDE-
treated subjects were headache, fatigue,
dizziness, and nausea. In these trials, the most
common adverse reactions of moderate to
severe intensity (grades 2-4) were diarrhea,
dyspepsia, nausea, vomiting, fatigue,
headache, dizziness, somnolence, and
insomnia.
• In the decompensated liver disease trial,
the most common adverse reactions of
any severity among patients treated with
BARACLUDE, regardless of causality,
i n c l u d e d: p e r i p h e r a l e d e m a (16%),
a s c i te s (15%), py re x ia (14%), h e p a t i c
encephalopathy (10%), and upper respiratory
infection (10%). In this trial, 18% (18/102) of
BARACLUDE patients and 20% (18/89) of
adefovir patients died during the first 48
weeks of therapy. The majority of those
deaths were due to liver related causes.
Please see Brief Summary of Full Prescribing Information,
including Boxed WARNINGS, following the next pages.
Drug Interactions
BARACLUDE is primarily eliminated by
the kidneys, therefore coadministration of
BARACLUDE with drugs that reduce renal
function or compete for active tubular secretion
may increase serum concentrations of either
entecavir or the coadministered drug. Patients
should be monitored closely when receiving
BARACLUDE with other renally-eliminated
drugs.
Pregnancy and Nursing Mothers
• There are no adequate and well-controlled
studies of BARACLUDE in pregnant women.
BARACLUDE should be used during
pregnancy only if clearly needed and after
careful consideration of the risks and benefits.
• There are no studies on the effect of
BARACLUDE on transmission of HBV from
mother to infant. Therefore, appropriate
interventions should be used to prevent
neonatal acquisition of HBV.
• It is not known whether BARACLUDE is
excreted into human milk; however, many
drugs are excreted into breast milk. Due to
the potential for serious adverse reactions
in nursing infants from BARACLUDE, risks
and benefits should be considered when
deciding whether to discontinue breast-
feeding or discontinue BARACLUDE in
nursing women.
Pediatric Use
• Safety and effectiveness of BARACLUDE in
pediatric patients below the age of 16 years
have not been established.
Renal Impairment
• Dosage adjustment of BARACLUDE is
recommended for patients with a creatinine
clearance <50 mL/min, including those on
(continued on the following page)
For nucleoside-naïve chronic hepatitis B (CHB) adults with evidence of active virus and
either evidence of persistent elevations in ALT or AST or histologically active disease

BARACLUDE (entecavir) is also recommended

as a first-line therapy in the publication:
The Management of Chronic Hepatitis B
in Asian Americans9

Approved and available for CHB in

over 50 countries and regions worldwide

Important Safety Information (continued)

Renal Impairment (continued)
hemodialysis or continuous
peritoneal dialysis.
Liver Transplant Recipients
• Renal function must be carefully monitored
both before and during treatment with
BARACLUDE (entecavir) in a liver transplant
recipient who has received or is receiving an
immunosuppressant that may affect renal
function, such as cyclosporine or tacrolimus.
Dosage and Administration
BARACLUDE should be administered on an
empty stomach (at least 2 hours after a meal
and at least 2 hours before the next meal).
The recommended dose of BARACLUDE:
• in nucleoside-naïve adults and
adolescents (16+ yrs) with compensated
liver disease is 0.5 mg once daily
• in adults and adolescents (16+ yrs) with
compensated liver disease, and refractory
ambulatory to lamivudine or with known lamivudine
or telbivudine resistance mutations
(rtM204I/V with or without rtL180M,
rtL80I/V, or rtV173L) is 1 mg once daily
• in adults with decompensated liver
disease is 1 mg once daily
The optimal duration of treatment with
BARACLUDE for patients with chronic HBV
infection and the relationship between
treatment and long-term outcomes such as
cirrhosis and hepatocellular carcinoma are
unknown.
Additional Information
BARACLUDE is not a cure for HBV. Patients
should be advised that treatment with
BARACLUDE has not been shown to reduce the
risk of transmission of HBV to others through
sexual contact or blood contamination.

Please see following pages for Brief Summary of Full Prescribing Information,
including Boxed WARNINGS.

REFERENCES: 1. IMS Health Custom Analysis (February 13, 2013), LifeLINK, MIDAS. 2. Lok ASF, McMahon BJ. AASLD Guidelines.
Chronic hepatitis B: update 2009. Hepatology. 2009;50(3):1–36. 3. Keeffe EB, Dieterich DT, Han SHB, et al. A treatment algorithm for
the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol. 2008;6(12):1315–
1341. 4. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B.
J Hepatol. 2012;57:167–185. 5. Liaw YF, Leung N, Kao JH, et al; for the chronic hepatitis B guideline working party of the Asian-Pacific
Association for the Study of Liver. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update.
Hepatol Int. 2008;2(3):263–283. 6. Chinese Society of Hepatology, Chinese Medical Association and Chinese Society of Infectious
Diseases, Chinese Medical Association. Guideline on prevention and treatment of chronic hepatitis B in China (2005). Chin Med
J. 2007;120(24):2159–2173. 7. Lee KS, Kim DJ. The Korean Association for the Study of Liver (KASL) Guidelines. Chronic hepatitis B
treatment. Korean J Hepatol. 2007;13(4):447–488. 8. Kumada H, Okanoue T, Onji M, et al. Guidelines for the treatment of chronic
hepatitis and cirrhosis due to hepatitis B virus infection for the fiscal year 2008 in Japan. Hepatol Res. 2010;40(1):1-7. 9. Tong MJ, Pan
CQ, Hann HW, et al. The management of chronic hepatitis B in Asian Americans. Dig Dis Sci. 2011;56(11):3143–3162.

BARACLUDE is a registered trademark of Bristol-Myers Squibb Company.

©2014 Bristol-Myers Squibb Company, Princeton, NJ 08543 USA
686US14BR01544-02-01 07/14
BARACLUDE® (entecavir) tablets, for oral use BARACLUDE® (entecavir)
BARACLUDE® (entecavir) oral solution
Table 1: Clinical Adverse Reactionsa of Moderate-Severe Intensity (Grades 2-4) Reported in
Brief Summary of Prescribing Information. For complete prescribing information consult official Four Entecavir Clinical Trials Through 2 Years
package insert.
Nucleoside-Inhibitor-Naïveb Lamivudine-Refractoryc
BARACLUDE LVD BARACLUDE LVD
WARNING: SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS CO-INFECTED Body System/ 0.5 mg 100 mg 1 mg 100 mg
WITH HIV AND HBV, and LACTIC ACIDOSIS AND HEPATOMEGALY Adverse Reaction n=679 n=668 n=183 n=190
Any Grade 2-4 15% 18% 22% 23%
Severe acute exacerbations of hepatitis B have been reported in patients who have adverse reactiona
discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should Gastrointestinal
be monitored closely with both clinical and laboratory follow-up for at least several Diarrhea <1% 0 1% 0
months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of Dyspepsia <1% <1% 1% 0
anti-hepatitis B therapy may be warranted [see Warnings and Precautions]. Nausea <1% <1% <1% 2%
Limited clinical experience suggests there is a potential for the development of Vomiting <1% <1% <1% 0
resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase General
Fatigue 1% 1% 3% 3%
inhibitors if BARACLUDE (entecavir) is used to treat chronic hepatitis B virus (HBV) Nervous System
infection in patients with HIV infection that is not being treated. Therapy with Headache 2% 2% 4% 1%
BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also Dizziness <1% <1% 0 1%
receiving highly active antiretroviral therapy (HAART) [see Warnings and Precautions]. Somnolence <1% <1% 0 0
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been Psychiatric
reported with the use of nucleoside analogue inhibitors alone or in combination with Insomnia <1% <1% 0 <1%
antiretrovirals [see Warnings and Precautions]. a
Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Studies
AI463022 and AI463027. c Includes Study AI463026 and the BARACLUDE 1 mg and lamivudine treatment
arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of
CONTRAINDICATIONS: None. BARACLUDE (0.1, 0.5, and 1 mg) once daily versus continued lamivudine 100 mg once daily for up to 52
weeks in subjects who experienced recurrent viremia on lamivudine therapy. LVD = Lamivudine.
WARNINGS AND PRECAUTIONS: Severe Acute Exacerbations of Hepatitis B - Severe acute
exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B Laboratory Abnormalities - Frequencies of selected treatment-emergent laboratory abnormalities
therapy, including entecavir [see Adverse Reactions]. Hepatic function should be monitored closely
reported during therapy in four clinical trials of BARACLUDE compared with lamivudine are listed in Table 2.
with both clinical and laboratory follow-up for at least several months in patients who discontinue
anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted. Table 2: Selected Treatment-Emergenta Laboratory Abnormalities Reported in Four Entecavir
Clinical Trials Through 2 Years
Patients Co-infected with HIV and HBV - BARACLUDE has not been evaluated in HIV/HBV co-infected
patients who were not simultaneously receiving effective HIV treatment. Limited clinical experience Nucleoside-Inhibitor-Naïveb Lamivudine-Refractoryc
suggests there is a potential for the development of resistance to HIV nucleoside reverse transcriptase BARACLUDE LVD BARACLUDE LVD
inhibitors if BARACLUDE is used to treat chronic hepatitis B virus infection in patients with HIV infection 0.5 mg 100 mg 1 mg 100 mg
that is not being treated [see Microbiology (12.4) in full Prescribing Information]. Therefore, therapy Test n=679 n=668 n=183 n=190
with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving Any Grade 3-4 35% 36% 37% 45%
laboratory
HAART. Before initiating BARACLUDE therapy, HIV antibody testing should be offered to all patients. abnormalityd
BARACLUDE has not been studied as a treatment for HIV infection and is not recommended for this use. ALT >10 x ULN and 2% 4% 2% 11%
Lactic Acidosis and Severe Hepatomegaly with Steatosis - Lactic acidosis and severe hepatomegaly >2 x baseline
with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors, ALT >5 x ULN 11% 16% 12% 24%
including BARACLUDE, alone or in combination with antiretrovirals. A majority of these cases have been Albumin <2.5 g/dL <1% <1% 0 2%
in women. Obesity and prolonged nucleoside inhibitor exposure may be risk factors. Particular caution Total bilirubin 2% 2% 3% 2%
should be exercised when administering nucleoside analogue inhibitors to any patient with known risk >2.5 x ULN
factors for liver disease; however, cases have also been reported in patients with no known risk factors. Lipase ≥2.1 x ULN 7% 6% 7% 7%
Creatinine >3 x ULN 0 0 0 0
Lactic acidosis with BARACLUDE use has been reported, often in association with hepatic Confirmed creatinine 1% 1% 2% 1%
decompensation, other serious medical conditions, or drug exposures. Patients with decompensated increase ≥0.5 mg/dL
liver disease may be at higher risk for lactic acidosis. Treatment with BARACLUDE should be suspended Hyperglycemia, fasting 2% 1% 3% 1%
in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced >250 mg/dL
hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked Glycosuriae 4% 3% 4% 6%
transaminase elevations). Hematuriaf 9% 10% 9% 6%
Platelets <50,000/mm3 <1% <1% <1% <1%
ADVERSE REACTIONS: The following adverse reactions are discussed in other sections of the labeling:
a
On-treatment value worsened from baseline to Grade 3 or Grade 4 for all parameters except albumin
• Exacerbations of hepatitis after discontinuation of treatment [see Boxed Warning, Warnings and (any on-treatment value <2.5 g/dL), confirmed creatinine increase ≥0.5 mg/dL, and ALT >10 x ULN
Precautions]. and >2 x baseline. b Studies AI463022 and AI463027. c Includes Study AI463026 and the BARACLUDE
1 mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational,
• Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and randomized, double-blind study of three doses of BARACLUDE (0.1, 0.5, and 1 mg)
Precautions]. once daily versus continued lamivudine 100 mg once daily for up to 52 weeks in subjects who experienced
recurrent viremia on lamivudine therapy. d Includes hematology, routine chemistries, renal and liver
Clinical Trial Experience in Adults - Because clinical trials are conducted under widely varying function tests, pancreatic enzymes, and urinalysis. e Grade 3 = 3+, large, ≥500 mg/dL; Grade 4 = 4+,
conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared marked, severe. f Grade 3 = 3+, large; Grade 4 = ≥4+, marked, severe, many. LVD = Lamivudine, ULN
to rates in the clinical trials of another drug and may not reflect the rates observed in practice. = upper limit of normal.
Compensated Liver Disease - Assessment of adverse reactions is based on four studies (AI463014, Among BARACLUDE-treated subjects in these studies, on-treatment ALT elevations greater than
AI463022, AI463026, and AI463027) in which 1720 subjects with chronic hepatitis B virus infection 10 times the upper limit of normal (ULN) and greater than 2 times baseline generally resolved with
and compensated liver disease received double-blind treatment with BARACLUDE 0.5 mg/day (n=679),
continued treatment. A majority of these exacerbations were associated with a ≥2 log10/mL reduction
BARACLUDE 1 mg/day (n=183), or lamivudine (n=858) for up to 2 years. Median duration of therapy
was 69 weeks for BARACLUDE-treated subjects and 63 weeks for lamivudine-treated subjects in in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function
Studies AI463022 and AI463027 and 73 weeks for BARACLUDE-treated subjects and 51 weeks for is recommended during treatment.
lamivudine-treated subjects in Studies AI463026 and AI463014. The safety profiles of BARACLUDE and Exacerbations of Hepatitis after Discontinuation of Treatment - An exacerbation of hepatitis
lamivudine were comparable in these studies. or ALT flare was defined as ALT >10 x ULN and >2 x the subject’s reference level (minimum
of the baseline or last measurement at end of dosing). For all subjects who discontinued
The most common adverse reactions of any severity (≥3%) with at least a possible relation to treatment (regardless of reason), the proportion of subjects who experienced post-treatment
study drug for BARACLUDE-treated subjects were headache, fatigue, dizziness, and nausea. The
ALT flares was as follows: 2% (4/174) in the BARACLUDE-treated group and 9% (13/147)
most common adverse reactions among lamivudine-treated subjects were headache, fatigue, and
dizziness. One percent of BARACLUDE-treated subjects in these four studies compared with 4% of in the lamivudine-treated group in nucleoside-inhibitor-naïve, HBeAg-positive subjects
lamivudine-treated subjects discontinued for adverse events or abnormal laboratory test results. in study AI463022; 8% (24/302) in the BARACLUDE-treated group and 11% (30/270) in the
lamivudine-treated group in nucleoside-inhibitor-naïve HBeAg-negative subjects in study AI463027;
Clinical adverse reactions of moderate-severe intensity and considered at least possibly related to 12% (6/52) in the BARACLUDE-treated group and 0% (0/16) in the lamivudine-treated group among
treatment occurring during therapy in four clinical studies in which BARACLUDE was compared with lamivudine-refractory subjects in study AI463026. The median time to off-treatment exacerbation
lamivudine are presented in Table 1. was 23 weeks for BARACLUDE-treated subjects and 10 weeks for lamivudine-treated subjects.
In these studies, a subset of subjects was allowed to discontinue treatment at or after 52 weeks if
they achieved a protocol-defined response to therapy. If BARACLUDE is discontinued without regard to
treatment response, the rate of post-treatment flares could be higher. [See Warnings and Precautions.]
Decompensated Liver Disease - Study AI463048 was a randomized, open-label study of
BARACLUDE 1 mg once daily versus adefovir dipivoxil 10 mg once daily given for up to 48 weeks
in adult subjects with chronic HBV infection and evidence of hepatic decompensation, defined as
a Child-Turcotte-Pugh (CTP) score of 7 or higher [see Clinical Studies (14.1) in full Prescribing
Information]. Among the 102 subjects receiving BARACLUDE, the most common treatment-emergent
adverse events of any severity, regardless of causality, occurring through Week 48 were peripheral
BARACLUDE® (entecavir)
edema (16%), ascites (15%), pyrexia (14%), hepatic encephalopathy (10%), and upper respiratory infection
(10%). Clinical adverse reactions not listed in Table 1 that were observed through Week 48 include blood
bicarbonate decreased (2%) and renal failure (<1%).
Eighteen of 102 (18%) subjects treated with BARACLUDE and 18/89 (20%) subjects treated with adefovir
dipivoxil died during the first 48 weeks of therapy. The majority of deaths (11 in the BARACLUDE group
and 16 in the adefovir dipivoxil group) were due to liver-related causes such as hepatic failure, hepatic
encephalopathy, hepatorenal syndrome, and upper gastrointestinal hemorrhage. The rate of hepatocellular
carcinoma (HCC) through Week 48 was 6% (6/102) for subjects treated with BARACLUDE and 8% (7/89)
for subjects treated with adefovir dipivoxil. Five percent of subjects in either treatment arm discontinued
therapy due to an adverse event through Week 48.
No subject in either treatment arm experienced an on-treatment hepatic flare (ALT >2 x baseline and >10
x ULN) through Week 48. Eleven of 102 (11%) subjects treated with BARACLUDE and 11/89 (13%) subjects
treated with adefovir dipivoxil had a confirmed increase in serum creatinine of 0.5 mg/dL through Week 48.
HIV/HBV Co-infected - The safety profile of BARACLUDE 1 mg (n=51) in HIV/HBV co-infected subjects
enrolled in Study AI463038 was similar to that of placebo (n=17) through 24 weeks of blinded treatment
and similar to that seen in non-HIV infected subjects [see Warnings and Precautions].
Liver Transplant Recipients - Among 65 subjects receiving BARACLUDE in an open-label, post-liver
transplant trial [see Use in Specific Populations], the frequency and nature of adverse events were
consistent with those expected in patients who have received a liver transplant and the known safety
profile of BARACLUDE.
Clinical Trial Experience in Pediatric Subjects - Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly
compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of BARACLUDE in pediatric subjects 2 to less than 18 years of age is based on two ongoing
clinical trials in subjects with chronic HBV infection (one Phase 2 pharmacokinetic trial [AI463028] and
one Phase 3 trial [AI463189]). These trials provide experience in 168 HBeAg-positive subjects treated with
BARACLUDE for a median duration of 72 weeks. The adverse reactions observed in pediatric subjects who
received treatment with BARACLUDE were consistent with those observed in clinical trials of BARACLUDE in
adults. Adverse drug reactions reported in greater than 1% of pediatric subjects included abdominal pain,
rash events, poor palatability (“product taste abnormal”), nausea, diarrhea, and vomiting.
Postmarketing Experience - The following adverse reactions have been reported during postmarketing
use of BARACLUDE. Because these reactions were reported voluntarily from a population of unknown
size, it is not possible to reliably estimate their frequency or establish a causal relationship to
BARACLUDE exposure. Immune system disorders: Anaphylactoid reaction. Metabolism and nutrition
disorders: Lactic acidosis. Hepatobiliary disorders: Increased transaminases. Skin and subcutaneous
tissue disorders: Alopecia, rash.
DRUG INTERACTIONS: Since entecavir is primarily eliminated by the kidneys [see Clinical Pharmacology
(12.3) in full Prescribing Information], coadministration of BARACLUDE with drugs that reduce renal
function or compete for active tubular secretion may increase serum concentrations of either entecavir
or the coadministered drug. Coadministration of entecavir with lamivudine, adefovir dipivoxil, or tenofovir
disoproxil fumarate did not result in significant drug interactions. The effects of coadministration of
BARACLUDE with other drugs that are renally eliminated or are known to affect renal function have
not been evaluated, and patients should be monitored closely for adverse events when BARACLUDE is
coadministered with such drugs.
USE IN SPECIFIC POPULATIONS: Pregnancy - Pregnancy Category C. There are no adequate and well-
controlled studies of BARACLUDE in pregnant women. Because animal reproduction studies are not always
predictive of human response, BARACLUDE should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to
BARACLUDE, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are
encouraged to register patients by calling 1-800-258-4263.
Animal Data - Animal reproduction studies with entecavir in rats and rabbits revealed no evidence of
teratogenicity. Developmental toxicity studies were performed in rats and rabbits. There were no signs
of embryofetal or maternal toxicity when pregnant animals received oral entecavir at approximately
28 (rat) and 212 (rabbit) times the human exposure achieved at the highest recommended human dose
of 1 mg/day. In rats, maternal toxicity, embryofetal toxicity (resorptions), lower fetal body weights, tail and
vertebral malformations, reduced ossification (vertebrae, sternebrae, and phalanges), and extra lumbar
vertebrae and ribs were observed at exposures 3100 times those in humans. In rabbits, embryofetal
toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at
exposures 883 times those in humans. In a peri-postnatal study, no adverse effects on offspring occurred
when rats received oral entecavir at exposures greater than 94 times those in humans.
Labor and Delivery - There are no studies in pregnant women and no data on the effect of BARACLUDE on
transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent
neonatal acquisition of HBV.
Nursing Mothers - It is not known whether BARACLUDE is excreted into human milk; however, entecavir
is excreted into the milk of rats. Because many drugs are excreted into human milk and because of the
potential for serious adverse reactions in nursing infants from BARACLUDE, a decision should be made to
discontinue nursing or to discontinue BARACLUDE taking into consideration the importance of continued
hepatitis B therapy to the mother and the known benefits of breastfeeding.
Pediatric Use - BARACLUDE was evaluated in two clinical trials of pediatric subjects 2 years of age
and older with HBeAg-positive chronic HBV infection and compensated liver disease. The exposure of
BARACLUDE in nucleoside-inhibitor-treatment-naïve and lamivudine-experienced pediatric subjects
2 years of age and older with HBeAg-positive chronic HBV infection and compensated liver disease
receiving 0.015 mg/kg (up to 0.5 mg once daily) or 0.03 mg/kg (up to 1 mg once daily), respectively,
was evaluated in Study AI463028. Safety and efficacy of the selected dose in treatment-naïve pediatric
subjects were confirmed in Study AI463189, a randomized, placebo-controlled treatment trial [see Adverse
Reactions and Indications and Usage (1), Dosage and Administration (2.3), Clinical Pharmacology (12.3),
and Clinical Studies (14.2) in full Prescribing Information].
There are limited data available on the use of BARACLUDE in lamivudine-experienced pediatric patients;
BARACLUDE should be used in these patients only if the potential benefit justifies the potential risk to
the child. Since some pediatric patients may require long-term or even lifetime management of chronic
active hepatitis B, consideration should be given to the impact of BARACLUDE on future treatment options
[see Microbiology (12.4) in full Prescribing Information].
The efficacy and safety of BARACLUDE have not been established in patients less than 2 years of age.
Use of BARACLUDE in this age group has not been evaluated because treatment of HBV in this age group
is rarely required.
BARACLUDE® (entecavir)
Geriatric Use - Clinical studies of BARACLUDE did not include sufficient numbers of subjects aged
65 years and over to determine whether they respond differently from younger subjects. Entecavir
is substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater
in patients with impaired renal function. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection, and it may be useful to monitor renal function
[see Dosage and Administration (2.4) in full Prescribing Information].
Racial/Ethnic Groups - There are no significant racial differences in entecavir pharmacokinetics.
The safety and efficacy of BARACLUDE 0.5 mg once daily were assessed in a single-arm, open-label
trial of HBeAg-positive or -negative, nucleoside-inhibitor-naïve, Black/African American (n=40) and
Hispanic (n=6) subjects with chronic HBV infection. In this trial, 76% of subjects were male, the mean
age was 42 years, 57% were HBeAg-positive, the mean baseline HBV DNA was 7.0 log10 IU/mL,
and the mean baseline ALT was 162 U/L. At Week 48 of treatment, 32 of 46 (70%) subjects had
HBV DNA <50 IU/mL (approximately 300 copies/mL), 31 of 46 (67%) subjects had ALT normalization
(≤1 × ULN), and 12 of 26 (46%) HBeAg-positive subjects had HBe seroconversion. Safety data were
similar to those observed in the larger controlled clinical trials.
Because of low enrollment, safety and efficacy have not been established in the US Hispanic population.
Renal Impairment - Dosage adjustment of BARACLUDE is recommended for patients with creatinine
clearance less than 50 mL/min, including patients on hemodialysis or CAPD [see Dosage and
Administration (2.4) and Clinical Pharmacology (12.3) in full Prescribing Information].
Liver Transplant Recipients - The safety and efficacy of BARACLUDE were assessed in a single-arm,
open-label trial in 65 subjects who received a liver transplant for complications of chronic HBV infection.
Eligible subjects who had HBV DNA less than 172 IU/mL (approximately 1000 copies/mL) at the time
of transplant were treated with BARACLUDE 1 mg once daily in addition to usual post-transplantation
management, including hepatitis B immune globulin. The trial population was 82% male, 39% Caucasian,
and 37% Asian, with a mean age of 49 years; 89% of subjects had HBeAg-negative disease at the time
of transplant.
Four of the 65 subjects received 4 weeks or less of BARACLUDE (2 deaths, 1 retransplantation, and
1 protocol violation) and were not considered evaluable. Of the 61 subjects who received more
than 4 weeks of BARACLUDE, 60 received hepatitis B immune globulin post-transplant. Fifty-three
subjects (82% of all 65 subjects treated) completed the trial and had HBV DNA measurements at or
after 72 weeks treatment post-transplant. All 53 subjects had HBV DNA <50 IU/mL (approximately
300 copies/mL). Eight evaluable subjects did not have HBV DNA data available at 72 weeks, including 3
subjects who died prior to study completion. No subjects had HBV DNA values ≥50 IU/mL while receiving
BARACLUDE (plus hepatitis B immune globulin). All 61 evaluable subjects lost HBsAg post-transplant;
2 of these subjects experienced recurrence of measurable HBsAg without recurrence of HBV viremia.
This trial was not designed to determine whether addition of BARACLUDE to hepatitis B immune
globulin decreased the proportion of subjects with measurable HBV DNA post-transplant compared to
hepatitis B immune globulin alone.
If BARACLUDE treatment is determined to be necessary for a liver transplant recipient who has received
or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus,
renal function must be carefully monitored both before and during treatment with BARACLUDE [see
Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in full Prescribing Information].
OVERDOSAGE: There is limited experience of entecavir overdosage reported in patients. Healthy subjects
who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days
had no increase in or unexpected adverse events. If overdose occurs, the patient must be monitored for
evidence of toxicity, and standard supportive treatment applied as necessary.
Following a single 1 mg dose of entecavir, a 4-hour hemodialysis session removed approximately 13%
of the entecavir dose.
NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, Impairment of Fertility.
Carcinogenesis - Long-term oral carcinogenicity studies of entecavir in mice and rats were carried
out at exposures up to approximately 42 times (mice) and 35 times (rats) those observed in humans
at the highest recommended dose of 1 mg/day. In mouse and rat studies, entecavir was positive for
carcinogenic findings.
In mice, lung adenomas were increased in males and females at exposures 3 and 40 times those in
humans. Lung carcinomas in both male and female mice were increased at exposures 40 times those
in humans. Combined lung adenomas and carcinomas were increased in male mice at exposures 3
times and in female mice at exposures 40 times those in humans. Tumor development was preceded
by pneumocyte proliferation in the lung, which was not observed in rats, dogs, or monkeys administered
entecavir, supporting the conclusion that lung tumors in mice may be a species-specific event.
Hepatocellular carcinomas were increased in males and combined liver adenomas and carcinomas were
also increased at exposures 42 times those in humans. Vascular tumors in female mice (hemangiomas
of ovaries and uterus and hemangiosarcomas of spleen) were increased at exposures 40 times those
in humans. In rats, hepatocellular adenomas were increased in females at exposures 24 times those in
humans; combined adenomas and carcinomas were also increased in females at exposures 24 times
those in humans. Brain gliomas were induced in both males and females at exposures 35 and 24 times
those in humans. Skin fibromas were induced in females at exposures 4 times those in humans.
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
Mutagenesis - Entecavir was clastogenic to human lymphocyte cultures. Entecavir was not mutagenic
in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence
or absence of metabolic activation, a mammalian-cell gene mutation assay, and a transformation assay
with Syrian hamster embryo cells. Entecavir was also negative in an oral micronucleus study and an oral
DNA repair study in rats.
Impairment of Fertility - In reproductive toxicology studies, in which animals were administered
entecavir at up to 30 mg/kg for up to 4 weeks, no evidence of impaired fertility was seen in male or
female rats at systemic exposures greater than 90 times those achieved in humans at the highest
recommended dose of 1 mg/day. In rodent and dog toxicology studies, seminiferous tubular degeneration
was observed at exposures 35 times or greater than those achieved in humans. No testicular changes
were evident in monkeys.
1323583 Rev May 2014
686US14BR01514-02-01
OFFICIAL JOURNAL OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES
Editor
Michael H. Nathanson, New Haven, CT

SENIOR ASSOCIATE EDITORS CONSULTING BIOSTATISTICIAN CLINICAL OBSERVATIONS IN HEPATOLOGY

James L. Boyer, New Haven, CT James Dziura, New Haven, CT Victor J. Navarro, Philadelphia, PA
Roberto J. Groszmann, New Haven, CT Simona Jakab, New Haven, CT
ASSOCIATE EDITORS HEPATOLOGY ELSEWHERE
Frank A. Anania, Atlanta, GA Yasuko Iwakiri, New Haven, CT HEPATOLOGY HIGHLIGHTS
Jorge A. Bezerra, Cincinnati, OH Tamar H. Taddei, New Haven, CT Jean-François Dufour, Bern, Switzerland
Guadalupe Garcia-Tsao, New Haven, CT
Stephen A. Harrison, Fort Sam Houston, TX EDITORS EMERITUS
Donald M. Jensen, Chicago, IL Irwin M. Arias, Boston, MA, Founding Editor PRODUCTION STAFF
Brett Lindenbach, New Haven, CT Steven Schenker, San Antonio, TX Ann Haran, Managing Editor
Jacquelyn Maher, San Francisco, CA Paul D. Berk, New York, NY Kareytis Martinez, Editorial Assistant
Wajahat Mehal, New Haven, CT D. Montgomery Bissell, San Francisco, CA Tazeen Shirazi, Editorial Assistant
Lola M. Reid, Chapel Hill, NC Andres T. Blei, Chicago, IL Dana Lombardi, Editorial Assistant
Mario Strazzabosco, New Haven, CT Keith D. Lindor, Rochester, MN Kara Cheatham, Editorial Assistant
Norah Terrault, San Francisco, CA
Snorri S. Thorgeirsson, Bethesda, MD
Michael Trauner, Vienna, Austria

EDITORIAL BOARD
Manal Abdelmalek, Durham, NC Ivo Graziadei, Innsbruck, Austria Markus Peck-Radosavljevic, Vienna, Austria
Juan Abraldes, Alberta, Canada Kenichi Ikejima, Tokyo, Japan Robert Perrillo, Dallas, TX
Gianfranco Alpini, Temple, TX Ira Jacobson, New York, NY Massimo Pinzani, Florence, Italy
Raul Andrade, Ma´laga, Spain Dhanpat Jain, New Haven, CT Jeffrey Pollak, New Haven, CT
Mario Angelico, Rome, Italy Harmut Jaeschke, Kansas City, KS Fred Poordad, Los Angeles, CA
Paul Angulo, Lexington, KY Peter Jansen, Netherlands Elizabeth Powell, Brisbane, Australia
Meena Bansal, New York, NY Harry Janssen, Rotterdam, Netherlands Nancy Reau, Chicago, IL
Ulrich Beuers, Amsterdam, Netherlands Cynthia Ju, Denver, CO K. Rajender Reddy, Philadelphia, PA
Jordi Bruix, Barcelona, Spain Patrick Kamath, Rochester, MN Mary Rinella, Chicago, IL
Elizabeth Brunt, St. Louis, MO Neil Kaplowitz, Los Angeles, CA Cristina Ripoll, Halle an der Saale, Germany
John Bucuvalas, Cincinatti, OH Tom Karlsen, Oslo, Norway Lewis R. Roberts, Rochester, MN
Michael Charlton, Rochester, MN Saul Karpen, Atlanta, GA Sammy Saab, Los Angeles, CA
John Chiang, Rootstown, OH W. Ray Kim, Rochester, MN Francesco Salerno, Milan, Italy
David Cohen, Boston, MA Curtis Klaassen, Kansas City, KS Peter Schirmacher, Heidelberg, Germany
Kenneth Cusi, San Antonio, TX Percy Knolle, Bonn, Germany Robert Schwabe, New York, NY
Mark Czaja, New York, NY Sanjay Kulkarni, New Haven, CT Gamel Shiha, Almansoura, Egypt
Gennaro D’Amico, Palermo, Italy William Lee, Dallas, TX Ben Shneider, Pittsburgh, PA
Gary Davis, Dallas, TX Stanley Lemon, Chapel Hill, NC Ron Sokol, Aurora, CO
Anna Mae Diehl, Durham, NC Massimo Levrero, Rome, Italy Bruno Stieger, Zurich, Switzerland
Alvaro Domenico, Rome, Italy Joseph Lim, New Haven, CT Fred Suchy, Denver, CO
Jean Dubuisson, Lille, France Maribel Lucena, Ma´laga, Spain Mark Sulkowski, Baltimore, MD
Ronald Oude Elferink, Amsterdam, Netherlands Derek Mann, Newcastle Upon Tyne, United Kingdom Gyongyi Szabo, Worchester, MA
Jeff Esko, Manchester, United Kingdom M. Michele Manos, Oakland, CA Puneeta Tandon, Edmonton, Canada
Michael Fallon, Houston, TX Fabio Marra, Florence, Italy Neil Theise, New York, NY
Jordan Feld, Toronto, Canada Jane McKeating, Birmingham, United Kingdom Zhigang Tian, Hefei, China
Ariel Feldstein, Cleveland, OH Brian McMahon, Anchorage, Alaska Dawn Torres, Baltimore, MD
Andrew Feranchak, Dallas, TX Philip Meuleman, Ghent, Belgium Augusto Villanueva, Barcelona, Spain
Peter Ferenci, Vienna, Austria Pram Mistry, New Haven, CT Miriam Vos, Atlanta, GA
Jose Fernandez-Checa, Barcelona, Spain Atsushi Miyajima, Tokyo, Japan Fu-Sheng Wang, Beijing, China
Peter Fickert, Graz, Austria Satdarshan Monga (Paul) Singh, Pittsburgh, PA Yunfang Wang, Beijing, China
Stuart Forbes, Edinburgh, United Kingdom Richard Moreau, Beaujon, France Xin Wei Wang, Bethesda, MD
Michael Fried, Chapel Hill, NC Masaki Mori, Osaka, Japan Rebecca Wells, Philadelphia, PA
Mark Furth, Winston-Salem, NC Antonio Moschetta, Bari, Italy Brian West, New Haven, CT
Bin Gao, Bethesda, MD Andrew Muir, Durham, NC Reiner Wiest, Regensberg, Germany
Juan Carlos Garcia-Pagán, Barcelona, Spain Kevin Mullen, Cleveland, OH Florence Wong, Toronto, Canada
Eugenio Gaudio, Rome, Italy Laura Nagy, Cleveland, OH Hushan Yang, Philadelphia, PA
Eric Gershwin, Sacramento, CA David Nelson, Bethesda, MD Min You, San Francisco, CA
Jim D Gorham, Lebanon, NH James Neuberger, Birmingham, United Kingdom Nizar Zein, Cleveland, OH
Arash Grakoui, Atlanta, GA Young-Nyun Park, Yonsei, Korea Jessica Zucman-Rossi, Paris, France

American Association for the Study of Liver Diseases—Governing Board 2014

President Past President Councilors-at-Large
Adrian M. Di Bisceglie, St. Louis, MO J. Gregory Fitz, Dallas, TX Raymond T. Chung, Boston, MA
President-Elect Councilors Susan Orloff, Portland, OR
Gyongi Szabo, Worcester, MA Keith D. Lindor, Tempe, AZ K. Rajender Reddy, Philadelphia, PA
Secretary Anna S.F. Lok, Ann Arbor, MI Publications Committee Chair
Gary L. Davis, Simpsonville, SC Ronald J. Sokol, Aurora, CO Theo Heller, Bethesda, MD
Treasurer
W. Ray Kim, Stanford, CA
AASLD National Headquarters: 1001 North Fairfax Street, Suite 400, Alexandria, VA 22314. Phone: 703-299-9766; Fax: 703-299-9622; E-mail: AASLD@AASLD.org.
Chief Executive Officer, Steven Echard
Editorial Office: 1001 North Fairfax Street, Suite 400, Alexandria, VA 22314. Phone: 703-299-9766; Fax: 703-299-9676; E-mail: hepatology@aasld.org
HEPATOLOGY (Print ISSN 0270-9139; Online ISSN 1527-3350 at Wiley Online Library (wileyonlinelibrary.com)) is published monthly in two indexed volumes through Wiley Subscription
Services, a Wiley Company, 111 River St., Hoboken, NJ 07030. Subscription rates for Volumes 59-60, 2014. Institution (includes Liver Transplantation, Volume 20, 2014) Print only: in U.S.,
$2,440. For all other prices please consult the journal’s website at onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3352. Prices subject to change without notice. Periodicals postage paid
at Hoboken, NJ, and at additional mailing offices.
Delivery Terms and Legal Title: Where the subscription price includes print issues and delivery is to the recipient’s address, delivery terms are Delivered at Place (DAP); the recipient is
responsible for paying any import duty or taxes. Title to all issues transfers FOB our shipping point, freight prepaid. We will endeavor to fulfill claims for missing or damaged copies within
six months of publication, within our reasonable discretion and subject to availability. POSTMASTER: Send all address changes to HEPATOLOGY, John Wiley & Sons Inc., c/o The Sheridan
Press, PO Box 465, Hanover, PA 17331. Copyright V C 2014 by the American Association for the Study of Liver Diseases. All rights reserved. Printed in the United States of America by Cadmus
Communications, a Cenveo company. Printed on acid-free paper effective with Volume 11, Number 2, 1990.
 2015 Research and Career Development Awards
We understand the phenomenal return on investment that research can provide. Several
young investigators began their careers in biomedical research thanks to funding from
our program, demonstrating the importance of these awards not only to investigators and
practitioners, but to the very endeavor of medical and hepatobiliary research itself.

Application Deadline: Research Awards

DECEMBER 4, 2014 Pinnacle Research Award in Liver Disease
$300,000—3 year award
*NP/PA Clinical Hepatology NEW IN 2015
Fellowship Application Deadline:
FEBRUARY 5, 2015 Clinical and Translational Research Awards in Liver Diseases
$150,000—2 year award
Recipient Notification:
MAY 2015
Career Development Award in Liver Transplantation
$90,000—2 year award
Award Start Date:
JULY 1, 2015
Career Development Awards
NP/PA Clinical Hepatology Fellowship*
$78,000—1 year award

AASLD/LIFER Clinical and Translational Research Fellowship

$75,000—1 year award
Awards applications
are available at Advanced/Transplant Hepatology Fellowship
WWW.AASLD.ORG/AWARDS $60,000—1 year award
Accreditation and Continuing Education Information
The overall goal of The Liver Meeting® is to provide a forum
for the exchange of ground breaking research and clinical
information in diseases of the liver and biliary tract and in liver
transplantation.
Target Audience
Groups include clinical hepatologists, gastroenterologists,
other health care providers (midlevel providers, internists,
pediatricians, family practitioners), and trainees (students,
residents, and specialty fellows). The target audience also
encompasses scientists studying the development, physiology,
pathology, translational medicine, and clinical trials related to
the liver and biliary tract and liver transplantation.
AASLD takes responsibility for the content, quality, and scientific
integrity of this live activity.
Learning Objectives
Upon participation in this live educational activity, learners will
be able to:
• Incorporate new scientific evidence into clinical care
protocols and improve the outcome of adults and children
with acute and chronic diseases of the liver and biliary tract.
• Establish new collaborations, implement new clinical trials,
develop comparative effectiveness projects, and complete
investigative efforts that will improve the outcome of adults
and children with acute and chronic diseases of the liver and
biliary tract.
• Implement effective care plans to improve the long-term
outcome of the transplanted patient.
Continuing Medical Education (CME)
Accreditation Statement
The American Association for the Study of Liver Diseases
(AASLD) is accredited by the Accreditation Council for
Continuing Medical Education (ACCME) to provide continuing
medical education for physicians.
Credit Designation Statement
AASLD designates these live activities for AMA PRA Category 1
Credits™. Physicians should claim only the credit commensurate
with the extent of their participation in the activity.
Maximum Credits Available
Annual Meeting (State-of-the-Art Lectures; President’s Choice;
General Hepatology Update; Advances for Practitioners;
Plenaries and Parallel Sessions; Global Forum; MOC Session;
Value-Based Medicine in Hepatology; and
Emerging Trends) . . . . . . . . . . . . . . . . . . 20.5 CME Credits
Postgraduate Course. . . . . . . . . . . . . . . . 12.0 CME Credits
Basic Research Workshop . . . . . . . . . . . . . 4.0 CME Credits
Hepatology Associates Course . . . . . . . . . . 5.5 CME Credits
AASLD/ILTS Transplant Course* . . . . . . . . . 6.5 CME Credits
iiA
AASLD/NASPGHAN
  Pediatric Symposium**. . . . . . . . . . . . . . 3.0 CME Credits
AASLD/ASGE Endoscopy Course** . . . . . . . 7.0 CME Credits
Transplant Surgery Workshop . . . . . . . . . . 3.5 CME Credits
*This activity has been planned and implemented in accordance
with the Essential Areas and Policies of the Accreditation Council for
Continuing Medical Education through the joint providership of the
American Association for the Study of Liver Diseases (AASLD), and the
International Liver Transplantation Society (ILTS). AASLD is accredited
by the ACCME to provide continuing medical education for physicians.
**Co-sponsored activity: The American Association for the Study of
Liver Diseases (AASLD) is accredited by the Accreditation Council for
Continuing Medical Education to provide continuing medical education
for physicians.
Please note: As an accredited provider, AASLD ensures the content of
all CME activities and related materials will promote improvements or
quality in health care, and not a specific proprietary business interest
of a commercial interest. As such, some sessions or ticketed activities
may not offer CME credits.
Continuing Education (CE)
The Institute for Advancement of Human Behavior (IAHB) is accredited
as a provider of continuing nursing education by the American Nurses
Credentialing Center’s Commission on Accreditation. These activities
are co-provided by IAHB and AASLD. Maximum 20 contact hours.
The following ticketed activities will award nurse continuing education
contact hours:
• AASLD/ILTS Transplant Course – 5 contact hours
• Postgraduate Course – 10 contact hours
• Hepatology Associates Course – 5 contact hours
Faculty Disclosure
It is the policy of AASLD to ensure balance, independence,
objectivity, and scientific rigor in all its individually or jointly
sponsored educational programs.
All faculty/authors participating in any AASLD sponsored
programs, as well as planners and committee members are
expected to disclose any real or apparent conflict(s) of interest
that may have a direct bearing on the subject matter of the
continuing medical education program.
When an unlabeled use of a commercial product, or an
investigational use not yet approved for any purpose is
discussed during an educational activity, the speaker shall
disclose to the audience that the product is not labeled for the
use under discussion or that the product is still investigational.
All disclosure information is provided to the activity participant
prior to the start of the educational activity. In addition,
disclosure slides will be the first slide in each oral presentation
viewed by participants. AASLD will identify and resolve all
conflicts of interest prior to program implementation.
Accreditation and Continuing Education Information
Disclaimer Statement
Statements, opinions, and results of studies presented at The
Liver Meeting® are solely those of the authors and do not reflect
the policy or position of AASLD. AASLD does not provide any
warranty to the accuracy or reliability of information presented
either verbally or in writing by presenters. No responsibility is
assumed by AASLD for any injury and/or damage to persons
or property resulting from any use of such information.
Use of AASLD Scientific Program Content
Information presented during the 65th Annual Meeting is the
property of AASLD and the presenter. Information may not
be recorded, photographed, copied, photocopied, transferred
to electronic format, reproduced, or distributed without the
written permission of AASLD and the presenter. Any use of
the program content, which includes, but is not limited to oral
presentations, audiovisual materials used by speakers, and
program handouts, without the written consent of AASLD is
prohibited.
iiiA
Claiming CME/CE Credit and
Certificates of Attendance
The CME/CE evaluations are electronic and can be completed
using the following options:
• Upon download, use the meeting app to evaluate the
sessions in real-time
• Using your personal device, link to the CME and/or CE
evaluation on The Liver Meeting® website
• Visit Tech Connect to access the evaluation from any
available kiosk
CME and CE credit will be awarded upon completion of the
electronic evaluation. You will have the ability to download
and/or print a certificate for your records once you have
completed the CME and/or CE evaluations.
Certificates of Attendance are also available. Certificates may
be downloaded and/or printed upon completion of The Liver
Meeting® evaluation.
Outcomes Follow-up Survey
A follow-up survey will be sent to all attendees within three
months of the conclusion of the meeting to assess the new skills
and competencies learned as a result of participating in this
live activity.
Future Meetings 2015
Digestive Disease Week® (DDW)
May 16 – 19
Walter E. Washington Convention Center
Washington, DC

Clinical Hepatology: State-of-the-Art Management

June 27 – 28
The Westin Chicago River North
Chicago, Illinois

Emerging Trends Conference

AASLD Industry Colloquium: Novel Targets and Therapies in Liver Disease
Spring 2015
Location TBD

The Liver Meeting®

November 13 – 17
Moscone West Convention Center
San Francisco, California

Postgraduate Course
Managing Liver Disease - From the Clinic to the Community
November 14
Moscone West Convention Center
San Francisco, California

ivA
Table of Contents
THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES
65th ANNUAL MEETING AND POSTGRADUATE COURSE

The Liver Meeting ®

2O14
N O V E M B E R 7 – N O V E M B E R 1 1   •   B O S T O N , M A

Meeting-at-a-Glance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2A The Scientific Program Committee has created an exciting

General Meeting Information . . . . . . . . . . . . . . . . . . . . . . . 5A and diverse scientific program that highlights new technology,
Limited License . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7A current clinical issues and hot topics facing the hepatology
community. Members include:
Disclosure Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8A

Adrian M. Di Bisceglie, MD, FACP, Co-Chair

Oral Sessions
Friday, November 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32A Gary L. Davis, MD, Co-Chair
Saturday, November 8 . . . . . . . . . . . . . . . . . . . . . . . . . . 39A Carla W. Brady, MD
Sunday, November 9 . . . . . . . . . . . . . . . . . . . . . . . . . . . 43A Kenneth D. Chavin, MD, PhD
Monday, November 10 . . . . . . . . . . . . . . . . . . . . . . . . . . 65A Mark J. Czaja, MD
Tuesday, November 11 . . . . . . . . . . . . . . . . . . . . . . . . . . 85A Marc G. Ghany, MD
Saul J. Karpen, MD, PhD
Poster Sessions Keith D. Lindor, MD
Saturday, November 8 . . . . . . . . . . . . . . . . . . . . . . . . . . 92A Gyongyi Szabo, MD, PhD
Sunday, November 9 . . . . . . . . . . . . . . . . . . . . . . . . . . 119A Rebecca T. Wells, MD
Monday, November 10 . . . . . . . . . . . . . . . . . . . . . . . . . 146A
Tuesday, November 11 . . . . . . . . . . . . . . . . . . . . . . . . . 169A

Abstracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197A
Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1206A
Category Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1256A

vA
 NP/PA Clinical Hepatology Fellowship Program
$
78,000, One Year*

Pursue a full year of training in clinical hepatology—apply for the NP/PA Clinical
Hepatology Fellowship. If you are new to the field or interested in a shift in focus to
clinical hepatology—the NP/PA Clinical Hepatology Fellowship provides $78,000* for
one year of clinical training for those committed to the field of hepatology and better
treatment for patients with liver disease.

The application is available at www.aasld.org/awards

Application Deadline: *Salary and benefit support only—AASLD provides equal opportunity for all
FEBRUARY 5, 2015 research and fellowship award applicants without regard to race, color, creed,
religion, gender, sexual orientation, national origin, age, marital status, mental
or physical disability, pregnancy, military or veteran status, or any other basis
Award Start Date: prohibited by state or federal law.
JULY 1, 2015
Free Board Review
Questions
Earn CME and prepare for your internal medicine,
gastroenterology, or transplant hepatology exam
with board-style practice questions from Clinical
Liver Disease (CLD). Each question set helps
you identify areas for further review and links to
free online resources—articles, videos, webinars,
and podcasts—that can help you update your
knowledge on a variety of hepatology topics.

Nurses and physician assistants will also

benefit from the review questions and from the
full spectrum of clinical education available
through CLD.

Visit cldlearning.com/questions to start today.

CLD is an online learning resource of the American

Association for the Study of Liver Diseases.
 NEW Practice
Guidelines in 2014
■■ Hepatic Encephalopathy in Chronic Liver Disease
■■ Evaluation for Liver Transplantation in Adults
■■ Evaluation of the Pediatric Patient for Liver Transplantation

Available at www.aasld.org

YOU CAN ALSO DOWNLOAD THESE

PRACTICE GUIDELINE TOPICS FOR LIVER DISEASE
■■ Acute Liver Failure ■■ Hepatocellular ■■ Non-alcoholic Fatty
■■ Alcoholic Liver Carcinoma Liver Disease
Disease ■■ Liver Biopsy ■■ Primary Biliary
■■ Ascites due ■■ Long-Term Cirrhosis
to Cirrhosis Management of ■■ Primary Sclerosing
■■ Autoimmune Adult Patients Cholangitis
Hepatitis After Liver ■■ TIPS in
Transplantation Management of
■■ Gastroesophageal
Varices and Variceal ■■ Long-Term Portal Hypertension
Hemorrhage Management ■■ Vascular Disorders
in Cirrhosis of Pediatric of the Liver
Patients After Liver
■■ Hemochromatosis Transplantation ■■ Wilson Disease
■■ Hepatitis B, Chronic
OUT MOR
ND E
FI
These evidence-based guidelines are developed and
updated regularly by a committee of experts and include Visit the AASLD Pavilion
recommendations of preferred approaches to the diagnostic, Just outside registration

therapeutic, and preventative aspects of care. AT

TH N
E PA V I L I O
Meeting-at-a-Glance
The majority of events during The Liver Meeting® will take place in the Hynes Convention Center. Those events not taking
place at the convention center will be noted. Sessions marked with an asterisk * require a ticket for entrance.

Day/Time Activity Location Page

Friday, November 7
7:55 am – 3:00 pm AASLD/ASGE Endoscopy Course * Room 302 32A
8:00 am – 2:45 pm AASLD/ ILTS Transplant Course * Ballroom B/C 33A
10:00 am – Noon Career Development Workshop * Room 311 34A
Noon – 3:00 pm AASLD/NASPGHAN Pediatric Symposium * Room 312 35A
12:30 – 2:45 pm Competency Training Workshop Room 309 36A
12:30 – 3:30 pm Clinical Research Workshop * Room 304/306 37A
3:30 – 7:30 pm Postgraduate Course * Auditorium 38A

Saturday, November 8
8:00 am – 5:00 pm Postgraduate Course * Auditorium 39A
9:00 am – Noon SIG Program: Outreach in Liver Transplant Room 302 40A
12:20 – 1:40 pm Meet-the-Professor Luncheons * Check your Ticket 41A
2:00 – 7:30 pm Poster Session I Hall C
• Ascites, Renal Dysfunction and Hepatorenal Syndrome 92A
• Behavioral, Quality of Life, and Practice Issues 93A
• Cholangiocyte Biology 93A
• Cholestasis and Autoimmune Liver Disease 94A
• Donor Factors and Allocation 97A
• Encephalopathy and Other Complications 98A
• Experimental Cholestasis 101A
• Fibrosis: Clinical and Translational 101A
• Hemochromatosis, Wilson Disease, a-1 Antitrypsin Deficiency 104A
• Imaging in Cancer 104A
• Imaging in Fibrosis 105A
• Immunosuppression 106A
• Infections and Acute on Chronic Liver Failure 110A
• Inflammation and Immunobiology: Animal Models 112A
• Innate Immunity and Adaptive 113A
• Living Donor and Split Transplant 114A
• Mechanisms of Injury 115A
• Metabolic and Genetic Diseases 115A
• Viral and Autoimmune Hepatitis 116A
• Viral Hepatitis and Liver Transplant 116A
3:30 – 7:00 pm Transplant Surgery Workshop * Room 302 42A
5:15 – 6:15 pm AASLD Business Meeting (Members Only) Auditorium 42A
5:00 – 7:30 pm Exhibits Open Hall D 41A
5:00 – 7:30 pm Opening Reception Hall C/D 41A

Sunday, November 9
6:45 – 7:45 am Early Morning Workshops * Check your ticket 43A
8:00 – 9:30 am Transplant Plenary I Auditorium 44A
8:00 am – Noon Basic Research Workshop * Ballroom A 45A
8:00 am – 1:30 pm Hepatology Associates Course * Room 304/306 46A
8:00 am – 5:30 pm Poster Session II Hall C
• Acute Liver Failure 119A
• Basic Fibrosis 121A
• Clinical Steatohepatitis 123A
• Experimental Hepatocarcinogenesis 129A
• Hepatitis C: Approved Therapeutic Agents 132A
• Hepatotoxicity: Drug Metabolism 138A
• Hepatotoxicity: Mechanisms 139A
• Imaging of Steatohepatitis 140A
• Steatohepatitis 140A
• Transport, Bilirubin, Cholesterol, Lipids and Bile Salts 145A

2A
Meeting-at-a-Glance (continued)
Day/Time Activity Location Page
Sunday, November 9
9:30 – 10:00 am Thomas E. Starzl Transplant Surgery State-of-the-Art Lecture Auditorium 47A
9:30 am – 3:00 pm Exhibits Open Hall D 44A
10:00 – 10:30 am Coffee Break Hall D 47A
10:00 – 11:30 am Emerging Trends Symposium Room 312 48A
10:30 am – Noon Transplant Plenary II Auditorium 49A
Noon – 12:30 pm Hans Popper Basic Science State-of-the-Art Lecture Auditorium 50A
1:00 – 3:00 pm Value-based Medicine in Hepatology Room 302 50A
1:15 – 2:45 pm Maintenance of Certification (MOC) Update Room 210 51A
1:30 – 2:00 pm Snack Break Hall D 51A
2:00 – 2:30 pm Ethics and Humanities State-of-the-Art Lecture Auditorium 52A
2:45 – 3:00 pm Distinguished Clinician Educator / Mentor Award Auditorium 52A
3:00 – 4:30 pm General Hepatology Update Ballroom A/B/C 52A
3:00 – 4:30 pm Parallel Sessions
1. Advances in Fibrosis Imaging Room 309 53A
2. Antivirals, Acute Liver Failure in Liver Transplantation Room 312 53A
3. Basic Mechanisms of Liver Fibrosis Sheraton, Republic Ballroom 54A
4. Cholestatic and Autoimmune Liver Disease Room 302 54A
5. Experimental Hepatocarcinogenesis Sheraton, Back Bay Ballroom C 55A
6. Hepatitis C: Currently Approved Drugs Auditorium 55A
7. Mechanisms of Hepatotoxicity Room 210 56A
8. Novel Approaches in Diagnosis and Treatment
in NAFLD and NASH Room 304/306 56A
9. Tissue Damage in Liver Disease and Inflammatory and Viral Room 311 57A
4:45 – 6:15 pm Parallel Sessions
10. HBV Diagnosis, Epidemiology, Prevention and Natural History Room 312 57A
11. Hepatitis C: Health Economics and Cost-effectiveness Room 304/306 58A
12. Hepatitis C: New Agents – Part 1 Auditorium 58A
13. Machine Perfusion and Cellular Therapy Room 309 59A
14. Outcomes in Cirrhosis Ballroom A/B/C 59A
15. Steatohepatitis: Experimental Room 311 60A
4:45 – 6:45 pm SIG Program: Pharmacogenomic Approaches in DILI Research Room 210 61A
4:45 – 7:00 pm SIG Program: Primary Liver Carcinomas with Intermediate/Stem Cell
Features: Microscopic to Genomic Evidence and Back Sheraton, Back Bay Ballroom C 62A
4:45 – 7:00 pm SIG Program: Controversies in the Management
of PSC in Children and Adults Room 302 63A
4:45 – 7:45 pm SIG Program: The Cell Biology of Hepatic Disease Sheraton, Republic Ballroom 64A

Monday, November 10
6:45 – 7:45 am Early Morning Workshops * Check your ticket 65A
8:00 – 9:30 am Basic Plenary Auditorium 66A
8:00 am – 5:30 pm Poster Session III Hall C
• Alcohol: Clinical and Basic Mechanisms 146A
• Basic Hepatobiliary Neoplasia 148A
• Biliary Atresia and Cholestasis 150A
• Cellular and Molecular Biology 150A
• Cellular Immunobiology 152A
• Clinical Hepatobiliary Neoplasia 153A
• Cost-effectiveness 160A
• HCV: Diagnostics, Epidemiology, and Natural History 160A
• Health Care Delivery 166A
• Pediatric Liver Disease – Basic Science 168A
• Pediatric Liver Transplantation 168A
9:30 – 10:00 am Distinguished Service and Achievement Awards Auditorium 66A
9:30 am – 3:00 pm Exhibits Open Hall D 66A
10:00 – 10:30 am Hyman J. Zimmerman Hepatotoxicity State-of-the-Art Lecture Auditorium 67A
10:30 – 11:00 am Coffee Break Hall D 67A
11:00 am – 12:30 pm Clinical Plenary Auditorium 68A
11:00 am – 12:30 pm Advances for Practitioners Ballroom A/B/C 69A
11:45 am – 1:15 pm Professional Development Workshop * Sheraton, Republic Ballroom 70A

3A
Meeting-at-a-Glance (continued)
Day/Time Activity Location Page
Monday, November 10
1:30 – 2:00 pm Snack Break Hall D 70A
2:00 – 4:00 pm Global Forum Room 304/306 71A
2:15 – 2:45 pm President’s Choice Auditorium 72A
2:45 – 4:30 pm Late-breaking Abstract Session Auditorium 72A
3:00 – 4:30 pm Parallel Sessions
16. Access, Delivery, and Cost of Care Room 210 73A
17. Allocation, MELD, and Liver Transplantation Room 312 73A
18. Basic Hepatobiliary Neoplasia Room 310 74A
19. Cholestatic Liver Disease Room 302 74A
20. Mechanisms and Mortality in Alcoholic Liver Disease Room 313 75A
21. Molecular and Cellular Biology Room 309 75A
22. Pediatric Liver Diseases: Models, Modifiers, Mechanisms,
and Markers Room 311 76A
23. Pharmacologic Therapies for Cirrhosis Complications Ballroom A/B/C 76A
4:45 – 6:15 pm HCV Symposium: #What’s Trending in Hepatitis C? Auditorium 77A
4:45 – 6:15 pm Parallel Sessions
24. Clinical Hepatobiliary Neoplasia Room 302 78A
25. Hepatitis C: Diagnosis, Epidemiology and Natural History Room 312 78A
26. Living Donor and Split Liver Transplantation, Hepatobiliary Surgery Room 210 79A
27. Pediatric Liver Diseases: Clinical and Translational Studies Room 311 79A
28. The Good and Bad of Innate Immunity in Liver Disease Room 309 80A
4:45 – 6:50 pm SIG Program: Non-invasive Methods to Stratify Risk in Patients
with Compensated Cirrhosis Ballroom A/B/C 81A
4:45 – 6:55 pm SIG Program: Immunity and Lipids as New Drivers in Inflammation
and Fibrosis of Non-Alcoholic Steatohepatitis Sheraton, Back Bay Ballroom C 82A
4:45 – 7:25 pm SIG Program: Renal Dysfunction in Cirrhosis: Should We Change
the Way we Manage These Patients? Sheraton, Republic Ballroom 83A
4:45 – 7:50 pm SIG Program: The Next Generation of HBV Therapy:
From Discovery to Cure Room 304/306 84A

Tuesday, November 11
6:45 – 7:45 am Early Morning Workshops * Check your ticket 85A
8:00 – 9:30 am Hepatitis Plenary Auditorium 86A
8:00 am – Noon Poster Session IV Hall C
• HBV: Diagnostics, Epidemiology, and Natural History 169A
• HBV: Virology and Pathogenesis 174A
• HCV: Health Economics and Cost-effectiveness 177A
• HCV: Virology, Pathogenesis and Immunology 178A
• Hepatitis B Therapy 182A
• Hepatitis C: New Agents (Not Approved) 187A
• Hepatitis C: Preclinical Development 191A
• Portal Hypertension: Experimental 192A
• Stem Cell Biology 194A
• Varices and Bleeding 194A
9:45 – 10:30 am Hepatitis Debrief Auditorium 86A
10:30 – 11:00 am Leon Schiff State-of-the-Art Lecture Auditorium 87A
11:15 am – 12:45 pm Parallel Sessions
29. Biliary Biology and Pathobiology: Mechanisms and Treatments Room 210 88A
30. Correlates of Complications in Cirrhosis Room 302 88A
31. Emerging Trends in NASH Room 304/306 89A
32. HBV Basic Virology Room 311 89A
33. HCV Pathogenesis: Is the Battle Over? Room 312 90A
34. Hepatitis B: Outcomes of Approved Therapy Ballroom A/B/C 90A
35. Hepatitis C: New Agents – Part 2 Auditorium 91A

*Indicates a ticket is required for entrance.

4A
General Information
Abstracts their public disclosure that the complete and final results will be
presented at The Liver Meeting®. AASLD will also require the
Abstract information and text selected for presentation at The
inclusion of unreleased and unique data in such a presentation
Liver Meeting® are available in many formats:
at The Liver Meeting®.
• USB drive distributed at registration*
• Online Itinerary Planner* Public release of a journal article relevant to the abstract will be
• LiverLearning® considered an exception to the Embargo Policy if at the time of
• ePosters* the abstract submission deadline, the decision concerning the
• October supplement to Hepatology (members and sub- manuscript had not been revealed to the authors.
scribers) – in order to minimize waste, additional copies
of this supplement will not be available at the meeting. ADA Compliance
• Meeting app*
The Hynes Convention Center and all participating hotels at
*The Abstracts on USB Flash-drive is supported by AbbVie The Liver Meeting® are fully accessible to the physically chal-
*The online Itinerary Planner is supported by Bristol-Myers lenged. Anyone who has a need for special assistance should
Squibb notify the appropriate hotel or the Hynes Convention Center
*ePosters are supported by Merck and indicate the type of assistance needed. AASLD cannot
* Meeting app supported by Bayer HealthCare and ensure the availability of appropriate assistance without prior
Onyx Pharmaceuticals notice.

Abstract Embargo Exhibit Hall • Hall D

Accepted abstracts are made available to the public on the The Exhibit Hall, an informative and important component of
AASLD website and are published in the October supplement of The Liver Meeting®, provides you with a valuable opportunity
Hepatology. Information contained in those abstracts may not to meet with representatives from various organizations that
be released until the abstracts appear on the AASLD website. are committed to the field of hepatology. A complete listing of
Academic institutions, private organizations, and companies exhibitors and their product descriptions can be found on our
with products whose values may be influenced by information website at www.thelivermeeting.org/exhibitors
contained in an abstract may issue a press release to coincide
with the availability of an abstract on the AASLD website. How- Exhibit Hours
ever, information beyond that contained in the abstract, e.g., Saturday, November 8 5:00 – 7:30 pm
discussion of the abstract done as part of a scientific presenta- Sunday, November 9 9:30 am – 3:00 pm
tion or presentation of additional or new information that will be Monday, November 10 9:30 am – 3:00 pm
available at the time of the meeting is embargoed from release
to the general public until the first day of The Liver Meeting®.
Posters • Hall C
Information released prior to this day is a violation of the AASLD
The Poster Sessions are an important event during The Liver
Abstract Embargo Policy and the abstract is subject to with-
Meeting®. Approximately 470 posters will be displayed daily.
drawal from The Liver Meeting® program. Authors are responsi-
The top 10% of posters accepted are designated in the pro-
ble for notifying financial and other sponsors about this policy.
gram as a “Presidential Poster of Distinction”.
AASLD may allow for exceptions, on a case-by-case basis, to
Posters should be set-up and viewed during the following times:
the Abstract Embargo Policy for compelled disclosures man-
dated by federal securities laws. However, AASLD requires the Poster Session I
company President, General Counsel, or other appropriate offi-
Saturday, November 8
cial of a company seeking such an exception to attest in writing
Set-up: 8:00 am – 2:00 pm
to the specific facts in support of the request, including exactly
Viewing Time: 2:00 – 7:30 pm
how the securities laws are implicated, with statutory citation(s).
Presentation Time: 5:30 – 7:00 pm*
General statements of the need to comply with the law will not
*Posters must be displayed until 7:30 pm
be considered sufficient. Requests for an exception must be
Dismantle Time: 7:30 – 8:00 pm
sent to the AASLD CEO. AASLD requires a minimum of five
(5) days from receipt of the request to evaluate the request. In
granting an exception, AASLD requires the company to state in

5A
General Information (continued)
Poster Session II
Sunday, November 9
Set-up: 6:30 – 8:00 am
Viewing Time: 8:00 am – 5:30 pm
Presentation Time: 12:30 – 2:00 pm*
*Posters must be displayed until 5:30 pm
Dismantle Time: 5:30 – 6:00 pm
Poster Session III
Monday, November 10
Set-up: 6:30 – 8:00 am
Viewing Time: 8:00 am – 5:30 pm
Presentation Time: 12:30 – 2:00 pm*
*Posters must be displayed until 5:30 pm
Dismantle Time: 5:30 – 6:00 pm
Poster Session IV
Tuesday, November 11
Set-up: 6:30 – 8:00 am
Viewing Time: 8:00 am – Noon
Presentation Time: 10:30 am – Noon*
*Posters must be displayed until Noon
Dismantle Time: Noon – 12:30 pm
Posters must be dismantled immediately following the viewing
time. Posters left on the boards will be removed and discarded.
Note: No CME will be provided for Poster Sessions.
ePosters • AASLD Pavilion
ePosters are an interactive technologically advanced viewing
system that brings posters to virtual life for all of The Liver Meet-
ing® attendees and archived in LiverLearning®. ePosters will
be available from the first day of the meeting in the AASLD
Pavilion.
ePosters are supported by Merck
When citing an abstract, please use the following format:
Desai RJ, Schnitzler MA, Di Bisceglie AM. Estimated impact of screening and anitviral treatment on
prevention of HBV reactivation associated with cancer chemotherapy [Abstract]. Hepatology 2014,
60(4Suppl.1):[Page]A.
6A
Press Room • Room 208
Friday, November 7 1:00 pm – 5:00 pm
Saturday, November 8 8:00 am – 6:00 pm
Sunday, November 9 8:00 am – 5:00 pm
Monday, November 10 8:00 am – 5:00 pm
Tuesday, November 11 8:00 am – Noon
The official press contact for The Liver Meeting® is:
Ann Haran
AASLD
1001 N. Fairfax Street, Suite 400
Alexandria, VA 22314-2720
Telephone: 703-299-9766
Fax: 703-299-9676
Email: aharan@aasld.org
Website: www.thelivermeeting.org/press
Registration Hours • Hall A
Thursday, November 6 2:00 – 8:00 pm
Friday, November 7 6:30 am – 7:30 pm
Saturday, November 8 6:30 am – 7:30 pm
Sunday, November 9 6:30 am – 6:00 pm
Monday, November 10 6:30 am – 6:00 pm
Tuesday, November 11 6:30 am – 12:30 pm
Speaker Ready Room • Room 207
Presenters should check-in 24 hours in advance, or no later than
2 hours prior to your session. If you are a speaker/presenter,
review the presenter tab at www.thelivermeeting.org prior to
the meeting for presentation tips, instructions, and guidelines.
Friday, November 7 6:30 am – 7:30 pm
Saturday, November 8 6:30 am – 7:30 pm
Sunday, November 9 6:30 am – 6:00 pm
Monday, November 10 6:30 am – 6:00 pm
Tuesday, November 11 6:30 am – 12:30 pm
Limited License for Use
The Liver Meeting® is protected by copyright, trademark, and/
or other applicable laws. Any use of The Liver Meeting ®,
including recordings and the development of derivative works,
is prohibited. The name, logo and acronym of the American
Association for the Study of Liver Diseases and The Liver Meet-
ing® are the exclusive property of and are trademarked by
AASLD. They may not be used in any way, for any purpose,
or at any time (including but not limited to announcements,
invitations, emails, Web publications, etc.) without the express
written permission of AASLD.
Without limiting the foregoing, Information presented during
The Liver Meeting® is the property of AASLD and the presenter.
Information may not be recorded, photographed, copied,
photocopied, transferred to electronic format, reproduced, or
distributed without the written permission of AASLD and the
presenter. Any use of the program content which includes,
but is not limited to, oral presentations, audiovisual materials
used by speakers, and program handouts, without the written
consent of AASLD is prohibited.
Notwithstanding the above, AASLD grants a non-exclusive,
non-transferable, royalty-free license to nonprofit, §501(c) (3),
AAMC-accredited educational institutions to conduct a “Best of
AASLD” conference or similar event (“Event”) of up to eight (8)
hours in length that features highlights from AASLD sessions at
the most recent occurrence of The Liver Meeting® and to utilize
the name of AASLD in connection with the same. No Event
may be held, nor may the name of AASLD be utilized, except
pursuant to this Limited License or as otherwise authorized by
AASLD in writing.
When using the term “AASLD” or “The Liver Meeting®”, you
must attribute AASLD’s trademark as follows: The Liver Meet-
ing® and AASLD are registered trademarks of the American
Association for the Study of Liver Diseases. You may not use
the AASLD trademark(s):
• In, as, or as part of your own trademarks
• To identify products or services that do not belong to AASLD
• In a manner likely to cause confusion, including colors and
fonts
• In a manner that implies inaccurately that AASLD sponsors or
endorses, or is otherwise connected with your own activities,
products and services
7A
The content of an Event shall be of the highest quality and
shall accurately reflect material and information presented at
the AASLD sessions. No Event shall include any statements or
other communication that maligns or disparages AASLD or any
AASLD session, presenter, or representative.
All Event announcements, brochures, descriptions, and mate-
rials, whether in print or electronic form, shall clearly identify
the content as being derived from AASLD sessions by including
the following statement: “All content is derived from presenta-
tions and similar offerings made at The Liver Meeting® 2014
and is presented with permission of the American Association
for the Study of Liver Diseases.” As between AASLD and any
institution, AASLD is the owner of all AASLD programming and
AASLD does not relinquish any such ownership rights by virtue
of this Limited License.
AASLD disclaims all warranties, express and implied, as to
any information or materials presented in connection with any
AASLD session or meeting, including as to intellectual property
ownership. AASLD shall not be liable for any direct, indirect,
punitive, consequential, or other damages in any way arising
or resulting from the Event or the use of information or materi-
als from AASLD sessions by any institution. Should any claim
or suit be brought against AASLD arising from an Event, the
institution shall indemnify and hold AASLD harmless for any
damages, liability, and costs, including attorney fees, suffered
or incurred by AASLD in defense and satisfaction thereof.
This Limited License does not create a partnership, joint ven-
ture, or similar relationship between AASLD and any institution.
This Limited License is non-transferable, including by sale or
sublicense.
This Limited License shall terminate automatically upon violation
of any of its terms. In addition, AASLD may terminate, or mod-
ify the terms of, this Limited License in its discretion, generally
or with respect to any particular institution.
This Limited License shall be construed in accordance with
the laws of the Commonwealth of Virginia, without regard
to conflicts principles, and, as applicable, federal copyright
and trademark laws. A court of competent jurisdiction in or
for Alexandria, Virginia shall be the exclusive forum for the
resolution of any dispute between AASLD and any institution,
and institutions irrevocably consent to the personal and subject
matter jurisdiction, and venue, of such court.
Continuing Medical Education and Disclosures
Statement on Disclosure
AASLD is committed to ensuring balance, independence objectivity and scientific rigor in its sponsored and jointly sponsored
educational activities. Individuals in a position to control the content of an AASLD-sponsored activity (program planners, course
directors, speakers, etc.) are expected to disclose all relevant financial relationships during the past 12 months.

When an unlabeled use of a commercial product or an investigational use not yet approved for any purpose is discussed during
an educational activity, the speaker shall disclose to the audience that the product is not labeled for the use under discussion or
that the product is still investigational.

All disclosure information is provided to the activity participant prior to the start of the educational activity. In addition, disclosure
slides will be the first side in each oral presentation viewed by participants. AASLD will identify and resolve all conflicts of interest
prior to program implementation.

Invited speakers, course directors, moderators, program planners, abstract reviewers and staff have provided the following
disclosures:

2014 Committee, Abstract Reviewer and Staff Disclosures

Afdhal, Nezam H., MD Aytaman, Ayse, MD
(Abstract Reviewer) (Abstract Reviewer)
Consulting: Abbott, Pharmasett, Gilead, Springbank, Nothing to disclose
GlaxoSmithKline, Idenix, Merck, Vertex
Grants/Research Support: Merck, Vertex, Idenix, GlaxoSmithKline, Bajaj, Jasmohan S., MD
Springbank, Gilead, Pharmasett, Abbott (Clinical Research Committee, Abstract Reviewer)
Grants/Research Support: Salix, Otsuka, Grifols
Adhami, Talal, MD Advisory Board: American College of Gastroenterology, Grifols,
(Program Evaluation Committee) Salix, Merz, Otsuka, Ocera
Speaking and Teaching: Gilead
Bambha, Kiran, MD
Ahmad, Jawad, MD (Abstract Reviewer)
(Abstract Reviewer) Nothing to disclose
Nothing to disclose
Bass, Nathan M., MD, PhD
Alberti, Alfredo, MD (Abstract Reviewer)
(Abstract Reviewer) Nothing to disclose
Grants/Research Support: Merck, Gilead
Advisory Board: Merck, Roche, Gilead Beaven, Simon, MD
Speaking and Teaching: Novartis, Bristol-Myers Squibb (Abstract Reviewer)
Nothing to disclose
Al-Osaimi, Abdullah, MD
(Abstract Reviewer) Beavers, Kimberly, MD
Nothing to disclose (Program Evaluation Committee)
Nothing to disclose
Alvarez, Fernando, MD
(Abstract Reviewer) Befeler, Alex, MD
Nothing to disclose (Program Evaluation Committee, Abstract Reviewer)
Advisory Board: Gilead
Angeli, Paolo, MD, PhD Stock: Amgen, Gilead
(Abstract Reviewer)
Advisory Board: Sequana Medical Bergasa, Nora V., MD
(Abstract Reviewer)
Aranda-Michel, Jaime, MD Nothing to disclose
(Abstract Reviewer)
Nothing to disclose Beier, Juliane Ingeborg, PhD
(Education Committee)
Arteel, Gavin E., PhD Nothing to disclose
(Basic Research Committee, Abstract Reviewer)
Grants/Research Support: NIH Berzigotti, Annalisa, MD, PhD
(Education Committee)
Asrani, Sumeet, MD Nothing to disclose
(Abstract Reviewer)
Nothing to disclose
8A
Continuing Medical Education and Disclosures (continued)
Bhamba, Kiran, MD Buck, Martina, PhD
(Clinical Research Committee) (Basic Research Committee)
Nothing to disclose Grants/Research Support: NIH
Speaking and Teaching: Conatus, Gilead
Biggins, Scott W., MD
(Abstract Reviewer) Caravan, Peter, PhD
Nothing to disclose (Abstract Reviewer)
Stock: Factor IA, LLC, Collagen Medical
Boelsterli, Urs A., PhD Consulting: Biogen Idec
(Abstract Reviewer)
Nothing to disclose Carithers, Robert L., MD
(Abstract Reviewer)
Bologna, Gregory Nothing to disclose
(Staff)
Nothing to disclose Carr, Rotonya M., MD
(Basic Research Committee)
Bosch, Jaime, MD Nothing to disclose
(Abstract Reviewer)
Consulting: Falk, Gilead Science, Norgine, ONO-USA, Intercept Chalasani, Naga P., MD
Pharma, Exalenz, Almirall, Conatus (Abstract Reviewer)
Grants/Research Support: Gore Grants/Research Support: Galectin, Cumberland, Gilead,
Intercept, Lilly
Bowlus, Christopher L., MD Consulting: Salix, AbbVie, Lilly, Boehringer Ingelheim, Aegerion
(Education Committee)
Advisory Board: Lumena Chavin, Kenneth D., MD, PhD
Grants/Research Support: Gilead, Lumena, Intercept (Scientific Program Committee, Surgery and Liver Transplantation
Committee)
Brady, Carla W., MD Grants/Research Support: Novartis
(Program Evaluation Committee, Scientific Program Committee) Scientific Consultant: Bridge to Life
Nothing to disclose
Chojkier, Mario, MD
Brenner, David A., MD (Abstract Reviewer)
(Abstract Reviewer) Nothing to disclose
Nothing to disclose
Chung, Raymond T., MD
Brigstock, David R., PhD (Governing Board, Basic Research Committee, Abstract Reviewer)
(Basic Research Committee) Scientific Consultant: AbbVie
Intellectual Property Rights: FibroGen, Inc. Grants/Research Support: Gilead, Mass Biologics, Transzyme,
Vertex
Brosgart, Carol, MD
(Abstract Reviewer) Cohen, Stanley M., MD
Nothing to disclose (Training and Workforce Committee)
Nothing to disclose
Brown, Kimberly Ann, MD
(Abstract Reviewer) Colquhoun, Steven D., MD
Advisory Board: CLDF, Merck, Salix, Gilead, Vertex, Novartis, (Abstract Reviewer)
Genentech, Janssen, Salix Nothing to disclose
Grants/Research Support: CLDF, Gilead, Exalenz, CDC, Bristol-
Myers Squibb, Bayer-Onyx, Ikaria, Hyperion, Merck Corbett, Ruth J., MSN, APRN
Speaking and Teaching: Salix, Merck, Genentech, Gilead, CLDF, (Training and Workforce Committee, Abstract Reviewer)
Vertex Nothing to disclose
Consulting: Salix, Blue Cross Transplant Centers
Corey, Kathleen E., MD
Browning, Jeffrey D., MD (Clinical Research Committee)
(Basic Research Committee) Nothing to disclose
Nothing to disclose
Cotler, Scott, MD
Bruce, Heidi (Clinical Research Committee, Abstract Reviewer)
(Staff) Nothing to disclose
Nothing to disclose
Crawford, James, MD, PhD
Brunt, Elizabeth M., MD (Abstract Reviewer)
(Abstract Reviewer) Nothing to disclose
Consulting: Synageva
Speaking and Teaching: Geneva Foundation, Independent
Contractor: Kadmon, Rottapharm

9A
Continuing Medical Education and Disclosures (continued)
Currie, Sue, EdD, MA Dieterich, Douglas, MD
(Hepatology Associates Committee) (Abstract Reviewer)
Employee, Officer, Director: Health Interactions Consulting: Gilead, Bristol-Myers Squibb
Advisory Board: Merck, Idenix, Janssen
Cusi, Kenneth, MD, PhD
(Abstract Reviewer) Dolganiuc, Angela, MD
Nothing to disclose (Abstract Reviewer)
Nothing to disclose
Czaja, Mark J., MD
(Scientific Program Committee, Basic Research Committee, Doo, Edward, MD
Abstract Reviewer) (Abstract Reviewer)
Consulting: Oncozyme Pharma, Inc. Nothing to disclose
Grants/Research Support: Oncozyme Pharma, Inc.
Echard, Steven
Daniel, James F., MD (Staff)
(Program Evaluation Committee) Nothing to disclose
Nothing to disclose
Eggers, Carol A., MSN, FNP
Davis, Gary L., MD (Program Evaluation Committee)
(Governing Board, Program Evaluation Committee, Scientific Nothing to disclose
Program Committee, Abstract Reviewer)
Nothing to disclose Eghtesad, Bijan, MD
(Surgery and Liver Transplantation Committee)
Dawson, Paul, MD Nothing to disclose
(Abstract Reviewer)
Consulting: GlaxoSmithKline, Isis Pharmaceuticals, Lumena Ekong, Udeme D., MD
Pharmaceuticals (Abstract Reviewer)
Stock: XenoPort, Inc. Nothing to disclose

Deal, Julie El-Serag, Hashem B., MD

(Staff) (Abstract Reviewer)
Stock: Bristol-Myers Squibb Nothing to disclose

Delgado-Borrego, Aymin, MD Emerick, Karan M., MD

(Program Evaluation Committee) (Abstract Reviewer)
Nothing to disclose Nothing to disclose

DeLeve, Laurie D., MD, PhD Emond, Jean C., MD

(Abstract Reviewer) (Abstract Reviewer)
Advisory Board: Pfizer, Takeda, Bristol-Myers Squibb Nothing to disclose

Di Bisceglie, Adrian M., MD, FACP Fallon, Michael B., MD

(Governing Board, Scientific Program Committee) (Abstract Reviewer)
Advisory Board: Gilead, Data Safety Monitoring Board, Bayer, Grants/Research Support: Bayer-Onyx, Eaisi, Gilead, Grifolis
Novartis
Grants/Research Support: AbbVie, Bristol-Myers Squibb, Gilead, Feld, Jordan J., MD
Janssen, Transgene, Vertex, Alpha-1 Foundation (Abstract Reviewer)
Royalties: Section Editor on Hepatitis C, UpToDate Advisory Board: Idenix, Merck, Janssen, Gilead, AbbVie, Merck,
Theravance, Bristol-Myers Squibb
Diaz, Susan M., PA-C, MPAS Grants/Research Support: AbbVie, Boehringer Ingelheim, Janssen,
(Surgery and Liver Transplantation Committee) Gilead, Merck
Nothing to disclose
Feldstein, Ariel E., MD
Dickson, Rolland C., MD (Abstract Reviewer)
(Education Committee, Abstract Reviewer) Nothing to disclose
Advisory Board: Bristol-Myers Squibb, Cowen and Associates
Grants/Research Support: Gilead, Roche, Tibotec, Vertex Feng, Sandy, MD, PhD
Scientific Consultant: Biotest (Abstract Reviewer)
Speaking and Teaching: Gilead Nothing to disclose

Diehl, Anna Mae, MD Fenkel, Jonathan M., MD

(Abstract Reviewer) (Abstract Reviewer)
Consulting: Roche Consulting: Gilead, Janssen
Grants/Research Support: Gilead, Genfit

10A
Continuing Medical Education and Disclosures (continued)
Fiel, Maria Isabel, MD George, Jacob, MD, PhD
(Education Committee) (Clinical Research Committee, Abstract Reviewer)
Leadership: HEPATOLOGY Advisory Board: Roche, Bristol-Myers Squibb, MSD, Gilead,
Speaking and Teaching: Richmond University Hospital Janssen
Grants/Research Support: P20 Mini Center, RO1 Detection of liver
fibrosis, HCC in non-cirrhotic liver Gerbes, Alexander L., MD
Expert Testimony: Fowler White Burnett, Kopff, Nardelli & Dopf, (Abstract Reviewer)
Bailly and McMillan McCormick Fitzpatrick Nothing to disclose

Firpi, Roberto J., MD Gershwin, M. Eric, MD

(Education Committee, Abstract Reviewer) (Abstract Reviewer)
Advisory Board: Gilead, Vertex Nothing to disclose
Grants/Research Support: Bayer, Boehringer, Bristol-Myers Squibb,
Gilead, Idenix, Novartis, Salix Ghany, Marc G., MD
(Scientific Program Committee, Clinical Research Committee)
Fitz, J. Gregory, MD Expert Testimony: Clinical Care Options
(Governing Board)
Nothing to disclose Gilles, HoChong, FNP
(Education Committee, Hepatology Associates Committee)
Fix, Oren K., MD Speaking and Teaching: Bayer
(Training and Workforce Committee, Abstract Reviewer)
Nothing to disclose Gish, Robert, MD
(Abstract Reviewer)
Forde, Kimberly A., MD Consulting: Arrowhead
(Clinical Research Committee) Advisory Board: Gilead, Bristol-Myers Squibb, Genentech,
Nothing to disclose Arrowhead
Stock: Arrowhead
Foster, Temitope Y., MD
(Program Evaluation Committee) Goacher, Elizabeth K., PA-C, MHS
Nothing to disclose (Clinical Research Committee)
Speaking and Teaching: Merck, Vertex
Friedman, Joshua, MD, PhD
(Abstract Reviewer) Gonzalez, Stevan, MD
Employment: Janssen Research & Development (Abstract Reviewer)
Speaking and Teaching: Gilead, Salix
Fuchs, Michael, MD, PhD
(Training and Workforce Committee) Gonzalez-Peralta, Regino P., MD
Nothing to disclose (Abstract Reviewer)
Consulting: Roche, Boehringer Ingelheim, Vertex
Fung, John J., MD Grants/Research Support: Bristol-Myers Squibb, Roche, Merck
(Abstract Reviewer)
Advisory Board: Astellas, Novartis Gordon, Fredric D., MD
Consulting: Vital Therapies (Abstract Reviewer)
Grants/Research Support: Sanofi Nothing to disclose

Gao, Bin, MD, PhD Gordon, Stuart C., MD

(Abstract Reviewer) (Abstract Reviewer)
Nothing to disclose Consulting: Bristol-Myers Squibb, Gilead, CVS Caremark, Merck
Grants/Research Support: Exalenz, Roche/Genentech, Vertex,
Gardenier, Donald, DNP, FNP-BC Gilead, Bristol-Myers Squibb, Abbott, Intercept
(Hepatology Associates Committee) Advisory Board: Tibotec
Scientific Consultant: BV, Elsevier
Leadership in Related Society: American Association of Nurse Grace, Norman D., MD
Practitioners (Abstract Reviewer)
Nothing to disclose
Gaspard, Gabrielle M., MPH
(Basic Research Committee) Green, Richard, MD
Nothing to disclose (Abstract Reviewer)
Nothing to disclose
Gautam, Manjushree, MD
(Abstract Reviewer) Guo, Grace, MD
Nothing to disclose (Abstract Reviewer)
Nothing to disclose

11A
Continuing Medical Education and Disclosures (continued)
Gupta, Sanjeev, MD Jonas, Maureen M., MD
(Abstract Reviewer) (Abstract Reviewer)
Nothing to disclose Consulting: Eisai
Grants/Research Support: Bristol-Myers Squibb, Roche, Merck
Hagedorn, Curt H., MD Advisory Board: Gilead
(Abstract Reviewer)
Nothing to disclose Kaestner, Klaus H., PhD
(Abstract Reviewer)
Harrison, Stephen, MD Nothing to disclose
(Education Committee, Abstract Reviewer)
Advisory Board: Galectin, Genfit Kamath, Patrick S., MD
Speaking and Teaching: Gilead (Abstract Reviewer)
Advisory Board: Sequana Medical
Hassanein, Tarek, MD
(Abstract Reviewer) Kaplowitz, Neil, MD
Grants/Research Support: AbbVie, Boehringer Ingelheim, Bristol- (Abstract Reviewer)
Myers Squibb, Eiasi, Gilead, Janssen, Idenix, Ikaria, Merck, Roche, Consulting: GlaxoSmithKline, JNJ, Merck, Novartis, Hepregen,
Ocera, Salix, Sundise, TaiGen, Takeda, Vital Therapies Takeda, Otsuka, Pfizer, Geron, Daiichi-Sanyo
Speaking and Teaching: Baxter, Bristol-Myers Squibb, Gilead, Independent Contractor: Acetaminophen Litigation
Salix
Advisory Board: AbbVie, Bristol-Myers Squibb Karpen, Saul J., MD, PhD
(Scientific Program Committee, Abstract Reviewer)
Heimbach, Julie, MD Nothing to disclose
(Abstract Reviewer)
Nothing to disclose Keaveny, Andrew, MD
(Education Committee)
Henderson, Neil C., MBChB, PhD Expert Testimony: UpToDate, Inc.
(Abstract Reviewer)
Nothing to disclose Kim, Arthur Y., MD
(Abstract Reviewer)
Horne, Patrick, MSN, ARNP Grants/Research Support: Gilead, Bristol-Myers Squibb
(Education Committee, Hepatology Associates Committee) Consulting: AbbVie, Gilead
Advisory Board: Gilead
Grants/Research Support: Bayer Kisseleva, Tatiana, MD, PhD
(Abstract Reviewer)
Horslen, Simon, MD Nothing to disclose
(Abstract Reviewer)
Nothing to disclose Klett, Janeil
(Staff)
Howell, Charles D., MD Stock: Merck, Pfizer
(Education Committee)
Grants/Research Support: Boehringer Ingelheim, Bristol-Myers Klintmalm, Goran, MD, PhD
Squibb, Gilead (Abstract Reviewer)
Leadership in a Related Society: National Medical Association Grants/Research Support: Astellas, Novartis, Opson, Quark
Hepatitis C Task Force Advisory Board: Novartis

Ioannou, George, MD Kneteman, Norman M., MD

(Clinical Research Committee) (Abstract Reviewer)
Nothing to disclose Nothing to disclose

Jalan, Rajiv, MD, PhD Knisely, Alexander S., MD

(Abstract Reviewer) (Abstract Reviewer)
Consulting: Ocera, Conatus Nothing to disclose
Grants/Research Support: Grifols, Gambro
Kohli, Rohit, MD
Janssen, Harry L.A., MD, PhD (Clinical Research Committee, Abstract Reviewer)
(Program Evaluation Committee, Abstract Reviewer) Grants/Research Support: Synageva Biopharma, Johnson and
Consulting: Santaris, Roche, Novartis, Medtronic, Merck, Gilead, Johnson
Debio, Abbott, Bristol-Myers Squibb Independent Contractor: Lumena Pharmaceuticals, Galectin
Grants/Research Support: Anadys, Bristol-Myers Squibb, Gilead, Therapeutics
Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, Santaris
Korenblat, Kevin M., MD
Jeong, Won-ll, DVM, PhD (Abstract Reviewer)
(Abstract Reviewer) Grants/Research Support: Merck
Nothing to disclose Advisory Board: Vertex

12A
Continuing Medical Education and Disclosures (continued)
Koteish, Ayman A., MD Lidofsky, Steven D., MD
(Program Evaluation Committee) (Abstract Reviewer)
Nothing to disclose Nothing to disclose

Kowdley, Kris V., MD Lim, Joseph K., MD

(Abstract Reviewer) (Abstract Reviewer)
Advisory Board: Janssen, Ikaria, Boehringer Ingelheim, Vertex, Grants/Research Support: Achillion, Abbott, Boehringer Ingelheim,
AbbVie, Gilead, Merck, Novartis, Trio Health Bristol-Myers Squibb, Genentech, Gilead, Janssen/Tibotec, Vertex
Grants/Research Support: AbbVie, Beckman, Boehringer Consulting: Merck, Vertex, Gilead, Bristol-Myers Squibb,
Ingelheim, Bristol-Myers Squibb, Gilead, Ikaria, Janssen, Merck, Boehringer Ingelheim
Mochida
Lindor, Keith, MD
Kulkarni, Sanjay, MD (Governing Board, Hepatology Associates Committee, Scientific
(Surgery and Liver Transplantation Committee) Program Committee)
Grants/Research Support: Alexion Advisory Board: Intercept, Lumena

Lai, Ching Lung, MD Ling, Simon C., MBChB, MRCP

(Abstract Reviewer) (Abstract Reviewer)
Nothing to disclose Grants/Research Support: Bristol-Myers Squibb

Larson, Anne M., MD Lippello, Anita, CRNP, NP-C, DNP

(Abstract Reviewer) (Hepatology Associates Committee)
Speaking and Teaching: Gilead, Genentech, Salix Nothing to disclose

Lau, George, MD Little, Ester C., MD

(Abstract Reviewer) (Education Committee)
Consulting: Novartis, Roche Nothing to disclose

Lauer, Georg M., MD Liu, Chen, MD, PhD

(Basic Research Committee, Abstract Reviewer) (Abstract Reviewer)
Nothing to disclose Nothing to disclose

Laurin, Jacqueline, MD Llovet, Josep M., MD

(Education Committee) (Abstract Reviewer)
Nothing to disclose Grants/Research Support: Beohringer Ingelheim, Bayer, Bristol-
Myers Squibb
Leise, Michael, MD Consulting: GlaxoSmithKline, Bayer, Bristol-Myers Squibb, Imclone,
(Abstract Reviewer) Biocompatibles, Novartis
Nothing to disclose Advisory Board: Nanostring, Blueprint Medicines

Leonis, Mike A., MD, PhD Lok, Anna S. F., MD

(Training and Workforce Committee) (Governing Board, Education Committee, Abstract Reviewer)
Grants/Research Support: NIH Advisory Board: Gilead, Immune Targeting System, MedImmune,
Leadership in Related Society: NASPGHAN Research Committee Arrowhead, Bayer, GlaxoSmithKline, Janssen, Novartis, ISIS,
member Tekmira
Grants/Research Support: Abbott, Bristol-Myers Squibb, Gilead,
Levitsky, Josh, MD Merck, Roche, Boehringer Ingelheim
(Training and Workforce Committee, Abstract Reviewer)
Consulting: Transplant Genomics, Inc. Loomba, Rohit, MD
Grants/Research Support: Novartis (Program Evaluation Committee, Abstract Reviewer)
Speaking and Teaching: Gilead, Salix Advisory Board: American Liver Foundation
Grants/Research Support: Daiichi Sankyo, Inc., Merck
Levy, Cynthia, MD Scientific Consultant: Gilead, J and J Inc., Merck
(Clinical Research Committee, Abstract Reviewer)
Consulting: Lumena, Gilead, Evidera Loomes, Kathleen M., MD
(Training and Workforce Committee)
Liangpunsakul, Suthat, MD Grants/Research Support: NIH
(Abstract Reviewer)
Nothing to disclose Lu, Shelly, MD
(Abstract Reviewer)
Liddle, Christopher, MD, PhD Nothing to disclose
(Abstract Reviewer)
Nothing to disclose Magee, John, MD
(Surgery and Liver Transplantation Committee, Abstract Reviewer)
Grants/Research Support: Novartis

13A
Continuing Medical Education and Disclosures (continued)
Mandrekar, Pranoti, MD Mulligan, David, MD
(Abstract Reviewer) (Abstract Reviewer)
Nothing to disclose Nothing to disclose

Marrero, Jorge A., MD Munoz, Santiago J., MD

(Abstract Reviewer) (Abstract Reviewer)
Grants/Research Support: Bayer, Bristol-Myers Squibb Nothing to disclose
Advisory Board: Bayer, Onyx
Nagorney, David M., MD
McCullough, Arthur J., MD (Abstract Reviewer)
(Abstract Reviewer) Nothing to disclose
Nothing to disclose
Narkewicz, Michael R., MD
McNiven, Mark A., MD, PhD (Education Committee, Abstract Reviewer)
(Abstract Reviewer) Grants/Research Support: Novartis, Vertex
Nothing to disclose Consulting: Vertex
Stock: Merck
Mehal, Wajahat Z., MD
(Basic Research Committee, Abstract Reviewer) Navasa, Miguel, MD
Management Position: Global BioResearch Partners (Abstract Reviewer)
Consulting: Novartis, Astellas
Menon, K.V. Narayanan, MD
(Surgery and Liver Transplantation Committee) Neuberger, James, MD
Speaking and Teaching: Salix (Abstract Reviewer)
Stock: Vertex Speaking and Teaching: Novartis, Astellas

Merriman, Raphael, MD Ng, Vicky I., MD

(Abstract Reviewer) (Surgery and Liver Transplantation Committee, Abstract Reviewer)
Nothing to disclose Nothing to disclose

Miethke, Alexander G., MD Nguyen, Mindie H., MD

(Basic Research Committee) (Education Committee, Hepatology Associates Committee)
Nothing to disclose Advisory Board: Bristol-Myers Squibb, Gilead, Janssen, Novartis,
Onyx
Mills, Rennie M., PA-C Grants/Research Support: Asian Health Foundation, Bristol-Myers
(Hepatology Associates Committee) Squibb, Gilead, Idenix, Novartis, Pacific Health Foundation
Nothing to disclose Scientific Consultant: Gilead
Leadership in Related Society: Asian Health Foundation, Pacific
Mistry, Pramod, MD, PhD Health Foundation
(Abstract Reviewer)
Grants/Research Support: Genzyme Corporation Nieto, Natalia, PhD
(Basic Research Committee, Abstract Reviewer)
Modi, Apurva A., MD Nothing to disclose
(Abstract Reviewer)
Speaking and Teaching: Salix, Merck Noureddin, Mazen, MD
(Program Evaluation Committee)
Moreau, Richard, MD Nothing to disclose
(Abstract Reviewer)
Nothing to disclose O’Leary, Jacqueline G., MD
(Abstract Reviewer)
Morgan, Timothy R., MD Consulting: Gilead, Janssen
(Abstract Reviewer)
Grants/Research Support: Merck, Vertex, Genentech, Gilead, Orloff, Susan, MD
Bristol-Myers Squibb (Governing Board, Surgery and Liver Transplantation Committee)
Nothing to disclose
Morrison, Maureen S., DNP
(Hepatology Associates Committee) Pan, Calvin Q., MD
Nothing to disclose (Abstract Reviewer)
Advisory Board: Gilead, Bristol-Myers Squibb
Mullen, Kevin D., MD Consulting: AbbVie, Janssen, Merck, Gilead, Bristol-Myers Squibb
(Abstract Reviewer) Grants/Research Support: Merck, Genentech, Bristol-Myers
Advisory Board: Salix Squibb, Gilead
Speaking and Teaching: AbbVie, Salix Speaking and Teaching: Gilead, Onyx, Bristol-Myers Squibb

14A
Continuing Medical Education and Disclosures (continued)
Parikh, Neehar Dilip, MD Rangnekar, Amol S., MD
(Surgery and Liver Transplantation Committee) (Training and Workforce Committee)
Nothing to disclose Nothing to disclose

Parrish, Melissa Reddy, K. Rajender, MD

(Staff) (Governing Board, Clinical Research Committee, Abstract
Nothing to disclose Reviewer)
Advisory Board: AbbVie, Bristol-Myers Squibb, Genentech, Gilead,
Patton, Heather M., MD Janssen, Merck, Vertex
(Abstract Reviewer) Grants/Research Support: AbbVie, Bristol-Myers Squibb, Genfit,
Nothing to disclose Gilead, Janssen, Vertex

Perumalswami, Ponni, MD Reynaert, Hendrik, MD

(Abstract Reviewer) (Abstract Reviewer)
Nothing to disclose Advisory Board: AbbVie, MSD, Gilead, Janssen, Bristol-Myers
Squibb
Peter, Joy A., RN, BSN Grants/Research Support: Roche
(Abstract Reviewer)
Nothing to disclose Richards, Lisa Maria, FNP, MSN
(Hepatology Associates Committee)
Peters, Marion G., MD Speaking and Teaching: Bristol-Myers Squibb, Kadmon, Merck,
(Abstract Reviewer) Vertex Pharmaceuticals
Consulting: Merck
Advisory Board: Janssen Ripoll, Christina, MD
Employment: Hoffman La Roche (Spouse) (Abstract Reviewer)
Nothing to disclose
Petty, Allyson
(Staff) Roayaie, Sasan, MD
Nothing to disclose (Surgery and Liver Transplantation Committee)
Nothing to disclose
Pocha, Christine, MD, PhD
(Abstract Reviewer) Roberts, Eve, MD
Nothing to disclose (Abstract Reviewer)
Nothing to disclose
Pockros, Paul J., MD
(Abstract Reviewer) Robson, Simon C., MD, PhD
Grants/Research Support: Novartis, Intercept, Janssen, Genentech, (Abstract Reviewer)
Bristol-Myers Squibb, Gilead, Vertex, Boehringer Ingelheim, Grants/Research Support: NIH, Pfizer
Lumena, Novartis, Merck, RMS, Beckman Coulter, AbbVie Stock: Puretech, Nanopharma
Advisory Board: Janssen, Merck, Genentech, Bristol-Myers Squibb, Speaking and Teaching: ACP, Elsevier, ATC
Gilead, Boehringer Ingelheim, AbbVie Independent Contractor: eBioscience, Biolegend, EMD Millipore,
Speaking and Teaching: Genentech, Bristol-Myers Squibb, Gilead Mersana
Consulting: Genentech, Lumena, Regulus, Beckman Coulter, RMS
Rockey, Don C., MD
Polyak, Stephen J., PhD (Abstract Reviewer)
(Basic Research Committee, Abstract Reviewer) Grants/Research Support: Gilead, Actelion
Nothing to disclose
Rodriguez-Torres, Maribel, MD
Pomfret, Elizabeth, MD, PhD (Abstract Reviewer)
(Abstract Reviewer) Advisory Board: Hoffman La Roche, Pharmasset, Bristol-Myers
Nothing to disclose Squibb, Inhibitex, Vertex, Janssen
Consulting: Theravance, Abbott, Akros, GlaxoSmithKline,
Post, Anthony B., MD Genentech, Janssen, Santaris, Scynexis
(Abstract Reviewer) Grants/Research Support: Genentech, Anadys, Novartis, Merck,
Advisory Board: Schering Plough, Onyx Vertex, Hoffman-LaRoche, Inhibitex, Bristol-Myers Squibb, Idera,
Speaking and Teaching: Gilead, Roche, Vertex, Roche Pharmasset, Sanofi-Aventis, Merck, Abbott, Pfizer, Human Genome
Stock: Amgen Sciences, Gilead, Johnson & Johnson, Zymogenetics, AKROS,
Scynexis, Santaris, Boehringer Ingelheim, Idenix, Beckman Coulter,
Pramuk, Edward Mochida Pharmaceutical, Theravance
(Staff)
Nothing to disclose Rossi, Simona, MD
(Program Evaluation Committee)
Rakela, Jorge L., MD Scientific Consultant: Bristol-Myers Squibb
(Basic Research Committee)
Nothing to disclose

15A
Continuing Medical Education and Disclosures (continued)
Rotman, Yaron, MD Sokol, Ronald J., MD
(Basic Research Committee) (Governing Board, Training and Workforce Committee)
Nothing to disclose Scientific Consultant: Cardax, Lumena, Ikaria, Roche, Mead
Johnson Nutrition, Yasoo Health, Inc.
Roy-Chowdhury, Jayanta, MD, PhD Grants/Research Support: NIH, Mead Johnson Nutrition, Alpha-
(Abstract Reviewer) One Foundation
Nothing to disclose
Soldevila-Pico, Consuelo, MD
Rudnick, David A., MD (Program Evaluation Committee)
(Abstract Reviewer) Nothing to disclose
Nothing to disclose
Squires, Robert H., MD
Russo, Mark W., MD (Abstract Reviewer)
(Training and Workforce Committee) Nothing to disclose
Advisory Board: Bayer
Grants/Research Support: Salix, Vertex Stadheim, Linda M., RN
Speaking and Teaching: Gilead, Salix, Vertex (Hepatology Associates Committee)
Nothing to disclose
Salerno, Francesco, MD
(Abstract Reviewer) Sterling, Richard K., MD
Nothing to disclose (Training and Workforce Committee)
Advisory Board: Abbott/AbbVie, Bayer, Bristol-Myers Squibb,
Sanabria, Juan R., MD Gilead, Merck, Salix, Vertex
(Education Committee) Grants/Research Support: Abbott, Bayer, Boehringer Ingelheim,
Nothing to disclose Bristol-Myers Squibb, Gilead, Merck, Vertex
Leadership in a Related Society: American College of
Schwartz, Robert E., MD, PhD Gastroenterology
(Basic Research Committee)
Nothing to disclose Strader, Doris B., MD
(Abstract Reviewer)
Schwimmer, Jeffrey B., MD Nothing to disclose
(Abstract Reviewer)
Speaking and Teaching: Daiichi Sankyo Strazzabosco, Mario, MD, PhD
(Basic Research Committee)
Seise, Denise Speaking and Teaching: Janssen
(Staff)
Nothing to disclose Sulkowski, Mark, MD
(Abstract Reviewer)
Shah, Vijay, MD Advisory Board: Merck, AbbVie, BIPI, Idenix, Janssen, Gilead,
(Abstract Reviewer) Bristol-Myers Squibb, Pfizer
Nothing to disclose Grants/Research Support: Merck, AbbVie, Vertex, Janssen, Gilead,
Bristol-Myers Squibb
Sherker, Averell H., MD
(Clinical Research Committee, Abstract Reviewer) Szabo, Gyongyi, MD, PhD
Nothing to disclose (Governing Board, Scientific Program Committee)
Advisory Board: Alcohol, Research and Health, HIAAA & ABMRF,
Shetty, Kirti, MD and Alcoholism-Clinical and Experimental Research
(Abstract Reviewer) Scientific Consultant: Dartmouth Medical School MD/PhD Program,
Nothing to disclose GLG Research, Institute of Translational Hepatology, Beijing China,
University of Southern California Alcohol Center, Yale University
Shouval, Daniel, MD Liver Center
(Abstract Reviewer) Grants/Research Support: Conatus, GlaxoSmithKline, Bristol-Myers
Advisory Board: Scigen Squibb, Idenix, Ideral Integrated Therapeutics, Intercept, Johnson
Speaking and Teaching: Biotest, GlaxoSmithKline and Johnson, NIH, Novartis, Novelos, Ocera, Roche, Schering-
Board Membership: Johnson & Johnson Plough, Vertex, Wyeth

Singal, Amit, MD Taddei, Tamar H., MD

(Abstract Reviewer) (Abstract Reviewer)
Speaking and Teaching: Onyx/Bayer Grants/Research Support: Bayer HealthCare
Advisory Board: Onyx/Bayer Consulting: Onyx

Smith, Alastair D., MD, ChB, FRCP Tandon, Puneeta, MD

(Surgery and Liver Transplantation Committee) (Clinical Research Committee)
Stock: Roche Nothing to disclose

16A
Continuing Medical Education and Disclosures (continued)
Taouli, Bachir, MD Wells, Rebecca G., MD
(Abstract Reviewer) (Education Committee, Scientific Program Committee, Abstract
Nothing to disclose Reviewer)
Nothing to disclose
Te, Helen S., MD
(Abstract Reviewer) Wentworth, Corinne, PA-C
Grants/Research Support: Bristol-Myers Squibb, AbbVie (Abstract Reviewer)
Advisory Board: Gilead, Janssen Consulting: Merck
Advisory Board: Merck, Vertex
Theise, Neil, MD Speaking and Teaching: ITSRX Pharmacy, Genentech, Gilead,
(Abstract Reviewer) Bayer, Merck, Vertex
Nothing to disclose
Wiesner, Russell H., MD
Thompson, Richard, MD (Abstract Reviewer)
(Abstract Reviewer) Nothing to disclose
Nothing to disclose
Wong, David K., MD
Thuluvath, Paul, MD (Abstract Reviewer)
(Abstract Reviewer) Grants/Research Support: Gilead, Bristol-Myers Squibb
Advisory Board: Bayer, Gilead, Vertex
Grants/Research Support: Gilead, Abbott, Bristol-Myers Squibb, Wong, Florence, MD
Isai, Salix (Abstract Reviewer)
Speaking and Teaching: Bayer/Onyx, Vertex, Gilead Consulting: Gore, Inc
Grants/Research Support: Grifols
Townshend-Bulson, Lisa J., NP, MSN
(Hepatology Associates Committee) Wong, John B., MD
Nothing to disclose (Abstract Reviewer)
Nothing to disclose
Tuttle-Newhall, Janet E., MD
(Surgery and Liver Transplantation Committee) Wrobel, Anne
Nothing to disclose (Staff)
Nothing to disclose
Vargas, Hugo E., MD
(Abstract Reviewer) Yim, Colina, RN, MN
Grants/Research Support: Ikaria, AbbVie, Merck, Gilead, Idenix, (Abstract Reviewer)
Novartis, Vertex, Janssen, Bristol-Myers Squibb Nothing to disclose
Advisory Board: Eisai
Yin, Xiao-Ming, MD
Verna, Elizabeth C., MD (Abstract Reviewer)
(Clinical Research Committee) Nothing to disclose
Nothing to disclose
Younossi, Zobair, MD
Voigt, Michael D., MD (Abstract Reviewer)
(Abstract Reviewer) Nothing to disclose
Nothing to disclose
Zaman, Atif, MD
Wands, Jack R., MD (Education Committee)
(Abstract Reviewer) Grants/Research Support: Bristol-Myers Squibb, Gilead, Merck
Nothing to disclose
Zoulim, Fabien, MD
Washburn, W. Kenneth, MD (Abstract Reviewer)
(Training and Workforce Committee) Advisory Board: Novira, AbbVie, Tykmera, Transgene, Janssen,
Nothing to disclose Gilead
Speaking and Teaching: Bristol-Myers Squibb, Gilead
Wattacheril, Julia, MD, PhD Grants/Research Support: Novartis, Gilead, Scynexis, Roche,
(Abstract Reviewer) Novira
Nothing to disclose

Weiland, Amanda Camp, MD

(Clinical Research Committee)
Nothing to disclose

Weinman, Steven A., MD, PhD

(Abstract Reviewer)
Consulting: MSD Japan

17A
Continuing Medical Education and Disclosures (continued)
2014 Presenter Disclosures
Abdelmalek, Manal F., MD Arora, Sanjeev, MD
(Early Morning Workshops) (SIG Program)
Consulting: Islet Sciences Nothing to disclose
Grant/Research Support: Mochida Pharmaceuticals, Gilead
Sciences, NIH/NIDDK, Synageva, Genfit Pharmaceuticals Arteel, Gavin E., PhD
(Early Morning Workshops)
Abecassis, Michael M., MD, MBA Nothing to disclose
(AASLD/ILTS Transplant Course)
Nothing to disclose Assis, David N., MD
(SIG Program)
Adams, David H., MD Nothing to disclose
(AASLD Postgraduate Course)
Advisory Committees or Review Panels: GSK, Proximagen Assis, David N., MD
Grant/Research Support: Takeda, Biotie Therapies, Novimmune, (SIG Program)
ChemoCentryx, Novimmune, Biotie Therapies Nothing to disclose
Patent Held/Filed: biotie therapies, Biotie Therapies, Biotie
Therapies, Biotie Therapies, Biotie Therapies, Biotie Therapies, Bajaj, Jasmohan S., MD
Biotie Therapies, Biotie Therapies (Emerging Trends Symposium, Meet-the-Professor Luncheon, SIG
Program)
Ahlenstiel, Golo Advisory Committees or Review Panels: Salix, Merz, otsuka, ocera,
(Parallel Session) grifols, american college of gastroenterology
Nothing to disclose Grant/Research Support: salix, otsuka, grifols

Aithal, Guruprasad P., MD, PhD Bala, Shashi, PhD

(SIG Program) (Early Morning Workshops)
Nothing to disclose Nothing to disclose

Allen, John I., MD Bambha, Kiran, MD

(Value Based Medicine) (Parallel Session)
Consulting: gMed, Pentax, Olympus, Myriad Genetics Nothing to disclose

Alonso, Estella M., MD Bamforth, Iain, MBChB, DLitt

(AASLD/NASPGHAN Pediatric Symposium, Clinical Research (State-of-the-Art Lecture)
Workshop) Nothing to disclose
Nothing to disclose
Bansal, Meena B., MD
Alpini, Gianfranco, PhD (Professional Development Workshop)
(Early Morning Workshops, SIG Program) Nothing to disclose
Nothing to disclose
Beier, Juliane I., PhD
Anania, Frank A., MD, FACP, AGAF (Parallel Session)
(Early Morning Workshops, Parallel Session, SIG Program) Nothing to disclose
Nothing to disclose
Bergquist, Annika, PhD
Andrade, Raul J., MD, PhD (SIG Program)
(Meet-the-Professor Luncheon) Nothing to disclose
Nothing to disclose
Beuers, Ulrich, MD
Angeli, Paolo, MD, PhD (AASLD Postgraduate Course)
(SIG Program) Consulting: Intercept, Novartis
Advisory Committees or Review Panels: Sequana Medical Grant/Research Support: Zambon
Speaking and Teaching: Falk Foundation, Gilead, Roche,
Anwer, Mohammed S., PhD, DMVH Scheringh, Zambon
(SIG Program)
Nothing to disclose Bezerra, Jorge A., MD
(AASLD Postgraduate Course, Early Morning Workshops)
Arnon, Ronen, MD Grant/Research Support: Molecular Genetics Laboratory, CHMC
(AASLD/NASPGHAN Pediatric Symposium)
Nothing to disclose Bhatia, Sangeeta, MD, PhD
(SIG Program)
Aronsohn, Andrew, MD Nothing to disclose
(Early Morning Workshops)
Nothing to disclose

18A
Continuing Medical Education and Disclosures (continued)
Block, Timothy M., PhD Bucuvalas, John, MD
(SIG Program) (Early Morning Workshops)
Advisory Committees or Review Panels: Bristol Myers Squibb, Nothing to disclose
Immunotope, Inc., Immunotope, Inc.
Board Membership: Contravir, Glycotest Bull, Laura, PhD
Consulting: Roche (Early Morning Workshops)
Nothing to disclose
Bonkovsky, Herbert L., MD
(Early Morning Workshops, Meet-the-Professor Luncheon) Bzowej, Natalie H., MD, PhD
Advisory Committees or Review Panels: Clinuvel, Inc., Novartis (Early Morning Workshops)
Pharmaceuticals, Clinuvel, Inc., Novartis Pharmaceuticals, Grant/Research Support: Gilead Sciences, Ocera Therapeutics
Clinuvel, Inc., Novartis Pharmaceuticals, Clinuvel, Inc., Novartis
Pharmaceuticals Caldwell, Stephen H., MD
Consulting: Alnylam, Inc, Clinuvel, Inc., Novartis Pharmaceuticals, (Early Morning Workshops, Meet-the-Professor Luncheon)
Lundbeck Pharmaceuticals, Boehringer-Ingelheim, Clinuvel, Inc., Advisory Committees or Review Panels: Vital Therapy
Novartis Pharmaceuticals, Lundbeck Pharmaceuticals, Boehringer- Consulting: Wellstat diagnostics
Ingelheim, Clinuvel, Inc., Novartis Pharmaceuticals, Recordati Rare Grant/Research Support: Genfit, Gilead Sciences
Chemicals, Clinuvel, Inc., Novartis Pharmaceuticals
Grant/Research Support: Clinuvel, Inc, Vertex, Novartis Caravan, Peter, PhD
Pharmaceuticals, Clinuvel, Inc, Vertex, Novartis Pharmaceuticals, (SIG Program)
Clinuvel, Inc, Vertex, Novartis Pharmaceuticals, Clinuvel, Inc, Grant/Research Support: Sanofi
Vertex Stock Shareholder: Collagen Medical
Speaking and Teaching: Lundbeck Pharmaceuticals, Lundbeck
Pharmaceuticals Carey, Elizabeth J., MD
(Parallel Session)
Bornstein, Jeffrey D., MD Nothing to disclose
(Clinical Research Workshop)
Employment: Gilead Sciences Castera, Laurent, MD, PhD
(SIG Program)
Bosch, Jaime, MD, PhD, FRCP Advisory Committees or Review Panels: Magnisense
(Parallel Session) Speaking and Teaching: Gilead, BMS, Janssen, Echosens, Abbvie
Consulting: Falk, Gilead Science, Norgine, ONO-USA, Intercept
pharma, Exalenz, Almirall, Conatus Cathcart, Sherrie H., CAE
Grant/Research Support: Gore (AASLD Distinguished Awards)
Nothing to disclose
Bowlus, Christopher L., MD
(Parallel Session) Chalasani, Naga P., MD
Advisory Committees or Review Panels: Gilead Sciences, Inc (AASLD Postgraduate Course, Early Morning Workshops)
Consulting: Takeda Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aegerion
Grant/Research Support: Gilead Sciences, Inc, Intercept Grant/Research Support: Intercept, Lilly, Gilead, Cumberland,
Pharmaceuticals, Bristol Meyers Squibb, Lumena Galectin
Speaking and Teaching: Gilead Sciences, Inc
Chandrasekhara, Vinay, MD
Brenner, David A., MD (AASLD/ASGE Endoscopy Course)
(AASLD Postgraduate Course, Basic Research Workshop) Consulting: Boston Scientific
Nothing to disclose
Chang, Kyong-Mi, MD
Brosgart, Carol (AASLD Postgraduate Course, Early Morning Workshops, Parallel
(Parallel Session) Session, SIG Program)
Board Membership: Tobira Therapeutics Stock Shareholder: BMS (spouse employment)
Consulting: Dynavax
Stock Shareholder: Alios Biopharma Chavin, Kenneth D., MD, PhD
(Parallel Session, Transplant Surgery Workshop)
Brown, Robert S., MD, MPH Advisory Committees or Review Panels: Novartis
(AASLD/ILTS Transplant Course) Grant/Research Support: Bridge to Life, Novartis, Sanofi
Advisory Committees or Review Panels: Vital Therapies
Consulting: Genentech, Gilead, Merck, Abbvie, Janssen Chopra, Kapil B., MD, FACP
Grant/Research Support: Gilead, Merck, Vertex, AbbVie, Salix, (Hepatology Associates Course)
Janssen, Vital Therapies Nothing to disclose

Brunt, Elizabeth M., MD Chung, Raymond T., MD

(AASLD Postgraduate Course, SIG Program, State-of-the-Art
Lecture)
Consulting: Synageva
Independent Contractor: Rottapharm, Kadmon
Speaking and Teaching: Geneva Foundation
(AASLD Postgraduate Course, Clinical Research Workshop)
Consulting: Abbvie
Grant/Research Support: Gilead, Mass Biologics

19A
Continuing Medical Education and Disclosures (continued)
Clemens, Mark G., PhD Di Bisceglie, Adrian M., MD, FACP
(Early Morning Workshops) (Plenary Session, State-of-the-Art Lecture)
Management Position: HepatoSys Inc Grant/Research Support: Genentech, Gilead, AbbVie, BMS
Stock Shareholder: HepatoSys Inc
Diaz, Geraldine, DO
Clària, Joan (AASLD/ILTS Transplant Course)
(SIG Program) Nothing to disclose
Nothing to disclose
Diehl, Anna Mae, MD
Cohen, David E., MD, PhD (AASLD Postgraduate Course)
(Early Morning Workshops) Consulting: Roche
Advisory Committees or Review Panels: Merck, Genzyme Grant/Research Support: Gilead, Genfit
Consulting: Novartis, Aegerion, Dignity Sciences, Intercept
Speaking and Teaching: Merck Dienstag, Jules L., MD
(AASLD Distinguished Awards)
Cohen, Stanley M., MD Advisory Committees or Review Panels: Bristol-Myers Squibb,
(Competency Training Workshop) Gilead, Genzyme, Merck, Ikaria, Medtronic, Achillion
Advisory Committees or Review Panels: Gilead, BMS Consulting: CVS/Caremark
Speaking and Teaching: Gilead, BMS Stock Shareholder: Achillion

Corey, Kathleen, MD, MPH Divanovic, Senad, PhD

(Early Morning Workshops) (SIG Program)
Advisory Committees or Review Panels: Gilead Nothing to disclose

Cox, Andrea, MD, PhD Dolganiuc, Angela, MD, PhD

(AASLD Postgraduate Course, Early Morning Workshops) (Parallel Session)
Nothing to disclose Nothing to disclose

Currie, Sue, PhD Doo, Edward, MD

(Hepatology Associates Course) (Parallel Session)
Nothing to disclose Nothing to disclose

Czaja, Mark J., MD Dranoff, Jonathan A., MD

(AASLD Postgraduate Course, Early Morning Workshops, Parallel (Early Morning Workshops)
Session) Nothing to disclose
Consulting: Oncozyme Pharma Inc.
Grant/Research Support: Oncozyme Pharma Inc. Duncan, Stephen A., D.Phil.
(State-of-the-Art Lecture)
Daly, Mark, PhD Consulting: Primorigen Biosciences
(SIG Program)
Nothing to disclose Durand, Francois, MD
(SIG Program)
Davidson, Nicholas O., MD Advisory Committees or Review Panels: Astellas, Novartis
(SIG Program) Speaking and Teaching: Gilead
Nothing to disclose
Durkalski, Valerie L., PhD, MPH
Davila, Marta L., MD, AGAF, FACG, FASGE (Clinical Research Workshop)
(AASLD/ASGE Endoscopy Course) Nothing to disclose
Nothing to disclose
Eghtesad, Bijan, MD
Davis, Gary L., MD (Transplant Surgery Workshop)
(Plenary Session) Nothing to disclose
Nothing to disclose
Emond, Jean C., MD
Dawson, Paul, PhD (Parallel Session, State-of-the-Art Lecture)
(Parallel Session) Nothing to disclose
Consulting: Lumena Pharmaceuticals
Stock Shareholder: Xenoport Inc Englesbe, Michael J., MD
(Transplant Surgery Workshop)
DeLeve, Laurie D., MD, PhD Nothing to disclose
(AASLD Postgraduate Course, Early Morning Workshops, Parallel
Session)
Advisory Committees or Review Panels: Pfizer, Takeda, Bristol-
Myers Squibb

20A
Continuing Medical Education and Disclosures (continued)
Everson, Gregory T., MD Fried, Michael W., MD
(Advances for Practitioners, Hepatology Associates Course) (HCV Symposium, Hepatitis Debrief)
Advisory Committees or Review Panels: Roche/Genentech, Abbvie, Consulting: Roche/Genentech, Janssen, Vertex, Merck, Bristol
Galectin, Boehringer-Ingelheim, Eisai, Bristol-Myers Squibb, HepC Myers Squibb, AbbVie, Merck, GlaxoSmithKline, Gilead
Connection, BioTest, Gilead, Merck Grant/Research Support: Roche/Genentech, Janssen, Vertex,
Board Membership: HepQuant LLC, PSC Partners, HepQuant LLC Merck, Bristol Myers Squibb, AbbVie, Merck, Gilead
Consulting: Abbvie, BMS, Gilead, Bristol-Myers Squibb
Grant/Research Support: Roche/Genentech, Pharmassett, Friedman, Lawrence S., MD
Vertex, Abbvie, Bristol-Myers Squibb, Merck, Eisai, Conatus, PSC (President’s Choice)
Partners, Vertex, Tibotec, GlobeImmune, Pfizer, Gilead, Conatus, Nothing to disclose
Zymogenetics
Management Position: HepQuant LLC, HepQuant LLC Friedman, Scott L., MD
Patent Held/Filed: Univ of Colorado (AASLD Postgraduate Course)
Speaking and Teaching: Abbvie, Gilead Advisory Committees or Review Panels: Pfizer Pharmaceutical,
Sanofi-Aventis
Fallon, Michael B., MD Consulting: Conatus Pharm, Exalenz, Genenetch, Glaxo Smith
(Meet-the-Professor Luncheon) Kline, Hoffman-La Roche, Intercept Pharma, Isis Pharmaceuticals,
Grant/Research Support: Bayer/Onyx, Eaisi, Gilead, Grifolis Melior Discovery, Nitto Denko Corp., Debio Pharm, Synageva,
Gilead Pharm., Ironwood Pharma, Alnylam Pharm, Tokai
Fang, John C., MD Pharmaceuticals, Bristol Myers Squibb, Takeda Pharmaceuticals,
(AASLD/ASGE Endoscopy Course) Nimbus Discovery, Bristol Myers Squibb, Intermune, Astra Zeneca,
Board Membership: Veritract Abbvie, Intermune
Consulting: Boston Scientific, Abbvie Grant/Research Support: Galectin Therapeutics, Tobira Pharm,
Vaccinex Therapeutics, Tobira
Feld, Jordan J., MD MPH Stock Shareholder: Angion Biomedica
(Parallel Session)
Advisory Committees or Review Panels: Idenix, Merck, Janssen, Fryzek, Nancy, RN, MBA
Gilead, AbbVie, Merck, Theravance, Bristol Meiers Squibb (Clinical Research Workshop)
Grant/Research Support: AbbVie, Boehringer Ingelheim, Janssen, Nothing to disclose
Gilead, Merck
Fuchs, Michael, MD, PhD, FEBG, AGAF
Feldstein, Ariel E., MD (Career Development Workshop)
(AASLD Postgraduate Course, Early Morning Workshops) Consulting: Intercept Pharmaceuticals
Nothing to disclose
Fung, John J., MD, PhD
Feng, Sandy, MD, PhD (Parallel Session)
(AASLD Postgraduate Course) Advisory Committees or Review Panels: Astellas, Novartis
Nothing to disclose Consulting: Vital Therapies
Grant/Research Support: Sanofi
Fenkel, Jonathan M., MD
(Parallel Session) Gaglio, Paul J., MD
Consulting: Gilead Pharmaceuticals, Janssen Therapeutics (AASLD/ILTS Transplant Course)
Advisory Committees or Review Panels: Merck, Vertex, Salix, BI,
Fiel, M. Isabel, MD BMS, Janssen
(Hepatology Associates Course) Grant/Research Support: Merck, Gilead, Vertex, Otsuka,
Nothing to disclose Genentech, BI
Speaking and Teaching: Merck, Gilead, Vertex, Salix, Otsuka,
Fitz, J. Gregory, MD Janssen
(Plenary Session)
Nothing to disclose Garcia-Pagan, Juan Carlos, MD
(SIG Program)
Fix, Oren K., MD, MSc Grant/Research Support: GORE
(ABIM Maintenance of Certification, Competency Training
Workshop, Parallel Session) Garcia-Tsao, Guadalupe, MD
Nothing to disclose (AASLD/ASGE Endoscopy Course, Global Forum, Meet-the-
Professor Luncheon, Professional Development Workshop, SIG
Fondevila, Constantino, MD, PhD Program, Value Based Medicine)
(AASLD/ILTS Transplant Course) Nothing to disclose
Nothing to disclose
Gardenier, Donald, DNP, FNP-BC
Fontana, Robert J., MD (Hepatology Associates Course)
(AASLD Postgraduate Course, Early Morning Workshops, Meet- Nothing to disclose
the-Professor Luncheon, SIG Program)
Consulting: GlaxoSmithKline Ghabril, Marwan S., MD
Grant/Research Support: Gilead, vertex, BMS, Jansen (Meet-the-Professor Luncheon)
Grant/Research Support: Salix

21A
Continuing Medical Education and Disclosures (continued)
Ghany, Marc G., MD, MHSc Guarerra, James, MD
(Clinical Research Workshop, Early Morning Workshops, Meet- (AASLD/ILTS Transplant Course)
the-Professor Luncheon, Parallel Session, SIG Program) Consulting: Organ Recovery Systems
Nothing to disclose Grant/Research Support: Organ Recovery Systems

Gines, Pere, MD Gunderson, Alan E., MD

(AASLD Postgraduate Course, Emerging Trends Symposium) (Competency Training Workshop)
Advisory Committees or Review Panels: Ferring Nothing to disclose
Grant/Research Support: Sequana Medical, Grifols
Guo, Grace L., PhD
Gish, Robert G., MD (Parallel Session)
(SIG Program) Nothing to disclose
Advisory Committees or Review Panels: Merck, Genentech, Roche,
BMS, Gilead, Arrowhead Guo, Ju-Tao, MD
Stock Shareholder: Hepahope, Kinex, Arrowhead (SIG Program)
Advisory Committees or Review Panels: Enantigen Therapeutics,
Goessling, Wolfram, MD, PhD Inc.
(SIG Program)
Consulting: Fate Therapeutics, Fate Therapeutics Gupta, Sanjeev, MD
Patent Held/Filed: Fate Therapeutics, Fate Therapeutics (Early Morning Workshops)
Nothing to disclose
Gonzalez, Stevan A., MD
(Parallel Session) Hagedorn, Curt H., MD
Speaking and Teaching: Gilead, Salix, AbbVie (Parallel Session)
Nothing to disclose
Gonzalez-Peralta, Regino P., MD
(Parallel Session) Harris, Matthew S., MD
Advisory Committees or Review Panels: Lumena, Kadmon (Clinical Research Workshop)
Consulting: Behringer-Ingelheim, Vertex, Roche Consulting: Theravance, Drais Pharmaceuticals, Symbiomix,
Grant/Research Support: Bristol Myers-Squibb, Roche, Schering- Rhythm Pharmaceuticals, BioMedical Systems
Plough (Merck), vertex, Gilead Stock Shareholder: Ocera Therapeutics, Avaxia Biologics

Gordon, Fredric D., MD Harrison, Stephen A., MD

(Parallel Session) (Meet-the-Professor Luncheon)
Nothing to disclose Advisory Committees or Review Panels: Merck, Nimbus Discovery
Grant/Research Support: Merck, Genentech
Gores, Gregory J., MD Speaking and Teaching: Merck, Vertex
(AASLD Postgraduate Course, Career Development Workshop,
Early Morning Workshops, SIG Program) Heimbach, Julie, MD
Advisory Committees or Review Panels: Delcath, Genentech, (AASLD/ILTS Transplant Course, Plenary Session, Transplant
IntegraGen, Generon Surgery Workshop)
Nothing to disclose
Grace, Norman D., MD
(Parallel Session) Heller, Theo, MD
Nothing to disclose (Early Morning Workshops, Parallel Session)
Nothing to disclose
Graham, Camilla S., MD, MPH
(HCV Symposium) Henderson, Neil C., MBChB, BSc, PhD
Nothing to disclose (Parallel Session)
Nothing to disclose
Grais, Linda, MD
(Professional Development Workshop) Heneghan, Michael A., MD, MRCP
Employment: Ocera Therapeutics (General Hepatology Update)
Speaking and Teaching: Falk
Green, Richard, MD
(Early Morning Workshops, Parallel Session) Hohmann, Elizabeth L., MD
Nothing to disclose (Clinical Research Workshop)
Nothing to disclose
Greten, Tim
(Early Morning Workshops) Hoofnagle, Jay H., MD
Nothing to disclose (State-of-the-Art Lecture)
Nothing to disclose
Gross, Seth A., MD
(AASLD/ASGE Endoscopy Course)
Nothing to disclose

22A
Continuing Medical Education and Disclosures (continued)
Horne, Patrick M., MSN, APRN, FNP-BC Karlsen, Tom H., MD, PhD
(Hepatology Associates Course) (SIG Program)
Consulting: Vertex Pharmaceuticals, Gilead Sciences, Kadmon Nothing to disclose
Pharmaceuticals
Grant/Research Support: Bayer Pharmaceuticals Karp, Seth J., MD
(Parallel Session)
Idle, Jeffrey, PhD Nothing to disclose
(SIG Program)
Nothing to disclose Karpen, Saul J., MD, PhD
(AASLD Postgraduate Course, Early Morning Workshops)
Israni, Ajay, MD, MS Nothing to disclose
(AASLD/ILTS Transplant Course)
Advisory Committees or Review Panels: Astellas Keaveny, Andrew, MD
Grant/Research Support: Novartis, BMS (Competency Training Workshop)
Nothing to disclose
Iwakiri, Yasuko, PhD
(SIG Program) Kim, W. Ray, MD
Nothing to disclose (Plenary Session)
Consulting: Bristol Myers Squibb, Gilead Sciences
Jacobson, Ira M., MD
(HCV Symposium) Kisseleva, Tatiana, MD, PhD
Consulting: Abbvie, Achillion, Boehringer Ingelheim, Bristol Myers (Parallel Session)
Squibb, Gilead, Idenix, Genentech, Merck, Janssen, Vertex Nothing to disclose
Grant/Research Support: Abbvie, Boehringer Ingelheim, Bristol
Myers Squibb, Gilead, Novartis, Genentech, Merck, Janssen, Kleiner, David E., MD, PhD
Vertex (AASLD Postgraduate Course)
Speaking and Teaching: Bristol Myers Squibb, Gilead, Genentech, Nothing to disclose
Vertex, Janssen
Klintmalm, Goran, MD, PhD
Jalan, Rajiv, MD, PhD (Parallel Session)
(AASLD Postgraduate Course) Advisory Committees or Review Panels: Novartis
Consulting: Ocera Therapeutics, Conatus Grant/Research Support: Astellas, Novartis, Opsona, Quark
Grant/Research Support: Grifols, Gambro
Kohli, Rohit, MD
Janssen, Harry L., MD, PhD (Early Morning Workshops)
(Early Morning Workshops, Meet-the-Professor Luncheon, Parallel Grant/Research Support: Johnson and Johnson, Synageva
Session) Biopharma
Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sciences, Independent Contractor: Lumena Pharmceuticals, Galectin
Merck, Medtronic, Novartis, Roche, Santaris Therapeutics
Grant/Research Support: Anadys, Bristol Myers Squibb, Gilead
Sciences, Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, Koshy, Rajen, PhD
Santaris (Parallel Session)
Nothing to disclose
Jensen, Donald M., MD
(Early Morning Workshops) Koteish, Ayman A., MD
Grant/Research Support: Abbvie, Boehringer, BMS, Genentech/ (Competency Training Workshop)
Roche, Janssen Nothing to disclose

Kamath, Binita M., MBBChir Kottilil, Shyam, MD, PhD

(Early Morning Workshops, Parallel Session) (Parallel Session)
Nothing to disclose Nothing to disclose

Kamath, Patrick S., MD Kowdley, Kris V., MD

(AASLD Postgraduate Course, Emerging Trends Symposium, Meet- (Meet-the-Professor Luncheon, Parallel Session)
the-Professor Luncheon) Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Advisory Committees or Review Panels: Sequana Medical Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen
Grant/Research Support: AbbVie, Beckman, Boeringer Ingelheim,
Kanwal, Fasiha, MD BMS, Gilead Sciences, Ikaria, Janssen, Merck, Mochida, Vertex
(Early Morning Workshops, Parallel Session)
Nothing to disclose Koziel, Margaret J., MD
(Early Morning Workshops)
Kapalko, Angela, MS, PA-C Stock Shareholder: Vertex
(Hepatology Associates Course)
Advisory Committees or Review Panels: Gilead Sciences Kramer, David J., MD
(Transplant Surgery Workshop)
Nothing to disclose

23A
Continuing Medical Education and Disclosures (continued)
Krowka, Michael J., MD Levitsky, Josh, MD, MS
(Meet-the-Professor Luncheon) (Meet-the-Professor Luncheon)
Nothing to disclose Consulting: Transplant Genomics Inc
Grant/Research Support: Novartis
Kulik, Laura M., MD Speaking and Teaching: Gilead, Salix
(Hepatology Associates Course, Meet-the-Professor Luncheon)
Advisory Committees or Review Panels: Bayer/ Onyx Levy, Cynthia, MD
Grant/Research Support: Bayer/Onyx (Early Morning Workshops, Parallel Session)
Speaking and Teaching: Bayer/Onyx, Nordion, Gilead Consulting: Lumena, Gilead, Evidera

Kwo, Paul Y., MD Levy, Michael J., MD

(Meet-the-Professor Luncheon) (AASLD/ASGE Endoscopy Course)
Advisory Committees or Review Panels: Abbott, Novartis, Merck, Nothing to disclose
Gilead, BMS, Janssen
Consulting: Vertex Liang, T. Jake, MD
Grant/Research Support: Roche, Vertex, GlaxoSmithKline, Merck, (SIG Program)
BMS, Abbott, Idenix, Vital Therapeutics, Gilead, Vertex, Merck, Nothing to disclose
Idenix
Speaking and Teaching: Merck, Merck Lindor, Keith D., MD
(Early Morning Workshops, Parallel Session)
Lake, John R., MD Nothing to disclose
(AASLD/ILTS Transplant Course)
Advisory Committees or Review Panels: BMS Lippello, Anita, CRNP, NP-C, DNP
Consulting: Vital Therapies, Novartis, HepaHope (Hepatology Associates Course)
Grant/Research Support: Gilead, Salix, Ocera, Essai Nothing to disclose

Larson, Anne M., MD Llovet, Josep M., MD

(Early Morning Workshops) (Parallel Session)
Speaking and Teaching: Gilead, Genentech, Salix Nothing to disclose

Lau, Daryl, MD, MPH Locarnini, Stephen, MD, PhD

(Parallel Session) (SIG Program)
Advisory Committees or Review Panels: Gilead, BMS Consulting: Gilead, Bristol-Myers Squibb
Consulting: Roche Employment: Melbourne Health
Grant/Research Support: Gilead, Merck
Lohse, Ansgar W., MD
Lavine, Joel E., MD, PhD (AASLD Postgraduate Course)
(Clinical Research Workshop) Grant/Research Support: Boehringer Ingelheim, Gilead
Consulting: Merck, Crosscare, Gilead, Takeda Millenium Speaking and Teaching: MSD, Falk
Grant/Research Support: Janssen
Lok, Anna S., MD
Lee, Thomas H., MD (Early Morning Workshops, Plenary Session, SIG Program)
(Value Based Medicine) Advisory Committees or Review Panels: Gilead, Immune Targeting
Board Membership: Geisinger Health System System, MedImmune, Arrowhead, Bayer, GSK, Janssen, Novartis,
Employment: Press Ganey ISIS, Tekmira
Grant/Research Support: Abbott, BMS, Gilead, Merck, Roche,
Lee, William M., MD Boehringer
(AASLD Distinguished Awards, Clinical Research Workshop)
Consulting: Eli Lilly, Novartis Loomba, Rohit, MD, MHSc
Grant/Research Support: Gilead, Roche, Vertex, BI, Anadys, BMS, (General Hepatology Update, Parallel Session)
merck Consulting: Gilead Inc, Corgenix Inc, Janssen and Janssen Inc
Speaking and Teaching: Merck Grant/Research Support: Daiichi Sankyo Inc, AGA, Merck Inc

Lemasters, John J., MD, PhD Lu, Shelly C., MD

(Early Morning Workshops) (AASLD Postgraduate Course, Parallel Session)
Nothing to disclose Nothing to disclose

Levitsky, Josh, MD, MS Lucey, Michael R., MD

(Competency Training Workshop) (Meet-the-Professor Luncheon)
Consulting: Transplant Genomics Inc Advisory Committees or Review Panels: Galectin
Grant/Research Support: Novartis Grant/Research Support: Vertex, Abbvie, Gilead, Salix
Speaking and Teaching: Gilead, Salix
Luxon, Bruce A., MD, PhD
Levitsky, Josh, MD, MS (AASLD/ILTS Transplant Course)
(Competency Training Workshop) Speaking and Teaching: Merck
Nothing to disclose

24A
Continuing Medical Education and Disclosures (continued)
Mack, Cara, MD McClain, Craig J., MD
(AASLD Postgraduate Course, SIG Program) (AASLD Postgraduate Course)
Nothing to disclose Consulting: Vertex, Gilead, Baxter, Celgene, Nestle, Danisco,
Abbott, Genentech
Maddrey, Willis C., MD Grant/Research Support: Ocera, Merck, Glaxo SmithKline
(President’s Choice) Speaking and Teaching: Roche
Nothing to disclose
McCullough, Arthur J., MD
Magee, John C., MD (Early Morning Workshops)
(Plenary Session, Transplant Surgery Workshop) Nothing to disclose
Grant/Research Support: Novartis, Alagille Syndrome Alliance
McKiernan, Patrick J., BSc, MRCP, FRCPCH
Maher, Jacquelyn J., MD (AASLD/NASPGHAN Pediatric Symposium)
(AASLD Postgraduate Course, Parallel Session) Advisory Committees or Review Panels: Swedish Orphan Biovitrum
Nothing to disclose AB

Manch, Richard A., MD McMahon, Brian J., MD

(SIG Program) (SIG Program)
Nothing to disclose Nothing to disclose

Mandrekar, Pranoti, PhD McNiven, Mark A., PhD

(Early Morning Workshops, Parallel Session) (Parallel Session, SIG Program)
Nothing to disclose Nothing to disclose

Mann, Derek A., PhD Mehal, Wajahat Z., MD

(Basic Research Workshop) (Early Morning Workshops, SIG Program)
Consulting: GSK, Theravance, Narrow River Management, Management Position: Gloabl BioReserach Partners
Novartis, UCB
Grant/Research Support: GSK Mehta, Savant, MD
(Early Morning Workshops)
Manns, Michael P., MD Nothing to disclose
(Early Morning Workshops)
Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Mehta, Savant, MD
Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics (Early Morning Workshops)
Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Nothing to disclose
Boehringer Ingelheim, BMS
Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Menon, KV Narayanan, MD
Janssen, GSK, Novartis (Transplant Surgery Workshop)
Nothing to disclose
Marcellin, Patrick, MD, PhD
(Early Morning Workshops, SIG Program) Mieli-Vergani, Giorgina, MD, PhD
Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, (SIG Program)
Abbvie, Alios BioPharma, Idenix, Akron Nothing to disclose
Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen,
MSD, Alios BioPharma Miller, Charles M., MD
Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, (AASLD/ILTS Transplant Course)
Janssen, MSD, Boehringer, Pfizer, Abbvie Nothing to disclose

Marra, Fabio, MD, PhD Mills, Rennie M., PA-C

(Early Morning Workshops) (Hepatology Associates Course)
Advisory Committees or Review Panels: Abbott Nothing to disclose
Consulting: Bayer Healthcare
Grant/Research Support: ViiV Miloh, Tamir A., MD
(SIG Program)
Mathurin, Philippe, MD, PhD Nothing to disclose
(Early Morning Workshops)
Board Membership: Schering-Plough, Janssen-Cilag, BMS, Gilead, Mishra, Lopa, MD
Abvie (AASLD Postgraduate Course, Early Morning Workshops, Parallel
Consulting: Roche, Bayer, Boehringer Session)
Nothing to disclose
Mayo, Marlyn J., MD
(Parallel Session) Mitchell, Mack C., MD
Grant/Research Support: Intercept, Salix, NGM, Lumena, Gilead (Meet-the-Professor Luncheon)
Consulting: Gilead

25A
Continuing Medical Education and Disclosures (continued)
Molleston, Jean P., MD Nieto, Natalia, PhD
(AASLD/NASPGHAN Pediatric Symposium, Meet-the-Professor (SIG Program)
Luncheon) Nothing to disclose
Grant/Research Support: scherring, roche, vertex
Northup, Patrick G., MD, MHS
Monkemuller, Klaus E., MD, PhD, FASGE (Parallel Session)
(AASLD/ASGE Endoscopy Course) Nothing to disclose
Grant/Research Support: Boston Scientific, USA
Speaking and Teaching: Cook Medical, USA, Ovesco, USA O’Farrelly, Cliona, PhD
(AASLD Postgraduate Course)
Morgan, Timothy R., MD Nothing to disclose
(Early Morning Workshops)
Grant/Research Support: Merck, Vertex, Genentech, Gilead, O’Leary, Jacqueline G., MD, MPH
Bristol Myers Squibb (AASLD/ILTS Transplant Course, Early Morning Workshops, SIG
Program)
Muir, Andrew J., MD Consulting: Gilead, Jansen
(Clinical Research Workshop, HCV Symposium)
Advisory Committees or Review Panels: Merck, Vertex, Gilead, Okolo, Patrick I., MD, MPH, FASGE
BMS, Abbvie, Achillion (AASLD/ASGE Endoscopy Course)
Consulting: Profectus, GSK Nothing to disclose
Grant/Research Support: Merck, Vertex, Roche, BMS, Gilead,
Achillion, Abbvie, Pfizer, Salix, GSK, Intercept, Lumena Orloff, Susan L., MD, FACS
(Plenary Session, Professional Development Workshop, Transplant
Mulligan, David C., MD, FACS Surgery Workshop)
(SIG Program, State-of-the-Art Lecture) Nothing to disclose
Nothing to disclose
Papatheodoridis, George V., MD
Murray, Jeffrey S., MD, MPH (Early Morning Workshops)
(Clinical Research Workshop) Advisory Committees or Review Panels: Janssen, Abbvie,
Nothing to disclose Boehringer Ingelheim, Novartis, BMS, Gilead, Roche, MSD
Consulting: Roche
Murray, Karen F., MD Grant/Research Support: BMS, Gilead, Roche, Abbvie, Janssen
(AASLD/NASPGHAN Pediatric Symposium) Speaking and Teaching: Janssen, Novartis, BMS, Gilead, Roche,
Grant/Research Support: Roche, Gilead, Vertex MSD, Abbvie
Stock Shareholder: Merck
Paradis, Valerie, MD PhD
Nadim, Mitra K., MD (SIG Program)
(AASLD/NASPGHAN Pediatric Symposium) Nothing to disclose
Consulting: Ikaria
Patel, Keyur, MD
Nagy, Laura E., PhD (Parallel Session)
(Early Morning Workshops) Advisory Committees or Review Panels: Merck
Nothing to disclose Consulting: Gilead Sciences, Santaris, Akros, Nitto Denko
Grant/Research Support: Bristol Myers Squibb
Navarro, Victor J., MD
(Early Morning Workshops) Patel, Tushar, MD
Consulting: Glaxo (AASLD Postgraduate Course)
Nothing to disclose
Navasa, Miguel, MD
(AASLD/ILTS Transplant Course) Pawlotsky, Jean-Michel, MD, PhD
Consulting: Novartis, Astellas (Early Morning Workshops)
Consulting: Abbott, Achillion, Boehringer-Ingelheim, Bristol-Myers
Nelson, David R., MD Squibb, Idenix, Gilead, Janssen, Madaus-Rottapharm, Merck,
(AASLD Postgraduate Course) Novartis, Roche
Advisory Committees or Review Panels: Merck Grant/Research Support: Gilead
Grant/Research Support: Abbot, BMS, Beohringer Ingelheim, Speaking and Teaching: Boehringer-Ingelheim, Bristol-Myers
Gilead, Genentech, Merck, Bayer, Idenix, Vertex, Jansen Squibb, Gilead, Madaus-Rottapharm, Merck, Janssen-Cilag,
Novartis, Abbott
Neuschwander-Tetri, Brent A., MD
(AASLD Postgraduate Course) Peck-Radosavljevic, Markus, MD MBA
Advisory Committees or Review Panels: Nimbus, Roche/Genetech, (Global Forum)
Boehringer Ingleheim Advisory Committees or Review Panels: Bayer, Gilead, Janssen,
BMS, AbbVie
Ng, Vicky L., MD Consulting: Bayer, Boehringer-Ingelheim, Jennerex, Eli Lilly, AbbVie
(Parallel Session) Grant/Research Support: Bayer, Roche, Gilead, MSD
Nothing to disclose Speaking and Teaching: Bayer, Roche, Gilead, MSD, Eli Lilly

26A
Continuing Medical Education and Disclosures (continued)
Perrillo, Robert P., MD Quigley, Eamonn M., MD
(Early Morning Workshops) (AASLD Postgraduate Course)
Advisory Committees or Review Panels: Novartis Advisory Committees or Review Panels: Salix, Shire, Almirall,
Speaking and Teaching: Bristol Myers Squibb, Gilead Sciences Ironwood/Forest
Board Membership: Alimentary Health
Peters, Marion G., MD Consulting: Alimentary Health, Vibrant
(Meet-the-Professor Luncheon) Grant/Research Support: Ironwood/Forest, Rhythm, Norgine
Advisory Committees or Review Panels: Janssen Speaking and Teaching: Procter and Gamble, Janssen, Shire,
Consulting: Merck Almirall
Employment: Hoffman La Roche -Spouse Stock Shareholder: Alimentary Health

Pinna, Antonio D., MD Rafii, Shahin, MD

(AASLD/ILTS Transplant Course) (Basic Research Workshop)
Nothing to disclose Consulting: Angiocrine Bioscience

Pinzani, Massimo, MD, PhD, FRCP Ramsay, Michael A., MD

(Basic Research Workshop) (Transplant Surgery Workshop)
Advisory Committees or Review Panels: Intercept Pharmaceutical, Grant/Research Support: Masimo Inc
Silence Therapeutic, Abbot
Consulting: UCB Reddy, K. Gautham, MD
Speaking and Teaching: Gilead, BMS (Competency Training Workshop)
Advisory Committees or Review Panels: AASLD Transplant
Pockros, Paul J., MD Hepatology Pilot Steering Committee, ACG Training Committee,
(Early Morning Workshops) Program Director’s Caucus Steering Committee
Advisory Committees or Review Panels: Janssen, Merck, Grant/Research Support: Intercept, Ocera, Merck, Lumena
Genentech, BMS, Gilead, Boehinger Ingelheim, AbbVioe
Consulting: Genentech, Lumena, Regulus, Beckman Coulter, RMS Reddy, K. Rajender, MD
Grant/Research Support: Novartis, Intercept, Janssen, Genentech, (Advances for Practitioners, Meet-the-Professor Luncheon)
BMS, Gilead, Vertex, Boehinger Ingelheim, Lumena, Beckman Advisory Committees or Review Panels: Genentech-Roche, Merck,
Coulter, AbbVie, RMS, Novartis, Merck Janssen, Vertex, Gilead, BMS, Novartis, Abbvie
Speaking and Teaching: Genentech, BMS, Gilead Grant/Research Support: Merck, BMS, Ikaria, Gilead, Janssen,
AbbVie
Podskalny, Judith, PhD
(Career Development Workshop) Rehermann, Barbara, MD
Nothing to disclose (AASLD Postgraduate Course, Early Morning Workshops, Parallel
Session)
Poelstra, Klaas, PhD Nothing to disclose
(Basic Research Workshop)
Consulting: BiOrion Technologies BV Reich, David J., MD
Grant/Research Support: BiOrion Technologies BV (Plenary Session)
Stock Shareholder: BiOrion Technologies BV Consulting: VTI
Grant/Research Support: VTI
Pomposelli, James, MD, PhD Speaking and Teaching: neuwave
(Parallel Session)
Nothing to disclose Renz, John F., MD, PhD
(AASLD/ILTS Transplant Course)
Poordad, Fred, MD Nothing to disclose
(General Hepatology Update)
Advisory Committees or Review Panels: Abbott, Achillion, BMS, Reuben, Adrian, MBBS, FRCP, FACG
Inhibitex, Boeheringer Ingelheim, Pfizer, Genentech, Idenix, (Early Morning Workshops, State-of-the-Art Lecture)
Gilead, Merck, Vertex, Salix, Janssen, Novartis Nothing to disclose
Grant/Research Support: Abbott, Anadys, Achillion, BMS,
Boehringer Ingelheim, Genentech, Idenix, Gilead, Merck, Rex, Douglas K., MD
Pharmassett, Vertex, Salix, Tibotec/Janssen, Novartis (AASLD/ASGE Endoscopy Course)
Advisory Committees or Review Panels: Given Imaging, American
Porte, Robert J., MD, PhD, FEBS BioOptics, CheckCap, Epigenomics, Exact Sciences
(AASLD/ILTS Transplant Course) Consulting: EndoAid
Advisory Committees or Review Panels: Organ Assist Grant/Research Support: Given Imaging, Olympus, Braintree
Speaking and Teaching: Olympus, Braintree, Boston Scientific

Rinella, Mary E., MD

(AASLD Postgraduate Course, Parallel Session)
Advisory Committees or Review Panels: Gilead

27A
Continuing Medical Education and Disclosures (continued)
Roberts, John P., MD, FACS Schirmacher, Peter, MD
(AASLD/ILTS Transplant Course) (SIG Program)
Nothing to disclose Advisory Committees or Review Panels: Novartis
Consulting: Novartis
Roberts, Lewis R., MB ChB, PhD Grant/Research Support: Novartis
(Parallel Session)
Grant/Research Support: Bristol Myers Squibb, ARIAD Schnabl, Bernd, MD
Pharmaceuticals, BTG, Wako Diagnostics, Inova Diagnostics, (Early Morning Workshops)
Gilead Sciences Nothing to disclose

Rockey, Don C., MD Schuppan, Detlef, MD, PhD

(Early Morning Workshops, Parallel Session) (Basic Research Workshop, Early Morning Workshops)
Grant/Research Support: Gilead, Actelion Consulting: Boehringer Ingelheim, Aegerion, Gilead, Genzyme,
GSK, Pfizer, Takeda, Sanofi Aventis, Silence
Rosen, Hugo R., MD
(Advances for Practitioners) Schwabe, Robert F., MD
Nothing to disclose (Basic Research Workshop)
Nothing to disclose
Rudnick, David A., MD, PhD
(Early Morning Workshops, Parallel Session) Schwarz, Kathleen B., MD
Nothing to disclose (Meet-the-Professor Luncheon)
Consulting: Novartis, Novartis
Runyon, Bruce A., MD Grant/Research Support: Bristol-Myers Squibb, Gilead, Roche/
(Hepatology Associates Course) Genentech, Bristol-Myers Squibb, Vertex, Roche
Nothing to disclose
Seeff, Leonard B., MD
Russo, Mark W., MD, MPH (Early Morning Workshops)
(ABIM Maintenance of Certification, Career Development Nothing to disclose
Workshop)
Grant/Research Support: Vertex, Merck Seki, Ekihiro, MD, PhD
Speaking and Teaching: Vertex, Gilead, BMS (Basic Research Workshop)
Grant/Research Support: Nippon Zoki
Sanchez, William, MD
(Competency Training Workshop) Shah, Vijay, MD
Nothing to disclose (AASLD Postgraduate Course, Early Morning Workshops)
Nothing to disclose
Sanyal, Arun J., MD
(AASLD Postgraduate Course) Sharma, Barjesh C., MD, DM
Advisory Committees or Review Panels: Bristol Myers, Gilead, (Global Forum)
Abbott, Ikaria Nothing to disclose
Consulting: Salix, Immuron, Exhalenz, Nimbus, Genentech,
Echosens, Takeda Sharma, Prateek, MD
Grant/Research Support: Salix, Genentech, Genfit, Intercept, (AASLD/ASGE Endoscopy Course)
Ikaria, Takeda, GalMed, Novartis, Gilead Grant/Research Support: Cook Medical, Cosmo Pharma, Olympus
Independent Contractor: UpToDate, Elsevier Inc, Ninepoint Medical

Sarin, Shiv K., MD Sheppard, Dean, MD

(Emerging Trends Symposium, Meet-the-Professor Luncheon) (Basic Research Workshop)
Nothing to disclose Advisory Committees or Review Panels: Moarae, Galera
Grant/Research Support: Biogen Idec, Pfizer
Sass, David A., MD Patent Held/Filed: Biogen Idec
(Hepatology Associates Course)
Nothing to disclose Sherker, Averell H., MD, FRCP(C)
(Clinical Research Workshop)
Schiff, Eugene R., MD Nothing to disclose
(SIG Program)
Advisory Committees or Review Panels: Bristol Myers Squibb, Sherman, Kenneth E., MD, PhD
Gilead, Merck, Janssen, Salix Pharmaceutical, Pfizer (Early Morning Workshops)
Grant/Research Support: Bristol Myers Squibb, Abbott / AbbVee, Advisory Committees or Review Panels: MedImmune, Bioline,
Gilead, Merck, Conatus, Medmira, Roche, Janssen, Orasure Janssen, Merck, Synteract
Technologies, Discovery Life Sciences, Siemens Grant/Research Support: Merck, Genentech/Roche, Gilead,
Anadys, Briston-Myers Squibb, Vertex
Schinazi, Raymond F., PhD, DSc
(SIG Program)
Board Membership: RFS Pharma, LLC
Stock Shareholder: RFS Pharma, LLC

28A
Continuing Medical Education and Disclosures (continued)
Sherman, Morris, MD, PhD Strader, Doris B., MD
(SIG Program) (Parallel Session)
Advisory Committees or Review Panels: Merck, Janssen, Roche, Nothing to disclose
Gilead, Celsion, Janssen, Eli Lilly, Arqule, Tekmira, Oncozyme,
Nimbus, Rheolysin Stravitz, R. Todd, MD
Speaking and Teaching: Gilead, Bristol Myers Squibb, Bayer (Early Morning Workshops)
Nothing to disclose
Shiffman, Mitchell L., MD
(Career Development Workshop, Early Morning Workshops) Strazzabosco, Mario, MD, PhD
Advisory Committees or Review Panels: Merck, Gilead, Boehringer- (Value Based Medicine)
Ingelheim, Bristol-Myers-Squibb, Abbvie, Janssen Nothing to disclose
Consulting: Roche/Genentech, Gen-Probe
Grant/Research Support: Merck, Gilead, Boehringer-Ingelheim, Subramanian, Ram M., MD
Bristol-Myers-Squibb, GSK, Abbvie, Beckman-Coulter, Achillion, (Early Morning Workshops)
Lumena, Intercept, Novarit, Gen-Probe Nothing to disclose
Speaking and Teaching: Roche/Genentech, Merck, Gilead, GSK,
Janssen, Bayer Suchy, Frederick J., MD
(AASLD/NASPGHAN Pediatric Symposium)
Shrestha, Roshan, MD Nothing to disclose
(SIG Program)
Nothing to disclose Sulkowski, Mark S., MD
(HCV Symposium, Meet-the-Professor Luncheon)
Silveira, Marina G., MD Advisory Committees or Review Panels: Merck, AbbVie, Idenix,
(Professional Development Workshop) Janssen, Gilead, BMS, Pfizer
Nothing to disclose Grant/Research Support: Merck, AbbVie, BIPI, Vertex, Janssen,
Gilead, BMS
Singal, Amit G., MD
(Early Morning Workshops, Parallel Session) Szabo, Gyongyi, MD, PhD
Speaking and Teaching: Bayer, Onyx (AASLD Postgraduate Course, Global Forum, Plenary Session)
Consulting: Idenix
Sirlin, Claude B., MD Grant/Research Support: BMS, GSK, Conatus, Idera,
(Parallel Session) Johnson&Johnson, Novartis, Ocera, Roche, Shering - Plough,
Advisory Committees or Review Panels: Bayer Wyeth, Integrated Therapeutics, Idera
Grant/Research Support: GE, Pfizer, Bayer
Speaking and Teaching: Bayer Taddei, Tamar H., MD
(Parallel Session)
Slivka, Adam, MD, PhD, FASGE Consulting: Onyx Pharmaceuticals
(AASLD/ASGE Endoscopy Course) Grant/Research Support: Bayer HealthCare
Consulting: Boston Scientific
Grant/Research Support: Mauna Kea Technology Talwalkar, Jayant A., MD, MPH
(Meet-the-Professor Luncheon)
Sokol, Ronald J., MD Nothing to disclose
(Early Morning Workshops, Parallel Session)
Advisory Committees or Review Panels: Yasoo Health, Inc., Ikaria, Teisberg, Elizabeth, MD
Yasoo Health, Inc., Ikaria (Value Based Medicine)
Consulting: Roche, Roche Nothing to disclose
Grant/Research Support: Lumena
Terrault, Norah, MD
Spearman, C. W., MBChB, PhD (AASLD Postgraduate Course, Clinical Research Workshop, Early
(Global Forum) Morning Workshops, Meet-the-Professor Luncheon)
Nothing to disclose Advisory Committees or Review Panels: Eisai, Biotest
Consulting: BMS, Merck
Sterling, Richard K., MD, MSc Grant/Research Support: Eisai, Biotest, Vertex, Gilead, AbbVie,
(ABIM Maintenance of Certification, Career Development Novartis, Merck
Workshop)
Advisory Committees or Review Panels: Merck, Vertex, Salix, Theise, Neil D., MD
Bayer, BMS, Abbott, Gilead (SIG Program)
Grant/Research Support: Merck, Roche/Genentech, Pfizer, Gilead, Nothing to disclose
Boehringer Ingelheim, Bayer, BMS, Abbott
Thiele, Dwain L., MD
Stewart, Charmaine, MD (AASLD Postgraduate Course)
(Parallel Session) Nothing to disclose
Nothing to disclose
Thimme, Robert, MD
(AASLD Postgraduate Course)
Nothing to disclose

29A
Continuing Medical Education and Disclosures (continued)
Thorgeirsson, Snorri S., MD, PhD Vos, Miriam B., MD
(SIG Program) (Meet-the-Professor Luncheon)
Nothing to disclose Nothing to disclose

Torok, Natalie, MD Wakil, Adil E., MD

(AASLD Postgraduate Course, Early Morning Workshops, SIG (SIG Program)
Program) Nothing to disclose
Consulting: Genentech/Roche
Wallace, Michael B., MD, MPH, FASGE
Tran, Tram T., MD (AASLD/ASGE Endoscopy Course)
(Early Morning Workshops) Advisory Committees or Review Panels: Ninepoint
Advisory Committees or Review Panels: Gilead, Bristol Myers Consulting: Fujinon, Endochoice
Squibb Grant/Research Support: Olympus, BSCI, Ninepoint
Consulting: Gilead, AbbVie, Janssen
Grant/Research Support: Bristol Myers Squibb Wands, Jack R., MD
Speaking and Teaching: Bristol Myers Squibb, Gilead (Parallel Session)
Nothing to disclose
Trotter, James F., MD
(Advances for Practitioners, SIG Program) Wang, Fu-Sheng, MD, PhD
Speaking and Teaching: Salix, Novartis (AASLD Postgraduate Course)
Nothing to disclose
Unalp-Arida, Aynur, MD, PhD
(Parallel Session) Wang, Xin W., PhD
Nothing to disclose (Early Morning Workshops)
Nothing to disclose
Urban, Stephan, PhD
(SIG Program) Watkins, Paul B., MD
Consulting: Gilead, Humabs (Early Morning Workshops)
Patent Held/Filed: Myr-GmbH, University Hospital Heidelberg, Consulting: Abbott, Actelion, Boerringer-Ingelheim, Cempra,
INSERM Genzyme, Roche, Merck, Medicine COmpany, Momenta, Janssen,
Novartis, Otsuka, Pfizer, Sanolfi, Takeda, UCB, Bristol-Myers
Urban, Thomas J., PharmD, PhD Squibb, GSK
(SIG Program)
Patent Held/Filed: Schering Plough Watt, Kymberly D., MD
(General Hepatology Update, Meet-the-Professor Luncheon,
Vargas, Hugo E., MD Professional Development Workshop, Transplant Surgery
(AASLD/ASGE Endoscopy Course, Parallel Session) Workshop)
Advisory Committees or Review Panels: Eisai Nothing to disclose
Grant/Research Support: Merck, Gilead, Idenix, Novartis, Vertex,
Janssen, Bristol Myers, Ikaria, AbbVie Wells, Rebecca G., MD
(AASLD Postgraduate Course, Basic Research Workshop, State-of-
Venick, Robert S., MD the-Art Lecture)
(AASLD/ILTS Transplant Course) Nothing to disclose
Nothing to disclose
Wolkoff, Allan W., MD
Vierling, John M., MD (SIG Program)
(Early Morning Workshops) Grant/Research Support: Merck
Advisory Committees or Review Panels: Abbvie, Bristol-Meyers-
Squibb, Gilead, Hyperion, Intercept, Janssen, Novartis, Merck, Wong, Florence, MD
Sundise, HepQuant, Salix (AASLD Postgraduate Course, Early Morning Workshops, General
Grant/Research Support: Abbvie, Bristol-Meyers-Squibb, Eisai, Hepatology Update, Meet-the-Professor Luncheon, Parallel Session,
Gilead, Hyperion, Intercept, Janssen, Novartis, Merck, Sundise, SIG Program)
Ocera, Mochida Consulting: Gore Inc
Speaking and Teaching: GALA, Chronic Liver Disease Foundation, Grant/Research Support: Grifols
ViralEd
Wright, Elizabeth C., PhD
Voigt, Michael D., MD (Clinical Research Workshop)
(Parallel Session) Nothing to disclose
Nothing to disclose
Wright, Teresa L., MD
Volk, Michael, MD (Career Development Workshop, Professional Development
(Early Morning Workshops) Workshop)
Nothing to disclose Employment: Genentech, Roche, Roche, Roche

30A
Continuing Medical Education and Disclosures (continued)
Yee, Hal F., MD, PhD
(Global Forum)
Nothing to disclose

Zeybel, Mujdat, MD
(SIG Program)
Nothing to disclose

Zoulim, Fabien, MD
(Parallel Session, SIG Program)
Advisory Committees or Review Panels: Janssen, Gilead, Novira,
Abbvie, Tykmera, Transgene
Consulting: Roche
Grant/Research Support: Novartis, Gilead, Scynexis, Roche,
Novira
Speaking and Teaching: Bristol Myers Squibb, Gilead

Zucman-Rossi, Jessica, MD, PhD

(State-of-the-Art Lecture)
Grants/Research Support: Integragen
Consulting: Pfizer
Speaking and Teaching: Bayer, Lilly
Advisory Board: Astellas, Celgene

31A
NOVEMBER 7 32A AASLD PROGRAM HEPATOLOGY, October, 2014

AASLD/ASGE Endoscopy Course 

FRIDAY

Friday, November 7 Session II: Portal Hypertension

7:55 AM - 3:00 PM Room 302 10:10 - 10:30 AM Esophageal Varices: Screening,
Primary and Secondary Prophylaxis
Endoscopy in the Management of Patients With Liver Guadalupe Garcia-Tsao, MD
Disease
10:30 - 10:50 AM Endoscopic Management of Gastric
COURSE DIRECTORS: Marta L. Davila, MD, AGAF, and Other Nonesophageal Varices
FACG, FASGE Klaus E. Monkemuller, MD, PhD, FASGE
Michael B. Wallace, MD, MPH, 10:50 - 11:10 AM Treatment of Portal Hypertensive
FASGE Gastropathy and GAVE
Seth A. Gross, MD
7 CME Credits
11:10 - 11:30 AM Feeding Tube Placement in Cirrhotics
John C. Fang, MD
11:30 - 11:50 AM Video Cases
Enhance your working knowledge of state-of-the-art practices in
the endoscopic management of patients with advanced cirrhosis, 11:50 AM - 12:10 PM Questions
biliary tract disease, chronic cholestatic conditions, and other liver 12:10 - 1:15 PM Lunch
diseases—both before and after liver transplantation. The course
will cover fundamental issues related to the quality and safety of Session III: Endoscopic Evaluation and Therapy of Biliary
endoscopic practice in the patient with liver disease, including safe Disease
administration of sedation as it relates to disease-specific issues
1:15 - 1:35 PM Endoscopic Management of
such as coagulopathy. Participants will learn about management
Choledocholithiasis and Cholelithiasis
and prevention of variceal hemorrhage, as well as advanced
in Cirrhotics
endoscopic techniques such as cholangioscopy for biliary disease.
Patrick I. Okolo, MD, MPH, FASGE

Learning Objectives: 1:35 - 1:55 PM ERCP for Post-Liver Transplant

Complications
Upon completion of this activity, participants will be able to: Adam Slivka, MD, PhD, FASGE
• Select patients with liver disease who may undergo endoscopic 1:55 - 2:15 PM The Role of EUS in the Diagnosis of
procedures. Cholangiocarcinoma
• Identify standards of care for treating portal hypertensive con- Michael J. Levy, MD
ditions, including esophageal and gastric varices and vascular 2:15 - 2:35 PM Video Cases
ectasia.
2:35 - 2:55 PM Questions
• Choose appropriate testing and staging procedures for patients
2:55
    - 3:00 PM Closing Remarks
with biliary strictures and suspected cholangiocarcinoma.
• Recommend appropriate endoscopic procedures for the man-
agement of biliary complications of transplantation.

7:55 - 8:00 AM Welcome

Session I: Endoscopy in Patients With Advanced Liver

Disease
8:00 - 8:20 AM Preparation of the Cirrhotic Patient for
Gastrointestinal Endoscopy
Hugo E. Vargas, MD
8:20 - 8:40 AM Safe Sedation and Anesthesia in the
Cirrhotic Patient
Vinay Chandrasekhara, MD
8:40 - 9:00 AM Colonoscopy and Polypectomy in
Patients With Liver Disease: Is It Safe?
Douglas K. Rex, MD, FASGE
9:00 - 9:20 AM Management of Esophageal Nodules
and Barrett’s Esophagus in the Setting
of Portal Hypertension
Prateek Sharma, MD
9:20 - 9:40 AM Questions
9:40 - 10:10 AM Break
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM 33A

NOVEMBER 7
AASLD/ILTS Transplant Course 

FRIDAY
Friday, November 7 Debate - A Bridge Too Far: We Have Overstepped the
8:00 AM - 2:45 PM Ballroom BC Line for Extended Deceased-Donors
Catalysts for Innovation in Liver Transplantation 9:05 - 9:15 AM (Pro)
Antonio D. Pinna, MD
COURSE DIRECTORS: Paul J. Gaglio, MD
9:15 - 9:25 AM (Con)
Miguel Navasa, MD Constantino Fondevila, MD, PhD
John F. Renz, MD, PhD
9:25 - 9:45 AM Discussion
6.5 CME Credits ​/ ​5 Contact Hours 9:45 - 10:05 AM Break
10:05 - 10:25 AM New Opportunities for Adult
Recipients
With the worldwide application of liver transplantation, the need Robert S. Brown, Jr., MD, MPH
for a stimulating clinical and translational research environment 10:25 - 10:45 AM Potential Catalysts in Post-Operative
has never been greater. However, a number of US donor and Management/Critical Care
recipient metrics over the past decade—including wait-list mor- Geraldine Diaz, DO
tality, donor utilization, and application of living donation—sug- 10:45 - 11:05 AM What is the Future of Pediatric Liver
gest a systemic plateau. This course will help you recognize new Transplantation?
opportunities while identifying clinical and scientific catalysts for Robert S. Venick, MD
innovation in transplantation. 11:05 - 11:25 AM Potential Catalysts in Therapeutics
Bruce A. Luxon, MD, PhD
Learning Objectives:
Upon completion of this activity, participants will be able to: Debate - A Bridge Too Far: NAFLD Will Exhaust the
• Review the current practice of liver transplantation and identify Donor Pool
potential new clinical opportunities. 11:25 - 11:35 AM (Pro)
• Identify recent advancements in immunosuppression, tolerance Julie Heimbach, MD
induction, and therapeutics that demonstrate substantial prom- 11:35 - 11:45 AM (Con)
ise. Jacqueline G. O’Leary, MD, MPH
• Assess current risk practices within the specialty of liver trans- 11:45 AM - 12:05 PM Discussion
plantation.
12:05 - 1:05 PM Lunch
• Identify policies, processes, and practices that impede or pro-
mote innovation.
Session II: Risk as a Catalyst for Innovation
• Propose novel metrics and processes to foster efficient transla-
tional research and program development within the current MODERATORS: Paul J. Gaglio, MD
healthcare environment. Miguel Navasa, MD
1:05 - 1:25 PM Stifling Innovation Regulation and
8:00 - 8:05 AM Introduction Risk Mentality
John P. Roberts, MD, FACS
1:25 - 1:45 PM Creating an Environment that
Session I: Catalysts for Expansion of Clinical Practice Supports Innovation
MODERATORS: Miguel Navasa, MD Michael M. Abecassis, MD, MBA
John F. Renz, MD, PhD 1:45 - 2:05 PM Designing Systematic and Center-
8:05 - 8:25 AM Clinical Frontiers in Liver Specific Metrics to Foster Innovation
Transplantation Ajay Israni, MD, MS
John R. Lake, MD 2:05 - 2:25 PM Preparing for Inevitable Failures
8:25 - 8:45 AM Donation: Where Are Our Charles M. Miller, MD
Opportunities for Expansion? 2:25 - 2:45 PM Discussion
James Guarerra, MD    

8:45 - 9:05 AM Opportunities for Scientific Expansion

of the Deceased Donor Pool
Robert J. Porte, MD, PhD, FEBS
NOVEMBER 7 34A AASLD PROGRAM HEPATOLOGY, October, 2014

Career Development Workshop 

FRIDAY

Friday, November 7 10:00 - 10:05 AM Introduction

Michael Fuchs, MD, PhD, FEBG, AGAF
10:00 AM - Noon Room 311
10:05 - 10:20 AM Hepatology Fellowship Tracks
Building Your Hepatology Career From Fellow to Faculty Richard K. Sterling, MD, MSc
and Beyond 10:20 - 10:35 AM Academic Hepatology
COURSE DIRECTORS: Michael Fuchs, MD, PhD, FEBG, Gregory J. Gores, MD
AGAF 10:35 - 10:50 AM Hepatology in Private Practice
Mark W. Russo, MD, MPH Mitchell L. Shiffman, MD
10:50 - 11:05 AM Hepatology in Industry
CME not offered Teresa L. Wright, MD
11:05 - 11:30 AM Panel Discussion
11:30 - 11:50 AM Early Career Funding from the NIH
This workshop is designed to assist clinical and research trainees
Judith Podskalny, PhD
as well as junior faculty members who are pursuing careers in
hepatology in a changing healthcare landscape. Participants will 11:50 AM - Noon Wrap-up
have the opportunity to interact with leaders in the field in the field    
Mark W. Russo, MD, MPH
to appreciate the different career pathways hepatology can offer.

Learning Objectives:
Upon completion of this activity, participants will be able to:
• Describe the fellowship training tracks available in hepatology
and transplant hepatology.
• Identify the best fit for a mentor.
• Apply skills essential to building a successful career.
• Recognize future trends in hepatology in a changing healthcare
system.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM 35A

NOVEMBER 7
AASLD/NASPGHAN Pediatric Symposium 

FRIDAY
Friday, November 7 Session I
Noon - 3:00 PM Room 312 Noon - 12:05 PM Introduction
The Kidney in the Child with Chronic Liver Disease 12:05 - 12:25 PM Management of Ascites in Children
Karen F. Murray, MD
COURSE DIRECTORS: Ronen Arnon, MD
Jean P. Molleston, MD 12:25 - 1:05 PM Renal Failure and Hepatorenal
Syndrome
Mitra K. Nadim, MD
3 CME Credits
1:05 - 1:25 PM Panel Discussion
1:25 - 1:45 PM Break
Examine the kidney’s role in children with chronic liver disease.
Experts in pediatrics, internal medicine, nephrology, and hepa- Session II
tology will discuss hepatorenal syndrome types I and II, and long- 1:45 - 2:05 PM Hepatic Fibrocystic Diseases
term renal function after liver transplantation. Coverage includes Frederick J. Suchy, MD
diseases that affect both the liver and kidney, requiring dual trans-
2:05 - 2:25 PM Combined Liver and Kidney
plantation. Participants will also receive updates on cystic disease
Transplantation in Children
of the liver and kidney.
Patrick J. McKiernan, BSc, MRCP,
FRCPCH
Learning Objectives:
2:25 - 2:45 PM Long-term Renal Outcomes After Liver
Upon completion of this activity, participants will be able to: Transplantation
• Apply knowledge of pathophysiology of renal dysfunction in Estella M. Alonso, MD
chronic liver disease when managing patients with cirrhosis and 2:45 - 3:00 PM Discussion
   
its complications.
• Recognize long-term renal outcomes after liver transplantation.
• Identify the role of liver/kidney combined transplantation in
managing several systemic diseases.
• Enhance knowledge of disease mechanisms in polycystic liver
and kidney disease.
NOVEMBER 7 36A AASLD PROGRAM HEPATOLOGY, October, 2014

Competency Training Workshop

FRIDAY

Friday, November 7 12:30 - 12:40 PM Introduction

Oren K. Fix, MD, MSc and Josh Levitsky,
12:30 - 2:45 PM Room 309
MD, MS
Competency Training Workshop 12:40 - 1:00 PM GI/Transplant Hepatology Training
COURSE DIRECTORS: Oren K. Fix, MD, MSc Pathways: Planning the Traditional
Josh Levitsky, MD, MS 4-Year Track
William Sanchez, MD
CME not offered 1:00 - 1:20 PM GI/Transplant Hepatology Training
Pathways: Planning the Pilot 3-Year
Track
Stanley M. Cohen, MD
Explore the knowledge and skills required to implement a com-
petency-based transplant hepatology curriculum in both the tradi-
tional 4-year and the pilot 3-year programs. Program coordinators, Debate: Traditional 4-Year Pathway Versus Pilot 3-Year
program directors, clinical faculty, and trainees in transplant Pathway
hepatology, gastroenterology, and internal medicine will find the 1:20 - 1:30 PM Pro: The 3-Year Pathway Is
workshop particularly helpful. Presenters will review the revised Appropriate For Most Trainees
Entrustable Professional Activities for transplant hepatology and Josh Levitsky, MD, MS
discuss how clinical competency committees can use these and
1:30 - 1:40 PM Con: The 3-Year Pathway Is
other assessment tools to inform the new ACGME reporting mile- Appropriate For Only Select Trainees
stones. Transplant hepatology fellows will share their perceptions Andrew Keaveny, MD
of the current training pathways.
1:40 - 2:00 PM Transplant Hepatology in the Next
Accreditation System: Reporting
Learning Objectives:
Milestones, Entrustable Professional
Upon completion of this activity, participants will be able to: Activities and the Clinical
• Identify the central components of transplant hepatology training Competency Committee
in a traditional 4-year track and a pilot 3-year track, including K. Gautham Reddy, MD
advantages and disadvantages of each pathway. 2:00 - 2:20 PM The Fellow’s Perspective on
• List methods of assessment for transplant hepatology trainees Transplant Hepatology Training:
including Entrustable Professional Activities and reporting mile- What Works and What Doesn’t
stones, and be able to integrate them within the framework of Work?
clinical competency committees. Alan E. Gunderson, MD
• Describe competency-based training in transplant hepatology 2:20 - 2:45 PM Panel Discussion
from the fellow’s perspective. Stanley M. Cohen, MD; Oren K. Fix, MD,
MSc; Alan E. Gunderson, MD; Andrew
Keaveny, MD; Ayman A. Koteish, MD;
Josh Levitsky, MD, MS; K. Gautham
   
Reddy, MD; and William Sanchez, MD
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM 37A

NOVEMBER 7
Clinical Research Workshop 

FRIDAY
Friday, November 7 Breakout Session I: The Regulatory Process
12:30 - 3:30 PM Room 304/306 MODERATORS: Jeffrey S. Murray, MD, MPH
M. Scott Harris, MD
Clinical Research Workshop - Clinical Trials From
Concept to Implementation
Breakout Session II: Collaborating With Industry
COURSE DIRECTORS: Marc G. Ghany, MD, MHSc
Andrew J. Muir, MD MODERATORS: Andrew J. Muir, MD
Averell H. Sherker, MD, FRCP(C) Jeffrey D. Bornstein, MD

CME not offered Breakout Session III: Working With the IRB
MODERATORS: Raymond T. Chung, MD
Elizabeth L. Hohmann, MD
Aspiring clinical investigators will get an overview of the nuts and
bolts of conducting a clinical trial, beginning with the research Breakout Session IV: Data Collection and Management
question, ending with enrollment, and covering all of the steps in
MODERATORS: Valerie L. Durkalski, PhD, MPH
between. The program will emphasize four broad topics: develop-
Elizabeth C. Wright, PhD
ment of a protocol, funding sources for clinical research, regulatory
issues, and assembly and management of a research team. Seven
breakout sessions will provide further specifics. Breakout Session V: The Nuts and Bolts of Implementing
Protocol
Learning Objectives: MODERATORS: Marc G. Ghany, MD, MHSc
Upon completion of this activity, participants will be able to: Norah Terrault, MD
• Apply the basic requirements to conduct clinical research.
• Enhance your role as an effective member of a research team. Breakout Session VI: Collaborative Research
• Identify common pitfalls that lead to failure in clinical research. MODERATORS: Averell H. Sherker, MD, FRCP(C)
William M. Lee, MD
Nancy Fryzek, RN, MBA
12:30 - 12:35 PM Introduction
12:35 - 12:55 PM How to Develop a Protocol
Norah Terrault, MD Breakout Session VII: Research In Kids/Special
Populations
12:55 - 1:15 PM Funding Sources for Clinical Research
Andrew J. Muir, MD MODERATORS: Joel E. Lavine, MD, PhD
Estella M. Alonso, MD
1:15 - 1:35 PM What You Need to Know About    
Regulatory Issues
Matthew S. Harris, MD
1:35 - 1:55 PM How to Assemble/Lead Research
Team
Paul J. Pockros, MD
1:55 - 2:00 PM Break
2:00 - 3:30 PM Breakout Sessions*

*Attendees may choose two breakout sessions which will feature

an interactive format and encourage discussion with the modera-
tors. Each breakout session will be 40 minutes.
NOVEMBER 7 38A AASLD PROGRAM HEPATOLOGY, October, 2014

AASLD Postgraduate Course 

FRIDAY

Friday, November 7 Session I: The ABC’s of Inflammation and Immunity in the

3:30 - 7:30 PM Auditorium Liver
MODERATORS: Elizabeth M. Brunt, MD
Clinical Implications of Inflammation and Immunity
Kyong-Mi Chang, MD
in Acute and Chronic Liver Diseases -Advances in
Diagnosis, Treatment and Clinical Practice 3:35 - 3:55 PM Inflammation and Immunity: A Primer
for Hepatologists
COURSE DIRECTORS: Gyongyi Szabo, MD, PhD Cliona O’Farrelly, PhD
Kyong-Mi Chang, MD 3:55 - 4:15 PM Clinical Consequences of Liver
Naga P. Chalasani, MD Inflammation: An Overview
Dwain L. Thiele, MD
12 CME Credits ​/ ​10 Contact Hours
4:15 - 4:35 PM Liver Disease and Immune Cells: The
Pathologist’s View
David E. Kleiner, MD, PhD
While inflammation and immunity are key elements in most acute 4:35 - 4:55 PM Gut–Liver Axis: Bugs, Probiotics,
and chronic liver diseases, the volume and complexity of infor- Bile Acids and Inflammation in Liver
mation on this topic can be overwhelming. This comprehensive Disease
update will provide the latest treatments and emerging therapies Eamonn M. Quigley, MD
while exploring the roles inflammation and immunity play in liver
4:55 - 5:10 PM Break
disease.

Learning Objectives: Session II: Acute Liver Injury: Dead Cells and Surviving
Patients
Upon completion of this activity, participants will be able to:
• Discuss the role of immune cells and inflammation in different MODERATORS: Norah Terrault, MD
etiologies of liver diseases. Mark J. Czaja, MD

• Describe the triggers and mechanisms of immune activation and 5:10 - 5:30 PM Sterile Inflammation in Acute Liver
inflammation in the liver. Injury: Myth or Mystery?
Jacquelyn J. Maher, MD
• Identify potential therapeutic targets that intervene with immune
and inflammation-mediated liver damage. 5:30 - 5:50 PM Acute Liver Failure or Multi-Organ
Dysfunction Syndrome?
• Improve clinical practice by understanding the consequences of Patrick S. Kamath, MD
chronic inflammation in the progression of liver disease.
5:50 - 6:10 PM ABC’s of Acute Viral Hepatitis
Andrea Cox, MD, PhD
3:30 - 3:35 PM Welcome and Introduction
Gyongyi Szabo, MD, PhD
Session III: Chronic Hepatitis: Controlling Infection or
Causing Inflammation?
MODERATORS: Raymond T. Chung, MD
Barbara Rehermann, MD
6:10 - 6:30 PM Immunity and Inflammation in
Chronic Hepatitis B in Adults – When
to Treat?
Fu-Sheng Wang, MD, PhD
6:30 - 6:50 PM Immunity and Inflammation in
Chronic Hepatitis C – Does Treatment
Help?
Robert Thimme, MD
6:50 - 7:20 PM Mechanisms and Strategies of
Antiviral Therapies in HCV
David R. Nelson, MD
7:20 - 7:30 PM
    Closing Remarks
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
AASLD Postgraduate Course 
Saturday, November 8
8:00 AM - 5:00 PM Auditorium
Session IV: Steatohepatitis: ASH and NASH
MODERATORS: Shelly C. Lu, MD
Vijay Shah, MD
8:00 - 8:20 AM Immune-Mediated Liver Damage: The
Troublemakers and The Peacekeepers
David H. Adams, MD
8:20 - 8:40 AM Alcoholic and Non-Alcoholic
Steatohepatitis: Similarities and Key
Differences in Treatment Options
Craig J. McClain, MD
8:40 - 9:00 AM Immune Activation in the Metabolic
Syndrome – Implications for the
Clinicians
Anna Mae Diehl, MD
9:00 - 9:20 AM Growing Kids and Growing
Concerns: Pediatric NAFLD
Ariel E. Feldstein, MD
9:20 - 9:40 AM Clinical Management, Current and
Emerging Pharmacotherapies in
NAFLD and NASH
Brent A. Neuschwander-Tetri, MD
9:40 - 10:00 AM Trimming the Fat: The Liver and
Beyond
Mary E. Rinella, MD
10:00 - 10:20 AM Break
Session V: Autoimmunity and Immune Tolerance in the
Liver
MODERATORS: Jorge A. Bezerra, MD
Saul J. Karpen, MD, PhD
10:20 - 10:40 AM Clinical Implications of Autoimmunity
– Autoimmune Hepatitis and Overlap
Syndrome
Ansgar W. Lohse, MD
10:40 - 11:00 AM Autoimmunity in Cholestatic Liver
Disease – New Concepts and
Therapies
Ulrich Beuers, MD
11:00 - 11:20 AM Biliary Atresia: Update on
Investigations of Pathogenesis and
Outcomes
Cara Mack, MD
39A
Autoimmune-Like Drug Induced Liver Injury Case
Presentation: 17 Year Old With New Onset Liver Disease
Who Is Taking Minocycline
NOVEMBER 8
SATURDAY
11:20 - 11:30 AM It Is All Due to Minocycline
Naga P. Chalasani, MD
11:30 - 11:40 AM Nevermind, It Is All Autoimmune Liver
Disease
Robert J. Fontana, MD
11:40 AM - Noon Liver Transplantation and Allograft
Rejection
Sandy Feng, MD, PhD
Noon - 12:20 PM Discussion
12:20 - 1:40 PM Lunch
Session VI: Reversibility of Chronic Liver Disease
MODERATORS: Laurie D. DeLeve, MD, PhD
Natalie Torok, MD
1:40 - 2:00 PM Liver Fibrosis: The Toll of Inflammation
David A. Brenner, MD
2:00 - 2:20 PM Acute on Chronic Liver Disease: Is
There Liver-Gut-Brain Crosstalk?
Rajiv Jalan, MD, PhD
What Causes Hepatorenal Syndrome?
2:20 - 2:35 PM It Is All Inflammation
Pere Gines, MD
2:35 - 2:50 PM It Is All Vasoconstriction
Florence Wong, MD
2:50 - 3:10 PM Emerging Therapies Targeting
Inflammation in Liver Disease
Gregory J. Gores, MD
3:10 - 3:30 PM Break
Session VII: From The Past to The Future: Targeted
Therapies
MODERATORS: Arun J. Sanyal, MD
Rebecca G. Wells, MD
3:30 - 3:50 PM When Immune Surveillance Fails:
Managing Hepatocellular Cancer
Tushar Patel, MBChB
3:50 - 4:10 PM Emerging Trends in Hepatology
Practice: Science Driven Care of Liver
Diseases and Cancer- From Stem
Cells to Genomics
Lopa Mishra, MD
4:10 - 4:35 PM In Search of the Magic Bullet: Can
Liver Inflammation and Fibrosis Be
Reversed With Medications?
Scott L. Friedman, MD
4:35 - 4:55 PM Ending Liver Inflammation and Curing
Liver Disease: From Test Tubes to
Patients
Gyongyi Szabo, MD, PhD
4:55 - 5:00 PM
    Wrap-up
 40A AASLD PROGRAM HEPATOLOGY, October, 2014

SIG Program
Saturday, November 8 9:00 - 9:05 AM Introduction
9:00 AM - Noon Room 302 9:05 - 9:35 AM The Development of Outreach at Cal
Pacific
NOVEMBER 8

Outreach in Liver Transplant

SATURDAY

Adil E. Wakil, MD
9:35 - 10:05 AM The Development of Outreach at
Sponsored by the Liver Transplantation and Surgery SIG Baylor
MODERATORS: David C. Mulligan, MD, FACS James F. Trotter, MD
James F. Trotter, MD 10:05 - 10:35 AM The ECHO Program
Sanjeev Arora, MD
Experts from outreach programs across the country will examine a
variety of issues linking outreach activity to program accomplish- 10:35 - 10:55 AM Implementation of the ECHO Program
ments, transplant referrals and site selection. Plan to attend this
in a Clinical Hepatology Practice
Richard A. Manch, MD
didactic discussion and share your knowledge of best practices in
establishing successful outreach programs. 10:55 - 11:25 AM Is the Juice Worth the Squeeze: Does
Outreach Achieve Value for Liver
Learning Objectives: Transplant Centers?
Roshan Shrestha, MD
Upon completion of this activity, participants will be able to:
11:25 AM - Noon Discussion/Questions
• Measure the value of outreach in a liver transplant program.    
• Develop, staff and fund an outreach program.
• Assess the problems with maturation of an outreach program.
• Integrate telemedicine within hepatology outreach.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
Meet-the-Professor Luncheons 
Saturday, November 8
12:20 - 1:40 PM Refer to your luncheon ticket for
meeting room location.
MTP-1 Hepatitis B: Treatment Choice and Monitoring
for Response and Resistance
Norah Terrault, MD and Harry L. Janssen, MD,
PhD
MTP-2 Hepatitis C: What to Offer Difficult to Treat
Patients
Kris V. Kowdley, MD and Mark S. Sulkowski, MD
MTP-3 Hepatitis C: Management Pre-and Post-Liver
Transplantation
Paul Y. Kwo, MD and Kymberly D. Watt, MD
MTP-4 HCC: Management From a Hepatologist’s
Perspective
Laura M. Kulik, MD and K. Rajender Reddy, MD
MTP-5 Renal Failure in Cirrhosis – Is it Pre-Renal, AKI
or HRS?
Florence Wong, MD and Josh Levitsky, MD, MS
MTP-6 Portal and Mesenteric Vein Thrombosis in
Cirrhosis
Patrick S. Kamath, MD and Guadalupe Garcia-
Tsao, MD
MTP-7 Bone Disease in Liver Disease – Don’t Forget
About It
Marion G. Peters, MD and Herbert L. Bonkovsky,
MD
Poster Session I
Saturday, November 8
2:00 – 7:30 PM
Hall C
Refer to page 92A for Poster Presentations
41A
MTP-8 Management of Gastric Varices: Beta-
blockers, Glue, or TIPS
Shiv K. Sarin, MD and Stephen H. Caldwell, MD
NOVEMBER 8
SATURDAY
MTP-9 How to Work Up a Patient With Suspected
NAFLD
Stephen A. Harrison, MD and Miriam B. Vos, MD
MTP-10 Portopulmonary Hypertension and New
Pulmonary Vasodilators
Michael J. Krowka, MD and Michael B. Fallon,
MD
MTP-11 Hepatic Encephalopathy: Current and Future
Treatments
Jasmohan S. Bajaj, MD and Marwan Ghabril, MD
MTP-12 DILI: Lessons Learned From the DILIN and the
Spanish DILI Registry
Raul J. Andrade, MD, PhD and Robert J. Fontana,
MD
MTP-13 Non-Invasive Assessment of Liver Fibrosis and
Liver Function
Jayant A. Talwalkar, MD, MPH and Marc G.
Ghany, MD, MHSc
MTP-14 Alcoholic Liver Disease: Approaches to
Diagnosis and Treatment of Moderate and
Severe Alcoholic Hepatitis
Michael R. Lucey, MD and Mack C. Mitchell, MD
MTP-15 What’s New in Pediatric Liver Disease in
2014?
Jean P. Molleston, MD and Kathleen B. Schwarz,
    MD
Exhibit Hall Opening and Reception
Saturday, November 8
5:00 – 7:30 PM
Hall D
 42A AASLD PROGRAM HEPATOLOGY, October, 2014

Transplant Surgery Workshop 

Saturday, November 8 Session II: Cardiovascular and Pulmonary Disease
3:30 - 7:00 PM Room 302 4:10 - 4:30 PM Cardiac Clearance for Major Surgery
in the Cirrhotic Patient
NOVEMBER 8

Management of Comorbidities for Successful Surgical

SATURDAY

Michael A. Ramsay, MD
Procedures, Hepatic Resections and Transplant
4:30 - 4:50 PM Pulmonary Hypertension Work-
COURSE DIRECTORS: Kenneth D. Chavin, MD, PhD up and Optimization for Surgery,
John C. Magee, MD Intraoperative Management, and
Short and Long Term Postoperative
3.5 CME Credits Management
David J. Kramer, MD
4:50 - 5:20 PM Nontransplant Liver Surgery in
Improve patient care and outcomes by increasing competence Cirrhotics: Who Is Too Sick?
in selecting appropriate management of comorbidities commonly KV Narayanan Menon, MD
encountered in patients with ESLD who are undergoing a surgical 5:20 - 5:40 PM Joint Discussion
intervention including hepatic resection and transplant. 5:40 - 6:00 PM Break
Learning Objectives:
Session III: Other Conditions and Issues
Upon completion of this activity, participants will be able to:
6:00 - 6:20 PM Futility for Transplant and Liver
• Identify risk factors and management of metabolic syndrome
Resection: When is Enough Enough?
and its effect on surgical outcomes.
Bijan Eghtesad, MD
• Identify risk factors and management of cardiovascular and pul-
monary disease and their effect on surgical outcomes.
Debate: Role of the Critical Care Team – Closed or Open
• Recommend futile surgery for patients with liver disease and the
Unit Care
role of the ICU on surgical outcomes.
6:20 - 6:35 PM Pro Speaker
Susan L. Orloff, MD, FACS
3:30 - 3:35 PM Introduction
6:35 - 6:50 PM Con Speaker
Kenneth D. Chavin, MD, PhD
Michael J. Englesbe, MD
6:50 - 7:00 PM Closing Remarks
Session I: Metabolic Syndrome John C. Magee, MD
   
3:35 - 3:50 PM Preoperative Workup and Surgical
Readiness
Kymberly D. Watt, MD
3:50 - 4:10 PM Obesity and Liver Transplantation/
Liver Resection
Julie Heimbach, MD

AASLD Business Meeting (Members Only)

Saturday, November 8
5:15 – 6:15 PM
Auditorium
Adrian M. Di Bisceglie, MD, FACP presiding
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
Early Morning Workshops 
Sunday, November 9
6:45 - 7:45 AM Refer to your ticket for meeting
room location.
Basic Early Morning Workshops
EMW-1 Alcoholic Liver Disease: Mechanisms and
Therapeutic Targets
Vijay Shah, MD and Pranoti Mandrekar, PhD
EMW-2 Stellate Cell Biology
Don C. Rockey, MD and Jonathan A. Dranoff, MD
EMW-3 Triggers of Fibrosis in NASH
Natalie Torok, MD and Detlef Schuppan, MD, PhD
EMW-4 Cholestasis and Cholangiocyte Pathobiology
Gianfranco Alpini, PhD and Laura Bull, PhD
EMW-5 Microbiome and Gut Permeability in Liver
Disease
Bernd Schnabl, MD and Gavin E. Arteel, PhD
EMW-6 Animal Models of NAFLD
Frank A. Anania, MD, FACP, AGAF and David E.
Cohen, MD, PhD
43A
Clinical Early Morning Workshops
EMW-7 New Drugs for Hepatitis B in the Pipeline
Anna S.F. Lok, MD and Tram T. Tran, MD
EMW-8 Reactivation of Hepatitis B During Chemo/
Immunosuppressive Therapy
Harry L. Janssen, MD, PhD and Robert P. Perrillo,
MD
EMW-9 Controversies in Pediatric ALF
Ronald J. Sokol, MD and David A. Rudnick, MD,
NOVEMBER 9
PhD
SUNDAY
EMW-10 Cardiopulmonary Complications of Liver
Disease in Children and Adults
Saul J. Karpen, MD, PhD and John Bucuvalas, MD
EMW-11 Causality Assessment and Autoimmunity in
Hepatotoxicity
Paul B. Watkins, MD and Victor J. Navarro, MD
EMW-12 New Anti-tumor Agents in Development for
HCC
Gregory J. Gores, MD and Amit G. Singal, MD
EMW-13 Quality Improvement in Management of
Patients With Liver Disease
Michael Volk, MD and Fasiha Kanwal, MD
EMW-14 Acute on Chronic Liver Failure
Ram M. Subramanian, MD and Anne M. Larson,
    MD
 44A AASLD PROGRAM HEPATOLOGY, October, 2014

Plenary Session
8:30 AM
Transplant Plenary I
3: Superior Survival Using Living Donors and Donor-
Sunday, November 9
Recipient Matching Using a Novel Living Donor Risk
8:00 - 9:30 AM Auditorium Index
David S. Goldberg, Benjamin French, Peter L. Abt, Kim M. Olthoff,
MODERATORS: Julie Heimbach, MD Abraham Shaked
John C. Magee, MD

8:45 AM
8:00 AM 4: Antiplatelet Therapy is Associated with Better
NOVEMBER 9

1: BPAR (Biopsy Proven Acute Rejection) During Prognosis in Patients with Hepatitis B Virus-Related
SUNDAY

Protocolized Immunosuppression Withdrawal (ISW) Hepatocellular Carcinoma after Resection Surgery

is Readily Reversed in Pediatric Liver Transplant (Tx)
Recipients
Veena L. Venkat, George V. Mazariegos, John Bucuvalas, Anthony
J. Demetris, Steven J. Lobritto, John C. Magee, Mercedes Martinez,
Yumirle P. Turmelle, Katharine Spain, Sandy Feng
8:15 AM
2: Risk Factors for Recurrence of Primary Sclerosing
Cholangitis in Live and Deceased Donor Liver Transplant
Recipients in the A2ALL Study
Fredric D. Gordon, David S. Goldberg, Nathan P. Goodrich,
Anna S. Lok, Elizabeth C. Verna, Nazia Selzner, R. Todd Stravitz,
Robert M. Merion
Chien-Wei Su, Pei-Chang Lee, Chia-Jen Liu, Teh-Ia Huo, Yi-Hsiang
Huang, Kuei-Chuan Lee, Han-Chieh Lin, Jaw-Ching Wu
9:00 AM
5: A Novel MELD Exception Point System for
Hepatocellular Carcinoma Promotes Equitable Liver
Allocation
Mamatha Bhat, Peter Ghali, Andre Roy, Prosanto Chaudhury,
Fernando Alvarez, Michel Carrier, Marc Bilodeau
9:15 AM
6: Liver Transplantation (LT) with the “Oldest Old” (≥80
years) Donor Livers: The U.S. National Experience
Suzanne R. Sharpton, Sandy Feng, Jennifer C. Lai

Poster Session II Exhibit Hall

Sunday, November 9 Sunday, November 9
8:00 AM – 5:30 PM 9:30 AM – 3:00 PM
Hall C Hall D
Refer to page 119A for Poster Presentations 10:00 – 10:30 AM
Coffee Break
1:30 – 2:00 PM
Snack Break
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM 45A

Basic Research Workshop 

Sunday, November 9 Session II: Mechanisms Regulating Hepatic Stellate Cell
8:00 AM - Noon Ballroom A Activation and Deactivation
MODERATORS: Detlef Schuppan, MD, PhD
Liver Fibrosis
Robert F. Schwabe, MD
COURSE DIRECTORS: Robert F. Schwabe, MD 8:45 - 9:05 AM Epigenetic Regulation of HSC
Ekihiro Seki, MD, PhD Activation
Derek A. Mann, PhD
4 CME Credits
9:05 - 9:25 AM Integrins and Fibrosis
Dean Sheppard, MD

NOVEMBER 9
9:25 - 9:45 AM Inflammation and Liver Fibrosis
Anti-fibrotic drugs remain unsuccessful in the treatment of liver

SUNDAY
Ekihiro Seki, MD, PhD
fibrosis—a key factor in the long-term outcome of chronic liver
disease. Learn about the underlying mechanisms and pathways of 9:45 - 10:15 AM Break
liver fibrosis and gain an understanding of anti-fibrotic strategies, 10:15 - 10:35 AM Contribution of Liver Sinusoidal
animal models, and translation into clinical trials. Endothelial Cells to Liver Fibrosis
Shahin Rafii, MD
Learning Objectives: 10:35 - 10:55 AM Hepatic Stellate Cell Reversal
Upon completion of this activity, participants will be able to: David A. Brenner, MD
• Develop concepts and therapies that directly prevent or reverse
liver fibrosis. Session III: Anti-fibrotic Therapies
• Review relevant fibrogenic cell populations and focus on mech- MODERATORS: David A. Brenner, MD
anisms that regulate the activation of hepatic stellate cells, the Dean Sheppard, MD
main fibrogenic cell type of the liver. 10:55 - 11:15 AM Stellate Cell Specific Targeting
• Discuss animal models of liver fibrosis and how they can be Approaches
employed to develop translational approaches for the treatment Klaas Poelstra, PhD
of liver fibrosis. 11:15 - 11:35 AM Animal Models and Preclinical
Studies: A Critical Evaluation
Session I: The Source of Fibrogenic Cells in the Liver Detlef Schuppan, MD, PhD

MODERATORS: Derek A. Mann, PhD

11:35 - 11:55 AM Antifibrotic Trials: Lost in Translation?
Massimo Pinzani, MD, PhD, FRCP
Ekihiro Seki, MD, PhD    
8:00 - 8:25 AM Hepatic Stellate Cells and Fibrosis:
Fate Tracing and Contribution to
Fibrosis
Robert F. Schwabe, MD
8:25 - 8:45 AM Disease-specific Fibrogenic Cells:
Role of Portal Myofibroblasts
Rebecca G. Wells, MD
 46A AASLD PROGRAM HEPATOLOGY, October, 2014

Hepatology Associates Course 

Sunday, November 9 8:00 - 8:05 AM Opening Remarks
8:00 AM - 1:30 PM Room 304/306
Session I
COURSE DIRECTORS: Anita Lippello, CRNP, NP-C, DNP
MODERATORS: Sue Currie, PhD
Donald Gardenier, DNP, FNP-BC Anita Lippello, CRNP, NP-C, DNP

5.5 CME Credits ​/ ​5 Contact Hours

8:05 - 8:35 AM New Challenges in Chronic Hepatitis
C Treatment
Patrick M. Horne, MSN, APRN, FNP-BC
8:35 - 9:05 AM Hepatic Decompensating Events:
Stay updated on new clinical guidelines on the management of
NOVEMBER 9

Ascites
hepatitis C and complications of liver disease by attending this
SUNDAY

Bruce A. Runyon, MD
comprehensive, patient-centered course. Advance your knowledge
of evidence-based care, increase your comfort level in caring for 9:05 - 9:20 AM Awarded Poster Presentation
patients with liver diseases, and improve patient outcomes as a Anna Marie Hefner, RN, PhD, CPNP,
MaEd
result. Nurses, nurse practitioners, physician assistants, and other
healthcare professionals will benefit from attending. 9:20 - 9:45 AM Infection Challenges in the Cirrhotic
Patient
Learning Objectives: Kapil B. Chopra, MD, FACP

Upon completion of this activity, participants will be able to: 9:45 - 10:20 AM HCV Treatement Pre-and-Post
Transplant: Update
• State the new treatment regimens, and select the most appropri-
Gregory T. Everson, MD
ate medications.
10:20 - 10:40 AM Discussion
• Identify potential side effects, and select appropriate manage-
ment strategies. 10:40 - 11:00 AM Break
• Effectively manage ascites in an outpatient setting.
• Distinguish when to use bacterial prophylaxis and how to treat Session II
infections. MODERATORS: Rennie M. Mills, PA-C
Donald Gardenier, DNP, FNP-BC
11:00 - 11:30 AM Diagnostic Challenges in Liver
Pathology: Consultations From the
Hepatology Practice
M. Isabel Fiel, MD
11:30 - 11:45 AM Awarded Poster Presentation
Rachel A. Annunziato, PhD
11:45 AM - 12:10 PM The Clinical Dilemma: Management
of Pruritus and Metabolic
Complications in Cholestasis
David A. Sass, MD
12:10 - 12:40 PM HCC Screening Update
Laura M. Kulik, MD
12:40 - 1:15 PM HCV/HIV Coinfection
Angela Kapalko, MS, PA-C
1:15 - 1:30 PM
    Discussion and Closings
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM 47A

Thomas E. Starzl Transplant Surgery State-of-the-Art Lecture

Sunday, November 9 This annual lecture recognizes the pioneering work that Dr. Starzl
9:30 - 10:00 AM Auditorium has done to elevate liver transplantation from an experimental pro-
cedure to one that saves thousands of lives annually. A restricted
Living Donor Liver Transplantation: Has it Fulfilled Its fund has been established to support the lecture in perpetuity and
Promise? AASLD gratefully acknowledges the donors to this fund.
SPEAKER: Jean C. Emond, MD    
MODERATOR: David C. Mulligan, MD, FACS

.5 CME Credit

NOVEMBER 9
SUNDAY
Discover the latest news on the Living Donor Liver Transplantation
(LDLT) program and become more confident in recommending and
selecting patients for this intervention. This lecture seeks to raise
awareness of the hepatology and surgical transplant communities
by identifying the newest methods of liver donations, and to dis-
seminate the latest approaches in recipient surgery.

Dr. Emond is Vice Chair and Chief of Liver Transplantation at New

York-Presbyterian/Columbia and Executive Director of the Trans-
plant Initiative. Regarded as one of the world’s foremost experts in
liver disease and transplantation, Dr. Emond was a key member
of Dr. Christoph Broelsch’s liver transplant team at the University
of Chicago, which performed the first partial liver transplants in
North America in 1985, the first split liver transplants in 1988,
and the first living donor transplants in 1989. Under his direction,
the Center for Liver Disease and Transplantation at New York-Pres-
byterian/Columbia has established a track record of distinguished
clinical research and superb outcomes for children and adults.

Learning Objectives:
Upon completion of this activity, participants will be able to:
• Review the history and establishment of Living Donor Liver Trans-
plantation (LDLT).
• Demonstrate the worldwide clinical activity in LDLT.
• Identify obstacles to expand use of this therapy.
• Propose solutions and a vision for the future of LDLT.

Exhibit Hall D
10:00 – 10:30 AM
Coffee Break
 48A AASLD PROGRAM HEPATOLOGY, October, 2014

Emerging Trends Symposium

Sunday, November 9 Learning Objectives:
10:00 - 11:30 AM Room 312 Upon completion of this activity, participants will be able to:

Acute on Chronic Liver Failure • Summarize the pathophysiology of ACLF.

• Discuss the role of infections and other precipitants of ACLF.
MODERATORS: Jasmohan S. Bajaj, MD
Patrick S. Kamath, MD • Identify unique clinical issues in patients with ACLF.
• Explain the efficacy of investigational therapies for ACLF includ-
1.5 CME Credits ing GCSF and bio-artificial liver support.

10:00 - 10:10 AM What is ACLF?

NOVEMBER 9

Find out the latest on Acute on Chronic Liver Failure (ACLF), an Patrick S. Kamath, MD
SUNDAY

increasingly identified yet poorly defined disease. Recognized by
acute decompensation of the patient with cirrhosis and charac-
terized by multiple organ failure, ACLF has a high mortality rate.
Learn about the pathophysiology of ACLF, the role of infections as
a precipitant, noninfectious causes, and promising therapies.
10:10 - 10:30 AM Infection Related ACLF
Jasmohan S. Bajaj, MD
10:30 - 10:35 AM Discussion
10:35 - 10:55 AM ACLF Not Related to Infection
Pere Gines, MD
10:55 - 11:00 AM Discussion
11:00 - 11:20 AM Therapy of ACLF
Shiv K. Sarin, MD
11:20 - 11:25 AM Discussion
11:25 - 11:30 AM Closing Remarks
Jasmohan S. Bajaj, MD
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
Plenary Session
Transplant Plenary II
Sunday, November 9
10:30 AM - Noon Auditorium
MODERATORS: Susan L. Orloff, MD, FACS
David J. Reich, MD
10:30 AM
7: Dynamic Characterization of Human Livers during ex
vivo Machine Perfusion
Bote G. Bruinsma, Gautham V. Sridharan, Pepijn D. Weeder,
James H. Avruch, Heidi Yeh, James F. Markmann, Martin L.
Yarmush, Korkut Uygun
10:45 AM
8: Ledipasvir/Sofosbuvir with Ribavirin for the
Treatment of HCV in Patients with Post Transplant
Recurrence: Preliminary Results of a Prospective,
Multicenter Study
K. Rajender Reddy, Gregory T. Everson, Steven L. Flamm, Jill M.
Denning, Sarah Arterburn, Theo Brandt-Sarif, Phillip S. Pang, John
G. McHutchison, Michael P. Curry, Michael Charlton
49A
11:00 AM
9: Multicenter Experience using Sofosbuvir and
Simeprevir with/without Ribavirin to Treat HCV
Genotype 1 after Liver Transplantation
Surakit Pungpapong, K Tuesday Werner, Bashar Aqel, Michael
D. Leise, Jennifer L. Murphy, Tanisha M. Henry, Kristen Ryland,
Amy E. Chervenak, Kymberly D. Watt, Hugo E. Vargas, Andrew
Keaveny
NOVEMBER 9
11:15 AM
SUNDAY
10: Activation of TGR5 in the brain is neuroprotective in
a murine model of hepatic encephalopathy due to acute
liver failure
Matthew McMillin, Gabriel A. Frampton, Cheryl Galindo, Sharon
DeMorrow
11:30 AM
11: Incremental dose model identified GSK3β and
β-catenin as potential targets for regenerative therapies
for acetaminophen-induced acute liver failure
Bharat Bhushan, Chad M. Walesky, Prachi C. Borude, Genea
Edwards, Michael Manley, Satdarshan (Paul) S. Monga, Udayan
Apte
11:45 AM
12: Microglia activation during hepatic encephalopathy
is driven by an imbalance of monocyte chemoattractant
protein 1/fractalkine due to bile acid signaling
Matthew McMillin, Gabriel A. Frampton, Cheryl Galindo, Holly A.
Standeford, Gianfranco Alpini, Sharon DeMorrow
 50A AASLD PROGRAM
Hans Popper Basic Science State-of-the-Art Lecture
Sunday, November 9
12:00 - 12:30 PM Auditorium
Induced Pluripotent Stem Cells and Their Use in the
Study of Liver Disease and Development
SPEAKER: Stephen A. Duncan, DPhil
MODERATOR: Rebecca G. Wells, MD
.5 CME Credit
NOVEMBER 9
SUNDAY
Learn about the latest advancements in novel therapeutic
approaches, including the use of patient specific induced pluripo-
tent stem cells (iPSCs) as a tool for the study of liver disease.
Stephen A. Duncan is a Professor of Cell Biology, Neurobiology
and Anatomy and Director of the Regenerative Medicine Program
at the Medical College of Wisconsin. He has authored over 80
articles in scientific journals and books, and his research focuses
on the use of mice and stem cells to understand the contribution of
transcription factors during embryonic development and function
of the liver. Traditionally his lab has relied on the use of mouse
models including knockout mice and mouse embryonic stem cells.
During this time his team has garnered a substantial understanding
of the basic molecular pathways controlling hepatic function and
development. While the mouse has been a valuable model, they
Value-based Medicine
Sunday, November 9
1:00 - 3:00 PM Room 302
Value-based Medicine in Hepatology
MODERATORS: Guadalupe Garcia-Tsao, MD
Mario Strazzabosco, MD, PhD
2 CME Credits
Discover the concept of value-based medicine and the importance
of returning the practice of hepatology to its appropriate focus:
enabling health and effective care of patients with liver disease.
Get up to date on the value-based medicine program piloted by
the University of Milan and learn how a shift in the current quality
movement can significantly impact the value of patient outcomes.
HEPATOLOGY, October, 2014
have introduced the use of induced human pluripotent stem cells
because as they offer a new and robust experimental model.
Dr. Duncan and his team have shown that they can control differen-
tiation of human pluripotent stem cells to hepatocytes with high effi-
ciency, to the extent that >95% of cells in the culture dish express
characteristic markers of differentiated hepatocytes. In addition
they have developed novel technologies to facilitate the efficient
culture and reprogramming of human iPSCs. Such approaches
have raised the possibility of using stem cell–derived cells for the
study of hepatocyte differentiation and to potentially treat liver dis-
ease. This view is supported by their work over the last five years,
and includes the establishment of a number of new projects and
collaborative initiatives in which they have significantly advanced
the use of human iPSCs in the liver field by demonstrating their
ability to model hepatocyte differentiation, probe infectious liver
disease, model inborn errors of hepatic metabolism, and to screen
for small molecules to promote hepatocyte maturation.
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Determine the advantages and disadvantages of using hepato-
cyte-like cells derived from iPSCs to study errors of hepatic
metabolism.
This annual lecture recognizes Dr. Popper, one of the founders of
the American Association for the Study of Liver Diseases (AASLD),
for his role in the establishment of Hepatology and his promotion
of the intellectual spirit of the Association.
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Apply the concept of value-based medicine.
• Use the results of the pilot program in health outcomes in hepa-
tology at the University of Milan.
• Impact health outcomes in the context of hepatology.
1:00 - 1:05 PM Introduction
Guadalupe Garcia-Tsao, MD
1:05 - 1:25 PM Health Outcomes: Definition,
Measurement, and Impact
John I. Allen, MD
1:25 - 1:45 PM Value-Based Medicine, Redefining
Healthcare
Elizabeth Teisberg, MD
1:45 - 2:05 PM Improving Value of Care in Chronic
Conditions
Thomas H. Lee, MD
2:05 - 2:25 PM Measuring Outcomes in Heptatology:
The Milano Experience
Mario Strazzabosco, MD, PhD
2:25
- 3:00 PM Discussion
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM 51A

ABIM Maintenance of Certification

Sunday, November 9 Learning Objectives:
1:15 - 2:45 PM Room 210 Upon completion of this activity, participants will be able to:

Keeping Up With Maintenance of Certification (MOC): A
Comprehensive Review of the ABIM MOC Program
MODERATORS: Oren K. Fix, MD, MSc
Mark W. Russo, MD, MPH
Richard K. Sterling, MD, MSc
• Describe current MOC requirements and highlight the recent
changes.
• List the immediate steps needed to determine one’s current status
in MOC.
• Identify various ways to earn MOC points in both Medical
Knowledge and Practice Assessment activities.

1.5 CME Credits • Explain the MOC requirements and benefits to trainees at an

NOVEMBER 9
early stage.

SUNDAY
ABIM certification is an important way to demonstrate to patients, 1:15 - 1:20 PM Introduction
the public and other stakeholders that a physician has met rigorous 1:20 - 1:45 PM MOC Update
standards within the six general competencies through self-assess- Oren K. Fix, MD, MSc
ment and evaluation. Additionally, certification demonstrates one’s 1:45 - 2:10 PM MOC Requirements
commitment to continual professional development and lifelong Mark W. Russo, MD, MPH
learning. Recent changes to ABIM’s Maintenance of Certification
2:10 - 2:35 PM MOC Maintenance
(MOC) requirements have left many confused and frustrated. This
Richard K. Sterling, MD, MSc
informational session is designed to provide hepatology physicians
and trainees with an up-to-date overview of MOC requirements 2:35 - 2:45 PM
    Discussion and Wrap-up
and the many steps in between to maintain certification.

Exhibit Hall D
1:30 – 2:00 PM
Snack Break
 52A AASLD PROGRAM HEPATOLOGY, October, 2014

Ethics and Humanities State-of-the-Art Lecture

Sunday, November 9 iness may present the possibility of the self-consciousness itself
2:00 - 2:30 PM Auditorium becoming a sickness (hypochondria). Could it be that contempo-
rary medicine and its instructions for living right is itself a sickness?
A Toxic History of Modernity: From Black Bile to Living
on Light Iain Bamforth grew up in Glasgow and graduated from its medical
SPEAKER: Iain Bamforth, MBChB, DLitt school. He has pursued a peripatetic career as a hospital doctor,
general practitioner, translator from French and German, lecturer
MODERATOR: Adrian Reuben, MBBS, FRCP, in comparative literature, and latterly public health consultant in
FACG several developing countries, principally in south-east Asia. He
writes for many periodicals and magazines including Times Liter-
NOVEMBER 9

.5 CME Credit ary Supplement, London Review of Books, Lapham’s Quarterly,

SUNDAY

The Threepenny Review, The Lancet and Bulletin of the World

Explore the curious paradox that health (in spite of the World
Health Organization’s controversial definition of it as a condition
of complete physical, mental, and social well-being) is actually
a negative state. Being healthy means being hale or whole, but
also being sublimely indifferent to our condition. Health happens
unawares. On the other hand, being conscious about our health-
Health Organization. He has published five collections of poetry
and his prose includes The Body in the Library (2003), a history of
modern medicine as told through literature, as well as The Good
European (2006), a collection of writings on European history and
ideas. Next year will see the publication of A Doctor’s Dictionary,
a collection of 26 essays on medicine and culture thematically
arranged as an abecedary: from A for Altruism to Z for Zoology.

AASLD Distinguished Awards

Sunday, November 9
2:45 - 3:00 PM Auditorium
AASLD Distinguished Clinician Educator/Mentor Award
Presented to: William M. Lee, MD
Presented by: J. Gregory Fitz, MD

General Hepatology Update

Sunday, November 9 Learning Objectives:
3:00 - 4:30 PM Room 210 Upon completion of this activity, participants will be able to:

General Hepatology Update • Apply the current guidelines for the diagnosis and management
of hepatorenal syndrome.
MODERATORS: Rohit Loomba, MD, MHSc • Review the current guidelines for the long-term care of liver trans-
Fred Poordad, MD plant recipients.
• Identify the current guidelines for the diagnosis and manage-
1.5 CME Credits
ment of autoimmune hepatitis.

Investigate the latest on clinical issues commonly seen in prac- 3:00 - 3:25 PM Management of Hepatorenal
tice. Diagnostic strategies and approaches to management will Syndrome
be reviewed to provide state-of-the-art guidelines, particularly for Florence Wong, MD
diagnostic dilemmas. 3:25 - 3:50 PM Long-term Care of the Post-transplant
Patient
Kymberly D. Watt, MD
3:50 - 4:15 PM Autoimmune Hepatitis
Michael A. Heneghan, MD, MRCP
4:15 - 4:30 PM
    Discussion
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
Parallel Session
Parallel 1: Advances in Fibrosis Imaging
Sunday, November 9
3:00 - 4:30 PM Room 309
MODERATORS: Keyur Patel, MD
Claude B. Sirlin, MD
3:00 PM
13: Factors Associated with and Prevalence of Liver
Fibrosis in a General Elderly Population: Results from
the Rotterdam Study
Elisabeth P. Plompen, Edith M. Koehler, Jeoffrey Schouten, Bettina
E. Hansen, Pavel Taimr, Albert Hofman, Frank W. Leebeek, Sarwa
Darwish Murad, Bruno H. Stricker, Laurent Castera, Harry L.
Janssen
3:15 PM
14: Increased liver stiffness is associated with higher
all-cause mortality in older adults: results from a
population-based study
Edith M. Koehler, Elisabeth P. Plompen, Jeoffrey Schouten, Bettina
E. Hansen, Frank J. van Rooij, Pavel Taimr, Jan Heeringa, Albert
Hofman, Bruno H. Stricker, Sarwa Darwish Murad, Laurent
Castera, Harry L. Janssen
3:30 PM
15: Supersonic shear wave elastography versus
transient elastography for the diagnosis of alcoholic
liver fibrosis: a biopsy controlled prospective study
Maja Thiele, Bjørn S. Madsen, Annette D. Fialla, Jonel Trebicka,
Aleksander Krag
3:45 PM
16: Assessment of Clinical Effectiveness of MR
Elastography and Vibration-Controlled Transient
Elastography for Detecting Hepatic Fibrosis
Jun Chen, Jayant A. Talwalkar, Meng Yin, Jennifer Oudry, Kevin
Glaser, Thomas C. Smyrk, Ehman Richard
4:00 PM
17: Quantitative molecular magnetic resonance imaging
(MRI) of lysyl oxidase-mediated collagen crosslinking
during liver fibrosis
Howard H. Chen, Lan Wei, Nicholas J. Rotile, Christian T. Farrar,
Kenneth K. Tanabe, Bryan C. Fuchs, Peter Caravan
4:15 PM
18: Molecular MR imaging of Collagen Accurately
Monitors Reduced Biliary Fibrosis Progression in
Response to Rapamycin
Bryan C. Fuchs, Christian T. Farrar, Danielle K. DePeralta, Helen
Day, Boris Keil, Gregory Y. Lauwers, Lan Wei, Arun Subramaniam,
Kenneth K. Tanabe, Peter Caravan
53A
Parallel 2: Antivirals, Acute Liver Failure
in Liver Transplantation
Sunday, November 9
3:00 - 4:30 PM Room 312
MODERATORS: Don C. Rockey, MD
John J. Fung, MD, PhD
NOVEMBER 9
3:00 PM
SUNDAY
19: The use of simeprevir and sofosbuvir to treat HCV
G1 in the Liver Transplant Setting: The experience in 3
US Centers
Bashar Aqel, Surakit Pungpapong, K Tuesday Werner, Amy E.
Chervenak, Jorge Rakela, Kymberly D. Watt, Michael D. Leise,
Jennifer L. Murphy, Tanisha M. Henry, Kristen Ryland, Andrew
Keaveny, Hugo E. Vargas
3:15 PM
20: Prevention of Hepatitis C Virus (HCV) Recurrence
with Peri-Transplant Hepatitis C Immune Globulin
Combined with Pre-Transplant (Pre-LT) Antiviral Therapy
(AVT)
Norah Terrault, Sanjaya K. Satapathy, George Therapondos,
Roshan Shrestha, Elizabeth C. Verna, Jeffrey Campsen, James
Spivey, Jens Rosenau, Thomas D. Schiano, Kalyan R. Bhamidimarri,
Sher Linda, John M. Vierling, Lewis W. Teperman, Gerond Lake-
Bakaar, Jacqueline G. O’Leary, Laura M. Kulik, Fredric D. Gordon,
Daniel Maluf, Shailesh Chavan, Christopher J. Dougherty
3:30 PM
21: High rates of virological response and major clinical
improvement during sofosbuvir and daclatasvir-based
regimens for the treatment of fibrosing cholestatic HCV-
recurrence after liver transplantation: The ANRS CO23
CUPILT study
Vincent Leroy, Jérôme Dumortier, Audrey Coilly, Mylene Sebagh,
Claire Fougerou-Leurent, Sylvie Radenne, Danielle Botta, Francois
Durand, Christine Silvain, Pascal Lebray, Pauline Houssel-Debry,
Nassim Kamar, Louis d’Alteroche, Yvon Calmus, Inga Bertucci,
Georges-Philippe Pageaux, Jean-Charles Duclos-Vallee
3:45 PM
22: Striking differences in wait-listing trends between
patients with viral hepatitis B and C: implications of
effective anti-viral therapy
Jennifer A. Flemming, W. Ray Kim, Carol Brosgart, Norah Terrault
4:00 PM
23: Sofosbuvir/Daclatasvir Therapy for Recurrent
Hepatitis C after Liver Transplantation: Preliminary
report from the parisian centers
Filomena Conti, Pascal Lebray, Astris Schielke, Helene Regnault,
Dominique Thabut, Daniel Eyraud, Armelle Poujol-Robert, Olivier
Chazouillères, Yvon Calmus
 54A AASLD PROGRAM
4:15 PM
24: Therapeutic misadventure with acetaminophen:
prospective evaluation of prerequisites, characteristics
and outcome
Alexandre Louvet, Charlotte Vanveuren, Sébastien Dharancy,
Amélie Cannesson, Florent Artru, Guillaume Lassailly, Valerie
Canva-Delcambre, Philippe Mathurin
Parallel 3: Basic Mechanisms of Liver
Fibrosis
Sunday, November 9
NOVEMBER 9
3:00 - 4:30 PM Sheraton, Republic Ballroom
SUNDAY
MODERATORS: Laurie D. DeLeve, MD, PhD
Neil C. Henderson, MBChB, BSc, PhD
3:00 PM
25: Hepatocyte-derived extracellular vesicles
released during lipotoxicity regulate hepatic stellate
cell phenotype via delivery of specific miRNAs and
modulation of PPAR-γ expression
Davide Povero, Nadia Panera, Akiko Eguchi, Anna Alisi, Valerio
Nobili, Ariel E. Feldstein
3:15 PM
26: Sphingosine kinase containing exosomes regulate
hepatic stellate cell activation
Ruisi Wang, Sheng Cao, Usman Yaqoob, Thiago de Assuncao,
Vijay Shah
3:30 PM
27: Deletion of fibrocytes in mice attenuates
experimental liver fibrosis
Jun Xu, Tae Jun Park, Min Cong, Xiao Liu, David A. Brenner,
Tatiana Kisseleva
3:45 PM
28: Liver Repopulation with Transplanted Liver
Sinusoidal Endothelial Cells (LSEC) Benefits From
Prior Disruption of Native Endothelial Cells as well as
Endothelin-1 Receptor Blockade in Donor Cells
Neelam Yadav, Antonia Follenzi, Ralf Bahde, Sanjeev Gupta
4:00 PM
29: Positive feedback loop between beta-catenin and
stearoyl-CoA desaturase in liver fibrosis
Soo-Mi Kweon, Keane Lai, Lan Qin, Jun Xu, Naoki Fujii, Samuel
W. French, James Ntambi, Hidekazu Tsukamoto
4:15 PM
30: VASP promotes myofibroblastic activation of
hepatic stellate cells by regulating Rab11 dependent
plasma membrane targeting of TGF-β receptors
Kangsheng Tu, Jiachu Li, Vijay Shah, Ningling Kang
HEPATOLOGY, October, 2014
Parallel 4: Cholestatic and Autoimmune
Liver Diseases
Sunday, November 9
3:00 - 4:30 PM Room 302
MODERATORS: Elizabeth J. Carey, MD
Marlyn J. Mayo, MD
3:00 PM
31: Does “genuine” acute autoimmune hepatitis have a
better prognosis?
Elze M. Oliveira, Ana Cristina A. Feldner, Patricia M. Oliveira,
Valéria P. Lanzoni, Renata M. Perez, Antonio Eduardo B. Silva,
Maria Lucia Ferraz
3:15 PM
32: Patients with Autoimmune Hepatitis and Advanced
Disease have Less Biochemical Response and Worse
Outcomes
James R. Bailey, Gouri Sreepati, Eric S. Orman, Raj Vuppalanchi,
Samer Gawrieh, Marwan Ghabril, Suthat Liangpunsakul, Naga P.
Chalasani, Craig Lammert
3:30 PM
33: Non-classical autoantibodies in Autoimmune
Hepatitis and Overlapping Syndromes: Do they
contribute with any relevant information?
Elze M. Oliveira, Patricia M. Oliveira, Ana Cristina A. Feldner,
Valéria P. Lanzoni, Renata M. Perez, Alessandra Dellavance,
Luis Eduardo C. Andrade, Antonio Eduardo B. Silva, Maria Lucia
Ferraz
3:45 PM
34: Depletion of B cells induce remission of autoimmune
hepatitis in mice through reduced antigen presentation
and help to T cells
Kathie Béland, Gabriel Marceau, Agathe Labardy, Sara
Bourbonnais, Fernando Alvarez
4:00 PM
35: A Preliminary Study Utilizing Social Media and
Crowdsourcing Shows an Inverse Relationship Between
Breast Feeding as an Infant and the Presence of
Autoimmune Hepatitis
Megan Comerford, Smitha Marri, Naga P. Chalasani, Craig
Lammert
4:15 PM
36: Predictors of Autoimmune Hepatitis in Patients with
Chronic Hepatitis C
Yun Ju Kim, Anthony Loria, Xiongce Zhao, David E. Kleiner, Marc
G. Ghany
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
Parallel 5: Experimental
Hepatocarcinogenesis
Sunday, November 9
3:00 - 4:30 PM Sheraton, Back Bay Ballroom C
MODERATORS: Jack R. Wands, MD
Ekihiro Seki, MD, PhD
3:00 PM
37: Liver carcinogenesis related to the metabolic
syndrome: Metformin as a new therapeutic tool
François Cauchy, Mouniya Mebarki, Pierre Bourgoin, Cindy
Neuzillet, Samira Laouirem, Miguel Albuquerque, Nicolas Poté,
Jacques Belghiti, Eric Raymond, Pierre Bedossa, Valerie Paradis
3:15 PM
38: Preclinical evidence of a novel anti-tumor effect of
metformin in cholangiocarcinoma (CCA)
Albert Ndzengue, Hassan M. Shaleh, Xiwei Ding, Kais Zakharia,
Catherine D. Moser, Scott H. Kaufmann, Martin E. Fernandez-
Zapico, Mitesh J. Borad, Roongruedee Chaiteerakij, Lewis R.
Roberts
3:30 PM
39: Molecular heterogeneity of multinodular
Hepatocellular Carcinoma
Daniela Sia, Andrew Harrington, Sara Toffanin, Zhongyang
Zhang, Xintong Chen, M. Isabel Fiel, Monica Higuera, Oriana
Miltiadous, Laia Cabellos, Helena Cornella, Sasan Roayaie, Yujin
Hoshida, Sander S. Florman, Myron Schwartz, Josep M. Llovet
3:45 PM
40: NGM282, a Potent Inhibitor of CYP7A1, Prevents
FGF19-Mediated HCC Tumor Development in db/db
and rasH2 Mice
Lei Ling, Van Phung, Xueyan Wang, Mei Zhou, Darrin Lindhout,
Marc Learned, Stephen Rossi, Alex M. DePaoli, Hui Tian
4:00 PM
41: Nardilysin deficiency attenuates promotion of
hepatocellular carcinoma through suppressing the
interleukin 6 signaling pathway
Kan Toriguchi, Eiichiro Nishi, Etsuro Hatano, Kazutaka Tanabe,
Kenji Takemoto, Satoru Seo, Kojiro Taura, Shinji Uemoto
4:15 PM
42: Predicting HCC Biological Behavior With In Vivo
Cirrhotic Mouse Model For Personalized Treatment
Daniel Huang, Lei Zhou, Alfred W. Kow, Krishnakumar Madhavan,
Shridhar G. Iyer, Stephen Chang, Yock Young Dan
55A
Parallel 6: Hepatitis C: Currently
Approved Drugs
Sunday, November 9
3:00 - 4:30 PM Auditorium
MODERATORS: Kris V. Kowdley, MD
Stevan A. Gonzalez, MD
3:00 PM
43: L159F and V321A Sofosbuvir Treatment-Emergent
HCV NS5B Substitutions
Evguenia S. Svarovskaia, Hadas Dvory-Sobol, Brian Doehle,
NOVEMBER 9
Edward J. Gane, Ira M. Jacobson, David R. Nelson, Eric Lawitz,
SUNDAY
Diana M. Brainard, John G. McHutchison, Michael D. Miller,
Hongmei Mo
3:15 PM
44: Effects of Sustained Virological Response (SVR) on
the risk of liver transplant, hepatocellular carcinoma,
death and re-infection: meta-analysis of 129 studies in
23,309 patients with Hepatitis C infection
Andrew M. Hill, Jawaad Saleem, Katherine A. Heath, Bryony
Simmons
3:30 PM
45: Safety and Efficacy of Sofosbuvir-Containing
Regimens for Hepatitis C: Real-World Experience in a
Diverse, Longitudinal Observational Cohort
Donald M. Jensen, Jacqueline G. O’Leary, Paul J. Pockros, Kenneth
E. Sherman, Paul Y. Kwo, Mark E. Mailliard, Kris V. Kowdley,
Andrew J. Muir, Rolland C. Dickson, Ananthakrishnan Ramani,
Michael P. Manns, Anna S. Lok, Lucy Akuskevich, David R. Nelson,
Michael W. Fried
3:45 PM
46: Evaluation of sofosbuvir and simeprevir-based
regimens in the TRIO network: academic and
community treatment of a real-world, heterogeneous
population
Douglas Dieterich, Bruce R. Bacon, Steven L. Flamm, Kris V.
Kowdley, Scott Milligan, Naoky Tsai, Zobair Younossi, Eric Lawitz
4:00 PM
47: Interferon-α plus ribavirin therapy yields 98%
sustained virologic response in children aged 1-5 years
with unsafe injection-acquired chronic hepatitis C
Shishu Zhu, Fu-Sheng Wang, Qing-Lei Zeng, Yi Dong, Zhiqiang
Xu, Limin Wang, Dawei Chen, Yu Gan, Fuchuan Wang, Jianguo
Yan, Lili Cao, Pu Wang, Xue-Xiu Zhang, Hongfei Zhang
4:15 PM
48: Cerebral MR spectroscopy and patient-reported
mental health outcomes in hepatitis C genotype 1 naïve
patients treated with ledipasvir and sofosbuvir
David Alsop, Zobair Younossi, Maria Stepanova, Nezam H.
Afdhal
 56A AASLD PROGRAM
Parallel 7: Mechanisms of
Hepatotoxicity
Sunday, November 9
3:00 - 4:30 PM Room 210
MODERATOR: Juliane I. Beier, PhD
Natalia Nieto, PhD
3:00 PM
49: JNK mediation of acetaminophen (APAP)
hepatotoxicity is determined by Sab (SH3BP5)
dependent dysregulation of intramitochondrial c-Src
NOVEMBER 9
kinase
SUNDAY
Sanda Win, Tin A. Than, Neil Kaplowitz
3:15 PM
50: NMDA Receptor Activity Contributes in Cellular DNA
Damage Following Acetaminophen Hepatotoxicity and
Offers Directions for Therapeutic Development
Nicole Pattamanuch, Preeti Viswanathan, Sylvia O. Suadicani,
David C. Spray, Sanjeev Gupta
3:30 PM
51: Lysosomal Cholesterol Accumulation Sensitizes To
Acetaminophen Hepatotoxicity By Impairing Mitophagy
Anna Baulies, Susana Nuñez, Vicent Ribas, Sandra Torres, Laura
Martinez, Neil Kaplowitz, Carmen Garcia-Ruiz, Jose Fernandez-
Checa
3:45 PM
52: Depletion of hepatic stellate cells abrogates
Concanavalin A-induced liver injury
Ashish Tandon, Anil Dangi, Sudhir Kumar, Jiang Wang,
Chandrashekhar R. Gandhi
4:00 PM
53: EPAC activation and glycogen synthase kinase
beta inhibition are cytoprotective in an in vivo model of
cholestasis
Cynthia Leveille-Webster, Andrea Johnston, Mohammed S. Anwer
4:15 PM
54: Loss of Grb2-associated binder 1 results in
enhanced hepatocyte necrosis and high mortality in
mice with acute liver failure
Kunimaro Furuta, Yuichi Yoshida, Takashi Kizu, Satoshi Ogura,
Mayumi Egawa, Norihiro Chatani, Yoshihiro Kamada, Shinichi
Kiso, Tetsuo Takehara
HEPATOLOGY, October, 2014
Parallel 8: Novel Approaches in
Diagnosis and Treatment in NAFLD and
NASH
Sunday, November 9
3:00 - 4:30 PM Room 304/306
MODERATORS: Mary E. Rinella, MD
Marc G. Ghany, MD, MHSc
3:00 PM
55: Antisteatotic Efficacy and Safety of the Liver X
Receptor alpha Inhibitor, Dithiolethione in Patients with
Nonalcoholic Fatty Liver Disease
Won Kim, June Sung Lee, Chun Kyon Lee, Jong Eun Yeon, Byeong
Gwan Kim, Yoon Jun Kim
3:15 PM
56: NASH Resolution is Associated with Improvements
in HDL and Triglycerides But Not in LDL or Non-HDL-C
Kathleen Corey, Raj Vuppalanchi, Laura Wilson, Oscar Cummings,
Naga P. Chalasani
3:30 PM
57: Early phase 1 clinical trial results of GR-MD-02, a
galectin-3 inhibitor, in patients having non-alcoholic
steatohepatitis (NASH) with advanced fibrosis
Stephen A. Harrison, Naga P. Chalasani, Eric Lawitz, Smitha
Marri, Mazen Noureddin, Arun J. Sanyal, Thomas D. Schiano,
Mohammad S. Siddiqui, Brent A. Neuschwander-Tetri, Peter G.
Traber
3:45 PM
58: Novel MRI and MRE in ezetimibe versus placebo
for the treatment of nonalcoholic steatohepatitis:
Randomized-controlled trial (MOZART Trial)
Rohit Loomba, Claude B. Sirlin, Brandon Ang, Ricki Bettencourt,
Rashmi Jain, Joanie Salotti, Linda M. Soaft, Jonathan Hooker,
Yuko Kono, Archana Bhatt, Laura D. Hernandez, Phirum Nguyen,
Mazen Noureddin, William Haufe, Catherine A. Hooker, Meng
Yin, Richard Ehman, Grace Y. Lin, Mark A. Valasek, David A.
Brenner, Lisa Richards
4:00 PM
59: The prognostic relevance of liver histology features
in nonalcoholic fatty liver disease: the PRELHIN study
Paul Angulo, David E. Kleiner, Sanne Dam-Larsen, Leon Adams,
Bjornsson S. Einar, Phunchai Charatcharoenwitthaya, Peter R.
Mills, Jill C. Keach, Svanhildur Haflidadottir, Flemming Bendtsen
4:15 PM
60: Metabolomic analysis identifies new biomarkers of
liver damage in NAFLD
Ester Vanni, Chiara Rosso, Lavinia Mezzabotta, Chiara Saponaro,
Melania Gaggini, Roberto Gambino, Ramy Ibrahim Kamal Jouness,
Francesca Saba, Emma Buzzigoli, Fabrizia Carli, Gian Paolo
Caviglia, Maria Lorena Abate, Antonina Smedile, Mario Rizzetto,
Maurizio Cassader, Amalia Gastaldelli, Elisabetta Bugianesi
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
Parallel 9: Tissue Damage in Liver
Diseases and Inflammatory and Viral
Sunday, November 9
3:00 - 4:30 PM Room 311
MODERATORS: Barbara Rehermann, MD
Jacquelyn J. Maher, MD
3:00 PM
61: HCV hijacks host exosomes for mediating
alternative active viral transmission and disease
persistence
Terence N. Bukong, Fatemah Momen-Heravi, Karen Kodys, Shashi
Bala, Gyongyi Szabo
3:15 PM
62: Dynamic Association of DDX3X with Stress Granules
and Lipid Droplets in Hepatocytes Confers Multiple
Functions of DDX3X in Hepatitis C Virus Infection
Veronique Pene, Qisheng Li, Catherine Sodroski, Ching-Sheng
Hsu, T. Jake Liang
3:30 PM
63: Interleukin-17 favors progenitor cell proliferation
and differentiation in regenerating liver through IL-27/
WSX-1 axis
Adrien Guillot, Nabila Hamdaoui, Julien Calderaro, Jean-Michel
Pawlotsky, Sophie Lotersztajn, Fouad Lafdil
3:45 PM
64: Patients with alcoholic hepatitis present strong Th1
cellular immune responses to alcohol dehydrogenase,
which are related to impairment of the PD-1/PD-L1
pathway
Laura J. Blackmore, Jennifer M. Ryan, Godhev K. Manakkat
Vijay, Xiaohong Huang, Charalambos G. Antoniades, Debbie
Shawcross, Yun Ma
4:00 PM
65: Blockage of CCL5/RANTES modifies immune
infiltration and the inflammatory milieu during chronic
liver disease
Antje Mohs, Francisco Javier Cubero, Nadine Kuttkat, Christian
Trautwein
4:15 PM
66: Inflammatory liver injury is associated with
altered alkaline phosphatase activity and hepatic
asialoglycoprotein receptor function
David P. Newton, Dean J. Tuma, Carol A. Casey, Benita L.
McVicker
57A
Parallel 10: HBV Diagnostics,
Epidemiology, Prevention, Natural
History
Sunday, November 9
4:45 - 6:15 PM Room 312
MODERATORS: Carol L. Brosgart, MD
Edward Doo, MD
4:45 PM
67: Multiplex PCR Assay for Simultaneous Detection of
NOVEMBER 9
Genomes of Hepatitis A, B, C, D and E Viruses
SUNDAY
Maja Kodani, Tonya Mixson-Hayden, Jan Drobeniuc, Saleem
Kamili
5:00 PM
68: Serologic Testing Rates among US Veterans with
Hepatitis B
Marina Serper, Kimberly A. Forde, David E. Kaplan
5:15 PM
69: Longitudinal serologic profiles up to 5 years in
hepatitis B surface antigen-negative chronic hepatitis B
Wai-Kay Seto, Yasuhito Tanaka, Danny Wong, Noboru Shinkai,
Ka-Shing Cheung, Sze Hang Kevin Liu, James Fung, Ching-Lung
Lai, Man-Fung Yuen
5:30 PM
70: Decades after recovery from acute hepatitis B virus
(HBV) infection the CD8+ T cell response against HBV
core is nearly undetectable
Helenie Kefalakes, Christoph Jochum, Gudrun Hilgard, Alisan
Kahraman, Anna M. Bohrer, Nicolai El Hindy, Guido Gerken,
Michael Roggendorf, Joerg Timm
5:45 PM
71: Primary resistance to HBV in a large population of
treatment-naive patients
Stephane Chevaliez, Christophe Rodriguez, Lila Poiteau,
Alexandre Soulier, Philippe Chevallier, Vincent Leroy, Veronique
Brodard, Cecile Brouard, Christine Larsen, Caroline Semaille,
Jean-Michel Pawlotsky
6:00 PM
72: Reactivation of Hepatitis B (HBV) in Patients Treated
with Anti-Tumor Necrosis Factor (anti-TNF) Agents
Mary Patricia Pauly, Lue-Yen Tucker, Jean-Luc Szpakowski, David
Baer, Joanna B. Ready, Jessica P. Hwang, Anna S. Lok
 58A AASLD PROGRAM
Parallel 11: Hepatitis C: Health
Economics and Cost-Effectiveness
Sunday, November 9
4:45 - 6:15 PM Room 304/306
MODERATORS: Fasiha Kanwal, MD
Curt H. Hagedorn, MD
4:45 PM
73: Projected Health and Economic Impact of Hepatitis
C on the United States Medicare System From 2010 to
2024
NOVEMBER 9
David B. Rein, John S. Wittenborn, Danielle Liffmann, Joshua M.
SUNDAY
Borton
5:00 PM
74: Minimum target prices for production of Direct
Acting Antivirals and associated diagnostics for
developing countries
Andrew M. Hill, Nikolien S. van de Ven, Bryony Simmons, Nathan
Ford, Saye H. Khoo, Joseph M. Fortunak
5:15 PM
75: Cost-Effectiveness of Novel Hepatitis C Drug
Regimens Among Treatment-Experienced U.S. Veterans
Alexis P. Chidi, Shari S. Rogal, Cindy L. Bryce, Michael J. Fine,
Chester B. Good, Larissa Myaskovsky, Vinod K. Rustgi, Allan
Tsung, Kenneth J. Smith
5:30 PM
76: Clinical efficacy of highly effective interferon-free
therapy in patients with chronic HCV infection and
compensated advanced hepatic fibrosis
Adriaan J. van der Meer, Raoel Maan, Jordan J. Feld, Heiner
Wedemeyer, Giovanna Fattovich, Jean-Francois Dufour, Frank
Lammert, Andres Duarte-Rojo, Michael P. Manns, Stefan Zeuzem,
Wolf P. Hofmann, Donatella Ieluzzi, Robert J. de Knegt, Bettina E.
Hansen, Bart J. Veldt, Harry L. Janssen
5:45 PM
77: Treatment with Interferon (IFN) and Ribavirin (RBV)-
Free Regimens with Ledipasvir (LDV) and Sofosbuvir
(SOF) Improves Patient-Reported Outcomes (PRO) for
Patients with Genotype 1 (GT1) Chronic Hepatitis C (CH-
C): Results from the ION-1,2 and 3 Clinical Trials
Zobair Younossi, Maria Stepanova, Patrick Marcellin, Nezam H.
Afdhal, Kris V. Kowdley, Stefan Zeuzem, Sharon L. Hunt
6:00 PM
78: Direct Care Costs for Hepatocellular Carcinoma in
patients with Hepatitis C cirrhosis
Andreea M. Catana, Daniel Mansuri, Nidhi Sethi, Annie Vong,
Saurabh Sethi, Nezam H. Afdhal
HEPATOLOGY, October, 2014
Parallel 12: Hepatitis C: New Agents -
Part 1
Sunday, November 9
4:45 - 6:15 PM Auditorium
MODERATORS: Hugo E. Vargas, MD
Jordan J. Feld, MD, MPH
4:45 PM
79: Once Daily Sofosbuvir with GS-5816 for 8 Weeks
with or without Ribavirin In Patients with HCV Genotype
3 without Cirrhosis Result in High Rates of SVR12: The
ELECTRON2 Study
Edward J. Gane, Robert H. Hyland, Di An, John McNally, Diana
M. Brainard, William T. Symonds, John G. McHutchison, Catherine
A. Stedman
5:00 PM
80: Safety and Efficacy of Treatment with
Sofosbuvir+GS-5816±Ribavirin for 8 or 12 Weeks
in Treatment Naïve Patients with Genotype 1-6 HCV
Infection
Tram T. Tran, Timothy R. Morgan, Paul J. Thuluvath, Kyle Etzkorn,
Federico Hinestrosa, Myron Tong, John McNally, Diana M.
Brainard, Lingling Han, Brian Doehle, Erik Mogalian, John G.
McHutchison, Raymond T. Chung, Gregory T. Everson
5:15 PM
81: TURQUOISE-II: Regimens of ABT-450/r/Ombitasvir
and Dasabuvir With Ribavirin Achieve High SVR12
Rates in HCV Genotype 1-Infected Patients with
Cirrhosis, Regardless of Baseline Characteristics
Michael W. Fried, Xavier Forns, Nancy Reau, Heiner Wedemeyer,
Mitchell L. Shiffman, Angeles Castro, David J. Mutimer, Samuel
S. Lee, Roger Trinh, Sandra S. Lovell, Leticia Canizaro, Marcos
Pedrosa, Thomas Berg
5:30 PM
82: An Integrated Safety and Efficacy Analysis of >500
Patients with Compensated Cirrhosis Treated with
Ledipasvir/Sofosbuvir with or without Ribavirin
Marc Bourlière, Mark S. Sulkowski, Masao Omata, Stefan
Zeuzem, Jordan J. Feld, Eric Lawitz, Patrick Marcellin, Robert H.
Hyland, Xiao Ding, Jenny C. Yang, Steven J. Knox, Phillip S. Pang,
Mani Subramanian, William T. Symonds, John G. McHutchison,
Alessandra Mangia, Edward J. Gane, K. Rajender Reddy, Masashi
Mizokami, Stanislas Pol, Nezam H. Afdhal
5:45 PM
83: Integrated Efficacy Analysis of Four Phase 3 Studies
in HCV Genotype 1a-Infected Patients Treated with
ABT-450/r/Ombitasvir and Dasabuvir With or Without
Ribavirin
Gregory T. Everson, Geoffrey Dusheiko, Eoin Coakley, Stephen
D. Shafran, Fabien Zoulim, Moises Diago, Bradley Freilich, Ravi
Ravinuthala, Suzanne Norris, Junyuan J. Xiong, Roger Trinh, Tolga
Baykal, Yan Luo, Mark S. Sulkowski
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
6:00 PM
84: High Efficacy of Sofosbuvir/Ledipasvir for the
Treatment of HCV Genotype 1 in Patients Coinfected
With HIV on or off Antiretroviral therapy: Results from
The NIAID ERADICATE Trial
Kerry S. Townsend, Anu Osinusi, Amy K. Nelson, Anita Kohli,
Chloe Gross, Michael A. Polis, Phillip S. Pang, Mohammad M.
Sajadi, Mani Subramanian, John G. McHutchison, Henry Masur,
Shyam Kottilil
Parallel 13: Machine Perfusion and
Cellular Therapy
Sunday, November 9
4:45 - 6:15 PM Room 309
MODERATORS: Oren K. Fix, MD, MSc
Goran Klintmalm, MD, PhD
4:45 PM
85: Sub-normothermic machine perfusion preservation
for graft selection and therapy in a mouse liver
transplantation model
Masato Fujiyoshi, Akinobu Taketomi
5:00 PM
86: A thyroid hormone receptor beta-selective T3
analog promotes liver repopulation in apolipoprotein
E-deficient mice, correcting hypercholesterolemia
Wei Zhang, Patrik Asp, Bhavapria Vaitheesvaran, Laibin Liu, Rafi
Kabarriti, Hillary Yaffe, Rani Sellers, Namita Roy-Chowdhury,
Jayanta Roy-Chowdhury, Markus Grompe, Thomas Scanlan,
Chandan Guha
5:15 PM
87: Controlled processing of a full-size porcine liver to a
decellularized matrix for tissue engineering
Nicola Buehler, Martin Schenk
5:30 PM
88: Transplantation of human fetal biliary tree stem/
progenitor cells into two patients with advanced liver
cirrhosis
Vincenzo Cardinale, Guido Carpino, Raffaele Gentile, Chiara
Napoletano, Hassan Rahimi, Antonio Franchitto, Rossella
Semeraro, Marianna Nuti, Paolo Onori, Pasquale Bartolomeo
Berloco, Massimo Rossi, Daniela Bosco, Roberto Brunelli, Alice
Fraveto, Cristina Napoli, Alessia Torrice, Manuela Gatto, Rosanna
Venere, Carlo Bastianelli, Camilla Aliberti, Filippo Maria Salvatori,
Adolfo F. Attili, Lola M. Reid, Eugenio Gaudio, Domenico Alvaro
59A
5:45 PM
89: Decellularized Human Liver as a Natural 3D
Scaffold for Organ Engineering and 3D-Disease
Modeling
Giuseppe Mazza, Krista Rombouts, Andrew R. Hall, Luca Urbani,
Lisa Longato, Alan M. Holmes, Panagiotis Maghsoudlou, Robert
Good, Amar P. Dhillon, Barry Fuller, Brian Davidson, Dipok K.
Dhar, Paolo De Coppi, Massimo M. Malago’, Massimo Pinzani
6:00 PM
90: Lymphocyte cell adhesion molecule L-selectin plays
a dynamic role in ischemia reperfusion injury of a
steatotic liver
NOVEMBER 9
Vasantha L. Kolachala, Abramowsky Carlos, Ming Shen, Alayna
SUNDAY
Feng, Allan D. Kirk, Nitika A. Gupta
Parallel 14: Outcomes in Cirrhosis
Sunday, November 9
4:45 - 6:15 PM Ballroom A/B/C
MODERATORS: Florence Wong, MD
Patrick G. Northup, MD, MHS
4:45 PM
91: Benefit of Paracentesis on In-hospital Mortality
Among Adults Admitted with Cirrhosis and Ascites
John N. Gaetano, Dejan Micic, Archita P. Desai, Andrew
Aronsohn, Nancy Reau, Helen S. Te, K. Gautham Reddy, Donald
M. Jensen
5:00 PM
92: Pathogenesis and clinical impact of relative
adrenal insufficiency in hospitalized patients with acute
decompensation of cirrhosis
Salvatore Piano, Elisa Favaretto, Silvano Fasolato, Carla Scaroni,
Elisabetta Gola, Alessandra Brocca, Antonietta Sticca, Filippo
Morando, Marta Cavallin, Antonietta Romano, Giacomo Zanus,
Angelo Gatta, Umberto Cillo, Paolo Angeli
5:15 PM
93: Prediction of Subclinical Coronary Atherosclerosis
Based on Coronary Calcification in Cirrhotic Candidates
for Liver Transplantation
Jihyun An, Ju Hyun Shim, Young-Suk Lim, Kang Mo Kim, Han Chu
Lee, Jonggi Choi, Gi-Ae Kim, Hyung-Don Kim, Young Joo Yang,
Yeonjung Ha, Mi-Jung Jun, Jee Eun Yang, Young-Hwa Chung,
Yung Sang Lee, Dong Jin Suh
5:30 PM
94: Hepatic Encephalopathy is Associated with
Persistent Cognitive Deficits Despite Adequate Medical
Treatment: A Multi-center, International Study
Silvia Nardelli, Sanath Allampati, Nicole Noble, Oliviero Riggio,
Kevin D. Mullen, Eugenia Onori, Ravi Prakash, Stefania Gioia,
Ariel Unser, Melanie White, Edith A. Gavis, Jasmohan S. Bajaj
 60A AASLD PROGRAM
5:45 PM
95: Facility and patient level predictors of endoscopic
variceal screening within the largest integrated
healthcare system in the United States
Varun Saxena, Jennifer A. Flemming, Hui Shen, Norah Terrault,
Alexander Monto, Catherine Rongey
6:00 PM
96: Changes on hepatic venous pressure gradient
induced by a physical exercise program in cirrhotic
patients: a randomized open clinical trial
Ricardo Macías-Rodríguez, Aldo Torre, Hermes Ilarraza-Lomelí,
Astrid Ruiz-Margáin, Octavio García-Flores, Andres Duarte-Rojo
NOVEMBER 9
SUNDAY
Parallel 15: Steatohepatitis:
Experimental
Sunday, November 9
4:45 - 6:15 PM Room 311
MODERATORS: Frank A. Anania, MD, FACP,
AGAF
Shelly C. Lu, MD
4:45 PM
97: Compromised intestinal epithelial barrier function
is a major contributor in the progression of diet
induced non-alcoholic fatty liver disease (NAFLD) to
steatohepatitis (NASH) and is driven primarily by innate
immune activation
Khalidur Rahman, Natalie Thorn, Pradeep Kumar, Asma Nusrat,
Charles A. Parkos, Frank A. Anania
HEPATOLOGY, October, 2014
5:00 PM
98: Mmu-miR-615-3p REGULATES LIPOAPOPTOSIS BY
INHIBITING C/EBP HOMOLOGOUS PROTEIN
Yasuhiro Miyamoto, Amy S. Mauer, Harmeet Malhi
5:15 PM
99: Impaired macrophage autophagy triggers
steatohepatitis in obese mice by promoting
proinflammatory macrophage polarization
Kun Liu, Enpeng Zhao, Ghulam Ilyas, Gadi Lalazar, Yu Lin, Kathryn
Tanaka, Mark J. Czaja
5:30 PM
100: Phosphatidylcholine Transfer Protein (PC-TP) and
Thioesterase Superfamily Member 2 (Them2) Promote
Endoplasmic Reticulum (ER) Stress by Increasing Acyl
Chain Saturation of Membrane Phospholipids and
Depleting Calcium
Baran A. Ersoy, Kristal M. Maner-Smith, Yingxia Li, Ipek
Alpertunga, David E. Cohen
5:45 PM
101: Fibroblast growth factor 21 treatment improves
atherogenic diet-induced liver injury and metabolic
syndrome in Ossabaw miniature swine
Samer Gawrieh, Mouhamad Alloosh, Rachel M. Sheridan, Tiebing
Liang, Howard C. Masuoka, Naga P. Chalasani, Michael Sturek
6:00 PM
102: Micro RNA 21 inhibition of SMAD 7 enhances
fibrogenesis via leptin mediated NADPH oxidase in
experimental nonalcoholic steatohepatitis
Diptadip Dattaroy, Ratanesh K. Seth, Suvarthi Das, Sahar
Pourhoseini, Mitzi Nagarkatti, Gregory A. Michelotti, Anna Mae
Diehl, Saurabh Chatterjee
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM 61A

SIG Program
Sunday, November 9 4:45 - 4:50 PM Introduction
Guruprasad P. Aithal, MD, PhD and
4:45 - 6:45 PM Room 210
Robert J. Fontana, MD
Pharmacogenomic Approaches in DILI Research 4:50 - 5:10 PM GWAS and Exome Chips in DILI:
What Have We Learned?
Sponsored by the Hepatotoxicity SIG Thomas J. Urban, PharmD, PhD

MODERATORS: Guruprasad P. Aithal, MD, PhD 5:10 - 5:15 PM Discussion

Robert J. Fontana, MD 5:15 - 5:35 PM Use of Whole Genome and Whole
Exome Approaches in DILI Research
Drug induced liver injury remains a vexing problem to clinicians, Mark Daly, PhD

NOVEMBER 9
scientists, regulators, and drug developers due to its unpredictable
5:35 - 5:40 PM Discussion

SUNDAY
nature and yet potential for significant morbidity and mortality.
High throughput genome wide association chips and platforms 5:40 - 6:00 PM HLA Genetic Polymorphisms in
provide a unique tool to discover potential genetic associations Adverse Drug Reactions: Molecular
for DILI and other rare ADR’s. Recent studies have demonstrated Mechanisms
strong and consistent associations in DILI susceptibility to individual Guruprasad P. Aithal, MD, PhD
drugs and various HLA alleles. It remains unclear if use of whole 6:00 - 6:05 PM Discussion
genome or whole exome approaches may further facilitate the 6:05 - 6:25 PM Use of Epigenetics in DILI Research
discovery of mechanistically relevant genetic associations. The aim Mujdat Zeybel, MD
of this 2 hour SIG Program will be to provide an update on the 6:25 - 6:35 PM Discussion
current and future use of pharmacogenomic approaches to DILI
6:35 - 6:45 PM Wrap-up
pathogenesis.

Learning Objectives:
Upon completion of this activity, participants will be able to:
• Review use of genome wide association chips and methods with
susceptibility to DILI from individual agents.
• Improve the role of HLA polymorphisms in DILI susceptibility and
potential molecular mechanisms.
• Apply epigenetic research principles in liver disease research
including DILI.
 62A AASLD PROGRAM HEPATOLOGY, October, 2014

SIG Program
Sunday, November 9 4:45 - 4:50 PM Introduction
Morris Sherman, MD, PhD and Elizabeth
4:45 - 7:00 PM Sheraton, Back Bay Ballroom C
M. Brunt, MD
Primary Liver Carcinomas with Intermediate/Stem Cell 4:50 - 5:10 PM Stem Cells and Hepatobiliary
Features - Microscopic to Genomic Evidence and Back Carcinogenesis: Theory, Definitions,
and Historical Findings
Sponsored by the Hepatobiliary Neoplasia SIG Neil D. Theise, MD
5:10 - 5:20 PM Discussion
MODERATORS: Morris Sherman, MD, PhD
Elizabeth M. Brunt, MD 5:20 - 5:40 PM Current Perspectives in Diagnosis:
Views from Pathology and Radiology
NOVEMBER 9

Addressing the need for a more widespread understanding of the Pathology

SUNDAY

pathways that lead to the development of hepatocellular carci- Valerie Paradis, MD, PhD
noma (HCC), this program will highlight new developments and
5:40 - 5:50 PM Discussion
current understanding of the role of stem cells in the development
of hepatocellular carcinoma and how this may affect treatments. 5:50 - 6:10 PM Gen- and Other –Omics: What is the
Evidence Showing?
Snorri S. Thorgeirsson, MD, PhD
Learning Objectives:
6:10 - 6:20 PM Discussion
Upon completion of this activity, participants will be able to:
6:20 - 6:40 PM Therapeutics for Primary Liver
• Discuss the pathogenesis of the development of intermediate
Carcinomas with Intermediate/Stem
forms of liver cancer, including those that have stem cell fea-
Cell Features: Current and Proposed
tures.
Options in an Era of Targeted
• Recognize how pathology affects treatment decisions. Therapy
Peter Schirmacher, MD
6:40 - 6:50 PM Discussion
6:50 - 7:00 PM Wrap-up
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM 63A

SIG Program
Sunday, November 9 4:45 - 4:50 PM Introduction
4:45 - 7:00 PM Room 302 4:50 - 5:10 PM PSC Presentation and Management:
Differences Between Adults and
Controversies in the Management of Primary Sclerosing Children
Cholangitis in Children and Adults Giorgina Mieli-Vergani, MD, PhD
5:10 - 5:25 PM Genetic Links in PSC: New
Sponsored by the Pediatric Liver Disorders, and Cholestatic Liver Discoveries
Disorders SIGs Tom H. Karlsen, MD, PhD
MODERATORS: Cara Mack, MD 5:25 - 5:45 PM Challenges in the Diagnosis
David N. Assis, MD and Treatment of PSC-related

NOVEMBER 9
Tom H. Karlsen, MD, PhD Cholangiocarcinoma

SUNDAY
Gregory J. Gores, MD
Primary Sclerosing Cholangitis (PSC) is a progressive biliary dis-
5:45 - 5:55 PM Panel Discussion
ease that affects children and adults, often resulting in liver trans-
plantation. The cause of PSC is incompletely understood and there 5:55 - 6:10 PM Liver Transplantation and PSC:
are no effective therapies for this disease, leading to controversies
Management of Immunosuppression
in Children and Adults
in the management of patients with PSC. Furthermore, difference
Tamir A. Miloh, MD
in clinical presentation and treatment exists between children and
adults, and hepatologists from both fields have the potential to 6:10 - 6:25 PM Liver Transplantation and PSC:
gain insight into the disease through understanding these differ- Controversies in Diagnosis and
ences. The goal of this symposium is to educate the audience on Management of Recurrent Disease
recent areas of advancement and debate in PSC. This program
and Colitis
Annika Bergquist, MD
is distinctive in that PSC experts from both pediatrics and adult
care will converge to discuss controversies in the management of 6:25 - 6:45 PM Future Directions: Novel
PSC, resulting in the identification of new research avenues and Pharmacological Therapies for PSC
opportunities. David N. Assis, MD
6:45 - 7:00 PM Panel Discussion
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Discuss how the pediatric patient may be managed differently
than adults.
• Discover cutting edge genetic and microbiome research that
provides evidence for PSC pathogenesis and susceptibility.
• Identify controversies related to the diagnosis and treatment of
cholangiocarcinoma and post-liver transplant recurrent PSC.
• Explain potential future PSC treatment options.
 64A AASLD PROGRAM HEPATOLOGY, October, 2014

SIG Program
Sunday, November 9 4:45 - 4:50 PM Introductory Remarks
Mark A. McNiven, PhD
4:45 - 7:45 PM Sheraton, Republic Ballroom
4:50 - 5:30 PM Keynote Speaker: The Liver
The Cell Biology of Hepatic Disease Microenvironment and Stem Cell
Differentiation
Sponsored by the Liver Cell Biology in Hepatic Disease, and Liver Sangeeta Bhatia, MD, PhD
Fibrosis SIGs 5:30 - 5:40 PM Break
MODERATORS: Mark A. McNiven, PhD 5:40 - 6:20 PM Keynote Speaker: Novel Regulators
Natalie Torok, MD of Liver Development and
Allan W. Wolkoff, MD Regeneration: Swimming from Fish
NOVEMBER 9

Natalia Nieto, PhD Tank to Bedside?

SUNDAY

Yasuko Iwakiri, PhD Wolfram Goessling, MD, PhD

Mohammed S. Anwer, PhD, DMVH 6:20 - 6:45 PM Novel Regulators of Liver Fibrosis
Yasuko Iwakiri, PhD
Learning Objectives: 6:45 - 6:55 PM Break
Upon completion of this activity, participants will be able to: 6:55 - 7:20 PM Cholangiocyte Proliferation and
• Discuss how the central processes listed below are altered and Repair in Biliary Disorders
tailored to suit the highly specialized functions of the liver includ- Gianfranco Alpini, PhD
ing regeneration, bile formation, endocytic-based filtering of the 7:20 - 7:45 PM Mechanisms of Liver Inflammation
blood, secretion of essential plasma proteins, and regulation of and Damage
the extracellular matrix.    
Gregory J. Gores, MD
• Identify how hepatocellular functions are usurped and modified
during hepatic diseases such as liver fibrosis and cancer.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
Early Morning Workshops 
Monday, November 10
6:45 - 7:45 AM Refer to your ticket for meeting
room location.
Basic Early Morning Workshops
EMW-15 Management of Coagulopathies in Chronic
Liver Disease
Stephen H. Caldwell, MD and R. Todd Stravitz,
MD
EMW-16 Parenchymal and Immune Cell Interactions in
Liver Disease
Fabio Marra, MD, PhD and Laura E. Nagy, PhD
EMW-17 Autophagy in ASH and NASH
Mark J. Czaja, MD and John J. Lemasters, MD,
PhD
EMW-18 Cell Death and Sterile Inflammation in Liver
Disease
Wajahat Z. Mehal, MD and Ariel E. Feldstein, MD
EMW-19 Noncoding RNAs in Liver Disease
Gregory J. Gores, MD and Shashi Bala, PhD
EMW-20 Viral Hepatitis: Immunology in Pathogenesis
Kyong-Mi Chang, MD and Barbara Rehermann,
MD
65A
Clinical Early Morning Workshops
EMW-21 Many Faces of PFIC
Jorge A. Bezerra, MD and Binita M. Kamath,
MBBChir
EMW-22 Herbal Hepatotoxicity
Leonard B. Seeff, MD and Mark G. Clemens, PhD
EMW-23 Emerging Therapies for Management of
NASH
Naga P. Chalasani, MD and Manal F.
Abdelmalek, MD
EMW-24 2014: Clinical Update in Alcoholic Liver
Disease
Philippe Mathurin, MD, PhD and Timothy R.
Morgan, MD
EMW-25 What Else to Come in HCV Therapy?
Jean-Michel Pawlotsky, MD, PhD and Paul J.
NOVEMBER 10
Pockros, MD
MONDAY
EMW-26 NASH: Diagnosis and Management
Arthur J. McCullough, MD and Rohit Kohli, MD
EMW-27 NASH: Comorbidities
Kathleen Corey, MD, MPH and Richard Green,
MD
EMW-28 Peritransplant Management of HCV Infection
Norah Terrault, MD and Jacqueline G. O’Leary,
    MD, MPH
 66A AASLD PROGRAM HEPATOLOGY, October, 2014

Plenary Session
8:45 AM
Basic Plenary
106: SQSTM1/p62-mediated Autophagic Removal
Monday, November 10
of Acetaminophen-Protein Adducts and Damaged
8:00 - 9:30 AM Auditorium Mitochondria Protects Against Acetaminophen-Induced
Liver Injury
MODERATORS: Gyongyi Szabo, MD, PhD Hong-Min Ni, Mitchell R. McGill, Hartmut Jaeschke, Wen-Xing
J. Gregory Fitz, MD Ding

8:00 AM
103: Engineering in vitro human hepatic organoids
Mohammad R Ebrahimkhani, Patrick Guye, Nathan Kipniss,
Jeremy Velazquez, Ron Weiss, Linda Griffith
8:15 AM
9:00 AM
107: Commensal microbiota is hepatoprotective and
suppresses liver fibrosis in mice
Magdalena Mazagova, Lirui Wang, Andrew T. Anfora, Max
Wissmueller, Scott A. Lesley, Caroline Westwater, David A.
Brenner, Bernd Schnabl

104: A novel toxin responsible for outbreaks of biliary

9:15 AM
NOVEMBER 10

atresia in livestock causes lumen obstruction in a

cholangiocyte spheroid model
MONDAY

108: A hepatocyte-targeted RNAi-based treatment

Orith Waisbourd-Zinman, Christine Dang, Kyung A. Koo, John R.
Porter, Michael Pack, Rebecca G. Wells
8:30 AM
105: Mitofusin-2 is a novel target of sirtuin 1 that
enhances autophagy and confers cytoprotection against
ischemia/reperfusion injury in human and mouse livers
Thomas Biel, Joseph A. Flores-Toro, Joseph W. Dean, Min-Ho Lee,
William A. Dunn, Ivan Zendejas, Kevin E. Behrns, Jae-Sung Kim
for liver disease associated with alpha-1-antitrypsin
deficiency
Christine I. Wooddell, Keith S. Blomenkamp, Steven Kanner, Qili
Chu, Holly L. Hamilton, Darren H. Wakefield, Lauren J. Almeida,
Julia O. Hegge, Jason J. Klein, Vladimir M. Subbotin, Guofeng
Zhang, Ryan M. Peterson, Dawn R. Christianson, James Hamilton,
Jeffrey Teckman, David L. Lewis

AASLD Distinguished Awards

Monday, November 10
9:30 - 9:45 AM Auditorium
AASLD Distinguished Achievement Award
Presented to: Jules L. Dienstag, MD
Presented by: Raymond T. Chung, MD
9:45 - 10:00 AM Auditorium
AASLD Distinguished Service Award
Presented to: Sherrie H. Cathcart, CAE
Presented by: Guadalupe Garcia-Tsao, MD

   

Poster Session III Exhibit Hall

Monday, November 10 Monday, November 10
8:00 AM – 5:30 PM 9:30 AM – 3:00 PM
Hall C Hall D
Refer to page 146A for Poster Presentations
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM 67A

Hyman J. Zimmerman Hepatotoxicity State-of-the-Art Lecture

Monday, November 10 Learning Objectives:
10:00 - 10:30 AM Auditorium Upon completion of this activity, participants will be able to:

Drug-induced Liver Injury • Recognize different forms of drug-induced liver injury and distin-
guish between idiosyncratic and direct hepatotoxicity.
SPEAKER: Jay H. Hoofnagle, MD • Identify the major clinical presentations of drug-induced liver
MODERATOR: Adrian M. Di Bisceglie, MD, FACP injury and how to best make the diagnosis and identify the caus-
ative agent.
.5 CME Credit • Evaluate the severity and prognosis of liver injury due to medica-
tions.

The annual presentation of this lecture continues to recognize

Keep up with the most current research, management and preven-
tion techniques in hepatotoxicity—the single major cause of acute
liver failure in the US. Recent research findings provide insight on
how to better care for patients and, for researchers, how to better
understand the causes and mechanisms of injury in hepatotoxicity.
Dr. Zimmerman’s contributions to the field by providing valuable
insights on liver toxicity and injury. A restricted fund has been
established to support the lecture in perpetuity and AASLD grate-
fully acknowledges Eli Lilly and Company for their generous sup-
port of this program.

NOVEMBER 10
Jay H. Hoofnagle is a graduate of Yale Medical School and did

MONDAY
subsequent post-graduate training in internal medicine at the Uni-
versity of Virginia Hospital and in gastroenterology-hepatology at
the Washington DC Veterans Administration Hospital (with Profes-
sor Hyman J. Zimmerman). Dr. Hoofnagle has been a senior inves-
tigator in the Liver Diseases Section/Branch of NIDDK since 1978.
He served as the director of the Division of Digestive Diseases and
Nutrition from 1988 to 2003, and as the deputy director of the
Division and director of the Liver Disease Research Branch since
2003. He is a former president of the AASLD (1991-2), a recipient
of the AASLD Distinguished Achievement Award (2001), and is the
author of more than 400 original articles, reviews, editorials and
book chapters on liver disease.

Exhibit Hall D
10:30 – 11:00 AM
Coffee Break
 68A AASLD PROGRAM
Plenary Session
Clinical Plenary
Monday, November 10
11:00 AM - 12:30 PM Auditorium
MODERATORS: Adrian M. Di Bisceglie, MD, FACP
Gary L. Davis, MD
11:00 AM
109: A Genome-wide Association Study Identifies
THBS2 as a Candidate Modifier of Liver Disease Severity
in Alagille Syndrome
Kathleen M. Loomes, Ellen Tsai, Lara A. Underkoffler, Christopher
Grochowski, Alexandra M. Falsey, Binita M. Kamath, Henry C.
Lin, Kurt D. Hankenson, Marcella Devoto, Nancy B. Spinner
NOVEMBER 10
11:15 AM
MONDAY
110: Lifestyle intervention by a 16-week programme of
supervised diet and physical exercise ameliorates portal
hypertension in patients with cirrhosis and obesity: the
SportDiet study
Annalisa Berzigotti, Agustin Albillos, Càndid Villanueva, Joan
Genescà, Alba Ardevol, Salvador Augustin, Jose Luis Calleja,
Rafael Bañares, Juan Carlos Garcia-Pagan, Francisco Mesonero,
Jaime Bosch
11:30 AM
111: Multicenter Study of Down-staging of
Hepatocellular Carcinoma (HCC) to within Milan Criteria
before Liver Transplantation (LT)
Neil Mehta, Jennifer Guy, Catherine T. Frenette, Monika Sarkar,
Robert W. Osorio, William B. Minteer, John P. Roberts, Francis
Y. Yao
HEPATOLOGY, October, 2014
11:45 AM
112: Salivary Microbiome shows Dysbiosis comparable
to Stool Microbiome in Cirrhotic Patients with Hepatic
Encephalopathy
Jasmohan S. Bajaj, Naga Betrapally, Phillip Hylemon, Melanie
White, Douglas M. Heuman, Masoumeh Sikaroodi, Kalyani Daita,
Patrick M. Gillevet
12:00 PM
113: A prospective open label randomized
noninferiority trial to compare the efficacy and safety
of monotherapy with noradrenaline and terlipressin in
patients of cirrhosis with septic shock admitted to the
Intensive care unit (NCT01836224)
Ashok K. Choudhury, Chitranshu Vashishtha, Deepak Saini,
Sachin Kumar, Shiv K. Sarin
12:15 PM
114: Initial Report of a Large, Randomized, Double
Blind, Placebo-controlled, Phase 3 Trial of Terlipressin
plus Albumin for the Treatment of Type 1Hepatorenal
Syndrome (HRS-1): The REVERSE Study
Thomas D. Boyer, Arun J. Sanyal, Florence Wong, R Todd
Frederick, John R. Lake, Jacqueline G. O’Leary, Daniel Ganger,
Terry D. Box, Khurram Jamil, Stephen Chris Pappas
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
Advances for Practitioners
Monday, November 10
11:00 AM - 12:30 PM Ballroom ABC
New Treatments for Hepatitis C
ORGANIZER: Hugo R. Rosen, MD
1.5 CME Credits
Review a comprehensive selection of recent publications on HCV
infection with a panel of experts. Emphasis will be placed on
understanding current and emerging regimens for treatment of
HCV, as well as identifying patients at risk of developing HCV-re-
lated hepatocellular carcinoma. Discussions from each study will
address lessons learned, clinical context, and limitations.
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Discuss how to use sofosbuvir in chronic HCV infection.
• Discover new interferon-free and ribavirin-free regimens for treat-
ment of HCV infection.
• Determine which patients with HCV-related cirrhosis are at a
greater risk of developing hepatocellular carcinoma.
11:00 - 11:10 AM Introduction
Hugo R. Rosen, MD
11:10 - 11:30 AM Topic: Sofosbuvir-based therapy for
patients with HCV infection
1. Nucleotide polymerase inhibitor
sofosbuvir plus ribavirin for hepatitis
C. N Engl J Med. 2013 Jan
3;368(1):34-44. doi: 10.1056/
NEJMoa1208953. Gane EJ1,
Stedman CA, Hyland RH, Ding X,
Svarovskaia E, Symonds WT, Hindes
RG, Berrey MM.
2. Sofosbuvir for hepatitis C
genotype 2 or 3 in patients without
treatment options. N Engl J Med.
2013 May 16;368(20):1867-77.
doi: 10.1056/NEJMoa1214854.
Epub 2013 Apr 23. Jacobson IM1,
Gordon SC, Kowdley KV, Yoshida
EM, Rodriguez-Torres M, Sulkowski
MS, Shiffman ML, Lawitz E, Everson
G, Bennett M, Schiff E, Al-Assi MT,
Subramanian GM, An D, Lin M,
McNally J, Brainard D, Symonds
WT, McHutchison JG, Patel K, Feld
J, Pianko S, Nelson DR; POSITRON
Study; FUSION Study
K. Rajender Reddy, MD
11:30 - 11:55 AM Topic: New Interferon-free and
ribavirin-free regimens for treatment
of HCV infection
1. Daclatasvir plus sofosbuvir for
previously treated or untreated
chronic HCV infection. N Engl J
Med. 2014 Jan 16;370(3):211-21.
69A
doi: 10.1056/NEJMoa1306218.
Sulkowski MS1, Gardiner DF,
Rodriguez-Torres M, Reddy KR,
Hassanein T, Jacobson I, Lawitz E,
Lok AS, Hinestrosa F, Thuluvath PJ,
Schwartz H, Nelson DR, Everson
GT, Eley T, Wind-Rotolo M, Huang
SP, Gao M, Hernandez D, McPhee
F, Sherman D, Hindes R, Symonds
W, Pasquinelli C, Grasela DM;
AI444040 Study Group.
2. Efficacy of an Interferon-
and Ribavirin-Free Regimen of
Daclatasvir, Asunaprevir, and
BMS-791325 in Treatment-Naive
Patients With HCV Genotype 1
Infection. Gastroenterology 2014;
146: 420-429. Gregory T. Everson,
NOVEMBER 10
Karen D. Sims, Maribel Rodriguez–
MONDAY
Torres, Christophe Hézode, Eric
Lawitz, Marc Bourlière, Veronique
Loustaud–Ratti, Vinod Rustgi, Howard
Schwartz, Harvey Tatum, Patrick
Marcellin, Stanislas Pol, Paul J.
Thuluvath, Timothy Eley, Xiaodong
Wang, Shu–Pang Huang, Fiona
McPhee, Megan Wind–Rotolo, Ellen
Chung, Claudio Pasquinelli, Dennis
M. Grasela, David F. Gardiner.
3. Phase 2b trial of interferon-
free therapy for hepatitis C virus
genotype 1. N Engl J Med. 2014 Jan
16;370(3):222-32. doi: 10.1056/
NEJMoa1306227. Kowdley KV1,
Lawitz E, Poordad F, Cohen DE,
Nelson DR, Zeuzem S, Everson GT,
Kwo P, Foster GR, Sulkowski MS, Xie
W, Pilot-Matias T, Liossis G, Larsen L,
Khatri A, Podsadecki T, Bernstein B
Gregory T. Everson, MD
11:55 AM - 12:10 PM Topic: Predicting development of
Hepatocellular Carcinoma in Patients
With Hepatitis C
1. A New Laboratory-Based
Algorithm to Predict Development of
Hepatocellular Carcinoma in Patients
With Hepatitis C and Cirrhosis.
Gastroenterology. 2014 Jan 23.
pii: S0016-5085(14)00104-8. doi:
10.1053/j.gastro.2014.01.045.
[Epub ahead of print] El-Serag HB1,
Kanwal F2, Davila JA3, Kramer J3,
Richardson P3
James F. Trotter, MD
12:10 - 12:30 PM Discussion and Wrap-up
   
 70A AASLD PROGRAM HEPATOLOGY, October, 2014

Professional Development Workshop 

Monday, November 10 Learning Objectives:
11:45 AM - 1:15 PM Sheraton, Republic Ballroom Upon completion of this activity, participants will be able to:

Choices and Career Paths in Hepatology
MODERATORS: Meena B. Bansal, MD
Susan L. Orloff, MD, FACS
Marina G. Silveira, MD
Kymberly D. Watt, MD
1.5 CME Credits
Explore the various career trajectories within the field of hepatol-
ogy through a panel of speakers who will offer insight into the
unique obstacles and opportunities each path brings. This activity
is specifically designed for individuals who are either considering
or already pursuing a hepatology-related career. Learn about suc-
NOVEMBER 10
• Compare the unique challenges and opportunities of the various
career paths in hepatology.
• Develop strategies for academic and personal success.
• Identify new networking and mentoring opportunities.
11:45 - 11:50 AM Introduction
11:50 AM - 12:10 PM One Day I Woke Up in Silicon
Valley…
Teresa L. Wright, MD
12:10 - 12:30 PM One Day I Woke Up as CEO…
Linda Grais, MD
12:30 - 12:50 PM One Day I Woke Up as President…
Guadalupe Garcia-Tsao, MD

12:50 - 1:15 PM Panel Discussion

cessful career development strategies, examine women’s profes-    
MONDAY

sional needs, discuss strategies to improve work-life balance, and

foster networking and mentoring opportunities.

Exhibit Hall D
1:30 – 2:00 PM
Snack Break
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM 71A

Global Forum
Monday, November 10 2:00 - 2:05 PM Introduction
2:00 - 4:00 PM Room 304/306 2:05 - 2:25 PM Health Care Disparities in the US:
Will the Affordable Care Act Make
Health Disparities in Liver Disease - The Haves and the a Difference for Patients with Liver
Have Nots Disease?
MODERATORS: Gyongyi Szabo, MD, PhD Hal F. Yee, MD, PhD
Abdul Kadir Dokmeci, MD 2:25 - 2:30 PM Discussion
2:30 - 2:50 PM Health Care Disparities in Europe:
2 CME Credits East vs. West or North vs. South?
Markus Peck-Radosavljevic, MD, MBA
2:50 - 2:55 PM Discussion
Learn the aspects of health disparities in the worldwide public 2:55 - 3:15 PM Health Care Disparities in Asia
health epidemic of liver diseases among the five major regions Barjesh C. Sharma, MD, DM
of the world: North America, Europe, Latin America, Asia and
3:15 - 3:20 PM Discussion
Africa. Speakers representing each region will discuss important
issues on heath disparities and/or barriers related to the epidemi- 3:20 - 3:40 PM Health Care Disparities in Africa
ology, diagnosis and management of liver diseases. The discussion C. W. Spearman, MBChB, PhD

NOVEMBER 10
will address the most important public health problems regarding 3:40 - 4:00 PM Panel Discussion and Wrap-up

MONDAY
   
access to care, diagnosis and treatments in each of these regions.

Learning Objectives:
Upon completion of this activity, participants will be able to:
• Discuss the concept of health disparities as it relates to liver
diseases.
• Recognize regional disparities that may exist between North
America, Europe, Latin America, Asia and Africa.
• Identify steps to improve the care of patients with liver disease in
populations with geographic or health disparities.
 72A AASLD PROGRAM HEPATOLOGY, October, 2014

President’s Choice Lecture

Monday, November 10
2:15 - 2:45 PM Auditorium
Four Decades of Progress in Hepatology
SPEAKER: Willis C. Maddrey, MD
MODERATOR: Lawrence S. Friedman, MD
.5 CME Credit
Take an in-depth look at the history of the AASLD and the advance-
ment of hepatology. Special emphasis will be placed on viral hep-
atitis, fatty liver, alcohol and drug-induced injury, and the evolution
of liver transplantation.
Willis C. Maddrey, MD, is Professor of Internal Medicine and
Assistant to the President at The University of Texas Southwest-
NOVEMBER 10
Dr. Maddrey is a member of several societies including the Amer-
ican Society for Clinical Investigation and the American Gas-
troenterological Association. He was President of the American
Association for the Study of Liver Diseases in 1981. He is a Master
of the American College of Physicians and served as President
of the American College of Physicians in 1992-93. He is also a
Fellow of the Royal College of Physicians of London, the Royal Col-
lege of Physicians of Glasgow, and the Royal Australasian College
of Physicians and Surgeons. Dr. Maddrey was named the Adelyn
and Edmund M. Hoffman Distinguished Chair in Medical Science
in 1998. Dr. Maddrey was awarded the George Stuart Outstand-
ing Teacher Award at The Johns Hopkins University School of
Medicine and the Christian R. and Mary F. Lindback Award for
distinguished teaching in the clinical sciences at Jefferson Medical
College in 1986. He received the Distinguished Service Citation
from Wake Forest University in 1991, and was awarded the Dis-
tinguished Educator Award by the American Gastroenterological

Association in 1998. He was awarded the Distinguished Service

ern Medical Center at Dallas. Dr. Maddrey received his medical
MONDAY

Award of the American Association for the Study of Liver Diseases

degree from The Johns Hopkins University School of Medicine in
in 2000.
Baltimore, Maryland, and completed his residency on the Osler
Medical Service of The Johns Hopkins Hospital. He was Chief
Learning Objectives:
Medical Resident in 1969. Additional postgraduate work includes
a fellowship in liver disease with Dr. Gerald Klatskin at Yale Uni- Upon completion of this activity, participants will be able to:
versity School of Medicine. From 1970 to 1981 Dr. Maddrey • Recognize the rich history of the AASLD and its role in hepatol-
directed the liver unit at The Johns Hopkins University School of ogy.
Medicine where he was Professor of Medicine and Associate Phy- • Discover how advancements in hepatology have occurred and
sician in Chief. From 1982 to 1990 he was Magee Professor and their incorporation into our practice.
Chairman of the Department of Medicine at Jefferson Medical Col- • Predict where hepatology is headed in the next 50 years.
lege. Dr. Maddrey has authored numerous scientific publications.
He has published extensively in the areas of chronic viral hepati-
tis, drug-induced liver disease, alcohol-induced liver disease, liver
transplantation, and primary biliary cirrhosis. He has authored
numerous publications focusing on hepatitis and liver disease. He
has edited or co-edited nine books including Transplantation of the
Liver which is now in its third edition, and Schiff’s Diseases of the
Liver, now in its ninth edition.

Late-Breaking Abstract Session

Monday, November 10
2:45 - 4:30 PM Auditorium
Presidential Address: Adrian M. Di Bisceglie, MD, FACP
MODERATORS: Keith D. Lindor, MD
Ronald J. Sokol, MD
   
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
Parallel Session
Parallel 16: Access, Delivery, and Cost
of Care
Monday, November 10
3:00 - 4:30 PM Room 210
MODERATORS: Michael D. Voigt, MBChB
Kiran Bambha, MD
3:00 PM
115: The Economic Impact of Sofosbuvir- and
Simeprevir-based HCV Treatment in the United States
Jagpreet Chhatwal, Fasiha Kanwal, Mark S. Roberts, Michael A.
Dunn
3:15 PM
116: The Use of All Oral Regimens for Treatment of
Chronic Hepatitis C (CHC) Coupled with Birth Cohort
Screening Is Highly Cost Effective: The Health and
Economic Impact on the U.S. Population
Zobair Younossi, Mendel Singer, Linda Henry, Sharon L. Hunt,
Thomas Jeffers, Spencer Frost, Brian P. Lam
3:30 PM
117: Alcoholic Liver Disease is the Primary Driver
of Increased Inpatient Charges Among Patients with
Cirrhosis: A National Inpatient Survey Analysis 2002-
2010
Monica Schmidt, Paul H. Hayashi, Ramon Bataller, Alfred S. Barritt
3:45 PM
118: Early physician follow up and reduction in 60-day
readmission in patients hospitalized for cirrhosis
Fasiha Kanwal, Yumei Cao, Sumeet K. Asrani, Hashem El-Serag,
Steven Asch, Jennifer R. Kramer
4:00 PM
119: Do liver transplant centers need different risk
adjustment of quality metrics of costs and early
readmission for managing hospitalized patients with
cirrhosis?
Marwan Ghabril, Samuel Hohmann, Eric S. Orman, Raj
Vuppalanchi, A. Joseph Tector, Paul Y. Kwo, Naga P. Chalasani
4:15 PM
120: Geographic differences in access to transplant care
among Medicaid enrollees with end-stage liver disease
David S. Goldberg, Benjamin French, James D. Lewis, Scott D.
Halpern
73A
Parallel 17: Allocation, MELD, and Liver
Transplantation
Monday, November 10
3:00 - 4:30 PM Room 312
MODERATORS: Kenneth D. Chavin, MD, PhD
Seth J. Karp, MD
3:00 PM
121: Ohio Solid Organ Transplantation Consortium
(OSOTC) Exception Criteria for Early Liver
Transplantation (LT) in Severe Alcoholic Hepatitis
Ibrahim A. Hanouneh, Annette Humberson, Ariana L. Fiorita,
Arthur J. McCullough, Robert O’Shea, Catherine Rosenbaum,
Jamile Wakim-Fleming, Laura E. Nagy, Nizar N. Zein
NOVEMBER 10
MONDAY
3:15 PM
122: Liver Transplantation for Neuroendocrine Tumors
Is Unlikely the Best Option
Nicholas Nissen, Edward M. Wolin, Trista Leong, James M.
Mirocha, Run Yu, Ashley Wachsman, Marc L. Friedman, Steven
D. Colquhoun
3:30 PM
123: Domino liver transplantation (DLT) using familial
amyloid polyneuropathy (FAP) grafts: Report from the
FAP world transplant registry (FAPWTR) and call for an
international collaborative study to assess the risk of de
novo FAP in domino recipients
Arie Stangou, Marie E. Larsson, Ole Suhr, Henryk E. Wilczek,
Bo-Goran Ericzon
3:45 PM
124: Predictors of Mortality in Patients with Low MELD
on the Liver Transplant Wait List
Swaytha Ganesh, Chandraprakash Umapathy, Abhinav Humar,
Christopher B. Hughes, Mark Sturdevant, Elizabeth A. Kallenborn,
Vinod K. Rustgi, Shahid M. Malik, Amit D. Tevar
4:00 PM
125: A preliminary analysis of liver allocation based on
the “Share 35” policy in UNOS region 4
James F. Trotter, Juan D. Arenas, J. S. Bynon, John Duffy, Hany A.
Elbeshbeshy, Preston F. Foster, Rafik M. Ghobrial, John A. Goss,
Goran Klintmalm, Vivek Kohli, Marlon F. Levy, Jorge A. Marrero,
Natalie G. Murray, Ken Washburn, Jeff Weinstein, Harlan Wright
4:15 PM
126: The impact of MELD score and hospitalization
status prior to liver transplantation on short-term post-
transplantation survival: a national study
Therese Bittermann, George A. Makar, David S. Goldberg
 74A AASLD PROGRAM HEPATOLOGY, October, 2014

Parallel 18: Basic Hepatobiliary Parallel 19: Cholestatic Liver Diseases

Neoplasia Monday, November 10
Monday, November 10 3:00 - 4:30 PM Room 302
3:00 - 4:30 PM Room 310 MODERATORS: Cynthia Levy, MD
Christopher L. Bowlus, MD
MODERATORS: Lopa Mishra, MD
Tamar H. Taddei, MD
3:00 PM
3:00 PM 133: Genetic insights into primary biliary cirrhosis
– an international collaborative meta-analysis and
127: Molecular markers of progenitor cells define
replication study
outcome of HCC patients beyond Milan criteria
Heather J. Cordell, Younghun Han, Yafang Li, George F. Mells,
undergoing liver transplantation
Gideon Hirschfield, Gang Xie, Brian D. Juran, M. Eric Gershwin,
Oriana Miltiadous, Yujin Hoshida, M. Isabel Fiel, Daniela Sia,
Pietro Invernizzi, Konstantinos Lazaridis, Carl A. Anderson,
Swan N. Thung, Andrew Harrington, Poh Seng Tan, Hui Dong,
Michael F. Seldin, Chris Amos, Richard N. Sandford, Katherine
Monica Higuera, Kate Revill, Charissa Y. Chang, Jorge Rakela,
Siminovitch
Thomas J. Byrne, Myron Schwartz, Sander S. Florman, Josep M.
Llovet
3:15 PM
NOVEMBER 10

3:15 PM 134: DNA Methylation Profiling of the X Chromosome

in Primary Biliary Cirrhosis
MONDAY

128: Using HNF4α Target Gene Signature Obtained

Ana Lleo, Ming Zhao, Yixin Tan, Francesca Bernuzzi, Bochen
from Combinatorial Bioinformatics as a Predictive Tool
Zhu, Qiqun Tan, Tingting Jiang, Lina Tan, Wei Liao, Maria F.
in Hepatocellular Carcinoma (HCC) Pathogenesis
Donato, Federica Malinverno, Luca Valenti, Edoardo A. Pulixi,
Chad M. Walesky, Sumedha S. Gunewardena, Byunggil Yoo,
Pietro Invernizzi, Quiajin Lu, M. Eric Gershwin
Genea T. Edwards, Udayan Apte

3:30 PM
3:30 PM
135: Soluble adenylyl cyclase (sAC, ADCY10)
129: TERT promoter mutation is an early somatic genetic
regulates bile-salt-induced apoptosis (BSIA) in human
alteration in the malignant transformation of cirrhotic
cholangiocytes: a link to primary biliary cirrhosis (PBC)
nodules in hepatocellular carcinoma
Jung-Chin Chang, Simei Go, Coen C. Paulusma, Ulrich Beuers,
Jean-Charles Nault, Julien Calderaro, Luca Di Tomaso, Charles
Ronald Oude Elferink
Balabaud, Elie S. Zafrani, Paulette Bioulac-Sage, Massimo
Roncalli, Jessica Zucman-Rossi
3:45 PM
3:45 PM 136: New model to identify UDCA-treated primary
biliary cirrhosis patients in need of additional therapy.
130: Gene alterations in β-catenin and p53/
Results of an international follow-up study of 4119
cell cycle control pathway are closely associated
patients
with development and prognosis of hepatocellular
Willem J. Lammers, Henk R. van Buuren, Cyriel Y. Ponsioen, Harry
carcinoma: Comprehensive analyses by next generation
L. Janssen, Annarosa Floreani, Gideon Hirschfield, Christophe
sequencing technology
Corpechot, Marlyn J. Mayo, Pietro Invernizzi, Pier Maria
Fukiko Kawai-Kitahata, Yasuhiro Asahina, Syun Kaneko, Hiroko
Battezzati, Albert Pares, Frederik Nevens, Andrew K. Burroughs,
Nagata, Fumio Goto, Satoshi Otani, Miki Taniguchi, Miyako
Andrew Mason, Kris V. Kowdley, Mohamad Imam, Kirsten
Murakawa, Sayuri Nitta, Takako Watanabe, Megumi Tasaka-
Boonstra, Angela C. Cheung, Teru Kumagi, Nora Cazzagon,
Fujita, Yasuhiro Itsui, Mina Nakagawa, Sei Kakinuma, Nobuyuki
Irene Franceschet, Palak J. Trivedi, Raoul Poupon, Ana Lleo,
Enomoto, Mamoru Watanabe
Llorenç Caballeria, Giulia Pieri, Keith D. Lindor, Bettina E. Hansen

4:00 PM
4:00 PM
131: Aspartate β-hydroxylase is a Therapeutic Target
137: The Impact of Age at Presentation on Symptoms in
for Intrahepatic Cholangiocarcinoma
Primary Biliary Cirrhosis
Chiung-Kuei Huang, Arihiro Aihara, Rolf I. Carlson, Mark Olsen,
Jessica K. Dyson, Laura Griffiths, Samantha J. Ducker, George F.
Tunan Yu, Jack R. Wands
Mells, Richard N. Sandford, David Jones

4:15 PM
132: Cohesins: Novel Markers for the Efficacy of
Sorafenib in Hepatocellular Carcinoma
Richard Kalman, Mart Dela Cruz, Ramesh Wali, Hemant Roy
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
4:15 PM
138: Probing the microbiota in PSC: the gut adherent
microbiota of PSC-IBD is distinct to that of IBD and
controls
Mohammed Nabil Quraishi, Martin Sergeant, Gemma L. Kay,
Tariq Iqbal, Chrystala Constantinidou, Jacqueline Z. Chan, Palak
J. Trivedi, James W. Ferguson, David H. Adams, Mark J. Pallen,
Gideon Hirschfield
Parallel 20: Mechanisms and Mortality
in Alcoholic Liver Disease
Monday, November 10
3:00 - 4:30 PM Room 313
MODERATORS: Angela Dolganiuc, MD, PhD
Richard Green, MD
3:00 PM
139: Clinical characteristics and outcomes of acute
alcoholic hepatitis–early report from the Translational
Research and Evolving Alcoholic hepatitis Treatment
(TREAT) consortium
Suthat Liangpunsakul, Vijay Shah, Arun J. Sanyal, Barry P. Katz,
Patrick S. Kamath, Puneet Puri, Megan Comerford, Behnam
Saberi, Zhangsheng Yu, Xiaowei Ren, Naga P. Chalasani, David
W. Crabb, Svetlana Radaeva
3:15 PM
140: Combinative use of baseline and dynamic models
in patients with severe alcoholic hepatitis: Prediction of
death as a continuum in risks of mortality
Alexandre Louvet, Julien Labreuche, Florent Artru, Jerome Boursier,
John G. O’Grady, Robert L. Carithers, Sylvie Naveau, Emmanuel
Diaz, Guillaume Lassailly, Amélie Cannesson, Valerie Canva-
Delcambre, Sébastien Dharancy, Timothy R. Morgan, Alain
Duhamel, Philippe Mathurin
3:30 PM
141: Impact of intensive enteral nutrition in association
with corticosteroids in the treatment of severe alcoholic
hepatitis: a multicenter randomized controlled trial
Christophe Moreno, Eric Trépo, Alexandre Louvet, Delphine
Degré, Boris Bastens, Axel Hittelet, Marie-Astrid Piquet, Wim
Laleman, Hans Orlent, Luc Lasser, Thomas Sersté, Peter Starkel,
Xavier Dekoninck, Sergio Negrin Dastis, Jean Delwaide, Isabelle
Colle, Chantal de Galocsy, Sven M. Francque, Philippe Langlet,
Virginie Putzeys, Hendrik Reynaert, Thierry Gustot, Pierre Deltenre
3:45 PM
142: The soluble mannose receptor (sCD206) is highly
elevated in alcoholic liver disease, predicts clinical
endpoints and correlates with macrophage activation
marker sCD163
Thomas D. Sandahl, Sidsel Støy, Sidsel Rødgaard-Hansen, Holger
J. Møller, Henning Grønbæk, Hendrik V. Vilstrup
75A
4:00 PM
143: High-mobility group box-1 participates in the
pathogenesis of alcoholic liver disease
Xiaodong Ge, Daniel J. Antoine, Yongke Lu, Elena Arriazu, Tung
Ming Leung, Arielle L. Klepper, Andrea D. Branch, M. Isabel Fiel,
Natalia Nieto
4:15 PM
144: Nogo-B (Reticulon B) in Kupffer cells promotes
alcohol-induced hepatic steatosis
Jin-Kyu Park, Teruo Utsumi, Yirang Jung, Yasuko Iwakiri
Parallel 21: Molecular and Cellular
Biology
Monday, November 10
3:00 - 4:30 PM Room 309
NOVEMBER 10
MODERATORS: Mark A. McNiven, PhD
Tatiana Kisseleva, MD, PhD
MONDAY
3:00 PM
145: Development and Characterization of Induced
Pluripotent Stem Cell-Derived Cholangiocytes
Thiago de Assuncao, Yan Sun, Bing Q. Huang, Yasuhiro Ikeda,
Robert C. Huebert
3:15 PM
146: Liver progenitor cells are derived from mature
hepatocytes
Branden Tarlow, Carl Pelz, Leslie A. Wakefield, Willscott E.
Naugler, Milton Finegold, Markus Grompe
3:30 PM
147: Gender Influence Liver Regeneration During Acute
Hepatic Injury
Francesco P. Russo, Rosa Di Liddo, Debora Bizzaro, Thomas
Bertalot, Giacomo C. Sturniolo, Maria Teresa Conconi, Patrizia
Burra
3:45 PM
148: Hepatic Growth Regulation and Tumorigenesis is
linked to Autophagy via the Hippo Tumor Suppressor
Pathway
Youngmin A. Lee, Luke A. Noon, Tingfang Lee, Kemal M. Akat,
Marie-Luise Berres, Hsin I Chou, Cathie Pfleger, Elisabeth G.
Kramer, Gareth John, M. Isabel Fiel, Ronald E. Gordon, Yujin
Hoshida, Mark J. Czaja, Scott L. Friedman
4:00 PM
149: Controlled repopulation of normal rat liver by WT
hepatocytes expressing a tamoxifen regulated liver
growth gene, YapERT2
Mladen Yovchev, Fadi L. Jaber, Zhonglei Lu, Shachi Patel, Joseph
Locker, Leslie E. Rogler, John W. Murray, Mariana D. Dabeva,
Liang Zhu, David A. Shafritz
 76A AASLD PROGRAM HEPATOLOGY, October, 2014

4:15 PM
150: Genome-wide identification of miRNA binding-
sites in primary human hepatic stellate cells
Kemal M. Akat, Youngmin A. Lee, Feng Hong, Marie-Luise
Berres, Swan N. Thung, Meena B. Bansal, Thomas Tuschl, Scott
L. Friedman
4:15 PM
156: The zebrafish ductbend mutation is a sensitizer to
toxin-induced biliary atresia and a potential homologue
of a human biliary atresia modifier
Xiao Zhao, Kristin Lorent, Weilong Gong, Kyung A. Koo, Steve
Whittaker, John R. Porter, Rebecca G. Wells, Michael Pack

Parallel 22: Pediatric Liver Diseases: Parallel 23: Pharmacologic Therapies

Models, Modifiers, Mechanisms, and for Cirrhosis Complications
Markers Monday, November 10
Monday, November 10 3:00 - 4:30 PM Ballroom A/B/C
3:00 - 4:30 PM Room 311 MODERATORS: Charmaine Stewart, MD
Norman D. Grace, MD
MODERATORS: David A. Rudnick, MD, PhD
Binita M. Kamath, MBBChir
3:00 PM
3:00 PM 157: Increased Natriuretic Effects of α2- vs.
NOVEMBER 10

α1-adrenergic Agonists, Alone or in Combination with

151: IL-1 signaling regulates bile duct injury and
MONDAY

Standard Diuretics, in Rats with Experimental Cirrhosis

obstruction in biliary atresia
and Ascites
Tatsuki Mizuochi, Pranavkumar Shivakumar, Reena Mourya,
Giovanni Sansoe, Manuela Aragno, Raffaella Mastrocola,
Stephanie Walters, Bryan Donnelly, Shiva K. Shanmukhappa,
Maurizio Parola
Jorge A. Bezerra

3:15 PM
3:15 PM
158: The effect of long-term use of non-selective beta-
152: IL-1β is a Critical Mediator of Parenteral Nutrition
blocker on the development of acute kidney injury in
Associated Cholestasis in Mice
patients with liver cirrhosis
Karim C. El Kasmi, Padade Vue, Aimee Anderson, Michael W.
Sang Gyune Kim, W. Ray Kim, Joseph J. Larson, Walter K.
Devereaux, Natarajan Balasubramaniyan, Frederick J. Suchy,
Kremers, Patrick S. Kamath
Ronald J. Sokol

3:30 PM
3:30 PM
159: Efficacy and safety of a probiotic preparation in
153: Treatment with the LXR agonist T0901317
the secondary prophylaxis of hepatic encephalopathy
ameliorates liver disease in Atp7b-/- (Wilson Disease)
in cirrhotic patients: Final results of a double blind,
mice
randomized, placebo controlled study
James P. Hamilton, Lahari Koganti, James J. Potter, Abigael
Radha K. Dhiman, Baldev S. Rana, Swastik Agrawal, Ashish Garg,
Muchenditsi, David L. Huso, Esteban Mezey, Svetlana Lutsenko
Madhu Chopra, Kiran K. Thumburu, Amit Khattri, Samir Malhotra,
Ajay K. Duseja, Yogesh K. Chawla
3:45 PM
154: LUM001, an Inhibitor of ASBT, Improves Liver 3:45 PM
Function and Tissue Pathology in a Rat Cholestasis
160: A prospective, open labeled, randomized
Model
controlled trial comparing Carvedilol + VSL#3 versus
Bradley T. Keller, Svetlana Nikoulina, Nicolaus Nazarenkov,
Bronislava Gedulin
EVL for primary prophylaxis of esophageal variceal
bleeding in cirrhotic patients non-responder to
carvedilol (NCT01196481)
4:00 PM Ankit Bhardwaj, Avinash Kumar, Devraj Rangegowda, Chandan
155: Pharmacological inhibition of intestinal bile acid K. Kedarisetty, Manoj Kumar, Chitranshu Vashishtha, Ajeet S.
re-uptake blocks inflammatory liver injury and fibrosis Bhadoria, Shiv K. Sarin
in a murine model of sclerosing cholangitis
Julia Simmons, Amy Taylor, Shiva K. Shanmukhappa, Bradley T.
Keller, Alexander G. Miethke
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM 77A

4:00 PM 4:15 PM
161: Effects of Non-Selective β-Blockers on 162: A randomized trial of ‘Imipenem versus Cefepime’
Hemodynamics and Paracentesis Induced Circulatory in difficult to treat spontaneous bacterial peritonitis (SBP)
Dysfunction in Patients with Cirrhosis Undergoing Large and to evaluate the risk factors for treatment failure
Volume Paracentesis: a Preliminary Report Ankur Jindal, Shiv K. Sarin
Alberto Ferrarese, Alberto Zanetto, Paolo Angeli, Edoardo Casiglia,
Silvano Fasolato, Giovanni Boschetti, Kryssia I. Rodriguez, Elena
Nadal, Ilaria Bortoluzzi, Francesco P. Russo, Giacomo Germani,
Patrizia Burra, Marco Senzolo

HCV Symposium
Monday, November 10 Learning Objectives:
4:45 - 6:15 PM Auditorium Upon completion of this activity, participants will be able to:

HCV Symposium: What’s #Trending in Hepatitis C? • Compare the strengths and limitations of all-oral regimens for
HCV.

NOVEMBER 10
MODERATORS: Michael W. Fried, MD • Develop new strategies for maximizing access to HCV care

MONDAY
Mark S. Sulkowski, MD across healthcare systems.
Combinations of direct-acting antiviral agents (DAAs) have • Identify approaches to optimize outcomes in unique and difficult
achieved unprecedented cure rates of HCV infection. The tolerabil- to cure populations.
ity and ease of administering these new regimens have the poten-
tial to expand treatment to many underserved populations and
those with previously difficult-to-cure characteristics. Explore how
4:45 - 5:05 PM Efficacy of Current and Future All-
Oral Regimens
to optimize current and future DAA regimens across diverse patient
Andrew J. Muir, MD
groups and discuss strategies for improving access to HCV care.
5:05 - 5:25 PM Screening and Linkage to Care:
Novel Approaches for Providers and
Healthcare Systems
Camilla S. Graham, MD, MPH
5:25 - 5:45 PM Practical Challenges with DAA
Therapy for HCV
Ira M. Jacobson, MD
5:45 - 6:15 PM
    Panel Discussion
 78A AASLD PROGRAM
Parallel Session
Parallel 24: Clinical Hepatobiliary
Neoplasia
Monday, November 10
4:45 - 6:15 PM Room 302
MODERATORS: Amit G. Singal, MD
Lewis R. Roberts, MB ChB, PhD
4:45 PM
163: Outcomes of Liver Transplantation in Patients with
Hepatitis C and Hepatocellular Carcinoma (HCC): The
U.S. Transplant Registry Data
Zobair Younossi, Maria Stepanova, Sammy Saab, Kameron
Tavakolian, Brian P. Lam, Manirath Srishord, Chapy Venkatesan,
James N. Cooper, Homan Wai, Linda Henry
NOVEMBER 10
MONDAY
5:00 PM
164: Real world risk score for hepatocellular carcinoma
(RWS-HCC): development and external validation of a
clinically practical predictive score to identify low risk
individuals
Zhongxian Poh, Liang Shen, Hwai-I Yang, Wai-Kay Seto, Vincent
W. Wong, Clement Y. Lin, Boon-Bee George Goh, Jason Chang,
Henry Lik-Yuen Chan, Man-Fung Yuen, Chien-Jen Chen, Chee-Kiat
Tan
5:15 PM
165: Diabetes mellitus is associated with an increased
risk of HCC in a large prospective cohort with long term
follow-up
Lindsay Y. King, Hamed Khalili, Edward S. Huang, Raymond T.
Chung, Andrew T. Chan
5:30 PM
166: Hepatocellular Carcinoma (HCC) Surveillance
Among Cirrhotic Patients with Commercial Health
Insurance: National Rates and Determinants of
Surveillance
David S. Goldberg, Adriana Valderama, Rajesh Kamalakar, Sujit
S. Sansgiry, Svetlana Babajanyan, James D. Lewis
5:45 PM
167: Achieving Equity among Patients With and
Without Hepatocellular Carcinoma (HCC) Who Are
Listed for Liver Transplantation (LT): A Scoring System
Utilizing MELD and Alpha Fetoprotein (AFP)
Mohannad Dugum, Nizar N. Zein, Rocio Lopez, Carlos J. Romero-
Marrero, Federico N. Aucejo, Bijan Eghtesad, Bradley Confer,
Ibrahim A. Hanouneh
HEPATOLOGY, October, 2014
6:00 PM
168: A Multicenter Randomized Controlled Trial of
Percutaneous Cryoablation Versus Radiofrequency
Ablation Therapy in Patients with Hepatocellular
Carcinoma
Chunping Wang, Huaming Wang, Wuwei Yang, Kaiwen Hu, Hui
Xie, Wenlin Bai, Zheng Dong, Yinying Lu, Zhen Zeng, Min Lou,
Hong Wang, Xudong Gao, Xiujuan Chang, Linjing An, Jianhui
Qu, Jin Li, Ke-Qin Hu, Yongping Yang
Parallel 25: Hepatitis C: Diagnosis,
Epidemiology and Natural History
Monday, November 10
4:45 - 6:15 PM Room 312
MODERATORS: Jonathan M. Fenkel, MD
Doris B. Strader, MD
4:45 PM
169: Molecular sequencing and phylogenetics as
enhanced surveillance tools for monitoring Hepatitis C
virus transmission dynamics in British Columbia
Andrea Olmstead, Vincent Montoya, Jeffrey Joy, Iris Luo, Naveed
Z. Janjua, Art Poon, Brendan Jacka, Francois Lamoury, Tanya L.
Applegate, Jason Grebely, Richard Harrigan, Mel Krajden
5:00 PM
170: HCV infection in opiod-using (OU) pregnant
women. Krans E, Rustgi V, Department of Obstetrics
and Gynecology, Magee-Womens Research Institute
and the Thomas Starzl Transplant Institute, University of
Pittsburgh
Elizabeth E. Krans, Vinod K. Rustgi
5:15 PM
171: Opioid agonist therapy is associated with lower
incidence of hepatitis C virus infection in young adult
persons who inject drugs
Judith I. Tsui, Jennifer Evans, Paula J. Lum, Judith A. Hahn, Kimberly
Page
5:30 PM
172: Hepatitis C Virus Infection Increases Risk of
Chronic Kidney Disease: REVEAL-HCV Study
Tai-Shuan Lai, Mei-Hsuan Lee, Hwai-I Yang, Yong Yuan, Gilbert
LItalien, Kuo-Liong Chien, Chien-Jen Chen
5:45 PM
173: Patients with chronic hepatitis C virus infection
have an increased risk of non-Hodgkin’s lymphoma
Tung-Hung Su, Chun-Jen Liu, Chi-Ling Chen, Tai-Chung Tseng,
Chen-Hua Liu, Hung-Chih Yang, Pei-Jer Chen, Ding-Shinn Chen,
Jia-Horng Kao
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
6:00 PM
174: Mortality and progression to decompensated
cirrhosis in chronic hepatitis C (CHC) patients with liver
biopsy confirmed fibrosis in the Chronic Hepatitis Cohort
Study (CHeCS)
Anne C. Moorman, Fujie Xu, Xin Tong, Stuart C. Gordon, Loralee
B. Rupp, Mei Lu, Philip R. Spradling, Eyasu H. Teshale, Joseph
A. Boscarino, Vinutha Vijayadeva, Mark A. Schmidt, Scott D.
Holmberg
Parallel 26: Living Donor and Split Liver
Transplantation, Hepatobiliary Surgery
Monday, November 10
4:45 - 6:15 PM Room 210
MODERATORS: James Pomposelli, MD, PhD
Jean C. Emond, MD
4:45 PM
175: Liver Stiffness Measurement Predicts
Posthepatectomy Liver Failure
Gen Yamamoto, Kojiro Taura, Yukinori Koyama, Kazutaka
Tanabe, Takahiro Nishio, Yukihiro Okuda, Etsuro Hatano, Shinji
Uemoto
5:00 PM
176: The Differential Impact of Donor-Specific
Antibodies in Living vs. Deceased Donor Liver
Transplantation
Josh Levitsky, Anat R. Tambur, R Carlin Walsh, Chunfa Jie, Joseph
Kang, Hugo Kaneku, Michael M. Abecassis
5:15 PM
177: Liver Resection for Cholangiocarcinoma: Biological
and Surgical Predictors of Outcome, Status Quo in
Additive Therapy
Arash Nickkholgh, Arianeb Mehrabi, Thomas Bruckner, Benjamin
Goeppert, Peter Schemmer
5:30 PM
178: Non-invasive biomarkers are superior to clinical
measures in predicting hepatic decompensation after
liver resection
James A. Thomas, Ashok S. Raj, Uthayanan Chelvaratnam,
Marrianne Black, Caroline Tallis, Linda Fletcher, Gerald Holtmann,
Jonathan Fawcett, Katherine Stuart
5:45 PM
179: Higher MELD scores at time of transplant are not
associated with lower survival following living donor
liver transplantation among patients with MELD <25
Ryan B. Perumpail, Robert Wong, Andrew M. Su, Clark A.
Bonham, Carlos O. Esquivel, Aijaz Ahmed
79A
6:00 PM
180: Outcomes and Complications of Right versus Left
Lobe Liver Donation
Hillary Braun, Jennifer L. Dodge, Chris Freise, Nancy L. Ascher,
John P. Roberts
Parallel 27: Pediatric Liver Diseases:
Clinical and Translational Studies
Monday, November 10
4:45 - 6:15 PM Room 311
MODERATORS: Vicky L. Ng, MD
Regino P. Gonzalez-Peralta, MD
4:45 PM
181: High Levels of Circulating Alpha-1-AT Mutant
Z Polymer Protein May Serve as the First Described
NOVEMBER 10
Disease-Specific Biomarker for Liver Disease in Alpha-1-
MONDAY
AT Deficiency
Jeffrey Teckman, Paula Buchanan, Lu Tan, David A. Lomas
5:00 PM
182: Dysregulation of Cholesterol 7 alpha-hydroxylase
(CYP7A1) is involved in the abnormal bile acid synthesis
in livers from biliary atresia children
Yasuhiro Hasegawa, Hiroki Kondou, Kazuhiko Bessho, Masanobu
Kawai, Kie Nakao, Takehisa Ueno, Yoshinori Satomura, Akiko
Konishi, Takeshi Kimura, Kayo Ikeda, Makiko Tachibna, Yoko
Miyoshi, Toshimi Michigami, Keiichi Ozono
5:15 PM
183: Progression to high-risk gastroesophageal varices
in biliary atresia children with low-risk signs at first
endoscopy
Oanez Ackermann, Mathieu Duché, Beatrice Ducot, Emmanuel
Jacquemin, Olivier Bernard
5:30 PM
184: Hepatic inflammation may influence liver stiffness
measurements by transient elastography in children and
young adults
Aileen Raizner, Nick M. Shillingford, Paul D. Mitchell, Sarah
Harney, Roshan Raza, Jessica Serino, Maureen M. Jonas, Christine
K. Lee
5:45 PM
185: Pediatric Nonalcoholic Fatty Liver Disease (NAFLD):
Histological Feature Changes Over Time in Paired
Biopsies from the NASH CRN
Elizabeth M. Brunt, David E. Kleiner, Patricia H. Belt, Jean
P. Molleston, Jeffrey B. Schwimmer, Joel E. Lavine, Brent A.
Neuschwander-Tetri
 80A AASLD PROGRAM
6:00 PM
186: Magnetic Resonance Imaging and Liver Histology
as Biomarkers of Hepatic Steatosis in Children with
Nonalcoholic Fatty Liver Disease
Jeffrey B. Schwimmer, Michael S. Middleton, Cynthia A. Behling,
Kimberly P. Newton, Hannah Awai, Melissa N. Paiz, Jonathan
Hooker, Gavin Hamilton, John Fontanesi, Claude B. Sirlin
Parallel 28: The Good and Bad of
Innate Immunity in Liver Disease
Monday, November 10
4:45 - 6:15 PM Room 309
MODERATORS: Pranoti Mandrekar, PhD
Mark J. Czaja, MD
4:45 PM
NOVEMBER 10
187: Stimulation of PPAR-γ reduces NFkB-dependent
MONDAY
inflammation in cystic fibrosis biliary epithelium
Roberto Scirpo, Romina Fiorotto, Ambra Villani, Luca Fabris,
Mario Strazzabosco
5:00 PM
188: PD-L1+ MDSCs are likely to become a new
biomarker in hepatocellular carcinoma patients
Tomoaki Iwata, Yasuteru Kondo, Osamu Kimura, Takayuki Kogure,
Tatsuki Morosawa, Yasuyuki Fujisaka, Tooru Shimosegawa
HEPATOLOGY, October, 2014
5:15 PM
189: Unraveling of multilevel inhibition of interferon
(IFN)-β production, signaling and target-gene induction
in PAMPs-activated immune cells from patients with
alcoholic cirrhosis
Emmanuel Weiss, Rakhi Maiwall, Pierre-Emmanuel Rautou, Magali
Fasseu, Mikhael Giabicani, Catherine Paugam-Burtz, Francois
Durand, Dominique Valla, Didier Lebrec, Sophie Lotersztajn, Pierre
de la Grange, Richard Moreau
5:30 PM
190: Arginine methylation of TRAF6 regulates TLR
signaling and susceptibility to spontaneous bacterial
peritonitis in cirrhosis
Irina Tikhanovich, Sudhakiranmayi Kuravi, Antonio Artigues,
Maria T. Villar, Kenneth Dorko, Atta M. Nawabi, Benjamin R.
Roberts, Steven A. Weinman
5:45 PM
191: Increased prevalence of deficient polymorphisms
of innate immune system in cirrhotic patients with
ascites and spontaneous bacterial infections
Veronica Prado, Anibal Silva, Miriam Castro, Francisco Lozano,
Ausgusto Villanueva, Juan Acevedo, Pere Gines, Vicente Arroyo,
Javier Fernandez
6:00 PM
192: Negative regulation of the interferon response by
an interferon-induced long non-coding RNA
Hiroto Kambara, Farshad Niazi, Lenche Kostadinova, Dilip
Moonka, Christopher T. Siegel, Anthony B. Post, Elena Carnero,
Marina Barriocanal, Puri Fortes, Donald D. Anthony, Saba
Valadkhan
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM 81A

SIG Program
Monday, November 10 4:45 - 4:50 PM Introduction
4:45 - 6:50 PM Ballroom A/B/C 4:50 - 5:10 PM Risk Stratification in Compensated
Cirrhosis
Non-Invasive Methods to Stratify Risk in Patients With Guadalupe Garcia-Tsao, MD
Compensated Cirrhosis 5:10 - 5:30 PM Non-invasive Tests Currently Used in
Risk Stratification
Sponsored by the Portal Hypertension SIG Laurent Castera, MD, PhD
MODERATORS: Guadalupe Garcia-Tsao, MD 5:30 - 5:45 PM Discussion
Juan Carlos Garcia-Pagan, MD 5:45 - 6:05 PM Metabolic Profiling and Systems
Biology As a Novel Way of
There is a clinical need for the development of new non-invasive
Assessing Prognosis in Cirrhosis
prediction tools capable of stratifying patients with compensated
Jeffrey Idle, PhD
cirrhosis into those requiring intensive follow-up vs. those for whom
follow-up can be lengthened. Learn from clinicians and investiga- 6:05 - 6:15 PM Discussion
tors working in the area of cirrhosis and portal hypertension and 6:15 - 6:35 PM New Imaging Probes (MRI, PET, NIR)
those studying new noninvasive biological markers (“omics”) and of Potential Use in Cirrhosis
imaging. Course moderators will identify key questions and tech- Peter Caravan, PhD

NOVEMBER 10
nologies for risk stratification and understanding mechanisms of 6:35 - 6:45 PM Discussion

MONDAY
decompensation in compensated cirrhosis. 6:45 - 6:50 PM Summary and Wrap-up
Juan Carlos Garcia-Pagan, MD
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Identify the current knowledge and the needs regarding risk
stratification in patients with compensated cirrhosis.
• Review potential noninvasive breakthrough technologies that
could add to the current knowledge regarding predictors of
outcomes and expand our knowledge on the mechanisms of
decompensation and/or HCC.
• Recognize opportunities for using new technologies to identify
and modulate mechanisms involved in deterioration in compen-
sated cirrhosis.
 82A AASLD PROGRAM HEPATOLOGY, October, 2014

SIG Program
Monday, November 10 4:45 - 4:50 PM Introduction
Frank A. Anania, MD, FACP, AGAF
4:45 - 6:55 PM Sheraton, Back Bay Ballroom C
4:50 - 5:15 PM Innate Immunity, NASH and Potential
Immunity and Lipids as New Drivers in Inflammation for Fibrosis
and Fibrosis of Non-Alcoholic Steatohepatitis Senad Divanovic, PhD
5:15 - 5:40 PM The Gut Microbiome and Intestinal
Sponsored by the Liver Fibrosis, and Steatosis/Steatohepatitis SIGs Dysbosis in NASH Pathogenesis
Wajahat Z. Mehal, MD
MODERATORS: Frank A. Anania, MD, FACP,
AGAF 5:40 - 6:00 PM Break
Nicholas O. Davidson, MD 6:00 - 6:05 PM Transition Remarks
Nicholas O. Davidson, MD
Examine the basic mechanisms of NASH progression and the regu-
lation of fibrogenesis in advanced NASH in this joint special inter- 6:05 - 6:30 PM PPARγ, Steatosis, and Fibrosis
est group program. Divided into sub-sections, the program covers Joan Clària, MD
the immunological aspects of NASH and the role of gut dysbiosis. 6:30 - 6:55 PM Hepatic Fat Storage – Location
Extending from these will be presentations on how fibrogenic pro- Matters for Cell Injury and Fibrosis
cesses are regulated by the localization of lipid stores and with a Nicholas O. Davidson, MD
NOVEMBER 10

strong emphasis on the regulation of lipogenesis as it relates to

MONDAY

liver fibrosis. The program provides a unique perspective on how

cellular processes are connected during NASH.

Learning Objectives:
Upon completion of this activity, participants will be able to:
• Explain the role of both the innate and acquired immune system
in the development of inflammation in fatty liver disease; and as
a consequence of changes in gut microbiota (dysbiosis) .
• Discuss the role of lipids as pro-fibrogenic molecules and how
the localization of lipid stores enhances the mechanisms of fibro-
genesis.
• Develop collaborations between the two SIG Groups resulting in
future translational/clinical studies.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM 83A

SIG Program
Monday, November 10 4:45 - 4:50 PM Introduction
4:45 - 7:25 PM Sheraton, Republic Ballroom 4:50 - 5:10 PM Accurately Measuring Renal Function
in Cirrhosis: Serum Creatinine vs.
Renal Dysfunction in Cirrhosis: Should we Change the Biomarkers?
Way We Manage These Patients? Francois Durand, MD
5:10 - 5:20 PM Discussion
Sponsored by the Acute on Chronic Liver Failure SIG
5:20 - 5:40 PM Diagnosing Renal Dysfunction in
MODERATORS: Florence Wong, MD Cirrhosis: Is One Scheme Better than
Paolo Angeli, MD, PhD the Other?
Florence Wong, MD
Are milder cases of renal dysfunction simply occurring at an earlier
5:40 - 5:50 PM Discussion
stage of the natural history of cirrhosis or do they have a different
pathophysiology? Determining how to prevent and manage renal 5:50 - 6:10 PM Precipitants of Acute Kidney Injury
dysfunction is still not well defined. Review the latest findings on in Cirrhosis: The Role of Bacterial
renal dysfunction in cirrhosis with a special focus on clinical prac- Infections
Jasmohan S. Bajaj, MD
tice. Learn the latest on the pathophysiology and treatment options
that will bring bench to bedside. 6:10 - 6:20 PM Discussion

NOVEMBER 10
6:20 - 6:40 PM Treatment of Renal Dysfunction in

MONDAY
Learning Objectives: Cirrhosis: The Role of Albumin and
Upon completion of this activity, participants will be able to: Vasoconstrictors
Paolo Angeli, MD, PhD
• Review the inadequacies of the different measures of renal func-
tion in cirrhosis. 6:40 - 6:50 PM Discussion
• Explain the rationale for needing to redefine renal dysfunction in 6:50 - 7:10 PM Treatment of Renal Dysfunction in
cirrhosis. Cirrhosis: The Role of Liver Transplant
vs. Simultaneous Liver-Kidney
• Compare the treatment options for renal dysfunction in cirrhosis
Transplant
including liver transplantation. Jacqueline G. O’Leary, MD, MPH
7:10 - 7:20 PM Discussion
7:20 - 7:25 PM Wrap-up
 84A AASLD PROGRAM HEPATOLOGY, October, 2014

SIG Program
Monday, November 10 4:45 - 4:50 PM Introduction
T. Jake Liang, MD and Timothy M. Block,
4:45 - 7:50 PM Room 304/306
PhD
The Next Generation of HBV Therapy: From Discovery 4:50 - 5:05 PM Currently Approved Hepatitis B
to Cure Therapeutics: Their Indications and
Limitations
Sponsored by the Hepatitis B SIG Brian J. McMahon, MD
5:05 - 5:15 PM Does Combination Therapy of
MODERATORS: T. Jake Liang, MD
Interferon and Nucleoside Analogs
Timothy M. Block, PhD Make Sense?
Chronic hepatitis B infection is associated with a significant risk Marc G. Ghany, MD, MHSc
of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). There
are now 7 approved medications to manage chronic hepatitis B, Session I: Direct Acting Antiviral Therapies
but these require indefinite periods of use, and are not indicated
MODERATORS: Raymond F. Schinazi, PhD, DSc and
for all chronic hepatitis B patients. Moreover, as currently used,
Robert G. Gish, MD
these medications reduce the risk of death due to liver disease
by only 50-60% after ten years of use. There is therefore a great 5:15 - 5:30 PM Entry Inhibitors: Myrcludex and
Cyclosporins
NOVEMBER 10

interest in the professional community in the understanding and

Stephan Urban, PhD
MONDAY

knowing about new therapeutics that complement or improve upon

the current portfolio. Management of patients with chronic hepa- 5:30 - 5:45 PM Eradication of cccDNA by Small
titis B and the discovery of new liver disease therapies is centrally Molecules
responsive to the AASLD mission. This Special Interest Group (SIG) Ju-Tao Guo, MD
session will address these issues through colloquia. 5:45 - 6:00 PM Assembly Inhibitors
Stephen Locarnini, MD, PhD
Learning Objectives: 6:00 - 6:20 PM Panel Discussion & Audience
Upon completion of this activity, participants will be able to: Comments/Questions
• Predict the next wave of HBV therapeutics. 6:20 - 6:30 PM Break
• Employ hepatitis research programs in response to the infor-
mation communicated at the meeting and stimulate interest in Session II: Indirect Acting Agents
collaborative studies.
MODERATORS: Patrick Marcellin, MD, PhD and
• Discuss the status of new HBV drugs in the development pipe- Eugene R. Schiff, MD
line.
6:30 - 6:45 PM Eradication of cccDNA by Immune
Modulators
T. Jake Liang, MD
6:45 - 7:00 PM Toll-like Receptor, PD1 and Other
Immune Modulators
Fabien Zoulim, MD
7:00 - 7:15 PM Therapeutic Vaccines, siRNA, Other
Nucleic Acid-based Technologies
Kyong-Mi Chang, MD
7:15 - 7:35 PM Panel Discussion & Audience
Comments/Questions
7:35 - 7:50 PM Summary
   
Anna S. Lok, MD
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM 85A

Early Morning Workshops 

Tuesday, November 11
6:45 - 7:45 AM Refer to your ticket for meeting
room location.
Basic Early Morning Workshops
EMW-29 Sinusoidal Endothelial Cells and Fibrogenesis
Laurie D. DeLeve, MD, PhD and Vijay Shah, MD
EMW-30 Stem Cells and Regeneration in Liver Disease
Sanjeev Gupta, MD and Lopa Mishra, MD
EMW-31 Novel Molecular Mechanisms and Targets in
HCC
TBD
Clinical Early Morning Workshops
EMW-32 Use of Livertox and Use of EMR Mining in
Hepatotoxicity
Herbert L. Bonkovsky, MD and Robert J. Fontana,
MD
EMW-33 When Can You Withdraw Treatment for
Hepatitis B?
Natalie H. Bzowej, MD, PhD and George V.
Papatheodoridis, MD
EMW-34 What’s New for HIV/HCV Coinfected
Patients in 2014?
Andrea Cox, MD, PhD and Kenneth E. Sherman,
MD, PhD
EMW-35 Streamlining HCV Therapy in Treatment
Naïve Patients
Margaret J. Koziel, MD and Donald M. Jensen,
MD
EMW-36 Streamlining HCV Therapy in Previous
Treatment Failures and Nonresponders
Marc G. Ghany, MD, MHSc and Patrick Marcellin,
MD, PhD
EMW-37 Ethical Considerations in the Practice of
Hepatology - Explaining Risks to Subjects
Adrian Reuben, MBBS, FRCP, FACG and Andrew
Aronsohn, MD
EMW-38 Update on Autoimmune Hepatitis
Michael P. Manns, MD and John M. Vierling, MD
EMW-39 TIPS in Cirrhosis: Benefits and Complications
Florence Wong, MD and Theo Heller, MD
EMW-40 Controversies and Updates in PSC and PBC
Cynthia Levy, MD and Keith D. Lindor, MD
EMW-41 Special Consideration in Private Practice for

NOVEMBER 11
the Hepatology Provider
Mitchell L. Shiffman, MD and Savant Mehta, MD

TUESDAY
   

Poster Session IV
Tuesday, November 11
8:00 AM – Noon
Hall C
Refer to page 169A for Poster Presentations
 86A AASLD PROGRAM HEPATOLOGY, October, 2014

Plenary Session
Hepatitis Plenary
Tuesday, November 11
8:00 - 9:30 AM Auditorium
MODERATORS: Anna S. Lok, MD
W. Ray Kim, MD
8:00 AM
193: HBsAg Loss with Tenofovir Disoproxil Fumarate
(TDF) plus Peginterferon alfa-2a (PEG) in Chronic
Hepatitis B (CHB): Results of a Global Randomized
Controlled Trial
Patrick Marcellin, Sang Hoon Ahn, Xiaoli Ma, Florin A. Caruntu,
Won Young Tak, Magdy Elkashab, Wan-Long Chuang, Fehmi
Tabak, Rajiv Mehta, Joerg Petersen, Eduardo B. Martins, Phillip
Dinh, Amoreena C. Corsa, Prista Charuworn, Mani Subramanian,
John G. McHutchison, Maria Buti, Giovanni B. Gaeta, George V.
Papatheodoridis, Robert Flisiak, Henry Lik-Yuen Chan
8:15 AM
8:45 AM
196: Efficacy and safety of MK-5172 and MK-8742 ±
ribavirin in hepatitis C genotype 1 infected patients with
cirrhosis or previous null response: Final results of the
C-WORTHY Study (Parts A and B)
Eric Lawitz, Edward J. Gane, Brian Pearlman, Edward Tam,
Wayne Ghesquiere, Dominique Guyader, Laurent Alric, Jean-
Pierre Bronowicki, Lorenzo Rossaro, William Sievert, Reem H.
Ghalib, Luis A. Balart, Fredrik Sund, Martin Lagging, Frank Dutko,
Anita Y. Howe, Melissa Shaughnessy, Peggy Hwang, Janice
Wahl, Michael Robertson, Barbara A. Haber
9:00 AM
197: High Efficacy of Treatment with
Sofosbuvir+GS-5816 ±Ribavirin for 12 Weeks in
Treatment Experienced Patients with Genotype 1 or 3
HCV Infection
Stephen Pianko, Steven L. Flamm, Mitchell L. Shiffman, Sonal
Kumar, Simone I. Strasser, Gregory J. Dore, John McNally, Diana
M. Brainard, Lingling Han, Brian Doehle, Erik Mogalian, John G.
McHutchison, K. Rajender Reddy, Stuart K. Roberts

194: Effectiveness of Hepatitis C Virus (HCV) Testing for

Persons Born during 1945-1965 – Summary Results 9:15 AM
NOVEMBER 11

from Three Randomized Controlled Trials 198: High Sustained Virologic Response Rates in Liver
TUESDAY

Bryce D. Smith, Anthony K. Yartel, Kimberly Ann Brown, Katherine Transplant Recipients With Recurrent HCV Genotype 1
Krauskopf, Omar I. Massoud, Cynthia E. Jordan, Natalie Kil, Alex Infection Receiving ABT-450/r/Ombitasvir+Dasabuvir
D. Federman, David R. Nerenz, Danielle Liffmann, David B. Rein Plus Ribavirin
Parvez S. Mantry, Paul Y. Kwo, Eoin Coakley, Helen S. Te, Hugo
8:30 AM E. Vargas, Robert S. Brown, Fredric D. Gordon, Josh Levitsky,
Norah Terrault, James R. Burton, Wangang Xie, Carolyn Setze,
195: Sofosbuvir and Ribavirin therapy for the Treatment Prajakta Badri, Regis A. Vilchez, Xavier Forns
of HIV/HCV coinfected patients with HCV GT1-4
Infection: The PHOTON-1 and -2 Trials
Juergen K. Rockstroh, Massimo Puoti, Maribel Rodriguez-Torres,
Douglas Dieterich, Anuj Gaggar, Liyun Ni, Benedetta Massetto,
Evguenia S. Svarovskaia, Diana M. Brainard, Mani Subramanian,
John G. McHutchison, Susanna Naggie, Chloe Orkin, Jean-Michel
Molina, Mark S. Sulkowski

Hepatitis Debrief
Tuesday, November 11
9:45 - 10:30 AM Auditorium
This session will provide a synthesis of new data on the treatment
of viral hepatitis presented at The Liver Meeting®. Attendees will
leave this session with practical knowledge of cutting-edge thera-
pies for chronic Hepatitis C.
9:45 - 10:30 AM Hepatitis Debrief
   
Michael W. Fried, MD
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
Leon Schiff State-of-the-Art Lecture
Tuesday, November 11
10:30 - 11:00 AM Auditorium
Benign Tumors of the Liver
SPEAKER: Jessica Zucman-Rossi, MD, PhD
MODERATOR: Elizabeth M. Brunt, MD
.5 CME Credit
Benign liver tumors are frequently difficult to diagnose in clinical
practice. Recent identification of the different molecular classes of
hepatocellular adenoma has enabled the development of new bio-
markers useful in improving the diagnostic and prognostic assess-
ment of these tumors. Keep on top of this molecular classification
and learn how to initiate the process of new, personalized patient
care.
Jessica Zucman-Rossi, MD, PhD, Professor of Medicine, Oncology,
University Paris Descartes, Hopital Européen Georges Pompidou.
She is head of the INSERM unit, Functional Genomic of Solid
Tumors, in Paris. Since the last 10 years, Prof Zucman’s team
works to identify new carcinogenetic pathways altered in HCC
and benign hepatocellular tumors using a strategy based on the
study of large series of human tumors.
87A
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Identify the different types of benign hepatocellular tumors, and
their clinical, pathological, imaging and epidemiological fea-
tures.
• Review the molecular classification of hepatocellular adenoma.
• Evaluate how new molecular markers will improve the diagnos-
tic and prognostic assessment of benign liver tumors.
• Translate molecular classification and improve personalized
care in patients.
This annual lecture recognizes Dr. Schiff’s work to elevate the study
and practice of hepatology to the discipline it is today. A restricted
fund has been established to support the lecture in perpetuity and
AASLD gratefully acknowledges the National Genetics Institute for
their generous support of this program.
NOVEMBER 11
TUESDAY
 88A AASLD PROGRAM
Parallel Session
Parallel 29: Biliary Biology and
Pathobiology: Mechanisms and
Treatments
Tuesday, November 11
11:15 AM - 12:45 PM Room 210
MODERATORS: Paul Dawson, PhD
Grace L. Guo, PhD
11:15 AM
199: The lipid flippase ATP11C-CDC50A heterodimer
is essential for basolateral localization of the hepatic
bile salt transporters OATP1B2 and NTCP in central
hepatocytes
Jyoti Naik, Dirk R. de Waart, Karina S. Utsunomiya, Kam Ho-Mok,
Suzanne Duijst, Ronald Oude Elferink, Piter J. Bosma, Coen C.
Paulusma
11:30 AM
200: The Cystic Fibrosis Conductance Regulator
(CFTR) controls c-Src tyrosine kinase signaling and
NOVEMBER 11
regulates innate immunity and epithelial polarity in
TUESDAY
cholangiocytes
Romina Fiorotto, Ambra Villani, Antonis Kourtidis, Roberto Scirpo,
Carlo Spirli, Panos Z. Anastasiadis, Mario Strazzabosco
11:45 AM
201: Interleukin-33 induces cholangiocyte proliferation
via IL13/IL-4R/STAT6 pathway
Jun Li, Reena Mourya, Stephanie Walters, Karis Kosar,
Pranavkumar Shivakumar, Stacey S. Huppert, Jorge A. Bezerra
12:00 PM
202: Ccl2-deficiency protects mice from cholestatic liver
injury by blocking hepatic leukocyte infiltration
Shi-Ying Cai, Xinshou Ouyang, Albert Mennone, Matthew R.
Smith, Carol J. Soroka, Wajahat Z. Mehal, James L. Boyer
12:15 PM
203: Identification and characterization of membrane
Syntaxins in mouse biliary epithelial cells: role in
regulated ATP release and bile formation
Razan Bader, Qin Li, Charles Kresge, Abhijit Bugde, Matthew A.
Lewis, Andrew P. Feranchak
12:30 PM
204: Hepatic transport of conjugated bile acids in
humans quantitated by 11C-cholylsarcosine PET/CT
Nikolaj W. Ørntoft, Kim Frisch, Peter Ott, Susanne Keiding,
Michael Sørensen
HEPATOLOGY, October, 2014
Parallel 30: Correlates of Complications
in Cirrhosis
Tuesday, November 11
11:15 AM - 12:45 PM Room 302
MODERATORS: Jaime Bosch, MD, PhD, FRCP
Theo Heller, MD
11:15 AM
205: Leucine mediated rescue of hyperammonemia
mediated impaired skeletal muscle protein synthesis in
cirrhosis
Dawid Krokowski, Ashok Runkana, Samjhana Thapaliya, Cynthia
Tsien, Gangarao Davuluri, Maria Hatzoglou, Srinivasan Dasarathy
11:30 AM
206: Jak2/Arhgef1 signaling correlates with severity
of liver disease and represents a target for therapy of
portal hypertension
Sabine Klein, Johanna Rick, Robert Schierwagen, Frank E. Uschner,
Christian P. Strassburg, Wim Laleman, Tilman Sauerbruch, Jonel
Trebicka
11:45 AM
207: Serum Cystatin C is a Powerful Prognostic
Indicator in Patients with Cirrhotic Ascites: A Multicenter
Prospective Observational Study
Yeon Seok Seo, Soo Young Park, Moon Young Kim, Sang Gyune
Kim, Jun Yong Park, Hyung Joon Yim, Byoung Kuk Jang, Seung Ha
Park, Ji Hoon Kim, Ki Tae Suk, Jin Dong Kim, Tae Yeob Kim, June
Sung Lee, Soung Won Jeong, Jae Young Jang, Hyonggin An, Won
Young Tak, Soon Koo Baik, Jaeseok Hwang, Young Seok Kim, Joo
Hyun Sohn, Soon Ho Um
12:00 PM
208: A low-cost, user-friendly EEG recording set for
Hepatic Encephalopathy assessment: a proof of concept,
preliminary study
Sami Schiff, Mariella Casa, Valeria Di Caro, Daniele Aprile,
Giuseppe Spinelli, Michele De Rui, Piero Amodio, Sara
Montagnese
12:15 PM
209: Total 25(OH) Vitamin D is Not an Accurate Marker
of Vitamin D Status in Patients with Cirrhosis and
Synthetic Dysfunction
Jennifer C. Lai, Norah Terrault, Daniel Bikle, Blanca C. Lizaola,
Janice B. Schwartz
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
12:30 PM
210: Optimizing muscle mass: therapeutic target to
prevent experimental hepatic encephalopathy
Sara Ghezzal, Marc-André Clément, Cristina R. Bosoi, Roxanne
Beauchamp, Mélanie Tremblay, Christopher F. Rose, Chantal
Bemeur
Parallel 31: Emerging Trends in NASH
Tuesday, November 11
11:15 AM - 12:45 PM Room 304/306
MODERATORS: Rohit Loomba, MD, MHSc
Aynur Unalp-Arida, MD, PhD
11:15 AM
211: The Severity of Steatosis Overestimates Liver
Fibrosis Diagnosis by liver Stiffness Measurement in
Patients with Nonalcoholic Fatty Liver Disease
Salvatore Petta, Vito Di Marco, Calogero Cammà, Daniela Cabibi,
Antonio Craxì
11:30 AM
212: Variants in Long non-Coding RNAs (lncRNAs)-
Genomic Regions may Contribute to Nonalcoholic Fatty
Liver Disease Severity
Carlos J. Pirola, Tomas Fernández Gianotti, Hernán Dopazo,
Cristian Rohr, Gustavo O. Castaño, Silvia Sookoian
11:45 AM
213: Effects of bariatric surgery on severe liver injury in
morbid obese patients with proven NASH: a prospective
study
Guillaume Lassailly, Robert Caiazzo, David Buob, Marie Pigeyre,
Helene Verkindt, Violetta Raverdy, Emmanuelle Leteurtre, Sebastien
Dharancy, Alexandre Louvet, Francois Pattou, Philippe Mathurin
12:00 PM
214: The association of vascular function and non-
alcoholic fatty liver disease: the Framingham Heart
Study
Michelle T. Long, Na Wang, Martin G. Larson, Gary F. Mitchell,
Joseph N. Palmisano, Vasan S. Ramachandran, Udo Hoffmann,
Elizabeth K. Speliotes, Joseph A. Vita, Emelia J. Benjamin, Caroline
S. Fox, Naomi Hamburg
12:15 PM
215: A Novel Epigenetic Landscape in the Biology
of Nonalcoholic Fatty Liver Disease: The role of
5-Hydroxymethylcytosine and Sequence Variation in
Ten-Eleven Translocation Family of Proteins
Carlos J. Pirola, Tomas Fernández Gianotti, Hernán Dopazo,
Cristian Rohr, Gustavo O. Castaño, Silvia Sookoian
89A
12:30 PM
216: The macrophage activation marker soluble CD163
is independently associated with liver inflammation and
fibrosis in patients with non-alcoholic fatty liver disease
Konstantin Kazankov, Francisco Barrera, Holger J. Møller,
Elisabetta Bugianesi, Chiara Rosso, Saeed Esmaili, Hendrik V.
Vilstrup, Jacob George, Henning Gronbaek
Parallel 32: HBV Basic Virology
Tuesday, November 11
11:15 AM - 12:45 PM Room 311
MODERATORS: Golo Ahlenstiel, MD
Fabien Zoulim, MD
11:15 AM
217: Intrahepatic Transcriptional Signature of Exhausted
T Cells in Chimpanzees Chronically Infected with HBV
Li Li, Peng Yue, Robert E. Lanford, Congrong Niu, Stephane Daffis,
Daniel Tumas, Abigail Fosdick, William E. Delaney, Simon P.
Fletcher
11:30 AM
218: Combined Gene and MicroRNA Expression
NOVEMBER 11
Profiling of Hepatitis B Virus (HBV)-Associated Acute
TUESDAY
Liver Failure (ALF) Reveals a Dominant B-Cell-Driven
Disease Signature
Patrizia Farci, Fausto Zamboni, Ashley B. Tice, Zhaochun Chen,
Ronald E. Engle, Giacomo Diaz
11:45 AM
219: Analysis of innate and adaptive host immunity
during combination therapy with peginterferon
Lambda-1a and Entecavir in patients with HBeAg(+)
chronic hepatitis B
Sandra Phillips, Sameer Mistry, Antonio Riva, Helen Cooksley,
Stefan Zeuzem, Clive Woffendin, Pei-Jer Chen, Cheng-Yuan Peng,
Ting-Tsung Chang, Stefan Lueth, Robert J. de Knegt, Moon Seok
Choi, Heiner Wedemeyer, Michael Dao, Chang Wook Kim,
Heng C. Chu, Megan Wind-Rotolo, Roger Williams, Elizabeth L.
Cooney, Shilpa Chokshi
12:00 PM
220: Silencing HBV transcription by targeting cccDNA-
bound chromatin modifiers
Gianna Aurora Palumbo, Laura Belloni, Sergio Valente, Dante
Rotili, Natalia Pediconi, Antonello Mai, Massimo Levrero
12:15 PM
221: Long-term persistence of patient-derived hepatitis
B virus infection in 3D microfluidic primary hepatocyte
cultures
Sann Nu Wai, Emma M. Large, David Hughes, Emma Sceats,
Marion Lussignol, Maria Teresa Catanese, Mark R. Thursz, Marcus
Dorner
 90A AASLD PROGRAM
12:30 PM
222: Modeling hepatitis B virus infection in primary
and in inducible pluripotent stem cell-derived human
hepatocytes to study virus-host interactions
Robert E. Schwartz, Amir Shlomai, Vyas Ramanan, Ankit Bhatta,
Ype P. De Jong, Sangeeta Bhatia, Charles M. Rice
Parallel 33: HCV Pathogenesis: Is the
Battle Over?
Tuesday, November 11
11:15 AM - 12:45 PM Room 312
MODERATORS: Steven Weinman, MD, PhD
Kyong-Mi Chang, MD
11:15 AM
223: Long-term therapy-induced viral clearance in
chronic HCV does not lead to normalization of the
intrahepatic T cell compartment
Michelle Spaan, Mark Claassen, Harry L. Janssen, Robert J. de
Knegt, Andre Boonstra
11:30 AM
224: Reversal of T cell exhaustion in chronic HCV-
NOVEMBER 11
infected patients receiving direct-acting antivirals
TUESDAY
Matthew A. Burchill, Lucy Golden-Mason, Hugo R. Rosen
11:45 AM
225: Rapid Decrease in Hepatitis C Virus Viremia by
Direct Acting Antivirals Improves the Innate Immune
Response to IFNα
Elisavet Serti, Heiyoung Park, T. Jake Liang, Marc G. Ghany,
Barbara Rehermann
12:00 PM
226: A P70S Variant of the IFNλ4 Protein Displaying
Decreased Activity is Associated with Improved
Hepatitis C Virus Clearance and Reduced Hepatic
Expression of Interferon-Stimulated Genes
Ewa Terczynska-Dyla, Stephanie Bibert, Francois H. Duong, Ilona
Krol, Emilie Collinet, Zoltan Kutalik, Vincent Aubert, Andreas
Cerny, Laurent Kaiser, Raffaele Malinverni, Alessandra Mangia,
Darius Moradpour, Beat Mullhaupt, Francesco Negro, Rosanna
Santoro, David Semela, Nasser Semmo, Markus H. Heim, Pierre-
Yves Bochud, Rune Hartmann
12:15 PM
227: Epigenetic Analysis of the IFNλ3 Gene Identifies a
Novel Marker for Response to Therapy in HCV-infected
Subjects
Jeffrey F. Waring, Emily Dumas, Eoin Coakley, Daniel E. Cohen,
Kenneth B. Idler, Ujjwal Das, Thomas Podsadecki, Sandeep Dutta
HEPATOLOGY, October, 2014
12:30 PM
228: Hepatitis C Virus Eludes IFN-mediated Antiviral
Responses by Producing a Genomic Reservoir Protected
in Double-stranded RNA; Ribavirin Blocks this Escape
Strategy
Arielle L. Klepper, Francis J. Eng, Adeeb Rahman, Brannon
Weeks, Ahmed El-Shamy, Erin H. Doyle, M. Isabel Fiel, Gonzalo
Carrasco-Avino, Sasan Roayaie, Meena B. Bansal, Margaret R.
MacDonald, Thomas D. Schiano, Andrea D. Branch
Parallel 34: Hepatitis B: Outcomes of
Approved Therapy
Tuesday, November 11
11:15 AM - 12:45 PM Ballroom A/B/C
MODERATORS: Harry L. Janssen, MD, PhD
Daryl Lau, MD, MPH
11:15 AM
229: Long Term Treatment with Tenofovir Disoproxil
Fumarate for Chronic Hepatitis B Infection is Safe and
Well Tolerated and Associated with Durable Virologic
Response with no Detectable Resistance: 8 Year Results
from Two Phase 3 Trials
Patrick Marcellin, Edward J. Gane, Robert Flisiak, Huy N. Trinh,
Joerg Petersen, Selim Gurel, Kelly D. Kaita, Iskren A. Kotzev,
Naoky Tsai, John F. Flaherty, Raul E. Aguilar Schall, Kathryn M.
Kitrinos, Mani Subramanian, John G. McHutchison, Jacob George,
Harry L. Janssen, Maria Buti
11:30 AM
230: The Safety and Efficacy of Entecavir and Tenofovir
Combination Therapy for Chronic Hepatitis B in Patients
with Previous Nucleos(t)ide Treatment Failure: Week 96
Results of the ENTEBE study
Fabien Zoulim, Maciej S. Jablkowski, Mircea. Diculescu, Joerg
Petersen, Patrick Marcellin, Soumaya Bendahmane, Aleksandra
Kedzierska, Krzysztof. Simon, Harry L. Janssen
11:45 AM
231: Tenofovir Disoproxil Fumarate Alone or in
Combination With Entecavir in Patients With Entecavir-
Resistant Chronic Hepatitis B: Multicenter Randomized
Trial
Young-Suk Lim, Kwan Soo Byun, Geum-Youn Gwak, Byung Chul
Yoo, So Young Kwon, Yoon Jun Kim, Jihyun An, Han Chu Lee,
Yung Sang Lee
12:00 PM
232: Incidence of Hepatocellular Carcinoma (HCC) in a
US Cohort of Chronic Hepatitis B (CHB) Patients by Age,
Gender, Cirrhosis and Antiviral Treatment Status
Derek Lin, Nghia H. Nguyen, Joseph Hoang, Vinh D. Vu, Huy N.
Trinh, Jiayi Li, Jian Q. Zhang, Huy A. Nguyen, Khanh Nguyen,
Mindie H. Nguyen
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD PROGRAM
12:15 PM
233: Timing of hepatocellular carcinoma (HCC)
development and predictability of a modified PAGE-B
risk score in caucasian chronic hepatitis B (CHB) patients
treated with entecavir (ETV) or tenofovir (TDF)
George V. Papatheodoridis, George N. Dalekos, Vana Sypsa,
Cihan Yurdaydin, Maria Buti, Ioannis Goulis, Heng Chi, Spilios
Manolakopoulos, Giampaolo Mangia, Nikolaos Gatselis,
Onur Keskin, Savvoula Savvidou, Bettina E. Hansen, Jiannis
Vlachogiannakos, Kostas Galanis, Ramazan Idilman, Massimo
Colombo, Rafael Esteban, Harry L. Janssen, Pietro Lampertico
12:30 PM
234: Understanding hepatitis delta virus dynamics and
antiviral efficacy of the prenylation inhibitor lonafarnib
Laetitia Canini, Christopher Koh, Scott Cotler, Cihan Yurdaydin,
Stewart Cooper, David Cory, Vanessa Haynes-Williams, Mark A.
Winters, Ingrid C. Choong, Jay H. Hoofnagle, Jeffrey Glenn, Theo
Heller, Harel Dahari
Parallel 35: Hepatitis C: New Agents -
Part 2
Tuesday, November 11
11:15 AM - 12:45 PM Auditorium
MODERATORS: Fredric D. Gordon, MD
Shyam Kottilil, MD, PhD
11:15 AM
235: Retreatment of Patients Who Failed Prior
Sofosbuvir-Based Regimens with All Oral Fixed-Dose
Combination Ledipasvir/Sofosbuvir Plus Ribavirin for
12 Weeks
David L. Wyles, Paul J. Pockros, Jenny C. Yang, Yanni Zhu, Phillip
S. Pang, John G. McHutchison, Steven L. Flamm, Eric Lawitz
11:30 AM
236: Efficacy and safety of MK-5172 + MK-8742
± ribavirin in HCV mono-infected and HIV/HCV
co-infected treatment-naïve, non-cirrhotic patients with
hepatitis C virus genotype 1 infection: The C-WORTHY
study (Final results, Parts A and B)
Mark S. Sulkowski, Christophe Hezode, Jan Gerstoft, John M.
Vierling, Josep Mallolas, Stanislas Pol, Marcelo Kugelmas, Abel
Murillo, Nina Weis, Ronald Nahass, Oren Shibolet, Lawrence
Serfaty, Marc Bourlière, Edwin DeJesus, Eli. Zuckerman, Frank
Dutko, Anita Y. Howe, Melissa Shaughnessy, Peggy Hwang,
Janice Wahl, Michael Robertson, Barbara A. Haber
91A
11:45 AM
237: Safety and Efficacy of Ledipasvir/Sofosbuvir
Single-Tablet-Regimen in African Americans with
Genotype 1 Chronic Hepatitis C Virus: A Retrospective
Analysis of Phase 3 Studies
Lennox J. Jeffers, Julius M. Wilder, Andrew J. Muir, Charles Howell,
Yanni Zhu, Star Seyedkazemi, Jenny C. Yang, Phillip S. Pang, John
G. McHutchison, K. Rajender Reddy
12:00 PM
238: The Pharmacokinetics and Safety of the Direct
Acting Antiviral Regimen of ABT-450/r, Ombitasvir
with/without Dasabuvir in Subjects with Mild, Moderate
and Severe Renal Impairment Compared to Subjects
with Normal Renal Function
Amit Khatri, Sandeep Dutta, Thomas C. Marbury, Richard A.
Preston, Lino Rodrigues-Jr, Haoyu Wang, Walid Awni, Rajeev
Menon
12:15 PM
239: Ledipasvir/Sofosbuvir with Ribavirin for the
Treatment of HCV in Patients with Decompensated
Cirrhosis: Preliminary Results of a Prospective,
Multicenter Study
Steven L. Flamm, Gregory T. Everson, Michael Charlton, Jill M.
Denning, Sarah Arterburn, Theo Brandt-Sarif, Phillip S. Pang, John
NOVEMBER 11
G. McHutchison, K. Rajender Reddy, Nezam H. Afdhal
TUESDAY
12:30 PM
240: All Oral Treatment for Genotype 4 Chronic
Hepatitis C Infection with Sofosbuvir and Ledipasvir:
Interim Results from the NIAID SYNERGY Trial
Rama Kapoor, Anita Kohli, Sreetha Sidharthan, Zayani Sims, Tess
L. Petersen, Anu Osinusi, Amy K. Nelson, Rachel Silk, Colleen
Kotb, Kate Sugarman, Brian P. Lam, Phillip S. Pang, Mani
Subramanian, John G. McHutchison, Henry Masur, Shyam Kottilil,
Vinod K. Rustgi
 92A POSTER SESSIONS
Poster Sessions
Poster Session 1
Saturday, November 8
POSTER VIEWING: 2:00 - 7:30 PM
Hall C
Presenters in attendance:
5:30 - 7:00 PM
Those posters identified as AASLD Presidential Poster of Distinction
by a ribbon icon have received review scores that place them
within the top 10 percent of all posters. We encourage you to
make them a priority as you visit the poster sessions.
Ascites, Renal Dysfunction and
Hepatorenal Syndrome
241: Reversal of Hepatorenal Syndrome Type 1
(HRS-1) with Terlipressin plus Albumin versus Placebo
plus Albumin - Not All Responses Are Created Equal -
An Analysis of the REVERSE and OT-0401 Trials
Arun J. Sanyal, Thomas D. Boyer, R Todd Frederick, Fredric
Regenstein, Lorenzo Rossaro, Victor Araya, Hugo E. Vargas, K.
Rajender Reddy, Khurram Jamil, Stephen Chris Pappas
242: New Multivariate Models to Predict Glomerular
Filtration Rate in Patients with Cirrhosis
Ayse L. Mindikoglu, Thomas C. Dowling, Laurence S. Magder,
Robert H. Christenson, Matthew R. Weir, Stephen L. Seliger,
William R. Hutson, Charles Howell
243: No evidence of reduced mortality due to albumin
NOVEMBER 8
substitution in HCC-free cirrhotic patients undergoing
SATURDAY
large volume paracentesis: a systematic review and
meta-analysis
Fabian Kütting, Jens Schubert, Jeremy Franklin, Agnes Pelc,
Andrea Bowe, Vera Hoffmann, Münevver Demir, Dirk Nierhoff,
Ulrich Toex, Hans-Michael Steffen
244: Serum creatinine within 48 hours after
hospitalization is a strong predictor of mortality in
patients with cirrhosis with complications provided the
peak creatinine is above 1.2 mg/dl
Anantha Nuthalapati, Nicholas Schluterman, Deborah Greenberg,
Anuj Khanna, Paul J. Thuluvath
245: Unprecipitated acute kidney injury can occur
amongst stable patients with cirrhosis and ascites but
no other complications
Florence Wong, Peter Jepsen, Hugh R. Watson, Hendrik V. Vilstrup
246: Evaluation of serum cystatin C as a marker of
early renal impairment in patients with liver cirrhosis
Mahmoud S. Omar, Wael Abdel-Razek, Gamal Abo-Raia, Medhat
Assem, Gasser El-Azab
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
247: Chronic Kidney Disease Epidemiology
Collaboration Equation combining Creatinine and
Cystatin C is superior to other Creatine- and Cystatin
C-based Equations in Assessing Renal Function in
Patients with Cirrhosis
Elisabeth Krones, Sabine Zitta, Stefan Neunherz, Katharina
Artinger, Tatjana Stojakovic, Gilbert Reibnegger, Franziska
Durchschein, Juliana Buchgrabner, Vanessa Stadlbauer, Peter
Fickert, Alexander R. Rosenkranz
248: Bile pigment nephropathy and acute tubular
necrosis in decompensated cirrhotics and acute on
chronic liver failure
Suman Nayak, Rajendra P. Mathur, Sivaramakrishnan
Ramanarayanan, Gyan Prakash, Shiv K. Sarin, Chitranshu
Vashishtha, Manoj Kumar, Rakhi Maiwall, Ajeet S. Bhadoria
249: Plasma Renin concentration is associated with
portal hypertension, liver dysfunction, ascites and
hyponatremia and may predict mortality in cirrhosis
Rafael Paternostro, Simona Bota, Philipp Schwabl, Remy
Schwarzer, Thomas Reiberger, Mattias Mandorfer, Monika
Ferlitsch, Michael Trauner, Markus Peck-Radosavljevic, Arnulf
Ferlitsch
250: Alpha-2a Adrenoceptor Subtype Stimulation by
Guanfacine Restores Diuretic Efficiency in Experimental
Cirrhosis and Refractory Ascites: Comparison with
Clonidine Effects
Giovanni Sansoe, Manuela Aragno, Raffaella Mastrocola,
Maurizio Parola
251: Albumin Infusions in Patients with Cirrhosis who
Present with Acute Kidney Injury and its Effect on Renal
Function
Derek J. Feussner, Amy P. Myers, James C. Slaughter, Andrew
Scanga
252: Nosocomial spontaneous bacterial peritonitis
is associated with increased mortality compared to
community-acquired spontaneous bacterial peritonitis
Nicolas M. Intagliata, Zachary Henry, Nitin K. Ahuja, Neeral L.
Shah, Curtis K. Argo, Stephen H. Caldwell, Patrick G. Northup
253: Microscopic Urinanalysis May Represent a
Sensitive Test for Kidney Injury in Cirrhotic and
Cholestatic Patients with Preserved Kidney Function
Elisabeth Krones, Julia Fritz, Christoph Schwarz, Franziska
Durchschein, Kathrin Eller, Gernot Zollner, Werner Ribitsch,
Tatjana Stojakovic, Sabine Zitta, Juliana Buchgrabner, Alexander
R. Rosenkranz, Peter Fickert
254: Relative Adrenal Insufficiency in Cirrhotic Patients
with Ascites
Virendra Singh, Rajiv R. Singh, Rama Walia, Naresh Sachdeva,
Ashish Bhalla, Navneet Sharma, Yogesh K. Chawla
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
255: Urinary NGAL Levels Reflect the Therapeutic Effects
of norUDCA in Mice with Cholemic Nephropathy
Elisabeth Krones, Dietmar Glaenzer, Franziska Durchschein,
Alexander Kirsch, Kathrin Eller, Michael Trauner, Alexander R.
Rosenkranz, Peter Fickert
256: Prevalence of hyperdynamic circulation in
cirrhosis: lack of association to presence and severity of
ascites
Cristina Ripoll, Phillip Hohaus, Marcus Hollenbach, Robin A.
Greinert, Alexander Zipprich
257: Outcomes in Patients Receiving Rifaximin along
with Systemic Antibiotics for the Inpatient Treatment of
Spontaneous Bacterial Peritonitis
Jennifer D. Twilla, Anuj Sharma, Satheesh Nair, Emily H. Wong,
Sanjaya K. Satapathy
258: Clinical Predictors of Morbidity and Mortality in
Hospitalized Children with Ascites
Grace Felix, Thammasin Ingviya, Ann O. Scheimann, Pavis
Laengvejkal, Alexandra Vasilescu, Hejab Imteyaz, Eric C.
Seaberg, Wikrom Karnsakul
259: Beyond Dr. Google: Early results of a personalized
weight-tracking smartphone application and alert
system for patients with ascites
Chanda Ho, Neil Shah, Nabil Alshurafa, Behnam Shahbazi,
Hassan Ghasemzadeh, Norah Terrault
260: Determination of renal function through creatinine
and cystatin C-dependent formulas in comparison to
DTPA-Tc-99 clearance in Mexican cirrhotic patients
Jonathan Aguirre-Valadez, Haydee Verduzco-Aguirre, Ariadna
K. Flores-Balbuena, Octavio R. García-Flores, Ricardo Macías-
Rodríguez, Cristino Cruz-Rivera, Jose A. Niño-Cruz, Ignacio
Garcia, Aldo Torre
261: Predictors for the Development of Cardiac Ascites
in Patients Referred for Cardiac Transplantation
Brian Kim, Amy Tan, Berkeley N. Limketkai, Sean Pinney, Thomas
D. Schiano
262: Computer-assisted image analysis of fibrosis on
liver biopsy : relationship with portal pressure, histology
and clinical data
Nicolas Goossens, Sophie Restellini, Sophie Clément, Laura
Rubbia-Brandt, Laurent Spahr
263: Non-invasive measurement of acute hemodynamic
changes using inert gas rebreathing during routine
therapeutic paracentesis in tense ascites
Christoph Antoni, Joachim Saur, Thomas Zimmerer, Nenad
Suvajac, Julia D. Michels, Matthias Ebert, Frederik Trinkmann
264: PTFE-covered TIPS position relative to the
hepatocaval junction and impact on shunt patency
Charles N. Weber, Gregory J. Nadolski, Michael C. Soulen
265: WITHDRAWN
Poster Viewing: 2:00 – 7:30 PM
93A
266: Response guided ascitic tap in spontaneous
bacterial peritonitis predicts outcome
Ashok K. Choudhury, Ankur Jindal, Chandan K. Kedarisetty,
Tanmay S. Vyas, Ajeet S. Bhadoria, Shiv K. Sarin
267: Does transjugular intrahepatic portosystemic shunt
(TIPS) with covered stents modify the natural course of
decompensed cirrhosis?
Xavier Adhoute, Paul Castellani, Guillaume Penaranda, Olivier
Monnet, Herve Perrier, Bernard L. Pol, Cyril Muller, Arthur Laquiere,
Valerie Oules, Patrick Beaurain, Christian Boustiere, Olivier Bayle,
Marc Bourlière
Behavioral, Quality of Life, and Practice
Issues
268: Factors associated with medication adherence
in patients living with cirrhosis
Suzanne Polis, Ling Zhang, Amany Zekry, Ritin Fernandez
269: Children with HCV: The impact of disease and
treatment on patients, caregivers and families
Rachel A. Annunziato, Samantha G. Lee, Elizabeth Galici,
Alexander Newcorn, Ronen Arnon
270: A single-center report of hepatitis A and
hepatitis B vaccination performance in patients with
chronic hepatitis C (CHC): A quality improvement project
Bobbi Jo Quigley, Matthew Kowgier, Colina Yim
271: Two Types of Fatigue in Subjects with Chronic
Liver Disease Can Be Distinguished Through Correlations
NOVEMBER 8
SATURDAY
with Physical Activity and Mental Symptoms
Ali A. Weinstein, Heibatollah Baghi, Carey Escheik, Lynn Gerber,
Zobair Younossi
272: Characteristics of Nutritional Intake in End-Stage
Liver Disease Secondary to Viral Hepatitis, NASH, and
Alcoholic Liver Disease
Anna Marie Hefner, Cynthia D. Connelly, Kathy S. James,
Catherine Hill, Preeti Reshamwala, Tarek Hassanein
Cholangiocyte Biology
273: Absence of the intestinal microbiota
exacerbates hepatobiliary disease in a murine model of
primary sclerosing cholangitis
James H. Tabibian, Steven P. O’Hara, Christy E. Trussoni, Pamela
S. Tietz, Patrick L. Splinter, Taofic Mounajjed, Lee R. Hagey,
Nicholas F. LaRusso
274: Lipopolysaccharide (LPS)-induced cholangiocyte
N-Ras activation requires epidermal growth factor
receptor (EGFR) activation
Christy E. Trussoni, Patrick L. Splinter, James H. Tabibian, Steven
P. O’Hara
Presenters in Attendance 5:30 – 7:00 PM
 94A POSTER SESSIONS
Poster Sessions
275: Ezrin, a membrane cytoskeletal cross-linker is
essential for the regulation of biliary flow in mice
Ryo Hatano, Kaori Akiyama, Shinji Asano
276: Regulation of cholangiocyte IL-6 release by
extracellular adenosine
Elise G. Lavoie, Jessica R. Goree, Michel Fausther, Jonathan A.
Dranoff
277: Role of the miR-125b- regulated HDC/histamine/
VEGF axis during the progression of biliary proliferation
in the PSC/MDR2-/- mouse model
Yuyan Han, Laura Hargrove, Lindsey Kennedy, Allyson B. Graf,
Sharon DeMorrow, Fanyin Meng, Quy P. Nguyen, Victoria Huynh,
Heather L. Francis
278: Characterization of cultured cholangiocytes
isolated from livers of patients with primary sclerosing
cholangitis
Christy Trussoni, James H. Tabibian, Steven P. O’Hara, Patrick L.
Splinter, Julie Heimbach, Nicholas F. LaRusso
Cholestasis and Autoimmune Liver
Disease
279: The Fraction of Bile Ducts Lost in Portal Areas
Correlates with Degree of Fibrosis and Alkaline
Phosphatase Levels in Patients with Primary Biliary
Cirrhosis
Mazen Noureddin, David E. Kleiner, Xiongce Zhao, Jason L.
Eccleston, Daniel Woolridge, Nabil Noureddin, T. Jake Liang, Jay
NOVEMBER 8
H. Hoofnagle, Theo Heller
SATURDAY
280: Altered Functional Connections in the Brain of
Patients With Primary Biliary Cirrhosis are Associated
with Fatigue
Victoria Mosher, Mark G. Swain, Robert P. Myers, Glenda M.
MacQueen, Bradley G. Goodyear
281: Sub-stratification of hepatocellular carcinoma
risk in men with primary biliary cirrhosis: results of an
international multicenter study
Palak J. Trivedi, Willem J. Lammers, Henk R. van Buuren, Annarosa
Floreani, Albert Pares, Angela C. Cheung, Cyriel Y. Ponsioen,
Christophe Corpechot, Marlyn J. Mayo, Pietro Invernizzi, Pier
Maria Battezzati, Frederik Nevens, Andrew Mason, Kris V.
Kowdley, Ka-Kit Li, Tony Bruns, Mohamad Imam, Teru Kumagi,
Nora Cazzagon, Irene Franceschet, Llorenc Caballeria, Kirsten
Boonstra, Raoul Poupon, Ana Lleo, Keith D. Lindor, Harry L.
Janssen, Bettina E. Hansen, Gideon Hirschfield
282: A Mouse Model of Fibrous Cholangiopathy
Sumera Rizvi, Anuradha Krishnan, Maria Eugenia Guicciardi,
Steven F. Bronk, Gregory J. Gores
283: Increased BMI is associated rapid progression
of fibrosis in Primary Sclerosing Cholangitis (PSC)
Aliya Gulamhusein, Danielle Reid, Bertus Eksteen
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
284: Activation of mDCs and CD8+ T cells is
associated with PSC-like cholangiopathy induced by
small bowel bacterial overgrowth in a mouse model of
autoimmune biliary disease
Qingqing Wang, Vijay Saxena, Bin Wang, Lili Miles, Marnie A.
Ryan, Jorge A. Bezerra, William M. Ridgway, Jaimie D. Nathan
285: Changes of the hepatic transcriptome in human
extrahepatic cholestasis
Frank G. Schaap, Marlon J. Jetten, Marcel H. Herwijnen, Maarten
L. Coonen, Jos C. Kleinjans, Peter L. Jansen, Steven Olde Damink
286: High serum levels and liver expression of
sclerostin in patients with primary biliary cirrhosis.
Association with markers of bone remodeling and
severity of cholangitis
Silvia Ruiz-Gaspa, Laia Gifre, Nuria Guañabens, Rosa Miquel,
Pilar Peris, Ana Monegal, Albert Pares
287: Contribution of polymorphic LINE-1
retrotransposon insertion in SLCO1B3 gene to
susceptibility to drug-induced cholestasis
Tatehiro Kagawa, Kazuya Anzai, Kota Tsuruya, Yoshitaka Arase,
Shunji Hirose, Koichi Shiraishi, Tetsuya Mine
288: The role of repeated brush cytology in detecting
dysplasia or cholangiocarcinoma in primary sclerosing
cholangitis before liver transplantation
Ammar Majeed, Annika Bergquist, Gunnar Söderdahl, Maria
Castedal, Karouk Said
289: Contribution of Next Generation Sequencing to
the genotyping of patients with hereditary cholestasis
and cholelithiasis
Véronique D. Barbu, Isabelle Jéru, Christophe Corpechot, Eric
Fernandez, Laure Muller, Fabienne Dufernez, Olivier Chazouillères,
Yannick Marie, Zhenyu Xu, Chantal Housset
290: Fenofibrate is Effective adjunctive Therapy in
the Treatment of Primary Biliary Cirrhosis: A Meta-
Analysis
Alla Grigorian, Houssam E. Mardini, Christophe Corpechot, Raoul
Poupon, Cynthia Levy
291: Fenofibrates do not improve transplant-free
survival despite biochemical response in patients with
primary biliary cirrhosis
Angela C. Cheung, Javier M. Meza-Cardona, Matthew Kowgier,
E. Jenny Heathcote, Harry L. Janssen, Jordan J. Feld
292: Assessment of Environmental Exposures among
1000 North American Primary Sclerosing Cholangitis
Patients with and without Inflammatory Bowel Disease
John E. Eaton, Brian D. Juran, Elizabeth J. Atkinson, Erik M.
Schlicht, Xiao Xie, Mariza de Andrade, Craig Lammert, Velimir
A. Luketic, Joseph A. Odin, Ayman A. Koteish, Kris V. Kowdley,
Kapil B. Chopra, Gideon M. Hirschfield, Naga P. Chalasani,
Konstantinos Lazaridis
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
293: Efficacy Trial of All-trans Retinoic Acid (ATRA)
in combination with Ursodeoxycholic Acid (UDCA) in
Primary Sclerosing Cholangitis (PSC)
David N. Assis, Osama Abdelghany, Shi-Ying Cai, Andrea A.
Gossard, John E. Eaton, Jill C. Keach, Yanhong Deng, Stephenson
W. Nkinin, Kenneth D R. Setchell, Maria Ciarleglio, Keith D.
Lindor, James L. Boyer
294: Galectin-3 Plays a Role in Primary Biliary
Cirrhosis by Mediating Inflammasome Signaling
Jijing Tian, Tzu-I Chao, Yu Sasaki, Fu-Tong Liu, M. Eric Gershwin,
Natalie Torok, Joy Jiang
295: An International Phase 3 Study of the FXR Agonist
Obeticholic Acid in PBC Patients: Effects on Markers
of Cholestasis Associated with Clinical Outcomes and
Hepatocellular Damage
Frederik Nevens, Pietro Andreone, Giuseppe Mazzella, Simone I.
Strasser, Christopher L. Bowlus, Pietro Invernizzi, Joost Drenth, Paul
J. Pockros, Jaroslaw Regula, Michael Trauner, Annarosa Floreani,
Simon Hohenester, Velimir A. Luketic, Mitchell L. Shiffman, Karel J.
van Erpecum, Victor Vargas, Catherine Vincent, Bettina E. Hansen,
Roya Hooshmand-Rad, Shawn Sheeron, David Shapiro
296: Noninvasive testing are poor surrogate markers
for fibrosis staging and liver-related outcomes in
patients with primary biliary cirrhosis who do not
respond to ursodeoxycholic acid
Angela C. Cheung, Javier M. Meza-Cardona, Matthew Kowgier,
Harry L. Janssen, Jordan J. Feld
297: Applicability and Prognostic Value of Histologic
Scoring Systems in Primary Sclerosing Cholangitis
Elisabeth M. de Vries, Joanne Verheij, Stefan G. Hubscher,
Mariska M. Leeflang, Kirsten Boonstra, Ulrich Beuers, Cyriel Y.
Ponsioen
298: Relation of gallbladder enlargement with bile
acid homeostasis and colorectal malignancy in primary
sclerosing cholangitis
Mourad Aissou, Lionel Arrivé, Dominique Rainteau, Sara Lemoinne,
Astrid Donald D. Kemgang Fankem, Delphine Firrincieli, Nicolas
Chignard, Christophe Corpechot, Olivier Chazouillères, Chantal
Housset
299: Do patients with “early” PBC benefit from UDCA
treatment? -results from the nationwide cohort study in
Japan-
Atsushi Tanaka, Junko Hirohara, Yasuni Nakanuma, Hirohito
Tsubouchi, Hajime Takikawa
300: A possible involvement of endoplasmic reticulum
stress in the process of biliary epithelial autophagy and
senescence in primary biliary cirrhosis
Motoko Sasaki, Masami Miyakoshi, Yasunori Sato, Yasuni
Nakanuma
301: Younger patients presenting with Primary Biliary
Cirrhosis are more likely to have cognitive impairment
Laura Griffiths, David Jones, Jessica K. Dyson, George F. Mells,
Richard N. Sandford
Poster Viewing: 2:00 – 7:30 PM
95A
302: Ongoing Activation of Autoantigen-Specific B cells
in Primary Biliary Cirrhosis
Jun Zhang, Weici Zhang, Patrick S. Leung, Christopher L. Bowlus,
Sandeep S. Dhaliwal, Ross L. Coppel, Aftab A. Ansari, Guo-Xiang
Yang, Jinjun Wang, Thomas P. Kenny, Xiao-Song He, M. Eric
Gershwin
303: Risk stratification in primary biliary cirrhosis using
the UK-PBC Research Cohort
Marco Carbone, Stephen Sharp, Michael A. Heneghan, James
Neuberger, Gideon M. Hirschfield, Andrew K. Burroughs, Andrew
Bathgate, Mervyn H. Davies, Carolyn Adgey, Paul Trembling, Kate
D. Williamson, Laura Griffiths, Teegan R. Lim, Nick Wareham,
David E. Jones, Graeme J. Alexander, Richard N. Sandford,
Heather J. Cordell, George F. Mells
304: NGM282 is a Potent Modulator of Bile Acid
Synthesis in Humans via Suppression of CYP7A1
Activity
Stephen Rossi, Michael Elliott, Kenneth D. Setchell, Stephenson W.
Nkinin, Jian Luo, Lei Ling, Krishna P. Allamneni, Hui Tian, Alex M.
DePaoli
305: Obeticholic Acid in PBC Patients: The Utility
of Titration Based on Therapeutic Response and
Tolerability
Christopher L. Bowlus, Paul J. Pockros, Joost Drenth, Annarosa
Floreani, Catherine Vincent, Velimir A. Luketic, Karel J. van
Erpecum, Victor Vargas, Mitchell L. Shiffman, Frederik Nevens,
Richard Pencek, Roya Hooshmand-Rad, David Shapiro
306: Clinical Course And Outcome Of Patients With
Sclerosing Cholangitis In Critically Ill Patients (Sc-Cip):
NOVEMBER 8
High Mortality Without Liver Transplantation
SATURDAY
Harald Hofer, Gernot Zollner, Peter Fickert, Ivo Graziadei, Michael
Trauner
307: Successful Immunotherapy of Autoimmune
Cholangitis by Adoptive Transfer of Foxp3+ Regulatory
T Cells
Hajime Tanaka, Weici Zhang, Guo-Xiang Yang, Koichi
Tsuneyama, Patrick S. Leung, Ross L. Coppel, Aftab A. Ansari,
Zhe-Xiong Lian, William M. Ridgway, M. Eric Gershwin
308: Protein Profiles of Apoptotic Bodies from Biliary
Epithelial Cells
Ana Lleo, Weici Zhang, W. Hayes McDonald, Patrick S. Leung,
Ross L. Coppel, Aftab A. Ansari, David H. Adams, Simon C.
Afford, Pietro Invernizzi, M. Eric Gershwin
309: Efficacy of Obeticholic Acid In Primary Biliary
Cirrhosis as Assessed by Response Criteria Associated
With Clinical Outcome: A Poise Analysis
Velimir A. Luketic, Pietro Invernizzi, Michael Trauner, Jaroslaw
Regula, Giuseppe Mazzella, Simone I. Strasser, Annarosa
Floreani, Simon Hohenester, Karel J. van Erpecum, Paul J. Pockros,
Bettina E. Hansen, Henk R. van Buuren, Frederik Nevens, Richard
Pencek, Roya Hooshmand-Rad, David Shapiro
Presenters in Attendance 5:30 – 7:00 PM
 96A POSTER SESSIONS
Poster Sessions
310: FXR Agonist Obeticholic Acid: Pruritus, A Common
Side Effect Ameliorated by Dose Titration
Ulrich Beuers, David E. Jones, Marlyn J. Mayo, Pietro Andreone,
Giuseppe Mazzella, Simon Hohenester, Annarosa Floreani,
Simone I. Strasser, Christopher L. Bowlus, Pietro Invernizzi, Joost
Drenth, Paul J. Pockros, Jaroslaw Regula, Velimir A. Luketic, Karel J.
van Erpecum, Victor Vargas, Catherine Vincent, Roya Hooshmand-
Rad, Shawn Sheeron, David Shapiro
311: Incidence of and Risk Factors for Primary Biliary
Cirrhosis-associated Hepatocellular Carcinoma: Large-
Scale Data from China
Xue-Xiu Zhang, Li-Feng Wang, Zheng Zhang, Fu-Sheng Wang
312: Possible impairment of mucosal-associated
invariant T cells in the liver of patients with primary
biliary cirrhosis
Toru Setsu, Satoshi Yamagiwa, Kentaro Tominaga, Naruhiro
Kimura, Hiroki Honda, Hiroteru Kamimura, Masaaki Takamura,
Minoru Nomoto
313: Circulating bile acids and sterol levels in patients
with cholestatic pruritus. Effects of albumin dialysis
using MARS
Albert Pares, Miriam Perez-Cormenzana, Alvaro Diaz-Gonzalez,
Rebeca Mayo, Azucena Castro, Antoni Mas
314: The neogenesis of high endothelial venules and the
formation of tertiary lymphoid organs in primary biliary
cirrhosis
Hayato Baba, Koichi Tsuneyama
315: Geoepidemiology of primary biliary cirrhosis in
NOVEMBER 8
Central Greece
SATURDAY
Nikolaos Gatselis, Kalliopi Zachou, Asterios I. Saitis, Elias Spyrou,
George K. Koukoulis, George N. Dalekos
316: Hepatic sarcoidosis: To treat or not to treat?
Nicole M. Welch, Andrew Aronsohn, K. Gautham Reddy, Nancy
Reau, Donald M. Jensen, Helen S. Te
317: Age at Presentation and Gender are Predictors
of Increased Mortality Over Long-Term Follow-Up in
Primary Biliary Cirrhosis (PBC)
Jessica K. Dyson, Laura Griffiths, Samantha J. Ducker, David E.
Jones
318: The FXR Agonist Obeticholic Acid (OCA) Improves
Liver Biochemistry Parameters Correlated With Clinical
Benefit Across a Range of Patient Characteristics
Pietro Andreone, Giuseppe Mazzella, Simone I. Strasser,
Christopher L. Bowlus, Pietro Invernizzi, Joost Drenth, Paul J.
Pockros, Jaroslaw Regula, Michael Trauner, Annarosa Floreani,
Simon Hohenester, Velimir A. Luketic, Mitchell L. Shiffman, Karel J.
van Erpecum, Victor Vargas, Catherine Vincent, Bettina E. Hansen,
Frederik Nevens, Richard Pencek, Roya Hooshmand-Rad, Shawn
Sheeron, David Shapiro
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
319: FXR Agonist Obeticholic Acid: Sustained
Improvement in Markers of Cholestasis and Long-Term
Safety in Patients with Primary Biliary Cirrhosis through
4 Years
Kris V. Kowdley, Richard Pencek, Tonya Marmon, David Shapiro,
Roya Hooshmand-Rad
320: Secondary Sclerosing Cholangitis Following Major
Burn Injury
Ella Veitsman, Yael Haviv-Yadid, Oranit Cohen-Ezra, Orit Pappo,
Yael Inbar, Josef Haik, Galia Rahav, Ziv Ben Ari
321: Discrepant Expression of miR-139-5p Between
Serum and Liver in Patients with Primary Biliary
Cirrhosis, and its Possible Cellular Origin
Tomohiro Katsumi, Masashi Ninomiya, Kyoko Tomita, Chikako
Sato, Kazuo Okumoto, Yuko Nishise, Hisayoshi Watanabe,
Takafumi Saito, Yoshiyuki Ueno
322: Patient Experience and Characteristics of
Cholestatic Pruritus in the UK-PBC Research Cohort
Vinod S. Hegade, George F. Mells, Ulrich Beuers, Andreas E.
Kremer, Pietro Invernizzi, Tom H. Karlsen, Gideon Hirschfield,
Richard N. Sandford, Stuart Kendrick, David E. Jones
323: HLA-DR3 transgenic NOD mice, a novel model for
autoantigen induced autoimmune hepatitis
Yipeng Wang, Muhammed Yuksel, Junhua Guo, Ningwen Tai,
Xiaoyan Xiao, Pascal Lapierre, David Chella, Huiping Yan, Isabelle
Colle, Giorgina Mieli Vergani, Diego Vergani, Yun Ma, Li Wen
324: Long term follow-up and 10-year outcomes of
second-line therapy in Autoimmune Hepatitis
Daniel Klintman, Naina Shah, Javier Bustamante, Michael A.
Heneghan
325: Circulating macrophage activation markers,
CD163 and CD206, are associated with disease severity
and treatment response in patients with autoimmune
hepatitis
Henning Gronbaek, Martin Kreutzfeldt, Niels Jessen, Sidsel
Rødgaard-Hansen, Konstantin Kazankov, Thomas D. Sandahl,
Hendrik V. Vilstrup, Holger J. Møller
326: Can a dietary supplement induce autoimmune
hepatitis?
Marina Roytman, Peter Poerzgen, Christine L. Lee, Leslie
Huddleston, Peter K. Bryant-Greenwood, Timothy Kuo, Linda L.
Wong, Naoky Tsai
327: Analysis of Liver Stiffness Measured by Transient
Elastography in Autoimmune Hepatitis
Ja Kyung Kim, Hae Won Kim, Jung Il Lee, Kwan Sik Lee
328: The IL-7/CD127 axis negatively modulates the
function of regulatory T-cells in autoimmune hepatitis
Rodrigo Liberal, Charlotte R. Grant, Yun Ma, Michael A.
Heneghan, Giorgina Mieli-Vergani, Diego Vergani, Maria Serena
Longhi
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
329: Down-regulation of hepcidin production in patients
with autoimmune liver diseases
Nikolaos Gatselis, Aggeliki Lyberopoulou, Kalliopi Zachou,
Georgia Chachami, Petros Eliades, Stella Gabeta, Efrosyni
Paraskeva, Avgi Mamalaki, George K. Koukoulis, George Simos,
George N. Dalekos
330: Prevalence, Natural History And Outcome Of
Overlap Syndrome Versus Autoimmune Hepatitis In The
Indian Continent
Lovkesh Anand, Cyriac A. Philips, Varsha Bhat, Chhagan Bihari,
Ajeet S. Bhadoria, Shiv K. Sarin
331: Prednisolone Changes mRNA and lincRNA
Expression Profiles to Suppress Autoimmunity in CD4+ T
Cells of Autoimmune Hepatitis Type 1
Ryo Nakagawa, Ryosuke Muroyama, Sayaka Ito, Keiko Takano,
Wenwen Li, Kaku Goto, Masanori Nakano, Chisato Saeki, Yasuo
Matsubara, Naoya Kato, Mikio Zeniya
332: Fast corticosteroid tapering and early fibrosis
stages: important risk factors for type 1 autoimmune
hepatitis relapse in Japan
Atsushi Takahashi, Kazumichi Abe, Hiromasa Ohira, Yasuhiro
Miyake, Masanori Abe, Kazuhide Yamamoto, Yoshiyuki Suzuki,
Morikazu Onji, Hirohito Tsubouchi
333: Serum sterol levels indicate distorted cholesterol
homeostasis in cirrhotic patients with primary biliary
cirrhosis
Marcin Krawczyk, Ewa Wunsch, Dieter Luetjohann, Frank Lammert,
Piotr Milkiewicz
334: Metabolic syndrome induces a more rapid
progression of fibrosis evaluated with transient
elastography in early primary biliary cirrhosis
Nora Cazzagon, Laura Costa, Irene Franceschet, Alessandra Buja,
Liliana Chemello, Luisa Cavalletto, Francesco P. Russo, Annarosa
Floreani
335: Fibrates improve liver tests in primary sclerosing
cholangitis with incomplete biochemical response to
ursodeoxycholic acid: update of a pilote study
Sara Lemoinne, Christophe Corpechot, Astrid Donald D. Kemgang
Fankem, Farid Gaouar, Raoul Poupon, Olivier Chazouillères
336: Related Factors for Treatment-Dependent
Autoimmune Hepatitis
Berna Gürsel, Fulya Gunsar, Funda Yilmaz, Zeki Karasu, Galip
ERsoz, Ulus S. Akarca
Donor Factors and Allocation
337: Successful ex-vivo normothermic oxygenated
machine perfusion of human donor livers
Janske Reiling, David S. Lockwood, Andrew H. Simpson, Catherine
M. Campbell, Kim Bridle, Nishreen Santrampurwala, Laurence J.
Britton, Darrell H. Crawford, Cornelis H. Dejong, Jonathan Fawcett
Poster Viewing: 2:00 – 7:30 PM
97A
338: Serum zinc levels are associated with
decompensated liver function and reduced survival in
patients awaiting liver transplantation
Kilian Friedrich, Christian Rupp, Andreas Wannhoff, Wolfgang
Stremmel, Daniel Gotthardt
339: The impact of Model for End Stage Liver
Disease Sodium (MELD-Na) prioritization for liver
transplantation on wait list and post-transplant survival
Sheeva Johnson, Barry Schlansky, Willscott E. Naugler
340: Impact of Donation after cardiac death (DCD)
allografts on incidence and severity of recurrent
hepatitis C (HCV) and graft survival post liver
transplantation (LT) for HCV
Shiva Kumar, Rachel Pedersen
341: Improving the Quality of MELD Upgrade Petitions
for Hepatocellular Carcinoma Beyond the Milan Criteria
in UNOS Region 8
Joel P. Wedd, Jane Gralla, Betsy Gans, Sue Dunn, Harvey
Solomon, Michael D. Voigt, Scott W. Biggins
342: Utilization of Simultaneous Liver-Kidney
Transplants Continues to Vary Dramatically by UNOS
Region
Paul J. Gaglio, Wendy Rabbenou, Sander S. Florman, Tomoaki
Kato, Milan Kinkhabwala, Glyn Morgan, Mark S. Orloff, Lewis
Teperman, Samantha DeLair
343: Palliative Care Utilization in ESLD Patients Denied
Transplant Candidacy
Sean G. Kelly, Parul D. Agarwal
NOVEMBER 8
SATURDAY
344: Waiting for liver transplant (LT): Outcomes for
LT candidates listed with low MELD without exception
points
Allison J. Kwong, Jennifer C. Lai, Jennifer L. Dodge, John P. Roberts
345: Predicting Recurrent Hepatocellular Carcinoma
and Survival after Liver Transplantation: The importance
of time to transplant
Marypat Pauly, Bradley Winston, Jean-Luc Szpakowski, Lisa M.
Nyberg, David H. Smith, Jin Sun, Alice Ducey, Celia D. Clarke,
Barbara Piasecki, Ruth Brentari
346: Value Of Preoperative Evaluation Of Cadavaric
Liver Donors With Transient Elastography In Marginal
Liver Donors
Remy Schwarzer, Simona Bota, Rafael Paternostro, Jagdeep
Singh, Tamara Braunschmid, Ferdinand Mühlbacher, Clemens
Kietaibl, Thomas Reiberger, Mattias Mandorfer, Michael Trauner,
Markus Peck-Radosavljevic, Gabriela Berlakovich, Arnulf Ferlitsch
347: Significance of Initial Poor Function after Liver
Transplantation
Gilles Uijtterhaegen, Thamara Perera, Jan R. Colpaert, Hans Van
Vlierberghe, Roberto Troisi, Xavier Rogiers, Darius Mirza
348: WITHDRAWN
Presenters in Attendance 5:30 – 7:00 PM
 98A POSTER SESSIONS HEPATOLOGY, October, 2014

Poster Sessions
349: Clinician Assessments of Health Status Predict
Need for Liver Transplant (LT) Independent of MELD,
Especially in Women
Jennifer C. Lai, Kenneth E. Covinsky, Hilary Hayssen, Blanca C.
Lizaola, John P. Roberts, Norah Terrault, Sandy Feng
350: Transplant-needed alcoholic cirrhosis: which
patients can reach the transplant waiting list? A
preliminary case-control study
Benjamin Rolland, Anne Clerget, Alexandre Louvet, Sébastien
Dharancy, Philippe Mathurin, Olivier COTTENCIN
351: The Impact of an Institutional Change in
Prothrombin Time Methodology on INR and MELD
Scores in Liver Transplant Evaluations
Dennis Kumral, Nicolas M. Intagliata, Neeral L. Shah, Stephen H.
Caldwell, Patrick G. Northup, Curtis K. Argo
Encephalopathy and Other
Complications
352: iPod Video Games Training Improves Overall
Cognitive Performance in Patients with Covert Hepatic
Encephalopathy
Jasmohan S. Bajaj, Leroy Thacker, Douglas M. Heuman, James
Hovermale, Edith A. Gavis, HoChong Gilles, Melanie White,
James Wade
353: The role of probiotics in the treatment of
minimal hepatic encephalopathy. A prospective,
randomized, placebo-controlled, double-blind study
NOVEMBER 8
358: Hepatic and Renal expression of the ammonia
transporter Rhesus protein (Rhcg) plays a critical
role in modulating hyperammonemia and hepatic
encephalopathy in liver failure
Yalda Sharifi, Gavin Wright, Nathan Davies, Abeba Habtesion,
Fausto Andreola, Rajiv Jalan
359: Pentoxifylline therapy for hepatopulmonary
syndrome: Longer duration is superior to combination
with rifaximin, a RCT
Naveen Kumar, Chandan K. Kedarisetty, Sachin Kumar, Ankur
Jindal, Ajeet S. Bhadoria, Shiv K. Sarin
360: Prevalence of Bone Disease in Cirrhosis
Mohamed A. Chinnaratha, Rosemary J. McCormick, Rachel
Wundke, Richard J. Woodman, Alan J. Wigg
361: Branched-chain amino acids improve intestinal
malabsorption of dietary long-chain fatty acids and
preserve intestinal fatty acid transporters in liver
cirrhosis
Yasunori Yamamoto, Hiroki Utsunomiya, Teruki Miyake, Keitaro
Kawasaki, Hiroaki Nunoi, Kenichirou Mori, Yoshio Ikeda, Yoichi
Hiasa
362: Association between Malnutrition in Patients
with Liver Cirrhosis and the Presence of Hepatic
Encephalopathy
Astrid Ruiz-Margáin, Ricardo Macías-Rodríguez, Andres Duarte-
Rojo, Angeles Espinosa-Cuevas, Aldo Torre
363: Bumetanide normalizes brain edema in rats
with bile duct ligation: evidence for increased BBB

Jiannis Vlachogiannakos, Panayota Vasianopoulou, Nikos Viazis,

permeability via NKCC1
SATURDAY

Matilda Chroni, Theodoros Voulgaris, Spiros D. Ladas, Dimitrios

Jimmy Huynh, Cristina R. Bosoi, Christian Parent-Robitaille,
G. Karamanolis
Mélanie Tremblay, Christopher F. Rose
354: Differential expression of neurodegeneration
364: Incidence and outcome of newly diagnosed portal
related genes in a new model of episodic hepatic
vein thrombosis in patients with cirrhosis awaiting liver
encephalopathy
transplantation
Teresa García-Lezana, Jordi Romero-Giménez, Laia Chavarria,
Cindy S. Law, Manjil Chatterji, Kristina Chacko, Thomas D.
Marc Oria, Joan Genescà, Juan Cordoba
Schiano, Charissa Y. Chang
355: Ammonia acts as a damage associated
365: The determination of prognosis and disease
molecular pattern (DAMP) producing multi organ injury
progression in patients with established cirrhosis
and inflammation through a Toll-Like-Receptor-4 (TLR4)
Zita Galvin, Audrey Dillon, Jennifer Russell, Damien Lowry,
dependent pathway
Stephen Stewart
Yalda Sharifi, Gavin Wright, Francesco De Chiara, Nathan
Davies, Laia Chavarria, Marc Oria, Francesco Scaravilli, Rajiv
366: Effect of lactulose administration on gut microbiota
Jalan
in patients with liver cirrhosis
Rakesh Aggarwal, Amit Goel, Aditya N. Sarangi, Ankur Singh,
356: Portal hypertension due to outflow block in non-
S. Avani
cirrhotic patients with nonalcoholic fatty liver disease
Yohei Koizumi, Masashi Hirooka, Hironori Ochi, Fujimasa Tada,
367: Relation of CT determined Sarcopenia to
Teruki Miyake, Yoshio Tokumoto, Atsushi Hiraoka, Masanori Abe,
Anthropometry, Dietary Calorific and Protein Intake and
Bunzo Matsuura, Yoichi Hiasa
Survival in Patients with Chronic Liver Disease
Sarah E. Brown, Ziva Mrevlje, Frances Dorman, Natasha Vidas,
357: Adrenal insufficiency is associated with the
Pauline A. Kane, Michael A. Heneghan, Julia Wendon, William
clinical outcome in patients with decompensated
Bernal
cirrhosis
Evangelos Cholongitas, Ioannis Goulis, George Kokkonis,
Parthenis Chalevas, Spyros Gerou, Evangelos Akriviadis
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
368: Comparison of Psychometric Hepatic
Encephalopathy Score (PHES) and Inhibitory Control Test
(ICT) in diagnosis of minimal hepatic encephalopathy
Jerzy Jaroszewicz, Justyna Zbrzezniak, Natalia Kilisinska,
Agnieszka Stawicka, Aleksandra Swiderska, Mateusz Panasiuk,
Tadeusz W. Lapinski, Robert Flisiak
369: Comorbid Conditions and Demographic Factors
Associated With Poor Outcome in Cirrhotic Patients
Undergoing Orthopedic Surgery in a Large Health
Maintenance Organization
Eric M. Nyberg, Michael Batech, T Craig Cheetham, Anshuman
Singh
370: The Challenging Diagnosis of Minimal Hepatic
Encephalopathy: Does Critical Flicker Frequency
Correlate to the Psychometric Hepatic Encephalopathy
Score?
Audrey Dillon, Zita Galvin, Stephen Stewart
371: Sarcopenia and Myosteatosis Increase the Risk of
Hepatic Encephalopathy in Cirrhotic Patients
Aldo J. Montano-Loza, Andres Duarte-Rojo, Christopher F. Rose
372: Bacterial antigen translocation in patients with
cirrhosis and minimal hepatic encephalopathy is
associated with increased serum ammonia and nitric
oxide levels
Pablo Bellot, Rocío Gallego-Durán, Alba Moratalla, Javier
Ampuero, Pedro Zapater, Manuela Roger, Blanca Figueruela,
Belén Martínez, José M. González-Navajas, Jose Such, Manuel
Romero-Gómez, Ruben Frances
373: Diabetes causes hepatic encephalopathy through
bacterial translocation—analysis of data from three
randomized controlled trials
Peter Jepsen, Hendrik V. Vilstrup, Hugh R. Watson
374: The combination of MELD-Score and Critical Flicker
Frequency could filter patients needing no further testing
for covert hepatic encephalopathy
Robin A. Greinert, Cristina Ripoll, Marcus Hollenbach, Alexander
Zipprich
375: High Prevalence of Nodular Regenerative
Hyperplasia in Patients with End-Stage Heart Failure
and Outcomes after Cardiac Transplantation
Ken D. Nguyen, Aung Kaung, Anish V. Patel, Michelle Kittleson,
Marc L. Friedman, Maha Guindi, Vinay Sundaram, Tram T. Tran
376: Algorithm for Correcting Vitamin D Deficiency
in Patients Awaiting or Being Evaluated for Liver
Transplantation
Shai Posner, Emily Schonfeld, Alexis Pappas, Dana R. Berg, Kian
Bichoupan, Thomas D. Schiano, Andrea D. Branch, Jonathan
Barsa
Poster Viewing: 2:00 – 7:30 PM
99A
377: Hepatopulmonary syndrome screening in a large
transplant center: Prevalence and impact on survival
Manuel Mendizabal, David S. Goldberg, Federico Piñero, Diego
T. Arufe, Pablo A. Testa, Juan M. Coronel, Maria Pia Raffa, Sergio
Baratta, Luis G. Podesta, Michael B. Fallon, Marcelo O. Silva
378: Disturbed sleep is highly prevalent in patients with
cirrhosis and is independently associated with poor
quality of life
Mollie Jackson, Raghavender Gotur, Edra Nordstrom, Eric S.
Orman, Raj Vuppalanchi, Naga P. Chalasani, Marwan Ghabril
379: Apraxia in Patients with Liver Cirrhosis. Influence
of Hepatic Encephalopathy
Montserrat O. Flavia, Victor Vargas, Carlos Jacas, M. Ventura,
Irene Conejo, Rafael Esteban, Joan Cordoba
380: Trends of Serial MELD Scores has an Incremental
Prognostic Value in Predicting In-Hospital Mortality of
ICU Cirrhotic Patients
Thoetchai Peeraphatdit, Charat Thongprayoon, Niyada Naksuk,
Roongruedee Chaiteerakij, Lewis R. Roberts
381: Metformin reduces hyperammonemia in
portacaval shunted rats inhibiting intestinal glutaminase
activity
Antonio Gil-Gómez, Isidora Ranchal, Ana Isabel Gomez-Sotelo,
Marta García-Valdecasas, Angela Rojas, Jose A. Del Campo,
Manuel Romero-Gómez
382: Cost-effectiveness of rifaximin treatment in patients
with hepatic encephalopathy
Duygu Bozkaya, Andrew C. Barrett, Kristen Migliaccio-Walle
NOVEMBER 8
SATURDAY
383: Fragmented QRS is an independent predictor of
mortality in patients with decompensated cirrhosis
Mehmet Demir
384: Pancreatic congestion in liver cirrhosis correlates
with impaired insulin secretion
Taira Kuroda, Masashi Hirooka, Mitsuhito Koizumi, Hironori Ochi,
Yoshiko Hisano, Kenji Bando, Bunzo Matsuura, Teru Kumagi,
Yoichi Hiasa
385: Correlations of portal hypertensive gastropathy
with clinical/hemodynamic complications and survival
in patients with liver cirrhosis
Hyo Sun Kim, Ki Tae Suk, Eun Jin Kim, Sang Hyun Park, Chang
Seok Bang, Dong Joon Kim
386: Portal vein thrombosis is not associated with
increased mortality in cirrhotic patients
Kristin Berry, Justin Taylor, Iris W. Liou, George N. Ioannou
387: Pre-Transplant Hepatic Encephalopathy is
Associated with Significantly Lower Survival Following
Liver Transplantation
Robert J. Wong, Robert G. Gish, Ramsey Cheung, Aijaz Ahmed
Presenters in Attendance 5:30 – 7:00 PM
 100A POSTER SESSIONS
Poster Sessions
388: Increased risk of Portal Vein Thrombosis in Non-
Alcoholic Steatohepatitis (NASH) and Cryptogenic
Cirrhosis: Evidence for a Thrombophilic State
Jonathan G. Stine, Neeral L. Shah, Curtis K. Argo, Shawn Pelletier,
Stephen H. Caldwell, Patrick G. Northup
389: Hypercalcemia: A complication and predictor of
mortality among patients with severe liver dysfunction
Suman Nayak, Rajendra P. Mathur, Sivaramakrishnan
Ramanarayanan, Gyan Prakash, Shiv K. Sarin, Manoj Kumar,
Chitranshu Vashishtha, Rakhi Maiwall, Ajeet S. Bhadoria
390: Platelet-derived microparticles in decompensated
cirrhosis: relation to blood platelet level and indices of
coagulation
Nicolas M. Intagliata, Stephen H. Caldwell, Christine K. Rudy, Tae
Hee Lee, Patrick G. Northup, Patcharin Pramoonjago, Josephine
Lannigan, Uta Erdbrugger
391: Splenomegaly : splenic volume measurement by
ultrasound, validity and reliability, clinical implications
in liver cirrhosis
Sang Gyune Kim, Young Seok Kim, Hee Jae Jung, Sae Hwan Lee,
Soung Won Jeong, Jae Young Jang, Young Don Kim, Gab Jin
Cheon, Hong Soo Kim, Boo Sung Kim
392: Hepatic encephalopathy may be associated with
enzymatic impairment of ammonia metabolism: Is there
a case for studying urea cycle function in cirrhosis?
Raghavender Gotur, Bryan E. Hainline, Qin Sun, Eric S. Orman,
Naga P. Chalasani, Marwan Ghabril
393: Nutritional assessment in cirrhotic outpatients and
NOVEMBER 8
its impact on quality of life
SATURDAY
Claudia I. Blanco, Ma Guadalupe Martinez Galindo, Alejandro
Ramon R. Angeles Labra, Jose Armando Carmona Castañeda,
Griselda Martínez Ramírez, Adriana López Luría, María D. Avila
Langarica, María A. Barragán Valarezo, Elizabeth Perez Cruz,
Dolores Enciso González, Felipe Zamarripa Dorsey
394: Splenic artery embolization is associated with
increased morbidity and mortality in patients with
cirrhosis or liver transplantation
Indira Donepudi, Narayan Dharel, Angelo H. Paredes, Richard K.
Sterling, R. Todd Stravitz, Brian J. Strife, Mohammad S. Siddiqui,
Scott Matherly, Puneet Puri, Velimir A. Luketic, Carolyn Driscoll,
Arun J. Sanyal
395: Clinical significance of minimal hepatic
encephalopathy
Zita Galvin, Audrey Dillon, Damien Lowry, Jennifer Russell,
Stephen Stewart
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
396: Hyperammonemia (HA) as a Predictor of Episodic
Neurocognitive Dysfunction: Lessons From Clinical
Studies of Patients with Urea Cycle Disorders (UCDs)
and Hepatic Encephalopathy (HE)
Bruce F. Scharschmidt, Richard Rowell, Marzena Jurek, Dion F.
Coakley, Masoud Mokhtarani, Uta Lichter-Konecki, Susan A.
Berry, George Diaz, Brendan Lee, William Rhead, Don C. Rockey,
Marwan Ghabril, Parvez S. Mantry, Robert S. Brown, John M.
Vierling
397: Hepatic Encephalopathy, A Preventable
Readmission: Implementation of Quality Indicators at a
Tertiary Care Center
Abdul Haseeb, Juan F. Gallegos-Orozco
398: Sarcopenia in patients with liver cirrhosis – a
gender specific complication?
Thomas Zimmerer, Thomas Hoertig, Christoph Antoni, Matthias
Ebert, Johanna C. Nissen
399: VIATORR endoprosthesis do not self-expand
to their nominal diameters in cirrhotic livers: new
evidence toward the risk reduction of post-TIPS hepatic
encephalopathy
Filippo Schepis, Francesco Vizzutti, Guido Marzocchi, Pietro
Quaretti, Antonio G. Rampoldi, Roberto Agazzi, Rita Golfieri,
Angelo Luca, Fabrizio Fanelli, Cristian Caporali, Stefano Colopi,
Luigi Rega, Umberto Arena, Ilaria Fiorina, Lorenzo Moramarco,
Aldo Airoldi, Roberto Nani, Matteo Renzulli, Cristina Mosconi,
Raffaele Bruno, Stefano Fagiuoli, Alessandro Cannavale, Tommaso
Di Maira, Stefano Gitto, Erica Villa
400: Portal vein thrombosis significantly increases
mortality in advanced cirrhosis with improved prognosis
being associated with portal vein recanalization
Carlos Noronha Ferreira, Teresa Rodrigues, Patrícia Sousa,
Fernando Ramalho, Paula Alexandrino, José F. Velosa
401: The Performance of Objective Nutrition Assessment
Tools and the Evaluation of Nutritional Intake in the Pre-
Liver Transplant Populatio
Kaleb J. Marr, Abdel Aziz M. Shaheen, Louisa Lam, Lauren
Schock, Melanie Stapleton, Kelly W. Burak, Maitreyi Raman
402: A multicenter survey of the efficacy and safety of
danaparoid sodium treatment for portal vein thrombosis
Takaaki Ohtake, Kunihiko Tsuji, Teruaki Kawanishi, Takuro
Machida, Hideyasu Takagi, Shinichi Mezawa, Yasuyuki Yazaki,
Yasuhisa Shinomura, Yutaka Kohgo
403: Change in epidemiology of chronic liver disease,
2004-2013
Sumeet K. Asrani, Maria A. Kouznetsova, Andrew Masica, Brett
Stauffer, Michael Hagan, Patrick Kamath, James F. Trotter, Fasiha
Kanwal
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
404: Blood Group Non-O is a Risk Factor for Portal
Vein Thrombosis
Elisabeth P. Plompen, Sarwa Darwish Murad, Massimo Primignani,
Elwyn Elias, Jonel Trebicka, Luc Lasser, Bettina E. Hansen, Juan
Carlos Garcia-Pagan, Dominique Valla, Frank W. Leebeek, Harry
L. Janssen
Experimental Cholestasis
405: Role of the microRNA-FoxA2 axis in biliary-
committed progenitor cells during cholestatic liver injury
Kelly McDaniel, Fanyin Meng, Heather L. Francis, Yuyan Han,
Julie Venter, Nan Wu, Morgan Quezada, Ying Wan, Shannon S.
Glaser, Gianfranco Alpini
406: Modulation of β-catenin in experimental
cholestasis: A therapeutic opportunity
Kari Nejak-Bowen, Satdarshan (Paul) S. Monga
407: Post-translational regulation of Polycystin 2 (PC2)
protein expression by ubiquitination and autophagy as
a novel mechanism of cholangiocyte repair and reaction
to biliary damage
Carlo Spirli, Carola M. Morell, Ambra Villani, Luca Fabris, Romina
Fiorotto, Mario Strazzabosco
408: ENDTP1/CD39 deficiency aggravates liver injury
and fibrosis in sclerosing cholangitis model in Mdr2-/-
mice
Zhen-Wei Peng, Naoki Ikenaga, Susan B. Liu, Simon C. Robson,
Yury Popov
409: High Systemic Autotaxin Induces Itch in Mice
Ruth Bolier, Dagmar Tolenaars, Andreas E. Kremer, Joanne
Verheij, Ulrich Beuers, Piter J. Bosma, Ronald Oude Elferink
410: Knockdown of the melatonin receptor, MT2,
enhances biliary hyperplasia and liver fibrosis in
cholestatic bile duct ligated (BDL) mice: novel evidence
for a hepatoprotective role of MT2
Nan Wu, Yuyan Han, Debolina Ray, Julie Venter, Kelly McDaniel,
Allyson Martinez, Shanika Avila, Eugenio Gaudio, Paolo Onori,
Antonio Franchitto, Fanyin Meng, Micheleine Guerrier, Holly A.
Standeford, Gianfranco Alpini, Shannon S. Glaser
411: Attenuated liver fibrosis modulated by miR-141
in secretin knockout mice during cholestatic liver injury
induced by bile duct ligation (BDL)
Yuyan Han, Allyson Martinez, Ying Wan, Kelly McDaniel, Julie
Venter, Heather L. Francis, Holly A. Standeford, Shanika Avila,
Debolina Ray, Haibo Bai, Nan Wu, Yoshiyuki Ueno, Shannon S.
Glaser, Gianfranco Alpini, Fanyin Meng
412: Activation of Sirtuin1 pathway reverses liver injury
in a cholic acid fed mouse model of cholestasis
Supriya Kulkarni, Carol J. Soroka, James L. Boyer
Poster Viewing: 2:00 – 7:30 PM
101A
413: Inhibition of mast cell histamine secretion by
cromolyn sodium treatment decreases BDL-induced liver
inflammation and fibrosis
Laura Hargrove, Fanyin Meng, Lindsey Kennedy, Allyson B. Graf,
Quy P. Nguyen, Yuyan Han, Victoria Huynh, Heather L. Francis
414: Disruption of the normal circadian cycle by
prolonged exposure to darkness attenuates biliary
hyperplasia and liver fibrosis in MDR2 KO mice by
modulation of core clock gene expression
Allyson Martinez, Debolina Ray, Yuyan Han, Fanyin Meng, Julie
Venter, Heather L. Francis, Sharon DeMorrow, Shanika Avila,
Micheleine Guerrier, Kelly McDaniel, Lindsey Kennedy, Haibo Bai,
Holly A. Standeford, Gianfranco Alpini, Shannon S. Glaser
415: Absence of BSEP/ABCB11 protects from cholestatic
liver injury in mice
Claudia D. Fuchs, Gustav Paumgartner, Annika Wahlström,
Peter Chiba, Tatjana Stojakovic, Thierry Claudel, Hanns-Ulrich
Marschall, Michael Trauner
416: Endoplasmic reticulum stress suppresses
hepatic Abcb11 expression but does not induce overt
cholestasis in mice
Anne S. Henkel, Brian E. LeCuyer, Shantel Olivares, Richard Green
417: Central expression of the hypothalamic
neuropeptide galanin is upregulated in rodent models
of primary sclerosing cholangitis
Matthew McMillin, Gabriel A. Frampton, Cheryl Galindo, Heather
L. Francis, Sharon DeMorrow
418: Ezetimibe prevents diosgenin-induced cholestatic
NOVEMBER 8
liver injury in mice
SATURDAY
Yuji Tanaka, Toshinori Kamisako
419: Necroptosis in human primary biliary cirrhosis and
in murine models of bile acid toxicity
Marta B. Afonso, Marta Caridade, Pedro M. Rodrigues, Helena
Cortez-Pinto, Rui E. Castro, Cecília M. Rodrigues
Fibrosis: Clinical and Translational
420: Paracrine Signaling From Transplanted
Hepatocytes But not From Liver Sinusoidal Endothelial
Cells (LSEC) Rescues Mice From Acetaminophen (APAP)-
Induced Acute Liver Failure (ALF)
Preeti Viswanathan, Yogeshwar Sharma, Sriram Bandi, Sanjeev
Gupta
421: Pleiotrophin Regulates the Ductular Reaction
by Controlling the Migration of Cells in Liver Progenitor
Niches
Gregory A. Michelotti, Anikia Tucker, Mariana V. Machado,
Marzena Swiderska-Syn, Steve S. Choi, Leandi Kruger, Katherine
S. Garman, Cynthia A. Moylan, Cynthia D. Guy, Heather
Himburg, John P. Chute, Anna Mae Diehl
Presenters in Attendance 5:30 – 7:00 PM
 102A POSTER SESSIONS
Poster Sessions
422: Vivo Morpholino local inhibition of hepatic
gonadotropin-releasing hormone (GnRH) expression
reduces liver fibrosis in cholestatic rats through
increased miR-125a expression
Debolina Ray, Yuyan Han, Fanyin Meng, Julie Venter, Heather L.
Francis, Sharon DeMorrow, Yoshiyuki Ueno, Matthew McMillin,
Paolo Onori, Haibo Bai, Allyson Martinez, Eugenio Gaudio,
Shannon S. Glaser, Gianfranco Alpini
423: Alternatively activated M2 macrophages promotes
hepatocyte differentiation in hepatic progenitor cell
mediated liver regeneration in acute on chronic liver
failure patients
Dhananjay Kumar, Sheetalnath Rooge, Smriti Shubham, Adil
Bhat, Charvi Syal, Archana Rastogi, Chhagan Bihari, Viniyendra
Pamecha, Anupam Kumar, Shiv K. Sarin
424: The pro-inflammatory and pro-fibrogenic actions
of the HIV-envelope protein gp120 are mediated by
inflammasome activation and miR-29b
Andrea Cappon, Raffaele Bruno, Sandra Gessani, Andrea
Masotti, Fabio Marra
425: Activation of Toll-Like-Receptors (TLR) on isolated
Kupffer cells (KC) and sinusoidal endothelial cells (SEC)
of the liver: Opposing effects on the production of the
vasoconstrictor Thromboxane B2
Julia Schewe, Lisa Selzner, Ingrid Liss, Burkhard Göke, Alexander
L. Gerbes, Christian J. Steib
426: Cannabinoid Receptor 1 is Involved in Hepatic
Inflammation and Fibrosis in Mice by Regulating Bone
Marrow-Derived Monocyte/Macrophage
NOVEMBER 8
SATURDAY
Ping Mai, Le Yang, Lin Wang, Lei Tian, Shuangshuang Jia,
Yuanyuan Zhang, Xin Liu, Lin Yang, Liying Li
427: Hepatic progenitor cells contribute to the
progression of liver fibrosis induced by 2-AAF/CCl4 in
rats through the non-canonical wnt pathway
Jiamei Chen, Yongping Mu, Yuyou Duan, Ping Liu
428: Downregulation of pro-fibrotic and pro-
inflammatory genes in liver sinusoidal endothelial cells
following activation of the bile acid receptors FXR and
TGR5
Rachel McMahan, Cara Porsche, Michael Edwards, Luciano
Adorini, Moshe Levi, Hugo R. Rosen
429: Repair-related Activation of Hedgehog
Signaling in Stromal Cells Promotes Intrahepatic
Hypothyroidism
Brittany Bohinc, Gregory A. Michelotti, Guanhua Xie, Herbert
Pang, Ayako Suzuki, Cynthia D. Guy, Dawn L. Piercy, Leandi
Kruger, Marzena Swiderska-Syn, Mariana V. Machado, Thiago
A. Pereira, Ann Marie Zavacki, Manal F. Abdelmalek, Anna Mae
Diehl
430: MicroRNA profiling of circulating exosomes
during experimental liver fibrosis
Li Chen, Ruju Chen, David Brigstock
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
431: Soluble CD146, a novel endothelial marker, is
related to the severity of liver disease
Efrossini Nomikou, Alexandra Alexopoulou, Larisa E. Vasilieva,
Danai Agiasotelli, Spyros P. Dourakis
432: Species differences in the antifibrotic effect of
imatinib
Inge M. Westra, Dorenda Oosterhuis, Rick Mutsaers, Geny M.
Groothuis, Peter Olinga
433: Precise liver fibrosis staging by automated
morphometry of liver biopsies: E-Metavir
Paul Cales, Julien Chaigneau, Jerome Boursier, Gilles Hunault,
Sophie Michalak, Frederic Oberti, Isabelle Fouchard-Hubert,
Sandrine Bertrais, Marie Christine Rousselet
434: Genome Wide Association Study (GWAS) identifies
a SNP near the MRC2 (mannose receptor C, type 2)
gene associated with increased liver collagen content in
Caucasian HBV patients
Nezam H. Afdhal, Thomas J. Urban, Zachary D. Goodman, Keyur
Patel, Dongliang Ge, Xin Guo, Zhaoshi Jiang, Xi Zhao, Matthew
Paulson, Anuj Gaggar, Jeffrey Bornstein, Mani Subramanian,
John G. McHutchison, Sarah E. Kleinstein, Nanye Long, David B.
Goldstein, Rohit Loomba, Alexander J. Thompson
435: Factors influencing liver stiffness in chronic liver
disease
Chikage Nakano, Hiroko Iijima, Tomoko Aoki, Kenji Hashimoto,
Masahiro Yoshida, Akio Ishii, Tomoyuki Takashima, Nobuhiro
Aizawa, Naoto Ikeda, Hironori Tanaka, Hirayuki Enomoto,
Masaki Saito, Seiichi Hirota, Shuhei Nishiguchi
436: Cartilage oligomeric matrix protein (COMP) serum
levels: a new non-invasive biomarker of liver fibrosis in
patients with chronic viral hepatitis
Stella Gabeta, Kalliopi Zachou, Zakera Shums, Nikolaos Gatselis,
George K. Koukoulis, Gary L. Norman, George N. Dalekos
437: New canine liver cirrhotic model to develop a less
invasive regeneration therapy using cultured autologous
bone marrow-derived cells
Takashi Matsuda, Taro Takami, Tsuyoshi Ishikawa, Naoki
Yamamoto, Shuji Terai, Isao Sakaida
438: Spleen prevents the development of liver fibrosis
by Kupffer cell deactivation through lipocalin-2
production in mice
Tomonori Aoyama, Akira Uchiyama, Kazuyoshi Kon, Hironao
Okubo, Shunhei Yamashina, Kenichi Ikejima, Shigehiro Kokubu,
Akihisa Miyazaki, Sumio Watanabe
439: Serum Lysyl Oxidase Like 2 (sLOXL2) Levels
Correlate with Ishak Fibrosis Score and Decrease with
Treatment with Tenofovir Disoproxil Fumarate (TDF) in
Patients with Chronic Hepatitis B (CHB)
W. Ray Kim, Rohit Loomba, Preeti Lal, Raul E. Aguilar Schall,
Ann D. Johnson, Jeffrey D. Bornstein, Mani Subramanian, John G.
McHutchison, Stephen A. Harrison, Arun J. Sanyal
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
440: How long a prognosis by liver fibrosis tests is
accurate?
Sandrine Bertrais, Jerome Boursier, Frédéric Oberti, Isabelle
Fouchard-Hubert, Valerie Moal, Paul Cales
441: Exhaled Breath Analysis Reveals New Biomarkers
to Diagnose Advanced Fibrosis in Patients with Chronic
Liver Disease
Mohammed Eyad Yaseen Alsabbagh, Ahmad Tarek Chami, Singh
Gurshawn, Mina Shaker, Ibrahim A. Hanouneh, David Grove,
Rocio Lopez, Nizar N. Zein, Raed Dweik, Naim Alkhouri
442: Oral Treatment with PBI-4050 Reduces Fibrosis in
Carbon Tetrachloride (CCl4)-Induced Hepatic Fibrosis
Brigitte Grouix, Kathy Hince, François Sarra-Bournet, Alexandra
Felton, Mikaël Tremblay, Shaun Abbott, Jean-Simon Duceppe,
Boulos Zacharie, Pierre Laurin, Lyne Gagnon
443: Wisteria floribunda agglutinin-positive Mac-2
binding protein as a predictor of liver fibrosis in patients
with non-alcoholic fatty liver disease
Masanori Abe, Teruki Miyake, Atsushi Kuno, Yasuharu Imai,
Yoshiyuki Sawai, Keisuke Hino, Yuichi Hara, Shuhei Hige, Michiie
Sakamoto, Masaaki Korenaga, Yoichi Hiasa, Masashi Mizokami,
Hisashi Narimatsu
444: Less invasive liver regeneration therapy for liver
cirrhosis using cultured autologous bone marrow-
derived mesenchymal stem cells with redox-regulatory
capacity
Taro Takami, Shuji Terai, Luiz Fernando Quintanilha, Bruno D.
Paredes, Koichi Fujisawa, Naoki Yamamoto, Isao Sakaida
445: A novel glycobiomarker: Wisteria floribunda
agglutinin Macrophage Colony-Stimulating Factor
Receptor for predicting carcinogenesis and survival of
liver cirrhosis patients
Etsuko Iio, Makoto Ocho, Akira Togayachi, Noboru Shinkai,
Masanori Nojima, Atsushi Kuno, Yuzuru Ikehara, Izumi Hasegawa,
Kei Fujiwara, Shunsuke Nojiri, Takashi Joh, Masashi Mizokami,
Hisashi Narimatsu, Yasuhito Tanaka
446: Cholecystectomy Is Associated with an Increased
Rate of Hepatic Fibrosis Development Compared to
Patients with Chronic Hepatitis C Infection who are Non-
responders to Interferon/Ribavirin
Donald J. Martin, Rick A. Weideman, Terri Crook, Geri Brown
447: Pro-C3-levels in patients with HIV/HCV coinfection
reflect fibrosis stage and degree of portal hypertension
Christian Jansen, Diana J. Leeming, Mattias Mandorfer, Inger
Byrjalsen, Robert Schierwagen, Philipp Schwabl, Morten A.
Karsdal, Evrim Anadol, Christian P. Strassburg, Jürgen K.
Rockstroh, Markus Peck-Radosavljevic, Søren Møller, Flemming
Bendtsen, Aleksander Krag, Thomas Reiberger, Jonel Trebicka
Poster Viewing: 2:00 – 7:30 PM
103A
448: Longitudinal hepatic and PBMC gene expression
profiling of HIV and/or HCV-infected patients with
advanced liver disease treated with simtuzumab, an
anti-LOXL2 antibody
Eric G. Meissner, Mary McLaughlin, Lindsay A. Matthews, Bittoo
Kanwar, Jeffrey D. Bornstein, Joseph A. Kovacs, Shyam Kottilil,
Caryn G. Morse
449: Aspirin Use is Associated with Lower Liver Fibrosis
Indices among Adults in the United States
Zhenghui G. Jiang, Linda Feldbrügge, Elliot B. Tapper, Yury Popov,
Tahereh Ghaziani, Simon C. Robson, Kenneth Mukamal
450: Fibrosis regression in hepatitis C patients with
cirrhosis: Ishak fibrosis score and CPA pre treatment
predict regression post sustained virological response
Paolo Nieddu, Ameet Dhar, Robert D. Goldin, Nimzing Ladep,
Sarosh Khan, Mark R. Thursz, Ashley S. Brown
451: Assessment of regression of fibrosis using
Fibroscan® in patients with chronic hepatitis B receiving
antiviral treatment beyond 5 years
Young Eun Chon, Myung Sung Min, Kyu Sik Jung, Kwang-Hyub
Han, Seung Up Kim, Do Young Kim, Sang Hoon Ahn, Jun Yong
Park
452: Development of Novel Lipidnanoparticle siRNA
Delivery System Targeting Collagen Chaperone Protein
HSP47 for Clinical Treatment of Liver Fibrosis
Wenbin Ying, Jun Zhang, Yun Liu, Li Wang, Jihua Liu, Jian Liu,
Jingyuan Yu, Jean-Pierre Clamme, Jiping Yao, Lishuang Xu, Donald
A. Kaiser, Yasunobu Tanaka, Miyono Miyazaki, Keiko Kajiwara,
Kenjiro Minomi, Yoshiro Niitsu
NOVEMBER 8
SATURDAY
453: Subclinical cirrhosis diagnosed by transient
elastography demonstrates increased risk of severe
clinical outcomes and HCC
Tianyan Chen, Remy E. Wong, Kathleen C. Rollet-Kurhajec, Rasha
Alshaalan, Philip Wong, Marc Deschenes, Peter Ghali, Giada
Sebastiani
454: Irbesartan for severe fibrosis in chronic hepatitis C:
a double-blind randomized trial (ANRS HC19 Fibrosar)
Paul Cales, Yannick Bacq, Jean-Pierre Vinel, Corinne Bonny,
Jean-Louis Payen, Dominique Guyader, Albert Tran, Dominique
G. Larrey, Christine Silvain, Marie Christine Rousselet, Frederic
Oberti, Mélanie Simony, Fabrice Carrat
455: Improvements in APRI and FIB-4 fibrosis scores
correlate with decreases in sCD14 in HIV-1 infected
adults receiving cenicriviroc over 48 weeks
Melanie Thompson, Will Chang, Helen Jenkins, Amy Flynt, Millie
Gottwald, Eric Lefebvre
456: A 6-Gene Score Associated With Advanced Stages
of Presymptomatic HBV Related Fibrosis
Mingyi Xu, Ying Qu, Qingqing Zhang, Lungen Lu
Presenters in Attendance 5:30 – 7:00 PM
 104A POSTER SESSIONS
Poster Sessions
457: Localizations and functional roles of MMP-1 in
the early and advanced stages of human non-alcoholic
steatohepatitis
Hiroaki Yokomori, Isao Okazaki, Masaya Oda, Wataru Ando,
Yutaka Suzuki, Tsutsui Nobuhiro, Eigoro Yamanouchi, Hajime
Kuroda, Soichi Kojima, Mitsuko Hara, Yutaka Inagaki
458: Increased autophagy is associated with ductular
reaction in human cirrhotic livers
Tzu-Min Hung, Po-Huang Lee
459: The hitch with non-invasive tests of liver fibrosis:
evaluated by binary AUROC but used with stage
classifications
Paul Cales, Jerome Boursier, Isabelle Fouchard-Hubert, Frederic
Oberti, Victor de Ledinghen, Vincent Leroy
Hemochromatosis, Wilson Disease, a-1
Antitrypsin Deficiency
460: Hfe and hemojuvelin regulate hepcidin
expression and iron metabolism via the same pathway:
Genetic evidence from single and double knockout mice
Patricia Kent, Nicole Wilkinson, Marco Constante, Konstantinos
Gkouvatsos, John Wagner, Manuela M. Santos, Kostas
Pantopoulos
461: Acute Intermittent Porphyria: High incidence of
Pathogenic HMB-Synthase (HMBS) Non-Synonymous
SNPs (nsSNPs) in Genomic Databases Suggests Other
Genetic/Environmental Factors Cause the Acute Attacks
NOVEMBER 8
Brenden Chen, Jörg Hakenberg, Ramakrishnan R. Srinivasan,
SATURDAY
Dana O. Doheny, Inga Peter, Constanza Solis-Villa, Rong Chen,
David F. Bishop, Makiko Yasuda, Robert J. Desnick
462: Lorcaserin Improves the NASH Clinical Score in the
Majority of High-Risk Patients: a Retrospective Analysis
of Three Phase 3 Studies
Wajahat Z. Mehal, Randi Fain, Alan Glicklich, Yuhan Li, William
Shanahan, William Soliman
463: No increased risk of hepatocellular carcinoma
in cirrhosis due to Wilson’s disease during long term
follow up
Suzanne van Meer, Robert A. de Man, Aad P. van den Berg,
Roderick Houwen, Francisca Linn, Peter D. Siersema, Karel J. van
Erpecum
464: Patients with Wilson disease without detectable
ATP7B mutations
Albert Stättermayer, Heinz M. Zoller, Karl Heinz Weiss, Ferenc
Szalay, Radan Bruha, Roderick Houwen, Rudolf E. Stauber, Petra
E. Steindl-Munda, Harald Hofer, Wolfgang Stremmel, Peter Ferenci
465: Sex differences in liver SAM:SAH ratios and
gene transcript levels after pre-and post-natal choline
supplementation and copper chelation treatment in an
animal model of Wilson disease
Valentina Medici, Noreene Shibata, Kusum K. Kharbanda,
Charles H. Halsted
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
466: Using hIPSCs to model liver disease associated
with classic mutations of alpha-1 antitrypsin
Tamara Taketani, Maria P. Ordonez, Lawrence S. Goldstein
467: A propensity score-matched cohort study of the
effect of vitamin E in NAFLD patients
Gi Hyun Kim, Jin Wook Kim, Jung Wha Chung, Eun Sun Jang,
Sook-Hyang Jeong
468: Variability in erythrocyte and plasma porphyrin
levels in erythropoietic protoporphyria and X-linked
protoporphyria
Eric Gou, John D. Phillips, Manisha Balwani, Montgomery Bissell,
Joseph R. Bloomer, Herbert L. Bonkovsky, Robert J. Desnick,
Hetanshi Naik, Karl E. Anderson
469: Osteoporosis and bone fractures in alcoholic liver
disease: A systematic review and meta-analysis
Chang Seok Bang, Hyo Sun Kim, Sang Hyun Park, Eun Jin Kim, Ki
Tae Suk, Dong Joon Kim
470: Elevated alkaline phosphatase predicts response
in polycystic liver disease during somatostatin analogue
therapy: a multi-center pooled analysis on individual
patient data
Tom J. Gevers, Frederik Nevens, Vicente E. Torres, Marie C.
Hogan, Joost Drenth
471: A Phase I Pharmacokinetic Profiling Study in
Patients Receiving Trientine Dihydrochloride for the
Treatment of Wilson Disease
Karl Heinz Weiss, Ulrike Teufel, Jan Pfeiffenberger, Christian
Rupp, Andreas Wannhoff, Wolfgang Stremmel, Daniel Gotthardt
Imaging in Cancer
472: Hemodynamic differences in the very early phase
of hepatocellular carcinoma (HCC) using contrast-
enhanced ultrasonography (CEUS)
Akiko Saito, Satoshi Katagiri, Masakazu Yamamoto, Keiko
Shiratori, Masayuki Nakano, Toshio Morizane
473: Correlation of Enhancement Pattern of CEUS with
Histopathologic Feature in Small Nodular Lesions in
Chronic Liver Disease
Seung Kak Shin, Yun Soo Kim, Oh Sang Kwon, Duck Joo Choi,
Ju Hyun Kim
474: Preoperative predictive value of
18F-fluorodeoxyglucose positron emission tomography/
computed tomography for microvascular invasion of
small hepatocellular carcinoma
Tomoki Kobayashi, Hiroshi Aikata, Hiromi Kan, Takayuki
Fukuhara, Noriaki Naeshiro, Tomokazu Kawaoka, Masataka
Tsuge, Akira Hiramatsu, Michio Imamura, Yoshiiku Kawakami,
Hideyuki Hyogo, Kazuaki Chayama
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
475: Indication of super-delayed phase image
acquisition of Gd-EOB-DTPA enhanced MRI to improve
poor contrast images on routine hepatobiliary phase
images for detection of liver lesion
Satoshi Kobayashi, Kazuto Kozaka, Azusa Kitao, Norihide
Yoneda, Hiroshi Ikeno, Osamu Matsui, Toshifumi Gabata
476: Single-center experience with stereotactic liver
surgery: A review over 5 years
Vanessa M. Banz, Pascale Tinguely, Mathias Worni, Philip
Mueller, Daniel Inderbitzin, Delphine Ribes, Matthias Peterhans,
Stefan Weber, Daniel Candinas
477: Complications related to percutaneous biopsies
of the liver, pancreas, lymph nodes and tumors in the
retroperitoneal space performed under ultrasound
control
Stoyan S. Handzhiev
478: Increased Rate of Pre-transplant Magnetic
Resonance Imaging Under-staging of Hepatocellular
Carcinoma in Patients With Transjugular Intrahepatic
Portosystemic Shunts
She-Yan Wong, Dina Halegoua-De Marzio, Colette Shaw, Jesse
M. Civan
479: Hepatic Angiomyolipoma Mimicking
Hepatocellular Carcinoma: Clinical, Magnetic Resonance
Imaging and Pathological Characteristics in 9 Cases
Chunping Wang, Hongyan Li, Hong Wang, Xiaodong Guo,
Changchun Liu, Xudong Gao, Jianhui Qu, Ze Liu, Xiu juan Chang,
Yin Ying Lu, Zhen Zeng, Min Lou, Ke-Qin Hu, Yongping Yang
480: Metabolic tumor volume by Fluorine-18
fluorodeoxyglucose positron emission tomography as
useful predictor for early recurrence after recurrence in
intrahepatic cholangiocarcinoma
Satoru Seo, Etsuro Hatano, Yuji Nakamoto, Kenji Takemoto, Kojiro
Taura, Tadahiro Uemura, Kentaro Yasuchika, Akira Mori, Toshimi
Kaido, Hideaki Okajima, Shinji Uemoto
481: A safety, feasibility and accuracy study of
laparoscopic computer-assisted navigated microwave
ablation of liver tumors
Pascale Tinguely, Delphine Ribes, Jacob Freedman, Silja Karlgren,
Fusagila Matteo, Matthias Peterhans, Stefan Weber, Daniel
Candinas, Henrik Nilsson
Imaging in Fibrosis
482: Diagnostic Accuracy and Reliability of Supersonic
Shear Imaging in Comparison with Transient
Elastography for Assessment of Liver Fibrosis in Patients
with Chronic Liver Disease
Masato Yoneda, Emmanuel Thomas, Seth N. Sclair, Eugene R.
Schiff
Poster Viewing: 2:00 – 7:30 PM
105A
483: Recombinant Human Acid Sphingomyelinase
Clears Hepatic Sphingomyelin in Adults with Niemann-
Pick Disease Type B
Beth Thurberg, Melissa Wasserstein, Simon Jones, Thomas D.
Schiano, Gerald F. Cox
484: Comparison of 2-dimensional and 3-dimensional
magnetic resonance elastography (MRE) for diagnosis
of advanced fibrosis in patients with biopsy-proven
NAFLD: A prospective study
Rohit Loomba, Tanya Wolfson, William Haufe, Jonathan Hooker,
Nikolaus M. Szeverenyi, Brandon Ang, Archana Bhatt, Cynthia A.
Behling, Mark A. Valasek, Grace Y. Lin, Anthony C. Gamst, David
A. Brenner, Meng Yin, Richard Ehman, Claude B. Sirlin
485: The feasability of Transient Elastography using M
and XL probes for assesing liver stiffness – a practice
audit of 3235 examinations on a multi-etiology cohort
Ioan Sporea, Flavia Motiu, Alina Popescu, Roxana Sirli, Ruxandra
G. Mare, Oana Gradinaru Tascau, Alexandra Deleanu, Isabel
Dan
486: Quantitative Assessment of Liver Fibrosis by Digital
Image Analysis: Relationship to Ishak Staging and
Elasticity by Shear-wave Elastography
Ender G. Yegin, Korkut Yegin, Faruk Erdem Kombak, Emrah
Karatay, Davut Tüney, Cigdem Ataizi Celikel, Osman C. Ozdogan
487: Accuracy of Real-Time Shear Wave Elastography
for Assessing Liver Fibrosis in Chronic Liver Disease: A
Pilot Study
Oranit Cohen-Ezra, Yeroham Kleinbaum, Orit Pappo, Muriel
Webb, Ella Veitsman, Tania Bradichevsky, Yael Inbar, Sima
NOVEMBER 8
Katsherginsky, Peretz Weiss, Keren Tsaraf, Ziv Ben-Ari
SATURDAY
488: The Usefulness of Non-invasive Liver Stiffness
Measurement by Fibroscan® for Risk Management
of HCC in Chronic Hepatitis C Patients Who Achieved
Sustained Virological Response (SVR)
Nobuhito Taniki, Hirotoshi Ebinuma, Nobuhiro Nakamoto, Akihiro
Yamaguchi, Takeru Amiya, Yuko Wakayama, Hiroko Murata,
Po-sung Chu, Shingo Usui, Hidetsugu Saito, Takanori Kanai
489: Magnetic resonance elastography is useful as non-
invasive diagnostic method for predicting liver fibrosis
in nonalcoholic fatty liver disease
Kento Imajo, Takaomi Kessoku, Yasushi Honda, Yuji Ogawa,
Hironori Mawatari, Masato Yoneda, Satoru Saito, Atsushi
Nakajima
490: Spleen stiffness correlates with spleen size but not
liver fibrosis in patients with alcoholic liver disease
Maja Thiele, Bjørn S. Madsen, Aleksander Krag
491: Muscle fat infiltration using total psoas density in
computed tomography predicts mortality in cirrhosis
Christos K. Triantos, Andreas Karatzas, Maria Kalafateli, Paraskevi
Tselekouni, Georgios Tsiaoussis, Nikolaos Koukias, Efstratios
Koutroumpakis, Konstatinos Thomopoulos, Vasiliki Nikolopoulou,
Christina Kalogeropoulou, Chrisoula Labropoulou-Karatza C
Presenters in Attendance 5:30 – 7:00 PM
 106A POSTER SESSIONS
Poster Sessions
492: Supersonic shear imaging predicts cirrhosis and
advanced fibrosis in chronic hepatitis C patients
Shih-Jer Hsu, Yu L. Tan, Ding-Shinn Chen, Jia-Horng Kao
493: The usefulness of spleen stiffness evaluated by
Acoustic Radiation Force Impulse (ARFI) elastography
for assessing liver fibrosis
Simona Bota, Ioan Sporea, Oana Gradinaru Tascau, Alina
Popescu, Roxana Sirli, Mirela Danila
494: Comparison between 2D-real time Shear Wave
Elastography (2D-SWE) and simple serological scores
for liver fibrosis assessment for clinical routine,
considering Transient Elastography (TE) as reference
method
Simona Bota, Rafael Paternostro, Alexandra Etschmaier, Remy
Schwarzer, Petra Salzl, Mattias Mandorfer, Tuul Purevsambuu,
Monika Ferlitsch, Christian Kienbacher, Thomas Reiberger,
Michael Trauner, Markus Peck-Radosavljevic, Arnulf Ferlitsch
495: The two faces of non-invasive assessment of liver
disease severity: correlation between liver stiffness and
hepatic vein arrival times
Francesco Ridolfi, Teresa Abbattista, Annamaria Schimizzi,
Eugenio Brunelli
496: Alkaline phosphatase, but not ongoing alcohol
abuse, influence liver stiffness measurements in
alcoholic liver disease
Maja Thiele, Bjørn S. Madsen, Christian Jansen, Christian P.
Strassburg, Jonel Trebicka, Aleksander Krag
497: Noninvasive evaluation of portal hypertension by
NOVEMBER 8
spleen elastography
SATURDAY
Karel Dvorak, Vaclav Smid, Renata Sroubkova, Jaromir Petrtyl,
Radan Bruha
498: Extracorporeal Shock Wave Lithotripsy for
Difficult-to-Retrieve Common Bile Duct Stones: A Seven
Year Single Center Experience
Syed M. Hassan, Kapeel Raja, Asad A. Khan, Nasir Hassan Luck,
Munnawar Khaliq, Muhammad Manzoor, Zaigham Abbas
499: The correlation between histology and the three
elastographic techniques available in our department
Ioan Sporea, Oana Gradinaru Tascau, Alina Popescu, Madalina
Popescu, Roxana Sirli, Flavia Motiu
500: Usefulness of Acoustic Noninvasive Assessment
of Liver Stiffness: Radiation Force Impulse (ARFI)
Elastography for staging of liver fibrosis and differential
diagnosis of hepatic tumor
Shunsuke Nakajima, Takaaki Ohtake, Takumu Hasebe, Koji
Sawada, Masami Abe, Yasuaki Suzuki, Mikihiro Fujiya, Yutaka
Kohgo
501: Assessment of hepatic fibrosis with Superb Micro-
vascular Imaging: a preliminary report
Nobuko Koyama, Jiro Hata, Takeshi Sato, Noriaki Manabe,
Hiroshi Imamura, Ken Haruma, Keisuke Hino
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
502: Shear Wave Elastography and Hepatorenal Index
for the Assessment of Liver Fibrosis and Steatosis:
a Novel technique and its Predictive Accuracy and
Optimal Measurement Location
George Therapondos, Michael T. Perry, Neal Savjani, Adriana
Dornelles, Edward I. Bluth
503: Liver stiffness measurement in psoriatic patients:
metabolic factor, disease factor or methotrexate play
important role?
Jamrus Pongpit, Saneerat Porntharukchareon, Wasana
Stitchantrakul, Ammarin Thakkinstian, Piyaporn Kaewdoung,
Kwannapa Promson, Supanna Petraksa, Natta Rajatanavin,
Chomsri Kositchaiwat, Abhasnee Sobhonslidsuk
Immunosuppression
504: Short Waiting Time Predicts Early Recurrence of
Hepatocellular Carcinoma after Liver Transplantation:
A Multicenter Study Supporting the “Ablate and Wait”
Principle
Neil Mehta, Julie Heimbach, Denise M. Harnois, Jennifer L. Dodge,
Justin M. Burns, David Lee, William Sanchez, John P. Roberts,
Francis Y. Yao
505: Biomarkers significantly improve the
performance of the Milan criteria in predicting
Hepatocellular carcinoma (HCC) recurrence post liver
transplantation (LT)
Roongruedee Chaiteerakij, Xiaodan Zhang, Benyam D. Addissie,
Essa A. Mohamed, William S. Harmsen, J Paul Theobald, Brian
E. Peters, Joseph Balsanek, Melissa M. Ward, Nasra H. Giama,
Catherine D. Moser, Abdul M. Oseini, Naoki Umeda, Denise M.
Harnois, Michael Charlton, Hiroyuki Yamada, Shinji Satomura,
Alicia Algeciras-Schimnich, Melissa R. Snyder, Terry M. Therneau,
Lewis R. Roberts
506: Injury of Peribiliary Glands of Donor Liver Bile
Ducts Plays a Pivotal Role in the Development of Non-
anastomotic Biliary Strictures after Liver Transplantation
Negin Karimian, Sanna op den Dries, Pepijn D. Weeder, Andrie
Westerkamp, Fernanda Bomfati, Janneke Wiersema-Buist, Bote
G. Bruinsma, Annette S. Gouw, James F. Markmann, Ton Lisman,
Heidi Yeh, Korkut Uygun, Paulo N. Martins, Robert J. Porte
507: Early Post-Operative Neutrophil Gelatinase
Associated Lipocalin (NGAL)-Associated Acute Kidney
Injury Predicts the Development of Chronic Kidney
Disease and Mortality Following Liver Transplantation
Elizabeth C. Verna, Giuseppe Cullaro, Joseph F. Pisa, Robert S.
Brown, Gebhard Wagener
508: The Impact of Deconditioning In Advanced
Cirrhosis
Michael A. Dunn, Deborah A. Josbeno, Mark Sturdevant, Amy
R. Schmotzer, Elizabeth A. Kallenborn, Jaideep Behari, Doug
Landsittel, Andrea DiMartini, Anthony Delitto
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
509: Narcotics Increase Rate of Rejection and Mortality
After Liver Transplantation Regardless of Underlying
Disease Etiology
Mina Pirzadeh, Amir Prushani, Syed-Mohammed R. Jafri, Maria
C. Segovia
510: Positive impact of everolimus on regulatory T cells
after liver transplantation
Clement Barjon, Kaldoun Ghazal, Geraldine Dahlqvist, Faouzi
Saliba, Francois Durand, Christophe Duvoux, Lynda Aoudjehane,
Yvon Calmus, Filomena Conti
511: Predictors of excessive alcohol use following liver
transplantation for alcoholic liver disease: A nationwide
competing risks analysis of psychiatric comorbidity and
occupational status (1990-2013)
Gro Askgaard, Janne S. Tolstrup, Thomas A. Gerds, Ole Hamberg,
Mette Kjær
512: Prevalence and prediction of major adverse
cardiovascular events after liver transplantation using a
novel database
Lisa B. VanWagner, Marina Serper, Raymond Kang, Anton I.
Skaro, Josh Levitsky, Samuel Hohmann, Donald M. Lloyd-Jones
513: Calcineurin inhibitor withdrawal following by
mycophenolate mofetil monotherapy using therapeutic
drug monitoring in maintenance liver transplant
recipients
Guillaume Lassailly, Franck Saint-Marcoux, Juliette Boulanger,
Valerie Canva, Philippe Mathurin, Alexandre Louvet, Odile Goria,
Stephanie Truant, Gilles Lebuffe, Emmanuel Boleslawski, François
René Pruvot, Sebastien Dharancy
514: Alpha-fetoprotein Slope >7.5 ng/mL/month
Predicts Post-transplant Tumor Recurrence and Micro-
vascular Invasion for Hepatocellular Carcinoma within
Milan Criteria
Jeanne-Marie Giard, Neil Mehta, Jennifer L. Dodge, John P.
Roberts, Francis Y. Yao
515: WITHDRAWN
516: Treatment of acute cellular rejection episodes does
not influence fibrosis progression rate in patients with
recurrence HCV after liver transplantation
Pinelopi Manousou, Emmanuel Tsochatzis, Ioanna Parisi,
Francesca Saffioti, Alexandra Mansell, Silvia Aspite, David W.
Patch, James O’Beirne, Douglas Thorburn, Tu Vinh Luong, Amar P.
Dhillon, Massimo Pinzani, Andrew K. Burroughs
517: Pre-transplant Type 2 Hepatorenal Syndrome is
Associated with Persistently Impaired Renal Function
after Liver Transplantation
Hiang K. Tan, Max Marquez, Florence Wong, Eberhard L. Renner
Poster Viewing: 2:00 – 7:30 PM
107A
518: A Single-Center Experience with Preoperative
Selective Internal Radiation Therapy (SIRT) with Y-90
with or without Transarterial Chemoembolization
(TACE), as a Bridging Procedure, in Liver Transplant
Recipients (OLT) with Unresectable Hepatocellular
Carcinoma (uHCC): Efficacy of Combination Therapy
(Rx)
Carlos G. Fasola, Parvez S. Mantry, Bahar Madani, Jeffrey S.
Weinstein, Abdullah Mubarak, Hector Nazario, Adil Habib,
Maisha N. Barnes, Alejandro Mejia, Richard Dickerman, Edward
A. Dominguez, Stephen Cheng
519: HMGB1 and nucleosomes as biomarkers of clinical
outcome in human liver transplantation
Antônio Márcio F. Andrade, Marcus V. Andrade, Agnaldo S.
Lima, Luciana C. Faria
520: Improved but persistent poor functional
performance at 1 year after liver transplantation:
Predictors of performance and opportunities for
intervention
Sarah Uttal, Lisa B. VanWagner, Brittany Lapin, Amanda
Jichlinkski, Joshua Lee, Madeleine Heldman, Brian Poole, Tanvi
Subramanian, Eduardo A. Bustamante, Suvai Gunasekaran,
Christopher S. Tapia, Annapoorani Veerappan, She-Yan Wong,
Josh Levitsky
521: Younger Hepatitis C Virus (HCV) Liver Transplant
(LT) Recipients have Significantly Reduced Graft Survival
Varun Saxena, Jennifer L. Dodge, John P. Roberts, Norah Terrault
522: Impact of portal vein thrombosis prior to liver
transplantation: a multi-center retrospective cohort study
NOVEMBER 8
Constantine J. Karvellas, Filipe S. Cardoso, Malcolm M. Wells,
SATURDAY
Fayaz A. Handoo, Lukasz Kwapisz, Mansour G. Alghanem,
Norman Kneteman, Paul Marotta, Bandar Al-Judaibi
523: Treatment with mTOR inhibitors after liver
transplantation enables a sustained increase in
regulatory T-cells while preserving their suppressive
capacity
Kaldoun Ghazal, Fabien Stenard, Clement Barjon, Lynda
Aoudjehane, Fabiano Perdigao, Olivier Scatton, Yvon Calmus,
Filomena Conti
524: Cardiovascular Risk in Liver Transplant Patients
Tommaso Di Maira, Lorena Puchades, Angel Rubin, Carmen
Vinaixa, María García Eliz, Fernando San Juan, Rafael López
Andujar, Erica Villa, Martin Prieto, Marina Berenguer
525: Long-Term Transplant Outcomes: The Role of Pre-
Transplant Depression
Shari S. Rogal, Gautam Mankaney, Viyan Udawatta, Christopher
B. Hughes, Amit D. Tevar, Mark Sturdevant, Abhinav Humar,
Andrea DiMartini
526: C4d is Present in Portal Venules in Plasma Cell
Hepatitis and May Also be Used as a Predictor for its
Development
Anshu Trivedi, Thomas D. Schiano, Stephen C. Ward, Swan N.
Thung, M. Isabel Fiel, Josh Levitsky
Presenters in Attendance 5:30 – 7:00 PM
 108A POSTER SESSIONS
Poster Sessions
527: Probiotic decreases post-liver transplant infection:
A meta analysis
Tarek Sawas, Shadi Al Halabi, Mubarak W. Sayyar, Won Kyoo
Cho
528: Should Patients Check (WWW.SRTR.ORG) Before
They Get a Liver Transplant?
Bashar M. Attar, David Van Thiel
529: Liver allograft provides immunoprotection for the
cardiac allograft in combined heart-liver transplantation
Tina W. Wong, John M. Stulak, Mark D. Stegall, Julie Heimbach,
Timucin Taner
530: Everolimus with early withdrawal or reduced dose
Calcineurin-Inhibitors (CNI) improves renal function in
Liver Transplant (LT) Recipients: A Meta analysis
Frahad Sahebjam, Sahil Mittal, Gagan K. Sood
531: Portal vein thrombosis is a risk factor for early
mortality and graft loss post liver transplantation:
Analysis of the UNOS database.
Marwan Ghabril, Saurabh Agrawal, Marco A. Lacerda, Eric S.
Orman, Raj Vuppalanchi, Craig Lammert, Howard C. Masuoka,
Samer Gawrieh, Suthat Liangpunsakul, Naga P. Chalasani, A.
Joseph Tector, Paul Y. Kwo
532: The association between early anemia and
the development of renal insuffiency after liver
transplantation
Dilip Moonka, Wadih Chacra, Mohammad Elbatta, Aishwarya
Kuchipudi, Alexander Weick, Charlotte Burmeister, George Divine
NOVEMBER 8
533: Impact of mTOR inhibition on expression of
SATURDAY
immune regulatory molecules by circulating dendritic
cells and regulatory T cells in stable liver transplant
patients
Antonino Castellaneta, Antonio Massaro, Maria Rendina,
Francesca D’Errico, Sonia Carparelli, Angus W. Thomson, Alfredo
Di Leo
534: Abusive drinking after liver transplantation for
pure alcoholic cirrhosis is associated with significant
allograft fibrosis
Marika Rudler, Géraldine Rousseau, Pascal Lebray, Corinne
Vezinet, Daniel Eyraud, Jean-Christophe Vaillant, Thierry Poynard,
Dominique Thabut
535: Early evaluation of regulatory T cells to predict
severity of HCV recurrence after liver transplantation
Kaldoun Ghazal, Morales Olivier, Clement Barjon, Geraldine
Dahlqvist, Lynda Aoudjehane, Laurissa Ouaguia, Yvon Calmus,
Delhem Nadira, Filomena Conti
536: Predictors of Delirium after Liver Transplantation
and its Relationship to Outcomes
Koki Yamada, Max Marquez, Khalid Mumtaz, Eberhard L. Renner
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
537: Bacterial antigen translocation persists after liver
transplantation in peripheral blood of patients with
decompensated cirrhosis
Gonzalo Rodriguez-Laiz, Pedro Zapater, Paola Melgar, Mariano
Franco, Cándido Alcázar, Sonia Pascual, Pablo Bellot, Jose María
Palazón, Jose Such, Félix Lluis, Ruben Frances
538: Early Liver Transplantation in Severe Alcoholic
Hepatitis: the U.S. Experience
Brian P. Lee, David W. Victor, R. Mark Ghobrial, Mary E. Rinella,
Zhiping Li
539: Deleterious Effect of Body Mass Index and Prior
Abdominal Surgery on Liver Transplant Complications
Angel Alsina, Jian Zheng, Alexia M. Makris, Jason Shim, Edson S.
Franco, Chris Albers, Nyingi M. Kemmer
540: Primary Non Function after liver transplant in
children in the PELD era: Analysis of UNOS database
Jaime Chu, Rachel A. Annunziato, Christie DiPietrantonio, Ailie M.
Posillico, Ronen Arnon
541: Pro-Atherogenic Lipoproteins And Metabolic
Biomakers Drive Serum Cardiovascular Risk In Liver
Transplant Recipients
Ravi Chhatrala, Mohammad B. Siddiqui, R. Todd Stravitz, Carolyn
Driscoll, Arun J. Sanyal, Robert A. Fisher, Carol Sargeant, Fareed
R. Riyaz, Velimir A. Luketic, Scott Matherly, Richard K. Sterling,
Puneet Puri, Mohammad S. Siddiqui
542: Coronary artery calcium score in evaluating
cardiovascular risk 1 and 4 years after liver transplant
Livia M. Linhares, Mario R. Alvares-da-Silva, Claudia P. Oliveira,
José Tadeu Stefano, Eloisa M. Gebrim, Flair J. Carrilho, Luiz C.
D`Albuquerque
543: Control of Diabetes Mellitus in Liver Transplant
Recipients:a multicentric spanish study
Beatriz Rodríguez-Medina, Diego Alvarez de Sotomayor, Carla
Satorres, Jose Ignacio Herrero, Trinidad Serrano, Manuel De la
Mata, Carmen Vinaixa, Victoria Aguilera, Angel Rubin, Martin
Prieto, Marina Berenguer
544: Non-coronary causes account for the majority
of early major adverse cardiac events after liver
transplantation
Lisa B. VanWagner, Bing Bing Weitner, Tanvi Subramanian,
Sarah Uttal, Alfred W. Rademaker, Josh Levitsky, Donald M. Lloyd-
Jones, Anton I. Skaro
545: Sphincter of Oddi Dysfunction after Liver
Transplantation: Experience in a High Volume
Transplant Center
Alejandro Fernandez Simon, Diego S. Royg, Oriol Sendino,
Claudio Zulli, Cristina Rodriguez de Miguel, Domingo Balderramo,
Gonzalo Crespo, Jordi Colmenero, Josep Llach, Miquel Navasa,
Andres Cardenas
546: Hyperhomocysteinemia is Associated with
Reduced Survival after Liver Transplantation
Rahima A. Bhanji, Mang M. Ma, Aldo J. Montano-Loza
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
547: Use of mTOR inhibitor is associated with increased
frequency of late anastomotic biliary strictures and need
for repeat ERCP in Orthotopic liver transplant recipients.
Cheri Ogwo, Satheesh Nair, Jason M. Vanatta, James Eason,
Sanjaya K. Satapathy
548: Sexual Functioning in Patients With End-Stage
Liver Disease Before and After Liver Transplantation (LT)
Beatriz Rodríguez-Medina, Diego Alvarez de Sotomayor, Carla
Satorres, Agustin Ramos-Prol, Carmen Vinaixa, Angel Rubin, María
García Eliz, Victoria Aguilera, Martin Prieto, Marina Berenguer
549: Adherence to Immunosuppressive therapy in Adult
and Adolescent Liver Transplant Recipients in a Multi-
Ethnic Asian Centre: A Questionnaire Survey
Kieron B. Lim, Juanda Leo Hartono, Yock Young Dan, Maung
Aye Thwin, Poh Seng Tan, Charlene Soon, Alfred W. Kow,
Krishnakumar Madhavan, Seng Gee Lim
550: Orthotopic liver transplantation for hepatocellular
carcinoma after successful downstaging: results from
the Belgian multicentre cohort
Jonas Schreiber, Jan P. Lerut, Chris Verslype, Hans Van Vlierberghe,
Valerio Lucidi, Olivier Detry, Luisa Vonghia, Francesco Puleo,
Eric Trépo, Milton E. Inostroza, Hélène Poels, Roberto Troisi,
Jean Delwaide, Sven M. Francque, Vincent Donckier, Christophe
Moreno
551: Outcomes for Patients with Decompensated
Cirrhosis Transferred from Outlying Hospitals to a
Tertiary Care Liver Transplant Center
Chad Cornish, Michael Winter, Thomas D. Rodgers, Gopal A.
Ramaraju, Benedict Maliakkal, Jonathan Huang
552: MELD score does not impact the outcomes of
simultaneous liver and kidney transplantation
Mohsen Hasanin, Siddharth Bansal, Yong-Fang Kuo, Ashwani K.
Singal, Russell H. Wiesner
553: WITHDRAWN
554: Diabetes Mellitus is associated with Lower Survival
following Simultaneous Liver Kidney Transplantation
Ryan B. Perumpail, Robert Wong, Andrew M. Su, Jane Tan, John
Scandling, Aijaz Ahmed
555: Histological correlates of ERCP confirmed biliary
anastomotic strictures
Fazal Yahya, Pamela B. Sylvestre, Saradasri Karri, Satheesh Nair,
Jason Vanatta, James Eason, Sanjaya K. Satapathy
556: Pre-operative renal failure predicts reduced
survival following liver transplantation but not liver
specific graft failure or death
Francis P. Robertson, Pulathis Siriwardana, Paul R. Bessell, Rafael
Diaz-Nieto, Nancy Rolando, Brian R. Davidson
557: Long term outcomes of patients with new portal
vein thrombosis occurring after liver transplantation
Scott Duncan, Laxmi B. Parsa, Nader Dbouk
Poster Viewing: 2:00 – 7:30 PM
109A
558: Evolving renal function in the post-operative
period correlates with over all graft survival following
liver transplantation
Francis P. Robertson, Pulathis Siriwardana, Paul R. Bessell, Rafael
Diaz-Nieto, Nancy Rolando, Brian R. Davidson
559: Listing practices for Morbidly Obese Patients at
Liver Transplant Centers in the United States
Dina Halegoua-De Marzio, She-Yan Wong, Jonathan M. Fenkel,
Cataldo Doria, David A. Sass
560: Racial/Ethnic Disparities in Simultaneous Liver
Kidney Transplantation: An Analysis from the UNOS
Database
Ryan B. Perumpail, Robert Wong, Andrew M. Su, Robert Isom,
John Scandling, Aijaz Ahmed
561: The mTOR inhibitor everolimus is safe within the
first month after liver transplantation
Indhira Perez Medrano, Manuel Rodríguez-Perálvarez, Marta
Guerrero Misas, Mercedes Muñoz Nuñez, Víctor M. González
Cosano, María Muñoz Garcia-Borruel, Antonio Poyato, Pilar
Barrera Baena, Enrique Fraga Rivas, Gustavo Ferrín, Guadalupe
Costan Rodero, Juan Carlos Pozo Laderas, Marina Sánchez Frías,
Ruben Ciria, Javier Briceño, Jose Luis Montero, Manuel De la Mata
562: Magnetic Resonance Cholangiopancreatography is
Significantly Superior to Ultrasound in the Diagnosis of
Biliary Anastomotic Strictures After Liver Transplantation
Anoop Prabhu, James Park, Jawad Ahmad
563: Primary Sclerosing Cholangitis is a Risk Factor for
Developing Intra-abdominal Thrombosis Following Liver
NOVEMBER 8
Transplantation
SATURDAY
Paul Reynolds, Elnaz Jafarimehr, Xiao Jing Wang, Ram M.
Subramanian
564: Prevalence and risk factors of metabolic syndrome
after liver transplantation: a single centre experience
Veronica Pepe, Giacomo Germani, Alberto Ferrarese, Alberto
Zanetto, Ilaria Bortoluzzi, Elena Nadal, Francesco P. Russo, Marco
Senzolo, Enrico Gringeri, Umberto Cillo, Patrizia Burra
565: 20 year followup of liver transplantation for HCV+
patients. Rustgi V, Landsittel D, Humar A, Hughes C,
Malik S, Behari J, Jazwinski A, Chopra K. The Thomas
Starzl Transplant Institute, Univ of Pittsburgh
Vinod K. Rustgi, Doug Landsittel, Abhinav Humar, Christopher B.
Hughes, Shahid M. Malik, Jaideep Behari, Alison Jazwinski, Kapil
B. Chopra
566: Serum aspartate transaminase levels on the third
post-operative day correlate with overall survival
and liver specific survival at 10 years following liver
transplantation
Francis P. Robertson, Paul R. Bessell, Rafael Diaz-Nieto, Nancy
Rolando, Brian R. Davidson
Presenters in Attendance 5:30 – 7:00 PM
 110A POSTER SESSIONS
Poster Sessions
567: Clinical impact of cholestasis after liver
transplantation: a retrospective cohort study
Constantine J. Karvellas, Filipe S. Cardoso, Andrew Mason,
Norman M. Kneteman, Glenda Meeberg, Aldo J. Montano-Loza
568: Analytic Morphomics Identifies Predictors of New-
Onset Diabetes After Transplantation
Valerie Vaughn-Sandler, David C. Cron, Michael Terjimanian,
Zachary Gala, Stewart C. Wang, Grace L. Su, Michael Volk
569: Everolimus treatment start POD 1 in combination
with low dose CNI is safe and effective post liver
transplantation
Martina Sterneck, Antonio Galante, Gesa Pamperin, Martina
Koch, Jun Li, Lutz Fischer, Bjoern Nashan
570: Non-adherence related mortality in adolescents
and young people after Liver transplantation
Marianne Samyn, Nigel Heaton, Michael A. Heneghan, Anil
Dhawan
571: Model to Predict Long-term Survival after Liver
Transplantation
Giuliano Testa, Giovanna Saracino, James F. Trotter, Greg J.
McKenna, Richard Ruiz, Nicholas Onaca, Tiffany Anthony, Peter
T. Kim, Marlon F. Levy, Robert M. Goldstein, Goran Klintmalm
572: Combined Heart and Liver Transplantation:
Analysis of a Single-Center Experience
Abimbola Aderinto, Maha R. Boktour, Mina Elnemr, Andrea M.
Cordero-Reyes, Jerry Estep, Sherilyn Gordon Burroughs, Ashish
Saharia, Barry Trachtenberg, Arvind Bhimaraj, Rafik M. Ghobrial,
Howard P. Monsour
NOVEMBER 8
SATURDAY
Infections and Acute on Chronic Liver
Failure
573: Clinical and prognostic relevance of albumin
dimers in patients with cirrhosis: a novel identified
structural alteration of the molecule
Maurizio Baldassarre, Marco Domenicali, Ferdinando A.
Giannone, Marina Naldi, Maristella Laggetta, Daniela Patrono,
Carlo Bertucci, Mauro Bernardi, Paolo Caraceni
574: The empirical antibiotic treatment of nosocomial
spontaneous bacterial peritonitis in patients with
decompensated liver cirrhosis: results of a randomized
controlled clinical trial
Salvatore Piano, Freddy Salinas, Filippo Morando, Marta Cavallin,
Antonietta Romano, Silvia Rosi, Marialuisa Stanco, Silvano
Fasolato, Antonietta Sticca, Marco Senzolo, Patrizia Burra, Enrico
Gringeri, Umberto Cillo, Angelo Gatta, Paolo Angeli
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
575: Determinants and prognostic significance of
bacterial infections occurring in patients with HBV- or
HCV-related compensated cirrhosis. A multicenter
prospective cohort study in 1672 patients (ANRS CO12
CirVir)
Pierre Nahon, Valérie Bourcier, Richard Layese, Nabila Talmat,
Patrick Marcellin, Dominique Guyader, Stanislas Pol, Dominique
G. Larrey, Victor de Ledinghen, Denis Ouzan, Fabien Zoulim, Jean
Claude Trinchet, Françoise Roudot-Thoraval
576: The detection of bacterial DNA by in situ
hybridization method may prove the evidence of
bacterial translocation in patients with decompensated
liver cirrhosis
Shingo Usui, Hirotoshi Ebinuma, Po-sung Chu, Nobuhito Taniki,
Yuko Wakayama, Nobuhiro Nakamoto, Yoshiyuki Yamagishi,
Kazuo Sugiyama, Hidetsugu Saito, Takanori Kanai
577: ‘Eastern type’ of Acute-on-chronic Liver Failure
(ACLF) is similar in pathophysiologic, diagnostic and
prognostic criteria to the ‘Western type’: A comparison
of Chinese hospitalized patients with Hepatitis B with
CANONIC data
Hai Li, Marco Pavesi, Bo Zeng, Liu-Ying Chen, Shu-Ting Li, De-Kai
Qiu, Richard Moreau, Pere Gines, Vicente Arroyo, Rajiv Jalan
578: Utility Of A Modified PIRO (Predisposition, Injury,
Response, Organ Failure) Model For Predicting Kidney
Failure In Patients With ACLF- A Multinational Cohort
Study
Rakhi Maiwall, Shiv K. Sarin, Chandan K. Kedarisetty, Richard
Moreau, Suman Kumar, Zaigham Abbas, Deepak N. Amarapurkar,
Ankit Bhardwaj, Ajeet S. Bhadoria, Chhagan Bihari, Amna S. Butt,
Chan Albert, Yogesh K. Chawla, Abdulkadir Dokmeci, Hasmik
Ghazinyan, Saeed S. Hamid, Cho Mong, George K. Lau, Guan
Huei Lee, Laurentius A. Lesmana, Mamun A. Mahtab, Qin Ning,
Viniyendra Pamecha, Diana A. Payawal, Archana Rastogi, Salimur
Rahman, Mohamed Rela, Amrish Sahney, Vivek A. Saraswat,
Samir R. Shah, Gamal Shiha, Barjesh C. Sharma, Manoj Kumar,
Soek Siam Tan, Chitranshu Vashishtha, Ashok Choudhary, Man
Fung Yuen, Osamu Yokosuka
579: Gene-specific control of inflammation during
lipopolysaccharide tolerance is altered in immune cells
from patients with advanced cirrhosis
Mikhael Giabicani, Emmanuel Weiss, Pierre-Emmanuel Rautou,
Magali Fasseu, Catherine Paugam-Burtz, Dominique Valla,
Francois Durand, Sophie Lotersztajn, Richard Moreau
580: Systemic Inflammatory Response Syndrome (SIRS)
- a potential clinical marker for early sepsis and
survival in Acute on chronic liver failure (ACLF)
Ashok K. Choudhury, Chitranshu Vashishtha, Chandan K.
Kedarisetty, Shiv K. Sarin
581: Genetic polymorphism of mannose binding lectin
2: a potential new risk factor for spontaneous bacterial
peritonitis in cirrhotic patients
Cornelius Engelmann, Janett Fischer, Sandra Krohn, Adam Herber,
Albrecht Boehlig, Danilo Deichsel, Stephan Boehm, Thomas Berg
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
582: Overexpression Of The Genetic Effector Pathway
Of Inflammasome In Peripheral Blood Mononucleated
Cells (Pbmc) Of Patients With Acute On Chronic Liver
Failure
Elisabetta Gola, Alessandra Brocca, Salvatore Piano, Antonietta
Sticca, Filippo Morando, Silvia Rosi, Marta Cavallin, Marialuisa
Stanco, Antonietta Romano, Silvano Fasolato, Angelo Gatta, Paolo
Angeli
583: CD64 Expression may be a Promising Marker for
Early Diagnosis of Sepsis in Hospitalized Patients with
Cirrhosis
Sakkarin Chirapongsathorn, Jody C. Olson, Stacy C. League,
Siddharth Singh, Sarah Jenkins, Roshini Abraham, Patrick Kamath
584: Improving survival for patients with cirrhosis
admitted to United Kingdom critical care units
Mark J. McPhail, Francesca Parrott, Julia Wendon, David A.
Harrison, Kathy M. Rowan, William Bernal
585: The Economic Burden and Mortality of Patients
with Acute on Chronic Liver Failure (ACLF) in the United
States
Alina M. Allen, W. Ray Kim, James P. Moriarty, Nilay Shah,
Patrick S. Kamath
586: Mortality risk associated with Acute on Chronic
Liver Failure varies dependent on inciting event: a
NACSELD study
Patrick S. Kamath, Jacqueline G. O’Leary, K. Rajender Reddy,
Florence Wong, Siddharth Singh, Michael B. Fallon, Guadalupe
Garcia-Tsao, Scott W. Biggins, Benedict Maliakkal, Ram M.
Subramanian, Heather M. Patton, Leroy Thacker, Jasmohan S.
Bajaj
587: The impact of nutritional status on infections in
liver cirrhosis
Aung Kaung, Ken D. Nguyen, Amit Rajaram, Phillip Zakowski,
Tram T. Tran, Vinay Sundaram
588: Delay in appropriate antimicrobial therapy
increases mortality in cirrhotics with spontaneous
bacterial peritonitis and septic shock
Constantine J. Karvellas, Juan G. Abraldes, Yaseen Arabi, Anand
Kumar
589: Prognostic Value of Procalcitonin in patients with
Spontaneous Bacterial Peritonitis: Preliminary Results
from a Multicenter Study in Argentina
Sebastian Marciano, Natalia Sobenko, Alfredo Martinez, Manuel
Mendizabal, Luis A. Gaite, Federico Piñero, Leila Haddad,
Marcelo O. Silva, Ezequiel Ridruejo, Oscar G. Mandó, Diego H.
Giunta, Adrian Gadano
590: CLIF-SOFA score and serum sodium are
independent predictors of short term survival in
decompensated cirrhosis. A prospective study
Gustavo Pereira, Flavia F. Fernandes, Vanessa L. Zenatti, Camila
M. Alcântara, Tatiana Valdeolivas, Zulane D. Veiga, Daniela M.
Mariz, João Luiz Pereira
Poster Viewing: 2:00 – 7:30 PM
111A
591: Alpha 2a adrenergic receptor antagonism
abrogates innate immune dysfunction and hepatic
inflammatory cytokine generation in a rodent model of
Acute-on-Chronic Liver Failure (AoCLF): Proof of concept
for a new target for therapy
Vikram Sharma, Junpei Soeda, Jane MacNaughtan, Abeba
Habtesion, Pamela Leckie, Nathan Davies, Rajiv Jalan, Rajeshwar
Mookerjee
592: Pathophysiological basis of Hepatic
Encephalopathy (HE) in patients with Acute-on-chronic
liver failure (ACLF): A prospective, longitudinal study
determining the role of ammonia, inflammation and
cerebral oxygenation
Rohit Sawhney, Peter Holland-Fischer, Rajeshwar Mookerjee,
Matteo Rosselli, Banwari Agarwal, Rajiv Jalan
593: Inhibition of MER receptor tyrosine kinase in
patients with acute on chronic liver failure: a potential
target for immunotherapy?
Christine Bernsmeier, Oltin T. Pop, Evangelos Triantafyllou,
Chris J. Weston, Stuart M. Curbishley, Vishal C. Patel, Arjuna
Singanayagam, Wafa Khamri, Christopher Willars, William
Bernal, Georg Auzinger, Michael A. Heneghan, Yun Ma, Wayel
Jassem, Nigel Heaton, David H. Adams, Mark R. Thursz, Alberto
Quaglia, Julia Wendon, Charalambos G. Antoniades
594: Acquired Hemophagocytic Lymphohistiocytosis
(HLH) mimicking acute hepatic insult presenting as Acute
on chronic liver failure (ACLF) is associated with high
mortality
Ankur Jindal, Ashok Choudhary, Shiv K. Sarin
NOVEMBER 8
595: Prognosis of cirrhotic patients admitted in Intensive
SATURDAY
care Unit: A Meta-analysis
Delphine Weil, Heng-Chih Pan, Eric Levesque, Bertrand Sauneuf,
Eleni Theocharidou, Evangelos Cholongitas, Constantine J.
Karvellas, René Robert, Arnaud Galbois, Jérôme Fichet, Rodrigo
Cavallazzi, Jean Paul Cervoni, Gaël Piton, Thierry Thevenot, Gilles
Capellier, Vincent Di Martino
596: Chronic Liver Failure Sequential Organ Failure
Assessment (CLIF-SOFA) is better than the Asia-Pacific
Association for the Study of Liver (APASL) criteria for
defining Acute-on-Chronic Liver Failure (ACLF) and
Predicting Outcome
Radha K. Dhiman, Tarana Gupta, Swastik Agrawal, Ajay K.
Duseja, Yogesh K. Chawla
597: Copeptin: a marker of circulatory derangement,
is independently associated with outcome in patients
admitted for acute decompensation of cirrhosis
Hein W. Verspaget, Amorós Àlex, Rajiv Jalan, Daniel Benten,
Francois Durand, Johan van der Reijden, Bart Van Hoek, Minneke
Coenraad
Presenters in Attendance 5:30 – 7:00 PM
 112A POSTER SESSIONS
Poster Sessions
598: High enrichment of circulating mononuclear cells
with transcripts encoding CXCL neutrophil-attracting
chemokines is a predictor of death in patients with
decompensated cirrhosis
Emmanuel Weiss, Rakhi Maiwall, Pierre-Emmanuel Rautou, Magali
Fasseu, Mikhael Giabicani, Francois Durand, Dominique Valla,
Didier Lebrec, Sophie Lotersztajn, Richard Moreau
599: Percutaneous Cholecystostomy (PC) for Acute
Cholecystitis (AC) in Advanced Cirrhosis is Associated
with High Morbidity and Poor Survival
Caitlin Sullivan, Charles Gabbert, Melissa Saul, Kapil B. Chopra,
Adam Slivka, Dhiraj Yadav
600: Epidemiologic trends in mortality of cirrhosis in the
intensive care unit: a large, Australasian, multi-centre
cohort
Avik Majumdar, Michael J. Bailey, William W. Kemp, Stuart K.
Roberts, David Pilcher
601: Bacterial translocation in liver failure: a possible
mechanism of impaired innate immune responses and
immuneparesis?
Vishal C. Patel, Susanne Knapp, Glory Y. Lai, Christine Bernsmeier,
Arjuna Singanayagam, Mark J. McPhail, Christopher Willars,
William Bernal, Georg Auzinger, Michael A. Heneghan, Krishna
Menon, Wayel Jassem, Parthi Srinivasan, Andreas Prachalias,
Hector Vilca-Melendez, Nigel Heaton, Mark R. Thursz, Julia
Wendon, Charalambos G. Antoniades
602: Number Needed to reTap: Assessing the Utility of
Repeat Diagnostic Paracentesis in Spontaneous Bacterial
Peritonitis
NOVEMBER 8
Aparna Goel, Mollie A. Biewald, Gopi Patel, Shirish Huprikar,
SATURDAY
Thomas D. Schiano, Gene Y. Im
603: Prognostic significance of Insulin-like growth
factor-1 (IGF-1) serum levels in patients admitted for
acute decompensation of cirrhosis
Bruno S. Colombo, Marcelo F. Ronsoni, Pedro E. Soares e Silva,
Leonardo Fayad, Letícia M. Wildner, Maria Luiza Bazzo, Esther B.
Dantas-Correa, Janaína L. Narciso-Schiavon, Leonardo L. Schiavon
604: Prognostic value of C-reactive protein in patients
with cirrhosis: external validation from the CANONIC
cohort
Jean Paul Cervoni, Amorós Àlex, Richard Moreau, Vicente Arroyo,
Rajiv Jalan, Faouzi Saliba, Francois Durand, Julia Wendon, Thierry
Gustot, Paolo Angeli, Pere Gines, Thierry Thevenot, Vincent Di
Martino
605: Factors associated with low cardiac T2* MRI in
liver transplant (LT) candidates at risk for iron overload
Moises Nevah Rubin, Monika Sarkar, Karen Ordovas, Oren K.
Fix, Neil Mehta
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
Inflammation and Immunobiology:
Animal Models
606: Involvement of the TNF and FasL produced by
CD11b Kupffer cells/macrophages in CCl4-induced
acute hepatic injury
Hiroyuki Nakashima, Atsushi Sato, Masahiro Nakashima, Masami
Ikarashi, Kiyoshi Nishiyama, Manabu Kinoshita, Shuhji Seki
607: Acid sphingomyelinase inhibits growth of
metastatic liver tumor
Yosuke Osawa, Jun Imamura, Kiminori Kimura
608: Dose-limiting toxicity of in vivo TLR7 ligation
differs according to the kinetics of systemic and hepatic
inflammation after LCMV infection
Thomas Vanwolleghem, Dowty Movita, Martijn D. van de Garde,
Florence Herschke, Gregory C. Fanning, Harry L. Janssen, Andre
Boonstra
609: Cytotoxic CD4+ Cells Play a Pivotal Role in
Cyclophosphamide-Mediated Cytotoxicity against
Hepatoma without Antigen Priming
Tatsushi Naito, Tomohisa Baba, Naofumi Mukaida, Yasunari
Nakamoto
610: Activation of cellular innate immunity during
primary Hepacivirus infection
Cordelia Manickam, R. Keith Reeves
611: DSS-induced colitis and simultaneous hepatic
inflammation lead to immunological tolerance in the
murine liver
Nobuhito Taniki, Nobuhiro Nakamoto, Hirotoshi Ebinuma, Hiroko
Murata, Yuko Wakayama, Po-sung Chu, Shingo Usui, Akihiro
Yamaguchi, Takeru Amiya, Hidetsugu Saito, Takanori Kanai
612: A novel mouse model of hepatocyte apoptosis-
induced sterile liver inflammation and wound healing
response
Heng-Fu Bu, Fangyi Liu, Xiao Wang, Pauline M. Chou, Catherine
Marek, Ke Tian, Peng Wang, Hua Geng, M. S. Rao, Suhail
Akhtar, Monique E. De Paepe, Xiao-Di Tan
613: Administration of antisense oligodeoxynucleotides
to nerve growth factor attenuates inflammation and
liver damage in acute liver damage models
Rafael Bruck, Einav Hubel, Isabel Zvibel
614: High fat diet impairs hepatic microRNAs related to
inflammation and macrophage infiltration contributing
to nonalcoholic steatohepatitis in a mouse model with
metabolic syndrome
Priya Handa, Vicki Morgan-Stevenson, Bryan D. Maliken, Yu Li,
James E. Nelson, Matthew M. Yeh, Kris V. Kowdley
615: Murine natural killer cells transiting through the
liver demonstrate hyporesponsiveness to activation
receptor mediated stimulation
Claire Meyer, Sandeep K. Tripathy
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
616: Characterization of the liver:lung axis in alcohol-
induced lung damage
Veronica L. Massey, Lauren G. Poole, Edilson Torres-Gonzalez,
Robin H. Schmidt, Michael L. Merchant, Keith C. Falkner, Jeffrey
D. Ritzenthaler, Jesse Roman, Gavin E. Arteel
617: DSS-induced Chronic Colitis Aggravates
Inflammation and Fibrogenesis in Mice with CCl4-
induced Hepatic Fibrosis
Xiaolan Zhang, Yufeng Liu, Guochao Niu, Libo Zheng
Innate Immunity and Adaptive
618: Beta-hydroxybutyrate and niacin protect
the murine liver from acute inflammatory injury via
activation of the Gpr109 receptor
Rafaz Hoque, Ahmad Farooq, Fred Gorelick, Wajahat Z. Mehal
619: Type III interferons, including IFNL4, drive
interferon-stimulated gene (ISG) pre-activation and the
interferon-refractory state
Jordan J. Feld, Vera A. Cherepanov, Nicholas Anand, Sonya A.
MacParland, Tawnya Hansen, Harry L. Janssen, Matthew Kowgier,
Ian McGilvray
620: Iron decreases IL-4- mediated STAT6
phosphorylation, Arginase-1 production and M2
activation, while increasing NF-KB phosphorylation,
INOS protein levels and M1 activation in primary
murine macrophages
Priya Handa, Vicki Morgan-Stevenson, Kris V. Kowdley
621: Role of NADPH oxidase 4 in hepatic inflammation
and TGFβ response mediated by Toll-like receptor 4
Bhargav Koduru, Rui-Ming Liu, Nicole L. Corder, Katrin Schroder,
Ralf P. Brandes, Jinah Choi
622: MicroRNA-155 deficiency attenuates chronic
alcohol induced hepatic and intestinal inflammation in
mice
Shashi Bala, Dora Lippai, Timea Csak, James V. Zatsiorsky, Donna
Catalano, Karen Kodys, Gyongyi Szabo
623: Human Mucosal Associated Invariant T
cells express high levels of MDR-1 and maintain
innate effector function following exposure to
immunosuppressive MDR-1 substrates
Joannah R. Fergusson, Lucy J. Walker, Paul Klenerman
624: Circulating monocytes from chronic HCV-infected
patients display a pro-fibrotic phenotype mediated by
IL-1β and correlates with liver fibrosis
Banishree Saha, Karen Kodys, Gyongyi Szabo
625: Glycine minimizes hepatic innate immune
responses and autoimmunity caused by double-
stranded RNA
Akira Uchiyama, Kenichi Ikejima, Kumiko Arai, Kazuyoshi Kon,
Kyoko Fukuhara, Tomonori Aoyama, Shunhei Yamashina, Sumio
Watanabe
Poster Viewing: 2:00 – 7:30 PM
113A
626: Neutrophil toll-like receptor 9 expression and
plasma lactoferrin in acute alcoholic hepatitis and the
susceptibility to fungal infection
Jennifer M. Ryan, Godhev K. Manakkat Vijay, (Robin) Daniel
Abeles, Thomas Tranah, Laura J. Blackmore, Victoria T. Kronsten,
Lee J. Markwick, Antonio Riva, Nikhil Vergis, Nicholas J. Taylor,
Shilpa Chokshi, Yun Ma, John G. O’Grady, Debbie Shawcross
627: TLR3/4 Signaling is Mediated via the MyD88-NF-
κB-CXCR4/7 Pathway in Human Alcoholic Hepatitis
and Non Alcoholic Steatohepatitis, Where Mallory-Denk
Bodies Form
Samuel W. French, Hui Liu, Barbara A. French, Brittany C. Tillman,
Jun Li
628: Liver Injury and Inflammation Leads to Profound
Hepatic Natural Killer Cell Dysfunction and Predisposes
the Liver to Metastatic Disease
Justin B. Mendel, Aryn Price, Arash Grakoui
629: Role of interactions of circulating monocytes in
vascular sprouting during liver regeneration in mice
Pedro Melgar-Lesmes, Elazer R. Edelman
630: Distinctive phenotypic features of human mucosal-
associated invariant T cells in the liver
Kentaro Tominaga, Toru Setsu, Satoshi Yamagiwa, Naruhiro
Kimura, Hiroki Honda, Hiroteru Kamimura, Masaaki Takamura,
Minoru Nomoto
631: Large scale biomarker profiling reveals distinct
cytokine and chemokine signatures distinguishing
different acute and chronic hepatitis virus infections
NOVEMBER 8
Svenja Hardtke, Julia Hengst, Katja Deterding, Michael P. Manns,
SATURDAY
Falk S. Christine, Markus Cornberg, Heiner Wedemeyer, Verena
Schlaphoff
632: Functional features of antigen-specific T-cell
receptors reflected clinical responses of α-fetoprotein-
derived peptides vaccine treatment for advanced
hepatocellular carcinoma
Hidetoshi Nakagawa, Eishiro Mizukoshi, Eiji Kobayashi, Takeshi
Terashima, Masaaki Kitahara, Noriho Iida, Hiroyuki Kishi, Atsushi
Muraguchi, Shuichi Kaneko
633: Immunomodulatory Effects of OK432-Stimulated
Monocyte-Derived Dendritic Cell Injection into
Hepatocellular Carcinoma after Radiofrequency
Ablation
Masaaki Kitahara, Eishiro Mizukoshi, Hidetoshi Nakagawa,
Noriho Iida, Hajime Sunagozaka, Kuniaki Arai, Tatsuya
Yamashita, Shuichi Kaneko
634: Identification of a Novel HLA-A2 Restricted
Immunotherapeutic Target Derived from an EGFR
Mutated Antigen for the Treatment of Metastatic Liver
Tumors
Kazuya Ofuji, Toshiaki Yoshikawa, Yoshitaka Tada, Manami
Shimomura, Yasunari Nakamoto, Tetsuya Nakatsura
Presenters in Attendance 5:30 – 7:00 PM
 114A POSTER SESSIONS
Poster Sessions
635: The dynamic changes of Th1/Th2/Th17 cytokines
in serum of patients with acute-on-chronic liver failure
Li Jin, Yingli He, Dan Du, Yuanyuan Li, Ruitian Yi, Jing Wang,
Tianyan Chen, Yingren Zhao
636: Regulation of hepatic inflammation by the
macrophage-expressed, sulfated steroid transporter,
Slc10a6
Astrid Kosters, Demesew Abebe, Julio Felix, Saul J. Karpen
Living Donors and Split Transplant
637: Living donor liver transplantation in high model
for end-stage liver disease score
Murat Dayangac, Murat Akyildiz, Yalcin Erdogan, Gokhan
Gungor, Yaman Tokat
638: Priming hepatocytes to G2 enhances liver
regeneration in elderly mice
Fatima K. Rehman, Toshiyuki Hata, Zhaoyu Li, Guojun Bu, Justin
H. Nguyen
639: Cadaveric versus Living donor Liver Transplant
Survival in Relation to MELD Score
Mohammed Al Sebayel, Almoutaz Hahim, Faisal A. Abaalkhail,
Hussien Elsiesy, Hamad M. Al-bahili, Saleh Alabbad, Mohamed
Shoukri, Markus U. Boehnert, Dieter C. Broering
640: Hepatocellular Carcinoma is associated with Lower
Survival following Living Donor Liver Transplantation in
the U.S
Ryan B. Perumpail, Robert Wong, Andrew M. Su, Clark A.
NOVEMBER 8
SATURDAY
Bonham, Carlos O. Esquivel, Aijaz Ahmed
641: Effect of Fully Laparoscopic Left Hepatectomy on
Donor Interest in Living Donor Liver Transplantation
(LDLT)
Anna Yegiants, Darby Santamour, Tarek Mansour, Joseph F. Pisa,
Jean C. Emond, Benjamin Samstein
642: “Patient positioning” in living liver donors –
reinventing the wheel each time
Daniela Ladner, Robert A. Fisher, James V. Guarrera, Elizabeth A.
Pomfret, Mary Ann Simpson, Donna Woods
643: Liver regeneration after right lobe donor
hepatectomy: serial changes of HGF, TNF α, IL6,
Interferon α, Interferon γ, TGF β1 and Thrombopoietine
Shridhar Sasturkar, Shreya Sharma, Paul David, Shiv K. Sarin,
Nirupma Trehanpati, Viniyendra Pamecha
644: Donor Safety in Live Left-Lobe Liver Donation
Roger Patron-Lozano, Manuel Rodriguez Davalos, James E. Tooley,
Armando Salim Munoz-Abraham, Peter S. Yoo, Brett E. Fortune,
Stephen M. Luczycki, Michael L. Schilsky, David C. Mulligan,
Sukru Emre
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
645: Impact of Donor Minimal Histological Changes on
the Outcome of Living Donor Liver Transplantation
Naglaa A. Allam, Wael Abdel-Razek, Nermine Ehsan, Asmaa
Gomaa, Deena El-Azab, Imam Waked
646: Surgical and Percutaneous Ablation are Both
Safe and Effective in Patients with Small Hepatocellular
Carcinoma
Jonathan M. Schwartz, Corbett Shelton, Aws Aljanabi, Mustafa
A. Alani, Dina Ginzberg, Akiva J. Marcus, Javier Chapochnick-
Friedmann, Sarah Bellemare, Yosef Golowa, Jacob Cynamon,
Andreas Kaubisch, Nitin Ohri, Milan Kinkhabwala
647: Role of Portocaval Shunt for Patients with
Glycogen Storage Disease Type I in the Era of Liver
Transplantation : Reappraisal of Portocaval Shunt for
Growth
YoungRok Choi, Nam-Joon Yi, Suk-won Suh, Jeong-moo Lee,
Hyeyoung Kim, Hae Won Lee, Kwang-Woong Lee, Kyung-Suk Suh
648: Success of meso-Rex bypass in the management of
extrahepatic portal vein obstruction in children
Andrew Wehrman, Nadia Ovchinsky, Adam Griesemer, Steven J.
Lobritto, Mercedes Martinez, Tomoaki Kato, Jean C. Emond
649: PET/CT Positivity Has Lower Survival in Adult
Living Donor Liver Transplantation for Hepatocellular
Carcinoma
Murat Akyildiz, Arzu Oezcelik, Gokhan Gungor, Nergis Ekmen,
Necdet Guler, Onur Yaprak, Yalcin Erdogan, Gulen B. Dogusoy,
Murat Dayangac, Yildiray Yuzer, Yaman Tokat
650: Adult Living Donor Liver Transplantation From
Donors with Gilbert’s Syndrome: is it Safe?
Murat Akyildiz, Gokhan Gungor, Necdet Guler, Arzu Oezcelik,
Tonguc Utku Yilmaz, Onur Yaprak, Yalcin Erdogan, Murat
Dayangac, Yildiray Yuzer, Yaman Tokat
651: Laparoscopic Liver Resection in the Pediatric
Population: A Single Center Case Series
Ashley Walther, Shrawan Gaitonde, Greg Tiao, Maria H. Alonso,
Jaimie D. Nathan
652: Novel colonoscopy preparation of organic
coconut water with Miralax and Dulcolax in split doses
for decompensated cirrhotics. A randomized double
blinded open labelled clinical pilot single centered
observational study. COSMIC Study
Patrick Basu, Niraj J. Shah, David Lee, M. Aloysius, Frank G.
Gress
653: The technical success rate and clinical efficacy of
Hepatic Vein Stenting of Hepatic Vein Outflow Stenosis
complicating Orthotropic Liver Transplant
Faiz Francis, Thomas Lowe, Matthew Johnson, David Agarwal,
Daniel E. Wertman, Sabah Butty, Thomas Casciani
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
Mechanisms of Injury
654: Elevated plasma DNA in patients with NASH and
reduced liver injury in mice with absence of TLR9 on
Kupffer cells
Irma Garcia-Martinez, Xinshou Ouyang, Nicola Santoro, Mark J.
Shlomchik, Wajahat Z. Mehal
655: Thalidomide Pretreatment Improves Cell
Engraftment and Liver Repopulation Independently
of Chemokines/Cytokines/Receptors Expressed after
Neutrophil or Kupffer cell Activation
Preeti Viswanathan, Sorabh Kapoor, Brigid Joseph, Ekaterine
Berishvili, Sanjeev Gupta
656: Low dose digoxin protects from NASH and
alcoholic hepatitis in mice by inhibiting a ROS-HIF-1α-
inflammasome pathway
Xinshou Ouyang, Ji-Yuan Zhang, Dechun Feng, Shi-Ying Cai, Irma
Garcia-Martinez, Fu-Sheng Wang, Bin Gao, Wajahat Z. Mehal
657: A distinct role for the TLR9 pathway in immune
activation and tolerance during acute liver injury in mice
Nobuhiro Nakamoto, Hirotoshi Ebinuma, Nobuhito Taniki, Yuko
Wakayama, Po-sung Chu, Akihiro Yamaguchi, Takeru Amiya,
Hidetsugu Saito, Takanori Kanai
658: Sonic hedgehog in microparticles from apoptotic T
cells modulate vascular endothelial function via a rho-
kinase pathway
Samantha A. Canipe, Nicole Feilen, Didier Dréau, Mark G.
Clemens
659: Chronic dietary iron overload in genetically obese
mice causes nonalcoholic steatosis, whereas acute iron
excess leads to increased inflammation and reduced
steatosis
Priya Handa, Vicki Morgan-Stevenson, Bryan D. Maliken, James E.
Nelson, Matthew M. Yeh, Kris V. Kowdley
660: NLRP3 inflammasome driven liver injury and
fibrosis: roles of IL- 17 and TNF-alpha
Alexander Wree, Matthew D. McGeough, Maria E. Inzaugarat,
Carla A. Pena, Alejandra Cherñavsky, Hal M. Hoffman, Ariel E.
Feldstein
661: PAD4-mediated neutrophil extracellular trap
formation increases liver ischemia/reperfusion injury in
mice
Samer Tohme, Hai Huang, Allan Tsung
662: Visceral Adipose Levels of mRNA Encoding GATA3
and FOXP3 Transcription Factors and CSF1 Marker
of Macrophage Infiltration Negatively Correlate with
Histologically Assessed Inflammatory Scores in Liver
Biopsies
Maria Keaton, Katherine Doyle, Lei Wang, Zahra Younoszai,
Rohini Mehta, Zachary D. Goodman, Aybike Birerdinc, Ancha
Baranova, Zobair Younossi
Poster Viewing: 2:00 – 7:30 PM
115A
663: A novel method for anti-TNF based-oral
immunotherapy: Oral administration of a plant cell-
expressed recombinant anti-TNF fusion protein for
treating of fatty liver disease
Yoseph Shaaltiel, Yehudit Shabat, Ami Ben Ya’acov, Sveta Gingis-
Velitski, Einat Almon, David Aviezer, Yaron Ilan
664: Liver lymphocytes from NLG4-/- (KO) mice
showed chronic oxidative stress with reduced
respiratory burst response
Johnny Amer, Sarit Doron, Ahmad Salhab, Rifaat Safadi
665: Warm ischemia and reperfusion causes
liver microcirculatory injury and acute endothelial
dysfunction. Simvastatin prevents these deleterious
events
Diana Hide, Marti Ortega-Ribera, Sergi Vila, Carmen Peralta,
Juan Carlos Garcia-Pagan, Jaime Bosch, Jordi Gracia-Sancho
Metabolic and Genetic Diseases
666: Analysis of surgical interruption of the
enterohepatic circulation as a treatment for pediatric
cholestasis: a retrospective, multi-institutional study
Kasper S. Wang, Benjamin L. Shneider, Colleen G. Azen, Ronen
Arnon, Lee M. Bass, Molly A. Bozic, Mary L. Brandt, Matthew S.
Clifton, Patrick A. Dillon, Annie Fecteau, Paula M. Hertel, Shinjiro
Hirose, Kishore Iyer, Binita M. Kamath, Saul J. Karpen, Frederick
M. Karrer, Nanda Kerkar, Kathleen M. Loomes, Cara Mack, Peter
Mattei, Alexander G. Miethke, Douglas Mogul, Philip Rosenthal,
Kyle A. Soltys, Riccardo Superina, Dylan Stewart, Greg Tiao,
Yumirle P. Turmelle, Karen West
NOVEMBER 8
SATURDAY
667: Oxidative Stress Caused by Nocturnal Hypoxia
is Related to the Severity of Pediatric Non-Alcoholic
Fatty Liver Disease
Shikha Sundaram, Ann C. Halbower, Zhaoxing Pan, Kristen N.
Robbins, Kelley E. Capocelli, Jelena Klawitter, Ronald J. Sokol
668: Monitoring of bile acid urine profile with Liquid
Chromatography-Tandem Mass Spectrography (LC-MS/
MS) allows achievement and maintenance of metabolic
control with minimal doses of chenodeoxycholic acid
in patients affected by 3β-hydroxy-Δ5-C27-steroid
dehydrogenase/isomerase deficiency
Giorgia Curia, Paola Gaio, Francesca Parata, Giuseppe
Giordano, Graziella Guariso, Mara Cananzi
669: Predictive factors of response to non-transplant
treatment strategies in progressive familial intrahepatic
cholestasis type II
Sharat Varma, Xavier Stephenne, Nicole Revencu, Isabelle
Scheers, Raymond Reding, Françoise Smets, Etienne M. Sokal
Presenters in Attendance 5:30 – 7:00 PM
 116A POSTER SESSIONS
Poster Sessions
670: Phase I/II clinical trial of Heterologous Human
Adult Liver-derived Progenitor Cells (HHALPC, hepastem)
in urea cycle disorders (UCD) and Crigler-Najjar
syndrome (CN): six months follow-up results
Etienne M. Sokal, Patrick J. McKiernan, Emmanuel Jacquemin,
Giuliano Torre, Pierre Broue, Francois Eyskens, Dries Dobbelaere,
Carlo Dionisi-vici, Paul Gissen, Philippe Clapuyt, Daniele Pariente,
Marc Yudkoff, Doreen Dekker, Joelle J. Thonnard, Beatrice A. De
Vos, Françoise Smets
671: Post-Developmental Genetic Screening for
Zebrafish Models of Inherited Liver Diseases
Seok-Hyung Kim, Simon Wu, Josh Gamse, Kevin Ess
672: Genetic, clinical, and histopathologic features of
intermediate tight junction protein 2 deficiency
Melissa Sambrotta, A. S. Knisely, Richard J. Thompson
673: The Burden of Pruritus on Patients with Alagille
Syndrome: Results from a Qualitative Study with
Pediatric Patients and their Caregivers
Linda Abetz-Webb, Ciara Kennedy, Bonnie Hepburn, Martha
Gauthier, Nathan Johnson, Sharon Medendorp, Alejandro
Dorenbaum, Benjamin L. Shneider, Binita M. Kamath
674: A Comparison of Controlled Attenuation
Parameter and Liver Biopsy to Assess Hepatic Steatosis
in Pediatric Patients
Nirav K. Desai, Sarah Harney, Roshan Raza, Paul D. Mitchell,
Maureen M. Jonas
675: Hepatic mast cell infiltration is associated with
progression of congenital hepatic fibrosis in the PCK rat
NOVEMBER 8
Pingping Fang, James Weemhoff, Seth Septer, Briana Holt,
SATURDAY
Udayan Apte, Michele Pritchard
676: Silent progression of liver disease and
development of cirrhosis in children several years after
cranial tumor resection
Anita K. Pai, Shengmei Zhou, Mark Krieger, Sophoclis
Alexopoulos, Yuri Genyk, Nanda Kerkar
677: Serial Enhanced Liver Fibrosis Test (ELF) to monitor
disease progression in Pediatric Non-Alcoholic Fatty
Liver Disease
Jeremy K. Rajanayagam, Andrew W. Lee, Patrick J. McKiernan
Viral and Autoimmune Hepatitis
678: Predicting future outcome in infancy-acquired
chronic hepatitis B – importance of quantitative HBeAg
and HBsAg plasma levels, HBV DNA viral load and
IP10 plasma levels
Mary Horner, Matthew J. Bruce, Sanjay Bansal, Sarah Tizzard,
Diego Vergani, Phillip M. Harrison, Kosh Agarwal, Giorgina Mieli-
Vergani, Ivana Carey
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
679: Association Between Hepatitis C Virus Infection
with Insulin Resistance and Total Cholesterol Levels in
Children and Youth
Aymin Delgado-Borrego, Roshan Raza, Michelle Godbee, Andrea
Barreto, Elsa Yumar, Betania Negre, David A. Ludwig, Maureen
M. Jonas, Raymond Chung
680: Differences in clinical characteristics of children
with chronic hepatitis B (CHB) by adoption status:
findings from the Hepatitis B Research Network (HBRN)
Simon C. Ling, Yona K. Cloonan, Philip Rosenthal, G. Johnson,
Karen F. Murray, Sarah J. Schwarzenberg, Norberto Rodriguez-
Baez, Jeffrey Teckman, Kathleen B. Schwarz
681: APRI, FIB-4 and Fibroscan in Prediction of
Significant Fibrosis in Adolescent Cancer Survivors in a
Resource Limited Country
Manal H. El-Sayed, Dalia N. Toaima, Fatma A. Marzouk, Amira
Mohsen, Aisha Elsharkawy, Gamal E. Esmat, Alaa El-Haddad
682: Pegylated Interferon Therapy in Chronic Hepatitis
B Infection- Is it the best option available in Children?
Vikrant Sood, Sanjeev K. Verma, Seema Alam, Rajeev Khanna,
Dinesh Rawat
683: Can expression of interferon-stimulated genes in
pre-treatment liver biopsy of chronic hepatitis B patients
predict therapy response and long-term HBV infection
outcome?
Ivana Carey, Kate Childs, Sanjay Bansal, Sarah Tizzard, Matthew
J. Bruce, Mary Horner, Diego Vergani, Kosh Agarwal, Giorgina
Mieli-Vergani
Viral Hepatitis and Liver Transplant
684: Impact of EGF, IL28B, and PNPLA3
polymorphisms on the outcome of allograft hepatitis C:
a multicenter study
Jessica L. Mueller, Lindsay Y. King, Kara B. Johnson, Tian Gao,
Lauren D. Nephew, Darshan Kothari, Mary Ann Simpson, Lan
Wei, Kathleen E. Corey, Joseph Misdraji, Joon Hyoek Lee, Bryan
C. Fuchs, Kenneth K. Tanabe, Frederic D. Gordon, Michael P.
Curry, Raymond T. Chung
685: Genetic polymorphisms of toll–like receptors
1 and 9 are associated with increased risk of severe
hepatitis C virus recurrence after liver transplantation
Ana Maria Duca, María J. Cítores, Sara de la Fuente, Isolina
Baños, Ana B. Cuenca, Valentin Cuervas-Mons
686: The influence of mTor-Inhibitors on HCV
replication after liver transplantation
Eva-Maria Ecker, Alexandra Frey, Katja Piras-Straub, Andreas
Walker, Guido Gerken, Kerstin Herzer
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
687: Hepatitis C Treatment Does Not Affect Waiting
Time for Liver Transplantation in Hepatitis C Positive
Patients
Mohannad Dugum, Nizar N. Zein, Naim Alkhouri, Rocio Lopez,
Brigette Bevly, Charles M. Miller, Teresa Diago, Ibrahim A.
Hanouneh
688: Sofosbuvir and ribavirinin in hcv-infected patients
listed for liver transplantation: a cost-effectiveness
analysis
Paolo A. Cortesi, Lorenzo G. Mantovani, Antonio Ciaccio, Matteo
Rota, Giancarlo Cesana, Mario Strazzabosco, Luca S Belli
689: Hepatitis E Virus (HEV) Infection is Rare Cause of
Hepatitis Among US Liver Transplant Recipients
Norah Terrault, Ronald E. Engle, Jennifer L. Dodge, Chris Freise,
Averell H. Sherker, Patrizia Farci, Robert H. Purcell
690: Characteristics of Post Transplantation Hepatitis
E Virus Infection Among Solid Organ Transplant
Recipients at a North American Transplant Center
Paul K. Sue, Nora Pisanic, Christopher D. Heaney, Kenrad Nelson,
Kathleen B. Schwarz, Alexandra Valsamakis, Michael Forman,
Annette M. Jackson, John R. Ticehurst, Robert A. Montgomery,
Wikrom Karnsakul
691: Validation of The Hepatitis Aggressiveness Score
in a Liver Transplant Population with Recurrent Hepatitis
C Zobair Younossi, Maria Stepanova, Sammy Saab, Gregory
Alberto Unzueta, Roger K. Moreira, Giovanni DePetris, Maxwell L.
Smith, Yu-Hui H. Chang, Meng-Ru Cheng, Angela Eyshou, Juan F.
Gallegos-Orozco, Bashar Aqel, Hugo E. Vargas
692: Living donor liver transplantation for hepatitis C
virus-positive recipients in Japan: a nationwide survey
Tomohiro Tanaka, Nobuhisa Akamatsu, Yasuhiko Sugawara,
Junichi Kaneko, Sumihito Tamura, Taku Aoki, Yoshihiro Sakamoto,
Kiyoshi Hasegawa, Norihiro Kokudo
693: Performance Characteristics of the Procleix HEV
Assay on the Fully Automated Procleix Panther System
Edgar Ong, Alanna Janssen, Robin Cory, Maria Babizki, Tim Shin,
Andre Lindquist, Ngoc-Anh Hoang, Lee P. Vang, Lisa Danzig,
Jeffrey M. Linnen
694: Sofosbuvir as the backbone of treatment for
HCV after liver transplantation: a real-life multicenter
experience
Rohit Satoskar, Joseph Ahn, Helen S. Te, Adam Deising, Andrew
Aronsohn, Suzanne Robertazzi, Thomas D. Schiano
695: The Impact of Pre-Transplant Obesity and
Diabetes on Survival Following Liver Transplantation
among Hepatitis C Virus Patients With and Without
Hepatocellular Carcinoma
Robert J. Wong, Ramsey Cheung, Edward W. Holt, Aijaz Ahmed
Poster Viewing: 2:00 – 7:30 PM
117A
696: Long-Term Results of Prophylaxis of De Novo
Hepatitis B Virus (HBV) Infection With Lamivudine in
HBsAg-negative Naive Recipients of anti-HBc-positive
Liver Grafts: A 13-year Single-center Experience
Martin Prieto, María García Eliz, Ana M. Braithwaite, Angel
Rubin, Victoria Aguilera, Salvador Benlloch, Marina Berenguer,
Carmen Vinaixa
697: Reinfection prophylaxis with entecavir
monotherapy is successful and safe in patients with
hepatitis B virus infection after liver transplantation
Kerstin Herzer, Ingmar Mederacke, Guido Gerken, Frank Lehner,
Juergen Klempnauer, Michael P. Manns, Karsten Wursthorn
698: Accessibility to Liver Transplantation for HIV-
HCV Coinfected Patients with End Stage Liver Disease:
the French Prospective Multicenter ANRS HC EP 25
PRETHEVIC COHORT
Maria Ostos, Moana Gelu-Simeon, Laetitia A. Johnson, Elina
Teicher, Hélène Fontaine, Pierre Tattevin, Isabelle Poizot-Martin,
Stephanie Dominguez, David Zucman, Julie Chas, Pascal P.
Crenn, Anne Gervais, Karine Lacombe, Philippe Morlat, Rodolphe
Anty, Faroudy Boufassa, Inga Bertucci, Georges-Philippe Pageaux,
Laurence Meyer, Jean-Charles Duclos-Vallée
699: Hepatitis C Virus Infection is an Independent
Predictor of Post-Liver Transplant Diabetes: Data from
the U.S. Scientific Registry of Transplant Recipients
Trimble, Alita Mishra, Shirley K. Kalwaney, Zahra Younoszai,
Fatema Nader, Linda Henry
700: Sustained Virologic Responses with Nitazoxanide
NOVEMBER 8
Therapy in Recurrent Hepatitis C (genotype 1) Infection
SATURDAY
Post Liver Transplantation
Marshall E. McCabe, Saurabh Agrawal, Marco A. Lacerda, A.
Joseph Tector, Paul Y. Kwo, Marwan Ghabril
701: Early Safety and Efficacy Profiles of Renal
Transplant Recipients with Chronic Hepatitis C Treated
with Sofosbuvir and Ribavirin
Genevieve Huard, Brian Kim, Anna Patel, Badr Aljarallah, Ponni
Perumalswami, Joseph A. Odin, Sara Geatrakas, Jawad Ahmad,
Douglas Dieterich, Vinay Nair, Thomas D. Schiano, Gene Y. Im
702: T Regulatory Cells in De Novo Hepatitis B Virus
Infection after Liver Transplantation
Yinjie Gao, Min Zhang, Jingmin Zhao, Hanwei Li
703: The long-term efficacy of combination of nucleos(t)
ide analogue treatment and low dose hepatitis b
immunoglobulin on posttransplant HBV recurrence
Ramazan Idilman, Murat Akyildiz, Onur Keskin, Ali Tuzun,
Tonguc U. Yilmaz, Necdet Guler, Onur Yaprak, Gokhan Gungor,
Yalcin Erdogan, Murat Dayangac, Deniz Balci, Kubilay Cinar,
Acar Tuzuner, Selcuk Hazinedaroglu, Yaman Tokat, Sadik Ersoz,
Abdulkadir Dokmeci
Presenters in Attendance 5:30 – 7:00 PM
 118A POSTER SESSIONS
Poster Sessions
704: Efficacy of protease inhibitor in combination with
pegylated interferon and ribavirin to treat hepatitis C
after living donor liver transplantation
Satoshi Miuma, Tatsuki Ichikawa, Hisamitsu Miyaaki, Naota
Taura, Kazuhiko Nakao
705: Post-transplant Treatment of Severe Recurrent
Hepatitis C (HCV) with Daclatasvir and Sofosbuvir Plus
or Minus Ribavirin
Natalie H. Bzowej, Shobha Joshi, George Therapondos, Nigel
Girgrah, Gia Tyson, Inna Goldvarg-Abud, Jennifer B. Scheuermann,
Humberto E. Bohorquez, Ari J. Cohen, Ian C. Carmody, Trevor W.
Reichman, David S. Bruce, George E. Loss
706: Sofosbuvir + Simeprevir is Safe in Liver Transplant
Recipients
Fredric D. Gordon, Andreana L. Kosinski, Sheila J. Coombs,
Pauline Goucher, Emad S. Aljahdli, Elizabeth A. Pomfret
707: Telbivudine is associated with improvement of
renal function in patients after liver transplantation
Evangelos Cholongitas, Themistoklis Vasiliadis, Ioannis Goulis,
Ioannis Fouzas, Vasileios Papanikolaou, Evangelos A. Akriviadis
NOVEMBER 8
SATURDAY
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
708: Survey on Pre- and Post-Transplant Management
of Hepatitis C: Response from Medical Directors of US
Transplant Programs
Paul J. Gaglio, Carly E. Glick, John F. Reinus
709: Liver transplantation for patients with HCV-related
end-stage liver disease and undetectable HCV-RNA: the
Turin Centre experience
Alessandro Risso, Francesco Tandoi, Silvia Martini, Renato
Romagnoli, Mauro Salizzoni
710: Safety and Efficacy of Hepatitis C Therapy with
Sofosbuvir and Simeprevir after Liver Transplantation
Julio A. Gutierrez, Alla Grigorian, Andres F. Carrion, Michael
D. Schweitzer, Danny J. Avalos, Kalyan R. Bhamidimarri, Adam
Peyton
711: The Combination of Simeprevir and Sofosbuvir
for the Treatment of HCV Infection in Patients Post Liver
Transplant With Significant Fibrosis
Idrees Suliman, Renee Pozza, Yaseen Kady, Catherine Hill,
Thomas
    A. Couturier, Preeti Reshamwala, Tarek Hassanein
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
Poster Session 2
Sunday, November 9
POSTER VIEWING: 8:00 AM - 5:30 PM
Hall C
Presenters in attendance:
12:30 - 2:00 PM
Those posters identified as AASLD Presidential Poster of Distinction
by a ribbon icon have received review scores that place them
within the top 10 percent of all posters. We encourage you to
make them a priority as you visit the poster sessions.
Acute Liver Failure
712: The Mortality of Acute-on-Chronic Liver Failure
by APASL vs. EASL-CLIF definition: A Multicenter,
Retrospective Cohort Study in Korea (KACLiF Study)
Tae Yeob Kim, Dong Joon Kim, Do Seon Song, Dong Hyun Sinn,
Eileen L Yoon, Joo Hyun Sohn, Chang wook Kim, Young Kul Jung,
Ki Tae Suk, Jin Mo Yang, Heon Ju Lee
713: Predicting Progression from Acute Liver Injury to
Acute Liver Failure Using a Machine Learning Algorithm
Jaime L. Speiser, David G. Koch, William M. Lee
714: Development and Validation of the CLIF-C
AD score for the prognosis of patients with acute
decompensation (AD) of cirrhosis not fulfilling diagnostic
criteria for acute-on-chronic liver failure (ACLF)
Rajiv Jalan, Marco Pavesi, Faouzi Saliba, Alex Amorós, Javier
Fernandez, Peter Holland-Fischer, Rohit Sawhney, Rajeshwar
Mookerjee, Paolo Caraceni, Tania M. Welzel, Richard Moreau,
Pere Gines, Francois Durand, Paolo Angeli, Carlo Alessandria,
Wim Laleman, Jonel Trebicka, Didier Samuel, Stefan Zeuzem,
Thierry Gustot, Alexander L. Gerbes, Julia Wendon, Mauro
Bernardi, Vicente Arroyo
715: Hyperammonaemia and systemic inflammation is
associated with intracellular lactate accumulation
Anne M. Witt, Fin Stolze Larsen, Peter N. Bjerring
716: Alginate biocompatibility for use in tissue
engineering and cell therapy applications: biological
responses to hydrogel-encapsulated HepG2 cells in
vitro - leukocyte cytokine release and peripheral blood
mononuclear cell proliferation
Jordi G. Molina, Graham Wright, Sam Coward, Hardeep Kalsi,
Eloy Erro, Barry Fuller, Clare Selden
717: Implanted human bone mesenchymal stem cells
rescue fulminant hepatic failure within one week
through paracrine and transdifferentiation in pigs
Jun Li, Dongyan Shi, Jianing Zhang, Ding Wenchao, Jiaojiao Xin,
Qian Zhou, Hongcui Cao, Xin Chen, Lanjuan Li
Poster Viewing: 8:00 AM – 5:30 PM
119A
718: Assessment of adrenal function in patients with
severe acute hepatitis: a growing interest of serum
free cortisol and salivary cortisol. A prospective
observational multicenter study
Thibault Degand, Elisabeth Monnet, Francois Durand, Emilie
Grandclement, Philippe Ichai, Franck Schillo, Arnaud Agin,
Alexandre Louvet, Jérôme Dumortier, Gilles Dumoulin, Vincent Di
Martino, Thierry Thevenot
719: Characterization of Acute-on-Chronic Liver Failure
And Prediction of Mortality in Patients with Alcoholic
Hepatitis
Hwi Young Kim, Yong Jin Jung, Byeong Gwan Kim, Kook Lae Lee,
Won Kim
720: Acute Liver Decompensation Following
Radioembolization For Liver Cancer: A Retrospective
Study
Michael Min, Totianna Prudhomme, Eduardo Ehrenwald, Jill May,
Kai Hanson, Andrew J. Henn, Joseph Leach, Coleman Smith
721: Improved survival of hepatocytes in co-culture with
mesenchymal stromal cells following exposure to acute
liver failure serum: the role of paracrine factors
Emer Fitzpatrick, Sunitha Vimalesvaran, Celine Filippi, Ragai R.
Mitry, Tracey Dew, Charalambos G. Antoniades, Anil Dhawan
722: Alpha fetoprotein: A biomarker for the recruitment
of progenitor cells in the liver of the patients with acute
liver injury/acute liver failure
Keisuke Kakisaka, Kojiro Kataoka, Yuji Suzuki, Yasuhiro
Miyamoto, Yasuhiro Takikawa
723: The Safety of Therapeutic Plasma Exchange in
Pediatric End Stage Liver Disease
Amy S. Arrington, Moreshwar S. Desai, Ayse Akcan Arikan, Jun
Teruya, Poyyapakkam R. Srivaths
724: Acetaminophen (APAP)-induced Acute Liver Failure
(ALF) Leads to Activation Of Endogenous Hepatic Stem/
Progenitor Cells with Inability to Complete Hepatic
NOVEMBER 9
Regeneration
SUNDAY
Nicole Pattamanuch, Preeti Viswanathan, Sriram Bandi, Leslie E.
Rogler, Charles E. Rogler, Sanjeev Gupta
725: TNF-α Induces Receptor Interacting Protein-3
Kinase to Mediate Necrotic Cell Death in Acute-on-
Chronic Liver Failure
Arshi Khanam, Nirupma Trehan Pati, Archana Rastogi, Shiv K.
Sarin
726: The Usefulness of Prognostic Factors of Acute-on-
Chronic Liver Failure in Patients with Liver Cirrhosis:
A Multicenter, Retrospective Cohort Study in Korea
(KACLiF Study)
Do Seon Song, Dong Joon Kim, Tae Yeob Kim, Dong Hyun Sinn,
Eileen L Yoon, Joo Hyun Sohn, Chang wook Kim, Young Kul Jung,
Ki Tae Suk, Jin Mo Yang, Heon Ju Lee
Presenters in Attendance 12:30 – 2:00 PM
 120A POSTER SESSIONS
Poster Sessions
727: Acute Liver Failure related to Drug reaction with
eosinophilia and systemic symptoms (DRESS): Outcome
and Predictive Factors for improvement
Philippe Ichai, Camille Besch, Catherine Guettier, Claire Francoz,
Laurence Valeyrie-Allanore, Sylvie Roussin-Bretagne, Olivier Roux,
Alexia Letierce, Faouzi Saliba, Florent Artru, Marc Boudon, Teresa
Maria Antonini, Francois Durand, Didier Samuel
728: A non-invasive method for enumerating cell
number in three dimensional cell cultures; the integrated
variable cell count, a tool for regenerative medicine,
enabling quality assurance of cell therapy applications
Eloy Erro, Hyun Woo Yu, Dominic Davis, James T. Bundy, Aurelie
Le lay, Humphrey Hodgson, Barry Fuller, Clare Selden
729: Arterial ammonia concentration determined
by point of care testing in acute liver failure; clinical
associations and utility in prediction of complications
and outcome
Vishal C. Patel, Beatriz Mateos Muñoz, Elizabeth Sizer,
Charalambos G. Antoniades, Christopher Willars, Georg
Auzinger, Julia Wendon, William Bernal
730: Impaired Neutrophil Function Aggravates Liver
Injury and Correlates with Clinical Severity Indices in
Acute-on-Chronic Liver Failure
Arshi Khanam, Nirupma Trehan Pati, Peggy Riese, Archana
Rastogi, Carlos A. Guzman, Shiv K. Sarin
731: Genome editing with Cas9 in adult mice corrects a
liver disease mutation and phenotype
Hao Yin
732: LDH in the determination of cause in acute liver
failure, revisited
Michelle Gottfried, Kurt Kleinschmidt, William M. Lee
733: Liver failure determines the extra-hepatic organ
failure and outcome in patients with acute-on-chronic
liver failure: Analysis of 1363 patients of AARC Data
Base
NOVEMBER 9
Chandan K. Kedarisetty, Shiv K. Sarin, Lovkesh Anand, Zaigham
SUNDAY
Abbas, Deepak N. Amarapurkar, Ankit Bhardwaj, Ajeet S.
Bhadoria, Chhagan Bihari, Amna S. Butt, Ashok Choudhary,
Chan Albert, Yogesh K. Chawla, Abdulkadir Dokmeci, Hitendra
K. Garg, Hasmik Ghazinyan, Saeed S. Hamid, Ankur Jindal,
Naveen Kumar, Avinash Kumar, Guan Huei Lee, Laurentius A.
Lesmana, Mamun A. Mahtab, Rakhi Maiwall, Qin Ning, Devraj
Rangegowda, Archana Rastogi, Amrish Sahney, Samir R. Shah,
Gamal Shiha, Barjesh C. Sharma, Manoj Kumar, Saggere M.
Shasthry, Soek Siam Tan, Chitranshu Vashishtha, Man-Fung Yuen,
Osamu Yokosuka
734: Higher thyroid-stimulating hormone,
triiodothyronine and thyroxine values are associated
with better outcome in acute liver failure
Olympia Anastasiou, Jan-Peter Sowa, Paul P. Manka, Christian D.
Fingas, Wing-Kin Syn, Antonios Katsounas, Dagmar Führer, Robert
K. Gieseler, Lars Bechmann, Guido Gerken, Lars C. Moeller, Ali
Canbay
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
735: Ambient temperature short-term preservation
of liver cells for bioengineering applications using
perfluorodecalin as an oxygen source
Darren L. Scroggie, Eloy Erro, James T. Bundy, Aurelie Le lay,
Dominic Davis, Sunil R. Modi, Barry Fuller, Clare Selden
736: Hepatocyte Krüppel-Like-Factor 6 expression
is upregulated in acute liver injury and represses
hepatocyte proliferation
Svenja Sydor, Jan Best, Paul P. Manka, Martin Schlattjan, Thomas
Schreiter, Diana Vetter, Andreas Paul, Scott L. Friedman, Guido
Gerken, Ali Canbay, Lars Bechmann
737: Impaired monocyte and macrophage function in
Hepatitis E Virus (HEV) infected pregnant women with
Acute Liver Failure
Rashi Sehgal, Paul David, Ashish Vyas, Arshi Khanam, Ankit
Bhardwaj, Preety Rawal, Syed Hissar, Sharda Patra, Shubha S.
Trivedi, Shyam Kottilil, Shiv K. Sarin, Nirupma Trehanpati
738: Increased neutrophil actin production and
translocation of myeloperoxidase in patients with
acetaminophen-induced acute liver failure may
contribute to multiorgan failure
Godhev K. Manakkat Vijay, Gema Vizcay-Barrena, Thomas
Tranah, Leanne Glover, Vishal C. Patel, Christine Bernsmeier,
Jennifer M. Ryan, Laura J. Blackmore, Xiaohong Huang, Victoria
T. Kronsten, Nicholas J. Taylor, William Bernal, Georg Auzinger,
Christopher Willars, Julia Wendon, Yun Ma, Barbara Bain, Alice
Warley, Debbie Shawcross
739: Granulocyte-colony stimulating factor for acute-
on-chronic liver failure: systematic review and meta-
analysis of randomized control trials
Victoria J. Ornelas-Arroyo, Desiree Vidaña-Pérez, Guadalupe
Delgado-Sánchez, Indira R. Mendiola Pastrana, Camilo Noreña-
Herrera, Tonatiuh Barrientos-Gutierrez, Eva Juárez Hernández,
Nahum Méndez-Sanchéz, Misael N. Uribe-Esquivel, Norberto C.
Chavez-Tapia
740: Etiology, Clinical Features and Outcome of Acute
Liver Failure in Japan
Nobuaki Nakayama, Hirohito Tsubouchi, Satoshi Mochida
741: Secretory Leukocyte Protease Inhibitor (SLPI)
promotes hepatic resolution responses in acute liver
failure (ALF)
Evangelos Triantafyllou, Oltin T. Pop, Evaggelia Liaskou, Christine
Bernsmeier, Wafa Khamri, Zania Stamataki, Yun Ma, Mark R.
Thursz, Julia Wendon, Alberto Quaglia, Chris J. Weston, Stuart M.
Curbishley, David H. Adams, Charalambos G. Antoniades
742: Characterization of disease-specific biomarkers in
hepatitis B virus-related acute-on-chronic liver failure
and their predictive value for mortality
Jun Li, Jiaojiao Xin, Ding Wenchao, Qian Zhou, Longyan Jiang,
Dongyan Shi, Lanjuan Li
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
743: Traditional prognostic factors do not differentiate
between survivors and non-survivors in pediatric liver
failure patients on renal support
Ayse Akcan Arikan, Keila L. de la Garza, Poyyapakkam R. Srivaths,
Alyssa Riley, Kathleen Thompson, Ryan Himes, Moreshwar S.
Desai
744: Inclusion of Admission Red Cell Distribution Width
(RDW) and Mean Corpuscular Volume (MCV) improves
predictive accuracy of prognostic models of Acute Liver
Failure (ALF)
Kimberly A. Forde, Thure Caire, Craig Newcomb, R. Todd Stravitz
745: Pre-existing liver diseases lead acute HEV infection
to progressive liver failure
Jong-Hon Kang, Takeshi Matsui, Kazumasa Nagai, Akiko
Tomonari, Kazunari Tanaka, Kunihiko Tsuji, HIroyuki Maguchi,
Yoshiyasu Karino, Itaru Ozeki, Shuhei Hige, Tomoaki Nakajima,
Takumi Ohmura, Kazuaki Takahashi, Masahiro Arai, Shunji
Mishiro
746: A pilot study to determine the efficacy and safety
of ribavirin in patients of acute severe hepatitis E
Rahul Gupta, Sandeep S. Sidhu, Varun Mehta, Ajit Sood
747: Granulocyte colony stimulating factor (G-CSF) to
treat acute (on chronic) liver failure: effect on immune
and stem cell mobilisation
Cornelius Engelmann, Katrin Splith, Thomas Berg, Moritz Schmelzle
748: C/EBP homologous protein (CHOP) promotes
hepatocyte death by ERO1α signaling during acute liver
failure
Ling Lu, Jianhua Rao, Haoming Zhou, Xuehao Wang
749: The clinical and immunological chracteristics of
acute liver failure with autoimmune features – for early
diagnosis and proper treatment–
Hirotoshi Ebinuma, Hidetsugu Saito, Yoshiyuki Yamagishi,
Nobuhiro Nakamoto, Po-sung Chu, Yuko Wakayama, Nobuhito
Taniki, Akihiro Yamaguchi, Shunsuke Shiba, Shingo Usui, Kazuo
Sugiyama, Takanori Kanai
750: Increased CD11b+CD163+ macrophages caused
liver injury in acute liver Failure (ALF) non-survivors
Rashi Sehgal, Arshi Khanam, Ashish Vyas, Shiv K. Sarin, Nirupma
Trehanpati
751: Micro RNAs miR-106a, miR-122 and mir-197
are increased in severe acute viral hepatitis with
coagulopathy
Lukas Weseslindtner, Iris F. Macheleidt, Hannah Eischeid, Robert
Paul Strassl, Theresia Popow-Kraupp, Harald Hofer, Margarete
Odenthal, Heidemarie Holzmann
Poster Viewing: 8:00 AM – 5:30 PM
121A
Basic Fibrosis
752: Raf kinase inhibitor 1 (Rkip1): a potential
modifier of fibrogenesis in liver and heart
Rabea A. Hall, Andrey Kazakov, Ulrich Laufs, Michael Boehm,
Frank Lammert
753: The Role of Toll Like Receptor 4 signaling by
Hepatic Stellate Cells in Hepatocarcinogenesis
Jinsheng Guo, Yangyang Ouyang, Chengzhao Lin, Yujing Wu,
Yuanqing Zhang, Yirong Cao, Shiyao Chen, Jiyao Wang, Scott
L. Friedman
754: Highly Efficient Gene Targeting of a LncRNA in
Human LX-2 Hepatic Stellate Cells using TALENs
Daniel L. Motola, Kaveh Daneshvar, Samuel R. York, Alan Mullen,
Raymond T. Chung
755: The role of Fyn in hepatic stellate cells activation
and liver fibrosis
Yin Ying Lu, Guanghua Rong, Dechun Feng, Chunping Wang,
Xiujuan Chang, Xudong Gao, Yan Chen, Jianhui Qu, Zhen Zeng,
Hong Wang, Bin Gao, Yongping Yang
756: A Hepatic Stellate Cell Expression Signature
Identifies Novel Cell Markers and Predicts Outcomes in
Chronic Liver Disease
David Zhang, Hsin I Chou, Yujin Hoshida, Scott L. Friedman
757: Grb2-associated binder 1 protects against
liver fibrosis via suppression of CCL5 production from
hepatocytes
Yuichi Yoshida, Takashi Kizu, Kunimaro Furuta, Satoshi Ogura,
Mayumi Egawa, Norihiro Chatani, Yoshihiro Kamada, Shinichi
Kiso, Tetsuo Takehara
758: The peripherally-restricted CB1 antagonist
AM6545 reduces liver fibrogenesis via growth
inhibitory effects for hepatic myofibroblasts and anti-
inflammatory properties
NOVEMBER 9
Jinghong Wan, Aida Habib, Jasper Lodder, Arthur Brouillet, Fouad
SUNDAY
Lafdil, Adrien Guillot, Catherine Pavoine, Richard Moreau, Ariane
Mallat, Sophie Lotersztajn
759: MicroRNA-155 (miR-155) deficiency attenuates
liver fibrosis and not liver injury or inflammation in an
animal model of steatohepatitis
Timea Csak, Shashi Bala, Dora Lippai, Karen Kodys, Donna
Catalano, Gyongyi Szabo
760: The adiponectin peptide agonist ADP355
attenuates CCl4-mediated liver fibrosis: therapeutic
implications by multiple molecular mechanisms in vivo
and in vitro
Pradeep Kumar, Tekla Smith, Khalidur Rahman, Natalie Thorn,
Frank A. Anania
Presenters in Attendance 12:30 – 2:00 PM
 122A POSTER SESSIONS
Poster Sessions
761: The interaction of beta-Arrestin-2 with AT1-
receptor signalling in liver fibrosis
Robert Schierwagen, Judith Heinzen, Sabine Klein, Frank E.
Uschner, Kanishka Hiththetiya, Christian P. Strassburg, Tilman
Sauerbruch, Jonel Trebicka
762: Identification of long noncoding RNAs induced
in hepatic stellate cell myofibroblasts
Samuel R. York, Chan Zhou, Jennifer Y. Chen, Kaveh Daneshvar,
Alan Mullen
763: Genetic or pharmacologic inhibition of
microRNA-21 does not prevent liver fibrosis or
hepatocellular carcinoma in mice
J Matias Caviglia, Myoung Kuk Jang, Geum-Youn Gwak, Ingmar
Mederacke, Xueru Mu, Dianne H. Dapito, Robert F. Schwabe
764: Pharmacological inhibition of apoptosis signal-
regulating kinase 1 (ASK1) in a murine model of NASH
with pre-existing disease blocks fibrosis, steatosis, and
insulin resistance
Satyajit Karnik, Michael Charlton, Yury Popov, Zachary D.
Goodman, Michelle Nash, Maisoun Sulfab, Vivian Barry, Erik
G. Huntzicker, Dorothy French, Kelvin Li, Martin Decaris, Claire
Emson, Scott M. Turner, David Breckenridge, Daniel Tumas
765: Inhibition of MAP3K5, Apoptosis signal-
regulating kinase 1, with an oral small molecule
inhibitor blocks hepatic fibrosis and steatosis in murine
models of NASH and PSC
Satyajit Karnik, Michael Charlton, Michelle Nash, Maisoun
Sulfab, Vivian Barry, Erik G. Huntzicker, Dorothy French, David
Breckenridge, Britton Corkey, Gregory Notte, James E. Nelson,
Kris V. Kowdley, Daniel Tumas
766: Differential roles of C5a receptors C5aR and
C5L2 in liver and kidney fibrosis
Ina V. Martin, Tammo Ostendorf, Jürgen Floege, Frank Lammert,
Susanne N. Weber
NOVEMBER 9
767: Coniferyl Ferulate Attenuated Liver Fibrosis
SUNDAY
Through Inhibition Of Transforming Growth Factor-Β
Receptor
Ya N. Zhou, Wen W. Fu, Ping Liu
768: Lysyl oxidase activity contributes to collagen
stabilization during liver fibrosis progression and limits
hepatic fibrosis reversal in mice
Susan B. Liu, Naoki Ikenaga, Deanna Sverdlov, Zhen-Wei Peng,
Detlef Schuppan, Yury Popov
769: Deficiency of stress induced heat shock
transcription factor 1 (HSF1) Exacerbates Liver Fibrosis:
Regulation of Inflammatory Cytokines and Fibrogenesis
Pranoti Mandrekar, Arlene Lim
770: Cthrc1 alleviates cholestatic liver fibrosis through a
negative feedback loop with p-smad3 in mice
Zhaolian Bian, Qi Miao, Wei Zhong, Xiong Ma
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
771: ‘Lucky grandchildren’: Inbred mice whose
grandparents developed liver fibrosis appear to be
protected against the same disease
Andrea Schmetz, Frank Lammert, Susanne N. Weber
772: Signaling via the osteopontin and high-mobility
group box-1 axis drives the fibrogenic response to liver
injury
Elena Arriazu, Xiaodong Ge, Tung Ming Leung, Aritz Lopategi,
Yongke Lu, Raquel Urtasun, Neil D. Theise, Natalia Nieto
773: Sortilin deficiency affects fibrosis differently in
hepatocellular versus cholangiocyte models of liver
injury
Rafael Bruck, Einav Hubel, Tamar Thurm, Isabel Zvibel
774: Linagliptin mediated DPP-4 inhibition ameliorates
inflammation and fibrosis in models of NASH and
biliary fibrosis
Xiao-Yu Wang, Shih-Yen Weng, Yong Ook Kim, Thomas Klein,
Detlef Schuppan
775: The Hippo pathway effector YAP is an early
regulator of hepatic stellate cell activation
Inge Mannaerts, Sofia B. Leite, Stefaan Verhulst, Lien F. Thoen,
Sofie Claerhout, Georg Halder, Leo A. van Grunsven
776: Toll-like Receptor 3 Accelerates Liver Fibrosis by
Enhancing IL-17 Production in Mice
Wonhyo Seo, Hyuk-Soo Eun, Young-Sun Lee, Hyon-Seung Yi, Jong-
Min Jeong, So Yeon Kim, Yoo Kyung Kang, Jin Yong Kim, Byung
Jun Choi, Won-Il Jeong
777: Deletion of the cytoplasmic domain of Tissue
Factor ameliorates liver fibrosis and decreases TGFβ
expression in a murine model of cirrhosis
Virginia Knight, Jorge Tchongue, Dinushka Lourensz, Alison X. Liu,
Peter Tipping, William Sievert
778: Platelets as a novel target in liver fibrosis:
extrahepatic supply of PDGF-B by platelets drives
hepatic stellate cell activation and biliary liver fibrosis
progression
Shuhei Yoshida, Naoki Ikenaga, Susan B. Liu, Deanna Sverdlov,
Masahiko Shimada, Maki Tobari, Tetsuya Hamano, Takayoshi
Nishino, Atsushi Mitsunaga, Detlef Schuppan, Yury Popov
779: Anti-fibrotic and anti-inflammatory activity of
the adenosine receptor 2b antagonist, GS-6201, in a
murine model of PSC
Satyajit Karnik, Yong Ook Kim, Michelle Nash, Maisoun Sulfab,
Dewan Zeng, Hongyan Zhong, Simon C. Robson, Detlef Schuppan,
Daniel Tumas
780: Role of LARP6 and nonmuscle myosin in
partitioning of collagen mRNAs to the ER membrane
Hao Wang, Yujie Zhang, Lela Stefanovic, Branko Stefanovic
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
781: Differential roles of non-receptor tyrosine kinase
Fak family members in TGF-β-mediated fibrogenic
signaling in hepatic stellate cells
Jonghwa Kim, SoHee Kang, Soohyun Park, Ju-Yeon Cho, Won
Sohn, Geum Youn Gwak, Byung Chul Yoo, David A. Brenner,
Yong-Han Paik
782: Liver injury and pro-fibrotic markers, but not frank
fibrosis, are enhanced in Has3-/- mice after carbon
tetrachloride exposure: potential role for enhanced
matrix metabolism
Jennifer M. McCracken, Krutika T. Deshpande, Michele Pritchard
783: Hepatic Stellate Cells Express the Hepatocyte-
enriched Transcription Factor, Hepatocyte Nuclear
Factor 4α
Marzena Swiderska-Syn, Guanhua Xie, Jason D. Coombes,
Gregory A. Michelotti, Anna Mae Diehl
784: Activation of JNK modulates the profibrogenic
actions of myostatin in hepatic stellate cells (HSC)
Alessandra Caligiuri, Wanda Delogu, Angela Provenzano, Chiara
Rosso, Elisabetta Bugianesi, Fabio Marra
785: Role of gamma-ketoaldehydes as novel mediators
of experimental fibrogenesis and stellate cells activation
Lisa Longato, Dipok K. Dhar, Sean S. Davies, Jackson L. Roberts,
Tu Vinh Luong, Brian Davidson, Giuseppe Fusai, Jude A. Oben,
Kevin Moore, Massimo Pinzani, Krista Rombouts
786: Keratinocyte growth factor inhibits hepatic
inflammation and fibrosis in murine models of hepatic
injury
Barbara Czech, Claus Hellerbrand
787: The Role of Receptor-Mediated Endocytosis
of H-ferritin in Induction of NFkappaB-dependent
Proinflammatory Signalling in Hepatic Stellate Cells
Manuel A. Fernandez-Rojo, Anita Burgess, Amber Glanfield, Diem
Hoang-Le, Grant A. Ramm
788: Alternative regulation of macrophages activation
by IL-4 receptor alpha in fibrosis progression and
reversal
Shih-Yen Weng, Santosh Vijayan, Xiao-Yu Wang, Kornelius
Padberg, Yong Ook Kim, Brombacher Frank, Detlef Schuppan
789: Hepatic stellate cell activation is regulated by
neuropilin-synectin mediated autophagic degradation of
PDGFR-α
Mary Drinane, Usman Yaqoob, Debabrata Mukhopadhyay,
Shengbing Huang, Frank A. Sinicrope, Sheng Cao, Vijay Shah
790: microRNA-194 regulates the expression of TNF-α,
IL-1α and IL-6 via modulating akt/NF-κB pathway in
hepatic stellate cells
Pushpendra K. Sahu, Satendra Kumar, Parul Gupta, Senthil K.
Venugopal
Poster Viewing: 8:00 AM – 5:30 PM
123A
791: Pharmacological modulation of IL-4Ralpha
regulates liver fibrosis progression and regression by
tuning M2 macrophage polarization
Shih-Yen Weng, Xiao-Yu Wang, Santosh Vijayan, Kornelius
Padberg, Yong Ook Kim, Jeff R. Crosby, Michael L. McCaleb,
Detlef Schuppan
792: Development of Sonic hedgehog transgenic mouse
models using hydrodynamics-based transfection
Sook In Chung, Hye Lim Ju, Kwang-Hyub Han, Weonsang S. Ro
793: Human neutrophil peptide-1 exacerbates hepatic
fibrosis associated with Kuppfer cell activation and
hepatocyte apoptosis in a murine model of alcoholic
liver disease
Rie Ibusuki, Hirofumi Uto, Kozono Masaya, Kohei Oda, Akihiko
Oshige, Kotaro Kumagai, Seiichi Mawatari, Tsutomu Tamai,
Akihiro Moriuchi, Hirohito Tsubouchi, Akio Ido
794: Epigallocatechin gallate treatment
decreases osteopontin expression and attenuates
N-Nitrosodimethylamine induced hepatic fibrosis in rats
Joseph George, Mikihiro Tsutsumi
795: Iron excess exacerbates proinflammatory and
fibrogenic gene expression in genetically obese mice
and in primary human hepatic stellate cells in response
to TNF- α or TGF-β
Priya Handa, Vicki Morgan-Stevenson, Bryan D. Maliken, James E.
Nelson, Matthew M. Yeh, Kris V. Kowdley
796: Modulating Tumor-Stromal Interactions by
Targeting Adenosine Monophosphate-Activated
Kinase (AMPK) in Human Hepatic Stellate Cells and
Hepatocellular Carcinoma
Katrin Schölzel, Lisa Longato, Tu Vinh Luong, Brian Davidson,
Giuseppe Fusai, Massimo Pinzani, Krista Rombouts
797: A new communication system regulating
extracellular matrix in liver fibrosis: RANK/RANKL/
OPG
NOVEMBER 9
Leonie Beljaars, Carian E. Boorsma, Burak Guney, Klaas Poelstra,
SUNDAY
Barbro N. Melgert
798: Markers of extracellular matrix remodeling can
elucidate the matrix turnover profile of the fibrotic liver
Niels Ulrik B. Hansen, Federica Genovese, Diana J. Leeming,
Morten A. Karsdal
Clinical Steatohepatitis
799: Role of Genetic Polymorphisms in the Development
of Nonalcoholic Fatty Liver Disease (NAFLD) and
Steatohepatitis (NASH)
Fernando Bril, Marina Kawaguchi-Suzuki, Reginald Frye, Paola
Portillo Sanchez, Maryann Maximos, Song Lai, Jean Hardies,
Fermin Tio, Kenneth Cusi
Presenters in Attendance 12:30 – 2:00 PM
 124A POSTER SESSIONS
Poster Sessions
800: Low serum vitamin D concentration in patients with
nonalcoholic fatty liver disease is not associated with
increased mortality: Results from the National Health
and Nutrition Examination Survey 18-year mortality
follow-up data
Ivo C. Ditah, Albert Ndzengue, Zeenat Y. Bhat, Chijioke Enweluzo,
Chobufo M. Ditah, Callistus Ditah, Michael Charlton, Patrick S.
Kamath
801: Prevalence of nonalcoholic fatty liver disease and
its association with aging
Ainara Cano, Cristina Alonso, Itziar Mincholé, David Balgoma,
Pablo Ortiz, Maria L. Martinez-Chantar, Shelly C. Lu, Jose M.
Mato
802: Hepatic Steatosis as a Component of Spinal and
Bulbar Muscular Atrophy (SBMA, Kennedy’s Disease)
Hawwa Alao, Derrick Fox, Angela Kokkinis, Colleen Hadigan,
Christopher Grunseich, Kenneth Fischbeck, Yaron Rotman
803: Protease-Activated Receptor-2 (PAR2)–A Novel
Therapeutic Target in Nonalcoholic Steatohepatitis
(NASH)
Andrew M. Shearer, Karyn Austin, Srijoy Guha, Nga Nguyen,
Richard Looby, Allyson Clappin, James Baleja, Lidija Covic, Athan
Kuliopulos
804: Cardiovascular Death in Recipients of Liver
Transplants with Nonalcoholic Steatohepatitis: An
Analysis of the UNOS Database
Emily H. Wong, Jason Vanatta, Donna Hathaway, Elizabeth A.
Tolley, Satheesh Nair, James Eason, Sanjaya K. Satapathy
805: Progression to hepatic steatosis and fibrosis by
serum biomarkers is frequent in HIV mono-infection and
is associated with black ethnicity, poor HIV control and
hyperglycemia: a 7-year study of 1,291 cases
Giada Sebastiani, Kathleen C. Rollet-Kurhajec, Norbert Gilmore,
Costas Pexos, Richard Lalonde, Marina B. Klein
806: Histological Severity And Glycemic Stage Drive The
NOVEMBER 9
Evolution Of Atherogenic Risk Profile In Nonalcoholic
SUNDAY
Fatty Liver Disease
Mohammad S. Siddiqui, Kavish Patidar, Ankit V. Patel, Velimir A.
Luketic, Sherry L. Boyett, Michael O. Idowu, R. Todd Stravitz, Scott
Matherly, Puneet Puri, Richard K. Sterling, Arun J. Sanyal
807: Validation of surrogate indexes of peripheral and
hepatic insulin resistance and evaluation of their utility
as non-invasive predictors of histological features in
patients with Non-Alcoholic Fatty Liver Disease
Chiara Rosso, Ester Vanni, Lavinia Mezzabotta, Roberto Gambino,
Francesca Saba, Federico Salomone, Ramy Ibrahim Kamal
Jouness, Melania Gaggini, Emma Buzzigoli, Chiara Saponaro,
Fabrizia Carli, Gian Paolo Caviglia, Maria Lorena Abate,
Antonina Smedile, Mario Rizzetto, Maurizio Cassader, Amalia
Gastaldelli, Elisabetta Bugianesi
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
808: Progression of early atherosclerotic vascular
damage in patients with NAFLD and in controls of
general population during 10 years of follow up
Anna Ludovica Fracanzani, Giuseppina Pisano, Silvia Tiraboschi,
Marianna Porzio, Rosa Lombardi, Cristina Bertelli, Luca Valenti,
Andrea Baragetti, Liliana Grigore, Alberico Catapano, Silvia
Fargion
809: 5-aminolevulinic acid combined with ferrous iron
protects from ischemia-reperfusion injury in mouse
steatotic liver model by inducing carbon monoxide
generation
Shao-Wei Li, Terumi Takahara, Toshiro Sugiyama, Kazuhiro
Tsukada, Tohru Tanaka, Xiao-Kang Li
810: Oral glucose tolerance test predicts hepatic fibrosis
in nonalcoholic fatty liver disease patients without overt
diabetes mellitus
Sohji Nishina, Hideyuki Hyogo, Miwa Kawanaka, Teruki Miyake,
Masanori Abe, Satoyoshi Yamashita, Hiroshi Tobita, Shuichi Sato,
Yoichi Hiasa, Kazuaki Chayama, Keisuke Hino
811: Natural history of NAFLD: A study of 108 patients
with paired liver biopsies
Stuart McPherson, Elsbeth Henderson, Timothy Hardy, Alastair D.
Burt, Chris Day, Quentin M. Anstee
812: Role of Genetic Polymorphisms on the
Improvement of Liver Histology after Pioglitazone
Treatment in Patients with Nonalcoholic Fatty Liver
Disease (NAFLD)
Marina Kawaguchi-Suzuki, Fernando Bril, Kenneth Cusi, Taimour
Langaee, Yan Gong, Reginald Frye
813: The Protease Fibroblast Activation Protein (FAP) in
Liver Disease
Mark D. Gorrell, Kathryn H. Williams, Ana Julia Vieira de Ribeiro,
Sumaiya Chowdhury, Elizabeth J. Hamson, Oliver Schilling, Emilia
Prakoso, Nicholas A. Shackel, Susan V. McLennan, William W.
Bachovchin, Fiona M. Keane, Geoffrey W. McCaughan, Amany
Zekry, Stephen Twigg
814: Association of Hepatic Nuclear Hormone Receptor
Expression Profiles with Features of Hepatic Histology in
Children with Nonalcoholic Fatty Liver Disease
Joel E. Lavine, Michael Downes, Kevin P. May, Ruth Yu, Jeffrey B.
Schwimmer, Cynthia A. Behling, Elizabeth M. Brunt, Mark L. van
Natta, James Tonascia, Ronald M. Evans
815: There is substantial phenotypic variability in lean
versus obese subjects with NAFLD across the world: The
Global NASH Study
Angelo H. Paredes, Lawrence Serfaty, Claudia P. Oliveira, Abhijit
Chowdhury, Sherry L. Boyett, Mohammad S. Siddiqui, Arun J.
Sanyal
816: Prevalence and Risk Factors for Advanced Liver
Fibrosis in Adults Undergoing Intestinal Transplantation
Genevieve Huard, M. Isabel Fiel, Jang Moon, Lauren Schwartz,
Kishore Iyer, Thomas D. Schiano
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
817: Racial disparities in nonalcoholic fatty liver
disease related mortality among US Adults: Results of
the National Health and Nutrition Examination Survey
18-year mortality follow-up data
Ivo C. Ditah, Taiwo N. Ngwa, Albert Ndzengue, Zeenat Y. Bhat,
Chijioke Enweluzo, Callistus Ditah, Michael Charlton, Patrick S.
Kamath
818: Steatosis Assessment By Cap™ Using Xl Probe
Victor de Ledinghen, Christophe Corpechot, Julien Vergniol, Pierre
Bedossa, Andrew R. Hall, Olivier Chazouillères, Yves Menu, Amar
P. Dhillon, Valerie Paradis
819: Distinction between non-alcoholic steatohepatitis
and simple steatosis according to the controlled
attenuation parameter and liver stiffness value using
transient elastography in patients with non-alcoholic
fatty liver disease: a Korean multicenter study
Young Eun Chon, Soo Young Park, Hana Park, Ja Kyung Kim, Jae
Young Jang, Chun Kyon Lee, Kwang-Hyub Han, Seung Up Kim
820: Non- Viral Liver Disease Burden In HIV Positive
Individuals: An Observational Retrospective Cohort
Study
Natalie Shur, Martin Fisher, Yvonne Gilleece, Sumita Verma
821: Patients with Non-Alcoholic Steatohepatitis are at
High Risk of Developing Post-Transplant Diabetes
Zobair Younossi, Maria Stepanova, Sammy Saab, Kelly E. Hoyle,
Rebecca Cable, Alita Mishra, Stephen C. Clement, Sharon L. Hunt
822: Population incidence of nonalcoholic fatty liver
disease: A prospective study using serial proton-
magnetic resonance spectroscopy and transient
elastography
Vincent W. Wong, Grace LH Wong, David K. Yeung, Winnie C.
Chu, Henry Lik-Yuen Chan
823: Prediction of 10-year clinical outcomes in NASH
by non-invasive fibrosis and steatosis tools, hepatic
venous pressure gradient (HVPG) and liver histology
Giada Sebastiani, Marc Deschenes, Rasha Alshaalan, Maria
Rubino, Philip Wong, Peter Metrakos, Maged Peter Ghali
824: Liver Fat and Insulin Resistance as Major
Determinants of Plasma Alanine Aminotransferase
Levels in Nonalcoholic Fatty Liver Disease
Maryann Maximos, Fernando Bril, Paola Portillo Sanchez, Romina
Lomonaco, Diane Biernacki, Amitabh Suman, Michelle Weber,
Beverly Orsak, Kenneth Cusi
825: Plasma cytokeratin-18 in a healthy population:
how does it correlate with metabolic risk factors,
alcohol consumption, steatosis and elastography
Sofia Carvalhana, Jorge Leitão, Ana C. Alves, Mafalda Bourbon,
Helena Cortez-Pinto
Poster Viewing: 8:00 AM – 5:30 PM
125A
826: Serum autotaxin levels are independently
associated with hepatic steatosis in morbidly obese
women
Vikrant Rachakonda, Valerie L. Reeves, Jules Aljammal, James P.
DeLany, Petra Kienesberger, Erin E. Kershaw
827: Circulating Cholesteryl Ester Transfer Protein is
Associated with Percentage of Collagen Deposition in
Patients with Nonalcoholic Fatty Liver Disease
Elzafir Elsheikh, Zahra Younoszai, Munkhzul Otgonsuren, Fanny
Monge, Lakshmi Alaparthi, Brian P. Lam, Sharon L. Hunt, Zachary
D. Goodman, Zobair Younossi
828: Body Fat Distribution and the Risk of Incident and
Remittent Nonalcoholic Fatty Liver Disease: Prospective
Cohort Study
Donghee Kim, Goh Eun Chung, Min-Sun Kwak, Won Kim, Yoon
Jun Kim, Jung-Hwan Yoon
829: Dynamicity of Adiposity determine evolution
of non-alcoholic fatty liver even in lean subjects: a
prospective cohort study
Pankaj Singh, Kausik Das, Debashis Misra, Gautam Ray, Amal
Santra, Abhijit Chowdhury
830: Lesser risk of advanced liver fibrosis in morbidly
obese patients
Fabio Nascimbeni, Judith Aron-Wisnewsky, Pierre Bedossa, Joan
Tordjman, Raluca Pais, Thierry Poynard, Karine Clément, Vlad
Ratziu
831: Altered Fasting and Postprandial Serum Bile Acids
in Patients with Non-Alcoholic Steatohepatitis (NASH)
Brian C. Ferslew, Curtis K. Johnston, Eleftheria Tsakalozou,
Mingming Su, Guoxiang Xie, Wei Jia, Kim L. Brouwer, Alfred S.
Barritt
832: HLA Class II Alleles Are Strongly Associated
with Non-alcoholic Fatty Liver Disease (NAFLD), Non-
alcoholic Steatohepatitis (NASH) and Fibrosis
Azza Karrar, Zheng Li, Ali M. Moosvi, Siddharth Hariharan, Yun
NOVEMBER 9
Fang, Maria Stepanova, Zachary D. Goodman, Zobair Younossi
SUNDAY
833: Serum soluble CD163 is associated with
steatohepatitis and advanced fibrosis in non-alcoholic
fatty liver disease
Eoin R. Feeney, Jessica L. Mueller, Kyle Malecki, Lindsay Y. King,
Joseph Misdraji, Kathleen E. Corey, Raymond T. Chung
834: Serum levels of apoptosis inhibitor of macrophage
(AIM) are associated with hepatic fibrosis and insulin
resistance in patients with nonalcoholic fatty liver
disease
Kohei Oda, Hirofumi Uto, Yoshio Sumida, Takeshi Okanoue,
Seiichi Mawatari, Rie Ibusuki, Hiroka Onishi, Haruka Sakae, Kaori
Ono, Eriko Toyokura, Akihiko Oshige, Dai Imanaka, Tsutomu
Tamai, Akihiro Moriuchi, Hirohito Tsubouchi, Akio Ido
Presenters in Attendance 12:30 – 2:00 PM
 126A POSTER SESSIONS
Poster Sessions
835: Moderate-Vigorous Physical Activity (MVPA)
Volume is an Important Factor for Management of Non-
Alcoholic Fatty Liver Disease: A Retrospective Study
Sechang Oh, Takashi Shida, Rina So, Takehiko Tsujimoto, Kiyoji
Tanaka, Junichi Shoda
836: Performance of FibroMax (SteatoTest, ActiTest,
FibroTest) in patients with NAFLD for predicting liver
lesions (Steatosis, Activity and Fibrosis) assessed by SAF
scoring system and FLIP algorithm
Mona Munteanu, Fabio Nascimbeni, Pierre Bedossa, Marion
Houot, Frederic Charlotte, Yen Ngo, Raluca Pais, Olivier Deckmyn,
Vlad Ratziu, Thierry Poynard
837: Adverse outcomes of pregnancy in mothers with
NAFLD and their offspring
Hannes Hagström, Jonas F. Ludvigsson, Anders Ekbom, Rolf W.
Hultcrantz, Olof Stephansson, Knut Stokkeland
838: Survey of Diagnostic and Treatment Patterns
of NAFLD and NASH in the United States: Real Life
Practices Differ From Published Guidelines
Zurabi Lominadze, Stephen A. Harrison, Michael Charlton, Rohit
Loomba, Brent A. Neuschwander-Tetri, Stephen H. Caldwell, Kris
V. Kowdley, Mary E. Rinella
839: The features and differences of GLP-1 analogues
and DPP-4 inhibitors as treatments for non-alcoholic
fatty liver disease patients with type 2 diabetes mellitus
Takamasa Ohki, Isogawa Akihiro, Koki Sato, Nobuo Toda
840: Metabolic Stressors Associated with Progressive
Nonalcoholic Fatty liver Disease and Liver
Transcriptional Activity of Alanine and Aspartate
Aminotransferases
Silvia Sookoian, Gustavo O. Castaño, Tomas Fernández Gianotti,
Romina Scian, Carlos J. Pirola
841: Irisin is associated with physical activity level
and hepatic steatosis grade in non-alcoholic fatty liver
disease subjects
NOVEMBER 9
Rina So, Sechang Oh, Takashi Shida, Kiyoji Tanaka, Junichi Shoda
SUNDAY
842: Is liver stiffness measurement (LSM) by Fibroscan
better than FIB4 score for prediction of clinically
significant fibrosis in patients with NAFLD?
Raj Vuppalanchi, Samer Gawrieh, Regina Weber, Naga P.
Chalasani
843: Endoscopic Duodenal–Jejunal Bypass Liner
(Endobarrier) Improves Hepatic Parameters of
Nonalcoholic Fatty Liver Disease in Obese Uncontrolled
type 2 Diabetes Mellitus Patients
Oranit Cohen-Ezra, Gabriella Segal-Lieberman, Alon Lang, Maor
Lahav, Yeroham Kleinbaum, Sima Katsherginsky, Keren Tsaraf,
Ziv Ben Ari
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
844: Fetuin-A negatively correlates with liver and
vascular fibrosis in NAFLD subjects
Yoshihiro Kamada, Motoya Sato, Yuri Takeda, Sachiho KIda,
Yuka Ohara, Hironobu Fujii, Maaya Akita, Kayo Mizutani, Yuichi
Yoshida, Makoto Yamada, Hidetaka Hougaku, Tetsuo Takehara,
Eiji Miyoshi
845: Clinical validation of the FLIP algorithm and the
SAF score in Non-Alcoholic Fatty Liver Disease
Fabio Nascimbeni, Pierre Bedossa, Larysa Fedchuk, Raluca
Pais, Sven M. Francque, Dominique G. Larrey, Guruprasad P.
Aithal, Lawrence Serfaty, Mihai Voiculescu, Pascal Lebray, Thierry
Poynard, Klaudia M. Traudtner, Vlad Ratziu
846: Serum Vitamin D Deficiency is Associated with
Nonalcoholic Steatohepatitis in Adults
James E. Nelson, Laura Wilson, Christian Roth, Matthew M. Yeh,
Kris V. Kowdley
847: Hepatic copper and PNPLA3 in patients with non-
alcoholic fatty liver disease
Albert Stättermayer, Stefan Traussnigg, Elmar Aigner, Christian
Kienbacher, Petra E. Steindl-Munda, Christian Datz, Fritz Wrba,
Michael Trauner, Peter Ferenci
848: Impact of Liver Histology on Hepatic Elastography
in Non-alcoholic Fatty Liver Disease
Ranesh Palan, William W. Kemp, Bastiaan DeBoer, Jeffrey M.
Hamdorf, Michael J. House, Gerry C. MacQuillan, George Garas,
Helena Ching, Ross Mac Nicholas, Stuart K. Roberts, Matthew T.
Kitson, Gary P. Jeffrey, Leon Adams
849: The association of soluble lectin-like oxidized LDL
receptor 1 (sLOX-1) level with histological severity in
NAFLD patients
Hiroshi Ishiba, Yoshio Sumida, Saiyu Tanaka, Kazuyuki Kanemasa,
Yuya Seko, Akira Okajima, Tasuku Hara, Hiroyoshi Taketani, Kanji
Yamaguchi, Michihisa Moriguchi, Hironori Mitsuyoshi, Kohichiroh
Yasui, Yoshito Itoh, Masahito Minami
850: Combination of Geniposide and Chlorogenic Acid
May Reverse NASH Pathogenesis by Improving Gut
Barrier Function
Qin Feng, Susan S. Baker, Wensheng Liu, Ricardo A. Arbizu,
Ghanim Aljomah, Maan Khatib, Colleen A. Nugent, Robert D.
Baker, Yiyang Hu, Lixin Zhu
851: The serum levels of SDF-1α correlated with the
fibrosis and suggested the appearance of hepatic
progenitor cells in the advanced stage of NASH
Wataru Ando, Hiroaki Yokomori, Yutaka Inagaki, Isao Okazaki,
Yutaka Suzuki, Tsutsui Nobuhiro, Eigoro Yamanouchi, Hiroki
Tanabe, Hajime Kuroda, Soichi Kojima, Mitsuko Hara, Masaya
Oda, Takako Komiyama
852: Should we screen diabetic patients for fatty liver
and advanced fibrosis? A prospective study with 2080
controlled attenuation parameter and liver stiffness
measurements
Raymond Kwok, Grace LH Wong, Henry Lik-Yuen Chan, Juliana C.
Chan, Alice P. Kong, Vincent W. Wong
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
853: Four simple risk factors predict post-transplant
cardiac mortality in patients with nonalcoholic
steatohepatitis
Lisa B. VanWagner, Brittany Lapin, Donald M. Lloyd-Jones, Anton
I. Skaro, Mary E. Rinella
854: Patients with non-alcoholic fat liver disease
(NAFLD) with lower levels of free serum copper and
ceruloplasmin have different clinical and biochemical
characteristics
Vinicius Nunes, Adriana R. Andrade, Ana Luiza V. Guedes,
Claudia P. Oliveira, Marcio A. Diniz, Jose Estefano, Daniel F.
Mazo, Eduardo Luiz R. Cancado
855: Tai chi ameliorates patient centered outcomes and
markers of systemic inflammation and liver injury in
subjects with nonalcoholic fatty liver disease
Angelo H. Paredes, Jo L. Robins, Jamie L. Sturgill, Mohammad S.
Siddiqui, Arun J. Sanyal
856: Atherogenic Dyslipidemia in the Setting of Insulin
Resistance Contributes to Cardiovascular Risk in Patients
with Nonalcoholic Fatty Liver Disease
Fernando Bril, John Sninsky, Arthur M. Baca, Robert H. Superko,
Paola Portillo Sanchez, Margaret C. Lo, Beverly Orsak, Kenneth
Cusi
857: High Density Lipoprotein Dysfunction in Patients
with Nonalcohol Steatohepatitis
Arthur J. McCullough, Jaividhya Dasarathy, Ling Li, Gregory
Brubaker, Belinda Willard, Srinivasan Dasarathy, Jonathan D.
Smith, Takhar Kasumov
858: Meta-Analysis Of Randomized Controlled Trials
Comparing Current Pharmacologic Agents Vs. Placebo
In Non-Alcoholic Fatty Liver Disease
Ahmed Akhter, Adnan Said
859: Bile acid serum levels in adolescents with NAFLD:
a biomarker for progression?
Jörg Jahnel, Zoehrer Evelyn, Günter Fauler, Hubert Scharnagl,
Tatjana Stojakovic, Valerio Nobili
860: Oxidative stress-inducible factors promote liver
fibrosis in patients with Non-Alcoholic Fatty Liver
Disease
Lavinia Mezzabotta, Chiara Rosso, Ester Vanni, Roberto
Gambino, Ramy Ibrahim Kamal Jouness, Francesca Saba,
Federico Salomone, Melania Gaggini, Emma Buzzigoli, Chiara
Saponaro, Fabrizia Carli, Gian Paolo Caviglia, Maria Lorena
Abate, Antonina Smedile, Mario Rizzetto, Maurizio Cassader,
Amalia Gastaldelli, Elisabetta Bugianesi
Poster Viewing: 8:00 AM – 5:30 PM
127A
861: Comparison of NAFLD Fibrosis Score (NFS)
and transient elastography (Fibroscan®), alone and
in combination, as non-invasive methods for the
evaluation of fibrosis in non-alcoholic fatty liver disease
(NAFLD)
Edric Hee, William W. Kemp, Bastiaan de Boer, Jeffrey M.
Hamdorf, Gerry C. MacQuillan, George Garas, Helena Ching,
Ross Mac Nicholas, Stuart K. Roberts, Matthew T. Kitson, Gary P.
Jeffrey, Leon Adams
862: Nonalcoholic Fatty Liver Disease Is Associated with
Left Ventricular Diastolic Dysfunction
Jeong-Hoon Lee, Donghee Kim, Goh Eun Chung, Min-Sun Kwak,
Yoon Jun Kim, Jung-Hwan Yoon, Hyo-Suk Lee
863: The relationship between ALT and liver histology
changes with age in NAFLD
Boon Bee George Goh, Mangesh Pagadala, Jaividhya Dasarathy,
Aynur Unalp, Ruth Sargent, Carol A. Hawkins, Achuthan
Sourianarayanane, Amer Khiyami, Lisa M. Yerian, Rish Pai,
Srinivasan Dasarathy, Arthur J. McCullough
864: Non-alcoholic fatty liver disease (NAFLD)
recurrence after liver transplant (OLT) for non-alcoholic
steatohepatitis(NASH)
Norio Kawamura, Mustafa Nazzal, Galal El-Gazzaz, Mario
Spaggiari, Masato Fujiki, Teresa Diago, Federico N. Aucejo, Koji
Hashimoto, Cristiano Quintini, Charles Winans, Bijan Eghtesad,
Charles M. Miller, John J. Fung, Naim Alkhouri, Dympna Kelly
865: Degree of hepatic fibrosis assessed using transient
elastography is independently related with coronary
artery calcification in nonalcoholic liver disease
Seng Chan You, Seung Up Kim, Beom Kyung Kim, Jun Yong Park,
Do Young Kim, Sang Hoon Ahn, Kwang-Hyub Han
866: Associations Between Helicobacter pylori, Leptin,
and Nonalcoholic Fatty Liver Disease (NAFLD)
Joseph Roberts, William LeBlanc, Kiran Bambha
867: Nonalcoholic Fatty Liver Disease Is Associated
NOVEMBER 9
With Arterial Stiffness Measured by Cardio-Ankle
SUNDAY
Vascular Index
Donghee Kim, Goh Eun Chung, Su-Yeon Choi, Min-Sun Kwak,
Won Kim, Yoon Jun Kim, Jung-Hwan Yoon
868: Extremely low awareness and under-diagnosis of
NAFLD in a population-based sample
Lisa B. VanWagner, Mary E. Rinella, Hongyan Ning, Donald M.
Lloyd-Jones, Cora E. Lewis, Miriam B. Vos
869: Assessment of glycemic variability by continuous
glucose monitoring system in patients with nonalcoholic
fatty liver disease
Makiko Taniai, Etsuko Hashimoto, Kazuhisa Kodama, Tomomi
Kogiso, Katsutoshi Tokushige, Keiko Shiratori
Presenters in Attendance 12:30 – 2:00 PM
 128A POSTER SESSIONS
Poster Sessions
870: Is fatty liver in diabetes a risk factor for HCC and
cardiovascular disease? Prospective 10-year cohort
study
Masataka Seike, Koichi Honda, Junya Oribe, Mizuki Endo, Mie
Yoshihara, Masanori Tokoro, Masao Iwao, Hiroki Syo, Kazunari
Murakami
871: Risk of severe fibrosis is associated with age at
menopause in nonalcoholic fatty liver disease (NAFLD)
Jagpal S. Klair, Ju Dong Yang, Manal F. Abdelmalek, Cynthia D.
Guy, Ryan M. Gill, Katherine P. Yates, Aynur Unalp-Arida, Joel E.
Lavine, Jeanne M. Clark, Anna Mae Diehl, Ayako Suzuki
872: Autoimmunity to Human Heat Shock Protein-70
is Associated with the Presence of Coronary Artery
Disease in Patients with Nonalcoholic Fatty Liver Disease
Elzafir Elsheikh, Zahra Younoszai, Munkhzul Otgonsuren, Maria
C. Albano, Ingrid Schneider, Hussain Allawi, Brian P. Lam, Yousef
Fazel, Michael L. Campbell, Thomas Jeffers, Spencer Frost, Bryan
Raybuck, Zobair Younossi
873: Performance and limitations of five steatosis
biomarkers in patients with Non-alcoholic Fatty Liver
Disease
Fabio Nascimbeni, Larysa Fedchuk, Raluca Pais, Frederic
Charlotte, Chantal Housset, Paola Loria, Vlad Ratziu
874: A deficiency in 25-OH vitamin D is associated with
increased steatohepatitis in alcoholic patients
Clémence M. Canivet, Rodolphe Anty, Stephanie Patouraux,
Antonio Iannelli, Patricia Panaia-Ferrari, Imed Ben Amor, Anne-
Sophie Schneck, Marie-Christine M. Saint-Paul, Jean Gugenheim,
Philippe Gual, Albert Tran
875: Association between Type 2 Diabetes Genetic
Susceptibility Loci and Hepatocellular Carcinoma
in Patients with Type 2 Diabetes as Determined by
Fibroscan
Masaaki Korenaga, Misuzu Ueyama, Nao Nishida, Keiko
Korenaga, Takumi Kawaguchi, Hideyuki Hyogo, Hiroshi Aikata,
NOVEMBER 9
Erina Kumagai, Yoshihiko Aoki, Masaya Sugiyama, Masatoshi
Imamura, Kazumoto Murata, Tatsuya Kanto, Naohiko Masaki,
SUNDAY
Masashi Mizokami
876: NAFLD: A marker of severe Acute Pancreatitis
Sarfaraz A. Jasdanwala, Shivank Madan, Rajagopalan
Sivaprasad, Capecomorin Pitchumoni
877: Berberine with Alfa Lipoic Acid (ALA) in Non
Alcoholic Steato-hepatitis (NASH). A randomized double
blinded placebo control trial. A Clinical pilot – The
BANISH Trial
Patrick Basu, Niraj J. Shah, M. Aloysius
878: Elevated biomarker-indicated liver disease
and pro-inflammatory cytokines are associated with
environmental PCB exposure in Anniston, Alabama
Heather B. Clair, Keith C. Falkner, Banrida Wahlang, Russell A.
Prough, Matthew C. Cave
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
879: Patients with type 2 diabetes mellitus (T2DM) and
normal plasma aminotransferases are at high risk of
nonalcoholic fatty liver disease (NAFLD)
Paola Portillo Sanchez, Fernando Bril, Maryann Maximos, Romina
Lomonaco, Diane Biernacki, Beverly Orsak, Joan Hecht, Kenneth
Cusi
880: Effects of Liraglutide on Carotid Intima-Media
Thickness in Patients with Type-2 Diabetes and Non-
Alcoholic Fatty Liver Disease: An 8-Month Prospective
Pilot Study
Angelo M. Patti, Manfredi Rizzo, Rosaria V. Giglio, Dragana
Nikolic, Antonino Terranova, Melchiorre Cervello, Alessandra
Ferlita, Valeria A. Giannone, Giovanna Aurilio, Valentina Mistretta,
Lydia Giannitrapani, Maurizio Soresi, Giuseppe Montalto
881: Oleuropein counteracts systemic inflammation and
hepatic immune cells infiltration in a mouse model of
NAFLD
Alessia Longo, Mario Arciello, Barbara Barbaro, Gabriele Toietta,
Roberta Maggio, Carmela Viscomi, Clara Balsano
882: Serum concentration of CDCA and TCDCA are
independently associated with Insulin sensitivity in a
large blood donor population
Alberto Porro, Francesco Azzaroli, Simoni Patrizia, Domenico
Fiorillo, Cecilia Camborata, Paolo Cecinato, Federica Buonfiglioli,
Davide Festi, Silvia Spinozzi, Paolo Parini, Rosario Arena, Marco
Montagnani, Rocco Maurizio Zagari, Franco Bazzoli, Aldo Roda,
Giuseppe Mazzella
883: The Development of a Non-invasive Model to
Predict the Presence of Nonalcoholic Steatohepatitis in
Patients with Nonalcoholic Fatty Liver Disease
Danny Issa, George Boon-Bee Goh, Rocio Lopez, Mangesh R.
Pagadala, Jaividhya Dasarathy, Achuthan Sourianarayanane, Ruth
Sargent, Carol A. Hawkins, Amer Khiyami, Lisa M. Yerian, Rish
Pai, Srinivasan Dasarathy, Naim Alkhouri, Arthur J. McCullough
884: Normal ALT and advanced liver fibrosis in
morbidly obese patients undergoing bariatric surgery
Fabio Nascimbeni, Judith Aron-Wisnewsky, Pierre Bedossa, Joan
Tordjman, Raluca Pais, Thierry Poynard, Vlad Ratziu
885: Central obesity is associated with portal vein
thrombosis
Julie Laurent, Camille Christol, Jean Bernard Ruidavets, Jean
Ferrieres, Marie Angele Robic, Jean-Marie Peron, Jean-Pierre
Vinel, Christophe Bureau
886: The quantitative amount of hepatic steatosis in
NAFLD patients predicts the risk of developing diabetes:
a prospective study with up to 25 years of follow-up
Patrik S. Nasr, Mattias Ekstedt, Ulrik L. Mathiesen, Stergios
Kechagias
887: Cryptogenic cirrhosis category masks three
quarters of NASH patients getting liver transplant
Angela Dolganiuc, Vikas Khullar, Virginia C. Clark, Roberto J.
Firpi
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
888: LUM002 Positive Metabolic Profile Shown after
Administration of 10mg For 28 Days in Type 2 Diabetes
Mellitus Patients Leading to Potential Treatment for
Patients with Nonalcoholic Steatohepatitis (NASH)
Renger Tiessen, Ciara Kennedy, Bradley T. Keller, Nancy Levin,
Lisette Acevedo, Dee Wynne, Bronislava Gedulin, Andre A. van
Vliet, Elizabeth Olek, Alejandro Dorenbaum
889: Apolipoprotein A-V Gene Expression in Non-
Alcoholic Steatohepatitis
Qin Feng, Susan S. Baker, Wensheng Liu, Robert D. Baker, Yiyang
Hu, Lixin Zhu
890: U.S. Physician Survey of Current Practices
in the Diagnosis and Treatment of Nonalcoholic
Steatohepatitis (NASH)
Stephen A. Harrison, Sheldon Y. Okada, Cathy A. Su, Matthew
Paulson, Jeffrey D. Bornstein, Arun J. Sanyal
891: Wfa-M2bp Levels Are Usefull Indicators Of
Progression And Inprovement For Monitoring Liver
Fibrosis In Patients With Nonalcoholic Steatohepatitis
Miwa Kawanaka, Ken Nishino, Jun Nakamura, Takahito Oka,
Noriyo Urata, Daisuke Goto, Mitsuhiko Suehiro, Hirofumi
Kawamoto, Gotaro Yamada
892: Vitamin D level is not associated with liver
histology in non-alcoholic steatohepatitis
Matthew T. Kitson, Stephen Casey, Alan Pham, Adam Gordon,
William W. Kemp, Peter Button, Stuart K. Roberts
893: Clinical and Histologic Differences Between HIV-
associated NAFLD and Primary NAFLD: A Case-control
Study
Irine Vodkin, Mark A. Valasek, Ricki Bettencourt, Edward R.
Cachay, Rohit Loomba
894: Non-alcoholic fatty liver disease Intermittent
Fasting Time Intervention (NIFTI): Fasting without calorie
restriction improves hepatic transient elastography,
visceral adiposity and insulin resistance compared to
standard care
Alexander Hodge, Alexandra Mack, Caroline Tuck, Jorge
Tchongue, Darcy Q. Holt, William Sievert, Gregory T. Moore
895: African American Race and Hepatitis C Virus are
associated with Lower Survival in Morbidly Obese
Patients following Liver Transplantation: An Analysis of
UNOS Data
Ryan B. Perumpail, Robert Wong, Andrew M. Su, Christina Chou,
Aijaz Ahmed
896: Acoustic structure quantification (ASQ): a
new ultrasound-based approach for non-invasive
quantification of liver fat content
Thomas Karlas, Joachim Berger, Nikita Garnov, Franziska Lindner,
Harald Busse, Rima Chakaroun, Bettina Relke, Michael Tröltzsch,
Volker Keim, Johannes Wiegand
Poster Viewing: 8:00 AM – 5:30 PM
129A
897: High-dose vitamin D supplementation does not
improve liver histology or metabolic profile in non-
alcoholic steatohepatitis – a pilot study
Matthew T. Kitson, Alan Pham, Adam Gordon, William W. Kemp,
Peter Button, Stuart K. Roberts
898: Comparison of M and XL FibroScan® probes for
diagnosis of clinically significant fibrosis in patients with
non-alcoholic fatty liver disease
Raj Vuppalanchi, Samer Gawrieh, Regina Weber, Naga P.
Chalasani
Experimental Hepatocarcinogenesis
899: iNOS overexpression activates the Ras pathway
in hepatocellular carcinoma, and targeted inhibition of
iNOS suppresses Ras signaling and tumor growth
Michael Li, Yujin Hoshida, Scott L. Friedman, Andrew Sikora
900: Sharpin promotes invasion of hepatocellular
carcinoma through trans-activating Versican expression
Yasuo Tanaka, Keisuke Tateishi, Takuma Nakatsuka, Yotaro Kudo,
Yoshinari Asaoka, Ryosuke Tateishi, Kazuhiko Koike
901: Genome-wide DNA methylation analysis in
hepatocellular carcinoma: Identification and validation
of STEAP4 as a novel methylated gene
Kohichiroh Yasui, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa
Moriguchi, Yoshio Sumida, Hironori Mitsuyoshi, Shinji Tanaka,
Shigeki Arii, Yoshito Itoh
902: Persistent Effects of Rapamycin on the Genetic
Signature of Preneoplastic Foci in a Rat Model of
Progenitor-Derived Hepatocellular Carcinoma (HCC)
Adeola O. Adebayo, Heather Francois-Vaughn, Kate E. Brilliant,
Philip A. Gruppuso, Jennifer A. Sanders
903: Diet Associated Obesity Enhances Development of
Hepatocellular Carcinoma Through Tenascin-C/Toll-like
NOVEMBER 9
Receptor 4 Signaling
SUNDAY
Jennifer H. Benbow, Kyle J. Thompson, Amber C. Smith, Tracy L.
Walling, Catherine R. Culberson, Iain H. McKillop, Ting Li, Laura
W. Schrum
904: Activation of the TGFβ/SMAD Pathway Underlies
a Novel Tumor Promoting Role of Sulfatase1 in
Hepatocellular Carcinoma
Renumathy Dhanasekaran, Chunling Hu, Gang Chen, Abdul M.
Oseini, Catherine D. Moser, Toin H. van Kuppevelt, Wei Zhou,
Jan van Deursen, Taofic Mounajjed, Martin E. Fernandez-Zapico,
Lewis R. Roberts
905: Identification of Hypermethylation and Non-
Synonymous Mutations in Genes Down-Regulated
during the Process of Hepatocarcinogenesis in a Model
of Chronic Hepatitis B
Yasunari Nakamoto, Taro Yamashita, Katsushi Hiramatsu,
Tomoyuki Nemoto, Hiroyuki Suto, Shuichi Kaneko
Presenters in Attendance 12:30 – 2:00 PM
 130A POSTER SESSIONS
Poster Sessions
906: The role of the tumor microenvironment for
the CSC phenotype and progression of liver cancer:
mechanistic findings and prognostic implications
Michael Fischer, Stefan Heinrich, Jesper B. Andersen, Martin F.
Sprinzl, Ines Gockel, Marcus A. Woerns, Snorri S. Thorgeirsson,
Peter R. Galle, Hauke Lang, Jens U. Marquardt
907: Branched-chain amino acids prevent hepatic
fibrosis and development of hepatocellular carcinoma in
a non-alcoholic steatohepatitis mouse model
Kai Takegoshi, Masao Honda, Hikari Okada, Naoto Matsuzawa,
Hisashi Takabatake, Toshinari Takamura, Takuji Tanaka, Shuichi
Kaneko
908: p53 does not only suppress tumor development,
but also regulates essential survival pathways in chronic
liver injury
Laura E. Buitrago, Silke Marhenke, Thomas Longerich, Michelle C.
Barton, Robert Geffers, Michael P. Manns, Arndt Vogel
909: Curcumin targets stem-like liver cancer cells by
NF-kB mediated inhibition of histone deacetylases
Jens U. Marquardt, Luis E. Gómez-Quiroz, Lucrecia O. Arreguin
Camacho, Frederico Pinna, Yun-Han Lee, Mitsuteru Kitade, Jesper
B. Andersen, Kai Breuhahn, Peter R. Galle, Valentina M. Factor,
Snorri S. Thorgeirsson
910: Antitumor effect of the novel sphingosine
kinase-2 inhibitor ABC294640 is enhanced by
inhibition of autophagy and by sorafenib in human
cholangiocarcinoma cells
Xiwei Ding, Roongruedee Chaiteerakij, Catherine D. Moser, Albert
Ndzengue, Hassan M. Shaleh, Gang Chen, Ying Li, Yanling
Zhou, Shengbing Huang, Frank A. Sinicrope, Melanie B. Thomas,
Charles D. Smith, Lewis R. Roberts
911: FABP4 but not FABP5 Promotes Human HCC Cell
Line Proliferation In Vitro
Shayan S. Nazari, Ryan Z. Swan, Iain H. McKillop, Kyle J.
Thompson
NOVEMBER 9
912: Preclinical Evaluation of a Selective Low-Density
SUNDAY
Lipoprotein-Docosahexaenoic Acid Nanomedicine: A
Promising Alternate Treatment Strategy for Unresectable
Hepatocellular Carcinoma
Ian Corbin, Xiaodong Wen, Lacy Reynolds, Rohit Mulik, Jorge A.
Marrero
913: Peretinoin, an acyclic retinoid, suppresses
steatohepatitis and development of tumorigenesis by
activated Atg16L1-dependent autophagy in mice fed an
atherogenic high-fat diet
Hikari Okada, Masao Honda, Kai Takegoshi, Naoto Matsuzawa,
Taro Yamashita, Yoshio Sakai, Toshinari Takamura, Takuji Tanaka,
Shuichi Kaneko
914: IL-33 Facilitates Oncogene Driven
Cholangiocarcinoma in Mice
Daisaku Yamada, Sumera Rizvi, Nataliya Razumilava, Steven F.
Bronk, Jun Li, Jorge A. Bezerra, Xin Chen, Gregory J. Gores
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
915: Role of Reptin in the regulation of DNA double
strand breaks repair in human hepatocellular
carcinoma
Anne-Aurélie Raymond, Véronique Neaud, Jean Rosenbaum
916: A potential role for type XVIII collagen as a
suppressor of hepatocellular carcinoma
Michael Duncan, Renumathy Dhanasekaran, Priyanka Thakur,
Lewis R. Roberts
917: Two microRNA polymorphisms are associated with
hepatitis B virus-related but not hepatitis C virus-related
hepatocellular carcinoma in the Japanese population
Daiki Miki, Hidenori Ochi, C. Nelson Hayes, Hiromi Abe,
Tomokazu Kawaoka, Atsushi Ono, Sakura Akamatsu, Takashi
Nakahara, Noriaki Seki, Eisuke Murakami, Yizhou Zhang, Takuro
Uchida, Yohji Honda, Keiichi Masaki, Hiromi Kan, Masataka
Tsuge, Nobuhiko Hiraga, Michio Imamura, Yoshiiku Kawakami,
Hiroshi Aikata, Michiaki Kubo, Kazuaki Chayama
918: The Molecular Basis of the Anti-Cyclin D1
Intrabody-Induced Inhibition of Hepatocellular
Carcinoma Progression
Yan Wu, An Cui, Hanwei Li, Weiwei Tang, Ying Zhang, Ning
Yang, Guannan Shen, Cynthia Ju, Guiying Li
919: Enhancing effect of retinoids on anti-cancer drugs
by regulating the metabolic pathways of hepatocellular
carcinoma cells
Goshi Shiota, Keita Kanki
920: CXCR4 inhibition in combination with anti-PD1
immunotherapy results in an effective immune response
during treatment with sorafenib in hepatocellular
carcinoma
Thomas Reiberger, Rakesh R. Ramjiawan, Yunching Chen, Mei
R. Ng, Tai Hato, Elizabeth C. Unan, Tejaswini P. Reddy, Yuhui
Huang, Hiroki Ochiai, Peigen Huang, Andrew X. Zhu, Rakesh K.
Jain, Dan G. Duda
921: Impact of connective tissue growth factor in Ras
pathway-activated hepatocytes on the development of
hepatocellular carcinoma
Yuki Makino, Hayato Hikita, Tsukasa Kawaguchi, Takahiro
Kodama, Minoru Shigekawa, Yugo Kai, Yasutoshi Nozaki, Tasuku
Nakabori, Yoshinobu Saito, Satoshi Tanaka, Ryotaro Sakamori,
Takuya Miyagi, Tomohide Tatsumi, Tetsuo Takehara
922: TSU-68 ameliorates the aggressiveness of
hepatocellular carcinoma through inhibition of
microenvironmental PDGF receptor signaling
Yasumasa Hara, Taro Yamashita, Naoki Oishi, Kouki Nio,
Takehiro Hayashi, Yoshimoto Nomura, Mariko Yoshida, Tomoyuki
Hayashi, Tomomi Hashiba, Hikari Okada, Masao Honda, Shuichi
Kaneko
923: miR-133b inhibits hepatocellular carcinoma cell
growth through suppression of MET proto-oncogene
Takayuki Kogure, Yasuteru Kondo, Jun Inoue, Yu Nakagome,
Osamu Kimura, Tomoaki Iwata, Tatsuki Morosawa, Yasuyuki
Fujisaka, Tooru Shimosegawa
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
924: Spink3 and Tff3 are overexpressed in autophagy-
deficient mice and may contribute to hepatocellular
carcinoma development
Michael C. Wallace, Youngmin A. Lee, Luke A. Noon, Kemal M.
Akat, Marie-Luise Berres, Scott L. Friedman
925: HCV NS5A blocks MG132-induced apoptosis in
hepatocytes through the inhibition of NF-κB activation
Xia Jiang, Tatsuo Kanda, Shuang Wu, Yuki Haga, Reina Sasaki,
Masato Nakamura, Shingo Nakamoto, Fumio Imazeki, Osamu
Yokosuka
926: Liver fibrosis enhances tumorigenicity of hepatoma
cells and makes them resistant to chemotherapy
Benoit Lacoste, Benoît Dupont, Grégory Merlen, Marc Bilodeau
927: Polo-Like Kinase 3 is associated with improved
Overall Survival in Cholangiocarcinoma
Benjamin Juntermanns, Svenja Sydor, Gernot M. Kaiser, Andreas
Paul, Hideo A. Baba, Ali Canbay, Christian Dominik Fingas
928: Notch signal-activated hepatoma cells are
associated with Jagged1 genomic abnormality, and
Notch inhibitors efficiently suppress EpCAM+ liver
cancer stem cells
Kazunori Kawaguchi, Masao Honda, Taro Yamashita, Kouki Nio,
Hikari Okada, Masashi Nishikawa, Kuniaki Arai, Yoshio Sakai,
Tatsuya Yamashita, Eishiro Mizukoshi, Shuichi Kaneko
929: Activation of mitochondrial pathway of apoptosis
in hepatocytes increases oxidative stress in hepatocytes
leading to liver tumorigenesis
Hayato Hikita, Tomohide Tatsumi, Yoshinobu Saito, Satoshi
Tanaka, Ryotaro Sakamori, Takuya Miyagi, Naoki Hiramatsu,
Tetsuo Takehara
930: Difference in pattern of somatic mutations
between primary sclerosing cholangitis (PSC)-related
cholangiocarcinoma (CCA) and non-PSC related CCA
Roongruedee Chaiteerakij, Emily G. Barr Fritcher, Jesse Voss,
Fergus J. Couch, Kevin C. Halling, Lewis R. Roberts, Benjamin R.
Kipp
931: Loss of heterozygosity at 5q13.2 and 8p23.1 in
dysplastic hepatocytes of cirrhotic liver are common
events in hepatocellular carcinoma
Zhang Zhao, Guang-Yong Chen, Jiang Long, Jian Huang
932: Sorafenib induces conversion to RAF dependence
and ERK activation as a mechanism of rapidly acquired
resistance in hepatocellular carcinoma
Rakesh R. Ramjiawan, Thomas Reiberger, Yunching Chen,
Annique M. Duyverman, Peigen Huang, Keith Flaherty, Andrew X.
Zhu, Rakesh K. Jain, Dan G. Duda
Poster Viewing: 8:00 AM – 5:30 PM
131A
933: Reduction in nuclear S100A4 in
Cholangiocarcinoma by low dose paclitaxel inhibits
tumor invasiveness and hematogenous metastatization
by interfering with Rho-A and Cdc42
Gaia Spagnuolo, Massimiliano Cadamuro, Luisa Sambado,
Stefano Indraccolo, Giorgia Nardo, Antonio Rosato, Carlo Spirli,
Mario Strazzabosco, Luca Fabris
934: Galnt1 Modifies Cell Surface O-Glycosylation
And Regulates Malignant Phenotypes In Hepatocellular
Carcinoma
Yao-Ming Wu, Miao-Juei Huang, Min-Chuan Huang
935: Role of histone demethylase Kdm3a in liver
tumorigenesis
Takuma Nakatsuka, Keisuke Tateishi, Yotaro Kudo, Keisuke
Yamamoto, Ryota Takahashi, Koji Miyabayashi, Yoshinari
Asaoka, Yasuo Tanaka, Hideaki Ijichi, Kazuhiko Koike
936: FAK is required for c-Met/β-catenin-driven
hepatocarcinogenesis
Na Shang, Maribel Arteaga, Jimmy Stauffer, Scott Cotler, Jiwang
Zhang, Wei Qiu
937: Inhibitory role of peroxisome proliferator-activated
receptor-β/δ in hepatocarcinogenesis in mice and in
vitro
Bo Shen, Ai min Li, Yu Qiang Nie, Yu-Jui Yvonne Wan, Yan Lei Du,
Yu Yuan Li, Gui Jia Shen
938: Germline variants of highly point-mutated genes in
hepatocellular carcinoma do not have strong effects on
HCV-related hepatocarcinogenesis
Daiki Miki, Hidenori Ochi, C. Nelson Hayes, Atsushi Ono, Sakura
Akamatsu, Yuji Urabe, Keiichi Masaki, Hiromi Abe, Tomokazu
Kawaoka, Takashi Nakahara, Noriaki Seki, Eisuke Murakami,
Yizhou Zhang, Takuro Uchida, Yohji Honda, Hiromi Kan,
Masataka Tsuge, Nobuhiko Hiraga, Michio Imamura, Yoshiiku
Kawakami, Hiroshi Aikata, Michiaki Kubo, Kazuaki Chayama
939: Statins interfere on TCTP and PI3K/AKT/
NOVEMBER 9
mTOR pathway and inhibit hepatocellular carcinoma
SUNDAY
progression
Marta García-Valdecasas, Antonio Gil-Gómez, Angela Rojas,
Jordi Muntané, Farncisco Javier PAdillo Ruiz, Manuel Romero-
Gomez, Jose Antonio Del Campo
940: Role of Fatty Acid-Binding Protein 4 in liver
carcinogenesis related to metabolic syndrome
Aurelie Sannier, Samira Laouirem, Mouna Mebarki, Miguel
Albuquerque, Jacques Belghiti, Pierre Bedossa, Valerie Paradis
941: Hepatic steatosis and high circulating free fatty
acid levels promote growth and invasiveness of
hepatocellular carcinoma
Andreas Koch, Claus Hellerbrand
Presenters in Attendance 12:30 – 2:00 PM
 132A POSTER SESSIONS
Poster Sessions
942: Antioxidative selenoenzyme glutathione
peroxidase 4 affects tumour vascularisation in a mice
model of hepatocellular carcinoma
Nataliya Rohr-Udilova, Dagmar Stoiber, Eva Bauer, Wen Li,
Martha Seif, Hubert Hayden, Gerald Timelthaler, Klaus Stolze,
Regina Brigelius-Flohe, Robert Eferl, Markus Peck-Radosavljevic
943: Interplay of adenosinergic signaling and TTK
mitotic kinase inhibition limits hepatocellular cancer cell
growth
Ruoyu Miao, Yan Wu, Haohai Zhang, Huandi Zhou, Xiaofeng
Sun, Eva Csizmadia, Lian He, Yi Zhao, Chengyu Jiang, Haitao
Zhao, Simon C. Robson
944: Impaired function of CD4+ follicular helper T(Tfh)
cells associated with progression of hepatocellular
carcinoma
Yiqiong Jia, Lifeng Wang, Zheng Zhang, Fu-Sheng Wang
945: The possibility of cancer stem cells among EpCAM-
positive cells of hepatocellular carcinoma
Osamu Kimura, Yasuteru Kondo, Takayuki Kogure, Jun Inoue, Yu
Nakagome, Tatsuki Morosawa, Tomoaki Iwata, Yasuyuki Fujisaka,
Teruyuki Umetsu
946: Platelet-Derived Growth Factor D-Induced
Secretion of Vascular Endothelial Growth Factor-C
by Cancer-associated Fibroblasts stimulates
lymphangiogenesis in Cholangiocarcinoma
Massimiliano Cadamuro, Marta Vismara, Simone Brivio, Mario
Strazzabosco, Luca Fabris
947: Targeting the raft-associated Akt signaling in
hepatocellular carcinoma
Jingmin Zhao, Yuan Liu, Jiyun Lv, Jian-Fei Shi, Jin Li, Mei Yang,
Xiaodong Guo, Zhiwei Li, Hong-Bo Wang, Shaogeng Zhang,
Zhenwen Liu, Jin-Biao Ding, Dong-Ping Xu
948: Hepatocyte specific Bid depletion reduces tumor
development via suppression of inflammation related
compensatory proliferation
NOVEMBER 9
Alexander Wree, Casey Johnson, Joan Font-Burgada, Michael
SUNDAY
Karin, Ariel E. Feldstein
949: Insulin treatment improves disorder of glycolipid
metabolism, but accelerates the progression of
hepatocellular carcinoma in DIAR-nSTZ mice, which is a
hepatocellular carcinoma model based on diabetes
Hayato Baba, Koichi Tsuneyama, Takeshi Nishida, Johji Imura
950: Hepatitis B virus X protein priors to induce
expression of alpha-fetoprotein to activate PI3K/mTOR
signal pathway in liver cells
Mingyue Zhu, Junli Guo, Hua Xia, Xieju Xie, Mengsen Li
951: Cell cycle-dependent regulation of FGFR4 in
cholangiocarcinoma
Ashley M. Mohr, Mary A. Smith, Sathish Kumar Natarajan, Cody
J. Wehrkamp, Carol A. Casey, Justin L. Mott
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
Hepatitis C: Approved Therapeutic
Agents
952: Significant Reduction of Hepatocellular
Carcinoma Risk in Chronic Hepatitis C Patients with Peg-
interferon plus Ribavirin Therapy: A Five-year Clinical
Cohort Study
Mei-Hsuan Lee, Yong Yuan, Ming-Lung Yu, Wan-Long Chuang, Jia-
Horng Kao, Chen-Hua Liu, Sheng-Nan Lu, I-Shyan Sheen, Gilbert J.
L’Italien, Hwai-I Yang, Chien-Jen Chen
953: Early Assessment of Hepatitis C Virologic
Response of US Veterans Receiving Sofosbuvir-based
Therapy
Lisa I. Backus, Pamela S. Belperio, Troy A. Shahoumian, Larry A.
Mole
954: Cost-effectiveness of sofosbuvir for the
treatment of chronic hepatitis C infected patients in the
UK
Sandrine Cure, Ines Guerra, Geoffrey M. Dusheiko
955: Safety and Efficacy of Sofosbuvir (SOF) in
Combination with Simeprevir (SIM) + Ribavirin (RBV)
in Patients with Genotype 1: Interim Results of a
Prospective, Observational Study
Mark S. Sulkowski, Hugo E. Vargas, Adrian M. Di Bisceglie,
Alexander Kuo, K. Rajender Reddy, Joseph K. Lim, Giuseppe
Morelli, Jordan J. Feld, Robert S. Brown, Lynn M. Frazier, Michael
W. Fried, David R. Nelson, Ira M. Jacobson
956: Safety and efficacy of Simeprevir +
Sofosobuvir with or without Ribavirin in Patients with
Decompensated Genotype 1 Hepatitis C induced
Cirrhosis
Apurva A. Modi, Hector Nazario, Stevan A. Gonzalez,
Manjushree Gautam, Jeffrey S. Weinstein, Parvez S. Mantry,
Maisha Barnes, Adil Habib, Jean L. McAfee, Olga Teachenor,
Lauren Tujague, James F. Trotter
957: Short duration response-guided treatment is
effective for most individuals with recent hepatitis C
infection: the ATAHC II Study
Marianne Martinello, Margaret Hellard, David Shaw, Kathy
Petoumenos, Tanya L. Applegate, Jason Grebely, Barbara Y.
Yeung, Laurence Maire, David M. Iser, Andrew R. Lloyd, Alexander
J. Thompson, Joe Sasadeusz, Paul Haber, Gregory J. Dore, Gail
Matthews
958: Decrease of Cirrhosis and Hepatocellular
Carcinoma (HCC) in African Americans (AA) Following
Successful Treatment for Chronic Hepatitis C (CHC)
Naveen Reddy, Paul Naylor, Zaher Hakim, Redwan Asbahi,
Karthik Ravindran, Murray N. Ehrinpreis, Milton G. Mutchnick
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
959: Sofosbuvir plus Ribavirin in the Treatment
of Egyptian Patients with Chronic Genotype 4 HCV
Infection
Gamal E. Esmat, Gamal Shiha, Rabab F. Omar, Mohamad
Hassany, Radi Hammad, Marwa Khairy, Waleed Samir, Reham
Soliman, Diana M. Brainard, Deyuan Jiang, Kathryn Kersey,
Steven J. Knox, Benedetta Massetto, John G. McHutchison, Wahid
H. Doss
960: Performance of Simeprevir- and Sofosbuvir-
based HCV Treatment in Real World Clinical Practice
Kian Bichoupan, Rachana Yalamanchili, Keith M. Sigel, Alyson
Harty, Michel Ng, Alicia Stivala, Donna Fanelli, Donald
Gardenier, David B. Motamed, Badr Aljarallah, David Sachs,
Michael Linderman, Viktoriya Khaitova, Meena B. Bansal, Priya
Grewal, Ritu Agarwal, Charissa Y. Chang, Jennifer Leong,
Gene Y. Im, Lawrence Liu, Joseph A. Odin, Nancy Bach, David
C. Perlman, Jonathan Yeh, Albert Min, Henry C. Bodenheimer,
Donald P. Kotler, Scott L. Friedman, Thomas D. Schiano, Ponni
Perumalswami, Douglas Dieterich, Andrea D. Branch
961: Resistance Analysis of Treatment-Experienced
HCV Genotype 1 Infected Patients Retreated with
Sofosbuvir
Hongmei Mo, Brian Doehle, Viktoria Gontcharova, Ramakrishna
K. Chodavarapu, Bittoo Kanwar, Ira M. Jacobson, Stanislas Pol,
Diana M. Brainard, John G. McHutchison, Michael D. Miller
962: Reducing Polymorphisms Consisting of (TA)n
Dinucleotide Repeat Near IL28B Gene Interact with the
Deviation of IL28B SNPs and Affect the Effectiveness of
PegIFN/RBV, but not PegIFN/RBV/TVR
Masaaki Korenaga, Masaya Sugiyama, Yoshihiko Aoki, Keiko
Korenaga, Yoko Yamagiwa, Masatoshi Imamura, Nao Nishida,
Kazumoto Murata, Tatsuya Kanto, Naohiko Masaki, Masashi
Mizokami
963: Efficacy and safety of sofosbuvir plus simeprevir in
patients with advanced HCV cirrhosis
Camelia I. Capraru, Magdalena Kuczynski, Danie La, Diana
Kaznowski, Matthew Kowgier, David K. Wong, Joshua Juan,
Hemant Shah, Alnoor Ramji, Harry L. Janssen, Jordan J. Feld
964: Burden of Side Effects Associated with Treatment
of Hepatitis C
Ami R. Buikema, Lisa C. Rosenblatt, Fang Liu, Boris Gorsh, John C.
White, Bruce E. Sill
965: Impact of host and therapeutic factors and
resistant associated variants on response to interferon
based- direct acting antiviral treatment in difficult-to-
treat chronic hepatitis C patients
Mina Nakagawa, Yasuhiro Asahina, Miki Taniguchi, Takako
Watanabe, Yuki Nishimura-Sakurai, Yasuhiro Itsui, Seishin Azuma,
Sei Kakinuma, Yujiro Tanaka, Mamoru Watanabe
Poster Viewing: 8:00 AM – 5:30 PM
133A
966: Safety, Anti-Viral Efficacy and Pharmacokinetics
(PK) of Sofosbuvir (SOF) in Patients with Severe Renal
Impairment
Edward J. Gane, Richard A. Robson, Maurizio Bonacini, Benedict
Maliakkal, Lin Liu, Karim Sajwani, Luisa M. Stamm, Diana M.
Brainard, John G. McHutchison, Catherine A. Stedman, Eric Lawitz
967: Plasma and Intracellular Ribavirin
Pharmacokinetics and Concentration-Effect Analyses in
Chronic Hepatitis C Virus Genotype 1 Patients Receiving
Sofosbuvir plus Ribavirin in the NIAID SPARE Trial
Joseph E. Rower, Eric G. Meissner, Leah C. Jimmerson, Anu
Osinusi, Zayani Sims, Tess L. Petersen, Lane Bushman, Pamela
Wolfe, John G. McHutchison, Shyam Kottilil, Jennifer J. Kiser
968: Baseline vitamin D level and sustained virologic
response to interferon-based antiviral therapy in chronic
hepatitis C: a systematic review and meta-analysis
Matthew T. Kitson, Christoph Sarrazin, Pierluigi Toniutto, Guy D.
Eslick, Stuart K. Roberts
969: Delayed early HCV RNA response during IFN-free
therapy with sofosbuvir in interferon-ineligible patients
with advanced cirrhosis
Katja Deterding, Christoph Hoener zu Siederdissen, Kerstin Port,
Janina Kirschner, Lisa Sollik, Carola Mix, Michael P. Manns,
Markus Cornberg, Heiner Wedemeyer
970: Response to IFN-based antiviral therapy
and long term effect of HCV eradication in Mixed
Cryoglobulinemia, with or without symptoms: a
prospective, controlled, open-label, long term, cohort
study
Laura Gragnani, Alessia Piluso, Elisa Fognani, Monica Monti,
Barbara Boldrini, Teresa Urraro, Alessio Fabbrizzi, Umberto
Arena, Stefania Moscarella, Jessica Ranieri, Cristina Stasi,
Giacomo Laffi, Anna Linda Zignego
971: Efficacy and safety of telaprevir based triple
therapy in coinfected patients with advanced fibrosis.
Final results of the spanish cohort
NOVEMBER 9
Miguel A. von Wichmann, Ana Moreno, Luis F. López Cortés,
SUNDAY
Enrique Ortega, Jose Antonio Mira, Carmen Quereda, Marisa L.
Montes, Maria Tellez, Miguel García del Toro, José A. Iribarren,
Angela M. Camacho, Luz Martin-Carbonero, Joseba Portu, José-
Ramón Blanco, Koldo Aguirrebengoa, Juan Berenguer, Juan
Gonzalez García, Manuel Márquez Solero
972: Safety and Effectiveness of Sofosbuvir (SOF) in
Combination with Simeprevir (SIM) or Ribavirin (RBV)
for the Treatment of Hepatitis C Virus (HCV) Recurrence
after Liver Transplant (LT)
Glen A. Lutchman, Nghia H. Nguyen, Tiffany I. Hsiao, Vinh D.
Vu, Vincent Chen, Aijaz Ahmed, Tami Daugherty, Gabriel Garcia,
Radhka Kumari, W. Ray Kim, Mindie H. Nguyen
Presenters in Attendance 12:30 – 2:00 PM
 134A POSTER SESSIONS
Poster Sessions
973: 97% Sustained Virologic Response in Japanese
Patients with Chronic Genotype 2 Hepatitis C Virus
Infection Receiving Sofosbuvir in Combination with
Ribavirin for 12 Weeks: Results from a Phase 3
Multicenter Study
Masao Omata, Shuhei Nishiguchi, Yoshiyuki Ueno, Hitoshi
Mochizuki, Namiki Izumi, Fusao Ikeda, Hidenori Toyoda, Osamu
Yokosuka, Kazushige Nirei, Takuya Genda, Takeji Umemura,
Tetsuo Takehara, Naoya Sakamoto, Yoichi Nishigaki, Kunio
Nakane, Nobuo Toda, Tatsuya Ide, Mikio Yanase, Keisuke
Hino, Juan Betular, Bing Gao, Akinobu Ishizaki, Masa Omote,
Diana M. Brainard, Steven J. Knox, William T. Symonds, John G.
McHutchison, Hiroshi Yatsuhashi, Masashi Mizokami
974: Modeling treatment scale up effect on hepatitis
C prevalence among persons who inject drugs in
metropolitan Chicago
Desarae Echevarria, Alexander Gutfraind, Basmattee Boodram,
Marian E. Major, Scott Cotler, Harel Dahari
975: Efficacy of sofosbuvir and simeprevir-based
regimens for 304 HCV treatment-experienced patients
in a real-life setting; data from the TRIO network
Bruce R. Bacon, Douglas Dieterich, Steven L. Flamm, Kris V.
Kowdley, Eric Lawitz, Scott Milligan, Zobair Younossi, Naoky Tsai
976: High Response Rate and Good Tolerability of
Genotype 6 Chronic Hepatitis C Patients to Pegylated
Interferon alfa combining Ribavirin in China
Lai Wei, ZhiLiang Gao, Qing Mao, Dazhi Zhang, Jianning Jiang,
Guozhong Gong, Zhibiao Yin, Qing Xie, Jian Sun, Huiying Rao,
Bo Feng, Ruifeng Yang, Haiying Zhang
977: Poor Sustained Virologic Response (SVR) in a
Multicenter Real-Life Cohort of Chronic Hepatitis C (CHC)
Patients Treated with Pegylated Interferon (PEG IFN)
and Ribavirin (RBV) plus Telaprevir (TVR) or Boceprevir
(BOC)
Kevin P. Vo, Philip Vutien, Matthew J. Akiyama, Vinh D. Vu, Joy I.
Piotrowski, Nghiem B. Ha, James M. Wantuck, Marina Roytman,
NOVEMBER 9
Ramsey Cheung, Jiayi Li, Naoky Tsai, Mindie H. Nguyen
SUNDAY
978: Treatment safety and efficacy of Boceprevir-based
triple therapy in genotype 1 hepatitis C: the Australian
multicentre Boceprevir real world experience (SABRE-C)
Anouk T. Dev, Joanne Mitchell, Kevan Polkinghorne, Richard
Skoien, Katherine Stuart, Wendy Cheng, Alice Lee, Miriam T.
Levy, John Lubel, Saroja Nazareth, Alan J. Wigg, Sherryne L.
Warner, Stuart K. Roberts
979: DDRGK1 variants are associated with platelet
decline during peginterferon and ribavirin therapy in
Caucasian patients with chronic HCV infection
Raoel Maan, Adriaan J. van der Meer, Willem Pieter Brouwer,
Elisabeth P. Plompen, Milan J. Sonneveld, Robert Roomer,
Annemiek A. van der Eijk, Zwier M. Groothuismink, Bettina E.
Hansen, Bart J. Veldt, Harry L. Janssen, Andre Boonstra, Robert
J. de Knegt
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
980: Impact of latest direct antiviral agents (DAAs) on
the cure rate and cost of hepatitis C infection treatment:
a meta-analysis
Siddharth Bansal, Mohamed G. Shoreibah, Brendan M. McGuire,
Ashwani K. Singal, Bhupinderjit S. Anand
981: A real life experience with COSMSOS regimen
in Genotype 1 chronic hepatitis C treatment: including
patients with East Asian ancestry and decompensated
cirrhosis
Marina Roytman, Resham Ramkissoon, Leena K. Hong, Leslie
Huddleston, Ruby Trujillo, Peter Poerzgen, Todd B. Seto, Naoky
Tsai
982: Sofosbuvir plus Ribavirin for the Treatment of
Russian Patients with Chronic HCV Genotype 1 or 3
Infection
Vladimir Chulanov, Konstantin Zhdanov, Kathryn Kersey,
Yanni Zhu, Benedetta Massetto, Sergey Zhuravel, Svetlana
Romanova, Elena Nurmukhametova, Viacheslav Morozov,
Galina Kozhevnikova, Larisa Gogova, Natalia Geyvandova,
Natalia Gankina, Evgenii Chesnokov, Eduard Z. Burnevich, Elena
Bessonova, Djamal Abdurakhmanov, Diana M. Brainard, John G.
McHutchison, Igor G. Bakulin, Vasily Isakov
983: Evaluation of efficacy of sofosbuvir and
simeprevir-based regimens in a real-life population of
345 HCV patients with cirrhosis; data from the TRIO
network
Steven L. Flamm, Bruce R. Bacon, Douglas Dieterich, Kris V.
Kowdley, Eric Lawitz, Scott Milligan, Naoky Tsai, Zobair Younossi
984: Interferon based therapies (IBT) against hepatitis
C (HCV) in previous kidney transplant (KT) recipients on
hemodialysis (HD) do not seem to increase the risk of
graft intolerance syndrome (GIS)
Javier-Enrique Hernandez Blanco, Josep M. Barrera, Sabela Lens,
Zoe Mariño, Francesc Maduell, Josep-Maria Campistol, Xavier
Forns, Maria-Carlota Londono
985: Telaprevir combination therapy in treatment-naïve
and -experienced patients co-infected with HCV/HIV
(INSIGHT STUDY): sustained virologic response at 12
weeks final analysis
Marisa L. Montes, Mark Nelson, Pierre-Marie Girard, Joe
Sasadeusz, Andrzej Horban, Beatriz Grinsztejn, Natalia
Zakharova, Antonio Rivero, Erkki Lathouwers, Katrien Janssen, Sivi
Ouwerkerk-Mahadevan, James Witek
986: Protease inhibitors impair renal function in HCV-
infected immunocompetent patients
Carlos Fernández-Carrillo, Juan Manuel Pascasio, Martin Prieto, J.
L. Montero, Javier Crespo, Inmaculada Fernández, Xavier Forns,
Javier García-Samaniego, Manuel Romero-Gomez, Juan Turnes,
J. Javier Moreno, Elba Llop, Cristina Serrano-Millan, Maria Buti,
Jose Luis Calleja
987: MCNs, reach and treat the HCV patients other
pathways can’t!
Jan Tait, Brian P. Stephens, Shirley Cleary, Paul G. McIntyre, John
F. Dillon
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
988: Analysis of HCV-RNA decrease until one week
after the start of the triple therapy including protease
inhibitor in patients chronically infected with hepatitis C
virus genotype 1
Satoru Hashimoto, Rumiko Nakao, Ayako Mine, Yuki Kugiyama,
Ryu Sasaki, Shigemune Bekki, Akira Saeki, Shinya Nagaoka,
Seigo Abiru, Kazumi Yamasaki, Atsumasa Komori, Hiroshi
Yatsuhashi
989: Inosine Triphosphatase and Interleukin 28B
Genetic Variants to Predict Sustained Virologic Response
in Hemodialysis Patients with Hepatitis C Virus
Genotype 1 or 2 Infection who Received Peginterferon
alfa-2a plus Low-Dose Ribavirin: Data Analysis from
HELPER-1 and HELPER-2 Trials
Chen-Hua Liu, Chun-Jen Liu, Chung-Feng Huang, Jou-Wei Lin,
Chia-Yen Dai, Cheng-Chao Liang, Jee-Fu Huang, Peir-Haur Hung,
Hung-Bin Tsai, Meng-Kun Tsai, Chih-Yuan Lee, Shih-I Chen, Sheng-
Shun Yang, Tung-Hung Su, Hung-Chih Yang, Pei-Jer Chen, Ding-
Shinn Chen, Wan-Long Chuang, Ming-Lung Yu, Jia-Horng Kao
990: Safety and Efficacy of Simeprevir, Sofosbuvir
and Riabviirn Combination Therapy in Liver Transplant
Recipients with Severe Recurrent HCV
Satheesh Nair, Nader Dbouk, Shilpa Lingala, Sanjaya K.
Satapathy
991: Effects of Ribavirin on Red Blood Cell
Concentrations of Endogenous Purines in Patients with
Hepatitis C Virus Undergoing Ribavirin-Based Treatment
Leah C. Jimmerson, James R. Burton, Fafa Baouchi, Aimee E.
Truesdale, Angie Price, Michelle Ray, Lane Bushman, Kyle
Hammond, Jacob Langness, Sarah Tise, Gregory T. Everson,
Jennifer Kiser
992: The Effect of Rifampin on the Pharmacokinetics of
Sofosbuvir in Healthy Volunteers
Kimberly L. Garrison, Yi Wang, Diana M. Brainard, Karim
Sajwani, Anita Mathias
993: Simeprevir and Sofosbuvir with modified doses
of Ribavirin (RBV) therapy on Telaprevir experienced
Co infected (with HIV) cirrhotics with chronic hepatitis
C (CHC) A randomized open label clinical pilot study:
STOP C
Patrick Basu, Niraj J. Shah, M. Aloysius
994: Real-World Data on HIV positive Patients with HCV
Genotype 1,2 and 3 on Sofosbuvir- and Simeprevir-
containing Regimens
David P. Del Bello, Kian Bichoupan, Rachana Yalamanchili,
Alyson Harty, Michel Ng, Alicia Stivala, Donald Gardenier,
Viktoriya Khaitova, Nadim Salomon, Donna Mildvan, David C.
Perlman, Lawrence U. Liu, Joseph A. Odin, Thomas D. Schiano,
Ponni Perumalswami, Daniel S. Fierer, Douglas Dieterich, Andrea
D. Branch
Poster Viewing: 8:00 AM – 5:30 PM
135A
995: Real World Experience with Sofosbuvir and
Simeprevir combination treatment in patients with HCV
genotype 1
Ming V. Lin, Neliswa A. Gogela, Jessica L. Wisocky, Michael
Thiim, Daniel S. Pratt, Karin L. Andersson, Nikroo Hashemi, Anna
E. Rutherford, Kathleen E. Corey, Lee F. Peng, Dahlene N. Fusco,
Arthur Y. Kim, Alan Mullen, Judith A. Bloom, Raymond T. Chung
996: Simeprevir plus Sofosbuvir for Patients with
Recurrence of Genotype 1 Hepatitis C Infection after
Liver Transplantation
Susan J. Ripper, Edward W. Holt, Stewart Cooper, Adil E. Wakil,
Timothy J. Davern, Raphael Merriman, Jennifer Guy, R. Todd
Frederick
997: The impact of plasma ribavirin concentration
on the efficacy of the interferon-sparing regimen,
sofosbuvir and ribavirin
Marianne Martinello, Maryam Alavi, Gregory J. Dore, Ana
Schteinman, Richard O. Day, Kenneth Williams, Gail Matthews
998: A real life experience with sofosbuvir-based
regimens, including patients with multiple factors
previously associated with inferior treatment response
Christina Wu, Marina Roytman, Leena K. Hong, Leslie Huddleston,
Ruby Trujillo, Alvin Cheung, Peter Poerzgen, Naoky Tsai
999: Higher sustained virologic response (SVR) in
patients with early virologic response (EVR) and
hepatitis C genotype 4 (HCV-4) compared to genotype
1 (HCV-1) with pegylated interferon and ribavirin (PEG
IFN+RBV): a comparative analysis from a meta-analysis
Brittany E. Yee, Derek Lin, Nghia H. Nguyen, Bing Zhang, Philip
Vutien, Carrie R. Wong, Glen A. Lutchman, Mindie H. Nguyen
1000: Renal Impairment under Triple Therapy with
Boceprevir in German Real-Life: Evidence for a Pivotal
Role for Peginterferon/Ribavirin Backbone, Female
Gender and Age >50 Years
Peter Buggisch, Hanns F. Loehr, Gerlinde Teuber, Hermann
Steffens, Michael R. R. Kraus, Christine John, Peter R. Geyer,
NOVEMBER 9
Bernd Weber, Thomas Witthoeft, Andreas Herrmann, Mark Hoesl,
SUNDAY
Uwe Naumann, Elmar Zehnter, Dagmar Hartmann, Bernd Dreher,
Manfred Bilzer
1001: Relevance of early virological assessment during
triple therapy combining telaprevir or boceprevir with
pegylated interferon/ribavirin in chronic hepatitis C
patients - The ANRS CO20 CUPIC study
François Bailly, Victor Virlogeux, Cécilie Dufour, Pierre Pradat,
Christophe Hezode, Dominique G. Larrey, Laurent Alric, Didier
Samuel, Marc Bourlière, Sophie Metivier, Jean-Pierre Zarski,
Hélène Fontaine, Veronique Loustaud-Ratti, Lawrence Serfaty, Jean-
Pierre Bronowicki, Ventzislava Petrov-Sanchez, Fabrice Carrat,
Fabien Zoulim
1002: Successful treatment of post liver transplant
patients with genotype 1 hepatitis C virus with
sofosbuvir and simeprevir
Carmi S. Punzalan, Curtis Barry, Isabel Zacharias, Julie Rodrigues,
Savant Mehta, Adel Bozorgzadeh, Graham Barnard
Presenters in Attendance 12:30 – 2:00 PM
 136A POSTER SESSIONS
Poster Sessions
1003: Safety and Efficacy of Simeprevir and Sofosbuvir
in Patients with Decompensated Cirrhosis
Shilpa Lingala, Sanjaya K. Satapathy, Nader Dbouk, Satheesh
Nair
1004: Urgent Treatment With Sofosbuvir Based
Regimen For Hepatitis C Genotype 1 Patients With
Severe Renal Insufficiency (GFR <30ml/min)
Kalyan R. Bhamidimarri, Julio A. Gutierrez, Alla Grigorian, Adam
L. Peyton, Cynthia Levy, Christopher O’Brien, Paul Martin
1005: Significant interindividual variability in Telaprevir
exposure in patients undergoing anti-HCV therapy -
need for “real world” PK studies to identify vulnerable
populations
Omar El-Sherif, Sujan Dilly Penchala, Laura J. Else, Suzanne
Norris, Saye H. Khoo
1006: Outcomes from the Irish national hepatitis C
prospective treatment registry
Emma Gray, Aisling O’Leary, Cathal Walsh, Colm J. Bergin,
Suzanne Norris
1007: Meta-analysis: Predictors for response-guided
therapy (RGT) in hepatitis C genotype 4 (HCV-4) patients
treated with pegylated interferon and ribavirin (PEG
IFN+RBV)
Brittany E. Yee, Nghia H. Nguyen, Bing Zhang, Philip Vutien,
Carrie R. Wong, Glen A. Lutchman, Mindie H. Nguyen
1008: A real life experience of Simeprevir, pegylated-
interferon and ribavirin therapy revealed high rate of
rapid virological response regardless of age, fibrosis
and NS3 polymorphisms
Shoko Suzuki, Namiki Izumi, Masayuki Kurosaki, Jun Itakura,
Kaoru Tsuchiya, Hiroyuki Nakanishi, Takanori Hosokawa, Yutaka
Yasui, Nobuharu Tamaki, Nobuhiro Hattori, Yu Asano, Shuya
Matsuda, Natsuko Nakakuki, Hitomi Takada, Koichi Gondou
1009: The impact of an inosine triphosphatase
polymorphism on bilirubin increases in patients with
NOVEMBER 9
hepatitis C virus infection treated with simeprevir,
SUNDAY
pegylated interferon plus ribavirin
Yuki Tahata, Naoki Hiramatsu, Tsugiko Oze, Naoki Morishita,
Naoki Harada, Ryoko Yamada, Takayuki Yakushijin, Yukiko Saji,
Sadaharu Iio, Akira Yamada, Eiji Mita, Hideki Hagiwara, Hiroyuki
Fukui, Masami Inada, Shinji Tamura, Harumasa Yoshihara, Atsuo
Inoue, Yasuharu Imai, Hayato Hikita, Ryotaro Sakamori, Takuya
Miyagi, Yuichi Yoshida, Tomohide Tatsumi, Akinori Kasahara,
Norio Hayashi, Tetsuo Takehara
1010: Efficacy and safety of telaprevir-based triple
therapy for patients aged 66 years and older with
genotype 1b chronic hepatitis C
Satoshi Yamagiwa, Toru Ishikawa, Shunsuke Tsubata, Nobuo
Waguri, Soichi Sugitani, Hiroto Wakabayashi, Masaaki
Takamura, Masato Igarashi, Minoru Nomoto
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1011: Interferon Induced Low Blood Cell Counts
Are Associated With Bleeding and Infection in Liver
Transplant Recipients on Hepatitis C Treatment
Ludi Koning, Kymberly D. Watt, Bettina E. Hansen, Julie Heimbach,
Robert J. de Knegt, Michael Charlton
1012: Analysis of the liver function and hepatic
reserve improvement effect, and liver carcinogenesis
suppressant effect of the Daclatasvir/Asnaprevir
combination therapy
Yoshiyasu Karino, Shuhei Hige, Itaru Ozeki, Tomoaki Nakajima,
Mutuumi Kimura, Tomohiro Arakawa, Yasuaki Kuwata, Takahiro
Sato, Takumi Ohmura, Joji Toyota
1013: Quality of Life for HCV-infected Patients
during Treatment: Are IFN-free Better than IFN-based
Regimens?
Jillian Nickerson, Kian Bichoupan, Alyson Harty, Jeffrey J. Weiss,
Ponni Perumalswami, Thomas D. Schiano, Douglas Dieterich,
Andrea D. Branch
1014: The risk factors for hepatocellular carcinoma
development in patients with hepatitis C virus
eradication
Masafumi Naito
1015: Frequency and Impact of Thyroid Dysfunction
on Early Virologic Response in Patients Undergoing
Boceprevir Triple Therapy for HCV Genotype 1 Infection
Peter Buggisch, Hanns F. Loehr, Gerlinde Teuber, Hermann
Steffens, Michael R. R. Kraus, Christine John, Peter R. Geyer,
Bernd Weber, Thomas Witthoeft, Andreas Herrmann, Mark Hoesl,
Uwe Naumann, Elmar Zehnter, Dagmar Hartmann, Bernd Dreher,
Manfred Bilzer
1016: Serious Adverse Events and Hepatic
Decompensation in Hepatitis C Virus infected Patients on
Sofosbuvir- and/or Simeprevir-based Therapies
Ponni Perumalswami, Kian Bichoupan, Rachana Yalamanchili,
Alyson Harty, Donald Gardenier, Michel Ng, David B. Motamed,
Viktoriya Khaitova, Nancy Bach, Charissa Y. Chang, Gene Y.
Im, Jennifer Leong, Lawrence Ku, Thomas D. Schiano, Douglas
Dieterich, Andrea D. Branch
1017: Influence of ribavirin plasma concentration on
the virological response and safety in patients with HCV
genotype 1 infection treated by combination therapy
with telaprevir or boceprevir
Marie Julia, Peggy Gandia, Mathieu Guivarch, Laura Coimet-
Berger, Florence Abravanel, Delphine Bonnet, Laurent Alric
1018: No differences of response to telaprevir based
therapy in cirrhotic and non cirrhotic patients with RVR:
a real life data from South Italy
Marcello Persico, Mario Masarone, Silvia Camera, Valerio Rosato,
Rocco Granata, Giovan Giuseppe Di Costanzo, Carmine Coppola,
Nicola Coppola, Angelo Salomone Megna, Ivan Gentile, Antonio
De Luna, Alessandro Federico, Davide F. Precone, Ernesto Claar,
Filomena Morisco
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1019: Orexigenic ghrelin secretion in HCV-infected
patients with telaprevir- or simeprevir-based triple
therapy
Toru Aoyama, Sumiko Nagoshi, Ryuichi Yamamoto, Naomi
Yamaguchi, Shino Ohno, Koji Yakabi
1020: Evaluation of liver fibrosis by acoustic radiation
force impulse (ARFI) imaging in hemodialysis patients
with chronic hepatitis C
Naoki Harada, Naoki Hiramatsu, Tsugiko Oze, Naoki Morishita,
Ryoko Yamada, Hayato Hikita, Ryotaro Sakamori, Takayuki
Yakushijin, Takuya Miyagi, Yuichi Yoshida, Tomohide Tatsumi,
Akinori Kasahara, Norio Hayashi, Tetsuo Takehara
1021: Ultra-deep sequencing analysis of resistant
variants in chronic hepatitis C patients treated with
simeprevir, peginterferon and ribavirin
Naoki Morishita, Naoki Hiramatsu, Tsugiko Oze, Yuki Tahata,
Naoki Harada, Ryoko Yamada, Takatoshi Nawa, Hayato Hikita,
Takayuki Yakushijin, Takuya Miyagi, Yuichi Yoshida, Tomohide
Tatsumi, Akira Yamada, Eiji Mita, Toshifumi Ito, Masami Inada,
Yasuharu Imai, Michio Kato, Tetsuo Takehara
1022: Daclatasvir, Simeprevir and Ribavirin as a new
IFN-free triple regimen for HCV recurrence after liver
transplantation: First results of safety and efficacy in 6
patients
Angela Papadopoulos-Köhn, Jörg Timm, Ali Canbay, Christoph
Jochum, Guido Gerken, Kerstin Herzer
1023: Final results of Boceprevir Early-Access For
Advanced Fibrosis/Cirrhosis In Asia-Pacific HCV
Genotype 1 Non-Responders/Relapser Patients (Beacon
Study)
Wattana Sukeepaisarnjaroen, Tri H. Pham, Tawesak Tanwandee,
Saroja Nazareth, Sam Galhenage, Lindsay Mollison, Leanne
Totten, Alan J. Wigg, Rosalie Altus, Anton Colman, Brenda
Morales, Susan Mason, Tracey L. Jones, Nadine Leembruggen,
Vince Fragomelli, Cheryl Sendall, Richard Guan, Dede Sutedja,
Soek Siam Tan, Yock Young Dan, Yin-Mei Lee, Widjaja Luman,
Eng Kiong Teo, Yin Min Than, Teerha Piratvisuth, Seng Gee Lim
1024: Delayed early HCV RNA response during IFN-
free therapy with sofosbuvir in interferon-ineligible
patients with advanced cirrhosis
Katja Deterding, Christoph Hoener zu Siederdissen, Kerstin Port,
Janina Kirschner, Lisa Sollik, Carola Mix, Michael P. Manns,
Markus Cornberg, Heiner Wedemeyer
1025: Treating Advanced Hepatitis C Virus with New
Direct Acting Antiviral Medications, a VA Experience
Joel P. Wedd, Becky Ashcraft, Kristin Babson, Nancy Boyd,
Marsha Costelow, Anthony Pepe, Yvette Tong, Hugo R. Rosen,
John Redington
1026: Ultra Rapid Virological Response as a Predictor
of Favorable Treatment Outcome for Acute Hepatitis C
Infection in Patients on Maintenance Hemodialysis
Syed M. Hassan, Arzoo Saeed, Muhammad Osama Butt, Nasir
Hassan Luck, Syed Mudassir Laeeq, Zaigham Abbas
Poster Viewing: 8:00 AM – 5:30 PM
137A
1027: Single Center Experience with Simeprevir/
Sofosbuvir Combination Therapy for Recurrent Hepatitis
C Virus Infection in Liver Transplant Recipients
Neil Crittenden, Eric G. Davis, Luis S. Marsano, Craig J. McClain,
Ashutosh Barve, Barbra A. Goshko, Robert R. Tatum, Michael G.
Hughes, Christopher M. Jones, Michael R. Marvin, Matthew C.
Cave
1028: Safety and efficacy of all-oral sofosbuvir-
based regimens to treat HCV recurrence post-liver
transplantation
Mohammed Eyad Yaseen Alsabbagh, Ibrahim A. Hanouneh, Binu
V. John, John K. Guirguis, Bijan Eghtesad, John J. Fung, Nizar N.
Zein, Naim Alkhouri
1029: Post-Liver Transplant Treatment of Hepatitis
C with a combination of Sofosbuvir, Simeprevir, +/-
Ribavirin at a High Volume Academic Transplant Center
Ryan M. Ford, Anjana Pillai, Nicole Cheng, Nikita M. Young,
Samir Parekh, JP Norvell, Ram Subramanian, James Spivey
1030: Early Viral Kinetics during Interferon-free
Sofosbuvir containing Treatment Regimen in a Real-life
Cohort of Chronic Hepatitis C Patients
Karin Kozbial, Robert Paul Strassl, Ramona Al Zoairy, Andreas
Maieron, Rudolf E. Stauber, Michael P. Strasser, Hermann Laferl,
Thomas Bamberger, Albert Staettermayer, Heinz M. Zoller, Peter
Knoflach, Katharina Staufer, Markus Peck-Radosavljevic, Petra E.
Steindl-Munda, Wolfgang Vogel, Peter Ferenci, Harald Hofer
1031: Factors associated with virologic response in
triple therapy with simeprevir, pegylated interferon and
ribavirin in Japanese patients with chronic hepatitis C
Tsugiko Oze, Naoki Hiramatsu, Takayuki Yakushijin, Ryoko
Yamada, Naoki Harada, Naoki Morishita, Yuki Tahata, Hayato
Hikita, Ryotaro Sakamori, Takuya Miyagi, Yuichi Yoshida,
Tomohide Tatsumi, Akira Yamada, Masahide Oshita, Hideki
Hagiwara, Eiji Mita, Toshifumi Ito, Yukinori Yamada, Taizo
Hijioka, Shinji Tamura, Kazuhiro Katayama, Harumasa Yoshihara,
Yasuharu Imai, Michio Kato, Norio Hayashi, Tetsuo Takehara
NOVEMBER 9
1032: Severe anemia with Sofosbuvir based therapy for
SUNDAY
Hepatitis C (HCV) recurrence post Liver transplantation
on mycophenolate mofetil (MMF)
Hussien Elsiesy, Aziza A. Ajlan, Ahmed Aljedai, Rania Alarieh,
Waleed K. Al-Hamoudi, Delal Alkortas, Mohammed Al Sebayel,
Dieter C. Broering, Faisal A. Abaalkhail
1033: Beneficial effect of treatment individualization for
patients with chronic hepatitis C receiving peginterferon
alfa-2a and ribavirin in a large non-interventional
cohort study
Wolf P. Hofmann, Stefan Mauss, Elmar Zehnter, Dietrich Hueppe,
Heike Pfeiffer-Vornkahl, Ulrich Alshuth, Eckart Schott
1034: Serum granulysin levels as a predictor of serious
telaprevir-induced dermatological reactions
Goki Suda, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka,
Naoya Sakamoto
Presenters in Attendance 12:30 – 2:00 PM
 138A POSTER SESSIONS
Poster Sessions
1035: Treatment of HCV in the SOF era: experience in
difficult to treat patients in a US liver transplant center
K Tuesday Werner, Amy E. Chervenak, Lorrie A. Hartel, Bashar
Aqel, Vijayan Balan, Thomas J. Byrne, Elizabeth J. Carey, Hugo E.
Vargas, Jorge Rakela
1036: Sustained Virological Response in Diabetic
Patients with Chronic Hepatitis C
Umit B. Dogan, Mustafa S. Akin, Gunay Camuz
1037: Clinical utility of NS3/4A protease inhibitor-
resistant variant detection for prediction of treatment
efficacy in HCV genotype 1
Norio Akuta, Fumitaka Suzuki, Yushi Sorin, Taito Fukushima,
Yusuke Kawamura, Hitomi Sezaki, Yoshiyuki Suzuki, Tetsuya
Hosaka, Masahiro Kobayashi, Satoshi Saitoh, Mariko Kobayashi,
Yasuji Arase, Kenji Ikeda, Hiromitsu Kumada
1038: Sofosbuvir-based therapy under real life
conditions in Germany
Peter Buggisch, Holger Hinrichsen, Stefan Mauss, Karl-Georg
Simon, Dietrich Hueppe, Joerg Petersen
1039: Treatment of Previously Untreated Patients with
Chronic HCV Genotype 1 Infection with Boceprevir in
German Real-Life: High End of Treatment Response >
90% in Patients with Early Virologic Response
Peter Buggisch, Hanns F. Loehr, Gerlinde Teuber, Hermann
Steffens, Michael R. R. Kraus, Christine John, Peter R. Geyer,
Bernd Weber, Thomas Witthoeft, Andreas Herrmann, Mark Hoesl,
Uwe Naumann, Elmar Zehnter, Dagmar Hartmann, Bernd Dreher,
Manfred Bilzer
1040: Treatment of Acute Hepatitis C (HCV) Infection
with Pegylated Interferon and Ribavirin (P/R) in Patients
Co-infected with Human Immunodeficiency Virus (HIV):
a systematic review and meta-analysis
Bing Zhang, Benjamin Yip, Nghia H. Nguyen, Brittany E. Yee,
Walid S. Ayoub, Mindie H. Nguyen, Glen A. Lutchman
1041: IFNL4/IL-28B haplotype structure and
NOVEMBER 9
predictability of their variations for spontaneous and
SUNDAY
treatment-induced clearance of HCV infection in the
Japanese population
Hidenori Ochi, Daiki Miki, C. Nelson Hayes, Hiromi Abe, Michiaki
Kubo, Kazuaki Chayama
1042: Estimated Glomerular Filtration Rate (eGFR) at
Baseline Strongly Predicts the Frequency of Anemia
in Patients Undergoing Boceprevir Triple Therapy in
German Real-Life
Gerlinde Teuber, Peter Buggisch, Hanns F. Loehr, Hermann
Steffens, Michael R. R. Kraus, Christine John, Peter R. Geyer,
Bernd Weber, Thomas Witthoeft, Andreas Herrmann, Mark Hoesl,
Uwe Naumann, Elmar Zehnter, Dagmar Hartmann, Bernd Dreher,
Manfred Bilzer
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1043: Interferon ineligible naive chronic hepatitis
C genotype I subjects treated with Simeprevir and
Sofosbuvir in special population (psychiatric). An open
label prospective clinical pilot study; INSPIRE C study
Patrick Basu, Niraj J. Shah, M. Aloysius, Robert S. Brown
1044: Final efficacy and safety of telaprevir, Peg-IFN-
alfa-2a, and ribavirin in combination with darunavir/
ritonavir-based HAART in HCV/HIV-1 co-infected
patients (INSIGHT substudy)
Marisa L. Montes, Enrique Ortega, Andrzej Horban, Mark
Nelson, Jacques Durant, Katrien de Backer, Katrien Janssen, Sivi
Ouwerkerk-Mahadevan
Hepatotoxicity: Drug Metabolism
1045: Lysosomal Iron Mobilization in Hepatotoxicity
after Acetaminophen in Vivo in Mice
Jiangting Hu, Hartmut Jaeschke, John J. Lemasters
1046: A common UGT1A haplotype of genetic
variants reduces the transcriptional responsiveness
towards the anti-cancer drug irinotecan
Sandra Kalthoff, Anja Winkler, Christian P. Strassburg
1047: ‘Dual function of Jnk1 and Jnk2 in hepatocytes
is indispensable against drug-induced liver injury’
Francisco Javier Cubero, Wei Hu, Gang Zhao, Jin Peng, Yulia
Nevzorova, Malika Al Masaoudi, Lars Bechmann, Mark V.
Boekschoten, Michael Muller, Nikolaus Gassler, Ali Canbay,
Christian Liedtke, Christian Trautwein
1048: Activation of AMPK prevents and reverses
drug induced mitochondrial and hepatocellular damage
in collagen sandwich culture of hepatocytes
Dong Fu, Geoffrey C. Farrell, Ghada Haydar
1049: Human mercapto-albumin of chronic liver disease
patients contributes to alterations in the functional
properties of human serum albumin
Hiroko Setoyama, Motohiko Tanaka, Hideaki Naoe, Takehisa
Watanabe, Masakuni Tateyama, Kotaro Fukubayashi, Youko
Yoshimaru, Takeshi Kawasaki, Satomi Fujie, Kazuhiro Izumi,
Hiroshi Watanabe, Toru Maruyama, Yutaka Sasaki
1050: Amoxicillin-clavulanate induced DILI: 113 cases
from the US Drug-Induced Liver Injury Network (DILIN)
Andrew deLemos, Marwan Ghabril, Don C. Rockey, Jiezhun Gu,
Huiman X. Barnhart, Mark W. Russo, Herbert L. Bonkovsky
1051: The Non-nucleoside Reverse Transcriptase
Inhibitor Efavirenz-induces an inflammatory response in
hepatic cells controlled by autophagy
Ana Blas-García, Fernando Alegre, Miriam Polo, Dolores Ortiz-
Masiá, Haryes A. Funes, Alberto Martí-Rodrigo, Nadezda
Apostolova, Juan V. Esplugues
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1052: The Long-Term Follow-up of 140 Patients
with Drug-Induced Liver Injury (DILI): Emphasis on
Phenotypes and Chronic Risk Factors
Wenjing Zhu, Xinyan Zhao, Tailing Wang, Hong Ma
1053: Pharmacological Inhibition of M1 Muscarinic
Receptors (M1R) Reduces Oxidative Stress in AML12
Hepatocytes
Ravirajsinh Jadeja, Sandeep Khurana
1054: Risk factors for chronicity in idiosyncratic drug-
induced liver injury (DILI)
I. Medina-Cáliz, B. Garcia-Muñoz, Mercedes Robles Diaz, C.
Stephens, Andrés González-Jiménez, Miren García-Cortés, A.
Ortega, Ramón Hidalgo, Maria Carmen Fernandez, Manuel
Romero-Gomez, J. M. Navarro, Hacibe Hallal, Ramon Planas, S.
Avila, S. Blanco, Agustin Castiella, E. Zapata, Miguel Jimenez, J.
M. Moreno-Planas, German Soriano, Carlos Guarner, E. Roman,
Joaquin Primo, A. Aldea, Martin Prieto, M. I. Lucena, Raul J.
Andrade
1055: Drug-induced Liver Injury (DILI) Associated
with Stevens-Johnson Syndrome or Toxic Epidermal
Necrolysis (SJS/TEN): Characteristics and Outcome
Harshad Devarbhavi, Sujata Raj, Keyur A. Sheth, Karnam
Ravikiran, Rajvir Singh, Venu H. Aradya, T. R. Vijaykumar,
Mallikarjun Patil, Adarsh Ck
1056: Characteristics of Efavirenz drug induced liver
injury - a cohort analysis
Mark W. Sonderup, Helen Wainwright, Mashiko Setshedi, C. W.
Spearman
1057: Endoplasmic Reticulum stress inhibitors diminish
acetaminophen toxicity
Annelies Paridaens, Yves-Paul Vandewynckel, Eliene Bogaerts,
Anja Van den Bussche, Hans Van Vlierberghe, Anja M. Geerts,
Isabelle Colle
1058: Brincidofovir (CMX001) Dose and Plasma
Exposure Correlates with Serum Alanine
Aminotransferase Elevations
Tom Brundage, Herve Mommeja-Marin, Marion Morrison,
Katherine J. Van Sickle
1059: Histological Changes That Reliably Differentiate
Autoimmune Hepatitis from Drug-Induced Autoimmune
Hepatitis: Important Role of Liver Biopsy
Sadhna Dhingra, Thomas D. Schiano, Jawad Ahmad, Joseph A.
Odin, M. Isabel Fiel
1060: The effect of acetaminophen on primary
hepatocytes isolated from transgenic mice with different
apolipoprotein E genotypes
Vojtech Mezera, Otto Kucera, Alena Moravcova, Eva Peterova,
David Rychtrmoc, Tomas Rousar, Ondrej Sobotka, Zuzana
Cervinkova
Poster Viewing: 8:00 AM – 5:30 PM
139A
1061: Hep-114, a Novel Drug Candidate with Potent
Activity against Toxic Liver Injury: Preliminary Phase 2
Results
George Tets
Hepatotoxicity: Mechanisms
1062: CD44 deficency exacerbates murine
acetaminophen(APAP) hepatotoxicity in association with
enhanced hepatic inflammation and impaired clearance
of hyaluronan fragments
Jo Suda, Luoluo Yang, Neil Kaplowitz, Zhang-Xu Liu
1063: Acetaminophen (APAP) Hepatotoxicity Leads
To DNA Damage-Induced Arrest of Injured Cells In G0/
G1 Through Involvement Of Cell Cycle Regulators
Preeti Viswanathan, Sriram Bandi, Sanjeev Gupta
1064: Liver fibrogenesis is controlled by innate
immune activation pathways in hepatocyte apoptosis
Arvin Iracheta-Vellve, Jan Petrasek, Abhishek Satishchandran,
Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald,
Gyongyi Szabo
1065: Sumoylation regulates Cytochrome P450 2E1
(CYP2E1) expression in alcoholic liver disease
Maria Lauda Tomasi, Minjung Ryoo, Diana Arsene
1066: Exposure to Vinyl Chloride Metabolites
Exacerbates Liver Injury Caused by High Fat Diet in
Mice
Lisanne C. Anders, Amanda N. Douglas, Adrienne M. Bushau,
Keith C. Falkner, Gavin E. Arteel, Matthew C. Cave, Craig J.
McClain, Juliane I. Beier
1067: Cholestatic Drug reactions are more likely to
cause persistent liver injury and impaired Quality of
Life during prolonged follow-up: Results from the DILIN
Prospective study
NOVEMBER 9
Robert J. Fontana, Paul H. Hayashi, Rajender Reddy, David E.
SUNDAY
Kleiner, Thomas Phillips, Huiman X. Barnhart, Jayant A. Talwalkar,
Naga P. Chalasani, William M. Lee, Andrew Stolz, Timothy J.
Davern, Paul B. Watkins, Jose Serrano
1068: Microsomal prostaglandin E synthase-1
(mPGES-1) prevents Fas-induced liver injury
Lu Yao, Chang Han, Tong Wu
1069: New insight into the role of liver in viral
hemorrhagic fever
Gavin E. Arteel, Juliane I. Beier, Jenny Jokinen, Patrick S. Whang,
Amah M. Martin, Nikole L. Warner, Igor S. Lukashevich
1070: Oxaloacetic Acid Protects the Liver Against
Warm Ischemia
Grégory Merlen, Benoit Lacoste, Benoît Dupont, Valérie-Ann
Raymond, Marc Bilodeau
Presenters in Attendance 12:30 – 2:00 PM
 140A POSTER SESSIONS
Poster Sessions
1071: Acetaldehyde Suppresses Interferon Alpha
Signaling In HCV-infected Hepatoma Cells By Impairing
Protein Methylation
Murali Ganesan, Lee K. Jaramillo, Kusum K. Kharbanda, Dean J.
Tuma, Natalia A. Osna
1072: A novel oral form of pentamidine (OCZ103)
blocks TNF-mediated mouse liver injury from GalN/LPS
Enpeng Zhao, Ghulam Ilyas, Yu Lin, Kathryn Tanaka, Francois
Ravenelle, Mark J. Czaja
1073: Hepatic Stellate Cells Are Activated In A Rac1
Dependent Mechanism After Engulfment Of Isoniazid
Exposed Dying Hepatocytes – Role In Drug Induced
Fibrogenesis
Suman Santra, Abhijit Chowdhury, Debasree Bishnu, Gopal K.
Dhali, Amal Santra
1074: Moderate (2% v/v) ethanol feeding delays liver
regeneration and enhances hepatic profibrotic markers
after carbon tetrachloride-induced liver injury in mice
Krutika T. Deshpande, Shinlan Liu, Michele Pritchard
1075: Early growth response 1 attenuates ethanol-
accelerated, carbon tetrachloride-induced profibrotic
signatures in liver: Novel role for NAD(P)H
dehydrogenase, quinone 1
Briana Holt, Krutika T. Deshpande, Michele Pritchard
1076: Profiles of serum microRNAs in acute drug-
induced liver injury and their prognostic significance
Mark W. Russo, James Norton, William Anderson, Nury
Steuerwald, Huiman X. Barnhart, Naga P. Chalasani, Robert J.
Fontana, Paul H. Hayashi, Jose Serrano, Herbert L. Bonkovsky
1077: Type XVIII collagen regulates hepatocyte cell
survival and the anti-oxidant response during elevated
oxidative stress conditions, in vitro
Ravirajsinh Jadeja, Priyanka Thakur, Sandeep Khurana, Michael
Duncan
NOVEMBER 9
1078: Severe liver and kidney injury in mouse models
SUNDAY
of acute-on-chronic alcoholic hepatitis
Shinji Furuya, Takeki Uehara, Yuki Kato, Oksana Kosyk, Gemma
Odena, Hiroshi Kono, Ramon Bataller, Ivan Rusyn
1079: A New Approach To The Mechanism Of
Paracetamol Hepatotoxicity: Liver 5-Ht7 Receptors
Zekai Halici, Elif Cadirci, Beyzagul Polat, Emre Karakus, Yasin
Bayir, Abdulmecit Albayrak, Deniz Unal
1080: Identification of alcohol-induced tubulin
acetylation sites by mass spectrometry
Jennifer L. Groebner, Dean J. Tuma, Pamela L. Tuma
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1081: Killer Ig-like receptors (KIR) profiles and HLA
class I ligands in amoxicillin-clavulanate-induced
hepatotoxicity
C. Stephens, Antonia Moreno-Casares, MAngel López-Nevot,
Miren García-Cortés, I. Medina-Cáliz, Hacibe Hallal, German
Soriano, Francisco. Ruiz-Cabello, Manuel Romero-Gomez, M. I.
Lucena, Raul J. Andrade
1082: Intrahepatic Neurons: Chronological Changes
after Liver Transplantation, and their Associations with
Liver Diseases
Kei Mizuno, Keigo Murakami, Tomohiro Katsumi, Kyoko Tomita,
Chikako Sato, Kazuo Okumoto, Yuko Nishise, Hisayoshi
Watanabe, Takafumi Saito, Naoki Kawagishi, Yoshiyuki Ueno
1083: What is the possible pathogen of the patients
with fever, elevated serum enzymes and inflammatory
markers, changes of WBC, PLT and Lymphocytes?
Jie Cai, Xiling Guo, Yin Chen, Yiyue Ge, Lunbiao Cui, Yali Weng
Imaging of Steatohepatitis
1084: Diagnosis and Quantification of Fatty Liver with
Quantitative Ultrasound using MRI-Derived Proton
Density Fat Fraction as Reference in Patients with and
without NAFLD
Steven C. Lin, Elhamy Heba, Tanya Wolfson, Brandon Ang,
Anthony C. Gamst, Aiguo Han, John W. Erdman, William D.
O’Brien, Michael P. Andre, Claude B. Sirlin, Rohit Loomba
1085: Multi-parametric MRI can diagnose
steatohepatitis and cirrhosis in patients with NAFLD
Michael Pavlides, Rajarshi Banerjee, Elizabeth M. Tunnicliffe, Jane
Collier, Lai Mun Wang, Fleming A. Kenneth, Stefan Neubauer,
Eleanor Barnes
1086: Visceral Adiposity but not Hepatic Steatosis
is Associated with Coronary Artery Calcification: a
Prospective Cohort Study
Kathleen Jacobs, Sharon S. Brouha, Ricki Bettencourt, Claude B.
Sirlin, Rohit Loomba
1087: T2* magnetic resonance imaging is more
sensitive than histology and serum ferritin for the
assessment of iron overload in patients with NAFLD
Michael Pavlides, Rajarshi Banerjee, Elizabeth M. Tunnicliffe, Lai
Mun Wang, John D. Ryan, Jeremy F. Cobbold, Stefan Neubauer,
Eleanor Barnes
Steatohepatitis
1088: Recipient but not Donor Adiponectin rs266729
Polymorphism is Linked to Post-Transplant Steatosis in
Patients Transplanted with Chronic Hepatitis C Infection
Binu V. John, Ari Garber, Taylor Aiken, Dawn Thomas, Dongxing
Chen, Venkata Rajesh Konjeti, Rocio Lopez, Stanley Mistak, Nizar
N. Zein, Medhat Askar
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1089: Notch-mediated epithelial/mesenchymal
interaction influences non-alcoholic steatohepatitis
(NASH) progression
Carola M. Morell, Romina Fiorotto, Marica Meroni, Aileen Raizner,
Massimiliano Cadamuro, Emanuele Albano, Mario Strazzabosco
1090: Hepatic Overexpression of Thioesterase
Superfamily Member 1 (Them1) Accelerates Glucose
Intolerance in High Fat Fed Mice: Pathogenic Role in
Non-Alcoholic Fatty Liver Disease (NAFLD)
Cafer Ozdemir, David E. Cohen
1091: Palmitic acid lipotoxicity is determined by the
interaction of JNK with mitochondrial Sab (SH3BP5)
Sanda Win, Tin A. Than, Carmen Garcia-Ruiz, Jose Fernandez-
Checa, Neil Kaplowitz
1092: Distinct CD4+ T cell subset composition in
peripheral blood and hepatic tissue of patients with
NAFLD, NASH and healthy controls
Monika Rau, Anne-Kristin Schilling, Ilona Hering, Jan Meertens,
Theodor Kudlich, Christian Jurowich, Niklas Beyersdorf, Andreas
Geier
1093: Dynamics of Hepatic Lipid Composition,
and Mitochondrial Function during the Evolution of
Fast Food-Induced NASH – From the First Mouthful to
Steatofibrosis
Anuradha Krishnan, Tasduq Abdullah, Toafic Mounajjed, Stella
Hartono, Andrea L. McConico, Thomas A. White, Ian Lanza,
Nathan K. LeBrasseur, k Sreekumaran Nair, Gregory J. Gores,
Michael Charlton
1094: Lipotoxicity-Induced Extracellular Vesicles
Activate Macrophages Through TRAIL Signaling
Petra Hirsova, Steven Bronk, Nathan W. Werneburg, Anuradha
Krishnan, Gregory J. Gores
1095: Circulating extracellular vesicles with a specific
Proteome and liver microRNAs are novel biomarkers for
liver injury in fatty liver disease
Davide Povero, Akiko Eguchi, Hongying Li, Casey Johnson,
Alexander Wree, Milos Lazic, Karen Messer, Ariel E. Feldstein
1096: Hepatocyte-derived mitochondrial DNA acts as
a “danger signal” to promote inflammation and fibrosis
in non-alcoholic steatohepatitis
Naoki Ikenaga, Makoto Miyamoto, Susan B. Liu, Zhen-Wei Peng,
Shuhei Yoshida, Konstantin Khrapko, Henry Koziel, Yury Popov
1097: Characterization Of A Diet-Induced Mouse
Model Of Nonalcoholic Fatty Liver Disease With
Reproducible Progression To Advanced Fibrosis And
Hepatocellular Carcinoma
Amon Asgharpour, Tommy Pacana, Robert Vincent, Sophie C.
Cazanave, Faridoddin Mirshahi, Mulugeta Seneshaw, Kalyani
Daita, Puneet Puri, Arun J. Sanyal
Poster Viewing: 8:00 AM – 5:30 PM
141A
1098: Targeting of Kupffer cells with anti-CD163
antibody-dexamethasone-conjugate strongly reduces
liver inflammation in rats with fructose-induced non-
alcoholic steatohepatitis (NASH)
Pia Svendsen, Jonas H. Graversen, Henning Gronbaek, Holger J.
Møller, Hendrik V. Vilstrup, Søren K. Moestrup
1099: Regulation of the microRNA-clock gene
network by melatonin during alcoholic liver injury
Ying Wan, Yuyan Han, Kelly McDaniel, Heather L. Francis, Haibo
Bai, Julie Venter, Nan Wu, Morgan Quezada, Shannon S. Glaser,
Gianfranco Alpini, Fanyin Meng
1100: Impaired metabolic compensation in adipose
tissues and functional alignment by complemented stem
cells in mice with progressive nonalcoholic fatty liver
disease
Taichiro Nishikawa, Kohichiroh Yasui, Hisakazu Nakajima,
Satoru Sugimoto, Ikuyo Itoh, Kazuki Koudou, Tomoki Nakajima,
Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sumida, Hironori
Mitsuyoshi, Masahito Minami, Yoshito Itoh
1101: TRAIL Receptor Signaling Promotes Hepatocyte
Apoptosis and Liver Inflammation in a Mouse Model of
Steatohepatitis
Leila Idrissova, Harmeet Malhi, Nathan W. Werneburg, Nathan
K. LeBrasseur, Steven F. Bronk, Christian Dominik Fingas, Tamar
Tchkonia, Tamar Pirtskhalava, Christian Liedtke, Christian
Trautwein, Niklas Finnberg, Wafik S. El-Deiry, James L. Kirkland,
Gregory J. Gores
1102: Liver-specific deletion of augmenter of liver
regeneration (ALR) induces accelerated steatohepatitis in
mice
Chandrashekhar R. Gandhi, J. Richard Chaillet, Michael A.
Nalesnik, Sudhir Kumar, Anil Dangi, Robert Ferrell, Tong Wu,
Senad Devanovic, Donna B. Stolz, Jiang Wang, Thomas Starzl
1103: Effects of liver-specific loss of lipin 1-mediated
phosphatidate phosphohydrolase activity
NOVEMBER 9
Nisreen Soufi, George G. Schweitzer, Zhouji Chen, Connie Gan,
SUNDAY
Kyle McCommis, Brian Finck
1104: Free-fatty acids activate cytokine expression in
cholangiocytes
Mary A. Smith, Sathish Kumar Natarajan, Justin L. Mott
1105: miR-451 inhibits Palmitic acid-induced
proinflammatory cytokine IL-8 expression through
AMPK/AKT pathway in non-alcoholic steatohepatitis
Wonhee Hur, Jung-Hee Kim, Joon Ho Lee, Sung Woo Hong,
Seung Kew Yoon
1106: HCV infection increases JNK phosphorylation
and accentuates hepatocyte lipoapoptosis
Hiroko Takaki, Yuko Akazawa, Hisamitsu Miyaaki, Satoshi
Miuma, Naota Taura, Hidetaka Shibata, Takuya Honda, Tsutomu
Kanda, Yoko Kido, Kazuhiko Nakao
Presenters in Attendance 12:30 – 2:00 PM
 142A POSTER SESSIONS
Poster Sessions
1107: eNOS dysfunction in Steatosis/Steatohepatitis
Mario Masarone, Albino Carrizzo, Alessandro Federico, Valerio
Rosato, Carmine Vecchione, Marcello Persico
1108: Bcl-3 modulates hepatic glucose and lipid
metabolism through insulin-signaling in a murine model
of non-alcoholic fatty liver disease (NAFLD)
Nadine Gehrke, Amrit Mann, Yvonne Alt, Arno Schad, Ari
Waisman, Peter R. Galle, Marcus A. Woerns, Jörn M. Schattenberg
1109: Involvement of CXCL1-S100A8 loop via
CXCR2 in the development of nonalcoholic fatty liver
disease
Kaori Mukai, Takuya Miyagi, Yoshinobu Yokoyama, Teppei
Yoshioka, Kumiko Nishio, Akira Nishio, Yoshiki Onishi, Satoshi
Aono, Yoshinobu Saito, Satoshi Tanaka, Hayato Hikita, Ryotaro
Sakamori, Naoki Hiramatsu, Harumasa Yoshihara, Yasuharu Imai,
Tomohide Tatsumi, Tetsuo Takehara
1110: Increased expression of Rubicon by high fat
diet suppresses autophagic flux and induces apoptosis
by increasing endoplasmic reticulum stress in mice: a
possible mechanism for pathogenesis of NASH
Satoshi Tanaka, Hayato Hikita, Yasutoshi Nozaki, Yugo Kai,
Tasuku Nakabori, Yoshinobu Saito, Ryotaro Sakamori, Takuya
Miyagi, Naoki Hiramatsu, Tomohide Tatsumi, Tetsuo Takehara
1111: Treatment with the FXR-TGR5 dual agonist INT-
767 decreases NAFLD-NASH in mice fed a Western diet
Xiaoxin Wang, Yuhuan Luo, Cherelle Parker, Rachel McMahan,
Hugo R. Rosen, David J. Orlicky, Luciano Adorini, Moshe Levi
1112: Aging Promotes Chronic Plus Binge Ethanol
Feeding-Induced Liver Injury by Inhibiting Sirt1-
Autophagy
Teresa Ramirez, Yongmei Li, Dechun Feng, Huan Xu, Bin Gao
1113: Generation of a TALEN-mediated stem cell model
to study non-alcoholic fatty liver disease associated with
a PNPLA3 polymorphism
NOVEMBER 9
Nidhi Goyal, Maria P. Ordonez, Lawrence S. Goldstein
SUNDAY
1114: NAFLD progression to NASH is associated with
cumulative danger signals, M1 macrophage phenotype
and increased microRNA-155 expression that
contributes to fibrosis in a high fat/cholesterol/sugar
diet feeding in mice
Michal Ganz, Timea Csak, Shashi Bala, Banishree Saha, Gyongyi
Szabo
1115: Thioesterase Superfamily Member 1 (Them1)
Suppresses Thermogenesis and Contributes to Diet-
Induced Obesity and Non-Alcoholic Fatty Liver Disease
(NAFLD)
Kosuke Okada, Katherine B. Leclair, Yongzhao Zhang, Susan J.
Hagen, David E. Cohen
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1116: Notch1 reprograms mitochondria metabolism
for hepatic macrophage M1 activation in ASH through
upregulation of pyruvate dehydrogenase (PDH) activity
and mtDNA transcription
Jun Xu, Feng Chi, Vasu Punj, WN Paul Lee, Samuel W. French,
Hidekazu Tsukamoto
1117: The association between dietary cholesterol,
hepatic cholesterol crystals and experimental NASH
George N. Ioannou, Alan Chait, Savitha Subramanian, W. G.
Haigh, Matthew M. Yeh, Christopher Savard
1118: Reduced Lipoapoptosis, Hedgehog Pathway
Activation, and Fibrosis in Caspase-2 deficient Mice
with Nonalcoholic Steatohepatitis
Mariana V. Machado, Gregory A. Michelotti, Thiago A. Pereira,
Leandi Kruger, Marzena Swiderska-Syn, Gamze Karaca,
Guanhua Xie, Cynthia D. Guy, Kelly Lindblom, Erika Johnson,
Sally Kornbluth, Anna Mae Diehl
1119: The Pivotal Role Played by Lipocalin-2 in
Experimental Alcohol-Induced Fatty Liver Injury in Mice
Alvin Jogasuria, Bin Gao, Min You
1120: Whole Exome Sequencing of Extreme Phenotypes
of NAFLD Identifies Potential Genetic Risk Factors for
Advanced Hepatic Fibrosis
Thomas J. Urban, Cynthia A. Moylan, Matthew Rein, Manal F.
Abdelmalek, David B. Goldstein, Anna Mae Diehl
1121: Fibroblast Growth Factor 21 Deficiency
Exacerbates Chronic Alcohol-Induced Hepatic Steatosis
and Injury in Mice
Cuiqing Zhao, Liming Liu, Fengyuan Li, Craig J. McClain, Wenke
Feng
1122: Diet-induced nonalcoholic fatty liver disease is
associated with sarcopenia and decreased serum insulin
growth factor-1
Alex Ruiz, Daniel Cabrera, Pablo Quintero, Margarita Pizarro,
Nancy Solis, Javiera Torres, Claudio Cabello-Verrugio, Enrique
Brandan, Francisco Barrera, Marco Arrese
1123: The protective role of CAR and PXR in Aroclor
1260-induced Steatohepatitis
Banrida Wahlang, Keith C. Falkner, Ming Song, Heather B. Clair,
Russell A. Prough, Matthew C. Cave
1124: Mechanism analysis of microRNA-27b causing
the fatty liver formation and insulin resistance at the
same onset
Takaomi Kessoku, Yasushi Honda, Yuji Ogawa, Wataru Tomeno,
Kento Imajo, Hironori Mawatari, Satoru Saito, Koichiro Wada,
Yuichiro Eguchi, Atsushi Nakajima
1125: Sevelamer improves hepatic steatosis and
modulates inflammation in a Western Diet mouse model
of non-alcoholic fatty liver disease (NAFLD)
Brett McGettigan, Rachel McMahan, Cara Porsche, David J.
Orlicky, Xiaoxin Wang, Yuhuan Luo, Moshe Levi, Hugo R. Rosen
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1126: L-carnitine improves high-fat diet-induced
steatohepatitis through insulin sensitization and
regulation of lipid metabolism
Kazuyoshi Kon, Kenichi Ikejima, Hiromi Kusama, Maki Morinaga,
Kumiko Arai, Akira Uchiyama, Tomonori Aoyama, Shunhei
Yamashina, Sumio Watanabe
1127: TIGAR is a ‘Mitochondrial-Preload’ Regulator that
Modulates Insulin Signaling and Fatty Acid Metabolism
in the Liver
Zoltan Derdak, Asa Ohsaki, Zohra Kalani, Ragheb Harb, Jack R.
Wands
1128: Human subcutaneous and visceral fat
inflammatory gene signatures accurately predict
histological severity of non-alcoholic fatty liver disease
Johannie du Plessis, Jos van Pelt, Hannelie Korf, Chantal Mathieu,
Matthias A. Lannoo, Gary K. Fetter, Simon Nayler, Tessa van der
Merwe, Luc van Gaal, Sven M. Francque, Frederik Nevens, Schalk
Van Der Merwe
1129: Osteopontin mediates fibrogenic effects of leptin
and enhances NASH progression
Jason D. Coombes, Steve S. Choi, Paul P. Manka, Marco A.
Briones-Orta, Marzena Swiderska-Syn, Naoto Kitamura, Rasha
Younis, Shanna Bitencourt, Laurent Dollé, Roger Williams, Leo A.
van Grunsven, Anna Mae Diehl, Ali Canbay, Wing-Kin Syn
1130: Suppression of Liver Monoacylglycerol
Acyltransferase 1 Reduces Triacylglycerol Content, but
not Inflammation and Injury in Livers of Mice with Non
Alcoholic Steatohepatitis
Nisreen Soufi, Angela Hall, Sara Collier, James Mathews,
Elizabeth M. Brunt, Carolyn J. Albert, Mark Graham, David A.
Ford, Brian Finck
1131: COX 7a2 Inhibition in Mitochondrial Complex
IV Induces Hepatic Oxidative Stress and Iron Metabolic
Disorder in C57BL/6N Mouse
Masaaki Korenaga, Mihoko Tsuji, Miyuki Kondo, Erina Kumagai,
Misuzu Ueyama, Keiko Korenaga, Kazumoto Murata, Tatsuya
Kanto, Naohiko Masaki, Masashi Mizokami
1132: Down regulation of CD98 receptors via siRNA
loaded nanoparticles attenuate NAFLD signs in mice
liver
Jenniffer L. Stetler, Brandon S. Canup, Qiang Ma, Russell P. Pucket,
Hamed Laroui
1133: Hepatocyte-specific deletion of UBXD8 induces
periportal steatosis after high-fat diet feeding
Norihiro Imai, Michitaka Suzuki, Yoji Ishizu, Teiji Kuzuya, Takashi
Honda, Kazuhiko Hayashi, Masatoshi Ishigami, Toyoshi Fujimoto,
Hidemi Goto
1134: Hepatic Xbp1 deficiency exacerbates high fat/
high fructose diet-induced injury in the murine liver
Xiaoying Liu, Anne S. Henkel, Brian E. LeCuyer, Richard Green
Poster Viewing: 8:00 AM – 5:30 PM
143A
1135: Long-term histological and biochemical
analyses of a mouse model of NASH using low-density
lipoprotein receptor knockout mice with choline-
deficient diet
Yuichiro Amano, Fumi Shimizu, Ayako Harada, Masami Suzuki,
Shuntarou Tsuchiya, Osamu Isono, Mari Asada, Mayumi Imai,
Shigemitsu Imai, Hiroshi Nagabukuro, Ryuichi Tozawa
1136: Resveratrol improve the pathogengesis of
nonalchoholic steatohepatitis with serum CD14 of high
value
Takaomi Kessoku, Yasushi Honda, Yuji Ogawa, Wataru Tomeno,
Kento Imajo, Hironori Mawatari, Satoru Saito, Atsushi Nakajima
1137: Association of IL-33/sST2 Axis with Non
Alcoholic Steatohepatitis (NASH) Severity
Gihan Naguib, Jason L. Eccleston, Koji Fujita, Niharika Samala,
Mary Walter, Yaron Rotman
1138: Pirfenidone improves NASH features induced by
high fat/carbohydrate diet in mice
Jose Macias-Barragan, Jose Vera-Cruz, Jesus Garcia-Banuelos,
David A. Lopez-de la Mora, Cibeles Sanchez-Roque, Krista
Rombouts, Fabio Marra, Massimo Pinzani, Juan Armendáriz-
Borunda
1139: Genetic characterization of variants and genes
at hepatic steatosis genome wide association study
associated loci
Yue Chen, Andrew W. Tai, Elizabeth K. Speliotes
1140: A Diet-Induced Mouse Model With Development
Of Severe Nash
Yong Ook Kim, Rambabu Surabattula, Kyoung-Sook Park, Shih-
yen Weng, Detlef Schuppan
1141: Beneficial effects of mineralocorticoid receptor
blockade in experimental non-alcoholic steatohepatitis
Margarita Pizarro, Nancy Solis, Pablo Quintero, Juan C. Roa,
Rene Baudrand, Carlos B. Fardella, Arnoldo Riquelme, Marco
Arrese
NOVEMBER 9
SUNDAY
1142: Plasma Amino Acid Metabolome In Human
Nonalcoholic Fatty Liver Disease Demonstrates Highly
Enriched Lysine Degradation Pathway With High
Arginine And Proline Pathway Impact
Puneet Puri, Andrew R. Joyce, Velimir A. Luketic, Mohammad
S. Siddiqui, Sherry L. Boyett, Jolene Schlosser, Carol Sargeant,
Kalyani Daita, Hae-Ki Min, Faridoddin Mirshahi, Arun J. Sanyal
1143: Effects of the Selective Estrogen Receptor
Modulator, Raloxifene, on Nonalcoholic Steatohepatitis
in Ovariectomized Mice
Fangqiong Luo, Masatoshi Ishigami, Yoji Ishizu, Teiji Kuzuya,
Takashi Honda, Kazuhiko Hayashi, Hidemi Goto
Presenters in Attendance 12:30 – 2:00 PM
 144A POSTER SESSIONS
Poster Sessions
1144: Oral Administration of Tributyrin Attenuates
Chronic Ethanol-Induced Hepatic Steatosis, Inflammation
and Injury
Hridgandh Donde, Jingwen Zhang, Smita Ghare, Leila Gobejishvili,
Swati Joshi-Barve, Vatsalya Vatsalya, Craig J. McClain, Shirish
Barve
1145: Metformin decreases lipid droplets accumulation
and inhibits intracellular inflammation by targeting a
new EZH2-phosphoSTAT3-miRNAs pathway in an in
vitro model of vescicular steatosis
Natalia Pediconi, Silvia Di Cocco, Debora Salerno, Laura Belloni,
Silvia Piconese, Vincenzo Barnaba, Massimo Levrero
1146: CD36 regulates hepatic lipid metabolism and the
development hepatic steatosis in mice
Camella Wilson, Jennifer L. Tran, Derek Erion, Maria Febbraio,
Ethan J. Weiss
1147: Hepatic steatosis impairs acidification of
autolysosomes via suppression of vacuolar ATPase
subunit in lysosomes
Eisuke Nakadera, Shunhei Yamashina, Yoshihiro Inami, Kousuke
Izumi, Tomonori Aoyama, Akira Uchiyama, Kazuyoshi Kon,
Kenichi Ikejima, Sumio Watanabe
1148: TLR7 signaling negatively regulates the
development of alcoholic steatohepatitis
Hiroshi Matsushita, Yoon Seok Roh, Bi Zhang, Shuang Liang,
Ekihiro Seki
1149: High-energy diets containing starch:oleate as
model carbohydrates:fats cause more hepatic steatosis
and liver pathology in mice than other macronutrient
combinations
Caroline C. Duwaerts, Andrew Pierce, Scott M. Turner, Carine
Beysen, Mark D. Fitch, James P. Grenert, Jacquelyn J. Maher
1150: Suppressive effects of group IVA phospholipase
A2-deficiency on the liver injury and hepatic fibrosis
induced by oxidative stress in mice
NOVEMBER 9
Shiho Kanai, Keiichi Ishihara, Satoshi Akiba
SUNDAY
1151: Pathological feature, oxidative DNA damage and
epigenetic alteration of tumor suppressor genes in non-
alcoholic fatty liver disease
Naoshi Nishida, Norihisa Yada, Hirokazu Chishina, Tadaaki
Arizumi, Masahiro Takita, Satoshi Kitai, Tatsuo Inoue, Satoru
Hagiwara, Yasunori Minami, Kazuomi Ueshima, Toshiharu
Sakurai, Masatoshi Kudo
1152: Prospective Assessment of the Abundance of
Drug Metabolizing Enzymes in the P450 Pathway in
Patients with Non Alcoholic Fatty Liver Disease (NAFLD)
Bashar Aqel, Paul Langlais, Hugo E. Vargas, Elizabeth J. Carey,
Michael Leonard, Lawrence J. Mandarino
1153: Hedgehog pathway regulates hepatic
inflammation in mice with nonalcoholic steatohepatitis
Hyunjoo Kwon, Kyoungsub Song, Chang Han, Tong Wu
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1154: In vitro treatment of HepG2 cells with saturated
fatty acids reproduces mitochondrial dysfunction found
in non-alcoholic steatohepatitis
José A. Solís-Herruzo, Pablo Solís-Muñoz, Daniel Fernández-
Moreira, Teresa Muñoz-Yagüe, Inmaculada García-Ruiz
1155: GFT505 reverses NASH pathology, obesity and
insulin resistance in the foz/foz model
Isabelle A. Leclercq, Vanessa Legry, Benoit Noel, Rémy Hanf,
Dean W. Hum, Robert Walczak
1156: Oral supplementation of BCAA alleviates hepatic
steatosis and liver injury associated with NASH
Takashi Honda, Masatoshi Ishigami, Fangqiong Luo, Yoji Ishizu,
Teiji Kuzuya, Kazuhiko Hayashi, Yoshiharu Shimomura, Hidemi
Goto
1157: L-carnitine prevents progression of non-alcoholic
steatohepatitis in a mouse model with upregulation of
mitochondrial pathway
Hisashi Ishikawa, Akinobu Takaki, Kazuhide Yamamoto
1158: Deletion of both p62 and Nrf2 spontaneously
leads to development of steatohepatitis in mice
Kentaro Akiyama, Eiji Warabi, Kosuke Okada, Miho Ikeuchi,
Tetsuya Ueda, Katsumi Kose, Junichi Shoda
1159: Effect of G-CSF on non- alcoholic fatty liver
disease model
Ho Hyun Nam, Dae Won Jun, Waqar K. Saeed, Sunmin Kim, Tae
Yeob Kim, Joo Hyun Sohn, Min Young Kim, Eun Kyung Kim
1160: M1 Polarization bias and subsequent NASH
progression is attenuated by nitric oxide donor DETA
NONOate via inhibition of CYP2E1 induced oxidative
stress
Ratanesh K. Seth, Suvarthi Das, Sahar Pourhoseini, Diptadip
Dattaroy, Stephen Igwe, Julie Basu Ray, Gregory A. Michelotti,
Anna Mae Diehl, Saurabh Chatterjee
1161: Blood ethanol levels in children and mice with
NAFLD: Connection of insulin resistance and ethanol
elimination
Anna Janina Engstler, Marion Duerr, Eva Weiss, Vanessa T. Rist,
Ina B. Maier, Chengjun Jin, Cathrin Sellmann, Ina Bergheim
1162: Genome-wide analysis reveals predisposing
nonalcoholic fatty liver disease related DNA methylation
loci in peripheral white cells
Ruinan Zhang, Qin Pan, Feng Shen, Guangyu Chen, Chanyan
Zhu, Jiafa Lu, Jiayu Wu, Yiming Chen, Jian-Gao Fan
1163: Expression of Cell Death-Inducing DFF45-Like
Effector (CIDE) Family of Proteins in Patients with
Obesity Associated Non-Alcoholic Fatty Liver Disease
(NAFLD)
Rohini Mehta, Katherine Doyle, Thomas Jeffers, Drew Venuto,
Aybike Birerdinc, Zobair Younossi
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1164: Functional Genomic Screen Identifies Novel
Mediators of Hepatocyte Lipotoxicity
Steven Bronk, Ying Peng, James A. Blau, Matthew J. Hangauer,
Michael McManus, Gregory J. Gores, Yi Guo
1165: Hepatocyte specific keap-1 deletion selectively
reduces triglyceride accumulation but not inflammation
in a diet-induced model of nonalcoholic steatohepatitis
Pierluigi Ramadori, Hannah K. Drescher, Fabienne Schumacher,
Stephanie Erschfeld, Athanassios Fragoulis, Christoph Wruck,
Christian Trautwein, Daniela C. Kroy, Konrad L. Streetz
1166: Establishment of repeated liver biopsy technique
in experimental mice
Koichi Tsuneyama, Takahiko Nakajima, Hayato Baba, Takeshi
Nishida, Shinichi Hayashi, Shigeharu Miwa, Johji Imura
1167: Does Citrulline prevent high fat high fructose-
induced non-alcoholic fatty liver disease?
Prasanthi Jegatheesan, Stéphanie Beutheu, Kim Freese, Gabrielle
Ventura, Wassila Ouelaa, Perrine Marquet-de-Rougé, Jean-Pascal
De Bandt
1168: Long-term plus multiple binge ethanol feeding
induces steatohepatitis and fibrosis in aged mice
Hua Wang, Ming-Jiang Xu, Adeline Bertola, Bin Gao
Transport, Bilirubin, Cholesterol, Lipids
and Bile Salts
1169: IL-1β generated by LPS-activated CCR2-
positive Hepatic Macrophages regulates expression of
Hepatocellular Sterol and Bile Transport Systems
Padade Vue, Karim C. El Kasmi, Aimee Anderson, Michael W.
Devereaux, Natarajan Balasubramaniyan, Frederick J. Suchy,
Ronald J. Sokol
1170: Short-term sleep deprivation and Western diet
alters the circadian rhythms of CYP7A1 and hepatic
clock genes, and lipid metabolism
Jessica M. Ferrell, Shannon M. Boehme, John Chiang
1171: Enterohepatic biomarkers of microbial
pathogenesis in Clostridium difficile infection
Mary Elizabeth M. Tessier, Petri T. Urvil, Cana Ross, Toni-Ann
Mistretta, Shaji K. Chacko, Michael Francis, Joseph Sorg, Alex G.
Peniche, Sara M. Dann, Kevin W. Garey, Tor Savidge
Poster Viewing: 8:00 AM – 5:30 PM
145A
1172: Hepatoprotective Effects of Farnesoid X Receptor
in a Mouse Chronic Alcohol Feeding Model
Bo Kong, Le Zhan, Jianliang Shen, Tanya Forostyan, Li Wang,
Wen-Xing Ding, Grace L. Guo
1173: Long non-coding (Lnc) RNA H19 is a critical
modulator of bile acid homeostasis
Yuxia Zhang, Hiroyuki Tsuchiya, Olivier Barbier, Rana Smalling,
James Cox, Don Delker, Curt H. Hagedorn, Li Wang
1174: FGF19 Exchange Across the Gut and Liver in
Humans
Kiran V. Koelfat, Frank Schaap, Johanne G. Bloemen, Peter L.
Jansen, Cornelis H. Dejong, Steven Olde Damink
1175: TUDC-dependent translocation of MRP2 to
the plasma membrane or retrieval from the plasma
membrane is determined by MKK3 status
Christopher M. Schonhoff, Se Won Park, Cynthia R. Webster,
Mohammed S. Anwer
1176: Defining the Effect of a Human Gut Microbiota on
Bile Acid Metabolism and FXR Signaling in Gnotobiotic
Mice
Annika Wahlström, Hanns-Ulrich Marschall, Petia Kovatcheva-
Datchary, Maria Johansson, Marcus Ståhlman, Fredrik Bäckhed
1177: Bile acids modulate pancreatic islet α cells to
promote glucose homeostasis
Divya P. Kumar, Sunila Mahavadi, Faridoddin Mirshahi, John R.
Grider, Karnam S. Murthy, Arun J. Sanyal
1178: Hepatic Xbp1 regulates bile acid homeostasis
and bile salt injury
Xiaoying Liu, Anne S. Henkel, Brian E. LeCuyer, Eric Zhang,
Richard Green
1179: 3-Dimensional Culturing of Hepatocytes Increases
Fluorescent Bile Acid Accumulation and Sensitivity to
Drug Induced Cell Death
John W. Murray, Allan W. Wolkoff
NOVEMBER 9
SUNDAY
1180: Cyclic AMP reverses taurolithocholate-induced
internalization of MRP2 in part by inhibiting TLC/PKCε/
MARCKS phosphorylation pathway
Se Won Park, Christopher M. Schonhoff, Cynthia R. Webster,
Mohammed S. Anwer
1181: Regulation of Multidrug and Toxin Extrusion
Pump-1 (MATE-1) in Cholestasis
Priscilla C. Encarnacao, Carol J. Soroka, James L. Boyer, Meena
Ananthanarayanan
Presenters in Attendance 12:30 – 2:00 PM
 146A POSTER SESSIONS
Poster Sessions
Poster Session 3
Monday, November 10
POSTER VIEWING: 8:00 AM - 5:30 PM
Hall C
Presenters in attendance:
12:30 - 2:00 PM
Those posters identified as AASLD Presidential Poster of Distinction
by a ribbon icon have received review scores that place them
within the top 10 percent of all posters. We encourage you to
make them a priority as you visit the poster sessions.
Alcohol: Clinical and Basic Mechanisms
1182: Apolipoprotein (apo)AV deficiency
exacerbates alcoholic liver injury, leading to a gradual
progression from simple steatosis to steatohepatitis, and
then to liver fibrosis in ethanol-fed mice
David Q. Wang, Ornella de Bari, Bin Gao, Helen H. Wang,
Piero Portincasa, Linda S. Zhang, David A. Ford, Brent A.
Neuschwander-Tetri, Patrick Tso
1183: Deletion of GSTA4 increases mitochondrial
oxidative stress contributing to increased hepatocellular
damage during chronic ethanol consumption
Colin T. Shearn, Kelly E. Mercer, Kristofer S. Fritz, James J.
Galligan, Bridgette Engi, David J. Orlicky, Piotr Zimniak, Martin J.
Ronis, Dennis R. Petersen
1184: Toll-Like Receptor 2 and 9 mediates alcoholic
steatohepatitis via CXCL1 production and neutrophil
recruitment
Yoon Seok Roh, Bi Zhang, Shuang Liang, Hiroshi Matsushita,
Ekihiro Seki
1185: FOXO3-dependent macrophage apoptosis
protects the liver from alcoholic injury
Zhuan Li, Jie Zhao, Sudhakiranmayi Kuravi, Josiah Cox, James
Helzberg, Irina Tikhanovich, Steven A. Weinman
1186: Progression of hepatic steatosis (HS) to
steatohepatitis (SH) stage in alcoholic liver disease (ALD)
in mice is largely dependent on Large-conductance
calcium-activated potassium (MaxiK) channels
Tracie C. Lo, Keisaku Sato, Angela Dolganiuc
NOVEMBER 10
1187: Sterile and Infection-Associated SIRS Predict
MONDAY
Multiple Organ Dysfunction in Alcoholic Hepatitis:
Diagnostic Value of Procalcitonin
Javier Michelena, Jose Altamirano, Juan G. Abraldes, Silvia Affò,
Oriol Morales-Ibanez, Pau Sancho-Bru, Marlene Dominguez,
Vicente Arroyo, Pere Gines, Juan Caballeria, Ramon Bataller
1188: Cannabinoïd CB2 receptor protects from
alcoholic liver disease via an autophagy-dependent
pathway in Kupffer cells
Timothé Denaës, Jasper Lodder, Marie-Noële Chobert, Jean-Michel
Pawlotsky, Sophie Lotersztajn, Fatima Teixeira-Clerc
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1189: Farnesoid X Receptor (FXR) Regulates FoxO3
Activation in Ethanol-Induced Autophagy and Liver
Injury
Sharon Manley, Hong-Min Ni, Jessica A. Williams, Grace L. Guo,
Wen-Xing Ding
1190: Dysbiosis-induced intestinal inflammation
activates TNFR-1 and mediates alcoholic liver disease in
mice
Peng Chen, Peter Starkel, Jerrold R. Turner, Samuel B. Ho, Bernd
Schnabl
1191: Pharmacological activation of aldehyde
dehydrogenase 2 reverses alcohol-induced hepatic
steatosis and cell death in mice
Wei Zhong, Wenliang Zhang, Qiong Li, Guoxiang Xie, Qian Sun,
Xiuhua Sun, Xiaobing Tan, Xinguo Sun, Zhanxiang Zhou
1192: Lipid-derived aldehyde, acrolein, is a critical
mediator of alcohol-induced gut-liver injury in alcoholic
liver disease
Wei-Yang Chen, Jingwen Zhang, Shirish Barve, Craig J. McClain,
Swati Joshi-Barve
1193: Functional role of cellular senescence in alcoholic
liver injury
Kelly McDaniel, Yuyan Han, Heather L. Francis, Haibo Bai, Julie
Venter, Nan Wu, Morgan Quezada, Ying Wan, Shannon S.
Glaser, Gianfranco Alpini, Fanyin Meng
1194: Alcohol stimulates release of hepatocyte derived
extracellular vesicles leading to macrophage activation
Vikas K. Verma, Patrick S. Kamath, Patricia C. Contreras, Gregory
J. Gores, Vijay Shah
1195: Monocyte Oxidative Burst defect is associated
with susceptibility to Infection in Alcoholic Hepatitis and
is restored by N-Acetylcysteine
Nikhil Vergis, Wafa Khamri, Jennifer M. Ryan, Debbie Shawcross,
Yun Ma, Charalambos G. Antoniades, Mark R. Thursz
1196: Ductular bilirubinostasis predicts the evolution to
acute-on-chronic liver failure in patients suspected with
severe alcoholic steatohepatitis
Len D. Verbeke, Tania Roskams, Chris Verslype, David Cassiman,
Schalk Van Der Merwe, Werner Van Steenbergen, Geert Maleux,
Alexander Wilmer, Wim Laleman, Frederik Nevens
1197: Serum metabolomic profiling in acute alcoholic
hepatitis identifies multiple dysregulated pathways
Vikrant Rachakonda, Charles Gabbert, Amit Raina, Shahid M.
Malik, Lauren N. Bell, Sara J. Cooper, Jaideep Behari
1198: Phosphodiesterase 4 (PDE4) plays a significant
role in alcohol induced dysregulation of lipid
metabolism and development of hepatic steatosis
Diana Avila, Jingwen Zhang, Craig J. McClain, Shirish Barve,
Leila Gobejishvili
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1199: Hepatic Gap Junction Inhibition Protects Against
Liver Injury and Inflammation in a Murine Model of
Alcoholic Steatohepatitis
Jay Luther, Kevin R. King, John Garber, Ricard Masia, Daniel L.
Motola, Martin L. Yarmush, Raymond T. Chung, Suraj J. Patel
1200: NOX4 regulates CCR2 mRNA stability in hepatic
stellate cells in alcoholic liver injury
Yu Sasaki, Joy Jiang, Tzu-I Chao, Jijing Tian, Natalie Torok
1201: Association of Two Novel Bitter Taste Receptor
2R38 (TAS2R38) Haplotypes with Alcohol Intake among
the Population of West Mexico
Oscar O. Ramos-Lopez, Sonia Roman, Claudia Ojeda-Granados,
Maricruz Sepulveda-Villegas, Rafael Torres-Valadez, Maria Elena
Trujillo-Trujillo, Karina Gonzalez-Aldaco, Erika Martinez-Lopez,
Arturo Panduro
1202: Alcoholic Cirrhosis is Associated with Neuro-
Inflammation and Impaired White Matter Integrity
despite Controlling for MELD score and Hepatic
Encephalopathy
Vishwadeep Ahluwalia, James Wade, Douglas M. Heuman,
Richard K. Sterling, Scott Matherly, Mohammad S. Siddiqui,
Velimir A. Luketic, R. Todd Stravitz, Arun J. Sanyal, Puneet Puri,
Melanie White, Nicole Noble, James Hovermale, Edith A. Gavis,
Jasmohan S. Bajaj
1203: Carriage of the Ile148Met Mutation in PNPLA3
has a Detrimental Effect on Survival In Patients with
Alcohol-Related Cirrhosis
Michael J. Way, Harriet M. Gordon, Jonathan C. Marshall,
Andrew McQuillin, Marsha Y. Morgan
1204: Unfolded Protein Response (UPR) and calcium-
dependent endoplasmic reticulum stress modulate
development of alcohol-induced liver disease in mice
Keisaku Sato, Tracie C. Lo, Angela Dolganiuc
1205: The Worsening Profile of Acute Alcoholic
Hepatitis in the United States
Tuyet A. Nguyen, Arun J. Sanyal, Jonathan P. DeShazo
1206: Fat-specific Protein 27/CIDE-C Promotes Liver
Injury in Chronic Plus Binge Ethanol Fed-mice And
Human Alcoholic Hepatitis
Ming-Jiang Xu, Yan Cai, José T. Altamirano, Binxia Chang,
Hua Wang, Adeline Bertola, Gemma Odena, Jim Lu, Kimihiko
Matsusue, Shioko Kimura, Frank J. Gonzalez, Ramon Bataller,
Bin Gao
1207: Distinct Intestinal Microbiome Signature In Obese
Subjects With Alcoholic Versus Nonalcoholic Fatty Liver
Disease
Puneet Puri, Mohammad S. Siddiqui, Sherry L. Boyett, Carol C.
Sargeant, Jolene Schlosser, Larry D. White, Richard K. Sterling,
R. Todd Stravitz, Scott Matherly, Velimir A. Luketic, Faridoddin
Mirshahi, Kalyani Daita, Masoumeh Sikaroodi, Andrew R. Joyce,
Patrick M. Gillevet, Arun J. Sanyal
Poster Viewing: 8:00 AM – 5:30 PM
147A
1208: Interleukin-1 receptor inhibition facilitates
recovery from liver inflammation and injury and
promotes regeneration of hepatocytes in alcoholic
hepatitis in mice
Jan Petrasek, Arvin Iracheta-Vellve, Shashi Bala, Timea Csak,
Karen Kodys, Evelyn A. Kurt-Jones, Gyongyi Szabo
1209: Imaging Mass Spectrometry (IMS) Visualization
of Hepatic Lipid Profiles in Experimental Steatohepatitis
Induced by Chronic Ethanol, Tobacco Nitrosamine
(NNK), or Both Exposures In Long Evans Rats
Emine Yalcin, Kavin M. Nunez, Ming Tong, Shannon Cornett,
Suzanne M. de la Monte
1210: 9(S)-hydroxy-octadecadienoic acid (HODE)
enhances interleukin-1β production of PBMCs from
alcoholic liver cirrhosis patients by activation of TRPV1
Qifa Xie, Mohammad K. Mohammad, Matthew C. Cave, Shirish
Barve, Irina Kirpich, Craig J. McClain
1211: Transient Receptor Potential Vanilloid 1 Gene
Deficiency Ameliorates Hepatic Injury in a Mouse Model
of Chronic-Binge-Induced Alcoholic Liver Disease
Irina Kirpich, Keith C. Falkner, Juliane I. Beier, Gavin E. Arteel,
Christopher Ramsden, Ariel E. Feldstein, Craig J. McClain
1212: Hepatic Stellate Cell Selective Deletion
of Neuropilin-1 is Protective against Alcoholic
Steatohepatitis in Mice
Douglas A. Simonetto, Vikas K. Verma, Jung Hee Kwon, Usman
Yaqoob, Thiago de Assuncao, Sheng Cao, Tatiana Kisseleva,
David A. Brenner, Vijay Shah
1213: Nuclear receptor SHP is a key regulator of
circadian clock mediated hyperhomocysteinemia
induced by alcohol
Hiroyuki Tsuchiya, Yuxia Zhang, Sangmin Lee, Rana Smalling, Li
Wang
1214: Calcineurin and NFAT drive the development of
steatosis component of alcoholic liver disease (ALD) in
mice by regulating Calcium-dependent signaling
Keisaku Sato, Tracie C. Lo, Angela Dolganiuc
1215: Zinc Sulfate for Alcoholic Cirrhosis (ZAC) Clinical
Trial - Interim Analysis of Clinical Parameters, Intestinal
Permeability and Liver Fibrosis Biomarkers
Ming Song, Mohammad K. Mohammad, Keith C. Falkner, Craig J.
NOVEMBER 10
McClain, Matthew C. Cave
MONDAY
1216: Decreased dietary fat attenuates ethanol induced
oxidative stress and upregulation of antioxidant
responses
Colin T. Shearn, David J. Orlicky, Rebecca Smathers-McCullough,
Kenneth N. Maclean, Dennis R. Petersen
Presenters in Attendance 12:30 – 2:00 PM
 148A POSTER SESSIONS
Poster Sessions
1217: Predictors of mortality and comparison of
prognostic models in 220 patients with alcoholic
hepatitis: a prospective study
Venu H. Aradya, Harshad Devarbhavi, Karnam Ravikiran, Keyur
A. Sheth, T. R. Vijaykumar, Rajvir Singh, Adarsh Ck, Mallikarjun
Patil
1218: Translational Bioenergetics: A novel biomarker in
the management of patients with alcoholic liver disease
Ashwani K. Singal, Philip A. Kramer, Saranya Ravi, Toni Seay,
Balu Chacko, Degui Zhi, Victor Darley-Usmar
1219: Betaine attenuates chronic ethanol-induced
disruption of intestinal epithelial integrity
Sarah Bligh, Kusum K. Kharbanda, Paul G. Thomes
1220: Pharmacological Restoration of WNT/β-Catenin
Signaling Attenuates Alcoholic Liver Disease Progression
in a Rat Model
Chiung-Kuei Huang, Tunan Yu, Zoltan Derdak, Suzanne M. de la
Monte, Jack R. Wands, Miran Kim
1221: Does the Alcoholic Pancreatitis CLDN2 High-Risk
Locus Predispose to Liver Disease?
Alison Jazwinski, Jyothsna Talluri, Gautam Mankaney, Jessica
LaRusch, David C. Whitcomb, Jaideep Behari
1222: Kupffer cell-specific calcium signaling drives
inflammation in alcoholic liver disease (ALD) in mice
Tracie C. Lo, Keisaku Sato, Angela Dolganiuc
1223: The inflammasome in alchohoic hepatitis: its
relationship with Mallory-Denk body formation
Cindy Peng, Barbara A. French, Brittany C. Tillman, Samuel W.
French
1224: Interactions between the gut permeability, blood
endotoxemia and liver injury in alcoholic patients
during detoxification
Irina Kirpich, John Umhau, Vatsalya Vatsalya, Melanie Schwandt,
Monte Phillips, Thomas Lionetti, Keith C. Falkner, Lucy Zhang,
Catey Harwell, David George, Markus Heilig, Craig J. McClain
1225: Repeated validation of AshTest as a non-invasive
alternative to liver biopsy in patients with suspicion of
severe acute alcoholic hepatitis (AH)
Marika Rudler, Sarah Mouri, Frederic Charlotte, Philippe Cluzel,
Yen Ngo, Mona Munteanu, Dominique Thabut, Thierry Poynard
NOVEMBER 10
MONDAY
1226: Metabolomics studies in Patients with Liver
Disease Identify Novel Plasma Analytes in Alcoholic
Hepatitis
Ibrahim A. Hanouneh, Stephanie Marshall, Zhen Wang, Raed
Dweik, Nizar N. Zein, David Grove, Laura E. Nagy, Arthur J.
McCullough, Rocio Lopez, Stanley L. Hazen, J. Mark Brown
1227: Does the Alcoholic Liver Disease/ Non-alcoholic
fatty liver disease Index (ANI) predict mortality in
Alcoholic Hepatitis?
Traci Murakami, Cristian E. Dominguez, Varun Takyar, Krunal
Patel, Thomas D. Boyer, Shahid Habib
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1228: Alcoholic versus non-alcoholic fatty liver:
Indistinguishable histology but distinct differences in
function and content of proteins involved in vesicle
trafficking and receptor-mediated endocytosis
Karuna Rasineni, Daniel Penrice, Edward N. Harris, Cliff I. Stains,
Jon Beck, Benita L. McVicker, Mark A. McNiven, Carol A. Casey
1229: Potential Contributions of the Tobacco-Specific
Nicotine-Derived Nitrosamino Ketone (NNK) in the
Pathogenesis of Steatohepatitis in a Chronic-Binge Rat
Model of Alcoholic Liver Disease (ALD)
Valerie Zabala, Ming Tong, Teresa Ramirez, Emine Yalcin, Silvia
Balbo, Elizabeth Silbermann, Chetram Deochand, Stephen Hecht,
Suzanne M. de la Monte
1230: Comparative Evaluation of Prediction Models in
Severe Alcoholic Hepatitis
Gene Y. Im, Aparna Goel, Thomas D. Schiano, Scott L. Friedman
1231: Zinc Sulfate for Alcoholic Cirrhosis (ZAC) Clinical
Trial - Interim Analysis of Liver Injury/Inflammation
Biomarkers
Mohammad K. Mohammad, Ming Song, Keith C. Falkner, Craig J.
McClain, Matthew C. Cave
1232: Serum fibroblast growth factor 19 levels are
increased in subjects with alcoholic cirrhosis and
positively associated with serum total bile acid levels
Cuiqing Zhao, Mohammad K. Mohammad, Liming Liu, Keith
C. Falkner, Zhanxiang Zhou, Craig J. McClain, Wenke Feng,
Matthew C. Cave
1233: Sarcopenia as a prognostic factor in patients with
severe alcoholic hepatitis
Do Seon Song, JinMo Yang, U Im Chang, Sang Wook Choi, Se
Hyun Cho, Joon-Yeol Han
1234: Hepatic cell proliferation and outcome in
alcoholic hepatitis: histology, gene expression and
effect of stem cell therapy
Nicolas Lanthier, Laura Rubbia-Brandt, Nathalie Lin-Marq, Sophie
Clément, Jean-Louis Frossard, Nicolas Goossens, Laurent Spahr
Basic Hepatobiliary Neoplasia
1235: Genetic profiling of circulating tumor cells in
hepatocellular carcinoma
Jennifer Au, Angel E. Dago, Kelly Bethel, Peter Kuhn, Randolph L.
Schaffer
1236: A Cell surface β-Hydroxylase is a biomarker and
therapeutic target for hepatocellular carcinoma
Arihiro Aihara, Chiung-Kuei Huang, Mark Olsen, Qiushi Lin,
Waihong Chung, Qi Tang, Xiaoqun Dong, Jack R. Wands
1237: Nodular regenerative hyperplasia: expression
pattern of glutamine synthetase and a potential role for
hepatic progenitor cells
Marie-Christine Guilbert, Geneviève Soucy, Dominique Trudel,
Bich N. Nguyen
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1238: Histopathologic Features as Surrogate Markers of
Molecular Classification of Hepatocellular Carcinoma
Poh Seng Tan, Anu Venkatesh, Stephen C. Ward, Claudia Canasto-
Chibuque, Anna Koh, Venugopalan Nair, Manjeet Deshmukh,
Shigeki Nakagawa, Xiaochen Sun, Masahiro Kobayashi,
Hiromitsu Kumada, Yujin Hoshida
1239: TPU0114 suppresses Bcl-xl to induce apoptosis in
human hepatocellular carcinoma
Tomoyuki Hayashi, Taro Yamashita, Naoki Oishi, Kouki Nio,
Takehiro Hayashi, Yasumasa Hara, Yoshimoto Nomura, Mariko
Yoshida, Tomomi Hashiba, Hikari Okada, Koji Miyanouchi,
Shuichi Kaneko
1240: Differential EGFR regulation in metastatic and
primary unresectable hepatoblastoma
Sarangarajan Ranganathan, Mylarappa Ningappa, Chethan
Ashokkumar, Brandon W. Higgs, Qing Sun, Lori Schmitt, Hakon
Hakonarson, Rakesh Sindhi
1241: Discovery of Novel DNA Methylation Markers for
the Detection of Cholangiocarcinoma by Methylome-
Wide Analysis
Mohammed M. Aboelsoud, William R. Taylor, Tracy C. Yab,
Patrick H. Foote, Douglas W. Mahoney, Thomas C. Smyrk, Lewis
R. Roberts, David Ahlquist, John B. Kisiel
1242: Clinical significance of serum cytokeratin 19
fragment (CYFRA 21-1) in biliary tract cancers: a
reliable biomarker for gallbladder carcinoma and
intrahepatic cholangiocarcinoma
Li Huang, Wei Chen, Peiwen Liang, Wenjie Hu, Kunsong Zhang,
Bin Chen, Yuyan Han, Fanyin Meng, Sharon DeMorrow, Xiaoyu
Yin, Jiaming Lai, Lijian Liang
1243: CD90+ and CD133+ Cancer Stem Cells Correlate
with Transcription Factor FOXM1 and Glycolytic Enzyme
Hexokinase II (HKII) Immunolevels, and Markers for
Oxidative and Nitrosative Stress Correlate with Disease
Progression in Hepatocellular Carcinoma
Lily Mei, Katherine M. Choi, Rajender Mulpuri, Dragana Kopanja,
Hari Sreedhar, Michael J. Walsh, Ming Jin, Costica Aloman,
Charmaine Stewart, Nissim Hay, Pradip Raychaudhuri, Grace
Guzman
1244: Identification of new tissue biomarkers to predict
biologic features of hepatocellular carcinoma
Yoriko Nomura, Sachiko Ogasawara, Jun Akiba, Hironori Kusano,
Masamichi Nakayama, Osamu Nakashima, Hirohisa Yano
1245: Metabolomic Analysis by 1H-NMR Spectroscopy
of Human Tissues reveals different metabolic
biomarkers of Hepato-Cellular Carcinoma according to
the underlying liver disease
Camille Teilhet, Daniel Morvan, Juliette Joubert-Zakeyh, Pierre
J. Déchelotte, Denis Pezet, Emmanuel Buc, Bruno Pereira, Anne-
Sophie Biesse, Géraldine Lamblin, Sylvie Massoulier, Michel
Peoc’h, Jack Porcheron, Marie-Paule Vasson, Aïcha Demidem,
Armando Abergel
Poster Viewing: 8:00 AM – 5:30 PM
149A
1246: Cartilage oligomeric matrix protein (COMP): A
novel non-invasive marker for assessing liver cirrhosis
and risk of progression to hepatocellular carcinoma
Gary L. Norman, Nikolaos Gatselis, Zakera Shums, Christos
Liaskos, Dimitrios P. Bogdanos, George K. Koukoulis, George N.
Dalekos
1247: Serum levels of advanced glycation end products
and pigment epithelium derived factor in patients with
hepatocellular carcinoma derived from non-alcoholic
steatohepatitis
Hiromi Kan, Hideyuki Hyogo, Hiroshi Aikata, Tomoki Kobayashi,
Takayuki Fukuhara, Noriaki Naeshiro, Yohji Honda, Tomokazu
Kawaoka, Masataka Tsuge, Akira Hiramatsu, Michio Imamura,
Yoshiiku Kawakami, Kazuaki Chayama
1248: Adenomatous polyposis coli-binding protein EB1
as an important predictive factor for the prognosis and
recurrence in hepatocellular carcinoma
Takeshi Aiyama, Tatsuya Orimo, Hideki Yokoo, Takanori Ohata,
Kanako Hatanaka, Yutaka Hatanaka, Yoshihiro Matsuno, Kenji
Wakayama, Tatsuhiko Kakisaka, Yosuke Tsuruga, Hirofumi
Kamachi, Toshiya Kamiyama, Akinobu Taketomi
1249: The expression of arginase-1, keratin (K)
8, and K18 and clinicopathologic significance of
phosphorylation K8 in combined hepatocellular-
cholangiocarcinoma, stem cell subtypes-intermediate-
cell type
Jun Akiba, Osamu Nakashima, Hirohisa Yano
1250: Performance of biomarkers for diagnosis of
hepatocellular carcinoma –alpha fetoprotein, protein
induced by vitamin K absence, osteopontin and
Dickkopf-1
Jong Ho Lee, Eun Sun Jang, Yun Suk Choi, Philippe Leissner,
Christian Brechot, Jung Wha Chung, Jin Wook Kim, Sook-Hyang
Jeong
1251: Cancer stem cell, TGF-β gene signatures, and
epithelial-mesenchymal transition are features of late
rather than early hepatocarcinogenesis
Hyungjin Rhee, Jeong Eun Yoo, Ei Yong Ahn, Luca Di Tomaso,
Bogdan Pintea, Massimo Roncalli, Young Nyun Park
1252: Oxidative stress in leucocytes of patients with
advanced hepatocellular carcinoma
Paloma Lluch, Laia Navarro López, Gloria Segarra, Guadalupe
NOVEMBER 10
Herrera, María Mora, Joan Tosca, Miguel Angel Serra, Pascual
MONDAY
Medina
1253: Serum Dickkopf-1 as a biomarker for the
diagnosis of hepatocellular carcinoma with stem cell
features
Hajime Sunagozaka, Taro Yamashita, Naoki Oishi, Takehiro
Hayashi, Hajime Takatori, Tetsuro Shimakami, Kazuya Kitamura,
Kuniaki Arai, Takashi Kagaya, Yoshio Sakai, Tatsuya Yamashita,
Eishiro Mizukoshi, Masao Honda, Shuichi Kaneko
Presenters in Attendance 12:30 – 2:00 PM
 150A POSTER SESSIONS
Poster Sessions
1254: Fatty Acid Binding Protein 5 promotes tumor
progression through epithelial-mesenchymal transition
in hepatocellular carcinoma
Takanori Ohata, Hideki Yokoo, Toshiya Kamiyama, Kenji
Wakayama, Tatsuya Orimo, Tatsuhiko Kakisaka, Yosuke Tsuruga,
Hirofumi Kamachi, Akinobu Taketomi
1255: The Autophagy-Related Marker P62 Is Useful For
Diagnosis In Human Hepatocellular Carcinoma
Changjae Hur, Byoung Kuk Jang, Jeong Min Kim, Kyung Ho Yang,
Hye min Park, Sang Min Lee, Eun Sung Choi, Jung Min Lee, Woo
Jin Chung, Jaeseok Hwang, Yoo Na Kang, Koo Jeong Kang
1256: A gene signature derived from sorafenib resistant
liver cancer cells identifies HCC patients with poor
prognosis
Jeroen Dekervel, Dusan Popovic, Hannah van Malenstein, Petra
Windmolders, Ashenafi S. Bulle, Bart De Moor, Frederik Nevens,
Chris Verslype, Jos van Pelt
1257: Effect of metabolic syndrome on patients with
viral hepatitis treated with local regional therapy for
hepatocellular carcinoma
Fei Wen Chen, Jacob George, Amany Zekry
1258: CUX1 downregulation causes apoptosis in HIF1-
alpha expressing HCC
Carmen Rothmund, Pietro Di Fazio, Heidi Griesmann, Benjamin
Kuehnemuth, Thomas Gress, Patrick Michl, Thaddaeus T.
Wissniowski
1259: Consecutive increment of serum alpha-feto
protein level is a useful surrogate marker in predicting
hepatocellular carcinoma in liver cirrhosis patients
Heechul Nam, Hae Lim Lee, Jung Suk Oh, Young Joon Lee, Ho
Jong Chun, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon
Biliary Atresia and Cholestasis
1260: C5aR distinguishes subsets of hepatic myeloid
and lymphoid cells promoting epithelial injury in
experimental biliary atresia
Pranavkumar Shivakumar, Stephanie Walters, Janet Pfister, Rachel
M. Sheridan
1261: The association of tetra-hydroxylated bile acids
with good prognosis in infantile intrahepatic cholestasis
NOVEMBER 10
Chee-Seng Lee, Kimura Akihiko, Jia-Feng Wu, Yen-Hsuan Ni,
MONDAY
Hong-Yuan Hsu, Mei-Hwei Chang, Huey-Ling Chen
1262: Portal hypertension in children; review of
management in the era of non-invasive prediction
markers
Anastasios Grammatikopoulos, Peter Witters, Dominic A. Hughes,
Palaniswamy Karthikeyan, Somashekara H Ramakrishna, Mark
Davenport, Anil Dhawan
1263: WITHDRAWN
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
Cellular and Molecular Biology
1264: The Small GTPase Rab7 as a Central Regulator
of Hepatocellular Lipophagy
Barbara Schroeder, Ryan J. Schulze, Shaun Weller, Arthur C.
Sletten, Carol A. Casey, Mark A. McNiven
1265: Characterization of Microtubule-based Motility
of Autophagic Vesicles from Mouse Liver
Xintao Wang, Eloy Bejarano-Fernandez, John W. Murray, Ana
Maria Cuervo, Allan W. Wolkoff
1266: Ca2+-depletion impairs transcytotic vesicle
fusion with the apical membrane by altering the SNARE
docking and fusion machinery in WIF-B cells
Alfonso Lopez Coral, Pamela L. Tuma, Julia F. Omotade
1267: Dual rab17 species have distinct biochemical
properties
Anneliese C. Striz, Pamela L. Tuma
1268: Insulin resistance of CD56dim NK cells
decrease NK killing ability in NASH patients with
advanced fibrosis
Johnny Amer, Sarit Doron, Ahmad Salhab, Rifaat Safadi
1269: C-Myc is a central regulator of liver
regeneration in mice with chronic liver injury
Stephanie Klett, Kristin Hanak, Bruno Guigas, Robert Geffers,
Jessica Endig, Laura E. Buitrago, Silke Marhenke, Michael P.
Manns, Arndt Vogel
1270: TIGAR Overexpression Increases
Chemosensitivity in Sorafenib-resistant Hepatocellular
Carcinoma Cells
Zoltan Derdak, Ragheb Harb, Jack R. Wands
1271: Mitoferrofluor – A New Approach to
Determine Mitochondrial Chelatable Iron
Andaleb Kholmukhamedov, Christopher C. Lindsey, Craig C.
Beeson, John J. Lemasters
1272: Concomitant loss of beta-catenin and gamma-
catenin in liver disrupts junctional integrity leading to
cholestasis, fibrosis and mortality
Lili Zhou, Kari Nejak-Bowen, Satdarshan (Paul) S. Monga
1273: The new platelet activating receptor C-type
Lectin Receptor -2 plays an essential role in the liver
regeneration after partial hepatectomy in mice
Hiroshi Kono, Hideki Fujii
1274: Betaine Mitigates Acetaldehyde-Induced Gut
Barrier Dysfunction
Paul G. Thomes, Sandra L. Todero, Dean J. Tuma, Kusum K.
Kharbanda
1275: Hepatocytes maintain their karyotype in spite of
being polyploid
Kristin Knouse, Angelika Amon
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1276: All-in-one liver cell preparation: high quality of
functional primary human hepatocytes, liver sinusoidal
endothelial cells, Kupffer cells and hepatic stellate cells
Melanie Lutterbeck, Catherine I. Real, Kathrin Skibbe, Joerg Timm,
Andreas Paul, Guido Gerken, Joerg F. Schlaak, Ruth Broering
1277: Nuclear receptor SHP and FOXA1 are novel
modulators of homocysteine metabolism via regulating
BHMT and CTH expression
Hiroyuki Tsuchiya, Kerry-Ann da Costa, Sangmin Lee, Barbara
Renga, Yuxia Zhang, Rana Smalling, Hartmut Jaeschke, Steven H.
Zeisel, Fiorucci Stefano, Li Wang
1278: The role of NF-kB in inflammation-induced
and obstructive cholestasis
Natarajan Balasubramaniyan, Meena Ananthanarayanan,
Frederick J. Suchy
1279: Enlarged livers in a human hepatocyte
repopulated mouse model are due to aberrant bile
acid signaling: potential mechanism underlying the
“hepatostat”
Willscott E. Naugler, Markus Grompe
1280: Yap reprograms glutamine metabolism
and supports growth during liver development and
tumorigenesis
Andrew G. Cox, Katie L. Hwang, Sebastian Beltz, Kimberley
Evason, Keelin O’Connor, Kristin Brown, Evan C. Lien, Sagar
Chhangawala, Yariv Houvras, Didier Y. Stainier, Wolfram
Goessling
1281: Increased circulating TGFβ1 following liver
failure suppresses neural IGF-1 that contributes to
hepatic encephalopathy
Matthew McMillin, Cheryl Galindo, Gabriel A. Frampton, Sharon
DeMorrow
1282: Endothelial nitric oxide synthase is a key
mediator of extracellular ATP-mediated mitogenic
signaling and proliferation of hepatocytes
Yu Mei, Sundararajah Thevananther
1283: Mechanisms of PKC-mediated enhancement of
HIF-1alpha activity and its inhibition by Vitamin K2 in
Hepatocellular carcinoma cells
Jinghe Xia, Iwata Ozaki, Sachiko Matsuhashi, Jingyan Qi, Shinji
Iwane, Hirokazu Takahashi, Yuichiro Eguchi, Toshihiko Mizuta,
Keizo Anzai
1284: PKCδ facilitates cAMP-induced NTCP
translocation and negatively regulates p38 MAPK
activation in mouse hepatocytes
Se Won Park, Christopher M. Schonhoff, Cynthia R. Webster,
Mohammed S. Anwer
Poster Viewing: 8:00 AM – 5:30 PM
151A
1285: Osteopontin isoforms are upregulated in human
cholangiocarcinoma cells and modulate levels of the
TGF-β repressor, SnoN
Marco A. Briones-Orta, Jason D. Coombes, Naoto Kitamura, Paul
P. Manka, Roger Williams, Ali Canbay, Salvatore Papa, Wing-Kin
Syn
1286: Post-translational modification of ERK mediates
impaired skeletal muscle protein synthesis during
hyperammonemia of cirrhosis
Gangarao Davuluri, Michela Giusto, Sathyamangla V. Naga
Prasad, Srinivasan Dasarathy
1287: Modulation of bile acid receptor TGR5 : novel
therapy for heart failure
Moreshwar S. Desai, Zainuer Shabier, Jorge Coss-Bu, Sundararajah
Thevananther, David D. Moore, Saul J. Karpen, Daniel J. Penny
1288: Steatogenesis in adult-onset type II citrullinemia
is associated with down-regulation of PPAR alpha
Takefumi Kimura
1289: Targeting activated Wnt/β-catenin signaling by
XAV939 and its derivative WXL-8 in hepatocellular
carcinoma
Li Ma, Xiaolin Wang, Wei Wei, Mei-Sze Chua, Samuel K. So
1290: Lysophosphatidic Acid Signaling Mediates
Human Hepatoma Cell Motility
Valentina Zuckerman, Eugene Sokolov, Jacob H. Swet, David A.
Iannitti, Iain H. McKillop
1291: PNPLA3 (rs738409), LYPLA1 (rs12137855),
and NCAN (rs2228603) are associated with elevated
transaminase levels in Mexican adults
Yvonne N. Flores, Manuel Bañuelos, Manuel Quiterio, Hal F. Yee,
Zuo-Feng Zhang, Rafael Velázquez-Cruz, Jorge Salmerón
1292: Evaluation of Yes associated protein as a
therapeutic target in primary liver malignancies
Haibo Bai, Qing-feng Zhu, Gianfranco Alpini, Robert A. Anders
1293: Interactions between Hedgehog and
inflammatory signaling reproduce aspects of biliary
atresia
Zenobia Cofer, Shuang Cui, Valerie Sapp, Randolph P. Matthews
1294: Inhibition of miR-122 Mediates the
NOVEMBER 10
Pathogenesis of Alcoholic Liver Disease
MONDAY
Abhishek Satishchandran, Nicita Mehta, Arvin Iracheta-Vellve, Jia
Li, Shashi Bala, Donna Catalano, Li Zhong, Jun Xie, Guangping
Gao, Gyongyi Szabo
1295: Expression of the Myc dominant interfering
miniprotein Omomyc prevents human hepatocellular
carcinoma cell growth
Barbara Barbaro, Cristiana Porcu, Gabriele Toietta, Roberta
Maggio, Mauro Savino, Sergio Nasi, Clara Balsano
Presenters in Attendance 12:30 – 2:00 PM
 152A POSTER SESSIONS
Poster Sessions
1296: Integrative role of histone lysine demethylase
LSD2 in hepatic energy metabolism: possible epigenetic
mechanism of nonalcoholic fatty liver disease
Katsuya Nagaoka, Shinjiro Hino, Yutaka Sasaki, Mitsuyoshi
Nakao
1297: Iron-overload alters lipid metabolism and Ras
signaling independent of oxidative stress in mouse liver
tissue by whole RNA sequencing
Hiroki Tanaka, Takaaki Ohtake, Lynda Addo, Masayo Yamamoto,
Yasumichi Toki, Koji Sawada, Shunsuke Nakajima, Takumu
Hasebe, Katsuya Ikuta, Katsunori Sasaki, Yoshihiro Torimoto,
Mikihiro Fujiya, Yutaka Kohgo
1298: Suppression of Dual Specificity Phosphatase I
inhibits Hepatitis C Virus Replication
Jung Eun Choi, Jung Hyun Kwon, Seung Kew Yoon, Sang Wook
Choi
1299: Endoplasmic reticulum stress activates the hepatic
activator protein 1 complex via mitogen activated
protein kinase-dependent signaling pathways
Shantel Olivares, Richard Green, Anne S. Henkel
1300: The pivotal role of anti-angiogenic activity in the
in vivo antitumor effects of type I interferon
Hirayuki Enomoto, Tohru Tsujimura, Masao Honda, Chikage
Nakano, Kunihiro Hasegawa, Ryo Takata, Tomoko Aoki, Kenji
Hashimoto, Akio Ishii, Tomoyuki Takashima, Yoshiyuki Sakai,
Nobuhiro Aizawa, Naoto Ikeda, Yoshinori Iwata, Hironori Tanaka,
Masaki Saito, Shuichi Kaneko, Hiroko Iijima, Shuhei Nishiguchi
1301: A pivotal role of KLF5 in regulation of cancer
stem-like cells in hepatocellular carcinoma
Mitsuteru Natsuizaka, Osamu Maehara, Fumiyuki Sato, Yoshimasa
Kubota, Goki Suda, Jun Itoh, Seiji Tsunematsu, Yoko Tsukuda,
Katsumi Terashita, Masato Nakai, Takuya Sho, Koji Ogawa,
Shunsuke Ohnishi, Naoya Sakamoto
1302: Characterization of Exosomal microRNA
(miRNA) Content Following Hepatic Injury And Roles
in Cytoprotection After Uptake of Exosomes By Injured
Hepatocytes
Yogeshwar Sharma, Tatyana Tchaikovskaya, Preeti Viswanathan,
David B. Rhee, Pilib Ó Broin, Tatyana Gorbacheva, Alexander Y.
Maslov, Aaron Golden, Sanjeev Gupta
1303: Heat Shock Factor 1 (HSF1) Involvement In
NOVEMBER 10
Tumour Recurrence After Radiofrequency Ablation In An
MONDAY
Animal Model Of Secondary Liver Cancer
Francesca Zanieri, Vinicio Carloni, Sara Omenetti, Claudio
Amabile, Nevio Tosoratti, Simone Cassarino, Sriram Saravanan
Shanmuga Velandy, Mark Kester, Massimo Pinzani, Krista
Rombouts
1304: Establishment of Liver-Targeting Delivery System
Using Hepatitis E Virus-Like Particles
Jung-Hee Kim, Wonhee Hur, Eun Byul Lee, Jung Eun Choi, Seung
Kew Yoon
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1305: Efficient and Safe HCC-specific Gene Therapy
and Its Possible Role of Immunogenic Cell Death via
Adenovirus Harboring mTERT-targeting Trans-splicing
Ribozyme, Liver-specific Promoter and MicroRNA
Regulation in Immunocompetent Mouse
Jin-Sook Jeong, Sang Young Han, Seong-Wook Lee, Mi Ha Ju,
Kyung Sook Cho
1306: Suppression of HCV replication by exosome-
mediated miR-199* delivery
Guohua Lou, Yanning Liu, Zhi Chen
1307: The efficiency of portal venous port-catheter
system as a route of siRNA delivery for the liver
metastasis
Toshio Kokuryo, Yukihiro Yokoyama, Masato Nagino
Cellular Immunobiology
1308: Plasma Microparticles Modulate
Vascular Inflammation and Liver Regeneration via
Ectonucleotidase-Dependent Levels of MicroRNA 142-3P
Stephanie Kuhn, Katrin Splith, Ines Kämmerer, Cindy Hegewald,
Linda Feldbrügge, Jan Schulte am Esch, Sven Jonas, Simon C.
Robson, Moritz Schmelzle
1309: Matrix-embedded endothelial cells
rescue median lobe from ischemia and switch
M1 macrophages to M2 phenotype after partial
hepatectomy in mice
Pedro Melgar-Lesmes, Elazer R. Edelman
1310: Serum transcriptomic analysis of liver transplant
recipients with hepatitis C: mild versus severe disease
Obaid S. Shaikh, Yue Chen, Chengli Shen, Phalguni Gupta
1311: Effect of continuous hypothermic oxygenated
machine perfusion(CHOP) on liver graft from donors
after cardiac death (DCD) following liver transplantation
Ling Lu, Jianhua Rao, Haoming Zhou, Xuehao Wang
1312: A novel model for reperfusion of the human liver
following organ preservation
James H. Avruch, Bote G. Bruinsma, Pepijn D. Weeder, Gautham
V. Sridharan, Heidi Yeh, Korkut Uygun, James F. Markmann
1313: Ischemic postconditioning (IPostC) in fibrotic livers
following warm ischemia: a new strategy to protect the
liver against ischemia-reperfusion injury
Julia Schewe, Ingrid Liss, Lisa Selzner, Marie-Christine Makeschin,
Burkhard Göke, Alexander L. Gerbes, Christian J. Steib
1314: TLR4 activation, ER stress induction and
autophagy inhibition: a tripartite synergy in interleukin
23 induction during liver ischemia and reperfusion
injury
Ling Lu, Jianhua Rao, Haoming Zhou, Xuehao Wang
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1315: Progressive biliary fibrosis stimulates liver
repopulation by either stem/progenitor cells or mature
hepatocytes
Mladen Yovchev, Joseph Locker, Michael Oertel
Clinical Hepatobiliary Neoplasia
1316: Analysis of Immune Responses in Patients
Vaccinated with Alpha-Fetoprotein-Derived Peptides in
the Treatment of Hepatocellular Carcinoma
Eishiro Mizukoshi, Tatsuya Yamashita, Kuniaki Arai, Hajime
Sunagozaka, Kazumi Fushimi, Hidetoshi Nakagawa, Noriho Iida,
Masaaki Kitahara, Shuichi Kaneko
1317: Prognostic Effect of Statins on Hepatocellular
Carcinoma in Presence and Absence of Metformin
intake
Reham Abdel-Wahab, Hesham M. Hassabo, Ahmed El Antably,
Kanwal Raghav, Ahmed O. Kaseb, H. Franklin Herlong, Young
Kwang Chae, Gehan Botrus, Harrys A. Torres, Ahmed S. Shalaby,
Manal Hassan
1318: Hepatocellular Carcinoma: Hospitalizations and
financial burden in the United States
Raxitkumar Jinjuvadia, Augustine Salami, Suthat Liangpunsakul,
Reena Salgia
1319: The risk of hepatocellular carcinoma (HCC)
in patients with HCV cirrhosis is predicted by a
polymorphism of MERTK gene
Vincenza Calvaruso, Stefania Grimaudo, Rosaria Maria Pipitone,
Maria Grazia Bavetta, Giuseppe Cabibbo, Elisabetta Conte,
Fabrizio Bronte, Antonio Craxì, Vito Di Marco
1320: Liver Transplantation for HIV-Infected Patients
with Hepatocellular Carcinoma (HCC)
Heather L. Platt, Caitlin C. Citti, Beatriz Minguez, Ting-Yi Chen,
Meritxell Ventura-Cots, Maria D. Hernandez, Ziba Jalali, Maaz
B. Badshah, Michael Yin, Ayse Aytaman, Mark Nelson, Jürgen K.
Rockstroh, Matthew B. Goetz, Myron Schwartz, Douglas Dieterich,
Judith Aberg, Yujin Hoshida, Norbert Bräu
1321: The management and prognosis of patients with
hepatocellular carcinoma: What has changed during 20
years?
Sun Young Yim, Yeon Seok Seo, Chang Ho Jung, Tae Hyung Kim,
Jae Min Lee, Hyonggin An, Ji Hoon Kim, Hyung Joon Yim, Jong
Eun Yeon, Kwan Soo Byun, Soon Ho Um, Ho Sang Ryu
1322: Predicting Survival of HIV-Infected Patients with
Liver Cancer – the SHILCA Score and Staging Model
Ting-Yi Chen, Nicolás Merchante, Caitlin C. Citti, Heather L. Platt,
Maaz B. Badshah, Meritxell Ventura-Cots, Esperanza Merino,
Luciana Kikuchi, Mamta K. Jain, Francisco Rodríguez-Arrondo,
Beatriz Minguez, Michael Yin, Ayse Aytaman, Cristina Tural,
Myron Schwartz, Douglas Dieterich, Judith Aberg, Juan Pineda,
Jorge A. Marrero, Morris Sherman, Yujin Hoshida, Norbert Bräu
Poster Viewing: 8:00 AM – 5:30 PM
153A
1323: Role of Occult HBV Infection in the Development
of non-B, non-C Hepatocellular Carcinoma: Analysis
from a Large Retrospective Multicenter Cohort Study
Ryosuke Tateishi, Takeshi Okanoue, Kiwamu Okita, Kendo
Kiyosawa, Masao Omata, Hiromitsu Kumada, Norio Hayashi,
Kazuhiko Koike
1324: The Effect of HBV DNA Level on The Development
of Hepatocelluar Carcinoma in Patients with Hepatitis
B Virus-associated Liver Cirrhosis during Entecavir
Treatment: A Multicenter Study
Oh Sang Kwon, Jong Eun Yeon, Jeong Han Kim, So Young Kwon,
Sang Jun Suh, Yun Soo Kim, Ju Hyun Kim
1325: Real Life Treatment of Hepatocellular Carcinoma:
Impact of Deviation from Guidelines Recommendation
Zahraa Alkhatib, Asmaa Gomaa, Eman A. Rewisha, Imam Waked
1326: Intrahepatic cholangiocarcinoma in patients with
nonalcoholic fatty liver disease
Takayoshi Nishioka, Shogo Tanaka, Shigekazu Takemura,
Takahiro Uenishi, Hiroji Shinkawa, Takatsugu Yamamoto,
Masahiko Kinoshita, Genya Hamano, Sayaka Tanaka, Yuko
Kuwae, Masahiko Ohsawa, Kenichi Wakasa, Shoji Kubo
1327: Validation for retreatment strategy and
survival analysis after second session of transarterial
chemoembolization in patient with hepatocellular
carcinoma
Yang J. Yoo, Ji Hoon Kim, Ji Hye Je, Seong Hee Kang, Hae Rim
Kim, Sang Jun Suh, Young Kul Jung, Yeon Seok Seo, Hyung Joon
Yim, Jong Eun Yeon, Kwan Soo Byun
1328: Wnt/beta-catenin signaling activates different
target genes depending on stem/maturational status
and HNF4α expression in hepatocellular carcinoma
Taro Yamashita, Masao Honda, Shuichi Kaneko
1329: N.I.A.C.E score: a new tool to better distribute
advanced hepatocellular carcinoma (BCLC C). Results
from four French cohorts comprising 703 patients
Xavier Adhoute, Guillaume Penaranda, Jean-Frédéric Blanc, Julien
Edeline, Guillaume Conroy, Paul Castellani, Valerie Oules, Olivier
Bayle, Olivier Monnet, Bernard L. Pol, Patrick Beaurain, Herve
Perrier, Jean-Luc Raoul, Jean-Pierre Bronowicki, Marc Bourlière
1330: Specialty Care is Associated with Early Diagnosis
of Hepatitis C-related Hepatocellular Carcinoma in U.S.
NOVEMBER 10
Veterans
MONDAY
Janice H. Jou, Lauren A. Beste, Yin Yang, Michael F. Chang,
Andrew J. Muir
1331: Circulating SCCA-IgM complex is a useful
biomarker to predict the outcome of therapy in HCC
patients
Maria Guarino, Giovan Giuseppe Di Costanzo, Andrea Gallotta,
Giorgio Fassina, Raffaella Tortora, Concetta Tuccillo, Francesco
Auriemma, Nicola Caporaso, Filomena Morisco
Presenters in Attendance 12:30 – 2:00 PM
 154A POSTER SESSIONS
Poster Sessions
1332: The combined use of sorafenib and branched
chain amino acids enhances antitumor effect in the
treatment of hepatocellular carcinoma
Yoshiki Onishi, Tomohide Tatsumi, Satoshi Aono, Seiichi Tawara,
Akira Nishio, Takatoshi Nawa, Atsuo Takigawa, Hayato Hikita,
Ryotaro Sakamori, Takuya Miyagi, Naoki Hiramatsu, Tetsuo
Takehara
1333: Prospective evaluation of the performance of per
ERCP bile aspiration combined to endobiliary brushing
in the diagnosis of malignant strictures of the biliary
tract
Roth Gael, Bichard Philippe, Fior-Gozlan Michele, Auroux Jean,
Christian Letoublon, Ivan Bricault, Vincent Leroy, Thomas Decaens
1334: The outcomes of transarterial infusion of
epirubicin and cisplatin combined with systemic infusion
of 5-fluorouracil compared to TACE using doxorubicin
for unresectable hepatocellular carcinoma
Sung Won Lee, Jung Hyun Kwon, Soon woo Nam, Jeong Won
Jang, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon
1335: Comparison of Safety and Efficacy of
Chemoembolization for unresectable Hepatocellular
Carcinoma: Doxorubicin-Eluting Beads versus
conventional TACE in Patients With and Without
Transjugular Intrahepatic Portosystemic Shunt
Ali Faramarzalian, KV Narayanan Menon, Baljendra Kapoor,
Amanjit Gill, Gordon McLennan, Amit Gupta, Benjamin Tritle,
Mark J. Sands, Federico N. Aucejo, Robert J. Pelley, Bassam
Estfan, Nancy Obuchowski
1336: Percutaneous thermal ablation for hepatocellular
carcinoma: A systematic review and meta-analysis
Mohamed A. Chinnaratha, Anthony Chuang, Robert Fraser,
Richard J. Woodman, Alan J. Wigg
1337: Serum dickkopf-1, osteopontin and midkine as
novel biomarkers for the diagnosis and pre-clinical
diagnosis of hepatocellular carcinoma
Roslyn Vongsuvanh, Jacob George, Tristan J. Iseli, Simone I.
Strasser, Geoffrey W. McCaughan, David van der Poorten
1338: Surveillance for Hepatocellular Carcinoma with
Magnetic Resonance Imaging Using a Liver-Specific
Contrast Agent Gadoxetic Acid and Ultrasonography in
High-Risk Patients with Cirrhosis
Young-Suk Lim, So Yeon Kim, Jae Ho Byun, Hyung Jin Won, So
NOVEMBER 10
Jung Lee, Seungbong Han, Jihyun An, Han Chu Lee, Yung Sang
MONDAY
Lee
1339: Epithelial to mesenchymal transition affects the
stemness of primary liver cancers
Naoki Oishi, Juling Ji, Taro Yamashita, Qinghai Ye, Shuichi
Kaneko, Xin W. Wang
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1340: Comparison of acute healthcare costs and effects
of Trans-arterial chemo-embolization using conventional
technique with drug eluting beads
Farooq A. Khan, Eleftherios Floros, Guruprasad P. Aithal, Mahal
Gurpreet, Martin W. James, Zergham Zia, Stephen D. Ryder,
Richard O’Neill
1341: Gross appearance of hepatocellular carcinoma
reflects expression of cancer stem cells, epithelial-
mesenchymal transition and hypoxia related genes
Hyungjin Rhee, Deuk Chae Na, Young Nyun Park
1342: Diffusion-weighted MRI is suitable to predict
malignant potential in small hepatocellular carcinoma
Shusuke Okamura, Tatsuyuki Tonan, Shuji Sumie, Masahito
Nakano, Manabu Satani, Ryoko Kuromatsu, Takuji Torimura
1343: Yttrium-90 radioembolization for HCC in the
transplant setting: feasibility, clinical and pathological
considerations. Can we give a better chance for locally
advanced HCC?
Raffaella Lionetti, Andrea Laurenzi, Giovanni Vennarecci, Roberto
Santoro, Marzia Montalbano, Ubaldo Visco Comandini, Elisa Busi
Rizzi, Rosa Sciuto, Pierluca Piselli, Lucia Rosalba Grillo, Gianpiero
D’Offizi, Giuseppe M. Ettorre
1344: Clinical characteristics of hepatocellular
carcinoma in elderly patients: A retrospective,
multicenter study
Naota Taura, Hisamitsu Miyaaki, Kazuhiko Nakao
1345: Hepatocellular carcinoma incidence in chronic
hepatitis C patients according to sustained virologic
response (SVR) and fluctuation of Alfa feto-protein levels
during antiviral treatment
Tuul Purevsambuu, Simona Bota, Florian Hucke, Harald Hofer,
Peter Ferenci, Wolfgang Sieghart, Markus Peck-Radosavljevic
1346: A nationwide all-inclusive analysis demonstrates
a decrease in adjusted survival of incident-cases of
hepatocellular carcinoma (HCC) among HIV+ patients
Nathalie GOUTTE, Philippe Sogni, Noelle Bendersky, Bruno
Falissard, Olivier Farges
1347: First generation protease inhibitor-based triple
therapy and risk of hepatocellular carcinoma
Jonathan M. Fenkel, Gloria Francis, Doris H. Chan, Dina Halegoua-
De Marzio, David A. Sass, Steven K. Herrine, Jesse M. Civan
1348: The Optimal Method for Measuring Intrahepatic
Hepatocellular Carcinomas in Liver Transplant
Candidates Undergoing Lipiodolized Transarterial
Chemoembolization
Hyung-Don Kim, Ju Hyun Shim, Yeonjung Ha, Mi-Jung Jun, Young
Joo Yang, Seung Bum Lee, Gi Ae Kim, Jee Eun Yang, Eui Ju Park,
Jihyun An, Danbi Lee, Kang Mo Kim, Young-Suk Lim, Han Chu Lee,
Young-Hwa Chung, Yung Sang Lee, Dong Jin Suh
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1349: Increased incidence but improved survival for
biliary tract cancers in Ontario from 1994-2012: A
population-based study
Jennifer A. Flemming, Senthuran Tharmalingam, Sulaiman Nanji,
Jina Zhang-Salomons, Christopher Booth
1350: Surveillance for hepatocellular carcinoma is
associated with better survival: Results from a large
cohort in the Netherlands
Suzanne van Meer, Robert A. de Man, Minneke Coenraad, Dave
Sprengers, Carin M. Van Nieuwkerk, Martijn van Oijen, Heinz-
Josef Klümpen, Peter L. Jansen, Peter D. Siersema, Karel J. van
Erpecum
1351: Impact of advanced age on the short- and long-
term postoperative outcomes in patients undergoing
hepatectomy for hepatocellular carcinoma
Hiroaki Motoyama, Akira Kobayashi, Takahide Yokoyama, Akira
Shimizu, Norihiko Furusawa, Hiroshi Sakai, Noriyuki Kitagawa,
Takuma Arai, Tomoki Shirota, Shinichi Miyagawa
1352: Systematic Identification of Long Intergenic Non-
coding RNAs expressed in Hepatocellular Carcinoma
Yuji Zhang, Asha Nair, Lewis R. Roberts, Tushar Patel
1353: ω-3 Polyunsaturated Fatty Acids Regulate the
Expression of 15-PGDH through miRNA26a and
miRNA26b in Cholangiocarcinoma
Lu Yao, Chang Han, Kyoungsub Song, Kyu Lim, Tong Wu
1354: Analytic Morphomics Improves the Prediction of
Survival in Patients with Hepatocellular Carcinoma
Peng Zhang, Pratima Sharma, Pranab Barman, Neehar D. Parikh,
Sampath kumar Santhanam Ethiraj, Venkat Krishnamurthy, Lu
Wang, Stewart C. Wang, Grace L. Su
1355: The Effect of Demographics and Socio-Economic
Factors on Survival in Metastatic Neuroendocrine
Tumors: a Surveillance, Epidemiology and End Results
(SEER) Population Study
Minzhi Xing, Nima Kokabi, Juan C. Camacho, Hyun S. Kim
1356: Clinical outcomes of early to intermediate
hepatocellular carcinoma treated with Trans-Arterial
chemoembolization versus Radiofrequency ablation
Wei Rong, Benjamin Tay, Jia Chen Lim, Alfred W. Kow, Shridhar
G. Iyer, Kin Yong, Stephen Stephen, Chern Hao Chong, Maureen
Da Costa, Krishnakumar Madhavan, Seng Gee Lim, Yock Young
Dan
1357: Inflammatory bowel disease (IBD) is a risk factor
for extrahepatic cholangiocarcinoma (ECC) in subjects
without underlying primary sclerosing cholangitis (PSC)
Hassan M. Ghoz, Esha Baichoo, Benyam D. Addissie, Lewis R.
Roberts, Roongruedee Chaiteerakij
Poster Viewing: 8:00 AM – 5:30 PM
155A
1358: There are significant differences in the risk factors
for perihilar cholangiocarcinoma (CCA) compared to
distal CCA: Rationale for approaching them as distinct
entities
Hassan M. Ghoz, Esha Baichoo, Benyam D. Addissie, Lewis R.
Roberts, Roongruedee Chaiteerakij
1359: Radiofrequency ablation of solid tumors in
combination with bortezomib causes ER-stress
Thaddaeus T. Wissniowski, Deike Strobel, Daniel Neureiter,
Thomas Gress, Patrick Michl, Pietro Di Fazio
1360: Clinical outcomes of intraoperative
radiofrequency ablation for primary hepatocelluar
carcinoma ineligible for percutaneous radiofrequency
ablation or surgical resection
Eun Chung, Jung Hyun Kwon, Soon woo Nam, Young Woon Kim,
Sung Won Lee, Young chul Yoon
1361: Ten-Year Outcomes of Cryoablation Therapy
for Small Hepatocellular Carcinoma and Child–Pugh
Class A or B Cirrhosis: A Single Center Large Cohort
Experience
Guanghua Rong, Wenlin Bai, Zheng Dong, Chunping Wang, Yin
Ying Lu, Ke-Qin Hu, Yongping Yang
1362: Prognostic factors for patients with recurrent
hepatocellular carcinoma following liver transplant. A
Euro-American study
Gonzalo Sapisochin, Nicolas Goldaracena, Santiago Astete,
Duncan Davidson, Rafael Ehab, Lluis Castells, Charbel Sandroussi,
Itxarone Bilbao, Les Lilly, Cristina Dopazo, Anand Ghanekar, Ian
McGilvray, Mark Cattral, Markus Selzner, David Grant, Ramon
Charco, Paul Greig
1363: Prognostic Significance of Hepatic Venous
Pressure Gradient in the Prediction of Hepatocellular
Carcinoma
Eun Jin Kim, Ki Tae Suk, Hyo Sun Kim, Sang Hyun Park, Chang
Seok Bang, Ji Won Park, Choong Kee Park, Sung Eun Kim,
Hyoung Su Kim, Myoung Kuk Jang, Sang Hoon Park, Myung Seok
Lee, Dong Joon Kim
1364: Eukaryotic elongation factor 2 is a prognostic
marker and its kinase a potential drug target in
hepatocellular carcinoma
Leona L. Pott, Henning Reis, Barbara Sitek, Hideo A. Baba
NOVEMBER 10
1365: A Prospective Randomized Study Comparing
MONDAY
Radiofrequency Ablation and Hepatic Resection for
Hepatocellular Carcinoma
Hae Won Lee, Kyung-Suk Suh, Hyeyoung Kim, YoungRok Choi,
Suk-Won Suh, Jaehong Jeong, Nam-Joon Yi, Kwang-Woong Lee
1366: Increased level of nucleolin confers to aggressive
tumor progression and poor prognosis in patients with
hepatocellular carcinoma after hepatectomy
Xiaodong Guo, Lingxiang Yu, Jinghui Dong, Ruisheng Li, Boan Li,
Huiqiang Liu, Mei Yang, Jingmin Zhao
Presenters in Attendance 12:30 – 2:00 PM
 156A POSTER SESSIONS
Poster Sessions
1367: A retrospective review of Hepatocellular
Carcinoma surveillance in 3 United Kingdom teaching
hospitals
Henry House, Nowlan Selvapatt, Ashley S. Brown
1368: ABSTRACT Survival of hepatocellular carcinoma
in patients with normal liver versus underlying cirrhosis:
Results from a large cohort in the Netherlands
Suzanne van Meer, Karel J. van Erpecum, Joanne Verheij, Minneke
Coenraad, Dave Sprengers, Carin M. Van Nieuwkerk, Heinz-Josef
Klümpen, Peter L. Jansen, Peter D. Siersema, Robert A. de Man
1369: A preclinical study of EpCAM-targeted therapy
for human hepatocellular carcinoma with stem cell
features
Shinji Tanaka, Kousuke Ogawa, Satoshi Matsumura, Arihiro
Aihara, Daisuke Ban, Takanori Ochiai, Takumi Irie, Atsushi Kudo,
Shigeki Arii, Minoru Tanabe
1370: Screening and Management of Hepatocellular
Carcinoma. Report of a Global Survey
Dalbir S. Sandhu, Antonio J. Sanchez
1371: Calculating the growth rate of small
hepatocellular carcinoma: implications for surveillance
and treatment
Ian A. Rowe, Debashis Haldar, Diarmaid D. Houlihan, Shishir
Shetty, Hynek Mergental, Tahir Shah
1372: Subgroup Analysis of Patients with HIV+HCC
Among a Cohort of 2322 Veterans Diagnosed with
Hepatocellular Carcinoma (HCC) from 2008-2010
David E. Kaplan, Ayse Aytaman, Michelle Baytarian, Kathryn
D’Addeo, Feng Dai, Rena K. Fox, Kristel K. Hunt, Astrid Knott, Rajni
Mehta, Marcos Pedrosa, Christine Pocha, Melissa Skanderson,
Adriana Valderama, Tamar H. Taddei
1373: Treatment outcome of Radiofrequency ablation
as first line treatment for Hepatocellular carcinoma
in Milan criteria : Analysis of 510 patients in a single
center
Se Young Jang, Soo Young Park, Won Young Tak, Young Oh
Kweon, Su Hyun Lee, Jung Gil Park
1374: High alpha-fetoprotein levels and presence of
clinically significant portal hypertension represent risk
factors for hepatocellular carcinoma development in
cirrhotic patients
NOVEMBER 10
Simona Bota, Florian Hucke, Matthias Pinter, Mattias Mandorfer,
MONDAY
Thomas Reiberger, Arnulf Ferlitsch, Michael Trauner, Wolfgang
Sieghart, Markus Peck-Radosavljevic
1375: Impact of surveillance on the survival of
patients with hepatocellular carcinoma: results from a
longitudinal study in Taiwan
Diana Chirovsky, Kristen Hassmiller Lich, Alfred S. Barritt, Pei-Jer
Chen, Stephanie B. Wheeler, Lucinda S. Orsini, Andrea K. Biddle
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1376: Hypercoagulability in cirrhotic patients with
hepatocellular carcinoma (HCC) and portal vein
thrombosis (PVT)
Alberto Zanetto, Alberto Ferrarese, Kryssia I. Rodriguez, Veronica
Pepe, Mariangela Fadin, Claudia M. Radu, Sabrina Gavasso,
Alessandro Vitale, Umberto Cillo, Fabio Farinati, Francesco P.
Russo, Giacomo Germani, Elena Nadal, Paolo Simioni, Patrizia
Burra, Marco Senzolo
1377: Clinical outcomes in patients who develop
hepatocellular carcinoma after hepatitis C viral
eradication by antiviral therapy
Kaoru Tsuchiya, Yutaka Yasui, Nobuharu Tamaki, Shoko Suzuki,
Takanori Hosokawa, Hiroyuki Nakanishi, Jun Itakura, Yuka
Takahashi, Masayuki Kurosaki, Yasuhiro Asahina, Namiki Izumi
1378: Absence of thrombocytopenia is correlated with
decreased survival in patients with advanced liver
disease and hepatocellular carcinoma
Marco Senzolo, Alessandro Vitale, Edoardo G. Giannini, Teh-Ia
Huo, Franco Trevisani, Fabio Farinati
1379: Beneficial effects of oral branched-chain amino
acid supplementation after local therapy for liver cancer
Shunsuke Nojiri, Kei Fujiwara, Noboru Shinkai, Etsuko Iio, Takashi
Joh
1380: Doubling Time of Des-gamma-carboxy
Prothrombin Can be Useful as a Prognostic Marker for
Hepatocellular Carcinoma
Nobuyuki Matsumoto, Hiroki Ikeda, Yohei Noguchi, Ryuta
Shigefuku, Kotaro Matsunaga, Chiaki Okuse, Michihiro Suzuki,
Fumio Itoh
1381: Role of Primovist-MR Imaging on Preoperative
Assessment of the Risk of Postoperative Liver Failure in
Patients with Hepatocellular Carcinoma
Sin-Il Kim, Young-Joo Jin, Soon Gu Cho, Ah Rhm Woo, Jin-Woo
Lee, Young Soo Kim
1382: Obesity and alfa-fetoprotein predict presence of
histopathologic features associated with hepatocellular
carcinoma recurrence after liver transplantation
Vinay Sundaram, Anish V. Patel, Alagappan A. Annamalai, Walid
S. Ayoub, Tram T. Tran, Andrew S. Klein
1383: Tumor volume doubling time in hepatocellular
carcinoma: a systematic literature review and meta-
analysis
Diana Chirovsky, Andrea K. Biddle, Richard C. Semelka, Kristen
Hassmiller Lich, Stephanie B. Wheeler, Lucinda S. Orsini, Alfred
S. Barritt
1384: Adherence to Hepatocellular Carcinoma
Diagnostic Guidelines: Single Veterans Affairs Medical
Center (VAMC) Experience
Thoetchai Peeraphatdit, Niyada Naksuk, Paola Ricci
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1385: Early response prediction of hepatocellular
carcinoma to conventional transcatheter
chemoembolization using intraprocedual plain cone-
beam CT
Yasunori Minami, Masatoshi Kudo
1386: Phase 2 trial of temozolomide and veliparib
combination therapy for sorafenib-refractory advanced
hepatocellular carcinoma (HCC)
Aiwu R. He, Narayan Shivapurkar, Anteneh A. Tesfaye, HongKun
Wang, Michael J. Pishvaian, Brandon G. Smaglo, John Marshall,
Karen Dorsch-Vogel, Jaydeep Kachhela
1387: WITHDRAWN
1388: Additive anti-Tumor Response to the Rabbit VX2
Hepatoma by Combined Radio Frequency Ablation and
Toll like Receptor 9 Stimulation
Barbara Behm, Pietro Di Fazio, Daniel Neureiter, Thomas Gress,
Patrick Michl, Detlef Schuppan, Thaddaeus T. Wissniowski
1389: Survival Benefit of Long-Term Sorafenib
Treatment in Patients with Advanced Hepatocellular
Carcinoma in Indonesia: Multicenter experience
Cosmas R. Lesmana, Rino A. Gani, Levina S. Pakasi, Irsan Hasan,
Agus S. Waspodo, Lianda Siregar, Poernomo Budi, Laurentius A.
Lesmana
1390: Trends and Patterns of Treatment for
Hepatocellular carcinoma in Korea
Youngmi Hong, Mong Cho, Ki Tae Yoon, Daehwan Kang,
Hyungwook Kim, Cheol Woong Choi, SuBum Park, Jeong Heo,
Hyun Young Woo, Won Lim
1391: HIV Viral Load Independently Predicts Survival
in HIV-Infected Patients With Hepatocellular Carcinoma
(HCC)
Caitlin C. Citti, Heather L. Platt, Maaz B. Badshah, Ting-Yi Chen,
Luciana Kikuchi, Meritxell Ventura-Cots, Noami Chaudhary,
Sonja Marcus, Michael Yin, Ayse Aytaman, Judith Aberg, Myron
Schwartz, Douglas Dieterich, Yujin Hoshida, Norbert Bräu
1392: Complete response at the first chemoembolization
is still the most robust factor for favorable outcome in
hepatocellular carcinoma
Hye Won Lee, Beom Kyung Kim, Seung Up Kim, Jun Yong Park,
Do Young Kim, Sang Hoon Ahn, Kwang-Hyub Han
1393: Radiofrequency ablation for initial recurrent
hepatocellular carcinoma after curative treatment:
Compared with primary cases
Takayuki Fukuhara, Hiroshi Aikata, Yohji Honda, Hiromi Kan,
Tomoki Kobayashi, Noriaki Naeshiro, Daisuke Miyaki, Tomokazu
Kawaoka, Masataka Tsuge, Akira Hiramatsu, Michio Imamura,
Hideyuki Hyogo, Yoshiiku Kawakami, C. Nelson Hayes, Kazuaki
Chayama
Poster Viewing: 8:00 AM – 5:30 PM
157A
1394: Retrospective Cohort study for liver
carcinogenesis prediction using VF map score : Virtual
Touch Quantification(VTQ), Fasting blood glucose(FBG),
male, age, platelet
Tomoko Aoki, Shuhei Nishiguchi, Chikage Nakano, Kenji
Hashimoto, Akio Ishii, Tomoyuki Takashima, Nobuhiro Aizawa,
Yoshiyuki Sakai, Naoto Ikeda, Hironori Tanaka, Yoshinori Iwata,
Hirayuki Enomoto, Masaki Saito, Jiro Fujimoto, Seiichi Hirota,
Hiroko Iijima
1395: Prognostic value of the Barcelona Clinic Liver
Cancer staging subclassification system for conventional
transarterial chemoembolization
Yutaka Yasui, Kaoru Tsuchiya, Masayuki Kurosaki, Koichi Gondou,
Natsuko Nakakuki, Hitomi Takada, Shuya Matsuda, Yu Asano,
Nobuhiro Hattori, Nobuharu Tamaki, Shoko Suzuki, Takanori
Hosokawa, Hiroyuki Nakanishi, Jun Itakura, Namiki Izumi
1396: Autophagy may be an early event in the stepwise
carcinogenesis via biliary intraepithelial neoplasia in
cholangiocarcinoma associated with hepatolithiasis
Motoko Sasaki, Takeo Nitta, Yasunori Sato, Yasuni Nakanuma
1397: In vitro validation of human glypican-3 specific
chimeric antigen receptors for hepatocellular carcinoma
Yonghai Li, David E. Kaplan
1398: The role of gut commensal bacteria in anti-tumor
effect of chemotherapy for hepatocellular carcinoma
Noriho Iida, Eishiro Mizukoshi, Tatsuya Yamashita, Shuichi
Kaneko
1399: Management of hepatocellular carcinoma in
elderly patients: an Italian “in field” experience
Elena Dionigi, Mauro Borzio, Angelo Rossini, Anna Toldi,
Giampiero Francica, Fabio Fornari, Andrea Salmi, Fabio Farinati,
Susanna Vicari, Massimo Marignani, Giancarlo Parisi, Fulvia
Terracciano, Ilario de Sio, Rodolfo Sacco
1400: Vascularization of hepatocellular adenomas and
carcinomas by co-option of portal tracts
Ashley E. Stueck, Masayuki Nakano, Ian R. Wanless
1401: Prognostic Assessment of Patients with Untreated
Hepatocellular Carcinoma
Edoardo G. Giannini, Fabio Farinati, Francesca Ciccarese, Anna
Pecorelli, Gian Ludovico Rapaccini, Mariella Di Marco, Eugenio
Caturelli, Marco Zoli, Franco Borzio, Franco Trevisani
NOVEMBER 10
MONDAY
1402: Clinical Impact of Additional Interferon
Administration on Sorafenib-treated Patients with
Recurrent Advanced Hepatocellular Carcinoma
Hisakazu Doi
1403: How Is BCLC Stage C HCC Treated In Real-Word
Practice And What Outcomes Are Obtained?
Sasan Roayaie, Ghalib Jibara, Parissa Tabrizian, Joong-Won Park,
Jijin Yang, Lunan Yan, Guohong Han, Francesco Izzo, Minshan
Chen, Jean-Frédéric Blanc, Phillip Johnson, Masatoshi Kudo, Lewis
R. Roberts, Morris Sherman
Presenters in Attendance 12:30 – 2:00 PM
 158A POSTER SESSIONS
Poster Sessions
1404: Characteristics and prognosis of hepatocellular
carcinoma after sustained virological response to
interferon therapy for hepatitis C
Koichi Honda, Masataka Seike, Junya Oribe, Mizuki Endo, Mie
Yoshihara, Hiroki Syo, Masao Iwao, Masanori Tokoro, Tetsu Mori,
Tsutomu Yamashita, Toyokichi Muro, Kazunari Murakami
1405: The decrease of alpha-fetoprotein and/or the
decrease of tumor stain on contrast enhanced CT
images after 2 weeks of sorafenib treatment predict
prognosis in patients with advanced hepatocellular
carcinoma
Teiji Kuzuya, Masatoshi Ishigami, Yoji Ishizu, Takashi Honda,
Kazuhiko Hayashi, Tetsuya Ishikawa, Hidemi Goto
1406: Incidental Microscopic Bile Duct Tumor Thrombi in
Hepatocellular Carcinoma after Curative Hepatectomy:
A Matched Study
Jong Man Kim, Ju-Yeon Cho, Geum Youn Gwak, Choon Hyuck
D. Kwon, Moon Seok Choi, Joon Hyeok Lee, Jae Won Joh, Seung
Woon Paik, Cheol Keun Park, Byung Chul Yoo
1407: Staged Doxorubicin Eluting Bead Transarterial
Chemoembolization Therapy for Unresectable
Hepatocellular Carcinoma Confers to Survival
Advantage with Preservation of Quality of Life
Minzhi Xing, Hasmukh J. Prajapati, Grant R. Webber, Hyun S. Kim
1408: Factors affecting tolerability of Yttrium-90
Radioembolization in patients with advanced
hepatocellular carcinoma – A large single center
analysis
Bahar Madani, Ashwini P. Mehta, Parvez S. Mantry, Carlos G.
Fasola, Aden Tadelle, Islam Shahin, Alejandro Mejia, Hector
Nazario, Jeffrey S. Weinstein, Maisha Barnes, Adil Habib,
Abdullah Mubarak, Steve Cheng
1409: Transarterial chemoembolization (TACE) caused
hypoxia may trigger a progenitor cell phenotype in
hepatocellular carcinoma (HCC)
Jinping Lai, Beatrice Knudsen, Maha Guindi
1410: Does Liver Regeneration Increase the
Postoperative Recurrence after Curative Resection of
Hepatocellular Carcinoma?
Jin Ho Lee, Gi Hong Choi, Dai Hoon Han, Jin Sub Choi
1411: Cancer Registries Underestimate Hepatocellular
NOVEMBER 10
Carcinoma Incidence: An Independent Population-Based
MONDAY
Epidemiological Study
Thai Hong, Alexander J. Thompson, Paul Gow, Michael A. Fink,
Anouk T. Dev, Virginia H. Knight, Marno C. Ryan, Ian Kronborg,
Niranjan J. Arachchi, Stuart K. Roberts, William W. Kemp,
Amanda J. Nicoll, John Lubel, Helen Farrugia, Vicky Thursfield,
Paul V. Desmond, Sally Bell
1412: Statins and metformin use improve prognosis
after diagnosis of hepatocelullar carcinoma
Javier Ampuero, Raquel Calle, Blanca Figueruela, Paula Ferrero,
Emilio Suarez, Manuel Romero-Gomez
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1413: Interleukin-8 level as predictive marker
for treatment response after transarterial
chemoembolization in hepatocellular carcinoma
Joohan Park, Soon Sun Kim, Hyo Jung Cho, Sun Young Park, Seon
Joo Ahn, Jae Youn Cheong, Sung Won Cho
1414: Predisposing factors for development of
hepatocellular carcinoma in chronically infected
hepatitis C virus patients who underwent pegylated
interferon plus ribavirin
Sin-Il Kim, Young-Joo Jin, Jihye Jang, Jin-Woo Lee, Young Soo Kim
1415: Does a Multidisciplinary Team (MDT) change
management in Hepatocellular Carcinoma (HCC)? A
Single Center Experience
Pierre M. Gholam, Anthony B. Post, Stanley M. Cohen, Kenneth
J. Woodside, Vanessa Humphreville, Badar Muneer, Edmund Q.
Sanchez, Christopher T. Siegel
1416: Selective Internal Radiation Therapy(SIRT) Using
Yttrium-90 In Patients With Advanced Hepatocellular
Carcinoma: A Large Single Center Experience
Bahar Madani, Ashwini P. Mehta, Parvez S. Mantry, Carlos G.
Fasola, Aden Tadelle, Islam Shahin, Alejandro Mejia, Hector
Nazario, Jeff Weinstein, Maisha Barnes, Adil Habib, Abdullah
Mubarak, Steve Cheng
1417: Array-based gene expression analysis of M1/
M2-polarized macrophages during treatment with multi-
kinase inhibitor Sorafenib
Martin F. Sprinzl, Jens U. Marquardt, Brigitte Bartsch, Hauke Lang,
Arndt Weinmann, Peter R. Galle
1418: Nuclear to Cytoplasmic Translocation of FOXO3
Determines the Sensitivity of Human Hepatocellular
Carcinoma to Doxorubicin
Josiah Cox, Anusha Vittal, Maura O’Neil, Zhuan Li, Sudhakiranmayi
Kuravi, Brian Bridges, Ahmad B. Abdulkarim, Steven A. Weinman
1419: Heterogeneity in risk factors and treatment
allocation, but comparable clinical presentation and
survival with hepatocellular carcinoma (HCC) among the
three largest Asian sub-populations in California
Channa R. Jayasekera, Lily H. Kim, James M. Wantuck, Benjamin
Yip, Mindie H. Nguyen
1420: Biphenotypic Tumors: Assessing Outcomes of
Hepatic Directed Therapies
Kathryn Fowler, Nael Saad, Elizabeth M. Brunt, Manik Amin,
Neeta Vachharajani, Maria Bernadetta Doyle, Benjamin Tan,
William C. Chapman
1421: Aberrant expression of microRNA according to
aging is participating in hepatocarcinogenesis
Yoshiki Murakami, Saori Itami, Hidenori Toyoda, Takashi Kumada,
Toshihito Tanahashi, Etsushi Kawamura, Atsushi Hagihara,
Sawako K. Uchida, Hiroyasu Morikawa, Masaru Enomoto, Akihiro
Tamori, Norifumi Kawada, Y-h Taguchi
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1422: Prognostic influence of spontaneous tumor
rupture on resectable hepatocellular carcinoma
Chan Albert, Ronnie T. Poon, Tan To Cheung, Kenneth S. Chok,
Sheung Tat Fan, Chung Mau Lo
1423: Occurrence of Hepatocellular Carcinoma Is
Comparable in Chronic HBV Infectors Treated with
Different Nucleos(t)ide Analogues: A 6-year Retro- and
Prospective Real World Cohort Study
Yuankai Wu, Xiangyong Li, Mingxing Huang, Guoli Lin, Shu-ru
Chen, Hong Shi, Yusheng Jie, Xin-Hua Li, Fangji Yang, Min Zhang,
Yunlong Ao, Yihua Pang, Yutian Chong
1424: Real-life Data of Sorafenib in Unresectable
Hepatocellular Carcinoma: Retrospective Analysis of
511 Consecutive Patients Treated with Sorafenib in a
Single Tertiary Referral Center
Yeonjung Ha, Hyung-Don Kim, Mi-Jung Jun, Young Joo Yang,
Seung Bum Lee, Jee Eun Yang, Gi Ae Kim, Eui Ju Park, Jihyun An,
Danbi Lee, Ju Hyun Shim, Kang Mo Kim, Young-Suk Lim, Han Chu
Lee, Young-Hwa Chung, Yung Sang Lee, Dong Jin Suh
1425: Etiological roles of diabetes, BMI and past
hepatitis B infection in the development of non-B non-C,
non-alcoholic hepatocellular carcinoma
Hae Lim Lee, Nam Ik Han, Sang Wook Choi, Joon-Yeol Han, Se
Hyun Cho, Jin-Mo Yang
1426: Decreased expression of PBLD correlates with a
poor prognosis and functions as a tumor suppressor in
human hepatocellular carcinoma
Aimin Li, Qun Yan, Side Liu, Yu Qiang Nie
1427: HBV DNA / Quantitative HBsAg Level Ratio,
but Not Either Quantitative HBsAg Level or HBV DNA,
Can Predict Hepatocellular Carcinoma Development in
HBeAg-Negative Chronic Hepatitis Patients with HBV
DNA ≥ 2000 IU/mL
Jem ma Ahn, Dong Hyun Sinn, Ju Yeon Cho, Won Sohn, Geum-
Youn Gwak, Yong-Han Paik, Moon Seok Choi, Joon Hyeok Lee,
Kwang Cheol Koh, Seung Woon Paik, Byung Chul Yoo
1428: Radiofrequency ablation with or without
transcatheter arterial chemoembolization for small
hepatocellular carcinoma; a propensity analysis
Hee Yeon Kim, Chang Wook Kim, Yu Seung Kim, Seung Kew
Yoon, Jong Young Choi, Si Hyun Bae, Chang Don Lee
1429: The importance of intrahepatic tumor in
hepatocellular carcinoma with extrahepatic spread in
patients treated with sorafenib
Won Sohn, Yong-Han Paik, Ju Yeon Cho, Jem-Ma Ahn, Dong
Hyun Sinn, Geum-Youn Gwak, Moon Seok Choi, Joon Hyeok Lee,
Kwang Cheol Koh, Seung Woon Paik, Byung Chul Yoo
Poster Viewing: 8:00 AM – 5:30 PM
159A
1430: Effect of hepatitis B virus reactivation on the
recurrence of HBV-related hepatocellular carcinoma
after curative resection in patients with low viral load
Won Sohn, Yong-Han Paik, Ju Yeon Cho, Jong Man Kim, Choon
Hyuck D. Kwon, Jae Won Joh, Jem-Ma Ahn, Dong Hyun Sinn,
Geum-Youn Gwak, Moon Seok Choi, Joon Hyeok Lee, Kwang
Cheol Koh, Seung Woon Paik, Byung Chul Yoo
1431: Sorafenib combined with hepatectomy in patients
with intermediate-stage and advanced hepatocellular
carcinoma
Lei Zhuang, Tianfu Wen, Mingqing Xu, Jiayin Yang, Wentao
Wang, Hong Wu, Lvnan Yan, Yonggang Wei, Bo Li
1432: Isolated Hepatitis B core Antibody positivity: a
potential risk factor for liver cancer
Linda L. Wong, Marina Roytman, Naoky Tsai
1433: The serum alpha-fetoprotein as predictor
of tumor recurrence after liver transplantation for
hepatocellular carcinoma
Luciana S. Schraiber, Angelo A. Mattos, Maria L. Zanotelli,
Guido Pio G. Cantisani, Ajacio B. Brandão, Claudio A. Marroni,
Guilhermo Kiss, Lucas Ernani, Livia C. Lionco
1434: Liver transplant for hepatocellular carcinoma
(HCC). Are we missing some factors in the procedure’s
outcomes? Single center 3-year experience
Rinjal Brahmbhatt, Lokesh K. Jha, Fedja A. Rochling, Daniel F.
Schafer, Timothy M. McCashland, Diana Gomez-Martin, Marco
A. Olivera-Martinez
1435: Impact of Underlying Liver Disease, Tumor
Burden and Performance Status on Survival after
Selective Internal Radiation Therapy: A Large Single
Center Experience
Parvez S. Mantry, Bahar Madani, Ashwini P. Mehta, Aden Tadelle,
Carlos Fasola, Islam Shahin, Hector Nazario, Alejandro Mejia,
Jeffrey S. Weinstein, Abdullah Mubarak, Steve Cheng
1436: Relationship between the mitochondria gene
abnormality in liver tissues in patients with chronic viral
hepatitis C and the hepatocarcinogenesis
Nobuhiro Aizawa, Chikage Nakano, Kunihiro Hasegawa, Ryo
Takata, Tomoko Aoki, Kenji Hashimoto, Akio Ishii, Tomoyuki
Takashima, Yoshiyuki Sakai, Naoto Ikeda, Hironori Tanaka,
Yoshinori Iwata, Hirayuki Enomoto, Masaki Saito, Hiroko Iijima,
Yuji Iimuro, Jiro Fujimoto, Shuhei Nishiguchi
NOVEMBER 10
MONDAY
1437: Down-staging of hepatocellular carcinoma
tumors at liver transplant centers in the United States
She-Yan Wong, Dina Halegoua-De Marzio, Jesse M. Civan
1438: Noninvasive Fibrosis Panels are more useful than
Inflammatory Markers for Prediction of Hepatocellular
carcinoma Recurrence after Radiofrequency ablation
Jeong Han Kim, Won Hyeok Choe, So Young Kwon
Presenters in Attendance 12:30 – 2:00 PM
 160A POSTER SESSIONS
Poster Sessions
Cost-Effectiveness
1439: Modeling Cost Avoidance For Preventing Disease
Progression In Hepatitis C Patients
Chris M. Kozma, Andrew Paris, George Wan
1440: Comorbidity and Resource Utilization in Older
Liver Transplant Recipients
Nyingi M. Kemmer, Chris Albers, Edson S. Franco, Husssein
Osman-Mohamed, Elizabeth Cece Fallon, Erin Parkinson, Jennifer
Horkan, Angel Alsina
1441: Insurance Approval Patterns for Second
Generation DAAs
Fredric D. Gordon, Amir A. Qamar, Patricia M. Hogan, Lois V.
Daponte, Mary Ann Simpson
1442: Patient-Reported Outcomes (PROs) in HIV-HCV
Co-infected Patients Treated with Sofosbuvir (SOF)-
containing Regimens
Zobair Younossi, Maria Stepanova, Mark S. Sulkowski, Susanna
Naggie, Sharon L. Hunt
1443: Cost-effectiveness of Telbivudine Renoprotection
in Chronic Hepatitis B Liver Cirrhosis
Yock Young Dan, Seng Gee Lim
1444: Regional disparities in total hospital charges for
the treatment of inpatients with alcoholic hepatitis in the
United States
Folasade P. May, Vineet Syan, Ashwini Lakshmanan, Vinay
Sundaram
HCV: Diagnostics, Epidemiology, and
Natural History
1445: Sustained Virologic Response with Ledipasvir
(LDV) and Sofosbuvir (SOF) Regimens Leads to
Substantial Improvement in Patient-Reported Outcomes
(PROs) Among Chronic Hepatitis C (CHC) Patients with
Early Hepatic Fibrosis as Well as Those with Advanced
Hepatic Fibrosis
Zobair Younossi, Maria Stepanova, Patrick Marcellin, Nezam H.
Afdhal, Kris V. Kowdley, Stefan Zeuzem, Sharon L. Hunt
1446: The Significance of NA5A-Y93H Mutation
NOVEMBER 10
Evaluated by a Novel Simple Assay System Using
MONDAY
Cycling Probe-Based Real-Time PCR in Patients with
HCV Infection
Yoshihito Uchida, Jun-ichi Kouyama, Kayoko Naiki, Satoshi
Mochida
1447: HCV Screening of “Baby Boomers” Increased
Significantly Following 2012 CDC Call to Action, But
Screening Rate Fell in Non-Baby Boomers: Results of a
Nationwide Lab Test Database Analysis
Carol Smyth, Jason Bhan, Tatiana Sorokina, Ajitpal S. Dhaliwal,
Nancy Reau
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1448: Check Hep C: A Community-Based Approach to
Hepatitis C Diagnosis in High-Risk Populations
Mary Ford, Ashly Jordan, Eric J. Rude, Nirah Johnson, Holly
Hagan, Fabienne Laraque, Jay K. Varma
1449: Historical and geographical trends in hepatitis C
virus (HCV) incident infection among people who inject
drugs: The International Collaboration on Incident HCV
and HIV Infection among PWID (InC3 Study)
Meghan D. Morris, Thomas M. Rice, Stephen Shiboski, Julie
Bruneau, Andrea Cox, Gregory J. Dore, Jason Grebely, Judith
A. Hahn, Arthur Y. Kim, Andrew R. Lloyd, Margaret Hellard, Lisa
Maher, Barbara H. McGovern, Maria Prins, Kimberly Page
1450: Senior Center Based Hepatitis C Screening in
Baltimore
Oluwaseun Falade-Nwulia, Risha Irvin, Ayesha M. McAdams-
Mahmoud, Shruti H. Mehta, Jackline Joy M. Lasola, Dorcas
Baker, Arnold Eppel, Patrick Chaulk, Kathleen R. Page, Mark S.
Sulkowski, David L. Thomas
1451: Impact of Hepatitis E Virus Seropositivity on
Chronic Liver Disease of Cancer Patients with Hepatitis C
Virus Infection
Andreas Kyvernitakis, Parag Mahale, Jiang Ying, Harrys A. Torres
1452: Add-on of Boceprevir in HIV-positive Patients
with Genotype 1 Acute Hepatitis C at high Risk for
Treatment Failure
Mattias Mandorfer, Sebastian Steiner, Philipp Schwabl, Berit
A. Payer, Maximilian C. Aichelburg, Gerold Lang, Katharina
Grabmeier-Pfistershammer, Michael Trauner, Markus Peck-
Radosavljevic, Thomas Reiberger
1453: The prevalence of naturally occurring resistance
mutations against NS3 protease inhibitors, NS5A
replication complex inhibitors, and NS5B polymerase
inhibitors in patients with hepatitis C virus genotype 1b
Kazuhiko Hayashi, Masatoshi Ishigami, Yoji Ishizu, Teiji Kuzuya,
Takashi Honda, Yoshiaki Katano, Yoshiki Hirooka, Hidemi Goto
1454: Next-generation sequencing revealed the
prevalence of multi-geno/subtypic multiple infection of
hepatitis C virus in hemophiliac patients in Japan
Masato Ogishi, Hiroshi Yotsuyanagi, Takeya Tsutsumi, Hiroyuki
Gatanaga, Kyoji Moriya, Kazuhiko Koike
1455: Health-related quality of life (HRQOL) is not
negatively impacted by therapy of MK-5172/MK-8742
during treatment of genotype (GT) 1 chronic hepatitis
C in contrast to pegylated-interferon (IFN) or ribavirin
(RBV)-containing therapy
Jean Marie Arduino, Boan Zhang, Chizoba Nwankwo, Shazia
Khawaja, Melissa Shaughnessy, Isaias N. Gendrano, Peggy
Hwang, Michael Robertson, Niloufar Mobashery, Barbara A.
Haber
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1456: Preliminary Assessment of Hepatitis C Antibody
Testing in the United States Before and After Publication
of CDC Screening Recommendations
Monina Klevens, Xiaohua Huang, Daulati Thakare, Anthony E.
Yeo, Mouneer Odeh, John W. Ward
1457: Patterns of hepatitis C virus RNA levels during
acute infection: the InC3 study
Behzad Hajarizadeh, Bart P. Grady, Kimberly Page, Arthur Y.
Kim, Barbara H. McGovern, Andrea Cox, Thomas M. Rice, Rachel
Sacks-Davis, Julie Bruneau, Meghan D. Morris, Janaki Amin, Janke
Schinkel, Tanya L. Applegate, Lisa Maher, Margaret Hellard,
Andrew R. Lloyd, Maria Prins, Gregory J. Dore, Jason Grebely
1458: Failure of Perinatal Hepatitis C Testing:
Philadelphia, 2011 - 2013
Danica Kuncio, Kendra Viner, Claire Newbern
1459: If You Build It, They Will Come: Preliminary
Results of the ACTonHCV Online Educational Program
Sue Currie, Joy A. Peter, HoChong Gilles, Vincent Keane, Janeil
Klett, Julie A. Deal, Norah Terrault, Guadalupe Garcia-Tsao
1460: HCV Awareness, Risk Assessment, and
Healthcare Utilization Among “Baby Boomers”
Presenting to the Emergency Department
Derek E. Wells, Grace N. Cain, Charles T. Prickett, Ricardo A.
Franco, Jordan M. Forsythe, Joel B. Rodgers, James W. Galbraith
1461: Improving HCV care cascade outcomes in a
community-based testing program by providing same
day confirmatory testing and patient navigation
Stacey B. Trooskin, Hwajin Lee, Joanna Poceta, Caitlin Towey,
Sophie C. Feller, Annajane Yolken, Najia Luqman, Ta-Wanda
Preston, Erin Smith, Amy Nunn
1462: The Different Incidences of HCV Genotypes Using
Two Different Regions of Classification: 5’NC and NS5B
in Vietnamese Patients at Medic Medical Center
Thu Thuy Pham Thi, Tan Dat Ho, Bao Toan Nguyen
1463: Factors Associated with Hepatitis C Treatment
Eligibility
Shari S. Rogal, Ada O. Youk, Michael K. Chapko, Barbara H.
Hanusa, Robert A. Arnold, Galen E. Switzer, Mary Ann Sevick,
Nichole K. Bayliss, Carolyn L. Zook, David S. Obrosky, Susan
Zickmund
1464: Association between (TA)n dinucleotide repeat
near IL28B gene and HCV spontaneous clearance in
Japanese and African American
Masaya Sugiyama, Satoshi Hiramine, Norihiro Furusyo, Akio
Ido, Hirohito Tsubouchi, Hisayoshi Watanabe, Yoshiyuki Ueno,
Masaaki Korenaga, Kazumoto Murata, Naohiko Masaki, Tatsuya
Kanto, Jun Hayashi, David L. Thomas, Masashi Mizokami
1465: An Innovative, Scalable and Sustainable Model
to Routinize HCV Testing and Linkage to Care in Five
Federally Qualified Health Centers
Catelyn Coyle
Poster Viewing: 8:00 AM – 5:30 PM
161A
1466: Unregulated Tattooing in an Urban Cohort: An
Analysis of Age, Gender, Risk Knowledge and Risk
Perception
Audun Lier, Amy Nunn, Sophie C. Feller, Caitlin Towey, Joanna
Poceta, Hwajin Lee, Gladys L. Thomas, Stacey B. Trooskin
1467: Overestimate of Fibrosis by FIBROSpect II in
African Americans Complicates Management of their
Chronic Hepatitis C
Paul Naylor, Maher Tama, Suhag Patel, Dhiraj Gulati, Johnny
Altawil, Karthik Ravindran, Murray N. Ehrinpreis, Milton G.
Mutchnick
1468: HCV-positive women of child-bearing age
have premature ovarian senescence, associated with
reproductive failure and more severe hepatic fibrosis
Aimilia Karampatou, Alessia Ciancio, Laura Turco, Enrica Baraldi,
Rosina Maria Critelli, Veronica Bernabucci, Simonetta Tagliavini,
Silvia Strona, Tommaso Trenti, Mario Rizzetto, Erica Villa
1469: Long-Term Impact of Hepatitis C Therapy on
Liver Fibrosis and Hepatic Events in HIV-HCV Coinfected
Patients
Pablo Labarga, José Vicente Fernández-Montero, Carmen de
Mendoza, Pablo Barreiro, Vincent Soriano
1470: Improving predictive models of risk of disease
progression among patients with chronic hepatitis C by
incorporating longitudinal data
Monica Konerman, Yiwei Zhang, Ji Zhu, Peter Higgins, Anna S.
Lok, Akbar K. Waljee
1471: FIB4 Score and Gender Predict the Incidence
of Hepatocellular Carcinoma (HCC) among Patients
with Chronic Hepatitis C Virus (HCV) Infection: Chronic
Hepatitis Cohort Study (CHeCS)
Fujie Xu, Jian Xing, Anne C. Moorman, Stuart C. Gordon, Loralee
B. Rupp, Mei Lu, Philip R. Spradling, Eyasu H. Teshale, Joseph A.
Boscarino, Vinutha Vijayadeva, Mark A. Schmidt
1472: Marijuana Use Is Not Associated With Liver
Fibrosis Progression in HCV/HIV Co-infected Women
Erin Kelly, Jennifer L. Dodge, Monika Sarkar, Audrey French, Phyllis
Tien, Marshall Glesby, Elizabeth T. Golub, Michael Augenbraun,
Michael Plankey, Marion G. Peters
1473: Performance of Cobas Taqman and Abbott
Realtime HCV RNA assays during protease inhibitor-
NOVEMBER 10
based triple therapy in patients with advanced liver
MONDAY
fibrosis and cirrhosis
Benjamin Maasoumy, Bela Hunyady, Vincenza Calvaruso,
Michael Makara, Johannes Vermehren, Attila Haragh, Simone
Susser, Birgit Bremer, Gavin A. Cloherty, Michael P. Manns,
Antonio Craxi, Heiner Wedemeyer, Christoph Sarrazin
1474: Spatial epidemiology and inter familial clustering
of hepatitis C infection: Secondary analysis of a country
wide national hepatitis survey of Pakistan
Saeed S. Hamid, Bilal Ahmed, Huma Qureshi
Presenters in Attendance 12:30 – 2:00 PM
 162A POSTER SESSIONS
Poster Sessions
1475: Hepatitis C virus network dynamics among
people who inject drugs in Vancouver, Canada
Brendan Jacka, Art Poon, Tanya L. Applegate, Mel Krajden,
Andrea Olmstead, Richard Harrigan, Brandon D. Marshall, Kora
DeBeck, M-J Milloy, Francois Lamoury, Oliver Pybus, Viviane Lima,
Gkikas Magiorkinis, Vincent Montoya, Julio Montaner, Jeffrey Joy,
Gregory J. Dore, Thomas Kerr, Evan Wood, Jason Grebely
1476: A genomic and clinical prognostic index for
hepatitis C-related early-stage cirrhosis
Lindsay Y. King, Claudia Canasto-Chibuque, Kara B. Johnson,
Shun Yip, Xintong Chen, Kensuke Kojima, Manjeet Deshmukh,
Anu Venkatesh, Poh Seng Tan, Xiaochen Sun, Augusto Villanueva,
Angelo Sangiovanni, Venugopalan Nair, Milind Mahajan,
Masahiro Kobayashi, Hiromitsu Kumada, Massimo Iavarone,
Massimo Colombo, M. Isabel Fiel, Scott L. Friedman, Josep M
Llovet, Raymond Chung, Yujin Hoshida
1477: Two hepatitis C antibody chemiluminescence
assays predict viremia by a different signal to cutoff
ratio in asymptomatic people with hepatitis C
Ana M. Contreras
1478: Birth cohort distribution and screening of viremic
HCV infections in Switzerland
Francesco Negro, Florian K. Bihl, Sarah Blach, Daniel Lavanchy,
Beat Mullhaupt, Homie Razavi, David Semela, Philip Bruggmann
1479: The global distribution and prevalence of HCV
genotypes
Janey Messina, Isla Humphreys, Abraham D. Flaxman, Anthony C.
Brown, Graham Cooke, Oliver Pybus, Eleanor Barnes
1480: Impact of HCV Triple Therapy on Liver Stiffness
Jillian Nickerson, Kian Bichoupan, Ponni Perumalswami, Douglas
Dieterich, Andrea D. Branch
1481: High Rates of Comorbidities and Polypharmacy
in Patients with Chronic Hepatitis C (CHC) in a Real-
World Setting: a Consequence of an Aging Population
Philip Vutien, Louis Brooks, Richard C. Livornese, Mindie H.
Nguyen
1482: Is the diagnostic accuracy of non-invasive
methods better than liver biopsy ? A Latent Class
Analysis on assessment of liver fibrosis in chronic
hepatitis C
Flavia F. Fernandes, Maria Lucia Ferraz, Hugo Perazzo, Luis
NOVEMBER 10
Eduardo C. Andrade, Alessandra Dellavance, Carlos Terra,
MONDAY
Gustavo Pereira, João Luiz Pereira, Frederico F. Campos, Fátima
A. Figueiredo, Renata M. Perez
1483: Impact of electronic reminder to improve hepatitis
C screening in age-appropriate patients: results of a
pilot quality improvement intervention
Thomas J. Byrne, Elizabeth J. Carey, Bashar Aqel, David D.
Douglas, Vickie Timm, Melissa Dosmann, Patricia Whitten, Monika
R. White, Jorge Rakela, Hugo E. Vargas
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1484: The impact of time on a scenario to minimize
complications of hepatitis C infection
David Semela, Sarah Blach, Florian K. Bihl, Philip Bruggmann,
Daniel Lavanchy, Francesco Negro, Homie Razavi, Beat Mullhaupt
1485: Identifying HCV Treatment Barriers Amongst High
Risk Population of Vancouver Downtown Eastside
Brian Conway, Behroz Rashidi, Shawn Sharma, Syune Hakobyan,
Osamah Alenezi, Amy Hung, Kevin Yen, Xinyang Huang, Harout
Tossonian
1486: Serum Cystatin C and NGAL levels at the start of
protease inhibitor antiviral therapy positively predict
renal dysfunction development and anaemia severity
Suman Verma, Ivana Carey, Kosh Agarwal
1487: Hepatitis C Virus (HCV) Infection in New Zealand:
Burden of Chronic Disease
Edward J. Gane, Cheryl R. Brunton, Chris Estes, Charles
Henderson, John Hornell, Sarah Radke, Homie Razavi, Catherine
A. Stedman
1488: The global burden of viremic chronic HCV
infection
Erin Gower, Chris Estes, Sarah Blach, Kathryn L. Razavi-Shearer,
Homie Razavi
1489: The relationship of Wisteria floribunda
agglutinin-positive human Mac-2 binding protein and
hepatocellular carcinoma developed after sustained
virological response against hepatitis C virus
Ryu Sasaki, Kazumi Yamasaki, Ayako Mine, Yuki Kugiyama,
Shigemune Bekki, Satoru Hashimoto, Akira Saeki, Shinya
Nagaoka, Seigo Abiru, Atsumasa Komori, Atsushi Kuno, Masaaki
Korenaga, Masashi Mizokami, Hisashi Narimatsu, Hiroshi
Yatsuhashi
1490: Non invasive markers of liver fibrosis: which one
to pick from a myriad of them! A study on 1602 liver
biopsies in patients with hepatitis C
Ragesh B. Thandassery, Anil John, Madiha E. Soofi, Saad R. Al
Kaabi
1491: HCV re-infection rates are low after long-term
follow up of acute HCV infection: The Australian Trial of
Acute Hepatitis C Recall study
Joseph S. Doyle, Gregory J. Dore, David Shaw, Jason Grebely,
Amanda Erratt, Margaret Hellard, Gail Matthews
1492: Simple serum markers models accurately predict
liver related survival, complications and HCC in chronic
HCV infection
Yi Huang, Leon Adams, Gerry C. MacQuillan, Enrico Rossi, Max
K. Bulsara, Gary P. Jeffrey
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1493: Factors associated with hepatitis C virus RNA
levels in early acute and early chronic infection: the InC3
study
Behzad Hajarizadeh, Bart P. Grady, Kimberly Page, Arthur Y.
Kim, Barbara H. McGovern, Andrea Cox, Thomas M. Rice, Rachel
Sacks-Davis, Julie Bruneau, Meghan D. Morris, Janaki Amin, Janke
Schinkel, Tanya L. Applegate, Lisa Maher, Margaret Hellard,
Andrew R. Lloyd, Maria Prins, Ronald Geskus, Gregory J. Dore,
Jason Grebely
1494: NS5A variability and dynamics of resistance-
associated mutations in HCV genotype 4 patients,
naive to treatment receiving triple therapy with
DACLATASVIR+PEG-IFN/RBV, assessed by ultra deep
sequencing
Barbara Bartolini, Raffaella Lionetti, Emanuela Giombini, Chiara
Taibi, Marzia Montalbano, Gianpiero D’Offizi, Fiona McPhee,
Eric A. Hughes, Giuseppe Ippolito, Anna Rosa Garbuglia, Maria
R. Capobianchi
1495: The impact of genetic polymorphism in PNPLA3
gene on fibrosis progression and hepatocellular
carcinoma development differs between hepatitis C and
hepatitis B
Masayuki Kurosaki, Kaoru Tsuchiya, Nobuharu Tamaki, Yutaka
Yasui, Takanori Hosokawa, Shoko Suzuki, Jun Itakura, Namiki
Izumi
1496: Cocaine/crack use is not associated with liver
fibrosis progression in HIV-HCV co-infected patients
Valerie Martel-Laferriere, Kathleen C. Rollet-Kurhajec, Joseph Cox,
Curtis Cooper, Mark Tyndall, Danielle Rouleau, Sharon Walmsley,
Marina B. Klein
1497: Response-guided Boceprevir-based Triple
Therapy in HIV/HCV-coinfected Patients: The
HIVCOBOC-RGT Study
Mattias Mandorfer, Sebastian Steiner, Philipp Schwabl, Berit
A. Payer, Maximilian C. Aichelburg, Gerold Lang, Katharina
Grabmeier-Pfistershammer, Michael Trauner, Markus Peck-
Radosavljevic, Thomas Reiberger
1498: Potential impact on mortality of HCV eradication
post-liver transplant in the era of direct anti-viral agents
Carmi S. Punzalan, Graham F. Barnard
1499: Most patients with hepatitis C virus (HCV)-
associated lymphoma present with mild liver disease at
cancer diagnosis - A call to revise indications for HCV
treatment
Harrys A. Torres, Parag Mahale
1500: Factors Associated with Spontaneous Resolution
of HCV Infection in Untreated Individuals, Philadelphia
Danica Kuncio, Amy Hueber, Claire Newbern, Kendra Viner
Poster Viewing: 8:00 AM – 5:30 PM
163A
1501: Near-infrared spectroscopy for the early
detection of prodromal phase of depression during
interferon-based therapy for patients with chronic
hepatitis C
Kazumichi Abe, Akira Wada, Sachie Oshima, Soichi Kono,
Atsushi Takahashi, Yukiko Kanno, Hiromichi Imaizumi, Manabu
Hayashi, Ken Okai, Shin-ichi Niwa, Hirooki Yabe, Hiromasa
Ohira
1502: Identifying the disease burden of hepatitis C virus
(HCV) infection and non-injection drug use: a systematic
review and meta-analysis of persons who use drugs but
do not inject
Rebecca L. Morgan, Natalie Blackburn, Anthony K. Yartel, Don
C. Des Jarlais
1503: ABCA1 SNPs rs2230806 and rs2230808 in
chronic hepatitis C are gender specific and influence
cholesterol metabolism and severity of liver disease
Joana Ferreira, Cilénia B. Costa, Ricardo Andrade, Manuel Bicho,
Fatima S. Serejo
1504: Time to hepatocellular carcinoma after
notification of hepatitis B or C infection: a population-
based cohort study, 1992–2007
Maryam Alavi, Matthew Law, Jason Grebely, Hla-Hla Thein,
Janaki Amin, Gregory J. Dore
1505: The Role Of Genetic Polymorphism Of LDL
Receptor In Egyptian Population Infected With Chronic
HCV, Regarding Response To Treatment
Mazen I. Naga, Mona A. Amin, Dina A. Algendy, Ahmed I. El
Badry, Mai M. Fawzi, Ayman R. Foda, Serag M. Esmat, Dina
Sabry, Laila A. Rashed, Samia M. Gabal, Manal Kamal
1506: Prevalence of viral hepatitis and liver fibrosis in
a population of incomers in French prisons. UCSASCAN
study
Julien Vergniol, Maylis Capdepont, Samy El Aouadi, Gildas
Le-Port, Gilles Gatineau-Sailliant, Valéry Hédouin, Catherine
Martineau, Juliette Foucher, Victor de Ledinghen
1507: Genetic variant of MICA in HCC development
among HCV patients post anti-viral therapy- a
longitudinal follow-up study
Ming-Lung Yu, Chung-Feng Huang, Chia-Yen Dai, Jee-Fu Huang,
Wan-Long Chuang
NOVEMBER 10
1508: Burden of Hepatitis C Virus and Chronic Liver
MONDAY
Disease amongst Hospitalized Inmates in Massachusetts
Alysse G. Wurcel, Michaela Superson, Kathryn Noonan, Arthur Y.
Kim, Barbara H. McGovern
1509: CDC new guidelines for testing for HCV: Does
one size fit all?
Mohamed G. Shoreibah, Cynthia E. Jordan, Shabnam Sarker,
Mary L. McCain, Arvind Tripathi, Omar Massoud
Presenters in Attendance 12:30 – 2:00 PM
 164A POSTER SESSIONS
Poster Sessions
1510: New Cut-off Points of Enhanced Liver Fibrosis
(ELF) Panel for Chronic Hepatitis C Patients
Flavia F. Fernandes, Alessandra Dellavance, Luis Eduardo C.
Andrade, Frederico F. Campos, Maria Chiara Chindamo, Joao
M. Araujo-Neto, Cristiane Villela-Nogueira, Henrique Sergio M.
Coelho, Carlos Terra, Gustavo Pereira, João Luiz Pereira, Fátima
A. Figueiredo, Renata M. Perez, Maria Lucia Ferraz
1511: Fear of a liver biopsy is the primary barrier
leading to disparities in the treatment and outcomes of
hepatitis C in Somali patients in Minnesota
Esther Connor, Albert Ndzengue, Nasra H. Giama, Jeremiah
Menk, Essa A. Mohamed, Saleh Elwir, Lewis R. Roberts, Mohamed
A. Hassan
1512: High Rates of HCV Active Infection in a Blood
Bank Study in Ghana, West Africa
Jennifer E. Layden, Richard O. Phillips, Fred S. Sarfo, Nallely Mora,
Dorcas O. Owusu, Stephanie Kliethermes, Shirley P. Owusu-Ofori,
Joseph Forbi, Ohene Opare-Sem, Kenrad Nelson, Richard Cooper
1513: Reduction of miR-20a, miR-92a and miR-122 in
patients with chronic hepatitis C and severe fibrosis
Kevin Appourchaux, Emilie Estrabaud, Philippe Broet, Martine
Lapalus, Michelle Martinot-Peignoux, Nathalie Boyer, Michel
Vidaud, Pierre Bedossa, Patrick Marcellin, Tarik Asselah
1514: Disease Burden of Chronic Hepatitis C Virus
(HCV) Infection in Ireland
Colm J. Bergin, Chris Estes, Diarmaid D. Houlihan, Homie Razavi,
Kathryn L. Razavi-Shearer, Lelia Thornton, Suzanne Norris
1515: A new serum biochemical model that accurately
predicts liver collagen proportional area
Yi Huang, Bastiaan de Boer, Leon Adams, Gerry C. MacQuillan,
Enrico Rossi, Max K. Bulsara, Gary P. Jeffrey
1516: Vitamin D binding protein gene polymorphism
rs222020, CYP2R1 can predict treatment response and
liver fibrosis of northern Chinese patients with chronic
hepatitis C
Ruqi Mei, Yu Pan, Xiumei Chi, Xiaomei Wang, Ruihong Wu,
Xiuzhu Gao, Jinglan Jin, Ge Yu, Jing Jiang, Junqi Niu
1517: Hepatitis C Virus (HCV) Infection in Argentina:
Burden of Chronic Disease
Ezequiel Ridruejo, Jorge Daruich, Chris Estes, Adrian Gadano,
Homie Razavi, Marcelo O. Silva, Federico G. Villamil, Fernando
NOVEMBER 10
Bessone
MONDAY
1518: Treatment Patterns and Clinical Outcomes of HCV
in Real World Practice in China
Huiying Rao, Hong Li, Hong Chen, Qing Xie, Shang Jia, Jun Li,
ZhiLiang Gao, Yongtao Sun, Jianning Jiang, Lunli Zhang, Lai Wei
1519: Hepatitis C lipoviral particle levels are associated
with spontaneous clearance of acute infection
David A. Sheridan, Behzad Hajarizadeh, Gail Matthews, Tanya
L. Applegate, Mark W. Douglas, Beverley Askew, Dermot Neely,
Margaret F. Bassendine, Gregory J. Dore, Andrew R. Lloyd, Jacob
George, Jason Grebely
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1520: Assessment of noninvasive hepatic fibrosis
markers among patients with chronic HCV infection and
advanced liver disease
Raoel Maan, Adriaan J. van der Meer, Jordan J. Feld, Heiner
Wedemeyer, Jean-Francois J. DuFour, Frank Lammert, Andres
Duarte-Rojo, Michael P. Manns, Stefan Zeuzem, Wolf P. Hofmann,
Harry L. Janssen, Bettina E. Hansen, Bart J. Veldt, Robert J. de
Knegt
1521: Prognostic factors of survival in HIV-
HCV coinfected patients after a first episode of
decompensation: the French prospective multicenter
ANRS HC EP 25 PRETHEVIC Cohort
Moana Gelu-Simeon, Tatiana Bayan, Maria Ostos, Elina Teicher,
Hélène Fontaine, Pierre Tattevin, Isabelle Poizot-Martin, Stephanie
Dominguez, David Zucman, Julie Chas, Pascal P. Crenn, Anne
Gervais, Karine Lacombe, Philippe Morlat, Rodolphe Anty,
Faroudy Boufassa, Inga Bertucci, Georges-Philippe Pageaux,
Laurence Meyer, Jean-Charles Duclos-Vallée
1522: Mutual Inhibition between Hepatitis B Virus (HBV)
and Hepatitis C Virus (HCV)
Ge Yu, Yu Pan, Ruihong Wu, Xiumei Chi, Xiaomei Wang, Xiuzhu
Gao, Fei Kong, Xiang-wei Feng, Jinglan Jin, Yue Qi, Junqi Niu
1523: Effect of Hemochromatosis gene mutation on HCV
response to treatment in the Egyptian population
Mazen I. Naga, Mona A. Amin, Dina A. Algendy, Ahmed I. El
Badry, Mai M. Fawzi, Ayman R. Foda, Serag M. Esmat, Dina
Sabry, Laila A. Rashed, Samia M. Gabal, Manal Kamal
1524: Hepatitis C infection is not associated with
metabolic syndrome irrespective of age, gender and
fibrosis
Chien-Wei Su, Yuan-Jen Wang, Keng-Hsin Lan, Teh-Ia Huo,
Yi-Hsiang Huang, Kuei-Chuan Lee, Han-Chieh Lin, Fa-Yauh Lee,
Jaw-Ching Wu, Shou-Dong Lee
1525: Boceprevir and telaprevir-based regimens for the
treatment of hepatitis C virus in a real world HIV/HCV
co-infected cohort
Lauren A. Beste, Pamela Green, George N. Ioannou
1526: Low albumin is independent risk factor for post-
sustained virologic response hepatocellular carcinoma
in chronic hepatitis C patients: A case control study
Qing-Lei Zeng, Bin Yang, Bing Li, Xue-Xiu Zhang, Fu-Sheng Wang
1527: HCV and HIV Co-Infection and Related Risks in
Injecting Drug Users From A Superspeciality Centre
Arun K. Sharma, Subodh Bn, Debasish Basu
1528: Audit of a universal antenatal hepatitis C virus
screening programme at a London hospital
Nowlan Selvapatt, Heather Bailey, Claire Thorne, Lay-May See,
Melanie Douglas, Mark R. Thursz, Gareth Tudor-Williams, Ashley
S. Brown
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1529: Clinical utility of the VERSANT HCV RNA 1.0
Assay (kPCR) for HCV-RNA quantification in patients
with HCV genotype 1-infection
Johannes Vermehren, Simone Susser, Dany Perner, Stefan Zeuzem,
Christoph Sarrazin
1530: Delay presentation to care is an independent
prognostic factor for clinical outcomes in patients with
chronic hepatitis C
Blaise K. Kutala, Laurent Cattan, Christine Aurière, Alexandrine Di
Pumpo, Beatrice Monnier, Nathalie Giuily, Kevin Appourchaux,
Corinne Castelnau, Patrick Marcellin, Nathalie Boyer
1531: VITRO-score (vWF-Ag/thrombocytes) predicting
mortality in HCV cirrhosis in comparison to MELD-score
Andreas Maieron, Stephanie Hametner, Silvia I. Hametner, Monika
Ferlitsch, Rainer Schöfl, Alexander Ziachehabi, Arnulf Ferlitsch
1532: Learning curve and intraobserver agreement of
liver stiffness measurement in chronic hepatitis C with or
without HIV co-infection
Hugo Perazzo, João Carlos Soares, Flavia F. Fernandes, Juliana
Fittipaldi, Sandra W. Cardoso, Beatriz Grinsztejn, Valdilea Veloso
1533: Hepatitis C virus infection in HIV-positive men
who have sex with men: Systematic review and meta-
analysis
Holly Hagan, Joshua Neuer, Ashly Jordan
1534: Urinary Metabolite Biomarker Panel for the
Detection of Hepatocellular Carcinoma in Hepatitis C
Infected Populations
Wendy S. Baker, John R. Petersen, Maen M. Masadeh, Feroze A.
Hussain, Heidi Spratt
1535: Clinical outcomes of chronic hepatitis C in Korea:
A prospective, multicenter cohort study
Kyeong Sam Ok, Sook-Hyang Jeong, Eun Sun Jang, Young Seok
Kim, Youn Jae Lee, Si Hyun Bae, Han Chu Lee, Mee-Kyung Kee,
Sung Soon Kim, Chun Kang
1536: Disease Burden of Chronic Hepatitis C Virus
(HCV) Infection in India
Pankaj Puri, Anil C. Anand, Vivek A. Saraswat, Subrat K. Acharya,
Shiv K. Sarin, Radha K. Dhiman, Rakesh Aggarwal, Shivaram P.
Singh, Deepak N. Amarapurkar, Anil Arora, Mohinish Chhabra,
Kamal Chetri, Gourdas Choudhuri, Abhijit Chowdhury, Vinod K.
Dixit, Ajay K. Duseja, Sarah Blach, Ajay K. Jain, Dharmesh Kapoor,
Premashis Kar, Abraham Koshy, Ashish Kumar, Kaushal Madan,
Sri P. Misra, Mohan V. Prasad, Aabha Nagral, Amarendra S. Puri,
Jeyamani Ramachandran, Homie Razavi, Sanjiv Saigal, Samir R.
Shah, Praveen K. Sharma, Ajit Sood, Sandeep Thareja, Manav
Wadhawan
1537: Characterization of Hepatitis C Patients who
fail to Achieve Sustained Virologic Response with
Triple Therapy (Peg-Interferon Alfa and Ribavirin with
Boceprevir or Telaprevir)
T Craig Cheetham, Yong Yuan, Fang Niu, Anupama Kalsekar,
Rulin Hechter, Kevin Chiang, Joel Hay, Lisa M. Nyberg
Poster Viewing: 8:00 AM – 5:30 PM
165A
1538: Identifying patients with chronic hepatitis C in
need of early treatment and intensive monitoring: A
systematic review of predictors and predictive models of
disease progression
Monica Konerman, Suna Yapali, Anna S. Lok
1539: Low Rates of Baby Boomer Screening for
Hepatitis C in Initial Primary Care Visits at a Tertiary
Care Center
Bonnie A. Ewald, Alysse G. Wurcel, Sonali Paul, Kathleen Viveiros
1540: Evidence for Multiple Transmission Pathways and
Geographic Variation of HCV infection in Ghana, West
Africa
Jennifer E. Layden, Richard O. Phillips, Fred S. Sarfo, Dorcas
O. Owusu, Nallely Mora, Joseph Forbi, Stephanie Kliethermes,
Shirley P. Owusu-Ofori, Ohene Opare-Sem, Kenrad Nelson,
Richard Cooper
1541: HCV genotypes and NS3-DAAs resistant
mutations in treatment naive HIV/HCV co-infected
population in the South of China
Fengyu Hu, Zhiwei Liang, Yun Lan, Xiaoping Tang, Weiping Cai
1542: Treatment of Latent Tuberculosis in Patients with
Hepatitis C and Advanced Fibrosis
Christini T. Emori, Silvia N. Uehara, Ana Cristina A. Feldner,
Antonio Eduardo B. Silva, Roberto J. Carvalho-Filho, Ivonete Silva,
Maria Lucia Ferraz
1543: Chronic Hepatitis C Infection May Be Associated
With Adverse Clinical Outcomes Following Renal
Transplantation
Charles Gabbert, Siva Talluri, Mordechai Rabinovitz
1544: Hepatitis C virus RNA and genotype, IL28B
genotype, and liver fibrosis scores in a regional cohort
of HIV-HCV co-infected patients under routine HIV care
in Asia
Nicolas Durier, Kiat Ruxrungtham, Anchalee Avihingsanon, Kinh
Nguyen Van, Bui Vu Huy, Evy Yunihastuti, Andri S. Sulaiman,
Sharifah Faridah binti Syed Omar, Ilias Adam Yee, Patricia
Morgan, David Boettiger, Gail Matthews
1545: Vitamin D status and liver stiffness in chronic
hepatitis C infection
Matthew T. Kitson, Paula Lewis, William W. Kemp, Adam Gordon,
Eldho Paul, Stuart K. Roberts
NOVEMBER 10
MONDAY
1546: Fibroscan has a low predictive performance
for hepatocellular carcinoma in HCV patients with or
without a sustained virological response
Philippe Sultanik, Damien Soudan, Samir Bouam, Jean-Francois
Meritet, Anaïs Vallet-Pichard, Hélène Fontaine, Laurence Bousquet,
Marion Corouge, Estelle Boueyre, Philippe Sogni, Stanislas Pol,
Vincent Mallet
Presenters in Attendance 12:30 – 2:00 PM
 166A POSTER SESSIONS
Poster Sessions
Health Care Delivery
1547: A value-based approach to the management
of patients with liver cirrhosis through the systematic
measurement of clinical outcome and quality of life
indicators
Stefano Okolicsanyi, Antonio Ciaccio, Paolo A. Cortesi, Matteo
Rota, Marta Gemma, Pietro Giani, Luciana Scalone, Lorenzo
G. Mantovani, Stefano Fagiuoli, Maria G. Valsecchi, Giancarlo
Cesana, Luca S Belli, Mario Strazzabosco
1548: Bi-Factor Item Response Theory (IRT) modeling
reveals that the Chronic Liver Disease Questionnaire
(CLDQ) overestimates the clinical relevance of liver
disease-specific subdomain scores
Sujit V. Janardhan, Andrew Aronsohn, Jason Morris, Robert
Gibbons, David G. Beiser
1549: CDC guidelines for hepatitis C screening have
no impact on screening or linkage to care
Mansi Kothari, Archita P. Desai, Andrew Aronsohn, K. Gautham
Reddy, Donald M. Jensen, Helen S. Te, Nancy Reau
1550: Benefit of Early Palliative Care Intervention
in End-stage Liver Disease Patients Awaiting Liver
Transplantation
Alexandra J. Baumann, David Wheeler, Marva James, Arthur
Siegel, Victor J. Navarro
1551: Barriers to Receipt of Recommended Chronic
Hepatitis B Care at a Tertiary Medical Center in
Northern California
Cara Torruellas, Moon Chen, Brian Chan, Susan Stewart, Julie
Dang, Tina T. Fung, Duke A. LeTran, Christopher L. Bowlus
1552: Inadequate Hepatitis B Care in Mothers After
Pregnancy
Ruma Rajbhandari, Anna C. Juncadella, Anna K. Rubin, Tokunbo
Ajayi, Ying Wu, Ashwin N. Ananthakrishnan, Raymond T. Chung
1553: Hospice Care Utilization Improves Outcome
of Medicare Patients Diagnosed with Hepatocellular
Carcinoma
Zobair Younossi, Li Zheng, Jessica Heintz, James N. Cooper,
Andrei Racila, Madeline Erario, Linda Henry, Alita Mishra, Sharon
L. Hunt, Gregory Trimble
1554: A quality improvement initiative decreases
NOVEMBER 10
30-day readmission rates in patients admitted to a
MONDAY
Hepatology Service
Elliot B. Tapper, Dan Finkelstein, Gail Piatkowski, Murray
Mittleman, Michelle Lai
1555: Information Technology Decision Support
Improves Hepatitis C Screening Rates But Not Diagnosis
Rates
Todd L. Burstain, Monika Ahuja, Michael D. Voigt
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1556: Predictors of 30-day Hospital Readmission after
Deceased Donor Liver Transplantation
Jessica Yu, Amy Hosmer, Tamara Parks, Christopher J. Sonnenday,
Pratima Sharma
1557: Hospice referral among veterans with cirrhosis
is infrequent and primarily utilized for malignancy, not
decompensated cirrhosis
Mina Rakoski, Grace L. Su, Anna S. Lok, Michael Volk
1558: Sero-prevalence of Hepatitis E In Patients With
Chronic Liver Disease
Niharika Samala, Elizabeth C. Wright, Joni Trenbeath, Ronald E.
Engle, Nancy Fryzek, Harvey J. Alter, Jay H. Hoofnagle, Marc G.
Ghany
1559: The impact of liver disease on the health-related
quality of life
Paolo A. Cortesi, Matteo Rota, Luciana Scalone, Paolo Cozzolino,
Giancarlo Cesana, Lorenzo G. Mantovani, Stefano Okolicsanyi,
Antonio Ciaccio, Marta Gemma, Stefano Fagiuoli, Maria G.
Valsecchi, Luca S Belli, Mario Strazzabosco
1560: Chronic liver disease related morbidity compared
to congestive heart failure and chronic obstructive
pulmonary disease
Sumeet K. Asrani, Maria A. Kouznetsova, Andrew Masica, Brett
Stauffer, James F. Trotter, Patrick Kamath, Fasiha Kanwal
1561: Variation in Liver Disease Related Mortality in the
United States
Archita P. Desai, Ricki Bettencourt, Rohit Loomba
1562: Severity of illness, referral patterns and
specialized care are important determinants of same-
center thirty day readmissions in patients with cirrhosis
Marwan Ghabril, Samuel Hohmann, Eric S. Orman, Raj
Vuppalanchi, Paul Y. Kwo, Naga P. Chalasani
1563: Healthcare Utilization Among Patients with
Cirrhosis: The Role of Inflammation, Medications, Pain,
and Depression
Shari S. Rogal, Klaus Bielefeldt, Susan Zickmund, Andrea DiMartini
1564: Predictors of Increased Healthcare Utilization
After Liver Transplantation
Shari S. Rogal, Gautam Mankaney, Viyan Udawatta, Christopher
B. Hughes, Amit D. Tevar, Mark Sturdevant, Abhinav Humar,
Andrea DiMartini
1565: Pneumonia Vaccination Prevalence in Liver
Cirrhosis
Tuyyab Hassan, Sulieman Abdal Raheem, Ripple Mehta, Omer J.
Deen, Naim Alkhouri, Annette Kyprianou
1566: Personalized Learning: A Novel Educational
Model to Prepare and Expand the Hepatitis C
Workforce
Nancy Reau, Tara G. Edmonds, Jennifer Garick, Catherine C.
Capparelli, Simi Hurst
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1567: Update from an HCV Screening Program in an
Emergency Department in the Southern US: Challenges
to Follow-up and Linkage to Care
Anne Zinski, Ricardo A. Franco, Henry E. Wang, Michael Saag,
Edgar T. Overton, Jordan M. Forsythe, Joel B. Rodgers, James W.
Galbraith
1568: Hepatitis B (HBV) knowledge in a large multi-
ethnic North American cohort with chronic hepatitis
B infection: Impact of ethnicity, migration status, and
language fluency
Mandana Khalili, Colina Yim, Donna M. Evon, Mauricio Lisker-
Melman, Harry L. Janssen, Mohamed A. Hassan, Coleman Smith,
Anna S. Lok
1569: Increased all-cause hospitalization among
hepatitis C virus (HCV)-infected persons: the Chronic
Hepatitis Cohort Study (CHeCS), 2006-2010
Eyasu H. Teshale, Jian Xing, Scott D. Holmberg, Anne C.
Moorman, Stuart C. Gordon, Loralee B. Rupp, Mei Lu, Philip
Spradling, Joseph A. Boscarino, Vinutha Vijayadeva, Mark A.
Schmidt, Fujie Xu
1570: Assessment of Readmission rates and mortality in
hospitalized Cirrhotic patients: A review of the state in
patient database
Shaheryar Siddiqui, Shivang Mehta, Sachin Batra, Victor I.
Machicao, Michael B. Fallon
1571: Vaccination Rates in Cirrhotic Liver Disease
Abhijeet Waghray, Nisheet Waghray, Annette Kyprianou, KV
Narayanan Menon
1572: A national audit on hepatocellular carcinoma
(HCC) epidemiology and management in a Western
country: survival factors including healthcare
organization and referral pattern
Nathalie GOUTTE, Philippe Sogni, Noelle Bendersky, Bruno
Falissard, Olivier Farges
1573: Fatigue of Compensated Chronic Liver Disease
is associated with Altered Sleep Pattern and Melatonin
Profile
Michele M. Tana, Hawwa Alao, Nevitt Morris, Mary Walter,
Jacob Hattenbach, Sarah Smyth, Robert Brychta, Xiongce Zhao,
Yaron Rotman
1574: AASLD Guidelines for Chronic Hepatitis B
Management: Knowledge and Adherence Among
HIV Providers and Hepatologists at a Large Academic
Medical Center
Bevin Hearn, Rachel Chasan, Kian Bichoupan, Maria Suprun,
Emilia Bagiella, Douglas Dieterich, Ponni Perumalswami, Andrea
D. Branch, Shirish Huprikar
1575: Interferon (INF)-Free Regimens for Chronic
Hepatitis C (CHC): Barriers to Treatment Candidacy and
Insurance Coverage
Zobair Younossi, Maria Stepanova, Brian P. Lam, Manirath
Srishord, Spencer Frost, Huong T. Pham, Andrei Racila, Mariam
Afendy, Thomas Jeffers
Poster Viewing: 8:00 AM – 5:30 PM
167A
1576: Overestimation of Decline in Health-Related
Quality of Life Occurs in a Third of Cirrhotic Patients
Compared to US Norms using PROMIS tools
Jasmohan S. Bajaj, Melanie White, Nicole Noble, Richard K.
Sterling, R. Todd Stravitz, Mohammad S. Siddiqui, Scott Matherly,
Arun J. Sanyal, Puneet Puri, Velimir A. Luketic, Douglas M.
Heuman, Michael Fuchs, James Wade
1577: Paradigm Shift in Access to Adult Liver
Transplantation
Nyingi M. Kemmer, Chris Albers, Edson S. Franco, Husssein
Osman-Mohamed, Erin Parkinson, Elizabeth Cece Fallon, Jennifer
Horkan, Angel Alsina
1578: Telehepatology improves provider satisfaction
and specialty care integration among rural Veterans
Affairs Primary Care Providers
Lauren A. Beste, Raimund Pichler, Maureen Germani, Michael F.
Chang, Bessie Young
1579: Preventative Care Quality Indicator Adherence
and Factors Affecting Quality Care Measurement in
Patients with Cirrhosis: A Single-centered Study
Steven J. Scaglione, Kirk Shepard, William Adams, Elizabeth
Pappano, Atif M. Ali, Amanda Cheung, Vishnu Vardhan Reddy
Naravadi, Justin Mitchell, Rebecca Tsang, Shaham Mumtaz,
Edward Villa, Susan Zelisko, Stephanie Kliethermes, Nina Clark,
Scott Cotler
1580: Predictors of Attendance at the Gastroenterology
Clinic to Discuss Treatment for Hepatitis C
Susan L. Zickmund, Michael K. Chapko, Barbara H. Hanusa, Ada
O. Youk, Galen E. Switzer, Mary Ann Sevick, David S. Obrosky,
Nichole K. Bayliss, Carolyn L. Zook, Robert A. Arnold
1581: Immigrant Status Influence on Chronic Hepatitis C
Virus Infection Management
Curtis Cooper, Kimberly Corace, Crystal D. Holly, Gary Garber
1582: Community-wide outreach and screening to
reduce hepatitis B and hepatitis C disparities among
Somali immigrants in Minnesota
Nasra H. Giama, Abdirashid Shire, Hassan M. Shaleh, Essa A.
Mohamed, Lewis R. Roberts
1583: Burden of chronic viral hepatitis and liver
cirrhosis in Brazil – The Brazilian Global Burden of
Disease Study
NOVEMBER 10
Juliana R. de Carvalho, Flávia B. Portugal, Luísa S. Flor, Mônica
MONDAY
R. Campos, Renata M. Perez, Cristiane Villela-Nogueira, Joyce
Mendes A. Schramm
1584: Use of non-invasive markers of fibrosis for
prioritizing HCV antiviral drug treatment
Samuel B. Ho, Paul Thuras, Erik J. Groessl, Eric Dieperink
1585: A Universal Testing Programme for Blood Borne
Viruses in an Urban Emergency Department – a call for
widespread ED testing in Ireland
Sarah O’Connell, Darren Lillis, Siobhan O’Dea, Helen Tuite,
Catherine Fleming, Helen Barry, Linda Dalby, Darragh Shields,
Suzanne Norris, Brendan Crowley, Patrick K. Plunkett, Colm J. Bergin
Presenters in Attendance 12:30 – 2:00 PM
 168A POSTER SESSIONS
Poster Sessions
1586: Barriers to Initiating Treatment for Hepatitis C:
Results of a Veteran Population
Susan L. Zickmund, Michael K. Chapko, Barbara H. Hanusa, Ada
O. Youk, Galen E. Switzer, Mary Ann Sevick, Nichole K. Bayliss,
Carolyn L. Zook, David S. Obrosky, Robert A. Arnold
1587: Results of a Strategy to Identify Kidney
Transplant Recipients with Chronic Hepatitis C for
Interferon-Free Therapies
Genevieve Huard, Anna Patel, Brian Kim, Badr Aljarallah, Ponni
Perumalswami, Joseph A. Odin, Sara Geatrakas, Jawad Ahmad,
Douglas Dieterich, Vinay Nair, Thomas D. Schiano, Gene Y. Im
1588: Outcomes of a HCV treatment programme in
PWID over 10 years support a disease eradication
strategy for all patients in the DAA era
Omar El-Sherif, Ciaran L. Bannan, Shay Keating, Susan McKiernan,
Colm J. Bergin, Suzanne Norris
1589: The Influence of Race on Patient Preferences and
Access to Orthotopic Liver Transplantation and Organ
Donation
Omobonike O. Oloruntoba, Julius M. Wilder, Alastair D. Smith,
Andrew J. Muir, Cynthia A. Moylan
1590: The burden of illness associated with cirrhosis
and impact of universal coverage public health care
system in Thailand: Nationwide study
Kittiyod Poovorawan, Sombat Treeprasertsuk, Kaewjai
Thepsuthammarat, Bubpha -. Kitsahawong, Kamthorn Phaosawasdi
1591: Predictors of Sub-Optimal Hepatitis C Treatment
Adherence: Improving Patient Outcomes
Kimberly Corace, Crystal D. Holly, Gary Garber, Mark Kaluzienski,
Craig Lee, Thomas Shaw-Stiffel, Louise Balfour, Curtis Cooper
1592: High morbidity and mortality in end-stage liver
disease and heart failure
Cristal L. Brown, Bradley G. Hammill, Laura G. Qualls, Lesley H.
Curtis, Andrew J. Muir
1593: Symptomatic Hypogonadism in Patients listed for
Liver Transplantation and Hepatocellular Carcinoma
Anish V. Patel, Vinay Sundaram, Tram T. Tran
1594: Variceal Screening in Cirrhotic Patients
Abhijeet Waghray, Nisheet Waghray, Annette Kyprianou, KV
Narayanan Menon
NOVEMBER 10
MONDAY
Pediatric Liver Disease - Basic Science
1595: Bile salt export pump and basolateral bile
salt uptake transporters are down-regulated in
hepatoblastoma and not in hepatocellular carcinoma
Corina G. Cotoi, Peter T. Clayton, Alberto Quaglia, A. S. Knisely
1596: Hepatic Encephalopathy in Children with Acute
Liver Failure – Utility of Serum Neuromarkers
Nicole A. Toney, Robert H. Squires, Steven H. Belle, Regina M.
Hardison, Michael J. Bell
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1597: Association of NADSYN1, DHCR7, GC and VDR
Genotypes With Steatosis And Liver Inflammation in UK
Paediatric Non-Alcoholic Fatty Liver Disease Patients
Philippa S. Gibson, Emer Fitzpatrick, Alberto Quaglia, Anil
Dhawan, Huihai Wu, Kathryn Hart, Susan Lanham-New, J
Bernadette Moore
1598: Microarray analysis of laser-captured portal
tracts of Jag1+/-Rfng+/- liver reveals possible sub-
population of hepatic progenitors
Lara A. Underkoffler, Emily K. McComb, John Dutton, Anthony
Nelson, Kathleen M. Loomes, Matthew J. Ryan
1599: Jag1+/- Rfng+/- murine livers show aberrant
differentiation of Sox9 progenitors by one week of age
Lara A. Underkoffler, Emily K. McComb, John Dutton, Anthony
Nelson, Kathleen M. Loomes, Matthew J. Ryan
Pediatric Liver Transplantation
1600: Data-Driven Modeling for Precision Medicine
in Pediatric Acute Liver Failure
Ruben Zamora, Yoram Vodovotz, Othman Abdul-Malak, Qi Mi,
Khalid Almahmoud, Rami A. Namas, Derek Barclay, Robert H.
Squires
1601: Analysis of Trends in Incidence, Management,
Etiology and Death [TIMED] due to Pediatric Acute Liver
Failure [ALF] in the United States: Results of Analysis of
the National Pediatric Health Information Systems [PHIS]
Database, 2008-2013
Sakil Kulkarni, Carla Perez, Caren Pichardo, Lina I. Castillo,
Michael A. Gagnon, Conseulo Beck-Sague, Erick Hernandez, Rani
S. Gereige
1602: Low Rate of Recurrent Primary Sclerosing
Cholangitis in Pediatric Orthotopic Liver Transplant
Recipients
Sarah Taylor, Steven J. Lobritto, Mercedes Martinez, Jennifer
Vittorio, Adam Griesemer, Tomoaki Kato, Jean C. Emond, Nadia
Ovchinsky
1603: Intravenous pentamidine is efficacious for
pneumocystis carinii/jiroveci pneumonia (PCP)
prophylaxis in pediatric liver and small bowel
transplant patients
Abigail Clark, Trina S. Hemmelgarn, Rohit Kohli, Lara Danziger-
Isakov, Ashley Teusink
1604: Nutritional Status and Perioperative Nutritional
Support in Children after Liver Transplantation
Jaime C. Silva, Stacey S. Beer, Ursula G. Kyle, Mariana Treviño
Ramos, Jennifer L. Lusk, Ryan Himes, Moreshwar Desai, John A.
Goss, Jorge Coss-Bu
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
Poster Session 4
Tuesday, November 11
POSTER VIEWING: 8:00 AM - Noon
Hall C
Presenters in attendance:
10:30 AM - NOON
Those posters identified as AASLD Presidential Poster of Distinction
by a ribbon icon have received review scores that place them
within the top 10 percent of all posters. We encourage you to
make them a priority as you visit the poster sessions.
HBV: Diagnostics, Epidemiology,
Prevention, Natural History
1605: Prevalence of Precore and Dual Basal Core
Promoter HBV Variants in a Racially Diverse Cohort of
Patients with Chronic HBV Infection in North America
Daryl Lau, Lilia Ganova-Raeva, Raymond T. Chung, Geoffrey
Johnson, Kyong-Mi Chang, Mauricio Lisker-Melman, Obaid S.
Shaikh, Harry L. Janssen, Abdus S. Wahed, Anna S. Lok
1606: Evolution rules of hepatic fibrosis at different
natural history phases of chronic HBV infection in 637
Chinese patients
Qing He, Xuejiao Liao, Shuling Ai, Qingrong Tang, Qi Yuan Tang,
Feijian Ao, Zhiyu Li, Bing Bai
1607: Influence of Delta Virus Infection on the
Clinical Spectrum, Serologic and Virologic Status in
Chronic Hepatitis B Virus Genotype D
Rabab F. Omar, Rasha Ahmed, Dina Sabry, Mahmoud Abdel
Alim, Mira Atef, Naglaa Zayed
1608: Incidence of Hepatocellular Carcinoma after
HBsAg seroclearance in Chronic Hepatitis B patients: a
need for Surveillance
Gi-Ae Kim, Han Chu Lee, Yeonjung Ha, Eui Ju Park, Jihyun An
1609: Effect of Race on the Risk of Hepatocellular
Cancer in U.S. Veterans with Chronic Hepatitis B Virus
Infection
Sahil Mittal, Jennifer R. Kramer, Peter Richardson, Hashem
El-Serag, Fasiha Kanwal
1610: Epidemiology of Hepatitis B Virus Infection
according to Genotype in Alaska Native People
Michael Bruce, Lance Ching, Prabhu P. Gounder, Lisa Bulkow,
Philip R. Spradling, Mary Snowball, Susan Negus, Brian J.
McMahon
1611: Hepatitis B Screening and Prevalence among
High-Risk Populations within the Department of
Veterans Affairs
Lisa I. Backus, Pamela S. Belperio, Timothy P. Loomis, Larry A.
Mole
Poster Viewing: 8:00 AM – Noon
169A
1612: Delta Hepatitis Within the Veterans Affairs
Medical System
Tatyana Kushner, David E. Kaplan
1613: Early on-treatment HDV RNA kinetics are not
predicitve for long-term response to a PEG-IFNa therapy
of hepatitis delta
Michael Wöbse, Cihan Yurdaydin, Stefanie Ernst, Svenja Hardtke,
Benjamin Heidrich, Birgit Bremer, Onur Keskin, Ramazan Idilman,
Armin Koch, Michael P. Manns, Heiner Wedemeyer
1614: Hepatocellular Carcinoma Risk By Genotype
Among Hepatitis B Virus Infected Alaska Native
Persons Who Are Below the Age For Which Guidelines
Recommend HCC Surveillance. A Population-Based
Retrospective Cohort Study
Prabhu P. Gounder, Lisa Bulkow, Mary Snowball, Susan Negus,
Philip R. Spradling, Michael Bruce, Brian J. McMahon
1615: Serological and Molecular Epidemiological
Outcomes after Two Decades of Universal Infant
Hepatitis B Virus (HBV) Vaccination in Nunavut, Canada
Chris Huynh, Gerald Y. Minuk, Julia Uhanova, Maureen Baikie,
Lianne Vardy, Thomas Wong, Carla Osiowy
1616: Prospective study of hepatitis B virus reactivation
in rheumatoid arthritis patients on immunosuppressive
therapy: Evaluation of both HBsAg-positive and
-negative cohorts
Akihiro Tamori, Hitoshi Goto, Masahiro Tada, Kentaro Inui, Etsushi
Kawamura, Atsushi Hagihara, Sawako Kobayashi, Hiroyasu
Morikawa, Masaru Enomoto, Yoshiki Murakami, Norifumi Kawada
1617: Loss of immune tolerance is associated with HBV
genotype specific patterns of accumulation of basal core
promotor and precore variants, leading to decline in
HBeAg and HBsAg levels
Gillian Rosenberg, Julianne Bayliss, Anuj Gaggar, Kathryn M.
Kitrinos, Mani Subramanian, Patrick Marcellin, Edward J. Gane,
Henry Lik-Yuen Chan, Rachel Hammond, Xin Li, Danni Colledge,
Margaret Littlejohn, Lilly Yuen, Rosalind Edwards, Kathy Jackson,
Sara Bonanzinga, Scott Bowden, Peter A. Revill, Stephen Locarnini,
Alexander J. Thompson
1618: Analysis of dynamic parameters predicting
HBsAg seroclearance in a cohort of European untreated
hepatitis B (HBV) infected patients: a prospective
longitudinal study (ALBATROS Study)
Viola Knop, Johannes Vermehren, Eva Herrmann, Joerg Petersen,
Peter Buggisch, Heiner Wedemeyer, Markus Cornberg, Stefan
Mauss, Martin F. Sprinzl, Dietrich Hueppe, Thomas Berg,
Florian van Boemmel, Michael Rausch, Tania M. Welzel, Judith
Wuerzburg, Simone Susser, Stefan Zeuzem, Christoph Sarrazin
1619: Anti-HBs loss and HBV Reactivation Between
NOVEMBER 11
Reduced Intensity versus Myeloablative Hematopoietic
TUESDAY
Stem Cell Transplant Regimens
Hawwa Alao, Jeddeo Paul, Robert N. Reger, Elizabeth C. Wright,
Kit Lu, Richard Childs, Marc G. Ghany
Presenters in Attendance 10:30 AM – Noon
 170A POSTER SESSIONS
Poster Sessions
1620: Increases in APRI are Associated with Liver-
Related Death in HIV-Viral Hepatitis Coinfection
Jennifer C. Price, Eric C. Seaberg, Claudia Hawkins, Susan L.
Koletar, Mallory Witt, Chloe L. Thio
1621: Increased risk of developing hepatocellular
carcinoma in chronic hepatitis B patients with transient
elastography-defined subclinical cirrhosis
Mi Na Kim, Beom Kyung Kim, Jun Yong Park, Do Young Kim,
Sang Hoon Ahn, Kwang-Hyub Han, Seung Up Kim
1622: Cirrhosis and its decompensation in chronic
hepatitis B patients with new onset hypertension: A
nationwide cohort study
Yi-Wen Huang, Szu-Chieh Fu, Ting Chuan Wang, Jui-Ting Hu,
Ding-Shinn Chen, Jia-Horng Kao, Sien-Sing Yang
1623: Mapping the HBsAg immune phenotype to
predict HBsAg loss or decline in chronic hepatitis B in
patients receiving nucleot(s)ide analogue therapy
Lucy Y. Lim, Lilly Yuen, Rachel Hammond, Peter W. Angus,
Alexander J. Thompson, Scott Patterson, Thomas Leary, Peng Yin,
Howard Thomas, Stephen Locarnini, Renae Walsh
1624: A newly developed prognosis index Improves
Mortality Prediction in Patients with HBV-related Acute-
on-chronic Liver Failure
Zhihong Wan, Yichen Wu, Shaoli You, HongLing Liu, Bing Zhu,
ShaoJie Xin
1625: The APOBEC3B gene deletion and hepatitis B
virus-associated hepatocellular carcinoma
Ping An, Zheng Zeng, Victor David, Cheryl A. Winkler
1626: HBV nucleic acid quantification from liver tissue
supports antiviral treatment decisions based on serum
markers, but not in all phases of infection
Andrzej Taranta, Magdalena Rogalska-Taranta, Benjamin
Maasoumy, Jerzy Jaroszewicz, Michael P. Manns, Robert Flisiak,
Karsten Wursthorn
1627: Evaluation of liver fibrosis and prediction of
hepatic carcinogenesis for patients with chronic hepatitis
B by a unique glycoprotein: Wisteria floribunda
agglutinin-positive Mac-2 binding protein (WFA+-M2BP)
Shuhei Hige, Itaru Ozeki, Mutuumi Kimura, Tomohiro Arakawa,
Tomoaki Nakajima, Yasuaki Kuwata, Takahiro Sato, Takumi
Ohmura, Yoshiyasu Karino, Joji Toyota, Masashi Mizokami,
Atsushi Kuno, Hisashi Narimatsu
1628: Changing Epidemiology of Hepatitis Delta
Virus Infection in an HBV Hyper-endemic Area with
Nationwide HBV Vaccination Program: the Need of
Booster for High Risk Groups
Hsi-Hsun Lin, Jaw-Ching Wu, Chien-Wei Su
NOVEMBER 11
1629: Prevalence and Molecular Virology of Hepatitis
TUESDAY
Delta Virus in the Western Pacific Region
Kathy Jackson, Meifang Han, Lilly Yuen, Rosalind Edwards, Uma
Devi, Scott Bowden, Qin Ning, Stephen Locarnini, Margaret
Littlejohn
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1630: Investigation of the efficacy of HBV DNA and
HBsAg quantifications and liver stiffness measurements
in identifying inactive HBV infection at a single time
point evaluation
Sergio Maimone, Gaia Caccamo, Giovanni Squadrito, Angela
Alibrandi, Francesca Saffioti, Rosaria Spinella, Giuseppina Raffa,
Teresa Pollicino, Giovanni Raimondo
1631: Serum Caspase-Cleaved Cytokeratin 18
Fragments As A Potential Marker For Predicting Poor
Outcome Of HBV Related Acute-On-Chronic Liver
Failure
ZhuJun Cao, FengDI Li, Kehui Liu, Weiliang Tang, Yuhan Liu, Lanyi
Lin, Hong Yu, Qing Xie, Hui Wang
1632: Efficacy of Third Trimester Maternal Tenofovir
Disoproxil Fumarate Treatment in Interrupting Mother-
to-Infant Transmission of Hepatitis B Virus
Huey-Ling Chen, Chien-Nan Lee, Chin-Hao Chang, Yen-Hsuan Ni,
Shih-Ming Chen, Jen-Jan Hu, Hans Hsienhong Lin, Shu-Chi Mu,
Ming-Wei Lai, Ming-Song Tsai, Ding-Shinn Chen, K. Arnold Chan,
Mei-Hwei Chang
1633: Risk of development of hepatocellular carcinoma
in chronic hepatitis B patients with normal or mildly
elevated alanine aminotransferase levels
Ji Hyeon Lee, Dong Hyun Sinn, Geum-Youn Gwak, Ju-Yeon Cho,
Won Sohn, Yong-Han Paik, Moon Seok Choi, Joon Hyeok Lee,
Kwang Cheol Koh, Seung Woon Paik, Byung Chul Yoo
1634: Tendency to Develop Acute Hepatitis B and its
Outcome in HIV Coinfection: Comparison with HBV
Infection Alone
Yuichi Nozaki, Akahito Sako, Shintaro Mikami, Yasushi Kojima,
Masatoshi Imamura, Nao Nishida, Masaya Sugiyama, Masaaki
Korenaga, Kazumoto Murata, Tatsuya Kanto, Hiroyuki Gatanaga,
Yoshimi Kikuchi, Shinichi Oka, Mikio Yanase, Naohiko Masaki,
Masashi Mizokami
1635: WITHDRAWN
1636: High levels of Hepatitis B surface antigen (HBsAg)
can exclude significant fibrosis and distinguishes true
‘immune-tolerance’ in children and young adults with
Chronic Hepatitis B
Navjyot K. Hansi, Upkar S. Gill, Amrita Banerjee, Neelan
Surendraraj, Chandni Patel, Sandhia Naik, Graham R. Foster,
Patrick T. Kennedy
1637: Lack of usefulness of serum makers for
assessment of significant liver fibrosis in inactive
carriers of hepatitis B infection
Mar Riveiro-Barciela, Francisco Rodríguez-Frías, Maria Homs,
David Tabernero, Maria Buti, Rafael Esteban
1638: Patients lost to follow up: the experience of an
Australian Hepatitis B Clinic
Phil Ha, Vanessa Bull, Natassia Tan, Stephanie Spring, Lukas J.
Sahhar, Suong T. Le, Anouk T. Dev
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1639: Diagnostic performance of transient elastography
(Fibroscan ®) for the assessment of liver fibrosis in
patients with chronic hepatitis B: Impact of ALT and HBV
DNA serum levels
NANA Koudbi Jean, Tarik Asselah, Michael Adler, Marie Noelle
Hilleret, Jean-Pierre H. Zarski, Alice Marlu, Vincent Leroy
1640: Hepatitis flares are common among patients
receiving chemotherapy for cancers
Jessica P. Hwang, Andrea G. Barbo, Anna S. Lok
1641: Antiviral Therapy and the Development of
Hepatocellular Carcinoma (HCC) in Chronic Hepatitis
B (CHB) Patients with and without Cirrhosis in a US
Population
Derek Lin, Nghia H. Nguyen, Joseph Hoang, Vinh D. Vu, Huy N.
Trinh, Jiayi Li, Jian Q. Zhang, Huy A. Nguyen, Khanh Nguyen,
Mindie H. Nguyen
1642: A Prospective and Large Sample Study for the
Long-term Safety and Clinic Outcome after Postpartum
Withdrawl of Telbivudine Therapy for The Prevention of
Perinatal Transmission of Hepatitis B Virus Infection
Jing Wang, Jinfeng Liu, Yingli He, Yuan Yang, Li Jin, Shulin Zhang,
Yingren Zhao, Tianyan Chen
1643: Clinical Relevance of Viral Blipping During Potent
Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B
Infection
Mayur Brahmania, Willem Pieter Brouwer, Tawnya Hansen, Matt
Kowgier, Jordan J. Feld, David K. Wong, Harry L. Janssen
1644: Preventing HBV reactivation: An automated
prompt to remind oncologists to screen was only
partially successful
Joshua Juan, Lisa K. Hicks, Lauren Lapointe-Shaw, Judy Truong,
Urszula Zurawska, Kelvin Chan, Jordan J. Feld
1645: Validation of Noninvasive Models to Predict Liver
Fibrosis in Patients with Chronic Hepatitis B
Jieyao Cheng, Hong Ma
1646: Factors Predisposing to Development of
Hepatocellular Carcinoma in Chronic Hepatitis B
Patients with Spontaneous Seroclearance of Hepatitis B
Surface Antigen
Eui Ju Park, Danbi Lee, Young-Hwa Chung, Ju Hyun Shim, Kang
Mo Kim, Young-Suk Lim, Han Chu Lee, Yung Sang Lee, Pyo Nyun
Kim, Neung Hwa Park
1647: A ten-year follow-up of patients with dual
chronic hepatitis B and C virus infections: Outcomes and
determinants
Chun-Jen Liu, Tai-Chung Tseng, Tung-Hung Su, Hung-Chih Yang,
Chen-Hua Liu, Pei-Jer Chen, Ding-Shinn Chen, Jia-Horng Kao
1648: Hepatocellular Carcinoma Surveillance Rates in
Non-Cirrhotic Patients with Chronic Hepatitis B in the
United States
David S. Goldberg, Adriana Valderama, Rajesh Kamalakar, Sujit
S. Sansgiry, Svetlana Babajanyan, James D. Lewis
Poster Viewing: 8:00 AM – Noon
171A
1649: Hepatitis D: Testing Rates and Seroprevalence at
Two Liver Centers in Northern California
Kidist K. Yimam, Margaret D. Clark, Cara Torruellas, Jennifer L.
Dodge, Jody L. Baron, Christopher L. Bowlus, Stewart Cooper
1650: Assessment of combined serum biomarkers
and fibroscan and dynamic computed tomography in
the detection of hepatic fibrosis in chronic hepatitis b
patients
Gurdal Yilmaz, Iftihar Koksal, Arif M. Cosar, Ugur Kostakoglu
1651: The transplacental hepatitis B core antibody
correlated to the responsiveness of the hepatitis B
vaccine in infants born to HBsAg-positive mothers
Taotao Yan, Jing Wang, Tianyan Chen, Jinfeng Liu, Dan Du, Li Jin,
Yingli He, Yuan Yang, Yuanyuan Li, Yingren Zhao
1652: Stepwise noninvasive assessment to predict
significant fibrosis in chronic hepatitis B patients who do
not meet definite treatment guideline
Jin Dong Kim, Jin Yong Jung, Sun Young Yim, Yeon Seok Seo,
Soon Ho Um, Ho Sang Ryu
1653: HBV Genotype, Drug Resistant Mutation &
Precore/Basal Core Promoter Mutation in Acute
Hepatitis B in Korea
Jong Ho Lee, Sun Pyo Hong, Eun Sun Jang, Sang Jong Park, Seong
Gyu Hwang, Sook-Kyoung Kang, Jin-Wook Kim, Sook-Hyang
Jeong
1654: Kinetics of Hepatitis B Surface Antigen Level
During Telbivudine and Entecavir Treatment Chronic
Hepatitis B Patients
Sun Young Yim, Soon Ho Um, Chang Ho Jung, Tae Hyung Kim,
Eun Sun Kim, Bora Keum, Yeon Seok Seo, Hyung Joon Yim, Hong
Sik Lee, Yoon Tae Jeen, Hoon Jai Chun, Chang Duck Kim, Ho
Sang Ryu
1655: LAW Index as a Novel Non-invasive Indicator for
the Initiation of Antiviral Agent in Patients with Chronic
Hepatitis B
Jae Min Lee, Yeon Seok Seo, Chang Ho Jung, Tae Hyung Kim, Sun
Young Yim, Hyonggin An, Soon Ho Um, Ho Sang Ryu
1656: A new dynamic prognostic model for acute-on-
chronic hepatitis B liver failure based on the clinical and
short-term changes of bio-markers
Zhonghui Duan, Li Chen, Yanmei Feng, Hong-Wei Yu, Zhen Li,
Meixin Ren, Yue-Ke Zhu, Chenggang Jin, Qinghua Meng
1657: Chronic Hepatitis B in Western Europe: A
Retrospective Cohort
Luis Maia, Ana Margarida S. Ribeiro, José Manuel Ferreira, Teresa
Moreira, Isabel Pedroto
NOVEMBER 11
1658: Hepatocellular Carcinoma Replicating Hepatitis B
Virus: a Clinical, Virological and Transcriptional Entity
TUESDAY
Boris Halgand, Guillaume Fallot, Lise Riviere, Christophe Desterke,
Mylene Sebagh, Julien Calderaro, Paulette Bioulac-Sage, Remy
Houlgatte, Marie-Annick Buendia, Didier Samuel, Christine
Neuveut, Cyrille Feray
Presenters in Attendance 10:30 AM – Noon
 172A POSTER SESSIONS
Poster Sessions
1659: The Urgent Unmet Need to Screen for Hepatitis
B virus in African born Patients within the US, and Link
them to Care
Aaron M. Vanderhoff, Hari Shankar, Demetri A. Blanas, Kian
Bichoupan, Daouda Ndiaye, Mulusew Bekele, Ellie Carmody,
Valerie Martel-Laferriere, Saba Bekele, Andrea D. Branch, Douglas
Dieterich, Kim E. Nichols, Ponni Perumalswami
1660: A risk for hepatocellular carcinoma persists long-
term after hepatitis B virus DNA clearance in patients
with associated advanced fibrosis
Blaise K. Kutala, Corinne Castelnau, Nathalie Boyer, Tarik
Asselah, Feryel Mouri, Emilie Estrabaud, Michelle Martinot-
Peignoux, Dominique Valla, Patrick Marcellin
1661: Tenofovir DF prevents HBV reactivation in anti-
HBc positive patients with hematologic malignancies
treated with Rituximab: 12-months results of a
randomized study (PREBLIN study)
Maria Buti, Maria L. Manzano, Rosa María Morillas, Montserrat
Garcia-Retortillo, Leticia Martin, Martin Prieto, Maria Luisa
Gutierrez, Emilio Suarez, Mariano Gomez-Rubio, Javier Lopez,
Francisco Gea, Manuel Rodríguez, Jose M. Zozaya, Miguel
A. Simon, Albert Pardo, Luis Morano, Jose Luis Calleja, Rafael
Esteban
1662: Electronic notifying system improved the
coverage of HBV-related serum markers in the
prevention of HBV reactivation hepatitis
Toshiki Komeda, Shinji Katsushima
1663: Is HBeAg Seroconversion a Valid Surrogate
Marker for Hepatocellular Carcinoma in Chronic
Hepatitis B Patients Treated with Lamivudine or
Entecavir?
Jihyun An, Hwa Jung Kim, Young-Suk Lim, Dong Jin Suh
1664: Pregnancy and chronic hepatitis B – what
markers change post-delivery?
Mary Horner, Matthew J. Bruce, Marie-Ange McLeod, Kath Oakes,
Teresa Bowyer, Thawab Al-Chalabi, Kate E. Childs, Suman Verma,
Phillip M. Harrison, Kosh Agarwal, Ivana Carey
1665: HBeAg levels predict HBeAg seroconversion
during the immune clearance phase of chronic hepatitis
B in patients receiving nucleot(s)ide analogue therapy
Julianne Bayliss, Alexander J. Thompson, Gillian Rosenberg,
Anuj Gaggar, Kathryn M. Kitrinos, Mani Subramanian, Patrick
Marcellin, Edward J. Gane, Henry Lik-Yuen Chan, Xin Li, Danni
Colledge, Margaret Littlejohn, Lilly Yuen, Rosalind Edwards, Kathy
Jackson, Sara Bonanzinga, Rachel Hammond, Scott Bowden,
Stephen Locarnini, Peter A. Revill
1666: The Incidence Of Hepatitis B Virus (HBV) Related
Hepatocellular Carcinoma (HCC) Is Reduced In North
NOVEMBER 11
American Chronic Hepatitis B (CHB) Patients Treated
TUESDAY
With Long-Term Nucleos(t)ide Analog Therapy
Carla S. Coffin, Maryam Rezaeeaval, Jack X. Pang, Lilibeth
Alcantara, Patricia Klein, Kelly W. Burak, Robert P. Myers
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1667: Analysis of hepatitis B surface antigen (HBsAg)
levels using the Lumipulse HBsAg-HQ assay in hepatitis
B virus carriers with HBsAg seroclearance according to
the Abbott ARCHITECT assay
Itaru Ozeki, Tomoaki Nakajima, Shuhei Hige, Yoshiyasu Karino,
Joji Toyota
1668: Associations of Adipokines with Liver Fibrosis
Stages in Patients with Chronic Hepatitis B Virus
Infection
Ching-Sheng Hsu, Wei-Liang Liu, Ding-Shinn Chen, Jia-Horng Kao
1669: Hepatitis B Virus Screening Rates Vary Across
Specialties in Patients Receiving Immunosuppressive
Therapy
Sonali Paul, Asim Shuja, Idy Tam, Sandra Kang, Leonid Kapulsky,
Kathleen Viveiros, Hannah Lee
1670: Understanding the Phases of Chronic Hepatitis
B; the problem and a novel solution using renamed
phases, the Hepatitis B Bear and a video (see “
Understanding Hepatitis B “ on YouTube)
Heidi L. Lord, Jamee Newland, Elena Cama, Carla Treloar, Miriam
T. Levy
1671: Prediction of liver disease in e antigen negative
chronic hepatitis B (CHB)
Gayatri Chakrabarty, Philip Rice, Nick Tatman, Sarah J. Clark,
Ken Laing, Daniel M. Forton
1672: The Neutralizing Activity of Monoclonal HBs
Antibodies Separated from Hepatitis B Vaccinated
Recipients and the Influence of the titers by Different
Measurement Methods
Takako Inoue, Noboru Shinkai, Kumiko Ohne, Shuko Murakami,
Susumu Tsutsumi, Kazuto Tajiri, Hiroyuki Kishi, Shintaro Ogawa,
Masanori Isogawa, Tsunamasa Watanabe, Yasuhito Tanaka
1673: A Newly Developed High-Sensitive HBsAg
Chemiluminescent Enzyme Immunoassay is a Precise
Application as a pre-Transfusion Screening Test to
Detect Occult HBV
Takako Inoue, Kumiko Ohne, Noriyo Ochi, Noboru Shinkai,
Shuko Murakami, Sayuki Iijima, Shintaro Ogawa, Tsunamasa
Watanabe, Yasuhito Tanaka
1674: Biomarkers to predict the clinical outcome of
hepatitis delta
Anika Wranke, Beatriz Calle Serrano, Stefanie Ernst, Benjamin
Heidrich, Janina Kirschner, Birgit Bremer, Svenja Hardtke, Markus
Cornberg, Armin Koch, Michael P. Manns, Christine S. Falk,
Heiner Wedemeyer
1675: Switch to the second generation of nucelos(t)
ide analogues from de-novo lamivudine+adefovir
in sequentially treated chronic hepatitis B patients
improves viral response and leads to sharper HBsAg
decline
Matthew J. Bruce, Mary Horner, Thawab Al-Chalabi, Kath Oakes,
Ashley Barnabas, Suman Verma, Phillip M. Harrison, Kosh
Agarwal, Ivana Carey
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1676: The efficacy of Telbivudine used in entire
pregnancy course in blocking mother-to-child HBV
transmission
Wei Yi, Yao Xie, Yu-Hong Hu, Ming-hui Li
1677: Hepatitis B Core Related Antigen Levels Differ
During The Natural History of Chronic Hepatitis B
Infection
Willem Pieter Brouwer, Gertine van Oord, Milan J. Sonneveld,
Thomas Vanwolleghem, Robert J. de Knegt, Bettina E. Hansen,
Andre Boonstra, Harry L. Janssen
1678: Immunogenicity of Recombinant Hepatitis B
Vaccine in Patients on Maintenance Hemodialysis and
Normal Population of Pakistani Origin
Syed M. Hassan, Arzoo Saeed, Muhammad Osama Butt, Nasir
Hassan Luck, Zaigham Abbas
1679: Higher rates of hepatitis B surface antigen
(HBsAg) seroclearance among males and non-Asian
patients with chronic hepatitis B (CHB) in a large, multi-
center U.S. cohort study
Long H. Nguyen, Christina Wang, Vinh D. Vu, Huy N. Trinh, Jiayi
Li, Jian Q. Zhang, Mindie H. Nguyen
1680: Are Patients with Hepatitis B Virus Infection
Receiving Evaluation and Treatment?: An Analysis of A
Large Insured U.S. Cohort
Loren G. Miller, Rajeshwari S. Punekar, Debra F. Eisenberg,
Samantha Eells, Rakesh Luthra, Thomas Wasser, Honghu Liu
1681: Epidemiological evolution of Chronic Hepatitis
Delta in Italy. An analysis of the Master-B cohort
Giuseppina Brancaccio, Tiziana Giuberti, Gabriella Verucchi,
Fabio Levantesi, Daria Sacchini, Giovanna Fattovich, Salvatore
Madonia, Massimo Fasano, Caius Gavrila, Alessandra Nardi,
Giovanni B. Gaeta
1682: Cross-sectional study to evaluate hepatitis B virus
(HBV) infection screening practices and outcomes in
patients with rheumatic diseases (REBIB-I Study)
Montserrat Garcia-Retortillo, Joana Villaverde, Blanca Sampedro,
Joaquin Cabezas-González, Albert Pardo, Ramon Fontova, Tarek
C. Salman, Maria Pilar Lisbona, Joan Maymo, Blai Dalmau,
Eduard Graell, Jose Inciarte, Raimon Sanmarti, Javier Crespo,
Ricard Sola
1683: Efficacy and safety of long term tenofovir in high
risk patients with hematological malignancies (HM)
to prevent Hepatitis B Virus (HBV) reactivation after
immunosuppressive therapies in real life
Giuseppe Gentile, Eleonora Russo, Federico De Angelis, Alice Di
Rocco, Angelo Fama, Alessandra Micozzi, Alessandro Pulsoni,
Maurizio Martelli, Francesca R. Mauro, Anna P. Iori, Teresa
Petrucci, Antonella Vitale, Guido Antonelli, Robin Foà
1684: Insulin resistance is associated with higher liver
stiffness and increased immune response in inactive
carriers of hepatitis B
Mar Riveiro-Barciela, Francisco Rodriguez-Frias, Maria Homs,
David Tabernero, Rafael Esteban, Maria Buti
Poster Viewing: 8:00 AM – Noon
173A
1685: Pre- and Post-Exposure Prophylaxis against
Hepatitis B Virus Infection by HBV-active Antiretroviral
Therapy
Tsunamasa Watanabe, Susumu Hamada-Tsutsumi, Noboru
Shinkai, Etsuko Iio, Kayoko Matsunami, Sayuki Iijima, Shuko
Murakami, Katsumi Omagari, Masanori Isogawa, Wataru
Sugiura, Yasuhito Tanaka
1686: Effectiveness of an Online, Tailored CME
Curriculum on Chronic Hepatitis B virus (CHB)
Management
Nancy Reau, Catherine C. Capparelli, Jennifer Garick, Wendy
Cerenzia, Simi Hurst
1687: HBV/HIV coinfection is associated with greater
mortality in hospitalized patients with HBV
Ruma Rajbhandari, Raymond T. Chung, Hamed Khalili, Ashwin N.
Ananthakrishnan
1688: The landscape of pregant women with hepatitis B
in a single centre
Enoka Gonsalkorala, Vi Nguyen, Carina Burns, Anne L. Glass,
Miriam T. Levy
1689: HBV infection is associated with greater mortality
in hospitalized patients compared to HCV infection or
alcoholic liver disease
Ruma Rajbhandari, Raymond T. Chung, Ashwin N.
Ananthakrishnan
1690: Hepatitis B core-related antigen (HBcrAg) levels
in patients with chronic hepatitis B undergoing NUC
therapy
Benjamin Maasoumy, Katja Deterding, Jerzy Jaroszewicz, Birgit
Bremer, Patrick Lehmann, Michael P. Manns, Heiner Wedemeyer,
Markus Cornberg
1691: Dynamic of liver stiffness values by Transient
Elastography in inactive HBV carriers
Milana Szilaski, Roxana Sirli, Cristian Ivascu, Oana Gradinaru
Tascau, Alexandra Deleanu, Isabel Dan, Ioan Sporea
1692: Genotype A HBV-persistent infection is associated
with high serum HBsAg concentration in treatment-
naïve patients
Jerzy Jaroszewicz, Malgorzata Pawlowska, Krzysztof
Tomasiewicz, Wlodzimierz W. Mazur, Krzysztof Simon, Anna
Piekarska, Marta Wawrzynowicz-Syczewska, Pawel Rajewski,
Magdalena widerska, Elzbieta Murias-Brylowska, Ewelina Zasik,
Pazgan Simon Monika, Waldemar Halota, Robert Flisiak
1693: Positive Response to Hepatitis B Virus Standard
Vaccination Scheme Among Patients in an HIV Program
Francisco Fuster, Jose Ignacio Vargas, Daniela Jensen, Valeska
Sarmiento, Felipe Peirano, Pedro Acuña, Sabrina Soto, Werner
NOVEMBER 11
Jensen, Rodrigo Ahumada, Marcos Huilcaman, Mario Bruna
TUESDAY
Presenters in Attendance 10:30 AM – Noon
 174A POSTER SESSIONS
Poster Sessions
1694: Identification of a four-gene model to
discriminate mild from moderate fibrosis in patients
with chronic hepatitis B
Emilie Estrabaud, Roberto J. Carvalho-Filho, Olivier Lada, Cédric
Laouénan, Simon Gosset, Ana Carolina F. Cardoso, Ivan Bieche,
Martine Lapalus, Michel Vidaud, Tarik Asselah, Patrick Marcellin
1695: The prevalence of 25(OH)D3 in the patients
of South China with chronic HBV infection and high
25(OH)D3 related with low HBV DNA viral load
Guoli Lin, Yunlong Ao, Xin-Hua Li, Yuankai Wu, Yusheng Jie, Hong
Shi, Xiangyong Li, Fangji Yang, Shu-ru Chen, Yutian Chong
HBV: Virology and Pathogenesis
1696: Associations of HLA-DPB1 with CHB infection
and HBV related HCC in Asia
Nao Nishida, Hiromi Sawai, Kouichi Kashiwase, Mutsuhiko
Minami, Ken Yamamoto, Takehiko Sasazuki, Masaya Sugiyama,
Wai-Kay Seto, Man-Fung Yuen, Yong Poovorawan, Sang Hoon
Ahn, Kwang-Hyub Han, Kentaro Matsuura, Yasuhito Tanaka,
Masayuki Kurosaki, Yasuhiro Asahina, Namiki Izumi, Jong-Hon
Kang, Shuhei Hige, Tatsuya Ide, Kazuhide Yamamoto, Isao
Sakaida, Yoshikazu Murawaki, Yoshito Itoh, Akihiro Tamori, Etsuro
Orito, Yoichi Hiasa, Masao Honda, Shuichi Kaneko, Eiji Mita,
Kazuyuki Suzuki, Keisuke Hino, Eiji Tanaka, Satoshi Mochida,
Masaaki Watanabe, Yuichiro Eguchi, Masaaki Korenaga, Minae
Kawashima, Katsushi Tokunaga, Masashi Mizokami
1697: Association between the expression of aldo-
keto reductase family 1 member B10 and the risk of
hepatitis B virus-related hepatocellular carcinoma
Masashi Mori, Takuya Genda, Takafumi Ichida, Ayato Murata,
Hironori Tsuzura, Shunsuke Sato, Yutaka Narita, Yoshio
Kanemitsu, Sachiko Ishikawa, Tetsu Kikuchi, Katsuharu Hirano,
Katsuyori Iijima, Ryo Wada, Sumio Watanabe
1698: Induction of hepatitis B virus-specific immune
responses in immunologically humanized mice
Satoshi Aono, Tomohide Tatsumi, Seiichi Tawara, Yoshiki Onishi,
Akira Nishio, Tadashi Kegasawa, Atsuo Takigawa, Hayato Hikita,
Ryotaro Sakamori, Takuya Miyagi, Naoki Hiramatsu, Hiroshi
Suemizu, Takeshi Takahashi, Tetsuo Takehara
1699: Epigenetic regulation of host immunity in HBV
infection
Jinglan Jin, Hongqin Xu, Xiumei Chi, Wanyu Li, Junqi Niu, Shibo Li
1700: A novel humanized cDNA-uPA/SCID mouse for
the study of HBV and HCV infections
Takuro Uchida, Nobuhiko Hiraga, Michio Imamura, Masataka
Tsuge, Hiromi Abe, C. Nelson Hayes, Hiroshi Aikata, Yuji Ishida,
Chise Tateno, Katsutoshi Yoshizato, Kazunari Murakami, Kazuaki
Chayama
NOVEMBER 11
TUESDAY
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1701: A novel TK-NOG based humanized mouse model
for the study of HBV and HCV infection
Nobuhiko Hiraga, Michio Imamura, Takuro Uchida, Tomokazu
Kawaoka, Masataka Tsuge, Hiromi Abe, C. Nelson Hayes,
Hiroshi Aikata, Yuji Ishida, Chise Tateno, Katsutoshi Yoshizato,
Kazuaki Chayama
1702: A detailed systems biology study identifies
unappreciated roles for B-cells in the differentiation
between HBV clinical phases
Thomas Vanwolleghem, Jun Hou, Gertine van Oord, Zwier M.
Groothuismink, Kim Kreefft, Suzan D. Pas, Harry L. Janssen, Andre
Boonstra
1703: Increased IL-17 producing TFh (CD4+CXCR5+
CCR6+) cells help in HBV seroconversion through TNF-α
secretion
Ashish Vyas, Shreya Sharma, Arshi Khanam, Ankit Bhardwaj,
Nirupma Trehanpati, Shiv K. Sarin
1704: Mutational profile of HLA-A2-restricted cytotoxic
T lymphocyte (CTL) epitope env183-191 in chronic HBV-
infected patients and the epitopic mutation’s influence
on CTL activities
Zhihui Xu, Yihui Rong, Yan Liu, Xiaodong Li, Shaoli You, Dongping
Xu, ShaoJie Xin
1705: HBx interact with and modulates the expression
of the DLEU2 lncRNA locus in HBV replicating cells
Francesca Guerrieri, Safaa Jeddari, Daniel D’Andrea, Anna
Tramontano, Massimo Levrero
1706: Differential expression of Fc gamma receptors
contributing to the diverse host immunity during HBV
infection
Jinglan Jin, Ruihong Wu, Xiumei Chi, Wanyu Li, Na Wu, Junqi Niu
1707: No Detectable Resistance to Tenofovir Disoproxil
Fumarate (TDF) in HBeAg+ and HBeAg- Patients with
Chronic Hepatitis B (CHB) After Eight Years of Treatment
Amoreena C. Corsa, Yang Liu, John F. Flaherty, Patrick Marcellin,
Michael D. Miller, Kathryn M. Kitrinos
1708: Functional innate immune responses are
restored with sequential NUC therapy following
Pegylated Interferon–Alpha exposure and not with NUC
monotherapy in Chronic Hepatitis B
Upkar S. Gill, Dimitra Peppa, Harsimran D. Singh, Lorenzo Micco,
Graham R. Foster, Mala K. Maini, Patrick T. Kennedy
1709: Mice with syngeneic human liver and immune
system to study cellular immunity to hepatitis B virus
Eva Billerbeck, Michiel C. Mommersteeg, Amir Shlomai, Jing
W. Xiao, Linda Andrus, Ankit Bhatta, Marcus Dorner, Anuradha
Krishnan, Michael Charlton, Luis Chiriboga, Charles M. Rice, Ype
P. De Jong
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1710: Effect of Immunosuppression and Antiviral
Therapy in Persistent Intracellular Replication among
Hepatitis B Virus and HIV Co-Infected Patients
Anders Boyd, Karine Lacombe, Fabien Lavocat, Sarah Maylin,
Patrick Miailhes, Caroline Lascoux-combe, Constance Delaugerre,
Pierre-Marie Girard, Fabien Zoulim
1711: Bile acids receptor FXR agonists repress HBV
replication in HepaRG cell
Pauline Radreau, Christophe Ramière, Marine Porcherot, Vincent
Lotteau, Patrice André
1712: Toll-like receptor 3-acivated non-parenchymal
liver cells control hepadnaviral replication in HBV-
transgenic mice lacking the surface antigen (HBsAg)
Catherine I. Real, Mengji Lu, Markus Hossbach, Kerstin Jahn-
Hofmann, Ludger M. Ickenstein, Matthias J. John, Hans-Peter
Vornlocher, Reinhold Schirmbeck, Melanie Lutterbeck, Kathrin
Gibbert, Ulf Dittmer, Guido Gerken, Joerg F. Schlaak, Ruth
Broering
1713: Frequency and role of NKp46 and NKG2A
expressing NK cells in patients with chronic hepatitis B
Teppei Yoshioka, Takuya Miyagi, Yoshinobu Yokoyama, Akira
Nishio, Kaori Mukai, Satoshi Aono, Kumiko Nishio, Takatoshi
Nawa, Hayato Hikita, Ryotaro Sakamori, Naoki Hiramatsu,
Tomohide Tatsumi, Tetsuo Takehara
1714: Hepatitis B virus enhances the endo-lysosomal
pathway through the activation of the small GTPase
Rab7 via an interaction between HBe and the Rab7
GAP, TBC1D15
Jun Inoue, Eugene W. Krueger, Jing Chen, Hong Cao, Tooru
Shimosegawa, Mark A. McNiven
1715: HBV infection in humanized chimeric mice has
multiphasic viral kinetics from inoculation to steady
state and an HBV half-life of 1 hr
Yuji Ishida, Tje Lin Chung, Michio Imamura, Nobuhiko Hiraga,
Laetitia Canini, Susan L. Uprichard, Alan S. Perelson, Chise
Tateno, Harel Dahari, Kazuaki Chayama
1716: Effect of bile acid on the entry of hepatitis B virus
via sodium taurocholate cotransporting polypeptide
Jung Wha Chung, Eun Sun Jang, In Young Moon, Gi Hyun Kim,
Kyeong Sam Ok, Jong Ho Lee, Sook-Hyang Jeong, Jin Wook Kim
1717: Distinct helper roles of dendritic cell subsets in NK
cell-dependent HBV suppression in bystander infected
cells
Sachiyo Yoshio, Tatsuya Kanto, Masaya Sugiyama, Hirotaka
Shoji, Yohei Mano, Yoshihiko Aoki, Nao Nishida, Masaaki
Korenaga, Kazumoto Murata, Masashi Mizokami
1718: Establishment of a mouse model of acute
hepatitis B by activation of human cytotoxic T
lymphocytes
Takuro Uchida, Nobuhiko Hiraga, Michio Imamura, Masataka
Tsuge, Hiromi Abe, C. Nelson Hayes, Hiroshi Aikata, Yuji Ishida,
Chise Tateno, Katsutoshi Yoshizato, Kazuaki Chayama
Poster Viewing: 8:00 AM – Noon
175A
1719: Increased fucosyltransferase 2 gene expression
in HBV infection enhances HBV replication
Takayuki Shiomoto, Masao Honda, Takayoshi Shirasaki, Kazuhisa
Murai, Tetsuro Shimakami, Seishi Murakami, Shuichi Kaneko
1720: Extensive Hepatitis B virus (HBV) Core Antigen
Mutation Associated with Massive Intrahepatic
Production of Germline Anti-core IgM and IgG Suggest
a Major Role of Humoral Immunity in the Pathogenesis
of HBV-Associated Acute Liver Failure (ALF)
Zhaochun Chen, Ronald E. Engle, Ashley B. Tice, Zhifeng Long,
Fausto Zamboni, Giacomo Diaz, Patrizia Farci
1721: Plasma Fibroblast Growth Factor 23
Concentration is Increased and Related with Liver Injury
in Patients with HBV Related Acute-on-chronic Liver
Failure
Fangfang Liu, ZhiHong Wan, Hong Zang, Shaoli You, HongLing
Liu, ShaoJie Xin
1722: Virologic and clinical characters of hepatitis B
virus mutations in basal core promoter and precore
region in children with chronic hepatitis B and hepatitis
B related liver cirrosis
Yanwei Zhong, Hongfei Zhang, Shishu Zhu, Yi Dong, Zhiqiang
Xu, Dawei Chen, Hui Dong, Fenglin Di, Limin Wang, Yu Gan,
Fuchuan Wang
1723: HBV genotype study by ultradeep
pyrosequencing reveals complex mixtures and inter-
genotype recombination
Andrea Caballero, Josep Gregori, Maria Homs, David Tabernero,
Maria Blasi, Rosario Casillas, Josep Quer, Leonardo Nieto, Henar
Valbuena, Rafael Esteban, Maria Buti, Francisco Rodriguez-Frias
1724: Analysis of the effect on HBV life cycle by HBV
genome editing using TALEN and CRISPR/Cas9 systems
Hiromi Abe, Tetsushi Sakuma, Masataka Tsuge, Nobuhiko Hiraga,
Michio Imamura, C. Nelson Hayes, Hiroshi Aikata, Takashi
Yamamoto, Kazuaki Chayama
1725: Serum Arginase-1 Levels Are Lower Than
Expected in Hepatitis B-related Acute Liver Failure
Perry H. Dubin, Jody A. Balko, Michelle Gottfried, William M. Lee
1726: Hepatitis B virus recurrence after liver
transplantation and evolution of viral quasispecies
Maria Buti, David Tabernero, Rosario Casillas, Antoni Mas, Maria
Homs, Martin Prieto, Fernando Casafont, Antonio Gonzalez,
Manuel Miras, Jose Ignacio Herrero, Lluis Castells, Rafael Esteban,
Francisco Rodriguez-Frias
1727: Hepatitis B Virus Core Protein Amino Acids 77-78
Play Vital Roles in Capsid Foramation and Function
Kai Deng, Dong Jiang, Lai Wei
NOVEMBER 11
1728: Cytokeratins 8 and 18 are responsible for
TUESDAY
intracellular distribution of the large hepatitis B virus
surface protein
Martin Roderfeld, Dirk Schröder, Yury Churin, Dieter Glebe, Elke
Roeb
Presenters in Attendance 10:30 AM – Noon
 176A POSTER SESSIONS
Poster Sessions
1729: Hepatitis B virus infection efficiency and immune
response decreases with cell density in primary cultured
hepatocytes
C. Nelson Hayes, Hiromi Abe, Sakura Akamatsu, Nobuhiko
Hiraga, Michio Imamura, Masataka Tsuge, Daiki Miki, Hiroshi
Aikata, Hidenori Ochi, Yuji Ishida, Chise Tateno, Kazuaki
Chayama
1730: The dual immunoregulatory roles of circulating
iNKT cells during chronic HBV infection
Man Li, Zhen-Hua Zhou, Xue-Hua Sun, Yue-Qiu Gao
1731: Pretreatment Cirrhosis and Higher Body Mass
Index Predicted Alanine Aminotransferase Abnormality
in Patients Achieved Undetectable Serum HBV DNA with
Nucleos(t)ide Analogs Therapy
Yuankai Wu, Yusheng Jie, Xiangyong Li, Guoli Lin, Shu-ru Chen,
Xin-Hua Li, Hong Shi, Fangji Yang, Min Zhang, Mingxing Huang,
Yunlong Ao, Yihua Pang, Yutian Chong
1732: Hepatitis B virus relapse after discontinuation of
long-term treatment with tenofovir in chronic HBeAg-
negative patients
Maria Buti, Maria Homs, Rosario Casillas, David Tabernero, Josep
Gregori, Carolina Gonzalez, Mar Riveiro-Barciela, Maria Teresa
Salcedo, Maria Blasi, Leonardo Nieto, Francisco Rodriguez-Frias,
Rafael Esteban
1733: Clonal Hepatocyte expansion in the young adult
HBV infected liver is at odds with the concept of a
generic immune tolerant disease phase: can additional
clinical parameters distinguish disease phase?
Patrick T. Kennedy, Upkar S. Gill, Antony Chen, Samuel Litwin,
Antonio Bertoletti, William Mason
1734: Toll like Receptor Polymorphisms in Spontaneous
HBsAg Seroconversion
Kamil Özdil, Levent Doganay, Adil Nigdelioglu, Seyma Katrinli,
Oguzhan Ozturk, Zuhal Caliskan, Mehmet Sokmen, Gizem Dinler
1735: Phenotypic Characteristics of PD-1, CTLA-4 and
FoxP3 Expression during Tenofovir therapy in Chronic
Hepatitis B
Hyosun Cho, Chang Wook Kim, Yu seung Kim, Hee Yeon Kim,
Jong Young Choi, Seung Kew Yoon, Chang Don Lee
1736: Hepatitis B virus (HBV) specifically induces
CD4+CD25+CD127-veFoxP3+ with increased anti-tumor
immunity in HBV related HCC compared to Non- HBV-
HCC
Shreya Sharma, Paul David, Rakhi Maiwall, Amrish Sahney, Ritu
Khosla, Ashish Vyas, Shiv K. Sarin, Nirupma Trehanpati
1737: Evaluation of Serum Cytokines and Chemokines
in HBeAg Negative Chronic Hepatitis B Patients
NOVEMBER 11
Yan Cheng, Veonice Bijin Au, John E. Connolly, Seng Gee Lim
TUESDAY
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1738: Associations of single nucleotide polymorphism
rs1053004 in signal transducer and activator of
transcription 3 (STAT3) for risk of hepatocellular
carcinoma in Thai patients with chronic hepatitis B
Nawin Chanthra, Sunchai Payungporn, Natthaya Chuaypen, Pisit
Tangkijvanich
1739: Immune system is required for HBV clearance,
but not enough for explaining the difference in HBV
genotype A and C clearance
Yoshinobu Yokoyama, Hayato Hikita, Teppei Yoshioka, Kaori
Mukai, Satoshi Aono, Takatoshi Nawa, Ryotaro Sakamori, Takuya
Miyagi, Kazuyoshi Ohkawa, Naoki Hiramatsu, Tomohide Tatsumi,
Tetsuo Takehara
1740: Nucleotide analogue improves interferon
responsiveness in HBV-infected human hepatocytes
Masataka Tsuge, Nobuhiko Hiraga, Eisuke Murakami, Michio
Imamura, Hiromi Abe, Daiki Miki, Hidenori Ochi, C. Nelson
Hayes, Kazuaki Chayama
1741: High alpha-fetoprotein is risk factor of
hepatocellular carcinoma in hepatitis B patients with
good efficacy of nucleoside analogues therapy
Noboru Shinkai, Etsuko Iio, Tsunamasa Watanabe, Kentaro
Matsuura, Kei Fujiwara, Shunsuke Nojiri, Yasuhito Tanaka
1742: NKP46 Is Potentially Involved in Control of
Hepatitis B Virus Replication and Modulation of Liver
inflammatory
Wanyu Li, Yanfang Jiang, Yanjun Cai, Yue Qi, Jinglan Jin, Xiaomei
Wang, Junqi Niu
1743: Serum soluble CD40 is associated with liver
injury in patients with chronic hepatitis B
Hong-hui Shen, Bing-ke Bai, Panyong Mao
1744: Association study of next-generation sequencing
determined HBV heterogeneity and antiviral efficacy of
Lamivudine treatment
Yue Han, Ling Gong, Xin-xin Zhang
1745: High-throughput hepatitis B and D virus model
systems for discovery of targets for viral cure
Eloi R. VERRIER, Charlotte Bach, Laura Heydmann, Amelie Weiss,
Rajeevkumar G. Tawar, Daniel Felmlee, Sarah Durand, David
Durantel, Fabien Zoulim, François Habersetzer, Michel Doffoel,
Catherine Schuster, Laurent Brino, Camille C. Sureau, Mirjam B.
Zeisel, Thomas F. Baumert
1746: Model of HBV/HDV super-infection to study
mechanisms of viral interplay and antivirals
Dulce Alfaiate, Natali A. Abeywickrama-Samarakoon, Barbara
Testoni, Julie Lucifora, Fabien Zoulim, Jean-Claude Cortay, Paul
Deny, David Durantel
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1747: Serial Changes of Cellular, Humoral, and Innate
Immune Responses following Immunosuppressive
Chemotherapies Responsible for Hepatitis B Virus
Reactivation
Hidetaka Matsuda, Tatsushi Naito, Takuto Nosaka, Tomoyuki
Nemoto, Masahiro Ohtani, Katsushi Hiramatsu, Hiroyuki Suto,
Yasunari Nakamoto
1748: The rtA181S mutation of hepatitis B virus
primarily confers resistance to adefovir dipivoxil
Yan Liu, Xiaodong Li, ShaoJie Xin, Zhihui Xu, Rongjuan Chen, Jing
Yang, Li Chen, Vincent W. Wong, Dongliang Yang, Henry Lik-
Yuen Chan, Dongping Xu
HCV: Health Economics and Cost
Effectiveness
1749: Projecting the budget impact of interferon
(IFN)-free direct-acting antiviral (DAA)-based regimens
for hepatitis C treatment in France: a model-based
analysis (ANRS 95141)
Sylvie Deuffic-Burban, Dorothee Obach, Valerie Canva-Delcambre,
Stanislas Pol, Francoise Roudot-Thoraval, Daniel Dhumeaux,
Yazdan Yazdanpanah
1750: Evaluation of the Long-Term Health Outcomes
of Ledipasivir/Sofosbuvir (LDV/SOF) and Sofosbuvir-
based Regimens for Patients With Chronic Hepatitis C
(CHC) And Liver Cirrhosis Across Genotypes 1 to 4 (GT
1-4): Results from a Decision-Analytic Markov Model
Stuart C. Gordon, Aijaz Ahmed, Sammy Saab, Zobair Younossi
1751: Evaluation of the Health Outcomes for
Ledipasvir/Sofosbuvir in Early vs. Delayed Treatment
According to Fibrosis Stage of Patients with Chronic
Hepatitis C Virus (HCV) Genotype 1 Infection: Results
from a Decision-Analytic Markov Model
Aijaz Ahmed, Stuart C. Gordon, Sammy Saab, Zobair Younossi
1752: Who should be prioritized for HCV antiviral
treatment? A cost-effectiveness analysis including
individual and population prevention benefits
Natasha K. Martin, Peter Vickerman, Gregory J. Dore, Jason
Grebely, Graham R. Foster, Alec Miners, Sharon Hutchinson,
David J. Goldberg, Thomas C. Martin
1753: Per-Protocol Subgroup Analysis of Ledipasvir
and Sofosbuvir for Chronic HCV in the ION-3 Trial
Thomas R. O’Brien, Krystle A. Kuhs, Ruth M. Pfeiffer
1754: A Decision- Analytic Markov Model To Evaluate
The Health Outcomes of Ledipasvir/Sofosbuvir (LDV/
SOF) for Patients with Chronic Hepatitis C (HCV)
Genotype 1 (GT1) Infection
Zobair Younossi, Sammy Saab, Aijaz Ahmed, Stuart C. Gordon
Poster Viewing: 8:00 AM – Noon
177A
1755: Sofosbuvir-Containing Regimens for Chronic
Hepatitis C (CHC) Infection: Insights from a Work
Productivity Economic Model
Zobair Younossi, Yushan Jiang, Nathaniel Smith, Maria Stepanova,
Rachel Beckerman
1756: Cost-effectiveness of the Hepatitis C Self-
Management Program
Erik J. Groessl, Samuel B. Ho, Marisa Sklar, Ted Ganiats
1757: Estimating the Number of Patients with Chronic
Hepatitis C Infection According to Liver Fibrosis Stage in
the United States
Fujie Xu, Andrew J. Leidner, Xin Tong, Scott D. Holmberg
1758: Pre-transplant sofosbuvir and ribavirin
for patients with advanced liver disease and
chronic hepatitis C awaiting deceased donor liver
transplantation: A cost-effectiveness analysis
Alissa J. Wright, Arthur Y. Kim, Jay A. Fishman, Benjamin P. Linas,
Raymond T. Chung
1759: Demographics and Clinical Characteristics
Associated with High Healthcare Resource Utilization
(HRU) and Costs among Chronic Hepatitis C (CHC)
Patients
Joyce LaMori, Neeta Tandon, François Laliberté, Guillaume
Germain, D. Pilon, Patrick Lefebvre, Avinash Prabhakar
1760: Disease Burden of Chronic Hepatitis C Virus
(HCV) Infection in Poland
Robert Flisiak, Waldemar Halota, Krzysztof Tomasiewicz, Kaja
Kostrzewska, Homie Razavi, Erin Gower
1761: Estimating projected costs and quality-adjusted
life expectancy associated with daclatasvir plus
asunaprevir in difficult to treat Japanese patients
chronically infected with hepatitis C genotype 1b
Philip McEwan, Thomas Ward, Yong Yuan, Anupama Kalsekar,
Isao Kamae, Mariko Kobayashi, Sachie Inoue, Ann C. Tang,
Hiromitsu Kumada
1762: Assessing the Health Economic Value of Each Unit
of SVR Improvement in HCV Infection
Thomas Ward, Hayley Bennett Wilton, Philip McEwan, Anupama
Kalsekar, Yong Yuan
1763: The impact of different strategies to reduce the
burden of chronic hepatitis C infection, using new direct
acting antivirals in Sweden
Ann-Sofi Duberg, Sarah Blach, Karolin Falconer, Martin Kåberg,
Homie Razavi, Soo Aleman
1764: Virologic outcomes, adverse events, and
healthcare costs associated with therapy of chronic HCV
NOVEMBER 11
infection in clinical practice: results from the CMPASS
study
TUESDAY
Stefan Mauss, Maria Buti, Stephen D. Ryder, Vasily A. Isakov,
Raymundo Paraná, Trong Le, Anupama Kalsekar, Gilbert J. L’Italien
Presenters in Attendance 10:30 AM – Noon
 178A POSTER SESSIONS
Poster Sessions
HCV: Virology, Pathogenesis, and
Immunology
1765: EFTUD2 alters hepatitis C virus replication by
modulating the RIG-I/MDA5 pathway
Chuanlong Zhu, Jian Hong, Dahlene Fusco, Cynthia Brisac,
Esperance A. Schaefer, Soung Wong Jeong, Lee F. Peng, Wenyu
Lin, Raymond T. Chung
1766: Impaired inhibition of HCV IRES translation by
Type I and Type III interferon in human hepatoma cell
line with an unfavorable SNP rs12979860 of IL-28B
gene
Pauline Ferraris, Partha K. Chandra, Rajesh Panigrahi, Fatma
Aboulnasr, Ramazan Kurt, Jean-Michel Pawlotsky, Ludwig Wilkens,
Tong Wu, Luis A. Balart, Srikanta Dash
1767: Identification of HCV-specific and non-specific
follicular T helper cell signatures during acute and
chronic HCV-infection in blood and liver
Bijan Raziorrouh, Kathrin Sacher, Rajeevkumar G. Tawar, Florian
Emmerich, Thomas F. Baumert, Robert Thimme, Tobias Boettler
1768: Induction of Obesity-related Gene PLA2G16
in Acute Homologous and Heterologous HCV Infection
Associated with Development of Viral Persistence
Lucy Golden-Mason, Hugo R. Rosen
1769: Mipomersen, an FDA-approved anti-sense
inhibitor of apoB100, has anti-HCV effect in-vitro
Esperance A. Schaefer, James Meixiong, Daniel L. Motola,
Dahlene Fusco, Cynthia Brisac, Shadi Salloum, Jay Luther, Wenyu
Lin, Mary P. McGowan, Lee F. Peng, Raymond T. Chung
1770: Novel in vitro models for assembly of VLDL and
low-density hepatitis C virus particles
Ursula Andreo, Margaret A. Scull, Ype P. De Jong, Vyas Ramanan,
Brenna Flatley, Robert E. Schwartz, Shengyong Ng, Alice A. Chen,
Edward A. Fisher, Sangeeta Bhatia, Charles M. Rice
1771: HIV and HCV co-operatively increase
transcriptional activation in hepatocytes and hepatic
stellate cells in a novel live reporter cell co-culture model
of infection
Shadi Salloum, Eoin R. Feeney, Rohit Jindal, Shyam Sundhar Bale,
Cynthia Brisac, Martin L. Yarmush, Raymond T. Chung
1772: Aminoterminal Amphipathic α-Helix AH1 of HCV
NS4B Possesses a Dual Role in RNA Replication and
Virus Production
Jerome Gouttenoire, Roland Montserret, David Paul, Simon Meister,
Rosa Castillo, Audrey Kennel, Ralf Bartenschlager, Francois Penin,
Darius Moradpour
1773: Specific variation of CpG methylation in non-
NOVEMBER 11
cancerous areas of hepatocellular carcinoma after
TUESDAY
successful hepatitis C virus treatment
Masashi Nishikawa, Masao Honda, Kazunori Kawaguchi, Rika
Horii, Tetsuro Shimakami, Kuniaki Arai, Taro Yamashita, Yoshio
Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, Shuichi Kaneko
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1774: TACSTD2 is a Novel HCV Host Cofactor that
Regulates Claudin and Occludin Localization and is
Downregulated in HCV-Associated Hepatocellular
Carcinoma (HCC)
Vandana Sekhar, Marta Melis, Giacomo Diaz, Ronald E. Engle,
Juraj Kabat, Ashley B. Tice, Nihal Altan-Bonnet, David E. Kleiner,
Paolo Lusso, Suzanne U. Emerson, Fausto Zamboni, Patrizia Farci
1775: Human liver sinusoidal endothelial cell-derived
exosomes augment intrinsic anti-viral pathways in HCV-
infected hepatocytes: Differential Effects of Type I vs
Type III Interferons
Michael Kriss, Silvia Giugliano, Michael Edwards, Evgenia
Dobrinskikh, Lucy Golden-Mason, Hugo R. Rosen
1776: Regulation of Hepatitis C Virus Infection by Long
Non-Coding RNAs
Tetsuro Shimakami, Masao Honda, Takayoshi Shirasaki, Fanwei
Liu, Masaya Funaki, Kazuhisa Murai, Takayuki Shiomoto, Seishi
Murakami, Shuichi Kaneko
1777: LECT2 specifically induced by IL28B regulates
interferon response and HCV replication
Takayoshi Shirasaki, Masao Honda, Tetsuro Shimakami, Kazuhisa
Murai, Takayuki Shiomoto, Hirofumi Misu, Toshinari Takamura,
Stanley M. Lemon, Seishi Murakami, Shuichi Kaneko
1778: The Hepatic Group 2 Innate Lymphocyte Cell
(ILC2)/IL-33 Axis is Dysregulated in Chronic HCV
Infection
Lucy Golden-Mason, Christina Christianson, Linling Cheng, Rafeul
Alam, Hugo R. Rosen
1779: Interleukin-22 mediates liver fibrosis via
activating hepatic stellate cells in patients with hepatitis
C
Jingmin Zhao, Liyuan Wu, Jin Li, Chaonan Guo, Hanwei Li,
Wenshu Li, Shuhong Liu, Keming Zhang, Ping Zhao
1780: Hepatitis C Promotes Diabetes by Increasing
Hepatic Insulin Resistance and Pancreatic Beta Cell
Failure Via Suppression of Betatrophin a Novel Islet Cell
Growth Factor
Robert K. Vincent, Sophie C. Cazanave, Hae-Ki Min, Faridoddin
Mirshahi, Divya P. Kumar, Amon Asgharpour, Kalyani Daita,
Karnam S. Murthy, T. Jake Liang, Arun J. Sanyal
1781: NS3, NS5A and NS5B Coevolution in Patients
Experiencing Virological-Failure with First-Generation
Protease Inhibitors
Velia Chiara Di Maio, Valeria Cento, Daniele Di Paolo, Francesco
De Leonardis, Alessandra F. Manunta, Valeria Micheli, Monica
Tontodonati, Ada Bertoli, FrancescoPaolo Antonucci, Lorenzo
Nosotti, Carlo F. Magni, Jacopo Vecchiet, Maria Stella Mura,
Massimo Andreoni, Filomena Morisco, Martina Spaziante, Nicola
Caporaso, Giustino Parruti, Giuliano Rizzardini, Sergio Babudieri,
Gloria Taliani, Mario Angelico, Carlo Federico Perno, Francesca
Ceccherini-Silberstein
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1782: HCV Minicores Are Heavily Secreted by Cells in
Apolipoprotein Complexes
Ahmed M. Elshamy, Francis J. Eng, Erin H. Doyle, Ursula Andreo,
Naga S. Veerapu, Arielle L. Klepper, Anthony S. Muerhoff, Suresh
M. Desai, Ronald E. Gordon, Charles M. Rice, Andrea D. Branch
1783: Treatment Response, IFNL3 (IL28B) and IFNL4
Genotype and Hepatic Expression of Interferons and
Interferon-Stimulated Genes in Patients with Chronic
Hepatitis C
Mazen Noureddin, Yaron Rotman, Emmanuel Thomas, Fang
Zhang, Heiyoung Park, Barbara Rehermann, T. Jake Liang
1784: Neutralising anti-envelope antibodies in
uninfected individuals that are repeatedly exposed to
HCV
Paraskevi Mandalou, Rachael Swann, Arvind H. Patel, Matthew
E. Cramp
1785: HCV specificity of the activating NK cell receptor
KIR2DS2
Sorcha A. Cassidy, Mengya Liu, Mohammed M. Naiyer, Arvind
H. Patel, Marco Purbhoo, Salim I. Khakoo
1786: The anti-HCV gene SART1 regulates EIF4G3 and
GORASP2 expression through exon splicing
Wenyu Lin, Jian Hong, Chuanlong Zhu, Dahlene Fusco, Esperance
A. Schaefer, Cynthia Brisac, Lee F. Peng, Raymond T. Chung
1787: Rapid normalization of proinflammatory cytokine
levels during potent antiviral therapy with sofosbuvir
plus ribavirin in patients with genotype 2 and 3 HCV
infection
David L. Wyles, Luisa M. Stamm, Matthew Paulson, Qinghua
Song, Diana M. Brainard, Robert T. Schooley
1788: Transmitted/Founder Hepatitis C Viruses Induce
Cell Type- and Genotype-Specific Differences within the
Liver
Angela Mitchell, Amy Stone, Linling Cheng, Kimberly Ballinger,
Michael Edwards, Mark B. Stoddard, Hui Li, Lucy Golden-Mason,
George M. Shaw, Salman Khetani, Hugo R. Rosen
1789: Virology analyses of HCV isolates from genotype
4 patients treated with simeprevir in combination with
peginterferon/ribavirin in the Phase III RESTORE study
Bart Fevery, Thierry Verbinnen, Monika Peeters, Mauro Zucchetto,
James Witek, Wolfgang Jessner, Sandra De Meyer, Oliver Lenz
1790: Serum Lipid and Sterol Analysis in Hepatitis
C (HCV) Genotype 2 and 3 Infections Treated with
Sofosbuvir (SOF) and Ribavirin (RBV) Regimens
Zobair Younossi, Maria Stepanova, Francesco Negro, James M.
Estep, Paul J. Clark, Sharon L. Hunt, Lisa E. Kratz, Qinghua Song,
Matthew Paulson, Luisa M. Stamm, Diana M. Brainard, Mani
Subramanian, John G. McHutchison, Keyur Patel
Poster Viewing: 8:00 AM – Noon
179A
1791: Different mechanisms mediate insulin and
interferon resistance in chronic hepatitis C patients with
early and late stage liver fibrosis
Kazuhisa Murai, Masao Honda, Tetsuro Shimakami, Takayoshi
Shirasaki, Takayuki Shiomoto, Hirofumi Misu, Toshinari Takamura,
Seishi Murakami, Shuichi Kaneko
1792: Behavioral risk changes in young people who
inject drugs following rapid HCV testing
Alice K. Asher, Jennifer Evans, Judith A. Hahn, Alya Briceno,
Kimberly Page
1793: The HCV NS3/4A protease-helicase binds to high
molecular weight telomerase holoenzyme complexes
Zhaowen Zhu, M. Meleah Mathahs, Warren N. Schmidt
1794: HCV Protein Expression Induces Activation of the
Akt1 Pathway In Hepatocytes, A Possible Trigger for
Hepatocarcinogenesis
Mohamed R. Imache, Jacqueline Polyte, Jean-Michel Pawlotsky,
Herve Lerat
1795: Cross-reactive and neutralizing E2 antibodies
from a spontaneous clearer without Hepatitis C virus
reinfection despite prolonged high-risk behavior
Sabrina Merat, Richard Molenkamp, Koen Wagner, Sylvie M.
Koekkoek, Dorien van den Berg, Etsuko Yasuda, Bart P. Grady,
Maria Prins, Arjen Q. Bakker, Menno D. de Jong, Hergen Spits,
Janke Schinkel, Tim Beaumont
1796: Introduction Of a Neutralization Resistant HCV-
1a Variant among HIV Positive Men Who Have Sex
With Men in Amsterdam
Sabrina Merat, Sylvie M. Koekkoek, Xiomara V. Thomas, Jan T.
van der Meer, Marc van der Valk, Menno D. de Jong, Hergen
Spits, Tim Beaumont, Richard Molenkamp, Janke Schinkel
1797: Expression of tumor suppressor PTPRD is
downregulated in HCV-infected primary human
hepatocytes and liver tissue of patients with chronic
HCV infection
Amina Ababsa, Francois H. Duong, Claire Gondeau, Markus H.
Heim, Thomas F. Baumert, Joachim Lupberger
1798: High-Level Resistance to Hepatitis C – A Possible
Role for Innate Immunity
Maggie M. Ow, Doha Hegazy, Usama Warshow, Matthew E.
Cramp
1799: Apolipoprotein E Functionally Obscures Hepatitis
C Virus from Neutralizing Antibodies
Daniel J. Felmlee*, Catherine Fauvelle*, Mathieu Lefèvre,
Laura Heydmann, Marie-Sophie Hiet, Isabel Fofana, François
Habersetzer, Ross Milne, Arvind H. Patel, Koen Vercauteren,
Philip Meuleman, Mirjam B. Zeisel, Ralf Bartenschlager, Catherine
NOVEMBER 11
Schuster, Thomas F. Baumert
TUESDAY
Presenters in Attendance 10:30 AM – Noon
 180A POSTER SESSIONS
Poster Sessions
1800: Expression of IFNλ4 in liver and PBMC is closely
associated with higher basal expression of ISGs and
impaired induction of IL28B by interferon treatment in
chronic hepatitis C non-responder patients
Miyako Murakawa, Yasuhiro Asahina, Mina Nakagawa, Naoya
Sakamoto, Sayuri Nitta, Fukiko Kawai-Kitahata, Miki Taniguchi,
Takako Watanabe, Yasuhiro Itsui, Sei Kakinuma, Mamoru
Watanabe
1801: Serum biomarker profile can predict the outcome
of acute HCV infection
Verena Schlaphoff, Katja Deterding, Svenja Hardtke, Julia Hengst,
Christine S. Falk, Birgit Bremer, Michael P. Manns, Markus
Cornberg, Heiner Wedemeyer
1802: Free apolipoprotein E inhibits HCV replication by
inducing an ABCG1-dependent cholesterol efflux
Emilie Crouchet, Mathieu Lefèvre, Eloi R. VERRIER, Thomas F.
Baumert, Catherine Schuster
1803: Impaired Insulin-Driven Gluconeogenesis Shut-
Down By HCV Proteins Through Uncoupling Of Foxo1/
AKT Signaling Leads To a Pre-Diabetic State In HCV
Transgenic Mice
Herve Lerat, Jacqueline Polyte, Aurore Gaudin, Mohamed R.
Imache, Christophe Magnan, Fabienne Foufelle, Jean-Michel
Pawlotsky
1804: Identification of OCIAD1 as Cellular Substrate of
the HCV NS3-4A Protease
Huong T.L. Tran, Kenichi Morikawa, Rose Zibi, Viet Loan Dao Thi,
Francois Penin, Markus H. Heim, Manfredo Quadroni, Jerome
Gouttenoire, Darius Moradpour
1805: Spontaneous HCV clearance in HIV-infected
individuals with chronic hepatitis C bearing IL28B-CC
alleles on antiretroviral therapy
Laura Benítez-Gutiérrez, Teodoro Martín, Alfonso Ángel-Moreno,
María J. Cítores, Francisca Portero Azorin, Valentin Cuervas-Mons,
Carmen de Mendoza
1806: A single amino acid substitution in HLA-DQB1 as
well as an IFNL4 variant strongly affect susceptibility to
chronic hepatitis C
Daiki Miki, Hidenori Ochi, Atsushi Takahashi, C. Nelson Hayes,
Yuji Urabe, Hiromi Abe, Atsushi Ono, Sakura Akamatsu, Takashi
Nakahara, Noriaki Seki, Eisuke Murakami, Yizhou Zhang, Takuro
Uchida, Yohji Honda, Satoshi Yoshimi, Tomoki Kobayashi, Keiichi
Masaki, Hiromi Kan, Tomokazu Kawaoka, Masataka Tsuge,
Nobuhiko Hiraga, Michio Imamura, Yoshiiku Kawakami, Hiroshi
Aikata, Shoichi Takahashi, Norio Akuta, Fumitaka Suzuki, Kenji
Ikeda, Hiromitsu Kumada, Yoshiyasu Karino, Joji Toyota, Tatsuhiko
Tsunoda, Michiaki Kubo, Naoyuki Kamatani, Yusuke Nakamura,
Kazuaki Chayama
NOVEMBER 11
1807: Replication of HCV RNA Depends on its
TUESDAY
Degradation by the Cellular RNAses and not on the
Translational Efficiency of its Untranslated Regions
Patrice Bruscella, Tony Durand, Michel Ventura, Jean-Michel
Pawlotsky, Cyrille Feray
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1808: Dynamics of the Virus-specific CD8 T cell
Repertoire during HCV Reinfection
Mohamed S. Abdel-Hakeem, Julie Bruneau, Hugo Soudeyns,
Naglaa H. Shoukry
1809: NK Cell Function Normalizes after 4 Weeks of
IFN-free Therapy of Chronic Hepatitis C
Elisavet Serti, Xenia Chepa-Lotrea, Yun Ju Kim, Nancy Fryzek, T.
Jake Liang, Marc G. Ghany, Barbara Rehermann
1810: Persistently infected HCV cell culture impairs RBV
antiviral activity through clathrin mediated trafficking of
ENT1
Rajesh Panigrahi, Partha K. Chandra, Pauline Ferraris, Ramazan
Kurt, Imogen Coe, Tomami Furihata, Robert F. Garry, Tong Wu,
Luis A. Balart, Srikanta Dash
1811: Vδ2 γδ T cell functional dichotomy in chronic
hepatitis C virus infections
Wenwei Yin, Qiongfang Zhang, Hong Ren, Dazhi Zhang
1812: Promoted liver fibrosis in hepatitis C virus
transgenic mouse fed an atherogenic high-fat diet is
accompanied by abnormal expression of the glycolysis-
related gene pyruvate kinase M2
Riuta Takabatake, Masao Honda, Hikari Okada, Tetsuro
Shimakami, Takayoshi Shirasaki, Taro Yamashita, Yoshio Sakai,
Takuji Tanaka, Shuichi Kaneko
1813: Involvement of hepatitis C virus infection in
the regulation of chemo-sensitivity of hepatocellular
carcinoma cells
Takatoshi Nawa, Tomohide Tatsumi, Akira Nishio, Seiichi Tawara,
Yoshiki Onishi, Satoshi Aono, Hayato Hikita, Ryotaro Sakamori,
Takuya Miyagi, Naoki Hiramatsu, Tetsuo Takehara
1814: Chaperone-mediated Autophagy Targets IFNAR1
for Lysosomal Degradation in Free Fatty Acid Treated
HCV Cell Culture
Ramazan Kurt, Partha K. Chandra, Fatma Aboulnasr, Rajesh
Panigrahi, Pauline Ferraris, Krzysztof Reiss, Tong Wu, Luis A.
Balart, Srikanta Dash
1815: Identification of a TSCM phenotype HCV-specific
CD8+ T cell response with superior functionality in
chronic HCV infection
Bertram Bengsch, Kristin Ladell, Bianca Martin, James E. McLaren,
Katja Nitschke, Christoph Neumann-Haefelin, David A. Price,
Robert Thimme
1816: Acute Hepatitis C Virus infection Induces Anti-
host Cell Receptor Antibodies with Virus-neutralizing
Properties
Rajeevkumar G. Tawar, Michael Roggendorf, Helga Meisel,
Nicolas Meyer, Francois-Loic Cosset, Thomas Berg, Mirjam B.
Zeisel, Thomas F. Baumert
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1817: Genetic polymorphism in interferon-λ4 gene and
treatment response to peginterferon and ribavirin in
Japanese chronic hepatitis C
Hisayoshi Watanabe, Ri Sho, Takafumi Saito, Kei Mizuno,
Tomohiro Katsumi, Chikako Sato, Kazuo Okumoto, Yuko Nishise,
Yoshiyuki Ueno
1818: Systematic identification of microRNAs
functionally involved in the HCV life cycle
Sophie Pernot, Simonetta Bandiera, Erika Girardi, Amelie Weiss,
Sarah Durand, Wolfgang Raffelsberger, Laurent Brino, Sebastien
Pfeffer, Thomas F. Baumert, Mirjam B. Zeisel
1819: Elevated hepatic lipid and interferon stimulated
gene (ISG) expression in patients infected with hepatitis
C virus genotype-3 (HCVGT-3) relative to patients with
non-alcoholic steatohepatitis (NASH)
Shikha Shrivastava, Eric G. Meissner, Emily K. Funk, Seerat
Poonia, Virendra Shokeen, Arun Thakur, Shyam Kottilil, Shiv K.
Sarin, Nirupma Trehanpati
1820: Full Length and Subgenomic HCV Infection,
Endosomal TLR Stimulation, and Differentiation Increase
Macrophage Immunoregulatory Galectin-9
Noah M. Harwood, Lucy Golden-Mason, Hugo R. Rosen, John A.
Mengshol
1821: IFNL4- and IFNL3-associated polymorphisms
strongly influence spontaneous expression of IFN-alpha
receptor-1 and response to exogenous IFN-alpha in
vitro in PBMC from HCV-infected patients
Eleonora Lalle, Licia Bordi, Claudia Caglioti, Anna Rosa
Garbuglia, Concetta Castilletti, Gianpiero D’Offizi, Chiara Taibi,
Maria R. Capobianchi
1822: Modulation of HCV infection through KHSRP-
Dependent Regulation of miRNA 122 Maturation and
Intracellular RNA Degradation
Patrice Bruscella, Jean-Michel Pawlotsky, Cyrille Feray
1823: Effect of aging on fibrotic change based on
sequential liver biopsy in chronic hepatitis C patient
who achieved an SVR
Yoshihiko Tachi
1824: NK cell anti-tumor activity was boosted by
SAHA identified to induce the expression of a GWAS-
discovered HCV-HCC susceptibility gene MICA
Kaku Goto, Ryosuke Muroyama, Wenwen Li, Ryo Nakagawa,
Yasuo Matsubara, Naoya Kato
1825: The Scaffold Protein IQGAP2 is Essential for the
Innate Control of HCV Infection in Hepatoma Cells
Cynthia Brisac, Shadi Salloum, Stephane Chevaliez, Eoin R.
Feeney, Esperance A. Schaefer, Chuanlong Zhu, Jian Hong,
Dahlene Fusco, Lee F. Peng, Wenyu Lin, Raymond T. Chung
1826: Allosteric Heat Shock Protein Inhibitors Block
Hepatitis C Virus Assembly
Ronik Khachatoorian, Ekambaram Ganapathy, Vaithilingaraja
Arumugaswami, Asim Dasgupta, Samuel W. French
Poster Viewing: 8:00 AM – Noon
181A
1827: The IL28B SNP has a stronger regulatory effect
on the expression of OAS1 than a nearby SNP located
downstream of OAS1 in chronic HCV patients
Daiki Miki, Hiromi Abe, C. Nelson Hayes, Hidenori Ochi,
Tomokazu Kawaoka, Sakura Akamatsu, Atsushi Ono, Takashi
Nakahara, Noriaki Seki, Eisuke Murakami, Yizhou Zhang, Takuro
Uchida, Yohji Honda, Keiichi Masaki, Hiromi Kan, Masataka
Tsuge, Nobuhiko Hiraga, Michio Imamura, Yoshiiku Kawakami,
Hiroshi Aikata, Michiaki Kubo, Kazuaki Chayama
1828: Pretreatment induction of ISGs in the presence
of IFNL4 in hepatocytes but not in white blood cells is
related with poor induction of ISGs following IFN-α
therapy
Hiromi Abe, C. Nelson Hayes, Nobuhiko Hiraga, Michio Imamura,
Masataka Tsuge, Daiki Miki, Hiroshi Aikata, Hidenori Ochi, Yuji
Ishida, Chise Tateno, Katsutoshi Yoshizato, Kazuaki Chayama
1829: Quercetin inhibits both replication and assembly
of hepatitis C virus by blocking the viral NS3 and the
host diacylglycerol acyltransferase type 1
Angela Rojas, Sophie Clément, Matthieu Lemasson, Jose A. Del
Campo, Marta García-Valdecasas, Antonio Gil-Gómez, Isidora
Ranchal, Juan Bautista, Arielle R. Rosenberg, Francesco Negro,
Manuel Romero-Gomez
1830: Infection and Replication of Hepatitis C Virus in
Vero cells Derived from Green Monkey Kidney
Asako Murayama, Nao Sugiyama, Takaji Wakita, Takanobu Kato
1831: Impact of Donor Host Genetics on HCV Viral
Evolution After Post Liver Transplantation
Sandra C. Silva Arrieta, Sandra Franco, María-Carlota Londoño,
Miguel Angel Martinez, Xavier Forns, Todd M. Allen, Alberto
Sanchez-Fueyo, Christian Brander
1832: Lysophosphatidylcholine acyltransferase 1
is downregulated by hepatitis C virus: impact on
production of lipo-viro-particles
Frauke Beilstein, Matthieu Lemasson, Veronique Pene, Arielle R.
Rosenberg, Sylvie Demignot
1833: Increased Frequency of CD39+ HCV-Specific CD4
T cells Correlates with Progression to Chronic Hepatitis C
Diana Y. Chen, Brandon Robilotti, Lyndon K. Matsubara, Joelle
Brown, Jasneet Aneja, Stephanie Kulaga, Lia Lewis-Ximenez,
Eddie A. James, William W. Kwok, Arthur Y. Kim, Georg M. Lauer
1834: Impaired IFN signaling in chronic hepatitis C
patients with advanced fibrosis via the TGF-β signaling
pathway
Masao Honda, Takayoshi Shirasaki, Tetsuro Shimakami, Kazuhisa
Murai, Takayuki Shiomoto, Hikari Okada, Riuta Takabatake,
Yoshio Sakai, Taro Yamashita, Stanley M. Lemon, Seishi
Murakami, Shuichi Kaneko
NOVEMBER 11
TUESDAY
Presenters in Attendance 10:30 AM – Noon
 182A POSTER SESSIONS
Poster Sessions
1835: Interferon Lambda-4 (IFNL4) TT allele is
associated with lower expression of genes associated
with early inflammation after initiation of treatment
J. Michael Estep, Kellie Perry, Kameron Tavakolian, Zahra
Younoszai, Maria Stepanova, Ali Noorzad, Richard Binder,
Zobair Younossi
1836: Hepatitis C Proteins Interact Directly with Early
Stage Autophagy Proteins
Ciara Harty, Orla M. Crosbie, Elizabeth Kenny-Walsh, Liam J.
Fanning
1837: Cryoglobulins and autoantibodies:Anti-nuclear
antibodies detection in cryoprecipitates of an Hepatitis C
Virus-positive cohort
Gian Ludovico Rapaccini, Umberto Basile, Francesca Gulli,
Eleonora Torti, Luigi Colacicco, Paola Cattani
1838: Anti-viral but not anti-fibrotic activity of natural
killer cells from HCV patients is significantly reduced by
liver normoxic conditions
Franziska Wolter, Andreas Glässner, Benjamin Krämer, Pavlos
Kokordelis, Claudia Zwank, Dominik J. Kaczmarek, Christian P.
Strassburg, Ulrich Spengler, Jacob Nattermann
1839: Down regulation of hsa-miR146b-5p might affect
the immunopathogenesis of chronic hepatitis C patients
Yasuteru Kondo, Masashi Ninomiya, Osamu Kimura, Takayuki
Kogure, Yasuhito Tanaka, Yu Nakagome, Tomoaki Iwata,
Tatsuki Morosawa, Yasuyuki Fujisaka, Tomoo Kobayashi, Tooru
Shimosegawa
1840: Monocytes-derived Galectin-9 induces the
cytotoxixcity of NK cells in chronic hepatitis C
Akira Nishio, Tomohide Tatsumi, Takahiro Suda, Atsuo Takigawa,
Tadashi Kegasawa, Onishi Yoshiki, Seiichi Tawara, Satoshi
Aono, Takatoshi Nawa, Hayato Hikita, Ryotaro Sakamori, Takuya
Miyagi, Naoki Hiramatsu, Tetsuo Takehara
1841: Characterization of a lymphotropic HCV-J6JFH1
replication in human primary B cells
Masato Nakai, Tsukasa Seya, Misako Matsumoto, Hussein H. Aly,
Jun Itoh, Seiji Tsunematsu, Fumiyuki Sato, Yoko Tsukuda, Katsumi
Terashita, Takuya Sho, Goki Suda, Mitsuteru Natsuizaka, Koji
Ogawa, Naoya Sakamoto
1842: Impaired expression of Type I and Type II
interferon-receptors in HCV infected chronic liver
disease and liver cirrhosis
Partha K. Chandra, Feyza Gunduz, Sidhartha Hazari, Ramazan
Kurt, Rajesh Panigrahi, Bret Poat, David S. Bruce, Ari J. Cohen,
Humberto E. Bohorquez, Ian C. Carmody, George E. Loss, Tong
Wu, Luis A. Balart, Srikanta Dash
1843: The CC allele at rs12979860 IL28B is associated
NOVEMBER 11
with higher hepatic fibrosis in HCV patients with
genotype 4
TUESDAY
Gamal E. Shiha, Waleed Samir, Seham Seif, Ayman Eldesoky,
Reham Soliman
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1844: Evidence of CD8+ T cell dysfunction in chronic
HCV infection with pronounced impairment of liver cells
compared to circulating cells
Stephanie C. Burke, Lorna Carrasco-Medina, Curtis Cooper,
Angela M. Crawley
1845: Prevalence of the NS3 protease Q80K naturally
occurring variant in Hepatitis C patients in Denmark
Anja Ernst, Henrik Krarup
1846: NKG2D Expression on Natural Killer T Cells, but
not NK Cells, Predicts Viral Response to DAA/ PEG-IFN/
RBV Therapy in Chronic Hepatitis C
Po-sung Chu, Hirotoshi Ebinuma, Nobuhiro Nakamoto, Shingo
Usui, Hidetsugu Saito, Takanori Kanai
1847: Assessment of Free Light Chains in HCV positive
patients undergoing Rituximab treatment
Umberto Basile, Laura Gragnani, Francesca Gulli, Alessia Piluso,
Cristina Stasi, Maria Teresa Dell’Abate, Eleonora Torti, Monica
Monti, Gian Ludovico Rapaccini, Anna Linda Zignego
1848: Emergence or selection of resistant associated
variant immediately after initiation of the therapy is
predictive for failure of direct acting antiviral therapy:
ultra-deep sequencing analyses for serial time points
Takako Watanabe, Yasuhiro Asahina, Mina Nakagawa, Sei
Kakinuma, Yasuhiro Itsui, Miki Taniguchi, Miyako Murakawa,
Hiroko Nagata, Mika Miura, Shinya Maekawa, Nobuyuki
Enomoto, Mamoru Watanabe
1849: Aldo-keto reductase family 1 member B10
expression predicts the risk of hepatocellular carcinoma
development in chronic hepatitis C patients who
achieved sustained virological response to interferon-
based anti-viral therapy
Ayato Murata, Takuya Genda, Takafumi Ichida, Shunsuke Sato,
Hironori Tsuzura, Yutaka Narita, Yoshio Kanemitsu, Sachiko
Ishikawa, Tetsu Kikuchi, Masashi Mori, Katsuharu Hirano,
Katsuyori Iijima, Ryo Wada, Sumio Watanabe
1850: Markers of Intestinal Enterocyte Injury and
Systemic Inflammation in HIV, HCV & HIV/HCV
co-infection
Alysse G. Wurcel, Paula Grasberger, Jessica K. Paulus, Gina
Masse, Christine Wanke, Tamsin A. Knox
Hepatitis B Therapy
1851: Tenofovir Disoproxil: Effective and Safe in
Prevention of Mother-to-child Transmission of Hepatitis
B Virus
Hongfei Huang, Quanxin Wu, Yuming Wang
1852: Incidence of Hepatocellular Carcinoma (HCC)
in non-cirrhotic chronic hepatitis B (CHB) patients with
low ALT levels in a multicenter US Cohort
Joseph K. Hoang, Nghia H. Nguyen, Derek Lin, Vinh D. Vu, Huy
N. Trinh, Jiayi Li, Jian Q. Zhang, Huy A. Nguyen, Khanh Nguyen,
Mindie H. Nguyen
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1853: Risk and Prediction of Hepatitis B Reactivation
in Inactive Carriers Receiving Pre-emptive Antiviral
Therapy During Cancer Chemotherapy
Jonggi Choi, Jihyun An, Ju Hyun Shim, Hyung-Don Kim, Yeon-Jung
Ha, Mi-Jung Jun, Young Joo Yang, Seung Bum Lee, Gi Ae Kim, Jee
Eun Yang, Eui Ju Park, Danbi Lee, Kang Mo Kim, Young-Suk Lim,
Han Chu Lee, Young-Hwa Chung, Yung Sang Lee, Dong Jin Suh
1854: Efficacy of Entecavir versus Lamivudine for
Antiviral Prophylaxis in Hepatitis B Patients Receiving
Cancer Chemotherapy
Jonggi Choi, Jihyun An, Ju Hyun Shim, Hyung-Don Kim, Yeon-Jung
Ha, Mi-Jung Jun, Young Joo Yang, Seung Bum Lee, Gi Ae Kim, Jee
Eun Yang, Eui Ju Park, Danbi Lee, Kang Mo Kim, Young-Suk Lim,
Han Chu Lee, Young-Hwa Chung, Yung Sang Lee, Dong Jin Suh
1855: Profound Reduction of HBV Covalently Closed
Circular DNA with Long-term Nucleoside/tide Analogue
Therapy
Ching-Lung Lai, Danny Wong, Philip Ip, Malgorzata Kopaniszen,
Wai-Kay Seto, James Fung, Fung-Yu Huang, Brian P. Lee, Giuseppe
Cullaro, Chi Hang Wu, Charles Cheng, Chi Hang J. Yuen, Vincent
Ngai, Man-Fung Yuen
1856: Long-term Nucleos(t)ide Analogue Consolidation
Therapy Reduces Risk of Relapse in Chronic Hepatitis B
Heng Chi, Bettina E. Hansen, Pauline Arends, Mahmoud Abu-
Amara, Colina Yim, Jordan J. Feld, Robert J. de Knegt, David K.
Wong, Harry L. Janssen
1857: ALN-HBV, a GalNAc-siRNA Enhanced
Stabilization Chemistry RNAi Therapeutic for the
Treatment of Chronic Hepatitis B Virus Infection
Laura Sepp-Lorenzino, Marc Abrams, Leon Carayannopoulos,
Martin Koser, Steve Ludmerer, Klaus B. Charisse, Daniel Freedman,
Vasant Jadhav, Kallanthottathil G. Rajeev, Greg Hinkle, Satya
Kuchimanchi, Martin A. Maier, Muthiah Manoharan, Rachel
Meyers, Stuart Milstein, Andrew G. Sprague
1858: On-treatment alpha-fetoprotein levels have
a strong association with hepatocellular carcinoma
development among chronic hepatitis B patients
receiving entecavir
Ryoko Yamada, Naoki Hiramatsu, Yuki Tahata, Naoki Morishita,
Naoki Harada, Tsugiko Oze, Takayuki Yakushijin, Sadaharu Iio,
Yoshinori Doi, Eiji Mita, Masahide Oshita, Toshifumi Ito, Taizo
Hijioka, Kazuhiro Katayama, Shinji Tamura, Harumasa Yoshihara,
Yasuharu Imai, Takuya Miyagi, Yuichi Yoshida, Tomohide Tatsumi,
Norio Hayashi, Tetsuo Takehara
1859: Risk of Hepatocellular Carcinoma Among Treated
Patients With Chronic Hepatitis B vs Chronic Hepatitis C
Gi-Ae Kim, Seungbong Han, Jihyun An, Young-Suk Lim
1860: Prenylation inhibition with lonafarnib decreases
hepatitis D levels in humans
Christopher Koh, Cihan Yurdaydin, Stewart Cooper, David Cory,
Harel Dahari, Vanessa Haynes-Williams, Mark A. Winters,
Matthew Bys, Ingrid C. Choong, Ramazan Idilman, Onur Keskin,
Laetitia Canini, Peter Pinto, Erin F. Wolff, Rachel Bishop, David E.
Kleiner, Jay H. Hoofnagle, Jeffrey Glenn, Theo Heller
Poster Viewing: 8:00 AM – Noon
183A
1861: Evidence for Ongoing Low-level Viremia in
Patients with Chronic Hepatitis B Receiving Long-term
Nucleos(t)ide Analog Therapy
Patrick Marcellin, Edward J. Gane, Robert Flisiak, Michael P.
Manns, Kelly D. Kaita, Anuj Gaggar, Lanjia Lin, Kathryn M. Kitrinos,
John F. Flaherty, Mani Subramanian, John G. McHutchison, Harry
L. Janssen, Maria Buti
1862: Clinical outcomes of tenofovir disoproxil
fumarate (TDF) treatment versus no treatment for
pregnant women with active chronic hepatitis B (CHB)
and elevated alanine aminotransaminase (ALT)
Wei Yi, Calvin Q. Pan, Min Liu, Haodong Cai
1863: HBsAg clearance after addition of 48 weeks of
PEGIFN in HBeAg negative CHB patients on Nucleos(t)
ide therapy with undetectable HBV DNA for at least one
year: a multicenter randomized controlled phase III trial
ANRS-HB06 PEGAN study: preliminary findings
Marc Bourlière, Pascaline Rabiega, Nathalie Ganne-Carrié,
Lawrence Serfaty, Patrick Marcellin, Noelle Pouget, Dominique
Guyader, Christophe Hezode, Magali Picon, Xavier Causse,
Vincent Leroy, Jean-Pierre Bronowicki, Ghassan Riachi, Isabelle
Rosa, Pierre Attali, Jean-Michel Molina, Yannick Bacq, Albert
Tran, Jean Didier Grange, Fabien Zoulim, Hélène Fontaine, Inga
Bertucci, Magali Bouvier-Alias, Fabrice Carrat, Yves Benhamou
1864: Efficacy and Safety of Telbivudine in Preventing
Mother-to-infant HBV Transmission in HBV-infected
Pregnant Women in Immune Tolerant Phase
Qiuju Sheng, Yang Ding, Han Bai, Jingyan Wang, Chong Zhang,
Lianrong Zhao, Xiaoguang Dou
1865: Entecavir Plus Tenofovir Combination Therapy in
Patients with Multi-drug Resistant Chronic Hepatitis B:
The 48-Week Results of A Multicenter, Prospective Study
Jun Yong Park, Chang Wook Kim, Si Hyun Bae, Sang Hoon Ahn
1866: Entecavir reduces the incidence of hepatocellular
carcinoma in patients with chronic hepatitis B
Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Tomonori Seno,
Koichi Takaguchi, Kazuhide Yamamoto
1867: Altered underlying tubular function in HBV
monoinfected patients receiving nucleos(t)ide analogs in
a real-world setting: MENTE Study
Sonia Rodriguez Novoa, Javier García-Samaniego, Martin Prieto,
Jose Luis Calleja, Juan Manuel Pascasio, Manuel B. Delgado,
Javier Crespo, Maria Buti, Lucía Bonet, Juan I. Arenas, Conrado
M. Fernandez Rodriguez, Ricard Sola, Enrique Fraga Rivas, Luisa
González-Diéguez, Óscar Núñez, Manuel Praga, Javier del Pino,
Manuel Romero-Gómez, Rosa María Morillas, Moisés Diago,
Angeles Castro
1868: Hepatitis B Core Related Antigen Levels Are
NOVEMBER 11
Associated With Response To ETV and PEG-IFN
TUESDAY
Treatment In HBeAg-Positive Chronic Hepatitis B Patients
Willem Pieter Brouwer, Milan J. Sonneveld, Qing Xie, Qing
Zhang, Fehmi Tabak, Adrian Streinu-cercel, Jiyao Wang, Gertine
van Oord, Thomas Vanwolleghem, Suzan D. Pas, Robert J. de
Knegt, Andre Boonstra, Bettina E. Hansen, Harry L. Janssen
Presenters in Attendance 10:30 AM – Noon
 184A POSTER SESSIONS
Poster Sessions
1869: IFNL4 polymorphisms predict sustained response
and HBsAg clearance in interferon treated HBeAg
negative chronic hepatitis B patients
Enrico Galmozzi, Pietro Lampertico, Floriana Facchetti, Federica
Invernizzi, Giampaolo Mangia, Mauro Viganò, Roberta Soffredini,
Massimo Colombo
1870: Incidence of Hepatocellular Carcinoma in a
National Cohort of Chronic Hepatitis B Patients on Long
Term Entecavir Treatment- the ENUMERATE study
Joseph Ahn, Joseph K. Lim, Hannah Lee, Calvin Q. Pan, Mindie
H. Nguyen, Huy N. Trinh, Tram T. Tran, Danny Chu, Albert Min,
Son T. Do, Jocelyn Woog, Ajitha Mannalithara, Anna S. Lok, W.
Ray Kim
1871: Entecavir Safety and Effectiveness in a National
Cohort of Chronic Hepatitis B Patients in the United
States - the ENUMERATE study
Joseph Ahn, Hannah Lee, Joseph K. Lim, Calvin Q. Pan, Mindie
H. Nguyen, W. Ray Kim, Huy N. Trinh, Tram T. Tran, Danny Chu,
Albert Min, Son T. Do, Jocelyn Woog, Ajitha Mannalithara, Anna
S. Lok
1872: Early hepatic flares during ETV treatment are
rare and do not require treatment adaptation in chronic
hepatitis B without cirrhosis
Pauline Arends, Heng Chi, Ivana Carey, Ashley S. Brown,
Massimo Fasano, David J. Mutimer, Katja Deterding, Ye H. Oo,
Joerg Petersen, Florian van Bömmel, Robert J. de Knegt, Jurrien G.
Reijnders, Thomas Berg, Tania M. Welzel, Stefan Zeuzem, Teresa
Santantonio, Heiner Wedemeyer, Maria Buti, Pierre Pradat,
Fabien Zoulim, Bettina E. Hansen, Harry L. Janssen
1873: The Antiviral Response to the Toll-Like Receptor
7 Agonist GS-9620 in Preclinical Models of Chronic
Hepatitis B is Associated with an Intrahepatic Cytotoxic
T Cell Transcriptional Signature
Li Li, Peng Yue, Robert E. Lanford, Stephan Menne, Congrong
Niu, Stephane Daffis, Daniel Tumas, Abigail Fosdick, William E.
Delaney, Simon P. Fletcher
1874: Long-Term HDV-RNA Suppression – HBsAg
Clearance in Chronic Hepatitis D Following Interferon
Therapy
Grazia A. Niro, Antonina Smedile, Rosanna Fontana, Antonella
Olivero, Alessia Ciancio, Fabrizia Pittalunga, Nicola Coppola,
Heiner Wedemeyer, Kalliopi Zachou, Aldo Marrone, Massimo
Fasano, Teresa Santantonio, Giuseppe Lotti, Angelo Andriulli,
Mario Rizzetto
1875: Decline in Quantitative Serum HBsAg Level
during Consolidation Therapy Following HBeAg Loss
in HBeAg-positive Chronic Hepatitis B Patients Treated
with Entecavir
Wen-Pang Su, Cheng-Yuan Peng, Hsueh-Chou Lai, Chia-Hsin Lin,
NOVEMBER 11
Po-Heng Chuang, Sheng-Hung Chen
TUESDAY
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1876: The role of hepatitis B surface antigen
quantification predict HBV reactivation after
discontinuation of nucleos(t)ide analogs treatment in
chronic hepatitis B patients with cirrhosis
Chien-Hung Chen, Chuan-Mo Lee, Tsung-Hui Hu, Chao-Hung
Hung, JIng-Houng Wang, Sheng-Nan Lu
1877: Entecavir Improves Liver Function and Fibrosis
in Patients with Hepatitis B Virus-associated Liver
Cirrhosis: A 2 Years-Multicenter Study
Seung Kak Shin, Oh Sang Kwon, Jong Eun Yeon, Jeong Han Kim,
So Young Kwon, Sang Jun Suh, Yun Soo Kim, Ju Hyun Kim
1878: Efficacy and safety of telbivudine versus tenofovir
treatment based on the Roadmap concept: Results
from a randomized, controlled trial in HBeAg-negative
chronic hepatitis B patients
Zahary Krastev, Iskren A. Kotzev, Mustafa K. Celen, David Mc
Neeley, Kamal A. Hamed
1879: Cytokines Induced by a Toll-Like Receptor 7
Agonist Potently Inhibit HBV RNA, DNA and Antigen
Levels in Primary Human Hepatocytes
Congrong Niu, Stephane Daffis, Mei Yu, Guofeng Cheng, William
E. Delaney, Simon P. Fletcher
1880: Tenofovir Mono-rescue therapy vs. Tenofovir
plus Entecavir combination-rescue therapy in chronic
hepatitis B with lamivudine and entecavir resistance: a
Korean multi-center study
Sangheun Lee, Jun Yong Park, Hana Park, Moon Young Kim, Sang
Hoon Ahn, Pumsoo Kim, Kwang-Hyub Han
1881: Increased HBsAg Decline in Sustained
Responders After Discontinuation of Long-term
Nucleos(t)ide Analogue Therapy in Chronic Hepatitis B
Heng Chi, Bettina E. Hansen, Mahmoud Abu-Amara, Colina Yim,
Pauline Arends, Jordan J. Feld, Annemiek A. van der Eijk, Robert J.
de Knegt, David K. Wong, Harry L. Janssen
1882: Addition of Peginterferon Alfa-2b During Long-
term Nucleos(t)ide Analogue Therapy Increases HBeAg
Seroconversion and HBsAg Decline – Week 48 Results
From a Multicenter Randomized Controlled Trial
(PEGON Study)
Heng Chi, Qing Xie, Ning-Ping Zhang, Xun Qi, Chen Liang, Simin
Guo, Qing Guo, Pauline Arends, Ji-yao Wang, Elke Verhey,
Robert J. de Knegt, Bettina E. Hansen, Harry L. Janssen
1883: Response-guided therapy to peginterferon
in chronic hepatitis B using on-treatment HBsAg
quantification: a meta-analysis
Hong Peng, Fang Wei, Junying Liu, Huaidong Hu, Peng Hu, Hong
Ren
1884: Prospective Observational Cohort Study For The
Durability Of Oral Antiviral Treatment In Patients With
Chronic Hepatitis B: Quit Study
Jun Yong Park, Kyu sik Chung, Young Eun Chon, Hyon Suk Kim,
Wonseok Kang, Seung Up Kim, Beom Kyung Kim, Do Young Kim,
Kwang-Hyub Han, Sang Hoon Ahn
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1885: A baseline predictive tool for selecting HBeAg-
negative chronic hepatitis B patients who have a high
probability of achieving sustained immune control with
peginterferon alfa-2a
Pietro Lampertico, Vivien Rothe, Antonietta Caputo, George V.
Papatheodoridis
1886: A predictive tool for selecting HBeAg-positive
chronic hepatitis B patients who have a high probability
of HBV DNA suppression and HBeAg seroconversion
with peginterferon alfa-2a
Henry Lik-Yuen Chan, George V. Papatheodoridis, Diethelm
Messinger, George Bakalos, Pietro Lampertico
1887: Randomized Controlled Trial of Switching
to Tenofovir Disoproxil Fumarate Monotherapy in
Lamivudine-Resistant Chronic Hepatitis B Patients with
Undetectable HBV Viral Load under Lamivudine/-
Adefovir Add-on Therapy: The First Interim Analysis
Yi-Hsiang Huang, Chien-Wei Su, Yuan-Jen Wang, Yi-Shin Huang,
Kuei-Chuan Lee, Ming-Chih Hou, Han-Chieh Lin
1888: 24 Weeks Of Peg-Ifn Is As Good As 48 Weeks
In Hbeag-Positive Genotype B Patients With An Early
Hbsag Response
Milan J. Sonneveld, Henry Lik-Yuen Chan, Teerha Piratvisuth,
Jidong Jia, Vincent W. Wong, Edward J. Gane, Bettina E. Hansen,
Yun -Fan Liaw, Harry L. Janssen
1889: The Pattern and Predictors of Serum HBsAg
Decline in Chronic Hepatitis B Patients Receiving Up to
Five Years of Entecavir Therapy
Hsueh-Chou Lai, Cheng-Yuan Peng, Wen- Pang Su, Chia-Hsin Lin,
Po-Heng Chuang, Sheng-Hung Chen
1890: Interferon-inducible protein 10 (IP10) serum
levels predict the decline of HBsAg serum levels in
HBeAg-negative chronic hepatitis B (CHBe-) patients
treated with tenofovir disoproxil fumarate (TDF)
George V. Papatheodoridis, Christos K. Triantos, Emilia
Hadziyannis, Konstantinos Zisimopoulos, Anastasia Georgiou,
Theodoros Voulgaris, Jiannis Vlachogiannakos, Vasiliki
Nikolopoulou, Spilios Manolakopoulos
1891: Quantitative hepatitis B core antibody level is a
new predictor for treatment response in HBeAg-positive
chronic hepatitis B patients receiving peginterferon
Gui-Qiang Wang, FengQin Hou, NingShao Xia
1892: Anti-HBV effectiveness and mechanisms of
Chinese herbal extract-Suduxing
Weiming Yao, Yan Liu, Zhihui Xu, Lanlan Si, Penggao Li, Lvping
Bo, Jinchu Lan, Dongping Xu
1893: Higher AFP during hepatitis B flare is associated
with greater reduction in HBsAg during Nuc therapy
Rachel Wen-Juei Jeng, Yi-Cheng Chen, Ming-Ling Chang, Yun -Fan
Liaw
Poster Viewing: 8:00 AM – Noon
185A
1894: Effect of antiviral treatment on liver stiffness
and its correlation to hepatocarcinogenesis in chronic
hepatitis B
Naoto Kawabe, Keisuke Osakabe, Senju Hashimoto, Michihito
Murao, Yoshifumi Nitta, Takuji Nakano, Hiroaki Shimazaki,
Toshiki Kan, Kazunori Nakaoka, Masashi Ohki, Takagawa Yuka,
Takamitsu Kurashita, Emi Matsuo, Tomoki Takamura, Aiko Fukui,
Toru Nishikawa, Naohiro Ichino, Kentaro Yoshioka
1895: Durability of HBeAg Seroconversion of
Telbivudine as Monotherapy and as Combination
Therapy with Adefovir Dipivoxil for Chronic Hepatitis B
Patients with High ALT Level: A Prospective, Multicenter,
Cohort Study
Yang Ding, Chong Zhang, Qiuju Sheng, Mingxiang Zhang,
Feng Wu, Baojun Song, Weili Zhu, Jingyan Wang, Lilan Shi,
Xiaoguang Dou
1896: Tenofovir versus Entecarvir in Antiviral-Naïve
Chronic Hepatitis B Patients: Preliminary 48-Week
Results
Young Joo Yang, Ju Hyun Shim, Hyung-Don Kim, Yeonjung Ha,
Mi-Jung Jun, Seung Bum Lee, Jee Eun Yang, Gi-Ae Kim, Eui Ju Park,
Jihyun An, Danbi Lee, Kang Mo Kim, Young-Suk Lim, Han Chu Lee,
Young-Hwa Chung, Yung Sang Lee, Dong Jin Suh
1897: Tenofoivr treatment in chronic hepatitis B patients
with suboptimal response to adefovir with prior
lamivudine resistance
Joohan Park, Hyo Jung Cho, Sun Young Park, Seon Joo Ahn, Soon
Sun Kim, Jae Youn Cheong, Sung Won Cho
1898: A prospective, open-label cohort study
comparing the efficacy, safety and drug resistance of
entecavir monotherapy versus de novo combination
of lamivudine and adefovir dipivoxil in naïve HBeAg-
positive chronic hepatitis B patients with high HBV viral
load (The Climber Study): a preliminary analysis
Wei Guo, Di Wu, Peng Wang, Jing-Feng Chen, Yan-hong Xu,
Weiming Yan, Ke Ma, Meifang Han, Jianxin Song, Junying Qi,
Jiaquan Huang, Yuancheng Huang, Xiping Zhao, Dong Xu, Qin
Ning
1899: Tenofovir Montherapy in Chronic Hepatitis B
Patients with Genotypic Resistance to Previous Antiviral
Therapy - a Cohort Study
Jihyun An, Young-Suk Lim, Gi Ae Kim, Hyung-Don Kim, Ju Hyun
Shim, Kang Mo Kim, Han Chu Lee, Young-Hwa Chung, Danbi Lee,
Yung Sang Lee, Dong Jin Suh
1900: Outcome of chronic hepatitis B patients who
discontinued nucleos(t)ide analogue therapy
Suna Yapali, Kelly Oberhelman, Anna S. Lok
1901: Efficacy of Entecavir plus Tenofovir Combination
NOVEMBER 11
Therapy for Chronic Hepatitis B Patients with Multi-Drug
TUESDAY
Resistant Strains
Yun Bin Lee, Jeong-Hoon Lee, Dong Hyeon Lee, Hyeki Cho,
Hongkeun Ahn, Won-Mook Choi, Young Youn Cho, Minjong Lee,
Jeong-Ju Yoo, Yuri Cho, Eun Ju Cho, Su Jong Yu, Yoon Jun Kim,
Jung-Hwan Yoon, Chung Yong Kim, Hyo-Suk Lee
Presenters in Attendance 10:30 AM – Noon
 186A POSTER SESSIONS
Poster Sessions
1902: Nucleoside Drug Resistance and Potential HBV
Vaccine-Escape Mutation Caused by Telbivudine
Treatment in a Chronic Hepatitis B Patient
Senol Comoglu, Ayten Kadanali, Behiye Dede, Gul Karagoz,
Kevser K. Tatar, Murat Sayan, Nur B. Ozdemir, Zeynep S. Çakar
1903: Entecavir plus adefovir or entecavir plus tenofovir
for patients with chronic hepatitis B resistant to
neucleot(s)ide analogues
Jung Gil Park, Young Oh Kweon, Won Young Tak, Se Young Jang,
Su Hyun Lee, Soo Young Park
1904: Estimating The Probability Of Response To
Peginterferon Alfa In Hbeag-Positive Chronic Hepatitis
B: The Epic-B Predictor
Milan J. Sonneveld, Vincent W. Wong, Jun Cheng, Teerha
Piratvisuth, Jidong Jia, Stefan Zeuzem, Edward J. Gane, Yun -Fan
Liaw, Willem Pieter Brouwer, Qing Xie, Jinlin Hou, Henry Lik-Yuen
Chan, Harry L. Janssen, Bettina E. Hansen
1905: Excellent Theraputic Response to Tenofovir
Dipivoxil Fumarate (TDF) in Chronic Hepatitis B Pregnant
Women with Resistance to Prior Anti-viral Therapy
Hua Zhang, Calvin Q. Pan, Xin Liu, Qian Bian, Qiumei Pang, Yun
X. Zhu, Qing Liu, Ruihua Tian
1906: Tenofovir versus entecavir in the treatment of
chronic hepatitis B with severe acute exacerbation
Chao-Hung Hung, Chien-Hung Chen, Sheng-Nan Lu, Tsung-Hui
Hu, JIng-Houng Wang, Chuan-Mo Lee
1907: Combination with Nucleoside Analogues was
not Superior to Tenofovir Monotherapy in Patients with
Drug-resistant Chronic Hepatitis B
Sae Hwan Lee, Hong Soo Kim, Sang Gyune Kim, Young Seok Kim,
Boo Sung Kim, Soung Won Jeong, Jae Young Jang, Young Don
Kim, Gab Jin Cheon
1908: Tenofovir-Induced Fanconi Syndrome In Chronic
Hepatitis B Monoinfected Patients Successfully Rescued
By Entecavir
Mauro Viganò, Alessandra Brocchieri, Angiola Spinetti, Serena
Zaltron, Giampaolo Mangia, Floriana Facchetti, Alessandro
Fugazza, Francesco Castelli, Massimo Colombo, Pietro Lampertico
1909: A Comparison of the Efficacy and Safety of
Entecavir Versus Lamivudine Through 240 Weeks of
Treatment in Korean Patients with HBeAg-negative
Chronic Hepatitis B
Kwan Sik Lee, Young-Oh Kweon, Soon Ho Um, Byung-Ho Kim,
Young Suk Lim, Seung Woon Paik, Jeong Heo, Heon Ju Lee, Dong
Joon Kim, Tae Hun Kim, Young Sok Lee, Kwan Soo Byun, Dae-
Ghon Kim, Myung Seok Lee, Cyril Llamoso, Kyungha Yu, Dong
Jin Suh
NOVEMBER 11
TUESDAY
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1910: Does interferon treatment reduce hepatocellular
carcinoma incidence in HBeAg positive chronic hepatitis
B patients?
Tetsuya Hosaka, Fumitaka Suzuki, Masahiro Kobayashi, Taito
Fukushima, Yusuke Kawamura, Hitomi Sezaki, Norio Akuta,
Yoshiyuki Suzuki, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda,
Mariko Kobayashi, Hiromitsu Kumada
1911: Association between Genotype and the
HBsAg Levels at HBeAg Loss in HBeAg-positive
Chronic Hepatitis B Patients Treated with Entecavir or
Peginterferon Alfa-2a
Cheng-Yuan Peng, Hsueh-Chou Lai, Wen- Pang Su, Chia-Hsin Lin,
Po-Heng Chuang, Sheng-Hung Chen
1912: Durability of HBeAg Seroconversion After
Treatment with Entecavir or Tenofovir in Chronic
Hepatitis B Patients
Tse-Ling Fong, Edward A. Mena, Andy S. Yu, Quang-Quoc Phan,
Steven-Huy B. Han, Andy Tien, Andrew J. Velasco, Vinh-Huy
Leduc, Myron J. Tong
1913: Nucleoside Analogues treatment in Patients with
Acute and Subacute liver failure related to hepatitis B
virus
Bing Zhu, Shaoli You, HongLing Liu, Yihui Rong, Hong Zang,
ZhiHong Wan, ShaoJie Xin
1914: Durability of Nucleos(t)ide Analogues Treatment
in Patients with Chronic Hepatitis B: The Role of APASL
Guideline
Yi-Hsiang Huang, I-Cheng Lee, Cheuk-Kay Sun, Chien-Wei Su,
Yuan-Jen Wang, Han-Chieh Lin
1915: Suppression of Hepatitis B Virus Replication by
Dandelion extracts and Traxasterol in Vitro
Ying Yang, Feng Chen, Jihua Xue, Jing Wang, Chaochao Qin, Yu
Shi, Weixia Liu, Zhi Chen
1916: The estimated glomerular filtration rate changes
in chronic hepatitis B patients during nucleos(t)ide
analogues treatment
Yi-Cheng Chen, Rachel Wen-Juei Jeng, Wei Teng, Chao-Wei Hsu,
Chun-Yen Lin, I-Shyan Sheen, Rong-Nan Chien, Yun -Fan Liaw
1917: Efficacy and Safety of Telbivudine in Chinese
Children and Adolescents with Chronic Hepatitis B
Hongfei Zhang, Shishu Zhu, Yi Dong, Limin Wang, Zhiqiang Xu,
Dawei Chen, Yu Gan, Fuchuan Wang
1918: Similar Renal Function Profile in Chronic Hepatitis
B (CHB) Patients Treated with Tenofovir (TDF) vs.
Entecavir (ETV) Monotherapy – A Multicenter Matched
Case Cohort Study
Nghi B. Ha, Kevin Ku, Nghiem B. Ha, Kevin T. Chaung, Huy N.
Trinh, Mindie H. Nguyen
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1919: Effect of achieving drug-free status and HBs
antigen decline in sequential therapy with Peg-IFN alfa-
2a on long-term nucleoside analog treated patients
Ken Nishino, Miwa Kawanaka, Jun Nakamura, Takahito Oka,
Noriyo Urata, Daisuke Goto, Mitsuhiko Suehiro, Hirofumi
Kawamoto, Gotaro Yamada
1920: Entecavir monotherapy vs. lamivudine-adefovir
combination therapy for chronic hepatitis B infection: a
5-year randomized controlled trial
Guan Huei Lee, Wah Wah Phyo, Yock Young Dan, Yin-Mei Lee,
How Cheng Low, Kieron B. Lim, Maung Aye Thwin, Poh Seng Tan,
Seng Gee Lim
1921: Long-term Follow-up and Treatment Rates of
Treatment-Eligible Chronic Hepatitis B (CHB) Patients: A
Multicenter Cohort Study
Vinh D. Vu, Ailinh Do, Nghia H. Nguyen, Lily H. Kim, Huy N.
Trinh, Huy A. Nguyen, Khanh Nguyen, Mindie H. Nguyen
1922: 2-years impact of entecavir (ETV) on liver fibrosis
and activity as assessed by FibroTest – ActiTest and
Liver Stiffness Measurement (LSM) in chronic hepatitis B
(CHB) patients
Fabien Zoulim, Xavier Causse, Vincent Leroy, Denis Ouzan,
Nathalie Ganne-Carrié, Valerie Bourcier, Victor de Ledinghen,
Philippe Mathurin, Marika Rudler, Joseph Moussalli, Dominique
Thabut, Luminita Bonyhay, Vlad Ratziu, Fabienne Drane, Yen Ngo,
Mona Munteanu, Thierry Poynard
1923: Efficacy of tenofovir disoproxil fumarate in
chronic hepatitis B patients with genotypic resistances to
other nucleos(t)ide analogues
Tae Jung Yun, Soon Ho Um, Chang Ho Jung, Tae Hyung Kim, Seok
Bae Yoon, Sun Young Yim, Bora Keum, Yeon Seok Seo, Hyung
Joon Yim, Yoon Tae Jeen, Hong Sik Lee, Hoon Jai Chun, Chang
Duck Kim, Ho Sang Ryu
1924: Factors relevant to relapse in chronic hepatitis B
patients after off-therapy of telbivudine and lamivudine:
focused on long-term durability
Hong-Ying Pan, Hong-Yi Pan, Li Chen, DanHong Yang, HaiJun
Huang, YongXi Tong, Cui-Rong Chen, XingJiang Jian
1925: Course of partial virological response to entecavir
under long-term entecavir therapy in ptatients with
chronic hepatitis B
Joohan Park, Hyo Jung Cho, Sun Young Park, Seon Joo Ahn, Soon
Sun Kim, Jae Youn Cheong, Sung Won Cho
Poster Viewing: 8:00 AM – Noon
187A
Hepatitis C: New Agents (Not
Approved)
1926: Baseline and Post-baseline Resistance
Analyses of Phase 2/3 Studies of Ledipasvir/Sofosbuvir
± RBV
Christoph Sarrazin, Hadas Dvory-Sobol, Evguenia S. Svarovskaia,
Brian Doehle, Joseph F. McCarville, Phillip S. Pang, Nezam H.
Afdhal, Kris V. Kowdley, Edward J. Gane, Eric Lawitz, John G.
McHutchison, Michael D. Miller, Hongmei Mo
1927: CPI-431-32, a Novel Cyclophilin A Inhibitor,
Simultaneously Blocks Replication of HCV and HIV-1
Viruses in a Novel in Vitro Co-Infection Model
Philippe Gallay, Michael Bobardt, Dan Trepanier, Daren Ure,
Cosme Ordonez, Robert T. Foster
1928: Interferon-Free Regimens of Ombitasvir and
ABT-450/r With or Without Ribavirin in Patients With
HCV Genotype 4 Infection: PEARL-I Study Results
Stanislas Pol, K. Rajender Reddy, Tolga Baykal, Christophe
Hezode, Tarek Hassanein, Patrick Marcellin, Marina Berenguer,
Katarzyna M. Fleischer-Stepniewska, Coleen Hall, Christine
Collins, Regis A. Vilchez
1929: 100% SVR4 in Japanese Patients with Chronic
Genotype 1 Hepatitis C Virus Infection Receiving
Ledipasvir/Sofosbuvir Fixed Dose Combination for 12
Weeks: Results from a Multicenter Phase 3 Study
Masashi Mizokami, Tetsuo Takehara, Osamu Yokosuka, Naoya
Sakamoto, Masaaki Korenaga, Hitoshi Mochizuki, Kunio Nakane,
Hirayuki Enomoto, Mikio Yanase, Hidenori Toyoda, Fusao Ikeda,
Takuya Genda, Takeji Umemura, Hiroshi Yatsuhashi, Tatsuya Ide,
Nobuo Toda, Kazushige Nirei, Yoshiyuki Ueno, Yoichi Nishigaki,
Juan Betular, Bing Gao, Akinobu Ishizaki, Masa Omote, Phillip S.
Pang, Steven J. Knox, William T. Symonds, John G. McHutchison,
Namiki Izumi, Masao Omata
1930: Alisporivir Selectively Eliminates HCV-Created
Double Membrane Vesicles by Disrupting CypA-NS5A
interactions in Infected Hepatocytes
Udayan Chatterji, Michael Bobardt, Malcolm Wood, Philippe
Gallay
1931: SVR12 Rate of 98.6% in 992 HCV Genotype
1b-Infected Patients Treated with ABT-450/r/
Ombitasvir and Dasabuvir With or Without Ribavirin
Massimo Colombo, Ola Weiland, Daniel E. Cohen, Jean-Francois
J. DuFour, Hendrik Reynaert, Moises Diago, Erica Villa, Adrian
Streinu-Cercel, Wangang Xie, Tolga Baykal, Jeffrey Enejosa, Eoin
Coakley, Roger Trinh, Thomas Podsadecki
1932: On Treatment HCV RNA as a Predictor of
Virologic Response in the Ledipasvir/Sofosbuvir Phase 3
Program for HCV Genotype 1 Infection: Analysis of the
NOVEMBER 11
ION-1, ION-2, and ION-3 Studies
TUESDAY
Tania M. Welzel, Eva Herrmann, Patrick Marcellin, Nezam H.
Afdhal, Kris V. Kowdley, Luisa M. Stamm, Yanni Zhu, Phillip S.
Pang, John G. McHutchison, Stefan Zeuzem
Presenters in Attendance 10:30 AM – Noon
 188A POSTER SESSIONS
Poster Sessions
1933: PEARL-IV Trial: Subgroup Analysis of
Genotype 1a-Infected Patients Treated With ABT-450/r/
Ombitasvir With Dasabuvir With or Without Ribavirin
David Eric Bernstein, Yan Luo, Jacob P. Lalezari, David L. Wyles,
William King, Naoky Tsai, Mitchell N. Davis, Thomas E. Sepe,
Jeffrey Fessel, Martin King, Thomas Podsadecki, Curtis Cooper
1934: SVR12 Rate of 95.7% in 209 HCV Genotype
1-Infected Null Responders Treated With ABT-450/r/
Ombitasvir and Dasabuvir With or Without Ribavirin
Ira M. Jacobson, Jean-Francois J. DuFour, Jeffrey Enejosa, Robert J.
de Knegt, Peter Ferenci, Hendrik Reynaert, Adrian M. Di Bisceglie,
Lois Larsen, Tolga Baykal, Lino Rodrigues-Jr, Thomas Podsadecki,
Donald M. Jensen, Fred Poordad
1935: Early Improvement in the HepQuant® (HQ)-
SHUNT Function Test during Treatment with Ledipasvir/
Sofosbuvir in Liver Transplant Recipients with Allograft
Fibrosis or Cirrhosis and Patients with Decompensated
Cirrhosis who have not undergone Transplantation
Jacqueline G. O’Leary, James R. Burton, Steve M. Helmke, Andrea
Herman, Michael W. Cookson, Shannon Lauriski, James F. Trotter,
Jill M. Denning, Phillip S. Pang, John G. McHutchison, Gregory T.
Everson
1936: Pooled analysis of resistance in patients
treated with ombitasvir/ABT-450/r and dasabuvir with
or without ribavirin in Phase 2 and Phase 3 clinical
trials
Preethi Krishnan, Rakesh Tripathi, Gretja Schnell, Thomas Reisch,
Jill Beyer, Michelle Irvin, Wangang Xie, Lois Larsen, Thomas
Podsadecki, Tami Pilot-Matias, Christine Collins
1937: All-oral Dual Combination of Daclatasvir
plus Asunaprevir Compared with Telaprevir plus
Peginterferon Alfa/Ribavirin in Treatment-naive
Japanese Patients Chronically Infected with HCV
Genotype 1b: Results from a Phase 3 Study
Kazuaki Chayama, Fumitaka Suzuki, Yoshiyuki Suzuki, Joji Toyota,
Yoshiyasu Karino, Yoshiiku Kawakami, Shigetoshi Fujiyama,
Takayoshi Ito, Yoshito Itoh, Etsuko Tamura, Tomoko Ueki, Hiroki
Ishikawa, Misti Linaberry, Eric A. Hughes, Hiromitsu Kumada
1938: ABT-450/r/Ombitasvir + Dasabuvir With or
Without Ribavirin in HCV Genotype 1-infected Patients
Receiving Stable Opioid Substitution Treatment: Pooled
Analysis of Efficacy and Safety in Phase 2 and Phase 3
Trials
Massimo Puoti, Curtis Cooper, Mark S. Sulkowski, Graham R.
Foster, Thomas Berg, Erica Villa, Federico Rodriguez-Perez, Vinod
Rustgi, David L. Wyles, Martin King, Barbara H. McGovern,
Heiner Wedemeyer
NOVEMBER 11
TUESDAY
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1939: TURQUOISE-I: 94% SVR12 in HCV/HIV-1
Coinfected Patients Treated with ABT-450/r/Ombitasvir,
Dasabuvir and Ribavirin
David L. Wyles, Mark S. Sulkowski, Joseph J. Eron, Roger Trinh,
Jay Lalezari, Jihad Slim, Joseph C. Gathe, Chia C. Wang, Richard
Elion, Fritz Bredeek, Robert O. Brennan, Gary Blick, Amit Khatri,
Krystal Gibbons, Yiran Hu, Linda Fredrick, Tami Pilot-Matias,
Barbara Da Silva-Tillmann, Barbara H. McGovern, Andrew L.
Campbell, Thomas Podsadecki
1940: Pharmacokinetics of Co-Administered HCV
Protease Inhibitor MK-5172 and NS5A Inhibitor
MK-8742 in Volunteers with End-Stage Renal Disease
on Hemodialysis or Severe Renal Impairment Not on
Hemodialysis
Wendy W. Yeh, Luzelena Caro, Zifang Guo, Hwa Ping Feng,
Henry U. Davis, Megan Kozisek, Daria Stypinski, Chun Feng,
Carrie Mitchell, Anne Gillespie, Nita Ichhpurani, William L.
Marshall, Kenneth C. Lasseter, Thomas C. Marbury, Joan R.
Butterton
1941: HELIX-2, A Phase II Study of Samatasvir in
Combination with Simeprevir, Low Dose Ritonavir-
boosted TMC647055 + Ribavirin in Treatment-naïve or
Interferon/ribavirin Treated, Relapsed Genotype 1 HCV-
infected Subjects
Eric Lawitz, Maribel Rodriguez-Torres, Tuan T. Nguyen, Aasim
M. Sheikh, Hillel Tobias, Joseph S. Galati, John M. Hill, Anna
S. Lok, David R. Nelson, Gloria Dubuc Patrick, Jie Chen, Dodie
Frank, Xiao-Jian Zhou, John Sullivan-Bolyai, Leen Vijgen, Pieter
Van Remoortere, René Verloes, Gaston Picchio, Douglas L. Mayers
1942: Resistance Analysis of Treatment-Naïve HCV
Genotype 1-6 Infected Patients Treated with Sofosbuvir
in Combination with GS-5816 for 12 Weeks
Brian Doehle, Viktoria Gontcharova, Ramakrishna K.
Chodavarapu, John McNally, Raymond T. Chung, Gregory T.
Everson, John G. McHutchison, Michael D. Miller, Hongmei Mo
1943: Daclatasvir in combination with asunaprevir and
BMS-791325 for prior null responders with chronic HCV
genotype 1 infection
Gregory T. Everson, Karen D. Sims, Paul J. Thuluvath, Howard
Schwartz, Tarek Hassanein, Eric Lawitz, Lynn R. Webster, Norbert
Brau, Taddese Desta, Joseph S. Galati, Reem H. Ghalib, Norman
Gitlin, Steven-Huy Han, Federico Hinestrosa, Maribel Rodriguez-
Torres, Ronald Nahass, Peter J. Ruane, Wen-Lin Luo, Fiona
McPhee, David F. Gardiner
1944: Safety of Ledipasvir/Sofosbuvir with and without
Ribavirin for the Treatment of Patients with Chronic HCV
Genotype 1 Infection: An Analysis of the Phase 3 ION
trials
Saleh Alqahtani, Nezam H. Afdhal, Stefan Zeuzem, Stuart C.
Gordon, Alessandra Mangia, Paul Y. Kwo, Jenny C. Yang, Xiao
Ding, Phillip S. Pang, John G. McHutchison, Patrick Marcellin, Kris
V. Kowdley, Mark S. Sulkowski
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1945: Virologic Response Rates to All Oral Fixed-
Dose Combination Ledipasvir/Sofosbuvir Regimens
Are Similar in Patients With and Without Traditional
Negative Predictive Factors in Phase 3 Clinical Trials
Ira M. Jacobson, Paul Y. Kwo, Kris V. Kowdley, Jenny C. Yang,
Yanni Zhu, Robert H. Hyland, Phillip S. Pang, John G. McHutchison,
Mark S. Sulkowski, Nezam H. Afdhal
1946: A Next Generation HCV DAA Combination:
Potent, Pangenotypic Inhibitors ABT-493 and ABT-530
with High Barriers to Resistance
Teresa Ng, Tami Pilot-Matias, Liangjun Lu, Thomas Reisch, Tanya
Dekhtyar, Preethi Krishnan, Jill Beyer, Rakesh Tripathi, Ron B.
Pithawalla, Armen Asatryan, Andrew L. Campbell, Jens Kort,
Christine Collins
1947: Concordance between SVR4, SVR12 and SVR24
in Genotype 1 HCV-Infected Patients who Received All
Oral Fixed-Dose Combination Ledipasvir/Sofosbuvir
With Or Without Ribavirin in Phase 3 Clinical Trials
David Eric Bernstein, Alessandra Mangia, Norbert Brau, Jenny
C. Yang, Julie Ma, Robert H. Hyland, Phillip S. Pang, John G.
McHutchison, K. Rajender Reddy, Michael W. Fried
1948: High Rates of SVR in Patients with Genotype
1 HCV Infection and Cirrhosis After Treatment with
Ledipasvir/Sofosbuvir+Ribavirin or Ledipasvir/
Sofosbuvir+GS-9669 for 8 weeks
Eric Lawitz, Fred Poordad, Robert H. Hyland, Jing Wang, Phillip
S. Pang, William T. Symonds, John G. McHutchison, Fernando E.
Membreno
1949: Evaluation of the Resistance Profile of Ledipasvir
(LDV), a Nonstructural Protein 5A (NS5A) Inhibitor,
in Genotype (GT) 1 Chronically Infected HCV Subjects
Treated with LDV-Containing Regimens without
Sofosbuvir (SOF)
Kathryn M. Kitrinos, David L. Wyles, Hadas Dvory-Sobol, Angela
Worth, Bin Han, Diana M. Brainard, Bittoo Kanwar, Michael D.
Miller, Hongmei Mo
1950: Time to Viral Suppression is Not Related to
Achievement of SVR12 in HCV GT1-infected Patients
Treated with ABT-450/r/Ombitasvir and Dasabuvir
With or Without Ribavirin
Mark S. Sulkowski, Michael W. Fried, Resat Ozaras, Vasily Isakov,
David L. Wyles, Peter Ferenci, Jordan J. Feld, Filipe Calinas,
Michael Gschwantler, Martin King, Tolga Baykal, Edward J. Gane
1951: Safety of ABT-450/r/Ombitasvir + Dasabuvir
With or Without Ribavirin in HCV Genotype 1-infected
Patients: Results From Phase 2 and Phase 3 Trials
Michael W. Fried, Adrian M. Di Bisceglie, John M. Vierling,
Edward J. Gane, Frederik Nevens, Simone I. Strasser, Ola
Weiland, Sorin Rugina, Sandra S. Lovell, Barbara Da Silva-
Tillmann, Nancy Shulman, Naoky Tsai, David R. Nelson
Poster Viewing: 8:00 AM – Noon
189A
1952: The Pharmacokinetics of Ledipasvir, an HCV
Specific NS5A Inhibitor, in HCV-Uninfected Subjects
with Severe Renal Impairment
Erik Mogalian, Anita Mathias, Jenny C. Yang, Phillip S. Pang, Lisa
Moorehead, Maria G. Hernandez, Kenneth C. Lasseter, Daniel
Ries, Richard A. Robson, Gernot Klein
1953: Adherence to Prescribed Doses of ABT-450/r/
Ombitasvir, Dasabuvir, and Ribavirin in the Phase 3
PEARL-II, PEARL-III, and PEARL-IV Trials
David Eric Bernstein, Rui T. Marinho, Daniel E. Cohen, Fritz
Bredeek, Ferenc Schneider, Gunnar P. Norkrans, Manuela G.
Curescu, Michael Bennett, Marina Maevskaya, Jeffrey Fessel,
Wangang Xie, Yan Luo, Jeffrey Enejosa
1954: Identification and treatment of multiple subtypes
of HCV genotype 4 in the PEARL-I study with ombitasvir
and ABT-450/r ± ribavirin
Gretja Schnell, Rakesh Tripathi, Jill Beyer, Thomas Reisch, Preethi
Krishnan, Tolga Baykal, Coleen Hall, Regis A. Vilchez, Tami Pilot-
Matias, Christine Collins
1955: Safety and efficacy outcomes of all-oral
daclatasvir-containing regimens in patients with or
without cirrhosis in phase 2 and 3 studies
Donald M. Jensen, Ira M. Jacobson, Hiromitsu Kumada, Joji
Toyota, Mark S. Sulkowski, Michael P. Manns, Jia-Horng Kao,
Jeong Heo, Philip Yin, Patricia Mendez, Eric A. Hughes, Stephanie
Noviello
1956: Potent Antiviral Activity of ABT-493 and ABT-530
With 3-Day Monotherapy in Patients With and Without
Compensated Cirrhosis With Hepatitis C Virus (HCV)
Genotype 1 Infection
Eric Lawitz, William D. O’Riordan, Bradley L. Freilich, Terry D.
Box, J. Scott Overcash, Wei Liu, Andrew L. Campbell, Chih-Wei
Lin, Armen Asatryan, Jens Kort
1957: Pharmacokinetics of Cyclosporine and
Tacrolimus, Following Coadministration with the Direct
Acting Antiviral Combination, ABT-450/r, Ombitasvir
and Dasabuvir, in Liver Transplant Patients with
Genotype-1 HCV Infection
Prajakta Badri, Apurvasena Parikh, Eoin Coakley, Bifeng Ding,
Walid Awni, Sandeep Dutta, Rajeev Menon
1958: No Differences in the Efficacy of Fixed-Dose
Combination Ledipasvir/Sofosbuvir in Patients
According to Fibrosis Stage Determined by Liver Biopsy
or Laboratory Biomarker in Phase 3 Clinical Trials
Stuart C. Gordon, Michael W. Fried, Paul Y. Kwo, Jenny C.
Yang, Yanni Zhu, Robert H. Hyland, Phillip S. Pang, John G.
McHutchison, K. Rajender Reddy, Patrick Marcellin
NOVEMBER 11
TUESDAY
Presenters in Attendance 10:30 AM – Noon
 190A POSTER SESSIONS
Poster Sessions
1959: HCVerso1: A phase III study of faldaprevir (FDV)
plus deleobuvir (DBV) and ribavirin (RBV) for chronic
HCV genotype (GT)-1b infection in treatment-naïve
patients
Christoph Sarrazin, Francesco Castelli, Massimo Puoti, Mitchell
L. Shiffman, Liliana Preotescu, Xavier Forns, Maria Buti, Eric M.
Yoshida, Marc Bourlière, Célia Oliveira, Jerry O. Stern, Wulf O.
Boecher, George Kukolj, Carla Haefner, Richard Vinisko, Miguel
Garcia, Federico J. Mensa
1960: Deep Sequencing Analysis Of Variants Resistant
To Ns5a Inhibitors In Patients With Genotype 1b
Hepatitis C Virus Infection
Shinya Maekawa, Mika Miura, Mitsuaki Sato, Nobutoshi Komatsu,
Yasuhiro Nakayama, Taisuke Inoue, Minoru Sakamoto, Nobuyuki
Enomoto
1961: Safety of ABT-450/r/Ombitasvir + Dasabuvir
With or Without Ribavirin in HCV Genotype 1-infected
Patients: Results From PEARL II, PEARL III, and PEARL IV
Jacob P. Lalezari, Ronald Pruitt, Yan Luo, Richard J. Aspinall,
Giovanni B. Gaeta, Iwona Olszok, William King, Selim Gurel,
Yiran Hu, Jeffrey Enejosa, Daniel E. Cohen, Nancy Shulman,
Velimir A. Luketic
1962: TURQUOISE-II: Trends in Liver Fibrosis Testing,
Hepatic Synthetic Function, and Platelet Counts at
Baseline and 12 Weeks After Treatment With ABT-
450/r/Ombitasvir and Dasabuvir With Ribavirin in
HCV Genotype 1-Infected Patients with Cirrhosis
Mitchell L. Shiffman, Kris V. Kowdley, Stefan Zeuzem, David J.
Mutimer, Marc Bourlière, Thomas Berg, Samuel S. Lee, Sandra S.
Lovell, Leticia Canizaro, Roger Trinh, Guy Neff, Paul Y. Kwo
1963: Impaired Early Viral Kinetics in Patients with
Cirrhosis treated with Interferon-free Regimens - The
Impact of Portal Pressure
Mattias Mandorfer, Karin Kozbial, Albert Stättermayer, Sandra
Beinhardt, Philipp Schwabl, Remy Schwarzer, Michael Trauner,
Arnulf Ferlitsch, Harald Hofer, Markus Peck-Radosavljevic, Peter
Ferenci
1964: Resistance Analysis of Hepatitis C Virus (HCV)
from Genotype 1 and 4 Treatment-naïve Subjects
Receiving Samatasvir in Combination with Simeprevir
and Ribavirin in a 12-week Phase II Clinical Trial
Bianca Heinrich, John P. Bilello, Eric Lawitz, Maribel Rodriguez-
Torres, Tuan T. Nguyen, Aasim M. Sheikh, Hillel Tobias, Joseph S.
Galati, John M. Hill, Anna S. Lok, David R. Nelson, Leen Vijgen,
Pieter Van Remoortere, René Verloes, Gaston Picchio, Gloria
Dubuc Patrick, Maria Seifer, Douglas L. Mayers
1965: Long-term follow-up of patients treated with
daclatasvir-based regimens in phase 2 and 3 studies
K. Rajender Reddy, Stanislas Pol, Paul J. Thuluvath, Hiromitsu
NOVEMBER 11
Kumada, Joji Toyota, Kazuaki Chayama, James M. Levin, Eric
TUESDAY
Lawitz, Adrian Gadano, Wayne Ghesquiere, Guido Gerken,
Maurizia R. Brunetto, Cheng-Yuan Peng, Ruben Terg, Marcelo O.
Silva, Simone I. Strasser, Jeong Heo, Fiona McPhee, Zhaohui Liu,
Misti Linaberry, Eric A. Hughes, Stephanie Noviello
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1966: HCVerso2: A phase III study of faldaprevir
(FDV) plus deleobuvir (DBV) and ribavirin (RBV) for
chronic HCV genotype (GT)-1b infection in treatment-
naïve patients including those ineligible for pegylated
interferon (PegIFN)
David R. Nelson, Pietro Andreone, Massimo Colombo, Filipe
Calinas, Antonio Olveira, Jean Delwaide, Dieter Häussinger,
Denis Ouzan, Simone I. Strasser, Tarik Asselah, Curtis Cooper,
Jerry O. Stern, Wulf O. Boecher, George Kukolj, Stella Aslanyan,
Qiqi Deng, Edward Wang, Federico J. Mensa
1967: Pharmacokinetics of asunaprevir, daclatasvir
and raltegravir in HCV/HIV co infected patients, with
or without cirrhosis, and previously null responders
to pegylated interferon + ribavirin (ANRS HC30 -
QUADRIH study)
Anne-Marie Taburet, Lionel Piroth, Hubert Paniez, Mélanie Simony,
Valerie Furlan, Aurélie Barrail-Tran, Corine Vincent, Eric Rosenthal,
Eric Billaud, Hugues Aumaître, François Bailly, Martine Resch,
Laurence Meyer, Jean-Michel Molina
1968: Efficacy by Race or Geographic Region in HCV
Genotype 1-infected Patients Treated with ABT-450/
ritonavir/Ombitasvir and Dasabuvir With or Without
Ribavirin
John M. Vierling, Massimo Puoti, David Eric Bernstein, Naoky Tsai,
Ola Weiland, Manuel Romero Gómez, Florin A. Caruntu, Jean-
Francois J. DuFour, Filipe Calinas, Lois Larsen, Fernando Tatsch,
Pietro Andreone
1969: Safety of ABT-450/r/Ombitasvir + Dasabuvir
With or Without Ribavirin in HCV Genotype 1-infected
Patients ≥65 Years of Age: Results From Phase 2 and 3
Trials
Steven L. Flamm, Edward J. Gane, Jean-Francois J. DuFour, Vinod
Rustgi, Vincent G. Bain, Darrell H. Crawford, Pietro Andreone,
Tarek Hassanein, Wlodzimierz W. Mazur, Sandra S. Lovell,
Barbara Da Silva-Tillmann, Nancy Shulman, Massimo Puoti, Terry
D. Box, Ira M. Jacobson
1970: Ledipasvir/Sofosbuvir is Safe and Effective in
Nosocomially Infected Patients with Advanced Age and
Significant Cardiac Co-Morbidities
Raymond T. Chung, Georg M. Lauer, Luisa M. Stamm, Lin Liu,
Hongmei Mo, Phillip S. Pang, Diana M. Brainard, John G.
McHutchison, Arthur Y. Kim
1971: Durability of Sustained Virologic Response in
Hepatitis C Infected Patients Treated with IFN-Free DAA
Regimens
Sara Jones, Miriam Marti, Zayani Sims, Anita Kohli, Sarah
Kattakuzhy, Tess L. Petersen, Rachel Silk, Michael A. Polis, Henry
Masur, Shyam Kottilil, Anu Osinusi
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
1972: ABT-450/r/Ombitasvir + Dasabuvir With or
Without Ribavirin in HCV Genotype 1-infected Patients
with History of Depression or Bipolar Disorder: Pooled
Analysis of Efficacy and Safety in Phase 3 Trials
David R. Nelson, K. Rajender Reddy, Adrian M. Di Bisceglie,
Peter Ferenci, Darrell H. Crawford, Rudolf E. Stauber, Alexey A.
Yakovlev, Victor de Ledinghen, Holger Hinrichsen, David Eric
Bernstein, Robert J. de Knegt, Tarek Hassanein, Suzanne Norris,
Junyuan J. Xiong, Barbara H. McGovern, Kosh Agarwal
1973: Characteristics of HCV-Infected Patients with
Cirrhosis Requiring Ribavirin Dose Reduction During
Treatment with Direct-Acting Antivirals
Ira M. Jacobson, Xavier Forns, Stefan Zeuzem, Christophe Hezode,
Mitchell L. Shiffman, Stanislas Pol, Marina Berenguer, Michael W.
Fried, Kosh Agarwal, Kris V. Kowdley, Sandra S. Lovell, Manal
Abunimeh, Roger Trinh, Barbara H. McGovern, Antonio Craxi
Hepatitis C: Preclinical Development
1974: A Phase I/IIa Study Assessing 7-day Dosing
of IDX21437 in Subjects Infected with Hepatitis C Virus
(HCV)
Edward J. Gane, Eric Sicard, Serghei Popa, Xiao-Jian Zhou, Marie-
Francoise Temam, Jie Chen, Dodie Frank, Eileen F. Donovan, Keith
Pietropaolo, Douglas L. Mayers
1975: A 4-N-Hydroxycytidine Ribonucleoside
Phosphoramidate Delivers Intracellularly Three Distinct
Active 5’-Triphosphate Nucleosides that are Potent
Inhibitors of HCV Polymerase
Raymond F. Schinazi, Franck Amblard, Sijia Tao, Maryam
Ehteshami, Sheida Amiralaei, Hao Li, Jadd Shelton, Tony Whitaker,
Tami R. McBrayer, Steven J. Coats
1976: Drug-Drug Interaction Profile Of The Fixed-
Dose Combination Tablet Ledipasvir/Sofosbuvir
Polina German, Phillip S. Pang, Liang Fang, Diana Chung, Anita
Mathias
1977: Hepatocellular carcinoma development of
hepatitis C virus patients with eradication to interferon
therapy: a large scale, long-term study of 2266 patients
Yuko Nagaoki, Hiroshi Aikata, Tomoki Kobayashi, Takayuki
Fukuhara, Noriaki Naeshiro, Daisuke Miyaki, Tomokazu
Kawaoka, Masataka Tsuge, Akira Hiramatsu, Michio Imamura,
Hideyuki Hyogo, Yoshiiku Kawakami, Hidenori Ochi, Kazuaki
Chayama
1978: ACH-3422, A Novel HCV NS5B RNA
Polymerase Nucleotide Inhibitor, Demonstrates
Improved Potency Over Sofosbuvir Against HCV
Genotype-3 Replicons In Vitro
Yongsen Zhao, Steven Podos, Joanne L. Fabrycki, Dharaben Patel,
Wengang Yang, Guangwei Yang, Jason Wiles, Avinash Phadke,
Mingjun Huang
Poster Viewing: 8:00 AM – Noon
191A
1979: MK-8408, A Potent and Selective NS5A Inhibitor
with a High Genetic Barrier to Resistance and Activity
Against HCV Genotypes 1-6
Ernest Asante-Appiah, Rong Liu, Stephanie Curry, Patricia
McMonagle, Sony Agrawal, Donna Carr, Laura Rokosz, Frederick
Lahser, Karin Bystol, Robert Chase, Stuart Black, Eric B. Ferrari,
Paul Ingravallo, Shiying Chen, Ling Tong, Wensheng Yu, Joseph
Kozlowski
1980: First Time in Human (FTIH) and Proof of Concept
(POC) Studies of GSK2878175 (GSK175), a Potent Pan-
Genotypic Non-Nucleoside NS5B Polymerase Inhibitor
of HCV Replication
Stephen D. Gardner, Joseph Kim, Benjamin Van Hecke, Maribel
Rodriguez-Torres, Lucinda Elko-Simms, Sharon Baptiste-Brown,
Vincent Lopez, Etienne F. Dumont, Robert Hamatake, Kevin Gan,
Z. Joe Zhu, Martin Leivers, Melanie T. Paff, Zhi Hong
1981: Modeling HCVcc infection reveals new insights
into the dynamics that maintain the in vitro HCV steady
state and the mechanisms of action of the NS5A
inhibitor daclatasvir
Natasha Sansone, Harel Dahari, Gitanjali Subramanya, Alan S.
Perelson, Susan L. Uprichard
1982: A Novel Approach to HCV Resistance Selection
Featuring Short Treatment Duration and Reduced
Interference from Host Cell Adaptation
Joanne L. Fabrycki, Yongsen Zhao, Dharaben Patel, Lingling Jia,
Guangwei Yang, Steven Podos, Avinash Phadke, Mingjun Huang,
Wengang Yang
1983: Preclinical Characterization of AL-516, a Potent
Guanosine Based Nucleotide Polymerase Inhibitor for
the Treatment of Chronic Hepatitis C
Hua Tan, Kenneth Shaw, Andreas Jekle, Jerome Deval, Zhinan Jin,
Amy Fung, Yuen Tam, Lawrence M. Blatt, Sushmita M. Chanda,
Qingling Zhang, Guangyi Wang, Natalia Dyatkina, Julian A.
Symons, Leo Beigelman, David B. Smith
1984: Prevention of HCV virologic breakthrough during
protease inhibitor monotherapy by addition of an SR-BI
targeting monoclonal antibody
Koen Vercauteren, Ahmed A. Mesalam, Richard Brown, Fulvia
Troise, Juliane Doerrbecker, Naomi Van Den Eede, Ali Farhoudi,
Riccardo Cortese, Geert Leroux-Roels, Thomas Pietschmann,
Alfredo Nicosia, Philip Meuleman
1985: Antiviral Activity and Resistance Emergence:
Combinations of the NS5B Nucleotide Inhibitor ACH-
3422 with Other Antiviral Agents in Vitro
Dharaben Patel, Yongsen Zhao, Joanne L. Fabrycki, Guangwei
Yang, Steven Podos, Jason Wiles, Avinash Phadke, Mingjun
Huang, Wengang Yang
NOVEMBER 11
TUESDAY
Presenters in Attendance 10:30 AM – Noon
 192A POSTER SESSIONS
Poster Sessions
1986: Pharmacokinetics and Safety of Pan-Genotypic,
Direct Acting Protease Inhibitor, ABT-493, and NS5A
Inhibitor, ABT-530, Following 3 day Monotherapy
in HCV Genotype-1 Infected Subjects with or without
Compensated Cirrhosis
Chih-Wei Lin, Wei Liu, Armen Asatryan, Andrew L. Campbell,
Sandeep Dutta
1987: Pharmacokinetics and Drug-Drug Interaction
between Samatasvir, an NS5A Inhibitor, and
Co-administered Simeprevir, an NS3/4A Protease
Inhibitor, and Low Dose Ritonavir-Boosted TMC647055,
a Non-Nucleoside NS5B Inhibitor, in Healthy Volunteers
and HCV-Infected Subjects
Xiao-Jian Zhou, Keith Pietropaolo, Dodie Frank, Jie Chen, Rolf
van Heeswijk, John Sullivan-Bolyai, Pieter Van Remoortere, René
Verloes, Douglas L. Mayers
1988: The Combination of MK-5172, an NS3 inhibitor,
and MK-8408, an NS5A Inhibitor, Presents a High
Genetic Barrier to Resistance in HCV Genotypes
Frederick Lahser, Karin Bystol, Stephanie Curry, Patricia
McMonagle, Rong Liu, Ellen Xia, Robert Chase, Stuart Black, Eric
B. Ferrari, Ling Tong, Wensheng Yu, Joseph Kozlowski, Ernest
Asante-Appiah
1989: AL-335, a Novel Potent anti-HCV Nucleotide
Analog, Demonstrates Synergistic Activity when
Given in Combination with other anti-HCV DAAs in a
Subgenomic Replicon System
Hua Tan, Kenneth Shaw, Natalia Dyatkina, Guangyi Wang, Leo
Beigelman, David B. Smith, Lawrence M. Blatt, Julian A. Symons
1990: Plasma microRNA-122 levels decrease
significantly in chronic hepatitis C patients treated with
miravirsen
Meike van der Ree, Adriaan J. van der Meer, Adrianus C. van
Nuenen, Soren Ottosen, Amy Patick, Harry L. Janssen, Neeltje A.
Kootstra, Hendrik W. Reesink
1991: HCV Nucleoside Inhibitors can Exhibit Genotype
Specific Differences in Activity
Elizabeth D. Anton, Kristi Strommen, Wei Huang, Amber A. Rivera,
Christos J. Petropoulos, Franck Amblard, Raymond F. Schinazi,
Jacqueline D. Reeves
1992: Prevention of hepatitis C virus infection by
adoptive allogeneic immunotherapy using suicide gene-
modified lymphocytes: an in vitro proof-of-concept
Céline Leboeuf, Joelle Roser-Schilder, Mélanie Lambotin, Sarah
Durand, Tao Wu, Marina Deschamps, Christophe Ferrand, Pierre
Tiberghien, Patrick Pessaux, Thomas F. Baumert, Eric Robinet
1993: Comparison of Three 2’-C-Methyl Guanosine
Prodrugs for Hepatitis C including a Novel β-D-2’-C-Me-
NOVEMBER 11
2,6-Diaminopurine Ribonucleoside Phosphoramidate
TUESDAY
(RS-1389): Interspecies Hepatocyte and Human
Cardiomyocyte Metabolism Profiles
Sijia Tao, Zhou Longhu, Hongwang Zhang, Shaoman Zhou,
Sheida Amiralaei, Jadd Shelton, Steven J. Coats, Raymond F.
Schinazi
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
1994: Evaluation of TG-2349, a novel HCV Protease
Inhibitor with Pan-Genotypic Activity, in Replicon-Mouse
Models with Luciferase Reporter
Ying-Huey Huang, Chih-Ming Chen, Hung-Ming Hsu, Chu-Chung
Lin, Chi-Hsin R. King, Ming-Chu Hsu
1995: HCV kinetics in uPA-SCID chimeric mice
with humanized livers during intravenous silibinin
monotherapy
Swati DebRoy, Nobuhiko Hiraga, Michio Imamura, Laetitia
Canini, Ralf T. Pohl, Stefano Persiani, Susan L. Uprichard, Alan S.
Perelson, Chise Tateno, Kazuaki Chayama, Harel Dahari
1996: The Antiviral Profile of TG-2349, a novel HCV
Protease Inhibitor with Pan-Genotypic Activity
Chih-Ming Chen, Yi-Fen Chen, Chu-Chung Lin, Chi-Hsin R. King,
Ming-Chu Hsu
1997: IDX21459, a Uridine Nucleotide Prodrug,
Shows a Favorable Preclinical Profile as a Direct-acting
Antiviral Agent (DAA) against HCV
Christopher D. Chapron, Kusum S. Gupta, Massimiliano La Colla,
Brenda Hernandez-Santiago, Maria Seifer, Hassan Rashidzadeh,
Ilaria Serra, Shouqi Luo, Xin-Ru Pan-Zhou, Christopher Brynczka,
Bianca Heinrich, Jinsoo Lim, Francois-Rene Alexandre, Roger Rush
1998: Lack of Clinically Relevant Pharmacokinetic
Drug-Drug Interaction between Norgestimate/Ethinyl
Estradiol and Pangenotypic HCV NS5A Inhibitor
GS-5816 in HCV-Uninfected Female Subjects
Erik Mogalian, Diana M. Brainard, John McNally, Gong Shen,
Jennifer Cuvin, Anita Mathias
Portal Hypertension - Experimental
1999: Partial Vasopressin 1α (V1α) Receptor Agonism
Reduces Portal Hypertension And Hyperaldosteronism
Thereby Inducing A Powerful Diuretic And Natriuretic
Effect In Cirrhotic Rats With Ascites
Guillermo Fernández-Varo, Denise Oró, Edward Cable, Kazimierz
Wisniewski, Pere Gines, Wladimiro Jiménez
2000: Changes in cardiac output, pulmonary dynamics
and incidence of volume overload in Cirrhotics receiving
20% Albumin infusion
Saggere M. Shasthry, Manoj Kumar, Jelen K. Singh, Shiv K. Sarin
2001: Sarcopenia of cirrhosis is mediated by
hyperammonemia-mediated transcriptional
upregulation of myostatin due to impaired β-catenin
signaling
Michela Giusto, Gangarao Davuluri, Samjhana Thapaliya, Uyen
Tran, Oliver Wessely, Sathyamangla V. Naga Prasad, Srinivasan
Dasarathy
2002: Hemodynamic effects of the oral non peptide
compound AVE0991
Sabine Klein, Chandana B. Herath, Frank E. Uschner, Josephine
A. Grace, Robert Schierwagen, Christian P. Strassburg, Tilman
Sauerbruch, Peter W. Angus, Jonel Trebicka
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
2003: Cerium Oxide Nanoparticles Reduce Portal
Hypertension and Show Antiinflammatory Properties in
CCl4-Treated Rats
Denise Oró, Guillermo Fernández-Varo, Vedrana Reichenbach,
Tetyana Yudina, Eudald Casals, Gregori Casals, Bernadino
Gonzalez de la Presa, Víctor Puntes, Wladimiro Jiménez
2004: A Large Animal Model of Portal Hypertension
and Cirrhosis in the FAH-Deficient Pig
Shennen A. Mao, Jaime Glorioso, Raymond D. Hickey, Meng
Yin, Joseph Lillegard, James E. Fisher, Ronald J. Marler, Markus
Grompe, Scott L. Nyberg
2005: NCX-6560, a nitric oxide-donating atorvastatin,
lowers portal pressure and has a better hepatic toxicity
profile than atorvastatin in cirrhotic rats
Sarai Rodríguez, Imma Raurell, Rafael Esteban, Joan Genescà,
María Martell
2006: The Beneficial Effects of P2X7 Antagonism on
Hepatic Fibrogenesis and Portal-Systemic Collaterals in
Rats with Bile Duct Ligation
Hung-Chun Tung, Teh-Ia Huo, Fa-Yauh Lee, Hui-Chun Huang
2007: In Cirrhosis, Calcium Desensitization Underlies
Reduced Myogenic Tone in Small Resistance Mesenteric
Arteries
Ravirajsinh Jadeja, Sandeep Khurana
2008: Obliterative Portal Venopathy in subjects without
portal hypertension: an unknown planet
Maria Guido, Samantha Sarcognato, Aurelio Sonzogni, Marco
Senzolo, Marco Pizzi, Stefano Fagiuoli, Maria Grazia Lucà,
Luciano Giacomelli, Guido Colloredo
2009: Hedgehog-signaling and angiogenesis in cirrhotic
and non-cirrhotic portal hypertension
Frank E. Uschner, Ganesh Ranabhat, Michaela Granzow, Steve S.
Choi, Sabine Klein, Robert Schierwagen, Esther Raskopf, Christian
P. Strassburg, Kanishka Hiththetiya, Tilman Sauerbruch, Anna Mae
Diehl, Jonel Trebicka
2010: Sarcopenia in alcoholic liver disease
accompanied by increased malondialdehyde-aldehyde
adducts and oxidative stress
Samjhana Thapaliya, Gangarao Davuluri, Megan R. McMullen,
Laura E. Nagy, Geoffrey M. Thiele, Sathyamangla V. Naga
Prasad, Srinivasan Dasarathy
2011: Rifaximin and propranolol combination therapy
is more effective than propranolol monotherapy in
the hepatic venous pressure gradient response and
propranolol dose reduction–A Pilot study
Youn zoo Cho, Moon Young Kim, Soon Koo Baik, Sang Ok Kwon,
Dong Joon Kim, Ki Tae Suk, Gab Jin Cheon, Young Don Kim, Dae
Hee Choi
Poster Viewing: 8:00 AM – Noon
193A
2012: Hemodynamic changes in hepatic circulation
and hepatic arterial buffer response after modulation
of splenic circulation in an in-vivo human experimental
model
Nobuhisa Akamatsu, Yasuhiko Sugawara, Taku Aoki, Tomohiro
Tanaka, Sumihito Tamura, Yoshihiro Sakamoto, Kiyoshi
Hasegawa, Junichi Kaneko, Norihiro Kokudo
2013: MicroRNA-128 is a Key Regulator of Hepatic
Dimethylarginine Dimethylaminohydrolase-1 (DDAH-1)
in a Rodent Model of Cirrhosis and Portal Hypertension
Gautam Mehta, Helen Jones, Vikram Sharma, Nathan Davies,
Rajiv Jalan, Rajeshwar Mookerjee
2014: Fibroblastic reticular cells are the major
contributors to splenomegaly and spleen stiffness in
portal hypertension
Chao Dong, Teruo Utsumi, Li Gong, Yasuko Iwakiri
2015: Systems Biology Analysis of Omeprazole Therapy
in Cirrhosis Demonstrates Significant Shifts in Gut
Microbiota Composition and Function
Jasmohan S. Bajaj, I. J. Cox, Naga Betrapally, Douglas M.
Heuman, Mitchell L. Schubert, Roger Williams, Melanie White,
Nicole Noble, Masoumeh Sikaroodi, Simon D. Taylor-Robinson,
Patrick M. Gillevet
2016: Oxidative stress plays an important role in
pathogenesis of hyperdynamic circulation in portal
hypertensive rats
Hongqun Liu, Noura Alhassan, Samuel S. Lee
2017: Blood brain barrier permeability is increased in
hepatic encephalopathy related to cirrhosis, through a
hyperammonemia-dependent mechanism
Sarah Mouri, Haquima El Mourabit, Colette Rey, Romain Morichon,
Dominique Wendum, Elisabeth Lasnier, Chantal Housset, Nicolas
Weiss, Dominique Thabut
2018: Prognostic Significance of the Hemodynamic and
Clinical Staging in the Prediction of Mortality in Patients
with Chronic Liver Disease
Sang Hyun Park, Ki Tae Suk, Eun Jin Kim, Hyo Sun Kim, Chang
Seok Bang, Hyoung Su Kim, Ji Won Park, Sung Eun Kim, Myoung
Kuk Jang, Choong Kee Park, Myung Seok Lee, Sang Hoon Park,
Dong Joon Kim
2019: Acute effect of Udenafil on portal pressure in
cirrhotic rats
Frank E. Uschner, Sabine Klein, Robert Schierwagen, Bernhard
Tewes, Christian P. Strassburg, Wolfgang Kreisel, Tilman
Sauerbruch, Jonel Trebicka
2020: Probiotic prevents the development of Portal
hypertension in a rabbit endotoxin induced portal
NOVEMBER 11
hypertension model
TUESDAY
Nidhi Chaudhary, Rashmi Babbar, Shiv K. Sarin
Presenters in Attendance 10:30 AM – Noon
 194A POSTER SESSIONS
Poster Sessions
2021: Bone Marrow Predicts Liver Regenerative
Response To Growth Factors In Decompensated
Cirrhosis
Lovkesh Anand, Avinash Kumar, Chhagan Bihari, Chandan K.
Kedarisetty, Anupam Kumar, Sheetalnath Rooge, Rakhi Maiwall,
Shiv K. Sarin
2022: Outcomes in Orthotopic Liver Transplantation;
Rotational Thromboelastrography (ROTEM) versus
Standard of Care: a Retrospective Study
Christopher M. Esber, Loren Brook, Nicole O’Bleness, A. James
Hanje
Stem Cell Biology
2023: DNMT1 is essential for postnatal liver
development
Kosuke Kaji, Valentina M. Factor, Jesper B. Andersen, Nikolay
Korokhov, Marian E. Durkin, Elizabeth A. Conner, Snorri S.
Thorgeirsson
2024: Matrix Metalloproteinase-14 regulates the
maturation of fetal hepatic stem/progenitor cells in mice
Satoshi Otani, Sei Kakinuma, Akihide Kamiya, Fumio Goto, Shun
Kaneko, Seishin Azuma, Yasuhiro Asahina, Mamoru Watanabe
2025: Targeting CD133(+) cancer stem cells by
inhibiting glycolytic metabolism through miR-122
Kyoungsub Song, Hyunjoo Kwon, Chang Han, Srikanta Dash,
Tong Wu
2026: Identification of a novel Wnt-responsive
hepatocyte stem cell population in the normal liver
Bruce M. Wang, Roel Nusse
2027: Long-term engineered cultures of iPSC-derived
human hepatocytes for disease modeling and drug
screening
Salman Khetani, Dustin Berger, Brenton R. Ware, Matthew
Davidson
2028: Recapitulation of Human Hepato-Biliary
Organogenesis in Self-assembled Liver Organoid
Culture
Dipen Vyas, Pedro M. Baptista, Emma Moran, Shay Soker
2029: Generation of human hepatocyte-like cells from
urine
Vanessa Sauer, Xia Wang, Krisztina Tar, Tatyana Tchaikowskaya,
Yanfeng Li, Chandan Guha, Namita Roy-Chowdhury, Jayanta Roy-
Chowdhury
2030: Human pluripotent stem cell derived hepatocyte-
like cells integrated in microfluidic platform for drug
NOVEMBER 11
screening applications
TUESDAY
Giovanni G. Giobbe, Federica Michielin, Alessandro Zambon,
Stefano Giulitti, Camilla Luni, Nicola Elvassore, Annarosa Floreani
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
2031: TSG-6 is involved in repair response in carbon
tetrachloride-induced acute liver injury in mice
Sihyung Wang, Jieun Kim, Jeongeun Hyun, Youngmi Jung
2032: Characterization and expansion mechanisms of
human iPS cell-derived hepatic progenitor-like cells
Kota Tsuruya, Akihide Kamiya, Hiromi Chikada, Kazuya Anzai,
Yoshitaka Arase, Shunji Hirose, Tatehiro Kagawa, Tetsuya Mine
2033: A Comprehensive Analysis of Gene Mutations in
Liver Cancer Stem Cells
Takehiro Hayashi, Taro Yamashita, Tsuyoshi Suda, Tomomi
Hashiba, Yoshirou Asahina, Mariko Yoshida, Tomoyuki Hayashi,
Yoshimoto Nomura, Yasumasa Hara, Kouki Nio, Naoki Oishi,
Hajime Sunagozaka, Hajime Takatori, Masao Honda, Shuichi
Kaneko
2034: Human biliary tree stem cells are efficiently
reprogrammed to functional β-pancreatic islet cells by a
synthetic human PDX1 peptide
Vincenzo Cardinale, Gaia Scafetta, Rosa Puca, Michele De Canio,
Francesca Sicilia, Guido Carpino, Domenico Casa, Rocco C.
Panetta, Pasquale Bartolomeo Berloco, Giorgio Federici, Eugenio
Gaudio, Marella Maroder, Domenico Alvaro
2035: Hyaluronic acid-based efficient cryopreservation
of human biliary tree stem/progenitor cells (hBTSCs)
demonstrated by biologic, genetic and molecular studies
Vincenzo Cardinale, Lorenzo Nevi, Raffaele Gentile, Guido
Carpino, Alice Fraveto, Alessia Torrice, Alfredo Cantafora,
Vincenzo Pasqualino, Giovanni Casella, Daniela Bosco,
Alessandro Pintore, Giuseppe Spagnolo, Michela Nardacci,
Pasquale Bartolomeo Berloco, Eugenio Gaudio, Domenico Alvaro
Varices and Bleeding
2036: Progression of hyperdynamic circulation in
compensated cirrhosis with portal hypertension and
response to β-blockers
Càndid Villanueva, Agustin Albillos, Joan Genescà, Juan G.
Abraldes, Jose Luis Calleja, Carles Aracil, Rafael Bañares, Rosa
María Morillas, Maria Poca, Beatriz Peñas, Salvador Aguustin,
Juan Carlos Garcia-Pagan, Oana Pavel, Jaime Bosch
2037: Effect of Simvastatin in Portal Hypertension
Priscila P. Flores, Guilherme F. Rezende, Ubiratan Cassano,
Monica Soldan
2038: Effect of Simvastatin in Portal Hypertension
Priscila P. Flores, Monica Soldan, Guilherme F. Rezende
2039: Variceal bleeding at diagnosis of portal vein
thrombosis does not increase mortality in patients with
cirrhosis
Carlos Noronha Ferreira, Teresa Rodrigues, Patrícia Sousa,
Fernando Ramalho, Paula Alexandrino, José F. Velosa
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) POSTER SESSIONS
Poster Sessions
2040: Osteopontin is a new non-invasive parameter of
portal hypertension in patients with liver cirrhosis
Radan Bruha, Marie Jachymova, Jaromir Petrtyl, Libor Vitek, Petr
Urbanek, Karel Dvorak
2041: Embolization of splenic artery contributes
to controlling elevated portal venous pressure and
promoting improved hepatic function induced by
occlusion of portosystemic shunts in patients with
cirrhosis
Tsuyoshi Ishikawa, Shogo Shiratsuki, Takashi Matsuda, Takuya
Iwamoto, Taro Takami, Shuji Terai, Isao Sakaida
2042: A simple scoring system using MELD-Na and the
stage of hepatocellular carcinoma for prediction of early
mortality after acute variceal bleeding in patients with
liver cirrhosis
Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Kazuhiko Hayashi,
Masatoshi Ishigami, Hidemi Goto
2043: Prognostic factors affecting treatment
outcomes of acute variceal bleeding in patients with
hepatocellular carcinoma: a single center prospective
study
Soo Young Park, Su Hyun Lee, Se Young Jang, Jung Gil Park, Won
Young Tak, Young Oh Kweon, Hyun Young Woo, Jeong Heo, Eun
Jeong Kang, Yu Rim Lee
2044: VITRO-score predicting clinically significant portal
hypertension
Stephanie Hametner, Alexandra Etschmaier, Arnulf Ferlitsch,
Alexander Ziachehabi, Rainer Schöfl, Monika Ferlitsch, Andreas
Maieron
2045: Indocyanine Green 15-min Retention test (ICG-
r15) as a predictor of clinical decompensation in
patients with compensated liver cirrhosis
Andrea Lisotti, Francesco Azzaroli, Buonfiglioli Federica, Marco
Montagnani, Paolo Cecinato, Claudio Calvanese, Simoni Patrizia,
Alberto Porro, Domenico Fiorillo, Alessandro Cucchetti, Antonio
Colecchia, Rita Golfieri, Davide Festi, Giuseppe Mazzella
2046: Prospective validation of Baveno V definitions
and criteria for failure to control bleeding in portal
hypertension
Won Young Tak, Soo Young Park, Young Oh Kweon, Se Young
Jang, Su Hyun Lee, Jung Gil Park, Jeong Heo, Hyun Young Woo
2047: Long-Term Outcome of 139 Patients with Liver
Cirrhosis Receiving Balloon-Occluded Retrograde
Transvenous Obliteration for Gastric Fundal Varices
Yukinori Imai, Manabu Nakazawa, Satsuki Ando, Kayoko
Sugawara, Satoshi Mochida
2048: WITHDRAWN
Poster Viewing: 8:00 AM – Noon
195A
2049: Survival of acute peptic ulcer bleeding in cirrhosis
as compared with variceal bleeding using current first-
line therapies
Alba Ardèvol, Jose Castellote, Joaquim Profitos, Carles Aracil,
Josep Castellvi, Oana Pavel, Gemma Ibañez Sanz, Diana Horta,
Josep M M. Calafat, Barbara Gomez-Pastrana, Càndid Villanueva
2050: Hemodynamic response to non-selective beta-
blockers is not influenced by the presence of metabolic
syndrome
Simona Bota, Philipp Schwabl, Mattias Mandorfer, Petra Salzl,
Arnulf Ferlitsch, Michael Trauner, Markus Peck-Radosavljevic,
Thomas Reiberger
2051: Impact of anticoagulant and antiaggregant
therapy on portal hypertension-related upper
gastrointestinal bleeding in patients with liver cirrhosis.
Results from a prospective multicentric observational
study
Dominique Thabut, Yann Le Bricquir, Nicolas Carbonell, Xavier
Causse, Jessica Coelho, Jean françois D. Cadranel, Jean Paul
Cervoni, Andre Jean Remy, Isabelle Archambeaud, Khaldoun
Elriz, Florent Ehrhard, Joanna Pofelski, Christophe Bureau, Bruno
Bour, Florian Rostain, Francois Dewaele, Julien Vergniol, Jacques
Arnaud Seyrig, Anne-Laure Pelletier, Farah Zerouala, Anne
Guillygomarc’h, Arnaud Pauwels
2052: Applicability of Early TIPS in a US Based Tertiary
Care Center
Swaytha Ganesh, Jyothsna Talluri, Siva Talluri, Ali Al-khafaji,
Shahid M. Malik
2053: The improvement of hepatic hemodynamics
and liver function before and after balloon - occluded
retorograde transvenous obliteration
Ryuta Shigefuku, Hideaki Takahashi, Yoshihito Yoshida, Tomohiro
Tamura, Yohei Noguchi, Hiroki Ikeda, Kotaro Matsunaga,
Nobuyuki Matsumoto, Chiaki Okuse, Fumio Itoh, Shigeru Sase,
Michihiro Suzuki
2054: HVPG predicting prognosis in patients with
cirrhosis. Does it matters to use free hepatic vein
pressure or inferior vena cava pressure?
Gilberto Silva-Junior, Anna Baiges, Fanny Turon, Karina G.
Ramírez Ibarra, Vera Costa Santos, Annalisa Berzigotti, Virginia
Hernandez-Gea, Jaime Bosch, Juan Carlos Garcia-Pagan
2055: Risk of esophageal varices predicted by share
wave velocity
Hiroko Iijima, Tomoko Aoki, Chikage Nakano, Kenji Hashimoto,
Akio Ishii, Tomoyuki Takashima, Nobuhiro Aizawa, Naoto Ikeda,
Yoshiyuki Sakai, Hironori Tanaka, Yoshinori Iwata, Hirayuki
Enomoto, Masaki Saito, Shuhei Nishiguchi
NOVEMBER 11
TUESDAY
Presenters in Attendance 10:30 AM – Noon
 196A POSTER SESSIONS
Poster Sessions
2056: Prospective observational study of portal-
hypertensive bleeding in 914 cirrhotic patients in France
(CHOC study) : high proportion of high-risk patients but
limited access to TIPS
Dominique Thabut, Andre Jean Remy, Nicolas Carbonell, Xavier
Causse, Jessica Coelho, Jean françois D. Cadranel, Jean Paul
Cervoni, Slim Bramli, Isabelle Archambeaud, Philippe Ah-soune,
Florent Ehrhard, Alexandre Pariente, Christophe Bureau, Jean-
Pierre Dupuychaffray, Florian Rostain, Florence Skinazi, Julien
Vergniol, Rl Vitte, Anne-Laure Pelletier, Jean Henrion, Anne
Guillygomarc’h, Stéphanie Combet, Arnaud Pauwels
2057: Should bleeding from gastric varices be
prevented? A portuguese center experience
Tiago Cúrdia Gonçalves, Joana Magalhães, Carla M. Marinho,
José Cotter
2058: Correction of coagulopathy in non-bleeding
cirrhotic patient undergoing Minor Invasive Procedures:
A Systematic Review
Matthew J. McConnell, Ruben Hernaez, Sarah Sewaralthahab,
Saleh Alqahtani
2059: The efficacy of balloon-occluded retrograde
transvenous obliteration (BRTO) and coil assisted
retrograde transvenous obliteration (CARTO) for the
treatment of bleeding gastric varices and hepatic
encepholopathy
Lisa N. Waller, Scott Schwartz, Dilip Moonka, Amir Prushani,
Syed-Mohammed R. Jafri
2060: Long-term result and safety of endoscopic
N-Butyl-2-cyanoacrylate injection of gastric varices :
Focused on the variceal location
Wonhyeong Park, Seo Young Yang, Do Young Kim, Woong Sun
Yoo, Tae Gyoon Kim, Tae Kyu Lim
NOVEMBER 11
TUESDAY
Denotes AASLD Presidential Poster of Distinction
HEPATOLOGY, October, 2014
2061: The Child-Turcotte-Pugh (CTP) score is best at
predicting 6-week mortality in patients with acute
variceal hemorrhage (AVH): Analysis of a U.S. Multi-
Center Prospective Study
Brett E. Fortune, Guadalupe Garcia-Tsao, Maria Ciarleglio,
Yanhong Deng, Michael B. Fallon, Samuel Sigal, Naga P.
Chalasani, Joseph K. Lim, Adrian Reuben, Hugo E. Vargas, Gary
Abrams, Michele Bishop Lewis, Tarek Hassanein, James F. Trotter,
Arun J. Sanyal, Kimberly L. Beavers, Daniel Ganger, Paul J.
Thuluvath, Norman D. Grace, Roberto J. Groszmann
2062: Clinically significant hyponatremia is a rare side
effect of terlipressin treatment for vericeal bleeding and
hepatorenal syndrome when used as first line agent
Ruth Bolier, Bart van Hoek, Hein W. Verspaget, Minneke Coenraad
2063: Cyanoacrylate Therapy for the Treatment of
Gastric Varices: A New Method
Virendra Singh, Rajiv R. Singh, Navneet Sharma
2064: The long-term clinical outcome of balloon-
occluded retrograde transvenous obliteration for gastric
varices
Noriaki Naeshiro, Hiroshi Aikata, Hiromi Kan, Tomoki Kobayashi,
Takayuki Fukuhara, Yohji Honda, Daisuke Miyaki, Tomokazu
Kawaoka, Masataka Tsuge, Akira Hiramatsu, Michio Imamura,
Yoshiiku Kawakami, Hideyuki Hyogo, C. Nelson Hayes, Kazuaki
Chayama
2065: Safety of Endoscopy in Patients with End-stage
Liver Disease
Prasun K. Jalal
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
1 Table 1: Characteristics of the 1st 20 Subjects With BPAR
BPAR (Biopsy Proven Acute Rejection) During Protoco-
lized Immunosuppression Withdrawal (ISW) is Readily
Reversed in Pediatric Liver Transplant (Tx) Recipients
Veena L. Venkat1, George V. Mazariegos2, John Bucuvalas3,
Anthony J. Demetris4, Steven J. Lobritto5, John C. Magee6, Mer-
cedes Martinez5, Yumirle P. Turmelle7, Katharine Spain8, Sandy
Feng9; 1Pediatrics, Children’s Hospital of Pittsburgh of UPMC,
Pittsburgh, PA; 2Hillman Center for Pediatric Transplantation, Chil-
dren’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA; 3Pediatric
Liver Care Center, Cincinnati Children’s Hospital Medical Center,
Cincinnati, OH; 4Pathology, University of Pittsburgh Medical Cen-
ter, Pittsburgh, PA; 5Pediatrics, New York-Presbyterian Hospital/
Columbia, New York, NY; 6Surgery, University of Michigan, Ann
Arbor, MI; 7Pediatrics, St. Louis Children’s Hospital, St. Louis, MO;
8Rho Inc., Chapel Hill, NC; 9Surgery, University of California, San
Francisco, San Francisco, CA
Background: iWITH (NCT101638559) is an NIH funded
trial that aims to determine the efficacy and safety (1° and
2° objectives) of ISW. We describe the timing, severity, and
treatment response in the 1st 20 subjects with BPAR. Meth-
ods: Between 9/1/12 and 3/1/14, 74 subjects (42% male;
31% living donor; 59% biliary atresia) <6 yrs old at tx and
>4 yrs post-tx, with ALT and GGT <50IU/ml and on calci-
neurin inhibitor monotherapy initiated ISW. Subjects with
infectious or autoimmune indications for tx, screening biopsy
with more than minimal/focal inflammation or Ishak fibrosis
stage>2 were excluded. ISW proceeded in 8 steps (75, 56,
40, 32, 24, 16, 8 and 0% of the pre-ISW dose) over 36-48
wks. Biopsy was mandated for ALT or GGT >100 IU/L and
graded using Banff criteria by a central pathologist. BPAR was
treated according to standard of care at each site. Results: As
of 3/31/14, 31(42%) subjects were off IS for a median(range)
of 12(0.7, 39.9) wks, 23(31%) were still undergoing ISW and
20(27%) subjects had BPAR, as described in Table 1. 15/20
BPAR episodes occurred at <33% of pre-ISW tacrolimus (TAC)
dose. Using Banff criteria, a central pathologist graded 14 as
mild and 5 as moderate with a median(range) rejection activ-
ity index of 4(3, 6); 1 specimen was inadequate. Treatment
was with corticosteroids (16 oral; 4 IV+oral) and TAC (15 to
max dose>pre-ISW; 5 to max dose ≤pre-ISW); none required
antibody therapy. One subject had concurrent biliary stricture.
ALT and GGT were <50IU/L in 45% of subjects by 4 wks and
90% by 16 wks after BPAR. Conclusion: Within a trial of pro-
tocolized and supervised ISW for stable, long-term pediatric
liver tx recipients, BPAR most often occurred at <1/3 of the
maintenance IS dose, has been histologically mild/moderate,
and readily reversible with steroids and TAC. Ongoing clinical
and histologic follow-up is needed to confirm that ISW is safe
in the short- and long-term.
197A
* Median(range)
Disclosures:
John C. Magee - Grant/Research Support: Novartis, Alagille Syndrome Alliance
The following people have nothing to disclose: Veena L. Venkat, George V.
Mazariegos, John Bucuvalas, Anthony J. Demetris, Steven J. Lobritto, Mercedes
Martinez, Yumirle P. Turmelle, Katharine Spain, Sandy Feng
2
Risk Factors for Recurrence of Primary Sclerosing Chol-
angitis in Live and Deceased Donor Liver Transplant
Recipients in the A2ALL Study
Fredric D. Gordon1, David S. Goldberg2, Nathan P. Goodrich3,
Anna S. Lok4, Elizabeth C. Verna5, Nazia Selzner6, R. Todd Strav-
itz7, Robert M. Merion3,4; 1Lahey Hospital & Medical Center, Burl-
ington, MA; 2University of Pennsylvania, Philadelphia, PA; 3Arbor
Research Collaborative for Health, Ann Arbor, MI; 4University of
Michigan, Ann Arbor, MI; 5Columbia University, New York, NY;
6University of Toronto, Toronto, ON, Canada; 7Virginia Common-
wealth University, Richmond, VA
Primary sclerosing cholangitis (PSC) recurs in 15-25% of
patients transplanted for PSC. Factors potentially associated
with an increased risk of PSC recurrence include high MELD
score, first-degree relative donors, post-transplant CMV infec-
tion, and early biliary anastomotic complications. The aims of
this study were to: 1) compare the risk of PSC recurrence in
living donor (LD) versus deceased donor (DD) recipients; and
2) identify risk factors for PSC recurrence. METHODS: 241 LD
liver transplant (LT) and 65 DDLT subjects transplanted between
1998 and 2013 enrolled in the A2ALL study were evaluated.
Median follow-up was 4.9 years. PSC recurrence was defined,
using the Mayo criteria, as the presence of radiographic intra-
or extra-hepatic, non-anastomotic strictures or histologic fibros-
ing duct lesions in ABO-compatible LT recipients with a normal
blood supply. PSC recurrence, graft failure, and mortality were
examined using Kaplan-Meier survival curves and differences
tested with the log-rank test. The following risk factors were
examined using Cox regression models: first degree relative
(compared to all other LD) among LDLT recipients, post-LT CMV
infection, lab MELD at LT, and time dependent biliary compli-
cation (stricture, leak, or cast) and acute rejection. RESULTS:
Overall PSC recurrence probabilities were 9% and 25% at 5
and 10 years post-LT, respectively. There was no significant
difference in the probability of recurrent PSC in DDLT versus
198A AASLD ABSTRACTS
LDLT recipients (Table 1, p=0.36). For DDLT and LDLT recip-
ients, respectively, unadjusted 10-year graft failure was 27%
and 21% (p=0.89) and patient mortality was 21% and 16%
(p=0.97). The following factors were not significant in models
of time to PSC recurrence: First degree relative donor (p=0.25),
post-LT CMV infection (p=0.37), and acute rejection (p=0.18).
Higher lab MELD at LT and onset of a biliary complication were
associated with increased risk of PSC recurrence (HR=1.04
per MELD point, p=0.03; HR=2.3 for biliary complication,
p=0.02). CONCLUSIONS: The risk of recurrent PSC was not
significantly different for DDLT and LDLT recipients. The risk of
recurrent PSC in a large North American cohort is considerably
lower than previously reported rates from Japan. Degree of
relatedness does not appear to be associated with risk of PSC
recurrence. Biliary complications were significantly associated
with risk of PSC recurrence.
Table 1. PSC recurrence by donor type
Disclosures:
Fredric D. Gordon - Advisory Committees or Review Panels: Gilead, AbbVie;
Grant/Research Support: BMS, Vertex, Gilead, AbbVie
David S. Goldberg - Grant/Research Support: Bayer Healthcare
Anna S. Lok - Advisory Committees or Review Panels: Gilead, Immune Targeting
System, MedImmune, Arrowhead, Bayer, GSK, Janssen, Novartis, ISIS, Tekmira;
Grant/Research Support: Abbott, BMS, Gilead, Merck, Roche, Boehringer
Elizabeth C. Verna - Advisory Committees or Review Panels: Gilead; Grant/
Research Support: Salix, Merck
The following people have nothing to disclose: Nathan P. Goodrich, Nazia
Selzner, R. Todd Stravitz, Robert M. Merion
3
Superior Survival Using Living Donors and Donor-Recip-
ient Matching Using a Novel Living Donor Risk Index
David S. Goldberg1,2, Benjamin French2,3, Peter L. Abt4, Kim M.
Olthoff4, Abraham Shaked4; 1Division of Gastroenterology, Hospi-
tal of the University of Pennsylvania, Philadelphia, PA; 2Center for
Clinical Epidemiology and Biostatistics, University of Pennsylvania,
Philadelphia, PA; 3Leonard Davis Institute of Health Economics,
University of Pennsylvania, Philadelphia, PA; 4Division of Trans-
plant Surgery, Perelman School of Medicine, University of Pennsyl-
vania, Philadelphia, PA
Background: Living donor liver transplantation (LDLT) can
help bridge the current organ-supply demand mismatch, but
accounts for only 3-4% of adult U.S. liver transplants. While
early national data demonstrated inferior outcomes in LDLT
recipients, recent A2ALL data reveals excellent LDLT outcomes
when performed at an experienced U.S. center. Despite this,
recent AASLD guidelines refer to LDLT as “controversial.”
Methods: We examined national OPTN/UNOS data from
2002-2012 to: 1) determine if LDLT confers a long-term sur-
vival benefit relative to deceased donor liver transplantation
(DDLT); and 2) develop a risk score to predict post-LDLT graft
outcomes to help identify optimal donor and recipient matches
and counsel waitlisted patients considering LDLT. Results: From
2002-2012, there were 2,103 LDLTs performed and 46,674
DDLTs that met the inclusion criteria. Overall unadjusted graft
and patient survival (Figure 1) was significantly higher for LDLT
transplant recipients (log-rank test p<0.001), although the ben-
efit was restricted to LDLTs performed at experienced centers
(>15 LDLTs). LDLT graft survival increased from 75% (2002-
2004) to 82% (2008). In multivariable models, LDLT recipients
transplanted at experienced centers with autoimmune hepatitis
HEPATOLOGY, October, 2014
or cholestatic liver disease had significantly less graft failure
(HR: 0.56, 95% CI: 0.37-0.84 and HR: 0.76, 95% CI: 0.63-
0.92, respectively), and increased patient survival. An LDLT
risk score facilitated stratification of LDLT recipients into high,
intermediate, and low-risk groups, with predicted 3-year graft
survival ranging from >87% in the lowest risk group to <74%
in the highest risk group. Conclusions: Current post-transplant
outcomes for LDLT are equivalent, if not superior to DDLT when
performed at experienced centers. An LDLT risk score can be
used to optimize LDLT outcomes and provides objective selec-
tion criteria for donor selection in LDLT.
Disclosures:
David S. Goldberg - Grant/Research Support: Bayer Healthcare
The following people have nothing to disclose: Benjamin French, Peter L. Abt, Kim
M. Olthoff, Abraham Shaked
4
Antiplatelet Therapy is Associated with Better Prognosis
in Patients with Hepatitis B Virus-Related Hepatocellular
Carcinoma after Resection Surgery
Chien-Wei Su1,2, Pei-Chang Lee1, Chia-Jen Liu3,2, Teh-Ia Huo1,4,
Yi-Hsiang Huang1,5, Kuei-Chuan Lee1,2, Han-Chieh Lin1,2, Jaw-
Ching Wu5,6; 1Division of Gastroenterology, Department of Med-
icine, Taipei Veterans General Hospital, Taipei, Taiwan; 2Faculty
of Medicine, School of Medicine, National Yang-Ming Univer-
sity, Taipei, Taiwan; 3Division of Hematology and Oncology,
Department of Medicine, Taipei Veterans General Hospital, Tai-
pei, Taiwan; 4Department and Institute of Pharmacology, National
Yang-Ming University, Taipei, Taiwan; 5Institute of Clinical Medi-
cine, School of Medicine, National Yang-Ming University, Taipei,
Taiwan; 6Division of Translational Research, Department of Med-
ical Research, Taipei Veterans General Hospital, Taipei, Taiwan
Backgrounds: Recurrence of hepatocellular carcinoma (HCC)
is common after surgical resection. Anti-platelet therapy with
aspirin and clopidogrel is recently revealed to prevent hepatic
carcinogenesis. However, whether anti-platelet therapy also
determines the prognoses of patients with HCC after resec-
tion surgery is still obscure. Aims: This population-based study
aimed to investigate the association between anti-platelet
treatment and the outcomes in patients with hepatitis B virus
(HBV)-related HCC after resection surgery. Method: By analyz-
ing the data from Taiwan National Health Insurance Research
Database, we identified 9,461 HBV-related HCC patients who
underwent curative liver resection between January 1997 and
December 2011. After one-to-four matching by sex, age and
propensity score, 2,210 patients were enrolled for analyses.
Kaplan-Meier method and modified Cox proportional hazard
models were employed for survival and multivariable, strati-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
fied analyses. Results: The recurrence-free survival after 1, 5,
10 years of observation was significantly better in the treated
cohort (84.62%, 46.80%, 28.30%) than untreated cohort
(76.47%, 38.51%, 23.78%) (p = 0.021). Meanwhile, the
1-, 5-, 10-year overall survival in the treated cohort (96.96%,
80.29%, 57.30%) was also better than untreated cohort
(92.28%, 62.47%, 45.50%) (p < 0.001). On the multivari-
able Cox regression analysis, anti-platelet therapy (HR, 0.73;
95% CI, 0.63–0.85; p < 0.001), statin use (HR, 0.66; 95% CI,
0.49–0.90; p = 0.008) and non-aspirin, non-steroidal anti-in-
flammatory drugs use (HR, 0.72; 95% CI, 0.62–0.83; p <
0.001) were independently related to lower risks of HCC recur-
rence or death. The multivariable stratified analyses showed
significantly better survivals in most subgroups of patients. Con-
clusion: Use of aspirin and clopidogrel was associated with
a better recurrence-free survival and overall survival among
patients with HBV-related HCC after liver resection.
Disclosures:
The following people have nothing to disclose: Chien-Wei Su, Pei-Chang Lee,
Chia-Jen Liu, Teh-Ia Huo, Yi-Hsiang Huang, Kuei-Chuan Lee, Han-Chieh Lin,
Jaw-Ching Wu
5
A Novel MELD Exception Point System for Hepatocellu-
lar Carcinoma Promotes Equitable Liver Allocation
Mamatha Bhat2, Peter Ghali2, Andre Roy3, Prosanto Chaudhury4,
Fernando Alvarez6, Michel Carrier5, Marc Bilodeau1; 1Medicine,
Division of Gastroenterology and Hepatology, Universite de Mon-
treal, Montreal, QC, Canada; 2Medicine, Division of Gastroenter-
ology and Hepatology, McGill University, Montreal, QC, Canada;
3Department of Surgery, Centre Hospitalier de l’Université de
Montréal, Montréal, QC, Canada; 4Surgery, McGill University
Health Centre, Montreal, QC, Canada; 5Montreal Heart Institute,
Montreal, QC, Canada; 6Division of Gastroenterology, Hepatol-
ogy and Nutrition, CHU Sainte-Justine, Department of Pediatrics,,
Université de Montréal, Montreal, QC, Canada
Hypothesis: The current Model for End-Stage Liver Disease
(MELD) point system for Hepatocellular Carcinoma (HCC) in
the U.S. tends to disproportionately favor these patients as
compared to those who undergo liver transplantation (LT) for
liver failure (LF) based on biological MELD scores. Given these
concerns, the Transplant-Québec liver committee decided in
July 2008 to implement a novel separate MELD pointing sys-
tem to allow liver allocation for patients with HCC based on
graded tumor diameters over time. Cutoffs were chosen based
on median MELD at LT over the preceding year. The aim of this
study was to determine the evolution of patients listed for HCC
with this scoring system, and how this compared to patients
transplanted for LF based on their MELD score. Methods: In this
retrospective study, we evaluated the evolution of all patients
listed for LT in Québec, from time of implementation of the
scoring system (detailed in the Table) up to May 2014. Points
were reassigned every 3 months or upon repeat imaging,
depending on changes in tumor size. Patients listed for fulmi-
nant liver failure, for exception point indications and children
were excluded. Results: 524 patients were listed for LT from
July 2008 to May 2014, of whom 94 (17.9%) were assigned
MELD HCC points. The majority were male (70.4%), with mean
age of 55.4 years. 83.7% underwent liver transplant. 28% of
patients listed for HCC required changes in allocated points
over time. The mean upgrade in number of points for all HCC
patients was 0.32 points+/-0.53. There was no difference
between the 2 indications with respect to transplantation rates
(HCC 86.1% versus LF 83.3%, p=0.48), waiting time in days
(HCC 258 versus LF 325; p=0.20) or waiting list death rates
199A
(HCC 0.6% versus LF 9.2%; p=0.11). At the time of LT, HCC
patients had a lower MELD score (HCC 22+/-0.3 versus LF
24+/-0.4; p=0.02): therefore, the allocated HCC-MELD score
did not seem to jeopardize LF over HCC patients. Discussion:
Our study demonstrates that a novel MELD point system for
HCC, which takes into account changes in tumor size as a
reflection of tumor biology over time, allows for a more equita-
ble allocation of organs. This system potentially represents an
improvement upon the standard MELD exception point system
for HCC employed in the U.S., but needs to be validated in a
broader context.
Quebec MELD HCC Point Attribution
Disclosures:
Marc Bilodeau - Advisory Committees or Review Panels: Oncozyme, Bayer, Astel-
las; Consulting: GSK; Grant/Research Support: Merck, Synageva; Speaking and
Teaching: Merck, Vertex, Abbvie, Aptalis, Roche
The following people have nothing to disclose: Mamatha Bhat, Peter Ghali,
Andre Roy, Prosanto Chaudhury, Fernando Alvarez, Michel Carrier
6
Liver Transplantation (LT) with the “Oldest Old” (≥80
years) Donor Livers: The U.S. National Experience
Suzanne R. Sharpton1, Sandy Feng2, Jennifer C. Lai1; 1Medicine,
University of California, San Francisco, San Francisco, CA; 2Sur-
gery, University of California, San Francisco, San Francisco, CA
Background: As the general population ages, utilization of
the “oldest old” of donor livers [≥80 years (y)] represents a
logical, if not necessary, means of donor pool expansion. Little
is known of national utilization practices and outcomes with
≥80y donors. Methods: Using UNOS registry data, all U.S.
adult recipients of primary deceased donor LT from 2/05-1/12
were evaluated (n=36,318). Centers (n=132) were catego-
rized based on the # of ≥80y livers transplanted: non- (n=95),
low- (n=31, range: 1-7 grafts/center), and high-utilizers (n=6,
range: 22-36 grafts/center). Regions (n=11) were categorized
as low-, mid-, and high-MELD based on tertiles of median
recipient LT-MELD. Cox models evaluated the effects of donor
age ≥80y on graft loss (death or re-LT). Results: 244 ≥80y
donor livers were transplanted. Donors ≥80y vs <80y differed
by %female (63 vs 40%), %with diabetes (15 vs 11%) and/
or hypertension (73 vs 35%), %died of stroke (75 vs 42%),
%donation after cardiac death (0 vs 5%), and %distributed
nationally (33 vs 6%) [p<0.01 for all], but not by cold ischemia
time (6.7 vs 6.6 hours; p=0.41). Recipients of ≥80y vs <80y
livers were older (median 60 vs 55y), more likely to be female
(42 vs 32%), less likely to have HCV (11 vs 27%), and had
lower median laboratory LT-MELD (17 vs 20) [p<0.01 for all],
but were similar for %hepatocellular carcinoma (18 vs 23%;
p=0.07). Only 37/132 (28%) centers transplanted ≥80y liv-
ers, but 174/244 (71%) of the ≥80y livers were transplanted
by 6 centers (high-utilizers), accounting for 2-8% of each cen-
ter’s total transplant volume; 3, 2, and 1 centers were in high-,
mid-, and low-MELD regions, respectively. The adjusted hazard
ratio (aHR) for graft loss of ≥80y livers was 1.15 (95% CI 0.93-
200A AASLD ABSTRACTS
1.43; p=0.20). Low- and high-utilizers did not differ in graft sur-
vival of ≥80y livers (aHR 1.88, 95% CI 0.85-4.13, p=0.12).
Overall graft survival of ≥80y vs <80y livers was 88% vs 91%
at 3 months (p=0.07), 75% vs 79% at 1y (p=0.14), and 48%
vs 47% at 3y after LT (p=0.67). Re-LT occurred in 7% and 5%
recipients of ≥80y vs <80y livers (p=0.01); %re-LT for ≥80y
graft recipients did not differ between low- and high-utilizers
(7 vs 7%; p=0.97). Among ≥80y grafts that failed within 1y
of LT, only recipient LT-MELD score predicted failure (OR 1.05
per MELD point, 95% CI 1.01-1.09; p=0.03). Conclusion: The
vast majority of ≥80y donor livers are accepted and trans-
planted by only 6 U.S. LT centers. Graft survival with ≥80y
livers was acceptable and did not vary by center experience
with ≥80y donors. Codification of objective selection criteria
may increase utilization of older donors while maintaining the
currently observed post-LT outcomes.
Disclosures:
The following people have nothing to disclose: Suzanne R. Sharpton, Sandy
Feng, Jennifer C. Lai
7 1University of Pennsylvania School of Medicine, Philadelphia, PA;
Dynamic Characterization of Human Livers during ex
vivo Machine Perfusion
Bote G. Bruinsma1, Gautham V. Sridharan1, Pepijn D. Weeder1,
James H. Avruch2, Heidi Yeh2, James F. Markmann2, Martin L.
Yarmush1, Korkut Uygun1; 1Center for Engineering in Medicine,
Massachusetts General Hospital, Boston, MA; 2Transplant Center,
Massachusetts General Hospital, Boston, MA
The severe shortage of donor liver for transplantation demands
novel, improved methods of ex vivo preservation. Machine
perfusion has the potential to not only recover livers that are
currently unsuitable for transplantation, but also provide an
opportunity to quantitatively assess the liver’s viability and
serve as a platform for pathology-specific intervention. In a
recent proof-of-concept study we demonstrated that a subnor-
mothermic machine perfusion (SNMP) system could support
and improve the quality of human livers that were discarded
for transplantation. In this work, 22 human livers were per-
fused with the purpose of characterizing the dynamics of livers
during SNMP to elucidate the underlying metabolic mecha-
nisms by which machine perfusion recovers marginal livers.
Livers were perfused for 3 hours with Williams’ medium E at
21°C following standard procurement and clinically relevant
cold ischemia (4-8 hours). Characteristics of the donor liver
varied over selected parameters including warm ischemic time
(WIT; 0 -54 min), macro- and microsteatosis (0-80%). Perfusion
hydrodynamics, functional and injury markers were determined
in the perfusion solution. The metabolic dynamics of SNMP
were characterized by targeted metabolomic analysis of hourly
time-course biopsies, identifying significant alterations for
~150 primary metabolites and ~300 lipid compounds, which
were mapped onto a hepatic network model, revealed several
canonical metabolic pathway modules. Briefly, SNMP appears
to replete intracellular ATP content, with a 2.7-fold increase
after 3 hours. Recovery is inferior in livers with increased mac-
rosteatosis (>30%) as well as longer WIT (>30 min). Moreover,
steatotic livers showed lower reduced glutathione (GSH:GSSG)
at the end of perfusion, suggesting increased free radical for-
mation. Overall, redox status improves during SNMP for all
livers, reflected by NADPH:NADP and NADH:NAD ratios.
The time-course dynamics of several intracellular metabolites,
such as uracil, show altered levels between high and low WIT
groups pre-perfusion but intriguingly reach the same level
post-perfusion, suggesting that SNMP metabolically conditions
the organ to a more uniform steady state regardless of donor
HEPATOLOGY, October, 2014
characteristics. Moreover, prolonged ischemia generally results
in a reduction of TCA cycle intermediates pre-perfusion, which
appear to increase again over the course of SNMP. These
observations aid in understanding machine perfusion recovery
mechanisms and pathology-specific identifiers and therapeutic
targets. Ongoing work aims to develop multivariate metrics to
provide comprehensive viability indicators and ex vivo recov-
ery mechanisms.
Disclosures:
The following people have nothing to disclose: Bote G. Bruinsma, Gautham V.
Sridharan, Pepijn D. Weeder, James H. Avruch, Heidi Yeh, James F. Markmann,
Martin L. Yarmush, Korkut Uygun
8
Ledipasvir/Sofosbuvir with Ribavirin for the Treatment
of HCV in Patients with Post Transplant Recurrence: Pre-
liminary Results of a Prospective, Multicenter Study
K. Rajender Reddy1, Gregory T. Everson2, Steven L. Flamm3, Jill M.
Denning4, Sarah Arterburn4, Theo Brandt-Sarif4, Phillip S. Pang4,
John G. McHutchison4, Michael P. Curry5, Michael Charlton6;
2University of Colorado Denver, Aurora, CO; 3Northwestern Fein-
berg School of Medicine, Chicago, IL; 4Gilead Sciences, Raleigh,
NC; 5Beth Israel Deaconess Medical Center, Boston, MA; 6Inter-
mountain Medical Center, Murray, MA
Background: In patients who are viremic at the time of liver
transplantation HCV recurrence is universal and associated
with reduced graft and patient survival. We evaluated the
safety and efficacy of ledipasvir/sofosbuvir (LDV/SOF) with
ribavirin in this population. Methods: GT 1 and 4, naïve and
treatment-experienced patients with HCV infection, who were
post liver transplantation (fibrosis score F0-F3, CPT class A,
B and C with cirrhosis) with an estimated glomerular filtra-
tion rate (GFR) > 40 mL/min, received 12 or 24 weeks of
LDV/SOF FDC with RBV. The primary efficacy endpoints
were SVR (HCV RNA <15 IU/mL) 12 weeks after completion
of study treatment, safety and tolerability. Results: To date,
223 patients have been randomized and treated. Most were
male (83%), Caucasian (87%), and had prior HCV treatment
(83%). The median time since liver transplant was 4.4 years
(0.4-23.3). Mean baseline HCV RNA was 6.4 log10 IU/mL
[range 2.4-7.8 log10 IU/mL]. Mean GFR was 65.5 [range
20.4-118.9 mL/min]. 112 patients had F0-F3 fibrosis, 52, 50
and 9 patients had CPT class A, B, and C cirrhosis, respec-
tively. Interim Observed SVR4 results are depicted in Table
1. The most common adverse events were fatigue, anemia,
headache and nausea. 9 SAEs in 8 patients were considered
related to study treatment; anemia (4) and hemolytic anemia
(2), sick sinus syndrome (1), sinus arrhythmia (1) and portal
vein thrombosis (1). 5 patients with cirrhosis died while in the
study due to; internal bleeding, multiorgan failure/intestinal
perforation, cardiac, complications of cirrhosis and progres-
sive multifocal leukoencephalitis. Median serum creatinine and
INR remained at baseline levels throughout treatment. Consis-
tent with patients who have moderate renal impairment and
who are receiving RBV, hemoglobin values decreased 2-3 g/
dL while on treatment. 33 patients received concomitant epoe-
tin or blood transfusions. Conclusions: Administration of LDV/
SOF+RBV in patients with HCV recurrence post transplantation
has been well tolerated. SVR4 rates suggest high efficacy, with
early data showing no apparent difference between 12 and
24 weeks of treatment. SVR12 results will be presented.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Table 1. Interim Observed SVR4 Results
Disclosures:
K. Rajender Reddy - Advisory Committees or Review Panels: Genentech-Roche,
Merck, Janssen, Vertex, Gilead, BMS, Novartis, Abbvie; Grant/Research Sup-
port: Merck, BMS, Ikaria, Gilead, Janssen, AbbVie
Gregory T. Everson - Advisory Committees or Review Panels: Roche/Genen-
tech, Abbvie, Galectin, Boehringer-Ingelheim, Eisai, Bristol-Myers Squibb, HepC
Connection, BioTest, Gilead, Merck; Board Membership: HepQuant LLC, PSC
Partners, HepQuant LLC; Consulting: Abbvie, BMS, Gilead, Bristol-Myers Squibb;
Grant/Research Support: Roche/Genentech, Pharmassett, Vertex, Abbvie, Bris-
tol-Myers Squibb, Merck, Eisai, Conatus, PSC Partners, Vertex, Tibotec, GlobeIm-
mune, Pfizer, Gilead, Conatus, Zymogenetics; Management Position: HepQuant
LLC, HepQuant LLC; Patent Held/Filed: Univ of Colorado; Speaking and Teach-
ing: Abbvie, Gilead
Steven L. Flamm - Advisory Committees or Review Panels: Gilead, Bristol Myers
Squibb, AbbVie, Janssen, Salix; Consulting: Merck, Janseen, Bristol Myers
Squibb, AbbVie, Salix, Gilead; Grant/Research Support: Janssen, Bristol Myers
Squibb, Merck, Vertex, Gilead, AbbVie, Boehringer Ingelheim; Speaking and
Teaching: Salix
Jill M. Denning - Employment: Gilead Sciences, Inc.
Sarah Arterburn - Employment: Gilead Sciences Inc.; Stock Shareholder: Gilead
Sciences Inc.
Phillip S. Pang - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Michael P. Curry - Grant/Research Support: Gilead Sciences, Mass Biologics,
Merck, Salix, Conatus; Stock Shareholder: Achilion, Idenix
The following people have nothing to disclose: Theo Brandt-Sarif, Michael Charl-
ton
9
Multicenter Experience using Sofosbuvir and Simeprevir
with/without Ribavirin to Treat HCV Genotype 1 after
Liver Transplantation
Surakit Pungpapong1, K Tuesday Werner2, Bashar Aqel2, Michael
D. Leise3, Jennifer L. Murphy1, Tanisha M. Henry1, Kristen Ryland1,
Amy E. Chervenak2, Kymberly D. Watt3, Hugo E. Vargas2,
Andrew Keaveny1; 1Transplant, Mayo Clinic, Jacksonville, FL;
2Hepatology, Mayo Clinic, Scottsdale, AZ; 3Gastroenterology and
Hepatology, Mayo Clinic, Rochester, MN
Background: The all-oral antiviral regimen using sofosbuvir
(SOF) and simeprevir (SMV) with/without ribavirin (RBV) has
been reported to lead to high sustained virologic response
(SVR) rates along with minimal adverse events (AE) when
treating patients with hepatitis C genotype 1 (HCV GT1).
The efficacy of this regimen in liver transplant (LT) recipients
has not been described to date. Objective: To report the viro-
logical response, safety, and tolerability of SOF+SMV with/
without RBV in treating LT recipients with HCV GT1 for 12
weeks. Results: To date, 77 patients met criteria to consider
treatment and 55 patients (78% male, 29% non-white, 73%
subtype 1a, 77% IL28B CT/TT, 87% HCV RNA >800,000
IU/mL, 24% F3-4 with 4% decompensation and 15% choles-
tatic recurrence, 7% status post kidney transplantation) have
received SOF+SMV, being followed for a median of 11 weeks
(range 1-23 weeks). 83% previously failed or did not tolerate
peginterferon+RBV (PR)-based treatments (68% with PR, 13%
with PR+telaprevir/boceprevir, and 2% with PR+SOF). Weight-
based RBV was used in 14 patients (25%) at the discretion of
the treating physicians. RBV dose reduction and/or erythro-
poietin administration was required in 64% of these patients.
Median time from LT to treatment was 22 months (range 2-272
months). Tacrolimus was the primary immunosuppression (IS) in
86% of patients, the remainder were on cyclosporine. Minimal
201A
IS dose adjustments were required during treatment. 4 patients
(7%) had estimated GFR <30 mL/min. On-treatment virolog-
ical response rates are shown in the Table. Of 40 patients
who received treatment ≥4 weeks, 39 patients achieved HCV
RNA <LLOD at a median of 4 weeks (range 2-8 weeks) and
remained negative thereafter. One patient (in no RBV group)
never achieved HCV RNA <LLOD and stopped treatment after
viral rebound occurred at week 6. Only 1 patient stopped
treatment due to a serious AE, after being hospitalized for
acute pancreatitis at day 5. No biopsy-proven acute rejec-
tion occurred. One patient (subtype 1a, IL28B CT, previously
failed PR+telaprevir triple regimen, in no RBV group) relapsed
4 weeks after completing treatment. Conclusions: An all-oral
antiviral regimen using SOF+SMV with/without RBV was very
well tolerated and resulted in an excellent on-treatment virolog-
ical response. SVR12 data will be reported when available.
LLOD = lower limit of detection, LLOQ = lower limit of quantifica-
tion
Disclosures:
Surakit Pungpapong - Grant/Research Support: BMS, Gilead
Hugo E. Vargas - Advisory Committees or Review Panels: Eisai; Grant/Research
Support: Merck, Gilead, Idenix, Novartis, Vertex, Janssen, Bristol Myers, Ikaria,
AbbVie
The following people have nothing to disclose: K Tuesday Werner, Bashar Aqel,
Michael D. Leise, Jennifer L. Murphy, Tanisha M. Henry, Kristen Ryland, Amy E.
Chervenak, Kymberly D. Watt, Andrew Keaveny
10
Activation of TGR5 in the brain is neuroprotective in a
murine model of hepatic encephalopathy due to acute
liver failure
Matthew McMillin1,2, Gabriel A. Frampton1,3, Cheryl Galindo1,2,
Sharon DeMorrow1,3; 1Texas A&M Health Science Center, Col-
lege of Medicine, Temple, TX; 2Baylor Scott & White Health, Tem-
ple, TX; 3Central Texas Veterans Healthcare System, Temple, TX
Hepatic encephalopathy (HE) is a neurological complication
following both acute liver failure and chronic liver diseases
with the potential to affect health-related quality of life, and
clinical management strategies. Associated with HE is a neu-
roinflammatory response involving the upregulation of proin-
flammatory cytokines and subsequent activation of microglia.
We have previously demonstrated an increase in bile acid
content in the brain following acute liver failure that contributes
to the molecular changes associated with HE, via a mechanism
involving FXR activation. Bile acids can also signal through
the membrane receptor TGR5, which is also expressed in the
brain, however the role of TGR5 in HE is unknown. Aims: The
aims of our study were to i) assess the cortical expression of
TGR5 in a murine model of acute liver failure and ii) determine
the effects of TGR5 activation on neurological decline and neu-
roinflammation. Methods: Male C57Bl/6 mice were injected
with azoxymethane (AOM; 100μg/g ip) and liver and brain
tissue collected at defined time points after injection. In paral-
lel, mice were infused with the TGR5 agonist betulinic acid (icv;
10pmol/day) for 3 days prior to AOM injection. Neurological
decline was assessed using the impairment of key reflexes,
presence of ataxia and time taken to reach to coma. TGR5
expression was assessed by qPCR and immunofluorescence.
Microglia activation was assessed by morphometric analysis of
202A AASLD ABSTRACTS
Iba-1 immunoreactivity. In vitro, cultured microglia cells were
activated by treatment with interferon gamma (15ng/ml) and
were co-treated with 10μM betulinic acid for 24 hr. Interleukin
(IL)-1β, TNFα, IL-6, and, chemokine ligand 2 (CCL2) expres-
sion were assessed by qPCR after betulinic acid treatment in
vivo and in vitro. Results: TGR5 expression was upregulated
in the frontal cortex prior to overt signs of neurological impair-
ment and declined at late stages of HE. Central activation of
TGR5 with betulinic acid protected against the AOM-induced
neurological decline without altering liver damage. Further-
more TGR5 activation decreased microglia activation and the
expression of AOM-induced proinflammatory cytokines IL-1β,
TNFα, IL-6, and CCL2. Treatment of activated microglia in vitro
with betulinic acid reduced the expression of the pro-inflamma-
tory cytokines IL-1β, TNFα, IL-6, and CCL2. Conclusions: These
data demonstrate that central TGR5 activation reduces neuroin-
flammation and is neuroprotective, but not hepatoprotective,
against HE induced by acute liver failure. Strategies targeting
TGR5 may prove to be viable options for the management of
HE
Disclosures:
The following people have nothing to disclose: Matthew McMillin, Gabriel A.
Frampton, Cheryl Galindo, Sharon DeMorrow
11
Incremental dose model identified GSK3β and β-catenin
as potential targets for regenerative therapies for acet-
aminophen-induced acute liver failure
Bharat Bhushan1, Chad M. Walesky1, Prachi C. Borude1, Genea
Edwards1, Michael Manley1, Satdarshan (Paul) S. Monga2,
Udayan Apte1; 1Department of Pharmacology, Toxicology & Ther-
apeutics, University of Kansas Medical Center, Kansas City, KS;
2Department of Pathology and Medicine, University of Pittsburgh
School of Medicine, Pittsburgh, PA
Overdose of acetaminophen (APAP) is the major cause of acute
liver failure (ALF) in the Western world with very limited treat-
ment options. Recent studies suggest that liver regeneration is
a critical determinant of overall survival following APAP over-
dose and may have therapeutic potential. However, the mecha-
nisms of liver regeneration following APAP-induced ALF are not
known. In the present study, we identified major signaling path-
ways involved in liver regeneration following APAP-induced
ALF using a novel incremental dose model. Two-month-old male
C57BL/6 mice were treated with either 300 mg/kg (APAP300,
a regenerating dose) or 600 mg/kg (APAP600, a non-regener-
ating dose) APAP. Liver injury and regeneration were studied
over a time course of 0 to 96 hr. APAP300 treated mice devel-
oped extensive liver injury initially, followed by significant liver
regeneration resulting in resolution of APAP-induced injury by
96 hr. In contrast, APAP600 treated mice exhibited significant
liver injury but substantial inhibition of liver regeneration result-
ing in sustained injury and decreased survival. The inhibition of
liver regeneration in APAP600 group was associated with cell
cycle arrest (at G0 and G1 phase), decreased cyclin D1 mRNA
and protein expression, decreased phosphorylation of Rb pro-
tein and sustained p21 expression. Further analysis revealed
that many known regenerative pathways, such as IL-6/STAT-3
signaling, growth factor signaling via EGFR and c-Met, and
downstream activation of MAPKs, were dose-dependently acti-
vated and remain highly activated even at APAP600, where
regeneration was inhibited. However, canonical Wnt/β-cat-
enin and NF-κB pathways were activated in APAP300 where
liver regeneration was stimulated and inhibited in APAP600
group where regeneration was decreased. Next, we investi-
gated role of Wnt/β-catenin in further detail. Chromatin immu-
HEPATOLOGY, October, 2014
noprecipitation (ChIP) analysis revealed increased binding of
β-catenin to cyclin D1 promoter specifically at APAP300 cor-
relating with higher cyclin D1 induction. Furthermore, overex-
pression of a stable form of β-catenin (S45D) in mice resulted in
improved liver regeneration following APAP overdose. Finally,
pharmacological inhibition of GSK3β, the upstream regula-
tor of β-catenin, starting as late as 4 hr after APAP600 dose
resulted in cyclin D1 induction, improved regeneration and
survival. Taken together, our incremental dose model has iden-
tified differential role of several signaling pathways in liver
regeneration after APAP overdose and highlighted GSK3β and
β-catenin as potential targets for regenerative therapies for
APAP-induced ALF.
Disclosures:
The following people have nothing to disclose: Bharat Bhushan, Chad M. Wale-
sky, Prachi C. Borude, Genea Edwards, Michael Manley, Satdarshan (Paul) S.
Monga, Udayan Apte
12
Microglia activation during hepatic encephalopathy is
driven by an imbalance of monocyte chemoattractant
protein 1/fractalkine due to bile acid signaling
Matthew McMillin1,3, Gabriel A. Frampton1,3, Cheryl Galindo1,2,
Holly A. Standeford2,1, Gianfranco Alpini2,1, Sharon DeMor-
row1,2; 1Texas A&M Health Science Center, College of Medicine,
Temple, TX; 2Central Texas Veterans Healthcare System, Temple,
TX; 3Digestive Disease Research Center, Scott & White Hospital,
Temple, TX
Neuroinflammation is an integral component of hepatic
encephalopathy (HE). The chemokine monocyte chemoattrac-
tant protein 1 (MCP-1) regulates microglia activation via bind-
ing the chemokine receptors 2 (CCR2) and 4 (CCR4). We have
previously shown that CCL2 is involved in the pathogenesis of
HE due to both acute and chronic liver injury. Conversely, the
chemokine fractalkine (FKN) is highly expressed in the brain
and serves as a suppressor of microglia activation. Bile acids
regulate a number of inflammatory processes in the liver. We
have shown that bile acids access the brain and contribute to
the progression of HE, though little is known about bile acid
signaling in the regulation of neuroinflammation. Therefore,
we tested the hypothesis that serum bile acids alter the balance
between MCP-1 and FKN expression, thereby supporting a
pro-inflammatory environment in a murine model of HE. Meth-
ods: HE was induced by injecting male C57Bl/6 mice with
azoxymethane (AOM) (100 μg/g ip) in the presence of CCR2
and CCR4 antagonists, or after feeding a diet enriched in the
bile acid sequestrant, cholestyramine, for 3 days. Neurological
decline was assessed by measuring reflex impairment, degree
of ataxia and time taken to reach to coma. Microglia activation
was assessed by morphometric analysis of Iba-1 immunoreac-
tivity. Primary cortical neuronal cultures were treated in vitro
with the bile acids cholic acid (CA) and taurocholic acid (TCA)
for 24 hr. MCP-1 and FKN expression was assessed in the
frontal cortex as well as neuronal cultures by qPCR and immu-
nofluorescence. Results: MCP-1 was upregulated and FKN
was downregulated in frontal cortex neurons rapidly following
AOM injection. Pretreatment of AOM-injected mice with CCR2
and CCR4 antagonists delayed neurological decline and
microglia activation, implicating MCP-1 signaling in HE. Treat-
ment of primary neurons with CA and TCA increased MCP-1
expression and decreased FKN expression. Cholestyramine
feeding reduced serum and brain bile acid levels and delayed
neurological decline without altering liver damage observed
after AOM injection. Furthermore, cholestyramine prevented
the AOM-induced increase in MCP-1 and decrease in FKN and
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
suppressed microglia activation. Conclusions: Our data demon-
strate that bile acids facilitate an imbalance between MCP-1
and FKN, which leads to a proinflammatory environment. Tar-
geting bile acid, FKN or MCP-1 signaling may prove to be
viable options for the management of HE during liver injury.
Disclosures:
The following people have nothing to disclose: Matthew McMillin, Gabriel A.
Frampton, Cheryl Galindo, Holly A. Standeford, Gianfranco Alpini, Sharon DeM-
orrow
13
Factors Associated with and Prevalence of Liver Fibrosis
in a General Elderly Population: Results from the Rotter-
dam Study
Elisabeth P. Plompen1, Edith M. Koehler1, Jeoffrey Schouten2,
Bettina E. Hansen1,3, Pavel Taimr1, Albert Hofman4, Frank W.
Leebeek5, Sarwa Darwish Murad1, Bruno H. Stricker4, Laurent
Castera6, Harry L. Janssen1,7; 1Gastroenterology and Hepatology,
Erasmus MC University Medical Center, Rotterdam, Netherlands;
2Gastroenterology and Hepatology, AZ Nikolaas, Sint-Niklaas,
Belgium; 3Public Health, Erasmus MC University Medical Center,
Rotterdam, Netherlands; 4Epidemiology, Erasmus MC University
Medical Center, Rotterdam, Netherlands; 5Hematology, Erasmus
MC University Medical Center, Rotterdam, Netherlands; 6Hepatol-
ogy, Hopital Beaujon, Clichy, France; 7Liver Centre, Toronto West-
ern and General Hospitals, University Health Network, Toronto,
ON, Canada
Background and aims: Liver fibrosis can be assessed non-inva-
sively by measuring liver stiffness (LS). The aim of this study was
to assess the prevalence of and factors associated with liver
fibrosis in a general elderly population, using LS as a proxy.
Methods: This study was part of the Rotterdam Study, a large
population-based cohort study of Caucasian subjects aged ≥55
years. Liver fibrosis was assessed with transient elastography
(TE). LS≥8.0 kPa was used as cut-off suggesting clinically rele-
vant fibrosis. Abdominal ultrasound was performed in all par-
ticipants to diagnose steatosis. Results: Of 3417 participants
who underwent TE, 3041 participants (mean age 66.0±7.6
years, 55% female, mean BMI 27.3±4.0) had reliable LS
measurements (TE failure or unreliable TE in 11.0%). Median
LS was 4.7 kPa (3.8-5.8). LS≥8.0 kPa was observed in 169
participants (5.6%). Multivariable logistic regression showed
that age (OR 1.1, 95%CI 1.0-1.1,p<0.001), diabetes mellitus
(OR 2.5, 95%CI 1.6-3.9,p<0.001), ALT (OR 1.02, 95%CI
1.0-1.0,p<0.001), use of M probe (OR 1.7, 95%CI 1.1-
2.5,p=0.01), HBsAg or anti-HCV positivity (OR 5.3, 95%CI
1.6-17.7,p=0.006), current or former smoking (OR 1.7, 95%CI
1.1-2.6,p=0.01), steatosis (OR 2.0, 95%CI 1.3-2.9,p=0.001)
and spleen size (OR 1.3, 95%CI 1.1-1.4,p<0.001) were inde-
pendently associated with having LS≥8.0 kPa. When adjusting
for these factors, the predicted probability of having LS≥8.0
kPa increased per age decade. The adjusted probability of
having LS≥8.0 kPa was 2.1% (1.5-3.5) for participants of
50-60 years of age and increased to 7.3% (4.4-12.6) for par-
ticipants of 80-90 years of age. The association between age
and LS≥8.0 kPa was significantly influenced by the presence
of steatosis (p for interaction=0.03). For each age decade,
participants with steatosis (n=1080 (35.5%)) had higher prob-
abilities of having LS≥8.0 kPa than those without steatosis. Par-
ticipants aged 80-90 with steatosis had a predicted probability
of LS≥8.0 kPa of 13.5% (10.0-22.1) as compared to a prob-
ability of 6.8% (4.1-11.1) in those of the same age without
steatosis (p<0.001); whereas this probability was 4.2% (3.0-
6.7) for participants aged 50-60 with steatosis as compared
to 1.7% (1.3-2.4) for those of the same age without steatosis
203A
(p<0.001). Conclusions: In this large population-based study,
5.6% had LS≥8.0 kPa, suggestive of clinically relevant fibrosis.
The probability of clinically relevant fibrosis increased with
age, with higher probabilities in participants with steatosis. In
the context of an aging population with an increasing preva-
lence of obesity and hence steatosis, liver fibrosis may become
a more prominent issue in the future.
Disclosures:
Laurent Castera - Advisory Committees or Review Panels: Magnisense; Speaking
and Teaching: Gilead, BMS, Janssen, Echosens, Abbvie
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sci-
ences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support:
Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck,
Medtronic, Novartis, Roche, Santaris
The following people have nothing to disclose: Elisabeth P. Plompen, Edith M.
Koehler, Jeoffrey Schouten, Bettina E. Hansen, Pavel Taimr, Albert Hofman, Frank
W. Leebeek, Sarwa Darwish Murad, Bruno H. Stricker
14
Increased liver stiffness is associated with higher all-
cause mortality in older adults: results from a popula-
tion-based study
Edith M. Koehler1, Elisabeth P. Plompen1, Jeoffrey Schouten2, Bet-
tina E. Hansen1,3, Frank J. van Rooij4, Pavel Taimr1, Jan Heeringa4,
Albert Hofman4, Bruno H. Stricker4,5, Sarwa Darwish Murad1,
Laurent Castera6, Harry L. Janssen7; 1Gastroenterology and Hepa-
tology, Erasmus MC University Hospital, Rotterdam, Netherlands;
2Gastroenterology and Hepatology, AZ Nikolaas, Sint-Niklaas,
Belgium; 3Public Health, Erasmus MC University Hospital, Rotter-
dam, Netherlands; 4Epidemiology, Erasmus MC University Hos-
pital, Rotterdam, Netherlands; 5Medical Informatics, Erasmus MC
University Hospital, Rotterdam, Netherlands; 6Hepatology, Hopital
Beaujon, Clichy, France; 7Toronto Centre for Liver Disease, Univer-
sity Health Network, Toronto, ON, Canada
Background:The aim of this study was to investigate the asso-
ciation between liver stiffness and all-cause mortality in a pop-
ulation-based cohort study. Methods:This study was part of the
Rotterdam Study, a large population-based cohort study of
Caucasian subjects aged ≥55 years. Participants that had reli-
able liver stiffness measurement (LSM) between January 2010
and March 2014, and a follow-up of at least 3 months were
included in the analyses. Mortality was monitored through
linkage with records of general physicians, municipal authori-
ties, hospitals and nursing homes. To analyze the association
between LSM≥8.0kPa, suggesting clinically relevant fibrosis,
or continuous (log-transformed) LSM and all-cause mortality,
we performed Cox regression analyses. In the full model we
adjusted for age, sex, serum total cholesterol, serum ALT, BMI,
diabetes mellitus, alcohol consumption, smoking status and
pack years of smoking. Results:In total, 2456 participants
(mean age 71±6.9 years; 55% female) were included. One
hundred eighty three (7.5%) participants had LSM≥8kPa, of
whom only 3 had positive HbsAg or anti-HCV and 57.9%
had liver steatosis on ultrasonography. During a median fol-
low-up of 18 months (IQR 10-27 months), 86 of 2456 (3.5%)
participants had died. Seventeen of these 86 (19.8%) par-
ticipants had LSM≥8.0kPa vs. 7.0% of participants alive at
censoring date (p<.001; see figure). LSM≥8.0kPa remained
associated with all-cause mortality after adjustment for age
and sex (HR2.26; 95%CI 1.32-3.88; p=.003), and in the full
model (HR2.44; 95%CI 1.35-4.42; p=.003). Liver stiffness, as
continuous (log-transformed) variable, was also associated with
all-cause mortality after adjustment for age and sex (p=.001)
and in the full model (p=0.004). Conclusions:Liver stiffness is
strongly associated with increased all-cause mortality in this
204A AASLD ABSTRACTS
population-based study of older individuals with short-term fol-
low-up.
Disclosures:
Laurent Castera - Advisory Committees or Review Panels: Magnisense; Speaking
and Teaching: Gilead, BMS, Janssen, Echosens, Abbvie
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sci-
ences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support:
Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck,
Medtronic, Novartis, Roche, Santaris
The following people have nothing to disclose: Edith M. Koehler, Elisabeth P.
Plompen, Jeoffrey Schouten, Bettina E. Hansen, Frank J. van Rooij, Pavel Taimr,
Jan Heeringa, Albert Hofman, Bruno H. Stricker, Sarwa Darwish Murad
15
Supersonic shear wave elastography versus transient
elastography for the diagnosis of alcoholic liver fibrosis:
a biopsy controlled prospective study
Maja Thiele1, Bjørn S. Madsen1, Annette D. Fialla1, Jonel Tre-
bicka2, Aleksander Krag1; 1Department of Gastroenterology and
Hepatology, Odense University Hospital, Odense C, Denmark;
2Department of Internal Medicine, University of Bonn, Bonn, Ger-
many
Background & Aims: Elastography for the diagnosis of alco-
holic liver fibrosis is insufficiently investigated. The new tech-
nology Supersonic shear wave elastography (SWE) is a
promising technique with potential advantages over transient
elastography (TE). Methods: 140 patients with current or prior
alcohol overuse, defined as minimum alcohol intake per day:
women >16g, men >24g, were included in a biopsy-controlled
prospective study of SWE and TE for non-invasive diagnosis
of alcoholic liver fibrosis. Exclusion criteria were: concurrent
liver disease, malignancy, cholestasis, right heart failure and
alcoholic hepatitis. Liver biopsy, SWE and TE were performed
on the same day in fasting conditions. ROC curve statistics
were used to calculate diagnostic accuracies. A paired test
for ROC curve equality were used to compare the diagnostic
accuracy of SWE and TE. Results: 104 males and 36 females
were included from two centers (Odense 135, Bonn 5). At
the time of inclusion, 69 patients were still drinking alcohol
(49%), and half of them were overusers (36 of 69). There were
no differences between the groups regarding ALT, alkaline
phosphatase, age or gender. The full spectrum of liver fibrosis
was represented (METAVIR F0=30, F1=34, F2=19, F3=9 and
F4=48). Cirrhotic patients (F4) were predominantely compen-
sated (Child A/B/C=34/13/1). SWE diagnosed significant
fibrosis (≥F2) and cirrhosis (F4) with AUROCs of 0.90 (95%
CI 0.84-0.96) and 0.94 (0.89-0.99). Using a cut-off value of
HEPATOLOGY, October, 2014
8.0 kPa, SWE diagnosed significant fibrosis with a sensitivity
of 90% and a specificity of 72% (correctly classifies 81% of
patients). For diagnosis of cirrhosis, the optimal cut-off was
12.1 kPa, with a sensitivity of 86% and a specificity of 92%
(correctly classifies 90% of patients). TE diagnosed significant
fibrosis and cirrhosis with AUROCs of 0.90 (0.85-0.96) and
0.95 (0.91-0.99). The optimal cut-off value was 8.7 kPa for
the diagnosis of significant fibrosis (sensitivity 83%, specific-
ity 86%, correctly classifies 84% of patients) and 16.2 kPa
for the diagnosis of cirrhosis (sensitivity 83%, specificity 95%,
correctly classifies 91% of patients). There were no differences
between the diagnostic accuracies of the two methods (test
for ROC curve inequality P=0.56 for ≥F2 and P=0.94 for F4).
The failure rate for SWE was 7% while TE failed in 9% of
cases (P=0.48). Conclusions: SWE and TE can be used for the
diagnosis of alcoholic liver fibrosis with excellent diagnostic
accuracies. The cut-off values are comparable for significant
fibrosis, whereas TE has a higher cut-off than SWE for cirrhosis.
SWE does not seem to be superior to TE in diagnostic accuracy
or failure rate.
Disclosures:
The following people have nothing to disclose: Maja Thiele, Bjørn S. Madsen,
Annette D. Fialla, Jonel Trebicka, Aleksander Krag
16
Assessment of Clinical Effectiveness of MR Elastography
and Vibration-Controlled Transient Elastography for
Detecting Hepatic Fibrosis
Jun Chen1, Jayant A. Talwalkar2, Meng Yin1, Jennifer Oudry4,
Kevin Glaser1, Thomas C. Smyrk3, Ehman Richard1; 1Radiology,
Mayo Clinic, Rochester, MN; 2Gastroenterology and Hepatology,
Mayo Clinic, Rochester, MN; 3Laboratory Medicine and Pathol-
ogy, Mayo Clinic, Rochester, MN; 4Echosens, Paris, France
Chronic liver disease and cirrhosis remain a leading cause of
mortality worldwide. Currently, liver biopsy is the reference
standard for detecting hepatic fibrosis yet its performance has
been questioned. Therefore, noninvasive imaging technologies
have been developed for assessing hepatic fibrosis, such as
MR Elastography (MRE) and Vibration-Controlled Transient
Elastography (VCTE). They provide quantitative measurements
of liver stiffness, either from in selected spot locations (VCTE)
or throughout a cross-sectional image of the liver (MRE). Aim:
To prospectively evaluate and compare the diagnostic perfor-
mance of MRE and VCTE in subjects with chronic liver disease.
Methods: This study was approved by our Institutional Review
Board. Subjects underwent 2D MRE and VCTE (XL or M probe)
within one month of liver biopsy. The operators were dou-
ble-blinded to imaging results. Histologic fibrosis staging was
done using METAVIR and Brunt classification systems (when
appropriate) by a single independent pathologist. JMP Pro 11
(SAS) was used for all statistical analysis. Results: 113 sub-
jects were enrolled, 65% (73/113) were female, age (95%
CIs) = 48 (46,50) years, BMI = 40 (39, 42) kg/m2. 2 sub-
jects did not have biopsy results; in the other 111 subjects,
the major liver disease etiologies were nonalcoholic fatty liver
disease (83%, 92/111), chronic hepatitis C (14%, 15/111)
and others (3%, 4/111). A total of 110 patients underwent
MRE exams; 5 of the 110 MRE exams could not be completed
due to claustrophobia or because the patient could not fit in the
scanner. VCTE was attempted in 97 patients but unsuccessful
in 4 exams due to high BMI. Of the 93 successful VCTE exams,
14/93 (15%) had unreliable results based on the published
criteria. For detecting clinically significant fibrosis (>=F2), the
area under the ROC curve (AUROC) values (95% CIs) were
calculated: MRE = 0.895 (0.811, 0.944), VCTE = 0.792
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS 205A

(0.686, 0.869), p = 0.0218; sensitivity, specificity, PPV, and

NPV: MRE = 82.5%, 83.1%, 75.0%, and 88.5% at 3.12 kPa
threshold; VCTE = 94.7%, 49.1%, 56.3%, and 93.1% at 6.10
kPa threshold. After rejecting the unreliable cases, the AUROC
of VCTE increased to 0.852 (0.748, 0.918) significantly (p
= 0.0016). Conclusions: The results of this prospective trial
demonstrate that the diagnostic performance (AUROC) for
detecting clinically significant hepatic fibrosis was 0.895 for
MRE and 0.792 for VCTE, p = 0.0218. If exams with unre-
liable VCTE results were excluded, then the AUROC of VCTE
was improved at the expense of a higher technical failure rate
(18/97).
Disclosures:
Jun Chen - Employment: Mayo Clinic; Stock Shareholder: Resoundant
Meng Yin - Patent Held/Filed: Mayo Clinic, Mayo Clinic, Mayo Clinic, Mayo
Clinic
Kevin Glaser - Patent Held/Filed: MR Elastography Technology; Stock Share-
holder: Resoundant
Ehman Richard - Management Position: Resoundant, Inc.; Patent Held/Filed:
Mayo Clinic; Stock Shareholder: Resoundant, Inc.
The following people have nothing to disclose: Jayant A. Talwalkar, Jennifer
Oudry, Thomas C. Smyrk Disclosures:
Kenneth K. Tanabe - Patent Held/Filed: EGF SNP and risk for HCC, EGFR inhibi-
tion and HCC, gene signature for prognosis in cirrhosis
Peter Caravan - Grant/Research Support: Sanofi; Stock Shareholder: Collagen
17 Medical
Quantitative molecular magnetic resonance imaging The following people have nothing to disclose: Howard H. Chen, Lan Wei, Nich-
(MRI) of lysyl oxidase-mediated collagen crosslinking olas J. Rotile, Christian T. Farrar, Bryan C. Fuchs
during liver fibrosis
Howard H. Chen1, Lan Wei2, Nicholas J. Rotile1, Christian T. Far-
rar1, Kenneth K. Tanabe2, Bryan C. Fuchs2, Peter Caravan1; 1Mar- 18
tinos Center for Biomedical Imaging, Radiology, Massachusetts Molecular MR imaging of Collagen Accurately Monitors
General Hospital, Harvard Medical School, Boston, MA; 2Division Reduced Biliary Fibrosis Progression in Response to
of Surgical Oncology, Massachusetts General Hospital Cancer Rapamycin
Center and Harvard Medical School, Boston, MA
Bryan C. Fuchs1, Christian T. Farrar2, Danielle K. DePeralta1,
Background: Liver fibrosis is a disease process in response to Helen Day2, Boris Keil2, Gregory Y. Lauwers3, Lan Wei1, Arun
repeated hepatic injury, resulting in the deposition of extracel- Subramaniam4, Kenneth K. Tanabe1, Peter Caravan2; 1Surgery,
lular matrix (ECM). Collagen, a main component of the ECM Massachusetts General Hospital, Boston, MA; 2Radiology, Massa-
scar, has been imaged successfully by MRI. During fibrogene- chusetts General Hospital, Boston, MA; 3Pathology, Massachusetts
sis, secreted collagen form fibrils that are crosslinked by lysyl General Hospital, Boston, MA; 4Sanofi, Framingham, MA
oxidase. We hypothesize that lysyl oxidase activity would be
Background: The gold standard in diagnosing liver fibrosis is
a suitable biomarker for imaging active fibrogenesis. Methods:
biopsy despite its limitations, including sampling error, and
We synthesized a gadolinium-based MRI probe (Gd-Hyd) that
complications related to the invasiveness of the procedure. Pre-
targets the product of the lysyl oxidase reaction and a close
viously thought to be irreversible, new therapeutic agents are
analog that was inactive (Gd-DiMe). Both probes have similar
currently be tested that could halt disease progression or poten-
size, relaxivity, and pharmacokinetics. A/J mice given oral
tially even reverse the course of disease. Because repeated
gavage (2-3x/week, 6 or 12 weeks) of carbon tetrachloride
biopsies are impractical due to the increased risk of compli-
(CCl4, fibrotic) or vehicle (control) were imaged on a 4.7T MR
cations and poor patient compliance, there is a critical unmet
scanner. We used a 3D T1-weighted gradient echo sequence
medical need for non-invasive methods to evaluate disease
and measured the contrast to noise ratio (CNR) by comparing
progression and response to treatment. Here, we use the colla-
the signal in the liver to the adjacent skeletal muscle before
gen-targeted, gadolinium (Gd)-based contrast agent EP-3533
and after i.v. probe injection (0.1 mmol/kg). Results: Gd-Hyd
to image biliary fibrosis progression and monitor response to
injection resulted in increased liver MR signal throughout the
rapamycin treatment. Methods: Male CD rats underwent bile
parenchyma (Fig A-B) of 12-week CCl4 mice, but not in control
duct ligation (BDL) or sham laparotomy and were magnetic res-
animals (Fig C-D). The change in CNR (ΔCNR, post - pre) for
onance (MR) imaged on post operative day 4 (n=9), 10 (n=10)
6- and 12-week CCl4 injured mice was 17- and 35-fold higher,
or 18 (n=8). Rapamycin treated rats (n=13) were administered
respectively, than control animals (p<0.05 and p<0.001,
3 mg/kg/day by oral gavage starting on day 4 and were
respectively). Gd-DiMe showed no significant difference in
imaged on day 18. Respiratory-gated, 3D inversion recovery
ΔCNR between CCl4 and control mice. The increased probe
(IR) FLASH images were acquired prior to and 1 hr following iv
uptake in the CCl4 mice liver was confirmed by ICP-MS for
administration of 10 μmol/kg EP-3533 on a clinical 1.5T scan-
Gd content and correlated with Ishak scores. Conclusion: Liver
ner using a home-built, transmit-receive solenoid coil. Longitudi-
fibrosis can be staged quantitatively in a mouse model using a
nal relaxation rate (R1) maps were generated from the images
novel Gd probe sensitive to lysyl oxidase activity. This probe
using a custom written MATLAB program for voxel wise fitting
raises new possibilities for translational and clinical imaging of
of the inversion recovery signal intensities as a function of the
hepatic fibrosis.
inversion recovery time. Following imaging, animals were sac-
rificed and liver tissue was subjected to pathologic scoring of
fibrosis and analyzed for Gd and hydroxyproline (Hyp) con-
206A AASLD ABSTRACTS
tent. Results: Collagen deposition in response to BDL increased
over time as assessed by Hyp analysis and Sirius red staining.
Compared to sham controls, liver ΔR1 increased significantly
in BDL rats at 10 and 18 days (p=0.04 and p<0.01, respec-
tively). Liver ΔR1 also correlated with ex vivo Gd concentration
(R=0.65). Rapamycin inhibited biliary fibrosis progression as
measured by Sirius red staining (p<0.01). Consistently, a sig-
nificant decrease in ΔR1 was observed in BDL rats that received
rapamycin (p=0.01). Interestingly, marked heterogeneity was
observed by Sirius red staining between the left and right lobes
of a “non-responder” rapamycin-treated rat, and this difference
was detected on the ΔR1 maps. Conclusion. Quantitative 3D
ΔR1 maps can be used to monitor progression of biliary fibro-
sis throughout the entire liver, and ΔR1 is sensitive to changes
in liver fibrosis in response to rapamycin treatment. EP-3533
should be examined for its ability to image liver fibrosis in
humans.
Disclosures:
Kenneth K. Tanabe - Patent Held/Filed: EGF SNP and risk for HCC, EGFR inhibi-
tion and HCC, gene signature for prognosis in cirrhosis
Peter Caravan - Grant/Research Support: Sanofi; Stock Shareholder: Collagen
Medical
The following people have nothing to disclose: Bryan C. Fuchs, Christian T.
Farrar, Danielle K. DePeralta, Helen Day, Boris Keil, Gregory Y. Lauwers, Lan
Wei, Arun Subramaniam
19
The use of simeprevir and sofosbuvir to treat HCV G1
in the Liver Transplant Setting: The experience in 3 US
Centers
Bashar Aqel1, Surakit Pungpapong2, K Tuesday Werner1, Amy E.
Chervenak1, Jorge Rakela1, Kymberly D. Watt3, Michael D. Leise3,
Jennifer L. Murphy2, Tanisha M. Henry2, Kristen Ryland2, Andrew
Keaveny2, Hugo E. Vargas1; 1Hepatology, Mayo Clinic Arizona,
Phoenix, AZ; 2Transplantation, Mayo Clinic Florida, Jacksonville,
FL; 3Gastroenterology/Hepatology, Mayo Clinic Minnesota, Roch-
ester, MN
Results from a phase II study (COSMOS) suggested that HCV
G1 infection can be treated effectively with a combination of
sofosbuvir (SOF) and simeprevir (SMV) with or without rib-
avirin (RBV) for 12 weeks. The regimen is suitable for IFN
ineligible patients and those who have failed prior treatment
with advanced fibrosis. Objective: To report the experience
of treating patients who were IFN ineligible/prior treatment
failures with SOF/ SMV combination in 3 U.S. liver transplant
(LT) centers. Results: We identified 127 patients with G1 dis-
ease who required this IFN-free treatment. To date 91 (71.7%)
have initiated treatment. Of the 91 patients, 60.4% were male,
89% were Caucasian. 55% had failed prior treatment, 15%
relapsed and 30% were treatment naïve. 82.4% had cirrhosis
and of those 36% are listed for LT. (median MELD was 9, range
6-22). To date, 19 have completed 12 weeks of therapy treat-
ment; 70% were HCV RNA negative at week 4; all were HCV
RNA negative at week 12. So far, no treatment relapses have
occurred in these patients; 1 patient received a LT 6 weeks
after she became virus negative and remains virus negative
2 weeks post-LT. No serious adverse events or episodes of
hepatic decompensation have been observed. Four patients
have reported self-limited vertigo on treatment. Conclusion:
SMV/SOF combination has been well tolerated in our difficult
to treat population of patients a majority of whom are cirrhotic,
and who are ineligible, previously intolerant or non-responsive
to IFN-based therapy. No episodes of hepatic decompensation
have been documented with this regimen to date. A major bar-
rier to initiating SMV/SOF combination treatment is the slow
approval process, even in patients with advanced liver dis-
HEPATOLOGY, October, 2014
ease. SVR 12 data will be presented as it becomes available
that will allow better characterization of the benefit of SMV/
SOF therapy in cirrhotic patients.
Disclosures:
Surakit Pungpapong - Grant/Research Support: BMS, Gilead
Hugo E. Vargas - Advisory Committees or Review Panels: Eisai; Grant/Research
Support: Merck, Gilead, Idenix, Novartis, Vertex, Janssen, Bristol Myers, Ikaria,
AbbVie
The following people have nothing to disclose: Bashar Aqel, K Tuesday Werner,
Amy E. Chervenak, Jorge Rakela, Kymberly D. Watt, Michael D. Leise, Jennifer
L. Murphy, Tanisha M. Henry, Kristen Ryland, Andrew Keaveny
20
Prevention of Hepatitis C Virus (HCV) Recurrence with
Peri-Transplant Hepatitis C Immune Globulin Combined
with Pre-Transplant (Pre-LT) Antiviral Therapy (AVT)
Norah Terrault1, Sanjaya K. Satapathy2, George Therapondos3,
Roshan Shrestha4, Elizabeth C. Verna5, Jeffrey Campsen6, James
Spivey7, Jens Rosenau8, Thomas D. Schiano9, Kalyan R. Bhamidi-
marri10, Sher Linda11, John M. Vierling12, Lewis W. Teperman13,
Gerond Lake-Bakaar14, Jacqueline G. O’Leary15, Laura M. Kulik16,
Fredric D. Gordon17, Daniel Maluf18, Shailesh Chavan19, Chris-
topher J. Dougherty19; 1University of California, San Francisco,
CA; 2University of Tennessee Health Sciences Center, Memphis,
TN; 3Ochsner Clinic Foundation, New Orleans, LA; 4Piedmont
Transplant Institute, atlanta, GA; 5Columbia University, New York,
NY; 6University of Utah, Salt Lake City, UT; 7Emory University,
Atlanta, GA; 8University of Kentucky, Lexington, KY; 9Mount Sinai
Medical Center, New York, NY; 10University of Miami, Miami,
FL; 11University of Southern California, Los Angeles, CA; 12Baylor
College of Medicine, Houston, TX; 13New York University, New
York, NY; 14Beth Israel Deaconess Medical Center, Boston, CT;
15Baylor University Medical Center, Dallas, TX; 16Northwestern
University Feinberg School of Medicine, Chicago, IL; 17Lahey Hos-
pital and Medical Center, Burlington, MA; 18University of Virginia
Health System, Charlottesville, VA; 19BIotest Pharmaceuticals, Boca
Raton, FL
Background and Aims: Safer HCV AVTs are available to treat
wait-listed patients to prevent post-LT HCV recurrence, but such
therapies are not uniformly effective and the optimal duration
of pre-LT AVT unknown. We evaluated the safety and efficacy
of Biotest-HCIG, a human hepatitis C immune globulin to pre-
vent HCV recurrence by neutralizing remaining HCV reservoirs
in patients on pre-LT HCV AVT at the time of LT. Methods: In this
phase 3, open-label randomized study, wait-listed patients with
chronic HCV infection (all genotypes) treated with any AVT and
who achieved HCV RNA <100 IU/ml prior to LT were eligible.
In total, 84 patients will be randomized 1:1:1 to Biotest-HCIG
(200 mg/kg or 300 mg/kg given on the day of LT and for 10
weeks post-LT) or observation. The primary endpoint is post-LT
sustained virologic response (pTVR), defined as HCV RNA <43
IU/ml at 12 wks post-LT treatment. Post-transplant immunosup-
pression is site-specific. Results: To date, 17 subjects (all male,
median age 59 yrs, 100% genotype 1, 94% with hepatocel-
lular carcinoma, 12% with living donors) have undergone LT.
Pre-LT AVT was telaprevir/peginterferon/ribavirin (RBV) (12%),
sofosbuvir/RBV (76%) or sofosbuvir/simeprevir (12%) given
for a median of 51 days (range 14-164 days) pre-LT with all
patients achieving HCV RNA <43 IU/mL pre-LT (71% also
undetectable). With median post-LT follow-up of 8 wks, post-LT
HCV recurrence has been documented in 2 patients - at wk
2 (control) and wk 3 (200 mg Biotest-HCIG) post-LT. Overall,
11/12 (92%) of Biotest-HCIG-treated patients have maintained
undetectable HCV RNA compared to 4/5 (80%) of controls
(Table). Among 4 patients who were viremic at the time of LT
and randomized to Biotest-HCIG, all have undetectable HCV
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
RNA at median 9 wks follow-up. Biotest-HCIG-related side
effects were infrequent and there were no discontinuations due
to adverse events. Conclusion: Biotest-HCIG is safe and well-tol-
erated. To date, HCV recurrence rates in patients on pre-LT AVT
are lower in Biotest-HCIG-treated patients compared with con-
trols (8% vs 20%) and all patients viremic at LT who received
Biotest-HCIG have undetectable HCV RNA. These preliminary
results suggest Biotest-HCIG may be beneficial as an adjuvant
therapy for HCV patients on AVT undergoing LT.
Disclosures:
Norah Terrault - Advisory Committees or Review Panels: Eisai, Biotest; Con-
sulting: BMS, Merck; Grant/Research Support: Eisai, Biotest, Vertex, Gilead,
AbbVie, Novartis, Merck
Sanjaya K. Satapathy - Advisory Committees or Review Panels: Gilead
Elizabeth C. Verna - Advisory Committees or Review Panels: Gilead; Grant/
Research Support: Salix, Merck
Thomas D. Schiano - Advisory Committees or Review Panels: vertex, salix, merck,
gilead, pfizer; Grant/Research Support: massbiologics, itherx
Sher Linda - Grant/Research Support: Biotest
John M. Vierling - Advisory Committees or Review Panels: Abbvie, Bristol-Mey-
ers-Squibb, Gilead, Hyperion, Intercept, Janssen, Novartis, Merck, Sundise,
HepQuant, Salix; Grant/Research Support: Abbvie, Bristol-Meyers-Squibb,
Eisai, Gilead, Hyperion, Intercept, Janssen, Novartis, Merck, Sundise, Ocera,
Mochida; Speaking and Teaching: GALA, Chronic Liver Disease Foundation,
ViralEd
Jacqueline G. O’Leary - Consulting: Gilead, Jansen
Laura M. Kulik - Advisory Committees or Review Panels: Bayer/ Onyx; Grant/
Research Support: Bayer/Onyx; Speaking and Teaching: Bayer/Onyx, Nordion,
Gilead
Shailesh Chavan - Employment: Biotest Pharmaceuticals
Christopher J. Dougherty - Employment: Biotest Pharmaceuitcals Corporation
The following people have nothing to disclose: George Therapondos, Roshan
Shrestha, Jeffrey Campsen, James Spivey, Jens Rosenau, Kalyan R. Bhamidi-
marri, Lewis W. Teperman, Gerond Lake-Bakaar, Fredric D. Gordon, Daniel
Maluf
21
High rates of virological response and major clinical
improvement during sofosbuvir and daclatasvir-based
regimens for the treatment of fibrosing cholestatic
HCV-recurrence after liver transplantation: The ANRS
CO23 CUPILT study
Vincent Leroy1, Jérôme Dumortier2, Audrey Coilly3, Mylene
Sebagh3, Claire Fougerou-Leurent4, Sylvie Radenne14, Danielle
Botta5, Francois Durand6, Christine Silvain7, Pascal Lebray8, Pau-
line Houssel-Debry4, Nassim Kamar9, Louis d’Alteroche10, Yvon
Calmus11, Inga Bertucci12, Georges-Philippe Pageaux13, Jean-
Charles Duclos-Vallee3; 1CHU de Grenoble, Grenoble, France;
2Hôpital Edourat Herriot, Lyon, France; 3Hôpital Paul Brousse,
Paris, France; 4CHU de Rennes, Rennes, France; 5APHM, Mar-
seille, France; 6Hôpital Beaujon, Clichy, France; 7CHU de Poitiers,
Poitiers, France; 8Hôpital LPS, Paris, France; 9CHU de Toulouse,
Toulouse, France; 10CHU de Tours, Tours, France; 11Hôpital St-An-
toine, Paris, France; 12ANRS, Paris, France; 13CHU de Montpel-
lier, Montpellier, France; 14Hôpital de la croix rousse, Lyon, France
Fibrosing cholestatic hepatitis (FCH) is a rare but severe form
of HCV-recurrence following liver transplantation (LT) leading
to poor short term survival. Therapeutic options are limited.
207A
Study aims were to assess efficacy and tolerance of sofosbuvir
(SOF) and daclatasvir (DCV)-based regimens in this setting.
Methods: The CUPILT study is a prospective nationwide cohort
including patients with HCV-recurrence following LT treated
by new antivirals. The present work focused on 21 patients
diagnosed with FCH and included between Oct 2013 and
Feb 2014. FCH diagnosis was based on strict criteria includ-
ing histological review by an expert pathologist. Treatment
regimens were prescribed at investigator’s discretion. Patients
were followed at W0, W1, W2, W3, W4, W6, W8 and
W12. Results: FCH was diagnosed after a median duration
of 6 months [range 1-18] following LT and therapy started at
10 months [2-38] post LT. Features of patients at W0 were:
median age: 53 years [36-67], men: 81%, G1: 76%, G3:
10%, G4: 14%, ALT: 128 IU/L [46-588], gGT: 595 IU [86-
5,511], bilirubin : 6.0 mg/dL [0.6-19], albumin : 3.2 g/dL
[1.6-4.0], HCV RNA : 6.9 log IU/ml [4.6-8.4]. Ascites was
observed in 8 (38%) patients. Four (19%) were HIV-co-infected
and 14 (67%) failed to antiviral therapy containing protease
inhibitors in 9 (43%) cases. The following regimens were used:
Peg-IFNa + SOF + RBV (n=2), SOF + RBV (n=6), SOF + DCV
(n=1) and SOF + DCV + RBV (n=12) for 24 weeks. All patients
were alive without re-transplantation at W12. HCV RNA was
not detectable at W2 and W4 in 1 (5%) and 3 (14%) patients,
respectively. At W12, 20 (95%) patients had HCV RNA <15
IU/ml and 17 (81%) were not detectable. Early viral kinetics
was not influenced by treatment regimens. The rates of ALT and
gGT normalization at W12 were 76% and 52%, respectively.
Median bilirubin serum levels rapidly decreased from 6.0 to
3.6 at W1 and 2.6 mg/dL at W2. The median time to achieve
bilirubin levels below 2 mg/dL was 6 weeks. At week 12,
19 (90%) of patients had bilirubin below 2 mg/dl, and 13
(69%) below 1 mg/dL. Albumin levels increased from 31 to 36
g/L at W12. This was accompanied by clinical improvement
including nutritional status (weight gain from 67.5 to 70.0 Kg).
Ascites disappeared in 4/8 patients, but remained stable in 2
patients who had initially refractory ascites. Complete clinical
response (no ascites and bilirubin < 2 mg/dL) was observed
at W12 in 15 (71%) patients. Tolerance was satisfactory. Con-
clusion: SOF and DCV based regimens show promising results
combining high rates of virological response and major clinical
improvement at W12. Durability of virological and clinical
response will be presented.
Disclosures:
Vincent Leroy - Board Membership: roche, merck, gilead, bms, roche, merck,
gilead, bms, roche, merck, gilead, bms, roche, merck, gilead, bms; Consulting:
jansen, jansen, jansen, jansen; Grant/Research Support: roche, gilead, bms,
roche, gilead, bms, roche, gilead, bms, roche, gilead, bms; Speaking and Teach-
ing: bms, merck, gilead, roche, bms, merck, gilead, roche, bms, merck, gilead,
roche, bms, merck, gilead, roche
Jérôme Dumortier - Board Membership: Novartis, Astellas, Roche; Consulting:
Novartis; Grant/Research Support: Novartis, Astellas, Roche, MSD, GSK
Audrey Coilly - Speaking and Teaching: Gilead, BMS, Janssen, MSD, Roche,
Novartis, Astellas
Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis;
Speaking and Teaching: Gilead
Pascal Lebray - Grant/Research Support: Merck, astellas; Speaking and Teach-
ing: Janssen, MSD, Gilead
Georges-Philippe Pageaux - Advisory Committees or Review Panels: Roche,
Roche, Roche, Roche; Board Membership: Astellas, Astellas, Astellas, Astellas
The following people have nothing to disclose: Mylene Sebagh, Claire Foug-
erou-Leurent, Sylvie Radenne, Danielle Botta, Christine Silvain, Pauline Hous-
sel-Debry, Nassim Kamar, Louis d’Alteroche, Yvon Calmus, Inga Bertucci,
Jean-Charles Duclos-Vallee
208A AASLD ABSTRACTS
22
Striking differences in wait-listing trends between
patients with viral hepatitis B and C: implications of
effective anti-viral therapy
Jennifer A. Flemming1, W. Ray Kim2, Carol Brosgart3, Norah Ter-
rault3; 1Medicine and Public Health Services, Queen’s University,
Kingston, ON, Canada; 2Medicine, Stanford University, Palo Alto,
CA; 3Medicine, University of California San Francisco, San Fran-
cisco, CA
Trends in wait-listing (WL) for liver transplantation (LT) reflect the
changing epidemiology of the cirrhotic population. We aimed
to analyze trends in LT WL for viral hepatitis in the United States
(US). Methods: Using the scientific registry of transplant recipi-
ents database from 2003-2013, we identified adults WL for LT
due to hepatitis C (HCV) and hepatitis B (HBV), with non-alco-
holic steatohepatitis (NASH) as a comparator. The indication
for WL was defined either as end-stage liver disease (ESLD) if
the MELD at WL was ≥ 15 or hepatocellular carcinoma (HCC).
Standardized annual incidence rates of WL based on etiol-
ogy and indication were calculated and time trends analyzed
using Poisson regression to calculate incidence rate ratios (IRR).
Results: 42,855 individuals were identified (HCV 74%, NASH
18%, HBV 8%), 71% male, median age 55 yrs (IQR 51 –
61). The age and sex adjusted incidence of LT WL increased
annually for HCV (IRR 1.03, 95% CI 1.02-1.03, P <.001) and
NASH (IRR 1.11, 95% CI 1.10-1.12, P <.001) and decreased
for HBV (IRR 0.987, 95% CI 0.976-0.999, P = 0.027). WL for
ESLD increased by 11% per year in NASH (IRR 1.11, 95% CI
1.10-1.12, P <.001) while it decreased by 4% per year in HBV
and 1% in HCV (HBV IRR 0.96, 95% CI 0.94-0.97, P <.001;
HCV IRR 0.99, 95% CI 0.98-0.99, P <.001; figure). WL for
HCC increased by 10% per year for HCV (IRR 1.10, 95% CI
1.09-1.11, P <.001), and 15% for NASH (IRR 1.15, 95% CI
1.12-1.17, P <.001), but was stable in HBV (HBV IRR 1.01,
95% CI 0.99-1.03, P = 0.261, figure). Conclusions: While
these trends in WL for HBV likely reflect the success of anti-viral
therapy, the effect of anti-HCV therapy is yet to become appar-
ent, especially for HCC. Future reduction in the need for WL
for HCV may help accommodate the growing need for LT for
NASH in the US.
Disclosures:
W. Ray Kim - Consulting: Bristol Myers Squibb, Gilead Sciences
Carol Brosgart - Board Membership: Tobira Therapeutics; Consulting: Dynavax;
Stock Shareholder: Alios Biopharma
Norah Terrault - Advisory Committees or Review Panels: Eisai, Biotest; Con-
sulting: BMS, Merck; Grant/Research Support: Eisai, Biotest, Vertex, Gilead,
AbbVie, Novartis, Merck
The following people have nothing to disclose: Jennifer A. Flemming
HEPATOLOGY, October, 2014
23
Sofosbuvir/Daclatasvir Therapy for Recurrent Hepatitis
C after Liver Transplantation: Preliminary report from
the parisian centers
Filomena Conti1, Pascal Lebray2, Astris Schielke1, Helene Reg-
nault2, Dominique Thabut2, Daniel Eyraud2, Armelle Poujol-Rob-
ert1, Olivier Chazouillères1, Yvon Calmus1; 1Liver Transplant unit,
Hôpital Saint Antoine, APHP, Paris, France; 2Hepatogastroenterol-
ogy and Liver Transplant units, Paris VI-Pitié-Salpêtrière Hospital,
Paris, France
Background: Recurrence of hepatitis C (HCV) infection is the
most common cause of graft loss and mortality in HCV-infected
liver-transplant recipients. Interferon-based antiviral regimens,
including those utilizing protease inhibitors, are poorly toler-
ated after transplantation and achieve lower sustained viro-
logic response rates (SVR) than in nontransplant patients. The
nucleotide HCV polymerase inhibitor sofosbuvir (SOF) and the
HCV nonstructural protein NS5A inhibitor daclatasvir (DTV)
have a high barrier to resistance, lack interactions with immu-
nosuppressive agents, and have a favourable safety profile.
Methods: In this ongoing single-arm, open-label interferon-free
pilot study, patients with recurrent HCV infection (any HCV
genotype) after liver transplantation received up to 24 weeks
of SOF 400 mg and DTV 60 mg/day. Patients were ≥18
years of age and at least 6 months post-transplantation. The
primary efficacy endpoint of this preliminary report was viro-
logic response (VR) (HCV RNA <15 IU/mL) 2, 4 and 8 weeks
after initiation of study treatment. Results: 55 patients (16 GT
1a, 18 GT 1b, 1 GT1g, 6 GT 2, 8 GT 3, 6 GT 4) have been
enrolled. Mean age was 56 ± 8.7 years, 85 % were males, 91
% have been previously treated. The mean baseline viral load
was 6.35 ± 2.95 log10 IU/mL [range 2.08- 7.50 log10 IU/
mL], 18 patients were F3/F4 and 4 had fibrosing cholestatic
hepatitis. By week 2, 4 and 8 of treatment, VR was 17, 50 and
85 %, respectively, while the viral load decreased to 3.14 ±
2.95, 0.90 ± 0.80 and 0.23 ± 0.25, respectively. Prothrombin
rate, albumin and creatinin levels remained unchanged during
the 8 first weeks of treatment.There was no episode of acute or
chronic rejection. No dose adjustment of immunosuppression
was required. The most common adverse events were fatigue,
arthralgia, headache, and diarrhea. 2 patients experienced
renal failure possibly related to antiviral therapy. No patient
discontinued treatment due to adverse event. Conclusions:
SOF/DTV therapy was well tolerated and achieved an early
VR of 50 and 85 % at W4 and W8 in these difficult to cure
patients. Sustained VR will be presented at the Liver Meeting.
Disclosures:
Pascal Lebray - Grant/Research Support: Merck, astellas; Speaking and Teach-
ing: Janssen, MSD, Gilead
Olivier Chazouillères - Consulting: APTALIS, MAYOLY-SPINDLER
The following people have nothing to disclose: Filomena Conti, Astris Schielke,
Helene Regnault, Dominique Thabut, Daniel Eyraud, Armelle Poujol-Robert, Yvon
Calmus
24
Therapeutic misadventure with acetaminophen: pro-
spective evaluation of prerequisites, characteristics and
outcome
Alexandre Louvet1,2, Charlotte Vanveuren1, Sébastien Dha-
rancy1,2, Amélie Cannesson1,2, Florent Artru1,2, Guillaume Las-
sailly1,2, Valerie Canva-Delcambre1, Philippe Mathurin1,2; 1Service
des maladies de l’appareil digestif, Hôpital Huriez, Lille, France;
2Unité 995, INSERM, Lille, France
Prerequisites leading to development of the so-called “therapeu-
tic misadventure with acetaminophen” have never been eval-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
uated in a prospective study with sufficient sample size. Such
study would enable to characterize not only outcome but also
pattern of acetaminophen intake. Methods: All patients admit-
ted with severe acetaminophen-related hepatitis were included
prospectively. Patients were divided into acute hepatitis related
to acetaminophen overdose (AO) or to acetaminophen use
at therapeutic dose (≤6g/day), termed acetaminophen thera-
peutic misadventure (ATM). We defined chronic drinkers by a
daily alcohol consumption of ≥30g/day. Results: From 2002
to 2014, 271 patients were included, 205 with AO and 66
with ATM. Only patients who were chronic alcohol drinkers
(89.4%) or who had starved for several days (9.6%) developed
ATM. As expected, acetaminophen intake was 16 g in AO vs.
3.15g in ATM (p<0.0001). In 70% of patients, acetamino-
phen intake was below the daily 4g-dose classically regarded
as safe. In contrast to AO, no patient developed ATM after
a single intake of acetaminophen as confirmed by a median
time of intake at 4 days in ATM vs. 1 day in AO (p<0.0001).
At admission, patients with ATM were older than AO (age 44
vs. 30.1 years; p<0.0001) and had a deeper impairment of
liver function (prothrombin time 30.7 vs. 22.1s, p=0.0003;
albumin 32.7 vs. 38.1 g/l, p<0.0001; bilirubin 47.1 vs. 25
mg/l, p<0.0001; lactate 3.31 vs. 1.95 mmol/l, p=0.009;
creatinine 9.8 vs. 8.7 mg/l, p=0.097). Transaminases were as
elevated in ATM as in AO: AST 4138 vs. 3983 IU/l (p=0.1),
ALT 2416 vs. 3831 IU/l (p=0.22). In ATM and AO, males
were 36.4% and 43.4% (p=0.31) and percentage of chronic
drinkers was 89.4 vs. 36.6% (p<0.0001), respectively. After
3 days, a drastic drop by 67% vs. 50.2% (p<0001) in ALT
and by 93.6 vs. 89.4% (p=0.02) in AST was observed in
ATM and AO respectively. One-month survival was 84.6% in
ATM and 92.6% in AO (p=0.05). On overall patients, among
factors associated with survival in univariate analysis, only the
number of King’s college criteria (risk ratio 3.15, 95%CI: 2.04-
4.88, p<0.0001) independently predicted 1-month mortality,
whereas albumin, age and alcohol consumption did not (p=
0.13, 0.41 and 0.75 respectively). Conclusion: Therapeu-
tic misadventure occurs after several days of acetaminophen
intake at a dose <6g/day and is mainly observed in chronic
alcohol consumers and rarely after prolonged starvation. This
entity has a worse outcome as compared to acetaminophen
overdose. Clinicians must be warned that repeated prescription
of acetaminophen must be carefully monitored in patients with
risk factors of misadventure.
Disclosures:
Sébastien Dharancy - Board Membership: NOVARTIS; Speaking and Teaching:
ROCHE, ASTELLAS
Philippe Mathurin - Board Membership: Schering-Plough, Janssen-Cilag, BMS,
Gilead, Abvie; Consulting: Roche, Bayer, Boehringer
The following people have nothing to disclose: Alexandre Louvet, Charlotte
Vanveuren, Amélie Cannesson, Florent Artru, Guillaume Lassailly, Valerie Can-
va-Delcambre
25
Hepatocyte-derived extracellular vesicles released
during lipotoxicity regulate hepatic stellate cell pheno-
type via delivery of specific miRNAs and modulation of
PPAR-γ expression
Davide Povero1, Nadia Panera2, Akiko Eguchi1, Anna Alisi2, Vale-
rio Nobili2, Ariel E. Feldstein1; 1Department of Pediatrics, Uni-
versity of California San Diego, La Jolla, CA; 2Hepato-Metabolic
Disease Unit and Liver Research Unit, Bambino-Gesu’ Children’s
Hospital, IRCCS, Roma, Italy
Background. Hepatic stellate cell (HSC) activation plays a
pivotal role in liver fibrosis and disease progression in non-
alcoholic fatty liver disease (NAFLD). The triggers for HSC acti-
209A
vation in this condition remain poorly understood. We have
recently demonstrated that during lipotoxicity, hepatocytes
release extracellular vesicles (EVs) enriched in miRNAs (Sci-
ence Sig. Oct 2013). Our aim is to investigate if extracellular
vesicles released by hepatocytes during lipotoxicity may modu-
late hepatic HSC phenotype by delivering specific microRNAs.
Methods. Human hepatoma cells (HepG2), and primary mouse
hepatocytes were exposed to the saturated free fatty acid (FFA)
palmitic acid for up to 24 hrs. EVs and EV-free supernatant
were isolated from cell-free supernatants by ultracentrifuga-
tion and quantitated by flow cytometry. HSC chemotaxis and
chemokinesis were assessed by Boyden’s chamber and wound
healing assay, respectively. HSC proliferation was assessed
by BrDu-FITC staining and quantitation of pro-fibrogenic tran-
scripts was performed for cell activation. EVs internalization
and delivery of miRNAs into HSC was addressed by immuno-
fluorescence. Specific PPAR-γ-targeting miRNAs identified and
quantified in EVs and HSCs by qPCR. Depletion of miRNAs
from EVs was achieved by anti-miRNA and specific siRNA on
maternal cells. A functional analysis of miRNA was assessed
by miRNA mimics. Results. Hepatocyte-derived EVs released
during lipotoxicity are efficiently internalized by HSCs result-
ing in their activation, as shown by marked up-regulation of
pro-fibrogenic genes, such as Collagen-I, α-SMA and TIMP-2,
proliferation (EVs vs. EVs-free supernatant, p<0.04), chemo-
taxis (EVs vs. EV-free supernatant, p<0.001) and chemokinesis
(EVs vs. EVs-free supernatant, p<0.002), mainly after 16-24
hrs. These changes were associated with suppression of PPAR-γ
expression in HSC. EVs internalization results in delivery of
their miRNA content into HSCs. Lipotoxic hepatocyte-derived
EVs miRNA content included various miRNAs that are known
inhibitors of PPAR-γ expression with miR-128a being the most
effective. Further loss- and gain-of-function studies identified
miR-128a as a central modulator of the effects of EVs on PPAR-γ
inhibition and HSC activation. Conclusion. Our study demon-
strates that EVs released by hepatocytes during lipotoxicity are
critical signals that contribute to HSC activation in a process
involving delivery of specific miRNAs and modulation of PPAR-γ
expression. These results uncover a novel miRNA-regulated
pathway committing HSC activation during lipotoxicity and
have important implications for development of therapeutic
strategies for patients with NAFLD.
Disclosures:
Akiko Eguchi - Grant/Research Support: Gilead
The following people have nothing to disclose: Davide Povero, Nadia Panera,
Anna Alisi, Valerio Nobili, Ariel E. Feldstein
26
Sphingosine kinase containing exosomes regulate
hepatic stellate cell activation
Ruisi Wang, Sheng Cao, Usman Yaqoob, Thiago de Assuncao,
Vijay Shah; Mayo Clinic, Rochester, MN
Background/Aims: Hepatic stellate cell (HSC) activation is
required for fibrogenesis therefore understanding mechanisms
governing HSC activation are important. Exosomes are cell
derived extracellular vesicles thought to promote intercellular
communication by interacting with recipient cells to deliver
specific content. The aim of this study was to determine whether
exosomes contribute to HSC activation during liver fibrosis.
Methods/Results: Exosomes were isolated from human serum
and conditional media of TSEC (immortalized mouse liver
endothelial cells) by differential ultracentrifugation, and char-
acterized based on size (90-110 nm) and marker (TSG101,
LAMP1, CD63 and CD81) characteristics. Incubation of LX2
HSC cell line with human serum derived exosomes was asso-
210A AASLD ABSTRACTS
ciated with increased AKT phosphorylation (8.3-fold, n=6,
p<0.05), increased mRNA levels of smooth muscle actin (1.7-
fold, n=3, p<0.05), fibronectin (1.8-fold, n=3, p<0.05) and
collagen (1.7-fold, n=3, p<0.05), and increased cell migration
(2.5-fold, n=3, p<0.05) in Transwell assays. Exosome activa-
tion of LX2 cells required exosome endocytosis since inhibi-
tion of endocytosis with transfection of the dominant negative
dynamin GTPase construct Dyn2K44A or by the pharmaco-
logical inhibitor, dynasore significantly attenuated exosome-in-
duced AKT phosphorylation (72% and 90%, respectively, n=3,
p<0.05). Exosome biotinylation studies showed that internal-
ized exosomes target initially to early endosomes and subse-
quently to lysosomes based on double immunofluorescence
staining using early endosome marker, EEA and lysosome
marker, LAMP1 (Pearson coefficients of colocalization= 0.32
and 0.36, respectively, n=5). Western blot analysis of exo-
somes for enrichment of molecules implicated in HSC activation
revealed presence of sphingosine kinase 1 (SK1), an enzyme
that produces sphingosine-1 phosphate (S1P). Indeed, exo-
somes derived from conditioned media of TSEC overexpressing
SK1 further increased LX2 cell S1P levels (2-fold, n=6, p<0.05)
and LX-2 migration (2-fold, n=3, p<0.05) suggesting that S1P
generated by exosomes may promote HSC activation. Finally,
S1P levels were increased in serum of mice with CCl4 induced
liver fibrosis (1.4-fold, n=17, p<0.05) and SK1 mRNA lev-
els were upregulated in human liver cirrhosis patient samples
(2.5-fold, n=3, p<0.05). Conclusion: These findings advance
our understanding of exosome-mediated HSC activation and
identify potential molecular targets for attenuating this process.
Disclosures:
The following people have nothing to disclose: Ruisi Wang, Sheng Cao, Usman
Yaqoob, Thiago de Assuncao, Vijay Shah
27
Deletion of fibrocytes in mice attenuates experimental
liver fibrosis
Jun Xu, Tae Jun Park, Min Cong, Xiao Liu, David A. Brenner, Tati-
ana Kisseleva; School of Medicine, UCSD, San Diego, CA
BACKGROUND: Liver fibrosis is characterized by extensive
accumulation of extracellular matrix, mostly Collagen Type I.
Bone marrow(BM)-derived fibrocytes, designated as CD45 and
Col1a1 expressing cells (CD45+Col1a1+ cells), are recruited
to fibrotic liver in response to chronic liver injury. However,
the role of fibrocytes in liver fibrosis remains unclear. AIM:
The contribution of BM-derived fibrocytes to experimental liver
fibrosis was studied in fibrocyte deleted BM chimeric mice,
in which fibrocyte death was induced throughout liver injury
by overexpression of DTA in CD45+Col1a1+ cells. The role
of Col1a1 in regulation of fibrocyte functions was studied in
BM chimeric Fibrocyte 5’SL-Col1a1 mice, in which mutation of
5’ stemloop abrupts Col1a1 translation. To study the function
of Col1a1 within fibrocytes, BM from 5’StemLoop knockout
mouse was transplanted into wildtype mice, which are defi-
cient of Col1a1 expression in fibrocytes. METHODS: Inducible
Col1a1-ER-Cre mice were crossed with Rosa26-YFP reporter
mice and Rosa26-DTA mice and were used as donors for BM
transplantation into wt mice to generate Fibrocyte deleted mice.
Upon tamoxifen administration, fibrocytes were labeled by YFP
expression in wt mice, while successful ablation of fibrocytes
(>95%) was achieved in Fibrocyte deleted mice, as indicated
by disappearance of YFP+ fibrocytes. To study the function of
Col1a1 in fibrocytes, the BM from 5’SL knockout mice was
transplanted into wt mice to generate Fibrocyte5’SL-Col1a1
mice. Mice were subjected to CCl4 (6w), livers were ana-
lyzed for development of liver fibrosis. The transcriptome of
HEPATOLOGY, October, 2014
fibrocytes were assessed by RNA-seq. RESULTS: Deletion of
fibrocytes in mice resulted in attenuation of CCl4-induced liver
fibrosis by 50%, as shown by reduced Sirius Red, and Col1a1,
alpha-SMA, TIMP1 and TGFbeta1 mRNA expression. We
determined that in fibrotic liver fibrocyte give rise to 10% of
myofibroblasts. Meanwhile, majority of fibrocytes contributes
to hepatic myeloid cells, which serve as a significant source
of TGFb1, and inflammatory cytokines such as IL-6 and IL1b1,
and also suppress anti-fibrogenic (M2) macrophages. We next
hypothesized that upregulation of Col1a1 may be important
for fibrocyte functions. Indeed, development of liver fibrosis
was reduced in Fibrocyte5’SL-Col1a1 mice by 30%, and was
associated with impaired activation and migration of HSCs and
reduced TGFβ1 and CCL5 in liver. CONCLUSION: Fibrocyte
contribute to myofibroblast population, but most importantly,
they mediate differentiation of proinflammatory macrophage
and secret profibrogenic cytokine TGFβ1. Furthermore, proper
collagen expression is required for fibrocyte function.
Disclosures:
The following people have nothing to disclose: Jun Xu, Tae Jun Park, Min Cong,
Xiao Liu, David A. Brenner, Tatiana Kisseleva
28
Liver Repopulation with Transplanted Liver Sinusoidal
Endothelial Cells (LSEC) Benefits From Prior Disruption of
Native Endothelial Cells as well as Endothelin-1 Recep-
tor Blockade in Donor Cells
Neelam Yadav1, Antonia Follenzi2, Ralf Bahde3, Sanjeev Gupta1;
1Medicine, Albert Einstein College of Medicine, New York, NY;
2Health Sciences, University of Piemonte Orientale, Novara, Italy;
3Surgery, Hopital of University of Muenster, Muenster, Germany
Background: To accomplish cell therapy with higher efficien-
cies, insights into transplanted cell fates is critical. The ability of
mature hepatocytes as well as LSEC to engraft and proliferate
in liver was of therapeutic benefit. However, early clearance of
transplanted cells was a major restriction in both cases. Clear-
ance of transplanted hepatocytes was largely due to second-
ary release of endothelin-1 (ET1) or of chemokines/cytokines/
receptors, e.g., TNF-a, from Kupffer cells and neutrophils,
whereas endothelial disruption and release of hepatoprotective
factors from hepatic stellate cells (HSC) benefited cell engraft-
ment. Based on these considerations, we defined mechanisms
for engrafting transplanted LSEC in liver. Methods: Mature
LSEC were isolated through collagenase digestion of liver from
C57BL/6 mice followed by Percoll gradient separation. Cells
(0.75-1 x106) were transplanted intraportally into multiple syn-
geneic DPPIV- C57BL/6 recipient mice and cell engraftment
was analyzed by DPPIV histochemistry. Onset of inflammation
was analyzed by carbon uptake by Kupffer cells and number
of myeloperoxidase+ neutrophils. Following drugs were given
before cell transplantation: etanercept (ETN) or thalidomide
(Thal) (TNF-alpha antagonists that block release from neutro-
phils or Kupffer cells of chemokines/cytokines/receptors),
naproxen (NAP) (nonselective Cox inhibitor that induces VEGF
release from HSC), doxorubicin (DOX) alone, monocrotaline
(MCT) alone, or MCT, rifampicin (RIF) plus phenytoin (Phen)
(to damage endothelial barrier), and cells were preincubated
with bosentan (nonselective ET1 receptor blocker that blocked
cytotoxin-mediated hepatotoxicity). Results: In control animals,
transplanted LSEC engrafted in liver without changes in cell
numbers over 1 month duration of studies. ETN, Thal or NAP
neither improved nor worsened LSEC engraftment, which was
related to less activation after LSEC transplantation of neutro-
phils and Kupffer cells versus after hepatocyte transplantation.
However, DOX impaired LSEC engraftment. By contrast, MCT
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
or MCT/Rif/Phen produced greatest increases in LSEC engraft-
ment followed by transplanted cell proliferation over 1 month.
Similarly, pretreatment of donor LSEC with bosentan improved
cell engraftment, which we found was due to the superior abil-
ity of bosentan-treated cells to withstand secondary cytotoxic
insults. Conclusions: The mechanisms by which transplanted
LSEC may repopulate the liver include prevention of ET1-de-
pendent cytotoxicity along with sustained disruption of hepatic
endothelial barrier. These insights will advance further devel-
opment of drug-based approaches for cell therapy in people.
Disclosures:
The following people have nothing to disclose: Neelam Yadav, Antonia Follenzi,
Ralf Bahde, Sanjeev Gupta
29
Positive feedback loop between beta-catenin and stea-
royl-CoA desaturase in liver fibrosis
Soo-Mi Kweon1, Keane Lai1, Lan Qin1, Jun Xu1, Naoki Fujii2, Sam-
uel W. French3, James Ntambi4, Hidekazu Tsukamoto1; 1Southern
California Research Center for ALPD and Cirrhosis, Keck School of
Medicine, University of Southern California, Los Angeles, CA; 2St.
Jude Children’s Research Hospital, Memphis, TN; 3Harbor-UCLA
Medical Center, Torrance, CA; 4University of Wisconsin-Madison,
Madison, WI
Evidence implicates WNT-beta-catenin (CTNNB1) pathway in
fibrosis of different organs (lung, skin, kidney, muscle, liver)
and in myofibroblastic activation of hepatic stellate cells
(HSCs). Yet, CTNNB1 targets essential for HSC activation are
unknown. Stearoyl-coA desaturase (SCD) which catalyzes the
biosynthesis of oleate (OA) and palmitoleate (POA), is impli-
cated in metabolic syndrome, tumorigenesis, and stemness,
but SCD’s roles in liver fibrosis and the mechanisms underlying
these functions are elusive. [Aim] We globally searched for
putative WNT-CTNNB targets in activated rat HSCs (aHSCs)
by identifying genes commonly suppressed with inhibitors
which work at three different levels of WNT-CTNNB path-
way: DKK1 at the LRP5/6; FJ9 at Dishevelled; and ICG-001
at CBP/CTNNB1 interaction. We studied the functionality and
mechanistic basis of the CTNNB-dependent genes (Scd1/2)
in HSC activation. [Methods] Microarray, promoter assay,
ChIP, IB were performed to assess CTNNB-dependent genes.
The SCD inhibitor A939572 or Scd1f/f or Scd2f/f mice were
used to test the roles of SCD1/2 in HSC activation and liver
fibrosis. [Results] Of 27,342 genes examined, 181 genes
are commonly suppressed with all three inhibitors. Two of the
genes conspicuously repressed are Scd1 and Scd2. Scd1/2
inductions are associated with increased desaturation index
of fatty acids in cultured aHSCs and are also confirmed in
HSCs isolated from CCl4-induced and cholestatic rat liver fibro-
sis. Cre-mediated ablation of Scd1f/f or Scd2f/f in HSCs or
A939572 treatment in culture, de-represses the HSC differen-
tiation gene Pparγ and reverses morphologic and biochemical
features of HSC activation. These effects are rescued with OA
or POA, the SCD products but not with their precursors, stea-
rate and palmitate. CTNNB1 is enriched at the Scd1 proximal
promoter site containing classical SRE and NF-Y element, and
re-ChIP confirms CTNNB1 association with SREBP-1c bound to
the site. CTNNB1 enhances ~10 fold SREBP-1c mediated Scd1
transcription, demonstrating CTNNB1 is a potent co-activa-
tor for the gene. SCD inhibition reduces integrin-linked kinase
(ILK) activity, p(S9)-GSK3β and p-AKT, and CTNNB1 stabili-
zation. Inhibition of ILK phenocopies the effects of SCD inhibi-
tion, however the latter but not the former effects are rescued
with OA, suggesting ILK is downstream of SCD. SCD inhibition
with A939572 or conditional knockout of Scd2 in aHSCs in
211A
Col1a1-Cre:Scd2f/f mice attenuates CCl4-induced liver αSMA
accumulation and fibrosis. [Conclusion] WNT/CTNNB1-in-
duced SCD positively feeds back to activate CTNNB1 and
HSCs via ILK and is a new potential therapeutic target for liver
fibrosis.
Disclosures:
Hidekazu Tsukamoto - Consulting: Shionogi & Co., S.P. Pharmaceutics; Grant/
Research Support: The Toray Co.
The following people have nothing to disclose: Soo-Mi Kweon, Keane Lai, Lan
Qin, Jun Xu, Naoki Fujii, Samuel W. French, James Ntambi
30
VASP promotes myofibroblastic activation of hepatic
stellate cells by regulating Rab11 dependent plasma
membrane targeting of TGF-β receptors
Kangsheng Tu1,3, Jiachu Li2, Vijay Shah1, Ningling Kang2; 1GI
Research Unit, Mayo Clinic, rochester, MN; 2The Hormel Institute,
Austin, MN; 3Department of Hepatobillary Surgery, 1st Affiliated
Hospital of Medical School, Xi’an Jiaotong University, Xi’an, China
Introduction: Liver microenvironment is a critical determinant for
development and progression of liver metastasis. Under TGF-β
stimulation, hepatic stellate cells (HSCs), which are liver specific
pericytes, transdifferentiate into myofibroblasts that promote
tumor implantation and growth in the liver. The regulation of
this HSC activation process in the liver however remains poorly
understood. In this study, we tested if actin binding protein
vasodilator-stimulated phosphoprotein (VASP) regulated TGF-β
mediated HSC activation and tumor growth in mice. Methods:
VASP expression in tumor activated HSCs was investigated
by immunofluorescence staining (IF) on liver biopsies of mice
and patients. The role of stellate cell VASP in tumor growth
was studied in a HSC/tumor coimplantation mouse model.
VASP shRNA and siRNA were used to knockdown VASP in
primary human HSCs and LX2 cells. TGF-β activation of HSCs
was quantitated by IF for alpha- smooth muscle actin (α-SMA)
and Western blot analysis (WB). TGF-β receptor II (TβRII) levels
were determined by WB, and plasma membrane TβRII was
quantitated by biotinylation of cell surface protein approach.
Double IF and co-immunoprecipitation were used to study pro-
tein-protein interactions. Results: In both an experimental liver
metastasis mouse model and cancer patients, colorectal cancer
cells reaching liver sinusoids induced upregulation of VASP
and α-SMA in HSCs as revealed by IF on liver biopsies. In a
HSC/tumor coimplantation model, VASP knockdown HSCs sig-
nificantly reduced tumor growth in mice as compared to control
HSCs. In vitro, TGF-β1 stimulation resulted in myofibroblastic
activation in more than 60% of HSCs as determined by α-SMA
IF. Two different VASP shRNAs and a VASP siRNA significantly
reduced this effect of TGF-β1 on HSC activation (P<0.05). The
effect of VASP knockdown on HSC activation was also con-
firmed in LX2 cells. Biotinylation study and IF revealed that
VASP knockdown reduced TβRII protein levels at the plasma
membrane. Furthermore, VASP formed a trimeric protein com-
plex with TβRII and Rab11, a Ras-like small GTPase and key
regulator of recycling endosomes. VASP knockdown impaired
Rab11 activity and Rab11 dependent targeting of TβRII to the
plasma membrane thereby desensitizing HSCs to TGF-β1 stim-
ulation. Conclusions: our study demonstrates a requirement of
VASP for TGF-β mediated HSC activation in the tumor micro-
environment by regulating Rab11 dependent recycling of TβRII
to the plasma membrane. VASP and its effector Rab11 in the
tumor microenvironment thus present therapeutic targets for
reducing tumor implantation and metastatic growth in the liver.
Disclosures:
212A AASLD ABSTRACTS
The following people have nothing to disclose: Kangsheng Tu, Jiachu Li, Vijay
Shah, Ningling Kang
31
Does “genuine” acute autoimmune hepatitis have a bet-
ter prognosis?
Elze M. Oliveira1, Ana Cristina A. Feldner1, Patricia M. Oliveira1,
Valéria P. Lanzoni2, Renata M. Perez3, Antonio Eduardo B. Silva1,
Maria Lucia Ferraz1; 1Gastroenterology, Federal University of Sao
Paulo, Sao Paulo, Brazil; 2Pathology, Federal University of Sao
Paulo, Sao Paulo, Brazil; 3Internal Medicine, Federal University of
Rio de Janeiro, Rio de Janeiro, Brazil
Background: Although most autoimmune hepatitis (AIH)
patients are classified at diagnosis as having chronic hepatitis
or cirrhosis, acute clinical presentation is not rare. However,
this type of acute clinical presentation may represent “genu-
ine” acute AIH or acute-on-chronic AIH. Aims: To evaluate the
prevalence, clinical features and prognostic factors related to
“genuine” acute AIH, comparing these cases with acute-on-
chronic AIH. Methods: Patients with acute AIH presentation,
defined as total bilirubin greater than 5 times the upper limit of
normal (ULN) and/or ALT greater than 10 times the ULN were
included. AIH diagnosis was based on international criteria
by International Autoimmune Hepatitis Group for chronic AIH
patients, and criteria described by Stravitz et al was used for
patients with findings compatible with acute hepatitis. Diagno-
sis of “genuine” acute HAI was based on histological features
in all cases. Results: One-hundred-thirty-one patients were eval-
uated. 95% were female and mean age was 32±17y; 54%
were Caucasian. Eighty patients (61%) presented with clinical
features of acute presentation of AIH. Six (7,5%) presented
histological criteria compatible to acute AIH and 72 (90%)
had a diagnosis of chronic hepatitis. Eight patients were not
submitted to liver biopsy. Comparative analysis revealed a
trend to higher average ALT levels in “genuine” acute AIH
(29±11 vs 20±12 xULN; p=0,06). No difference was found
regarding levels of AST, bilirubin, alkaline phosphatase, GGT
and gamaglobulin levels, as well as ANA and SMA titers.
Prothrombin activity was higher in “genuine” acute patients
(93±10% vs 66±21%;p<0,001), as well as albumin levels (3,9
±0,2 g/dL vs 3,4 ±0,5 g/dL; p<0,001). Biochemical response
to treatment was achieved in all cases of “genuine” acute HAI
(100%) vs 71% of acute-on-chronic patients (p=0,03) Con-
clusion: Acute presentation of AIH was common (61%) in our
series. However, “genuine” acute AIH was not a frequent find-
ing (7,5% of all acute presentation cases). “Genuine” acute
AIH presented with more preserved liver function tests, sug-
gesting that most cases presenting with loss of function are
acute-on-chronic AIH. Lastly, “genuine” acute AIH revealed
a better biochemical response to treatment, suggesting that
a more preserved liver function at presentation has a positive
therapeutic implication.
Disclosures:
The following people have nothing to disclose: Elze M. Oliveira, Ana Cristina
A. Feldner, Patricia M. Oliveira, Valéria P. Lanzoni, Renata M. Perez, Antonio
Eduardo B. Silva, Maria Lucia Ferraz
HEPATOLOGY, October, 2014
32
Patients with Autoimmune Hepatitis and Advanced
Disease have Less Biochemical Response and Worse
Outcomes
James R. Bailey1, Gouri Sreepati1, Eric S. Orman2, Raj Vuppalan-
chi2, Samer Gawrieh2, Marwan Ghabril2, Suthat Liangpunsakul2,
Naga P. Chalasani2, Craig Lammert2; 1Medicine, Indiana Univer-
sity, Indianapolis, IN; 2Gastroenterology and Hepatology, Indiana
University, Indianapolis, IN
Background: Treatment of autoimmune hepatitis (AIH) with con-
ventional immunosuppression is effective in preventing hepatic
failure in most patients. However, up to 40% of patients present
with advanced liver disease and are at risk for poor outcomes.
The rate of biochemical response and its impact on outcomes
among those with advanced disease is unknown. Aim: To
examine the relationship between biochemical response and
outcomes in AIH patients with advanced liver disease. Meth-
ods: 242 patients with AIH were identified from outpatient
visits at our tertiary referral center from 2000 to 2013. Study
inclusion required treatment with immunosuppression and
clinical follow-up of at least 6 months including laboratory
examination. Advanced disease was defined by biopsy (Lud-
wig stage III or IV) or by clinical, endoscopic or radiographic
findings consistent with cirrhosis. Biochemical response was
defined according to clinical practice guidelines (normal serum
AST or ALT, and bilirubin within one year of treatment start
or 50% improvement of all liver tests during the first month
of treatment, with AST or ALT levels less than twice the upper
normal limit within 6 months). Those who did not meet these
criteria were considered non-responders. Continuous variables
were summarized using medians and 25th and 75th percen-
tiles, and P values obtained with the Wilcoxon rank sum test.
Categorical variables were compared using the Chi-squared
test. Results: 186 patients had available data to assess both
disease severity at presentation and biochemical response.
97 (52%) patients had advanced disease and 89 (48%) had
non-advanced disease at presentation. Respectively, these
groups had a similar median age at diagnosis (50 (IQR 33,
61) vs 48 (32,55)) and gender (79% female vs 73%), however
they differed by race (77% Caucasian vs 90%, p=0.02). Bio-
chemical response was more frequent in non-advanced (91%)
versus advanced disease (51%, p=0.001). There was no dif-
ference among responders and non-responders according to
gender (74% female vs 73%), race (81% Caucasian vs 74%),
or any pretreatment liver test level (ALT, AST, TB, or alkaline
phosphatase), respectively. However, biochemical response
was associated with older age at diagnosis (54, (45, 64))
compared to non-responders (39 (22, 54), p=0.001). 96% of
patients with advanced disease and biochemical non-response
had the outcome of death or liver transplant compared to 2%
of responders (p=0.001). Conclusions: Biochemical response
is less frequent among AIH patients with advanced disease
at presentation. Among patients with advanced disease, bio-
chemical non-response is associated with death or transplant.
Disclosures:
Marwan Ghabril - Grant/Research Support: Salix
Naga P. Chalasani - Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-
rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin
The following people have nothing to disclose: James R. Bailey, Gouri Sreepati,
Eric S. Orman, Raj Vuppalanchi, Samer Gawrieh, Suthat Liangpunsakul, Craig
Lammert
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
33
Non-classical autoantibodies in Autoimmune Hepatitis
and Overlapping Syndromes: Do they contribute with
any relevant information?
Elze M. Oliveira1, Patricia M. Oliveira1, Ana Cristina A. Feldner1,
Valéria P. Lanzoni2, Renata M. Perez3, Alessandra Dellavance4,
Luis Eduardo C. Andrade4, Antonio Eduardo B. Silva1, Maria
Lucia Ferraz1; 1Gastroenterology, Federal University of Sao Paulo,
Sao Paulo, Brazil; 2Pathology, Federal University of Sao Paulo,
Sao Paulo, Brazil; 3Internal Medicine, Federal University of Rio de
Janeiro, Rio de Janeiro, Brazil; 4Research and Development, Fleury
Group, Sao Paulo, Brazil
Background: Antibodies against nuclear antigens (ANA),
smooth muscle (SMA) and liver kidney microssomes (LKM-1)
are classically used for diagnosis and classification of auto-
immune hepatitis (AIH); however, they are not good as prog-
nostic markers during follow-up. Anti-soluble liver antigen
(anti-SLA), anti-Ro-52, anti-liver citosol (anti-LC1), anti-Sp100
and anti-gp210 are considered non-classical antibodies (NCA)
and are currently under investigation as additional markers in
autoimmune liver disorders. Objectives: Our aim was to eval-
uate the prevalence and role of NCA in AIH and overlapping
syndromes (OS) and its correlation with clinical presentation
and response to treatment. Methods: One-hundred and thirty
AIH and OS patients were studied, from 1989 to 2013. AIH
diagnosis was based on international criteria by International
Autoimmune Hepatitis Group for chronic AIH patients, and
criteria described by Stravitz et al, for patients with findings
compatible with acute hepatitis. Diagnosis of OS was based in
EASL guidelines for cholestatic diseases. Results: Female gen-
der was more prevalent (91%); mean age was 33±18 years.
Type I AIH was diagnosed in 88% and OS in 12% of patients.
ANA was the most frequent classical serological marker (73%),
followed by SMA (55%). Regarding NCA, Ro52 was the most
prevalent (37%), followed by SLA (19%). Comparative analy-
sis of patients with positivity or negativity to Ro-52, SLA and
LC-1 was as follows: Ro-52 was related to lower frequency of
biochemical response (58% x 77% p 0.04), lower degree of
fibrosis (37% x 56% p 0,05) and a trend to a higher frequency
of associated autoimmune diseases (39% x 23% p 0,06 ). Anti-
SLA was related to lower frequency of biochemical response
(48% x 74% p 0,014 ). Anti-LC1 patients presented more fre-
quently with liver failure at presentation (67% x 29% p 0,07)
and a trend to higher gammaglobulin levels (3,9 ±1,4 x 2,8
±1,2 p 0,06). Comparative analysis of patients with positivity
or negativity to anti-Sp100 and anti-gp210 revealed that both
were related to older age (45±18 x 32±17 p 0,04 to Sp100
and 42±18 x 32±17 p 0,04 to gp210) and to the diagnosis
of OS (56% x 10% p 0,002 to anti-Sp100 and 40% x 9% p
0,005 to anti-gp210). Conclusion: NCAs are promising mark-
ers for the evaluation of AIH and OS patients. Besides having
a diagnostic role in some cases, they can help in planning strat-
egies for monitoring treatment, contributing for the early iden-
tification of more difficult cases and optimization of treatment.
Disclosures:
The following people have nothing to disclose: Elze M. Oliveira, Patricia M.
Oliveira, Ana Cristina A. Feldner, Valéria P. Lanzoni, Renata M. Perez, Ales-
sandra Dellavance, Luis Eduardo C. Andrade, Antonio Eduardo B. Silva, Maria
Lucia Ferraz
213A
34
Depletion of B cells induce remission of autoimmune
hepatitis in mice through reduced antigen presentation
and help to T cells
Kathie Béland1, Gabriel Marceau1, Agathe Labardy1, Sara
Bourbonnais1, Fernando Alvarez1,2; 1Gastroenterology, hepatol-
ogy and nutrition, CHU Sainte-Justine, Montréal, QC, Canada;
2Department of Pediatrics, University of Montreal, Montreal, QC,
Canada
INTRODUCTION: Autoimmune hepatitis (AIH) is a disease
of unknown aetiology, characterized by a loss of tolerance
toward liver antigens resulting in the progressive destruction
of the hepatic parenchyma. It is known as a disease mediated
by T-cells, with an important contribution from CD4+ Th1 cells.
However, recent studies from small cohorts of AIH patients
refractory to conventional treatment have reported successful
rescue therapy through B cells depletion with Rituximab, an
anti-CD20 monoclonal antibody. AIM: To study the outcome
of B-cell depletion in an animal model of AIH and understand
the mechanisms underlying the remission.METHODS: A model
of AIH in female C57BL/6 mice xenoimmunized with DNA
coding for human liver antigens was used. AIH mice were
treated with 1 injection of an anti-CD20 monoclonal antibody
(Genentech) at the peak of liver inflammation. Serum amino-
transferase levels, IP10 expression, circulating B cell levels,
autoantibody levels, and total IgG levels were monitored. Liver
inflammation and spleen architecture were evaluated. Spleen
and liver cell phenotypes were characterized by flow cytome-
try. B cell function as APCs was analyzed in a lymphoprolifer-
ative assay against liver antigens.RESULTS: In the AIH mouse
model, B cells were found in liver infiltrates, secreted IFN-γ
and TNF-α and proliferated to autoantigen. A single dose of
anti-CD20 resulted in more than 95% decrease in circulating B
cells (CD45+CD19+) followed by a progressive reconstitution
40 days after injection. A drastic reduction of liver inflamma-
tion was observed (p<0.0001), accompanied by a significant
reduction of ALT levels (p=0.0135) in treated mice compared
to controls. Remission was associated with a significant reduc-
tion of IP10 expression in the liver (p=0.0036). In contrast,
neither total IgG levels nor autoantibodies (anti-mFTCD) were
affected by the treatment. Tregs, Tr1 cells and B10 regulatory
cells, along with cytokine secretion from T cells, were not sig-
nificantly modified by treatment. T cells activation profile was
significantly changed as more naïve (CD62L+CD44-) and less
antigen-experienced (CD44+) CD4+ and CD8+ T cells were
found in the spleen and liver (p<0.05). T cell proliferation was
also significantly reduced following treatment (p<0.0001). In
a functional assay, B cells were shown to behave as a profes-
sional auto-antigen presenting cells to CD4+ T cells. CONCLU-
SIONS: B cells seem to play an active role in the pathogenesis
of AIH, mainly as antigen-presenting cells and T cell modulators
through cytokine secretion. Changes induced in T cell compart-
ment could explain the success of anti-CD20 depletion in AIH
remission in mice and patients.
Disclosures:
The following people have nothing to disclose: Kathie Béland, Gabriel Marceau,
Agathe Labardy, Sara Bourbonnais, Fernando Alvarez
214A AASLD ABSTRACTS
35
A Preliminary Study Utilizing Social Media and Crowd-
sourcing Shows an Inverse Relationship Between Breast
Feeding as an Infant and the Presence of Autoimmune
Hepatitis
Megan Comerford, Smitha Marri, Naga P. Chalasani, Craig Lam-
mert; Gastroenterology and Hepatology, Indiana University, Indi-
anapolis, IN
Background: Autoimmune hepatitis (AIH) is a chronic liver dis-
ease predominately found in women that can result in cirrhosis,
transplant, or death. Environmental exposures, in the setting
of genetic predisposition, have demonstrated a role in other
autoimmune liver disease pathogenesis. However, detailed
exposure assessments in AIH have yet to be performed. Aim:
To examine the relationship between environmental exposures
and AIH utilizing widely available social media and crowd-
sourcing platforms. Methods: We targeted seven AIH social
media groups (cases) with two independent survey tools. The
first, modeled after the National Health and Nutrition Food
Questionnaire, included 22 questions depicting demograph-
ics and dietary exposures. The second survey, 14 questions
in length, detailed demographics and lifetime tobacco use.
Healthy controls were recruited from Amazon’s Mechanical
Turk, a crowdsourcing website for the completion of requester
directed tasks. Continuous variables were summarized using
medians and P values obtained with the Wilcoxon rank sum
test. Categorical variables were compared using the Chi-
squared test. Results: 430 (152 cases, 278 controls) dietary
and 390 (164 cases, 226 controls) tobacco survey responses
were collected during each study period of 1 month. In both
cohorts, cases were more likely to be female, Caucasian, and
older compared to controls (p=0.01). Among subjects con-
suming at least one cup of coffee each month (119 cases and
230 controls), there were no differences between cases and
controls with regards to age at drinking coffee start (18 vs.
17, p=0.1) or average cups per month (61 vs. 61, p=0.3).
Among 226 survey respondents with stable long-term dietary
patterns (60 cases and 166 controls), there were no differences
in diets high in fruits and vegetables, sodium, or meats and fat
between cases and controls. A significantly lower number of
cases (49%) reported breast feeding as infants when compared
to controls (65%, p=0.002). Cases and controls were no differ-
ent according to history of regular tobacco product use (46%
vs 51%, p=0.3), history of smoking more than 100 cigarettes
ever (51% vs 53%, p=0.8), and smoking before age of 18
(38% vs 37%, p=0.8). However, controls were more likely to
be current smokers (13% vs 30%, p=0.01). Conclusions: This
study shows the feasibility of utilizing social media and crowd-
sourcing tools to conduct research in aspects of selected liver
diseases such as autoimmune hepatitis. This preliminary study
shows an inverse relationship between breast feeding as an
infant and the presence of AIH.
Disclosures:
Naga P. Chalasani - Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-
rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin
The following people have nothing to disclose: Megan Comerford, Smitha Marri,
Craig Lammert
HEPATOLOGY, October, 2014
36
Predictors of Autoimmune Hepatitis in Patients with
Chronic Hepatitis C
Yun Ju Kim1, Anthony Loria1, Xiongce Zhao2, David E. Kleiner3,
Marc G. Ghany1; 1Liver Diseases Branch, National Institute of
Diabetes and Digestive and Kidney Diseases, National Institutes of
Health, Bethesda, MD; 2Biostatistics, Intramural Research, National
Institute of Diabetes and Digestive and Kidney Diseases, National
Institutes of Health, Bethesda, MD; 3Laboratory of Pathology,
National Cancer Institute, National Institutes of Health, Bethesda,
MD
Background: Positivity for anti-nuclear antibody (ANA), in the
setting of elevated ALT levels often raises suspicion for the diag-
nosis of autoimmune hepatitis (AIH). The diagnosis of co-exis-
tent AIH in patients with chronic HCV infection is challenging
as ANA positivity has been reported to be associated with
chronic HCV infection. Aims: To determine the prevalence of
ANA positivity in patients with HCV and identify factors that
should raise clinical suspicion for HCV/AIH. Methods: A data-
base of adult, mono-infected chronic HCV patients with a mini-
mum of one ANA test performed was queried. HCV/AIH cases
were identified by histological features strongly suggestive of
AIH in the opinion of the pathologist. Patients were categorized
as HCV alone (never ANA+), HCV+ANA+ and HCV/AIH.
Baseline clinical characteristics were compared among these
3 groups using ANOVA. Significant variables were included
in multivariate analysis to predict the presence of HCV/AIH
in the total cohort. To identify histological features that could
differentiate HCV/AIH from chronic HCV infection, biopsies
from treatment-naïve patients with HCV/AIH were compared to
biopsies from HCV patients matched for ANA, ALT and sex for
the presence of plasma cells in portal and lobular areas, rosette
formation, emperipolesis, bridging necrosis and perivenular
necrosis. Results: 787 patients met inclusion criteria. Mean age
at baseline was 44 years, 59% were male, 69% were Cauca-
sian, 19% African American and 12% other. Among patients
with chronic HCV infection, 38% (n=302) were ANA+. Among
the 787, 62% (n=483) were categorized as HCV alone, 36%
(n=289) were HCV+ANA+ and 2% (n=15) had HCV/AIH.
Patients with HCV/AIH were predominantly female (73%),
ANA+ (87%), ASMA+ [33% (3/9)], anti-LKM+ [50% (4/8)]
and 13% (n=2) were related to interferon use. Patients with
HCV/AIH had higher serum ALT, IgG levels, globulin fraction
and greater periportal HAI scores on biopsy (p<.05). In mul-
tivariate analysis, independent predictors of HCV/AIH were
ANA positivity, female sex, higher HCV RNA, ALT and globulin
fraction. 11 liver biopsies from HCV/AIH cases were com-
pared to matched controls. There was no difference in the
presence of plasma cells in portal and lobular areas, rosette
formation, emperipolesis, bridging necrosis and perivenular
necrosis. However, HCV/AIH cases had higher periportal HAI
inflammatory scores (p=.008) despite similar ALT levels. Con-
clusion: ANA positivity is common in patients with HCV (38%).
Among patients with chronic HCV infection, ANA positivity,
female sex, higher baseline HCV RNA, ALT, globulin fraction
and greater periportal inflammation are suggestive of co-exis-
tent HCV/AIH.
Disclosures:
The following people have nothing to disclose: Yun Ju Kim, Anthony Loria,
Xiongce Zhao, David E. Kleiner, Marc G. Ghany
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
37
Liver carcinogenesis related to the metabolic syndrome:
Metformin as a new therapeutic tool
François Cauchy1,2, Mouniya Mebarki1, Pierre Bourgoin1, Cindy
Neuzillet1,4, Samira Laouirem1, Miguel Albuquerque1,3, Nicolas
Poté1,3, Jacques Belghiti2, Eric Raymond1,4, Pierre Bedossa1,3, Val-
erie Paradis1,3; 1Inflammation Research Centre, National institute
for health and medical research, Clichy, France; 2Department of
HPB surgery and liver transplantation, Beaujon Hospital, Clichy,
France; 3Department of Pathology, Beaujon Hospital, Clichy,
France; 4Department of Oncology, Beaujon Hospital, Clichy,
France
Introduction: The metabolic syndrome (MS) is becoming a
strong risk factor for the development of hepatocellular car-
cinoma (HCC). In this setting, liver tumorigenesis might be
complex, involving underlying non-alcoholic fatty liver dam-
ages and potential direct pro-tumoral actions of insulin-resis-
tance and obesity. Several studies have recently suggested
that metformin, apart from its antidiabetic action, also had
inner antineoplastic effects. The current study aimed to evalu-
ate the efficacy of metformin in liver carcinogenesis related to
MS and assess the molecular mechanisms involved. Methods:
The efficacy of metformin was assessed in vivo on orthotopic
and heterotopic HCC xenografted nude mice with insulin-re-
sistance (60% high-fat diet (HFD)), or steatosis (fructose 30%
diet) compared to standard chow (SC) mice. The molecular
mechanisms of the antitumoral action of metformin were ana-
lyzed on surgically resected HCCs samples from diabetic MS
patients preoperatively treated or not treated with metformin
and also on xenografted HCCs. Potential histological changes
induced by metformin were assessed by immunohistochemistry
(IHC) on xenografted HCCs and on surgical samples of HCCs
from diabetic MS patients. Finally, the direct antitumoral effects
of metformin were analyzed ex vivo in a model of human
and xenografted cultured HCC slices. Results: Hepatic tumor
engraftment rates were increased in HFD mice compared to
fructose 30% (79% vs 42%, p=0.05) and SC (79% vs 25%,
p<0.05) mice. Similarly, overall subcutaneous tumor growth
was significantly increased in HFD mice (+56% vs. fructose
30% and also vs. SC mice, p<0.05). In all three models, met-
formin (250 mg/kg/day) significantly (p<0.01) decreased
subcutaneous tumor growth, through a cell cycle blockage in
G0/G1 phase and an inhibition of the m-TOR pathway as
demonstrated by a reduction (p<0.05) in cyclin-D1 and both
p-mTOR and p-670S expressions. Both molecular mechanisms
were confirmed on human HCCs developed in diabetic MS
patients preoperatively treated with metformin. Although not
significant, IHC analysis of surgically resected HCCs from dia-
betic MS patients and of xenografted HCC revealed increased
CA-9 and decreased CD-34 stainings supporting hypoxic and
antiangiogenic effects of metformin. Finally, analysis of human
and xenografted cultured HCC slices showed that metformin
was associated with increased rates of tumor necrosis. Conclu-
sion: Metformin provides significant anti-HCC effects through
inactivation of the m-TOR pathway in a context of insulin-re-
sistance leading to antiangiogenic effects and could therefore
represent a valuable therapy in the management of patients
with HCC related to MS.
Disclosures:
Eric Raymond - Advisory Committees or Review Panels: BAYER; Consulting:
PFIZER, NOVARTIS
The following people have nothing to disclose: François Cauchy, Mouniya
Mebarki, Pierre Bourgoin, Cindy Neuzillet, Samira Laouirem, Miguel Albuquer-
que, Nicolas Poté, Jacques Belghiti, Pierre Bedossa, Valerie Paradis
215A
38
Preclinical evidence of a novel anti-tumor effect of met-
formin in cholangiocarcinoma (CCA)
Albert Ndzengue1, Hassan M. Shaleh1, Xiwei Ding1, Kais Zakh-
aria1, Catherine D. Moser1, Scott H. Kaufmann2,3, Martin E. Fer-
nandez-Zapico1,3, Mitesh J. Borad4, Roongruedee Chaiteerakij1,5,
Lewis R. Roberts1; 1Division of Gastroenterology and Hepatology,
College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center,
Rochester, MN; 2Division of Molecular Pharmacology and Experi-
mental Therapeutics, Mayo Clinic, Rochester, MN; 3Department of
Oncology, Mayo Clinic, Rochester, MN; 4Division of Hematology,
Division of Oncology, Mayo Clinic, Phoenix, AZ; 5Department
of Medicine, Faculty of Medicine, Chulalongkorn University and
King Chulalongkorn Memorial Hospital, Thai Red Cross Society,
Bangkok, Thailand
Background: There is an urgent need to develop effective ther-
apies for CCA due to the poor outcomes with the current stan-
dard gemcitabine (Gem) and cisplatin (Cis) therapy. Metformin
is associated with 60% risk reduction of intrahepatic CCA in
diabetic patients. We therefore investigated the anti-neoplastic
effect of metformin on CCA cells and the hepatic stellate cells
(HSC) responsible for the desmoplastic reaction in the tumor
microenvironment. Aims: To determine 1) whether metformin
has an anti-proliferative effect on CCA and hepatic stellate
cells; 2) if the anti-proliferative action of metformin occurs
through effects on AMP kinase (AMPK) and mTOR signaling;
and 3) whether the effect of metformin enhances that of Gem
and/or Cis in vitro and in vivo. Methods: CCK8 and colony
formation assays were used to assess cell viability in cultures of
HuCCT1, EGI-1, WITT and LX-2 (HSC) cell lines and the new
primary patient derived CCA cell line LIV27 after treatment
with metformin alone or in combination with Gem or Cis. The
half maximal inhibitory concentrations (IC50) were calculated.
Western immunoblotting was used to assess the effect of met-
formin on phospho-AMPK/total AMPK and phospho-mTOR/
total mTOR ratios in CCA cells. Tumor growth in mice bearing
the patient derived CCA xenograft (PDX) LIV27 and treated
continuously either with vehicle, metformin alone, combina-
tion Gem and Cis, or metformin plus Gem and Cis were com-
pared. Results: Metformin significantly decreased cell viability
of HuCCT1, EGI-1, WITT, LX-2 and LIV27 in a dose dependent
manner, with IC50 of 12.0, 5.9, 28.6, 21.5 and 20.3 mM
respectively. Metformin increased phospho-AMPK/total AMPK
and decreased phospho-mTOR/total mTOR ratios in CCA cell
lines, suggesting that it acts through the mTOR pathway. Addi-
tion of metformin to Cis but not Gem further decreased viability
of the HuCCT1 cell line. Metformin significantly inhibited the
growth of mouse PDX when compared to vehicle (p=0.009).
The combination of metformin, Gem and Cis was more potent
than metformin alone (p<0.0001) but was not superior to the
standard therapy with Gem and Cis (p=0.6). Conclusion: Met-
formin has an anti-proliferative effect on CCA models which
correlates with effects on AMPK and mTOR cell signaling. Met-
formin enhanced the anti-proliferative effect of Cis but not Gem
in vitro. A significant anti-tumoral effect of metformin on LIV27
PDX was demonstrated, but metformin did not augment the
effect of standard therapy with Gem and Cis. Additional stud-
ies are needed to validate and extend these findings, poten-
tially by identifying other agents that demonstrate synergy with
metformin in CCA.
Disclosures:
Lewis R. Roberts - Grant/Research Support: Bristol Myers Squibb, ARIAD Pharma-
ceuticals, BTG, Wako Diagnostics, Inova Diagnostics, Gilead Sciences
The following people have nothing to disclose: Albert Ndzengue, Hassan M.
Shaleh, Xiwei Ding, Kais Zakharia, Catherine D. Moser, Scott H. Kaufmann,
Martin E. Fernandez-Zapico, Mitesh J. Borad, Roongruedee Chaiteerakij
216A AASLD ABSTRACTS
39
Molecular heterogeneity of multinodular Hepatocellular
Carcinoma
Daniela Sia1,2, Andrew Harrington1, Sara Toffanin1, Zhongyang
Zhang1,4, Xintong Chen1, M. Isabel Fiel1, Monica Higuera3,
Oriana Miltiadous1, Laia Cabellos1, Helena Cornella3, Sasan
Roayaie5, Yujin Hoshida1, Sander S. Florman1, Myron Schwartz1,
Josep M. Llovet1,6; 1Mount Sinai Liver Cancer Program, Icahn
School of Medicine at Mount Sinai, New York, NY; 2Gastroin-
testinal Surgery and Liver Transplantation Unit, National Cancer
Institute, Milan, Italy; 3HCC Translational Research Laboratory,
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),
Barcelona, Spain; 4Icahn Institute for Multiscale Biology, Icahn
School of Medicine at Mount Sinai, New York, NY; 5Liver Cancer
Program, Hofstra-North Shore LIJ School of Medicine, Lenox Hill
Hospital, NEW YORK, NY; 6Institució Catalana de Recerca i Estu-
dis Avançats, Barcelona, Spain
Introduction: Hepatocellular Carcinoma (HCC) is the second
cause of cancer-related death worldwide. Whether multinod-
ular tumors result from intrahepatic metastasis (IM or clonal
tumors) or de novo cancers (synchronic tumors) has direct
implications in treatment decision-making. We aimed to assess
the genomic heterogeneity of multifocal HCC using single-nu-
cleotide polymorphism (SNP) and gene expression analyses.
Methods: For this study, among 544 HCCs consecutively trans-
planted at Mount Sinai Hospital between 1990 and 2007,
we selected 18 patients (2-3 non-satellite foci HCCs). Forma-
lin-fixed tissue blocks were collected for each tumor along with
corresponding clinico-pathological data. SNP array and gene
expression profiling was generated. Clonality was defined by
measuring SNP profiles similarity between two nodules and its
association with clinico-pathological parameters was assessed.
Gene expression-based unsupervised hierarchical clustering
was performed to measure genetic proximity. Results: A total
of 42 tumors have been analyzed (10 patients-2 tumors; 8- 3
tumors). Most patients were male (17/18, 95%) with HCV
(10/18, 56%) or HBV infection (6/18, 33%). Median tumor
size was 3 cm (range 1.5-6.5), satellites were present in 3
(17%) and vascular invasion in 11 patients (61%), respectively.
Copy number variation (CNV) profiles predicted clonal tumors
in 38% (6/16) and non-clonality in 62% of cases (10/16).
CNV profiles of the remaining 2 cases were not informative.
Clonal tumors were significantly associated with HCV infection
(5/6 vs 3/10, p=0.007), whereas all HBV-induced HCC were
synchronic tumors (0/6 v s 6/10, p=0.03). Clonal tumors were
significantly associated with satellites and shorter time-to-recur-
rence. Unsupervised clustering revealed that each clonal tumor
showed genetic proximity to its paired tumor and clustered
around the same node (6/6, 100%) as opposed to non-clonal
(2/9, 22%). When exploring molecular subclasses, while half
of clonal tumors retained the molecular fingerprint, the other
half switched to more aggressive subclasses. Conversely, all
non-clonal tumors within the same patient belonged to distinct
molecular subclasses. Conclusions: Multinodular HCCs under-
going transplantation are molecularly heterogeneous. Using
CNV profiling we identified clonal multinodular tumors (true
IM) in 40% of cases and de novo tumors in 60%. Clonal tumors
were significantly associated with HCV infection, satellites and
recurrence. Genetic proximity was observed in clonal tumors,
but molecular subclasses prediction revealed that IM share
more aggressive subclasses in half of the cases.
Disclosures:
Myron Schwartz - Consulting: Gilead, Inova
Josep M. Llovet - Advisory Committees or Review Panels: Nanostring, Blueprint
medicines; Consulting: Bayer Pharmaceutical, Bristol Myers Squibb, Imclone,
Biocompatibles, Novartis, GSK; Grant/Research Support: Bayer Pharmaceutical,
Bristol Myers Squibb, Boehringer-Ingelheim
HEPATOLOGY, October, 2014
The following people have nothing to disclose: Daniela Sia, Andrew Har-
rington, Sara Toffanin, Zhongyang Zhang, Xintong Chen, M. Isabel Fiel, Monica
Higuera, Oriana Miltiadous, Laia Cabellos, Helena Cornella, Sasan Roayaie,
Yujin Hoshida, Sander S. Florman
40
NGM282, a Potent Inhibitor of CYP7A1, Prevents
FGF19-Mediated HCC Tumor Development in db/db
and rasH2 Mice
Lei Ling, Van Phung, Xueyan Wang, Mei Zhou, Darrin Lindhout,
Marc Learned, Stephen Rossi, Alex M. DePaoli, Hui Tian; NGM
Biopharmaceuticals, Inc., South San Francisco, CA
Background and Aims: Human fibroblast growth factor 19
(FGF19) is an ileal hormone that directly regulates the classic
pathway of bile acid synthesis by altering CYP7A1 gene expres-
sion and enzyme activity. However, FGF19 causes hepatocel-
lular carcinoma (HCC) in mice and is variably associated with
an increased risk of post-resection HCC recurrence in humans.
NGM282 is a novel recombinant variant of FGF19 with potent
inhibition of CYP7A1 and has been engineered to eliminate
the abnormal proliferative activity observed with FGF19. We
evaluated the tumerogenic and potential HCC inhibitory effects
of NGM282 in mouse models. Methods: Sustained concentra-
tions of NGM282, FGF19 and control were achieved by ade-
no-associated virus (AAV)-mediated gene delivery. HCC tumor
development was assessed in db/db and rasH2 transgenic
mice exposed to NGM282, FGF19 or control. Additionally,
FGF19 was administered with and without NGM282 to db/db
mice to assess the inhibitory effects of NGM282 on FGF19-me-
diated tumor development. Liver tumor formation was assessed
at 24 weeks (db/db mice) or 52 weeks (rasH2 mice) following
AAV delivery. Gene expression of HCC-related biomarkers
was examined at 2 and 24 weeks post-AAV delivery in db/db
mice. Results: No hepatic tumor formation was observed with
high systemic exposure to NGM282 in either model whereas
significant tumor development was seen with FGF19 treatment
(Figure 1A and 1B). Additionally, the co-administration of
NGM282 with FGF19 blocks FGF19-mediated tumor develop-
ment possibly acting as a biased ligand blocking tumerogenic
signaling (Figure 1C). NGM282 significantly reduced hepatic
gene expression of alpha-fetoprotein, glypican-3, stearoyl-Co-
enzyme A desaturase-2 and aldo-keto reductase-1 C18 at both
2 weeks and 6 months compared to FGF19 in the db/db mice.
Conclusion: NGM282 does not promote HCC and appears to
block HCC tumor development seen with FGF19 in mice. Gene
expression of biomarkers associated with HCC development
are also suppressed. Further work is ongoing to identify the
specific mechanisms for this alteration in proliferative activity.
Clinical studies are currently underway in patients with chronic
cholestatic liver disease.
Figure 1 Hepatic Tumor Formation: NGM282 vs. FGF19
Disclosures:
Lei Ling - Employment: NGM Biopharmaceuticals, Inc.; Stock Shareholder: NGM
Biopharmaceuticals, Inc.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Van Phung - Employment: NGM Biopharmaceuticals; Stock Shareholder: NGM
Biopharmaceuticals
Xueyan Wang - Employment: NGM Biopharmaceuticals; Stock Shareholder:
NGM Pharmaceuticals
Darrin Lindhout - Patent Held/Filed: NGM Biopharmaceuticals; Stock Share-
holder: NGM Biopharmaceuticals
Marc Learned - Employment: NGM Biopharmaceuticals, Inc.; Stock Shareholder:
NGM Biopharmaceuticals, Inc.
Stephen Rossi - Employment: NGM Biopharmaceuticals, Inc; Stock Shareholder:
NGM Biopharmaceuticals, Gilead Sciences
Alex M. DePaoli - Employment: NGM Biopharmaceuticals
Hui Tian - Employment: NGM Biopharma
The following people have nothing to disclose: Mei Zhou
41
Nardilysin deficiency attenuates promotion of hepato-
cellular carcinoma through suppressing the interleukin 6
signaling pathway
Kan Toriguchi1, Eiichiro Nishi 2, Etsuro Hatano1, Kazutaka
Tanabe1, Kenji Takemoto1, Satoru Seo1, Kojiro Taura1, Shinji
Uemoto1; 1Surgery, Kyoto university, Kyoto, Japan; 2Cardiovascu-
lar Medicine, Kyoto university, Kyoto, Japan
Background & Aims: Low-grade chronic inflammation is
involved in the pathogenesis of hepatocellular carcinoma
(HCC), in which tumor necrosis factor (TNF) and interleukin 6
(IL6) are positively correlated with the progression of chronic
hepatitis to HCC. Nardilysin (NRDc), a metalloendopeptitase
of the M16 family, promotes ectodomain shedding of the mem-
brane precursor form of cytokines, such as TNF-alpha, by acti-
vating ADAM proteases. The aim of this study is to clarify the
role of NRDc in the progression of HCC. Methods: Serum con-
centration of NRDc was measured in HCC patients by Enzyme-
linked immunosorbent assay (ELISA). Protein expression level
of NRDc was also evaluated in surgically resected liver speci-
men from HCC patients by immunohistochemical staining. To
explore the role of NRDc in liver carcinogenesis, wild type
and the NRDc heterozygous knockout (NRDc+/-) mice at the
age of 14 days were injected with 25mg/kg of diethylnitro-
samin (DEN) intraperitoneally. Thirty six weeks later, the tumo-
riogenesis in the liver was evaluated. To assess the effect of
NRDc on tumor cell proliferation, cell growth was evaluated
in HCC cell lines, Huh7, HepG2 and Hep3B, in which NRDc
was knocked down by miRNA. Furthermore, tumor xenograft
of control cells or NRDc-knocked down cells was done in nude
mice, and tumor volume was measured up to 4 weeks after
the inoculation. Results: The serum concentration of NRDc was
significantly higher in HCC patients than that of healthy volun-
teers. Immunostaing of NRDc demonstrated that the expression
is significantly higher in parenchyma of cancer tissue than in
non-cancerous lesion. DEN-initiated carcinogenesis, evaluated
by the number and maximum diameters of tumors, was signifi-
cantly attenuated in NRDc+/- mice compared with wild type lit-
termates. The number of Ki67-positive proliferating tumor cells
was significantly lower in the tumor of NRDc+/- mice. Knock-
down of NRDc in HCC cell lines significantly attenuates the cell
growth in culture. In the tumor xenograft model, NRDc-knocked
down Huh7 cells showed markedly decreased tumorigenesis.
The mRNA expression of IL6 and the phosphorylation of Stat3
were significantly suppressed in NRDc-knocked down cells. Fur-
thermore, protein expression of SOCS3, a potent inhibitor of
IL6 signaling, was elevated in NRDc-knocked down cells, indi-
cating that NRDc regulates HCC cell growth through modulat-
ing IL6 signaling. Conclusions: The present study indicates that
the regulation of intrinsic IL-6-Stat3-SOCS3 signaling pathway
by NRDc is a key mechanism for the maintenance of HCC cell
217A
growth. These results suggested that NRDc might be a novel
therapeutic target of HCC.
Disclosures:
The following people have nothing to disclose: Kan Toriguchi, Eiichiro Nishi,
Etsuro Hatano, Kazutaka Tanabe, Kenji Takemoto, Satoru Seo, Kojiro Taura,
Shinji Uemoto
42
Predicting HCC Biological Behavior With In Vivo Cir-
rhotic Mouse Model For Personalized Treatment
Daniel Huang1, Lei Zhou2, Alfred W. Kow1, Krishnakumar Mad-
havan1, Shridhar G. Iyer1, Stephen Chang1, Yock Young Dan1;
1National University Health System, Singapore, Singapore;
2National University of Singapore, Singapore, Singapore
Introduction Hepatocellular carcinoma remains one of the most
lethal cancers. Although surgery and liver transplant are poten-
tially curative, the high recurrence rate results in treatment futil-
ity. Recent data has shown that biological behavior of HCC
subtypes can be identified based on distinct phenotypes, onco-
genic pathways and the interaction with the cirrhotic micro-
environment. We aim to create a mouse cirrhotic model of
xenotransplant that allows in vivo real life characterization of
these HCC subtypes to guide prognosis and targeted treat-
ment. Methodology To simulate a cirrhotic microenvironment,
we treated NOD Scid gamma (NSG) mice with thioamide for
4 months to induce full-fledged cirrhosis. 500000 cells from
3 separate cell lines representing spectrum of HCC subtype;
Hep G2 (well differentiated), Huh-7 (moderately differentiated)
and Sk-Hep 1 (metastatic HCC) were transplanted intraspleni-
cally before harvesting at 2 weeks. To validate in principle of
proof for clinical relevance, 6 primary human HCC were char-
acterized based on based on degree of differentiation, AFP,
Alb, EPCAM/CD44 and transplanted into NSG cirrhotic mice.
Results Large nodules of cell line derived HCC were identified
in all 9 (n=3 per group) transplanted animals. Huh-7 derived
HCC formed large but distinct proliferative nodules > 100 cell
colonies. Hep G2 HCC was smaller and cells appeared more
polygonal and differentiated. In contrast, Sk-Hep 1 HCC did
not form carcinomatous nodules but showed poorly differenti-
ated cells with diffuse infiltrative morphology. Lung metastases
were noted in the animals transplanted with Sk-Hep1 cells.
Of the 6 HCC samples transplanted, 1 sample with poorly
differentiated morphology microvascular involvement showed
massive engraftment in the liver as well as lung metastasis.
HCC nodules showed proliferation and were confirmed to
be of human origin by human MHC1 immunolabeling. This
HCC had null staining for AFP, albumin, EPCAM and CD44.
None of the other HCCs that were more differentiated, had
positive staining for either albumin, AFP or EPCAM/CD44,
resulted in engraftment. Conclusion The cell line and clinical
HCC transplant in cirrhotic model showed principle of proof of
in vivo simulation of biological behavior of HCC. The poorly
differentiated null-staining subclass had the most aggressive
biology and was independent of classical clinical indices such
as AFP levels or radiological size. Current efforts are aimed at
characterizing this subtype and identifying efficacious drugs in
invivo environment. The ability to predict the natural biology of
HCC in a clinically relevant cirrhotic model holds tremendous
implications for treatment of HCC.
Disclosures:
Yock Young Dan - Consulting: MSD
The following people have nothing to disclose: Daniel Huang, Lei Zhou, Alfred
W. Kow, Krishnakumar Madhavan, Shridhar G. Iyer, Stephen Chang
218A AASLD ABSTRACTS
43
L159F and V321A Sofosbuvir Treatment-Emergent HCV
NS5B Substitutions
Evguenia S. Svarovskaia1, Hadas Dvory-Sobol1, Brian Doehle1,
Edward J. Gane2, Ira M. Jacobson3, David R. Nelson4, Eric Law-
itz5, Diana M. Brainard1, John G. McHutchison1, Michael D.
Miller1, Hongmei Mo1; 1Gilead Sciences Inc, Foster City, CA;
2University of Auckland, Auckland City Hospital, Auckland, New
Zealand; 3Weill Cornell Medical College, New York, NY; 4Univer-
sity of Florida, Gainesville, FL; 5Texas Liver Institute, San Antonio,
TX
Introduction: Sofosbuvir (SOF) exhibits a high barrier to resis-
tance with no S282T or phenotypic resistance detected in the
Phase 3 studies. In these studies, L159F and V321A were
identified as SOF treatment-emergent NS5B substitutions using
a 10-15% standard population sequencing detection assay
cut-off. In vitro, these variants had <2 fold shift in SOF EC50
and were associated with reduced fitness compared to wild-
type. Here a more sensitive analysis was performed to evaluate
emergence of substitutions at NS5B positions L159, S282, and
V321 in 7 SOF studies and 5 SOF + ledipasvir (LDV) studies.
Methods: The NS5B gene from patients who did not achieve
SVR12 was deep sequenced with an assay cut-off at 1%. Emer-
gence of substitutions was evaluated at NS5B positions 159,
282, and 321 in patients from 7 SOF studies (NEUTRINO, FIS-
SION, POSITRON, FUSION, VALENCE, PHOTON-1 and the
liver pre-transplantation study P7977-2025) and 5 SOF+LDV
studies (LONESTAR, ELECTRON, ION1, ION2, and ION3).
Results: In the 7 SOF studies, 344 patients were included in
resistance analysis. L159F and V321A developed in 42/344
(12.2%) and 16/344 (4.7%) patients, respectively. L159F and
V321A were present as minor populations of viral quasispecies
(<10%) in 30/42 and 10/16 of those patients and would not
have been detected by standard population sequencing. L159F
and V321A declined in frequency in 13/19 and 9/10 patients
between 4-20 weeks post initial detection, respectively. No
S282T, but low levels of S282R, S282N, or S282G were
detected in 4/344 (1.2%) patients; these minor variants were
unable to be phenotyped in vitro. In 51 patients with virologic
failure in SOF+LDV studies, low levels of L159F and V321A
had developed in one patient each. S282T was detected in
1/51 patients at relapse. Conclusions: L159F and V321A
NS5B substitutions emerge in a subset of patients treated with
SOF upon virologic failure. These HCV variants were observed
mostly as minority viral variants and decreased in frequency
during post-treatment follow-up indicating lower replication
fitness in vivo as has been shown in vitro. The clinical signif-
icance of these variants and the mechanisms underlying their
emergence given their lack of significant phenotypic changes
to SOF remains to be determined.
HEPATOLOGY, October, 2014
Disclosures:
Evguenia S. Svarovskaia - Employment: Gilead Sciences Inc; Stock Shareholder:
Gilead Sciences Inc
Hadas Dvory-Sobol - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Brian Doehle - Employment: Gilead Sciences
Edward J. Gane - Advisory Committees or Review Panels: Novira, AbbVie,
Novartis, Gilead Sciences, Janssen Cilag, Vertex, Achillion, Tekmira, Merck, Ide-
nix; Speaking and Teaching: AbbVie, Novartis, Gilead Sciences, Janssen Cilag
Ira M. Jacobson - Consulting: Abbvie, Achillion, Boehringer Ingelheim, Bris-
tol Myers Squibb, Gilead, Idenix, Genentech, Merck, Janssen, Vertex; Grant/
Research Support: Abbvie, Boehringer Ingelheim, Bristol Myers Squibb, Gilead,
Novartis, Genentech, Merck, Janssen, Vertex; Speaking and Teaching: Bristol
Myers Squibb, Gilead, Genentech, Vertex, Janssen
David R. Nelson - Advisory Committees or Review Panels: Merck; Grant/Research
Support: Abbot, BMS, Beohringer Ingelheim, Gilead, Genentech, Merck, Bayer,
Idenix, Vertex, Jansen
Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharma-
ceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck &
Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals;
Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingel-
heim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharma-
ceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio,
Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teach-
ing: Gilead, Kadmon, Merck, Vertex
Diana M. Brainard - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Michael D. Miller - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gil-
ead Sciences, Inc.
Hongmei Mo - Employment: Gilead Science Inc
44
Effects of Sustained Virological Response (SVR) on the
risk of liver transplant, hepatocellular carcinoma, death
and re-infection: meta-analysis of 129 studies in 23,309
patients with Hepatitis C infection
Andrew M. Hill2, Jawaad Saleem1, Katherine A. Heath1, Bryony
Simmons1; 1School of Public Health, Imperial College London,
London, United Kingdom; 2Molecular and Clinical Pharmacology,
University of Liverpool, Liverpool, United Kingdom
Background: The cost-effectiveness of treatment for Hepatitis C
(HCV) depends on the extent of reductions in the risk of liver
transplantation, hepatocellular carcinoma (HCC), and all-cause
mortality for people achieving Sustained Virological Response
(SVR) during long-term follow up post-treatment, plus the risk of
re-infection with HCV. Methods: The MEDLINE and EMBASE
databases were searched via the OVIDSP search database for
all studies examining clinical outcomes (HCC, mortality, liver
transplantation) in patients achieving SVR versus those who
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
did not. A further search was performed for studies analysing
re-infection or late relapse rates in cohorts achieving SVR24.
Results: There were results available from 15,067 patients
with mono-HCV infection, 4987 patients with HCV and cir-
rhosis at baseline, 1170 patients who had already been trans-
planted, and 2085 with HIV-HCV co-infection. Table 1 shows
the relative risk of HCC and death for patients achieving SVR
versus not achieving SVR after treatment (predominantly with
pegylated interferon plus ribavirin). During follow up after treat-
ment, the annual absolute risk of death (all cause) was 0.71%
for HCV mono-infected patients achieving SVR versus 1.68%
for those not achieving SVR. Overall, the 10-year mortality rate
was 6.88% in patients achieving SVR and 15.59% in those
not achieving SVR; 10-year mortality rates by subgroup are
shown in Table 1. In five studies of 3123 patients, the risk of
liver transplantation was reduced by 90% (RR 0.10, 95% CI
0.04-0.23) for patients with SVR versus non-SVR, however the
absolute annual risk of transplantation was low in both groups
(0.03% vs 1.15% in SVR and non-SVR groups respectively).
After SVR24, the annual risk of re-infection or late relapse was
1.4% in mono-infected patients and 8.2% in HIV-HCV co-in-
fected patients. Conclusions: Achieving SVR after treatment for
Hepatitis C was associated with 68-79% reductions in the risk
of HCC, 60-84% reductions in the risk of death and a 90%
reduction in the risk of liver transplantation, compared with
patients who did not achieve SVR. However annual absolute
risk reductions in mortality were small (1%) in mono-infected
patients and there was a significant risk of subsequent re-infec-
tion after SVR in some studies.
Table 1. Risk of HCC and death for patients with SVR versus non-
SVR and 10-year mortality rates
Disclosures:
Andrew M. Hill - Consulting: Janssen
The following people have nothing to disclose: Jawaad Saleem, Katherine A.
Heath, Bryony Simmons
219A
45
Safety and Efficacy of Sofosbuvir-Containing Regimens
for Hepatitis C: Real-World Experience in a Diverse,
Longitudinal Observational Cohort
Donald M. Jensen1, Jacqueline G. O’Leary2, Paul J. Pockros3, Ken-
neth E. Sherman4, Paul Y. Kwo5, Mark E. Mailliard6, Kris V. Kow-
dley7, Andrew J. Muir8, Rolland C. Dickson9, Ananthakrishnan
Ramani10, Michael P. Manns11, Anna S. Lok12, Lucy Akuskevich13,
David R. Nelson14, Michael W. Fried13; 1Center for Liver Disease,
Univ of Chicago Medical Center, Chicago, IL; 2Baylor University
Medical Center, Dallas, TX; 3Scripps Clinic, LaJolla, CA; 4Univer-
sity of Cincinnati, Cincinnati, OH; 5Indiana University, Indianap-
olis, IN; 6University of Nebraska Medical Center, Omaha, NE;
7Virginia Mason Medical Center, Seattle, WA; 8Duke University,
Durham, NC; 9Dartmouth Hitchcock Medical Center, Lebanon,
NH; 10Mountainview Medical Center, Hudson, NY; 11Hannover
Medical School, Hannover, Germany; 12University of Michigan
Health System, Ann Arbor, MI; 13University of North Carolina,
Chapel Hill, NC; 14University of Florida, Gainesville, FL
The approval of direct-acting antivirals (DAA), such as sofosbu-
vir (SOF) and simeprevir (SIM), in late 2013 created a major
paradigm shift in the treatment of chronic hepatitis C. The aim
of the present study was to evaluate the safety and efficacy of
DAAs utilized in clinical practice. METHODS: HCV-TARGET
(HCVT) is a longitudinal observational study of patients treated
with DAAs at academic (n=43) and community medical centers
(n=13) in North America (n=51) and Europe (n=5). HCVT
utilizes a unique centralized data abstraction core along with
independent data monitors who systematically review data
entries for completeness and accuracy. Demographic, clinical,
adverse events, and virological data are collected throughout
treatment and post-treatment follow-up from enrolled patients.
RESULTS: Since January 2014, 1,950 patients have been
consented and 1,107 patients have started treatment and are
included in the current analysis (excluding n=6 pts receiving
PEG/RBV alone or with telaprevir or boceprevir) . Demograph-
ics by treatment regimens are shown in Table. Among patients
with genotype 1, 60% were treated with off-label SOF/SIM
+/- RBV, 28% with SOF/PEG/RBV, and 11% with SOF/RBV
alone. Over 95% of patients with genotype 2 or 3 were treated
with SOF/RBV regimen. SOF/SIM +/- RBV regimens were also
most frequently used among patients with cirrhosis (50%) and
post-liver transplantation (54%). To date, there have been 32
SAE reported in 26 patients and 2 deaths (SOF/RBV=1 multior-
gan failure and SOF/SIM = 1 hepatic decompensation). Only
10 patients have discontinued treatment prematurely, although
follow-up is ongoing. CONCLUSIONS: Sofosbuvir-containing
regimens are used almost exclusively for HCV treatment at the
present time. There is a high rate of off-label use of oral sofos-
buvir + simeprevir, particularly among patients with cirrhosis,
post-transplant, and in elderly populations. SVR12 and com-
plete safety data for the entire cohort will be reported.
Disclosures:
Donald M. Jensen - Grant/Research Support: Abbvie, Boehringer, BMS, Genen-
tech/Roche, Janssen
220A AASLD ABSTRACTS
Jacqueline G. O’Leary - Consulting: Gilead, Jansen
Paul J. Pockros - Advisory Committees or Review Panels: Janssen, Merck, Genen-
tech, BMS, Gilead, Boehinger Ingelheim, AbbVioe; Consulting: Genentech,
Lumena, Regulus, Beckman Coulter, RMS; Grant/Research Support: Novartis,
Intercept, Janssen, Genentech, BMS, Gilead, Vertex, Boehinger Ingelheim,
Lumena, Beckman Coulter, AbbVie, RMS, Novartis, Merck; Speaking and Teach-
ing: Genentech, BMS, Gilead
Kenneth E. Sherman - Advisory Committees or Review Panels: MedImmune, Bio-
line, Janssen, Merck, Synteract; Grant/Research Support: Merck, Genentech/
Roche, Gilead, Anadys, Briston-Myers Squibb, Vertex
Paul Y. Kwo - Advisory Committees or Review Panels: Abbott, Novartis, Merck,
Gilead, BMS, Janssen; Consulting: Vertex; Grant/Research Support: Roche, Ver-
tex, GlaxoSmithKline, Merck, BMS, Abbott, Idenix, Vital Therapeutics, Gilead,
Vertex, Merck, Idenix; Speaking and Teaching: Merck, Merck
Kris V. Kowdley - Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research
Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria,
Janssen, Merck, Mochida, Vertex
Andrew J. Muir - Advisory Committees or Review Panels: Merck, Vertex, Gilead,
BMS, Abbvie, Achillion; Consulting: Profectus, GSK; Grant/Research Support:
Merck, Vertex, Roche, BMS, Gilead, Achillion, Abbvie, Pfizer, Salix, GSK, Inter-
cept, Lumena
Rolland C. Dickson - Advisory Committees or Review Panels: Biotest; Speaking
and Teaching: gilead
Ananthakrishnan Ramani - Employment: columbia memorial hospital; Grant/
Research Support: Forest; Speaking and Teaching: Merck, VIIV, Gilead
Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim,
Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/
Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim,
BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK,
Novartis
Anna S. Lok - Advisory Committees or Review Panels: Gilead, Immune Targeting
System, MedImmune, Arrowhead, Bayer, GSK, Janssen, Novartis, ISIS, Tekmira;
Grant/Research Support: Abbott, BMS, Gilead, Merck, Roche, Boehringer
David R. Nelson - Advisory Committees or Review Panels: Merck; Grant/Research
Support: Abbot, BMS, Beohringer Ingelheim, Gilead, Genentech, Merck, Bayer,
Idenix, Vertex, Jansen
Michael W. Fried - Consulting: Genentech, Merck, Abbvie, Vertex, Janssen, Bris-
tol Myers Squibb, Gilead; Grant/Research Support: Genentech, Merck, AbbVie,
Vertex, Janssen, Bristol Myers Squibb, Gilead; Patent Held/Filed: HCCPlex
The following people have nothing to disclose: Mark E. Mailliard, Lucy Akus-
kevich
46
Evaluation of sofosbuvir and simeprevir-based regimens
in the TRIO network: academic and community treat-
ment of a real-world, heterogeneous population
Douglas Dieterich1, Bruce R. Bacon2, Steven L. Flamm3, Kris V.
Kowdley4,5, Scott Milligan6, Naoky Tsai7,8, Zobair Younossi9, Eric
Lawitz10; 1Mount Sinai School of Medicine, New York, NY; 2Saint
Louis University School of Medicine, St. Louis, MO; 3Northwestern
University Feinberg School of Medicine, Chicago, IL; 4Digestive
Disease Institute, Virginia Mason Medical Center, Seattle, WA;
5University of Washington, Seattle, WA; 6Trio Health Analytics,
Newton, MA; 7Queens Medical Center, Honolulu, HI; 8University
of Hawaii, Honolulu, HI; 9Center for Liver Diseases, Department of
Medicine, Inova Fairfax Hospital, Falls Church, VA; 10The Texas
Liver Institute, University of Texas Health Science Center, San Anto-
nio, TX
Trio Health is a disease management program for hepatitis C
that includes academic medical centers and community physi-
cians in partnership with specialty pharmacies to deliver opti-
mal care for HCV with a managed adherence and compliance
program. Since January 2014, Trio has been managing over
6000 HCV patients. AIM: To evaluate outcomes with newly
available agents sofosbuvir and simeprevir in a real-world,
heterogeneous population. METHODS: The Trio health data-
base was used to identify all patients who were included in the
outcomes data cohort who started medication prior to April 1st
2014. 1,010 patients were identified in 119 practices, 33% of
which were academic centers and 67% community practices,
HEPATOLOGY, October, 2014
and are included in this study report. RESULTS: Mean age
was 57 with 197 patients (20%) 65 years or older, 57% male
and mean BMI 27.9. Genotype 1 was seen in 669 patients
(66%), genotype 2 in 197 patients (20%), genotype 3 in 110
patients (11%), genotype 4 in 16 patients (2%), genotype 6
in 3 patients (<1%), mixed genotypes in 2 patients (<1%) and
an unknown genotype for 13 patients (1%). Comorbidities
included diabetes 12% and anxiety or depression in 14%.
Viral load > 800,000 IU was seen in 64%, mean ALT 82, AST
73 and platelets 177,000. 58% were treatment naïve and
42% had failed an interferon based regimen including patients
who were 1st generation protease inhibitor failures. Cirrhosis
was present in 34% of patients. TREATMENT REGIMENS: 12
week regimens for genotype 1 included PEG+RBV+SOF in
44% and SMV+SOF in 42% with 12% receiving a 24 week
regimen of RBV+SOF. 12 week RBV+SOF was used in 95%
of genotype 2 and 24 week RBV+SOF was used in 93% of
genotype 3. PEG+RBV+SOF was used in 1% and 6% for gen-
otypes 2 and 3 respectively. CONCLUSION: An examination
of a heterogeneous real life hepatitis C population is underway
and SVR data for all genotype 1 and 2 patients on 12 week
regimens will be available at the meeting.
Disclosures:
Douglas Dieterich - Advisory Committees or Review Panels: merck, Idenix, Jans-
sen ; Consulting: Gilead, BMS
Bruce R. Bacon - Advisory Committees or Review Panels: Bristol-Myers Squibb,
Kadmon, Janssen; Consulting: Merck, ISIS; Grant/Research Support: Merck, Bris-
tol-Myers Squibb, Kadmon, AbbVie; Speaking and Teaching: Merck, Kadmon,
AbbVie, Salix, Janssen
Steven L. Flamm - Advisory Committees or Review Panels: Gilead, Bristol Myers
Squibb, AbbVie, Janssen, Salix; Consulting: Merck, Janseen, Bristol Myers
Squibb, AbbVie, Salix, Gilead; Grant/Research Support: Janssen, Bristol Myers
Squibb, Merck, Vertex, Gilead, AbbVie, Boehringer Ingelheim; Speaking and
Teaching: Salix
Kris V. Kowdley - Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research
Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria,
Janssen, Merck, Mochida, Vertex
Scott Milligan - Grant/Research Support: Gilead
Naoky Tsai - Advisory Committees or Review Panels: Gilead, Vertex; Consulting:
BMS, Gilead, Merck; Grant/Research Support: BMS, Gilead, Genentech, Ver-
tex, Novartis, GSK, Bayer, Abbvie, Janssen, beckman; Speaking and Teaching:
BMS, Gilead, Genentech, Vertex, Merck, Salix, Bayer, Janssen
Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharma-
ceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck &
Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals;
Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingel-
heim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharma-
ceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio,
Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teach-
ing: Gilead, Kadmon, Merck, Vertex
The following people have nothing to disclose: Zobair Younossi
47
Interferon-α plus ribavirin therapy yields 98% sustained
virologic response in children aged 1-5 years with
unsafe injection-acquired chronic hepatitis C
Shishu Zhu1, Fu-Sheng Wang2,3, Qing-Lei Zeng3,2, Yi Dong1,
Zhiqiang Xu1, Limin Wang1, Dawei Chen1, Yu Gan1, Fuchuan
Wang1, Jianguo Yan1, Lili Cao1, Pu Wang1, Xue-Xiu Zhang3,2,
Hongfei Zhang1; 1Treatment and Research Center for Children’s
Liver Diseases, Beijing 302 Hospital, Beijing, China; 2Research
Center for Biological Therapy, Beijing 302 Hospital, Beijing,
China; 3The Institute of Translational Hepatology, Beijing 302 Hos-
pital, Peking University, Beijing, China
Backgroud: During the winter of 2011, a public health emer-
gency occurred, wherein hundreds of children contracted
hepatitis C virus (HCV) infection caused by the reuse of con-
taminated glass syringes in a rural clinic at the border between
the Henan and Anhui provinces in China. However, epide-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
miological, clinical, and antiviral efficacy data for children
aged 1-5 years is very scarce. Methods: We collected detailed
data of the epidemiological and clinical characteristics of 256
children aged 1-5 years with HCV infection during the period
when they were hospitalized in our unit. Antiviral therapy
with conventional interferon-α plus ribavirin was administered
to 162 children with HCV RNA-positive chronic hepatitis C,
and the efficacy was evaluated from the sustained virologic
response (SVR) and side effects. Results: The median age of
the 256 children was 2.7 years, and 165 (64.5%) were male.
Ninety-three (36.3%, 93/256) HCV-infected children exhibited
spontaneous clearance of HCV infection. Serum HCV RNA
positivity with a mean level of 4.6 log10 IU/mL was observed
in the remaining 63.7% (163/256) children, and HCV 1b and
2a were identified in 42% and 58% of the 133 genotype-de-
termined cases. The favorable IL-28B rs12979860 CC and
rs8099917 TT genotypes accounted for 88.7% and 90.3%
cases, respectively. The levels of alanine and aspartate amino-
transferases correlated positively with the HCV RNA levels (r =
0.43 and 0.38, respectively; p < 0.001 for both), and 100%
had normal total bilirubin and albumin levels and prothrombin
time activity. G1 histological inflammation and S1 fibrosis were
seen in majority of the liver biopsy specimens of 219 children
(79.9% and 60.7%, respectively). Overall, 97.5% (158/162)
children achieved SVR at both 12 and 24 weeks after the ces-
sation of therapy; the side effects were mild and the cost was
low. Adherence was found to be an independently predictive
factor associated with both SVR and viral breakthrough. Con-
clusions: This study fills the gap in the epidemiological and
clinical features of iatrogenic HCV infection in children aged
1–5 years and shows that conventional interferon-α plus riba-
virin therapy is the most cost-effective means of managing such
patients, and earlier antiviral treatment can achieve the best
efficacy for these patients. Shi-Shu Zhu, Qing-Lei Zeng, and
Yi Dong contributed equally to this study. Correspondence to:
Prof Fu-Sheng Wang, Research Center for Biological Therapy,
fswang302@163.com, or Hong-Fei Zhang, Treatment and
Research Center for Children’s Liver Disease, bjzhhf@aliyun.
com, both in Beijing 302 Hospital, No. 100, the 4th Western
Ring Middle Road, Beijing 100039, China.
Disclosures:
The following people have nothing to disclose: Shishu Zhu, Fu-Sheng Wang,
Qing-Lei Zeng, Yi Dong, Zhiqiang Xu, Limin Wang, Dawei Chen, Yu Gan,
Fuchuan Wang, Jianguo Yan, Lili Cao, Pu Wang, Xue-Xiu Zhang, Hongfei Zhang
48
Cerebral MR spectroscopy and patient-reported men-
tal health outcomes in hepatitis C genotype 1 naïve
patients treated with ledipasvir and sofosbuvir
David Alsop1, Zobair Younossi2, Maria Stepanova2, Nezam
H. Afdhal3; 1Dept of Radiology, Beth Israel Deaconess Medical
Center, Boston, MA; 2Betty and Guy Beatty Center for Integrated
Research,, Inova Health System, Falls Church, VA; 3Hepatology,
Beth Israel Deaconess Medical Center, Boston, MA
Background: Neurocognitive dysfunction has been reported in
hepatitis C patients with mild histological disease, with subse-
quent improvement after SVR with interferon-based treatment
(Byrnes V, J of Hepatol 2012). Changes associated with HCV
infection include increases in magnetic resonance spectroscopy
(MRS) measured myoinisitol (MI) and choline (CH) and reduced
n-acetyl aspartate (NAA). We hypothesized that effective viral
suppression can demonstrate reversal of such MRS measured
abnormalities. Aim: To show the effect of viral suppression
with ledipasvir/sofosbuvir (LDV/SOF) +/- ribavirin (RBV) on
neuronal function using MR spectroscopy and to correlate with
221A
Mental Health constructs of patient-reported outcomes (PROs).
Methods: HCV treatment-naïve patients with F0-F2 fibrosis
were enrolled from a single site in the ION-1 trial (Afdhal N,
NEJM 2014). Magnetic resonance spectroscopy (MRS) evalu-
ated signals from CH, creatine (Cr), NAA and MI from basal
ganglia, frontal and dorsolateral prefrontal regions at baseline,
week 4 of treatment and week 12 post-treatment (SVR). Quan-
tification by ratio to Cr was performed. PROs were determined
at the same time points using validated questionnaires, as was
ALT and viral load. Results: 14 patients (8 male, genotype 1a n
=11, VL > 800,000IU n=13, all with <F2 fibrosis, and none had
history of depression or fatigue before treatment) were enrolled
with 7 receiving LED/SOF and 7 LED/SOF plus RBV. 13 of 14
were HCV RNA undetected at week 4, and all achieved SVR.
ALT normalization was seen in all at week 4. MR spectros-
copy showed an increase in basal ganglia NAA/Cr ratio at
week 4 that became significant at SVR (p=0.0134) and more
apparent in the RBV-free group. At week 12 post-treatment, the
NAA/Cr ratio in left basal ganglia increased in the RBV-free
arm (p=0.0156) and remained unchanged the RBV-containing
arm (p>0.05) (p=0.0181 between the arms). After 12 weeks
post-treatment, some of the changes in the metabolite in left
basal ganglia shown by MRS correlated with changes in the
emotional function domain of CLDQ-HCV and in the mental
health scale of SF-36 (R up to -0.64, p=0.0134). Conclusions:
This exploratory study suggests that viral suppression can result
in improvement in MR spectroscopic measures consistent with
an overall improvement in neural health. Furthermore, changes
in the metabolite pattern captured by MRS may be associated
with changes in PROs related to mental health. The role of HCV
on neurocognition is undergoing further study in a double blind
placebo-controlled trial.
Disclosures:
David Alsop - Grant/Research Support: Gilead Sciences, GE Healthcare; Patent
Held/Filed: GE Healthcare
Nezam H. Afdhal - Consulting: Merck, Vertex, Idenix, GlaxoSmithKline, Spring-
bank, Gilead, Pharmasett, Abbott; Grant/Research Support: Merck, Vertex, Ide-
nix, GlaxoSmithKline, Springbank, Gilead, Pharmasett, Abbott
The following people have nothing to disclose: Zobair Younossi, Maria Ste-
panova
49
JNK mediation of acetaminophen (APAP) hepatotoxicity
is determined by Sab (SH3BP5) dependent dysregula-
tion of intramitochondrial c-Src kinase
Sanda Win, Tin A. Than, Neil Kaplowitz; Medicine, USC KSOM,
Los Angeles, CA
JNK plays a key role in hepatotoxicity by binding and phos-
phorylating Sab on the outer mitochondrial membrane (J Biol
Chem 286, 35071-8, 2011, Cell Death Dis; 5:e989, Jan 9,
2014). The mechanism for how this event on the cytoplasmic
face of the outer membrane leads to impaired mitochondrial
electron transport, increased ROS, and APAP-induced necrosis
is unknown. We focused our attention on dysregulation of tyro-
sine kinases (Src) because mitochondrial Src activity is known
to regulate multiple steps in electron transport in other contexts
(Biochem J. 447, 281-9,2012). Methods: Isolated mouse liver
mitochondria were exposed to pure activated JNK +/- ATP,
with or without Src or protein tyrosine phosphatase (Ptp) inhib-
itors. APAP (300mg/kg) or PBS was given by ip injection to
C57BL/6N mice; mitochondria and cytoplasm were prepared
at 1,2,4 hours and histology and serum ALT were assessed at
24 hours. Knockdown of target genes in liver was by adeno-
shRNA. Results: Using resistance to proteinase K digestion,
we identified intramitochondrial c-Src mainly in an activated
form (P-419-c-Src). Upon exposure of isolated mitochondria to
222A AASLD ABSTRACTS
P-JNK plus ATP, P-c-Src levels markedly decreased while total
c-Src was unchanged. The decrease of P-c-Src was accompa-
nied by inhibition of oxygen consumption rate (OCR), which
depended on Sab expression. Addition of Src inhibitors (PP2
or Src inhibitor 1) to normal mitochondria directly inhibited
OCR. Conversely the phosphatase inhibitor, sodium orthova-
nadate, prevented Src dephosphorylation and the inhibitory
effect of P-JNK/ATP on OCR. Following in vivo APAP, a rapid
decline in P-c-Src (not total Src) was observed in mitochondria
but not cytoplasm. Knockdown of Sab with adeno-shSab pre-
vented inactivation of mitochondrial c-Src after APAP in vivo.
Next we found that DOK-4, Src binder (J Biol Chem. 280,
26383-96,2005), was expressed exclusively in mitochondria
of hepatocytes. Liver mitochondria isolated after DOK-4 knock-
down were resistant to direct P-JNK/ATP mediated inhibition
of OCR. Knockdown of DOK-4 in vivo (adeno-shDOK-4) pre-
vented de-phosphorylation of active Src and markedly pro-
tected against APAP toxicity. Conclusions: The interaction of
JNK with Sab leads to inactivation of intramitochondrial c-Src
and impairment of respiration. The dephosphorylation of c-Src
is dependent on DOK-4, a platform for binding of Src and Ptp.
Knockdown of mitochondrial DOK-4 markedly protects against
APAP hepatotoxicity. Therefore, dysregulation of intramitochon-
drial c-Src kinase mediates the Sab dependent effects of JNK
leading to impaired mitochondrial function in APAP toxicity.
Disclosures:
Neil Kaplowitz - Consulting: GlaxoSmithKline, JNJ, Merck, Novartis, Hepregen,
Takeda, Otsuka, Pfizer, Geron, Daiichi-Sanyo; Independent Contractor: Acet-
aminophen Litigation
The following people have nothing to disclose: Sanda Win, Tin A. Than
50
NMDA Receptor Activity Contributes in Cellular DNA
Damage Following Acetaminophen Hepatotoxicity and
Offers Directions for Therapeutic Development
Nicole Pattamanuch1, Preeti Viswanathan1, Sylvia O. Suadicani2,3,
David C. Spray3,4, Sanjeev Gupta4,5; 1Pediatric Gastroenterology
and Hepatology, Children’s Hospital at Montefiore, Albert Einstein
College of Medicine, Bronx, NY; 2Urology, Albert Einstein College
of Medicine, Bronx, NY; 3Neuroscience, Albert Einstein College of
Medicine, Bronx, NY; 4Medicine, Albert Einstein College of Medi-
cine, Marion Bessin Liver Research Center, Bronx, NY; 5Pathology,
Albert Einstein College of Medicine, Bronx, NY
Mechanisms of drug-induced liver injury (DILI) are incompletely
understood. Hepatotoxicity from acetaminophen (APAP) poses
widespread problems, including acute liver failure (ALF), and
requires more therapeutic development. Although the cell
type-specific approach has typically been utilized for cytotoxic
mechanisms, recent studies identified sharing of toxicity path-
ways and processes in a cell-agnostic manner. For instance,
expression of N-methyl-D-aspartate receptors (NMDARs) is
classically associated with excitoxic injury in neuronal tissues,
e.g., ischemic or traumatic insults, Alzheimer’s, Parkinson’s,
schizophrenia, etc., but rodent and human hepatocytes also
expressed NMDAR activity after liver anoxia or injury. To deter-
mine whether NMDARs could contribute in APAP-induced hep-
atotoxicity, we performed studies in cultured HuH-7 cells and
primary mouse hepatocytes with or without NMDA and APAP,
as well as NMDAR antgonists, MK801 or memantine. MTT
assays were performed to assess cytotoxicity. Calcium fluxes
were measured in hepatocytes with NMDA and NMDAR block-
ers. Brain and liver tissues were examined for multiple NMDARs
by RT-PCR, western, and immunostaining. C57BL/6 mice were
used for studies with 500 mg/kg APAP with or without 30 mg/
kg memantine. Liver injury was evaluated by histology. We
HEPATOLOGY, October, 2014
found HuH-7 cells and mouse hepatocytes expressed NMDARs
and were sensitive to APAP-induced cytotoxicity, which was
abolished by MK801 or memantine. In mouse hepatocytes,
NMDA or quinolinic acid, another agonist of NMDAR, dose-de-
pendently induced calcium fluxes, APAP alone did not directly
stimulate calcium fluxes related to NMDARs. Although mito-
chondrial KATP channels were found to intersect with NMDAR
activity in neurons, studies with glibenclamide, a KATP channel
antagonist, and diazoxide, a KATP channel agonist, enhanced
or limited NMDA toxicity, respectively, without affecting APAP
toxicity. However, APAP caused extensive oxidative DNA
damage in cells, as indicated by gH2AX staining in nuclei
as well as Comet assays for double-stranded DNA breaks.
Memantine decreased this APAP-induced cellular DNA dam-
age. These findings was in agreement with greater NMDAR
expression in APAP-induced ALF in mice along with less liver
damage after memantine, including decreased gH2AX staining
in liver of APAP-treated mice with memantine therapy. Conclu-
sions: Expression of NMDARs contributed to DILI. Blockade of
NMDARs by drugs improved APAP-induced DNA damage in
cells and animals. This therapeutic benefit of NMDAR blockade
was independent of associated events, such as KATP channel
regulation, and offers further directions for controlling DILI in
the clinical context.
Disclosures:
The following people have nothing to disclose: Nicole Pattamanuch, Preeti Viswa-
nathan, Sylvia O. Suadicani, David C. Spray, Sanjeev Gupta
51
Lysosomal Cholesterol Accumulation Sensitizes To Acet-
aminophen Hepatotoxicity By Impairing Mitophagy
Anna Baulies1,2, Susana Nuñez1,2, Vicent Ribas1,2, Sandra Tor-
res1,2, Laura Martinez1,2, Neil Kaplowitz3, Carmen Garcia-Ruiz1,2,
Jose Fernandez-Checa1,2; 1Instituto Investigaciones Biomedicas
Barcelona, CSIC, Barcelona, Spain; 2IDIBAPS and CIBEREHD,
Barcelona, Spain; 3USC Researc Center for Liver Diseases, Los
Angeles, CA, CA
Acetaminophen (APAP) is a widely used pain reliever and a
dose related hepatotoxin and a major cause of acute liver
failure. Mitochondrial dysfunction, mitochondrial GSH (mGSH)
depletion and JNK activation are well-recognized factors of
APAP hepatotoxicity. Lysosomes are involved in APAP-induced
liver injury by a mechanism targeting mitochondria via lyso-
somal iron mobilization. Moreover, autophagy protects against
APAP hepatotoxicity. However, the role of lysosomal lipid stor-
age in APAP hepatotoxicity has not been examined. As acid
sphingomyelinase (ASMase) deficiency triggers a lysosomal
storage disorder characterized by lysosomal sphingomyelin
and cholesterol loading, our aim was to examine the role of
ASMase in APAP-induced liver injury. Methods: H&E, TUNEL,
ALT, GSH levels, protein adducts and JNK phosphorylation
were examined after APAP treatment (300mg/Kg). Survival
was examined in fasted mice following a lethal dose of APAP
(500 mg/kg). Cell viability was analysed in primary mouse
hepatocytes (PMH) with Sytox Green. Mitophagy was analysed
by confocal imaging in PMH expressing LAMP-GFP (lysosomal
staining) and mtKeima (mitochondria staining) following 5mM
APAP treatment. Moreover, PMH were treated with U18666A,
an inhibitor of intracellular cholesterol transport, with or with-
out 25-hydroxycholesterol (25-HC) to diminish lysosomal cho-
lesterol content. Cathepsin B was inhibited with Ca-074-Me.
Results: In vivo liver injury was higher and survival rate was
lower in ASMase-/- mice treated with APAP. Similar findings
were observed in PMH. However, protein adducts forma-
tion, JNK phosphorylation, mGSH depletion and connexin32
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
expression was similar in both types of mice. Lysosomal colo-
calization with mitochondria was lower in ASMase-/- PMH
following APAP treatment, compared to ASMase+/+ PMH.
ASMase+/+ PMH pre-treated with U18666A increased lyso-
somal cholesterol levels, impaired mitophagy (LAMP-GFP/
mtKeima colocalization) and sensitized to APAP-induced cell
death. Conversely, 25-HC reversed the lysosomal cholesterol
accumulation induced by U18666A, improved mitophagy
and protected against APAP-induced cell death. Moreover,
25-HC abolished the susceptibility of ASMase-/- PMH to APAP
exposure. Treatment with Ca-074Me to inhibit cathepsin B did
not affect APAP susceptibility of ASMase-/- PMH. Conclusions:
Our findings suggest that the underlying status of the pathway
leading to mitophagy may be an important risk factor for APAP
hepatotoxicity. The findings may have implications for patients
with lysosomal storage diseases who may exhibit susceptibility
to APAP-induced liver injury.
Disclosures:
Neil Kaplowitz - Consulting: GlaxoSmithKline, JNJ, Merck, Novartis, Hepregen,
Takeda, Otsuka, Pfizer, Geron, Daiichi-Sanyo; Independent Contractor: Acet-
aminophen Litigation
The following people have nothing to disclose: Anna Baulies, Susana Nuñez,
Vicent Ribas, Sandra Torres, Laura Martinez, Carmen Garcia-Ruiz, Jose Fernan-
dez-Checa
52
Depletion of hepatic stellate cells abrogates Concanav-
alin A-induced liver injury
Ashish Tandon1, Anil Dangi1, Sudhir Kumar1, Jiang Wang1, Chan-
drashekhar R. Gandhi1,2; 1Surgery, University of Cincinnati, Cin-
cinnati, OH; 2Pediatrics, Cincinnati Children’s Hospital Medical
Center, Cincinnati, OH
Background/Aims: Concanavalin A (ConA)-induced liver
injury is an established model of T cell-mediated hepatitis. CD4
T cells, NKT cells and Kupffer cells all were reported to con-
tribute to ConA-induced hepatitis. We and others have shown
that hepatic stellate cells (HSCs) play a major role in hepatic
inflammation and immune reactions. We recently developed
a novel HSC-depleted mouse, which is resistant to ischemia/
reperfusion- and endotoxin-induced liver injury. Here, we inves-
tigated mechanisms of ConA-induced hepatitis in the HSC-de-
pleted mouse. Methods: HSC-depleted and HSC-sufficient mice
(n=6 each) were injected 20 mg/kg ConA or vehicle (PBS)
(i.v.) and sacrificed 6h later. H/E-stained liver sections were
examined for histopathology and serum ALT measured. mRNA
expression of IFNβ, TNFα, IL10, CXCL1 and CXCL10 was
determined via qRT-PCR. In vitro HSCs were incubated in a
medium containing 10 mg/ml ConA or vehicle for 4 and 8h
and the medium was transferred to hepatocytes. Viability of
hepatocytes was examined by phase-contrast microscopy and
TUNEL staining. mRNA expression of INFβ, IRF1 and CXCL1
was measured in ConA-stimulated HSCs. Generation of reac-
tive oxygen species (ROS) in HSCs and oxidative stress in
hepatocytes was determined via DCFDA fluorescence. Results:
ConA treatment caused profound liver injury (primarily in
zone 2) accompanied by inflammatory infiltration, sinusoidal
congestion, and increased expression of IFNγ, TNFα, CXCL1
and CXCL10, and JNK1-MAPK activation in HSC-sufficient
mice but not in HSC-depleted mice. In contrast, IL10 expres-
sion increased in ConA-treated HSC-depleted mice but not in
HSC-sufficient mice. In vitro, ConA did not affect HSC viability
but increased IRF1, IFNβ and CXCL1 expression, JNK1-MAPK
activation and production of ROS, and IFNβ treatment led to
JNK activation and apoptosis of hepatocytes. ConA-stimulated
HSCs, but not Kupffer cells, caused strong oxidative stress,
and induced apoptosis (4h-conditioned HSC medium) and
223A
necrosis (8h-conditioned HSC medium) of hepatocytes. Con-
clusions: HSCs play a major role in ConA-induced hepatitis by
producing mediators of apoptosis (IFNβ) and necrosis (ROS),
and by recruiting inflammatory and immune cells. Increased
IFNγ expression in ConA-treated HSC-sufficient mice and of
IL10 in HSC-depleted mice indicate that HSCs regulate the
expression of these cytokines and possibly other mediators by
Kupffer cells as well as infiltrating cells. These data provide first
evidence that HSCs cause liver injury upon ConA challenge
directly and by influencing inflammatory cells and cells of the
immune system. Supported by VA Merit 1IO1BX001174; NIH
PO1AIO81678; NIH R21AA020846.
Disclosures:
The following people have nothing to disclose: Ashish Tandon, Anil Dangi, Sud-
hir Kumar, Jiang Wang, Chandrashekhar R. Gandhi
53
EPAC activation and glycogen synthase kinase beta
inhibition are cytoprotective in an in vivo model of
cholestasis
Cynthia Leveille-Webster, Andrea Johnston, Mohammed S. Anwer;
Tufts University, Grafton, MA
Bile acids accumulate in hepatocytes during cholestatic liver
disease and contribute to ongoing pathology. Our work has
established that cAMP cytoprotection against bile acid-induced
apoptosis in hepatocytes is due to activation of a cAMP-GEF
(also known as EPAC) RapGTP/PI3K/Akt pathway leading
to inhibition of glycogen synthase kinase 3 beta (GSK3) by
phosphorylation. EPAC activation or direct GSK3 inhibition
blocks bile acid apoptosis by attenuating ER stress mediated
phosphorylation of eIF2alpha, IRE1 and JNK. The aim of this
study was to determine the in-vivo relevance of these findings
by studying the effect of EPAC activation and GSK3 inhibition
on hepatocyte cell death in the bile duct ligated mouse. The first
series of studies determined the effect of pharmacological effect
of the EPAC activator (8-(4-chlorophenylthio)-2’-O-methylade-
nosine-3’,5’cyclic monophosphate (CPT-2-Me-cAMP) and the
GSK3 inhibitor, TDZD. C57BL/6 mice were treated with CPT-
2-Me-cAMP (25 mg/kg IP) or TDZD (10 mg/kg IP) for 3 days
followed by determination of pathways controlled by EPAC
activation (Akt and GSK3 phosphorylation by immunoblotting
and RapGTP activation by GTPase assay). Our results using
liver homogenates from these mice show that CPT-2Me-cAMP
increases Rap activity 3 fold and Akt and GSK3 phosphory-
lation by 1.7 and 2.3 fold, respectively, but has no effect on
CREB phosphorylation, a protein kinase A mediated event.
TDZD administration also increases GSK3 phosphorylation 4
fold and is associated with GSK inhibition as reflected by a
70% decrease in glycogen synthase phosphorylation and a
5 fold increase in beta-catenin expression. Neither the EPAC
analogue or TDZD has any effect on ALT activity or hepatic his-
topathology in the mice. In the next experiments, 12 week old
C57BL/6 mice underwent bile duct ligation or sham surgery
and were treated for 3 days with either CPT-2-Me-cAMP (25
mg/kg IP daily, control BDL received PBS injections) or TDZD
(10 mg/kg IP daily, control BDL mice were injected with equal
volume injection of DMSO vehicle). Both compounds improved
histological parameters of liver cell death (a 60% decrease in
the number of bile infarcts per 10 high power field). Serum ALT
decreased by 80% and 66% for TDZD and CPT-2Me-cAMP
treated mice, respectively. Biochemical indicators of cell death
(caspase 3 cleavage and JNK phosphorylation), and ER stress,
(IRE1 and eIF2alpha phosphorylation and CHOP expression)
were also significantly attenuated by both TDZD and CPT-2-Me-
cAMP treatment. Collectively, these results suggest that GSK
224A AASLD ABSTRACTS
inhibition and EPAC activation mediate cytoprotective effects
in cholestatic liver disease in vivo.
Disclosures:
The following people have nothing to disclose: Cynthia Leveille-Webster, Andrea
Johnston, Mohammed S. Anwer
54
Loss of Grb2-associated binder 1 results in enhanced
hepatocyte necrosis and high mortality in mice with
acute liver failure
Kunimaro Furuta, Yuichi Yoshida, Takashi Kizu, Satoshi Ogura,
Mayumi Egawa, Norihiro Chatani, Yoshihiro Kamada, Shinichi
Kiso, Tetsuo Takehara; Gastroenterology and Hepatology, Osaka
University Graduate School of Medicine, Suita, Japan
Background & Aims: Acute liver failure (ALF) is characterized
by severe hepatocyte death and impaired liver regeneration.
Acetaminophen (APAP) overdose is a leading cause of ALF in
Western countries. In APAP hepatotoxicity, it has been shown
that mitochondrial dysfunction is critical and that mitochondrial
translocation of a stress MAP kinase, JNK is associated with
this process. We previously demonstrated that Grb2-associated
binder 1 (Gab1) adaptor protein transmits mitogenic signals
via a MAP kinase, ERK in vitro and in vivo. However, the role
of Gab1 in hepatocyte death during APAP-induced ALF has
remained unclear. Here, we investigated the role of Gab1
in this process. Method: Hepatocyte specific Gab1 knock-out
(KO) and wild-type (WT) mice were intraperitoneally injected
with APAP (250 mg/kg bw) to induce ALF. Results: KO mice
showed significantly higher mortality rate compared with WT
mice at 72 hours after APAP treatment (75% in KO n=12 vs.
25% in WT n=12, p<0.05). This increased mortality in KO
mice was associated with elevated serum ALT levels (p<0.05),
increased TUNEL positive hepatocytes (p<0.05), and severe
centrilobular liver necrosis (p<0.01) at 6 hours after APAP
treatment. KO mice also showed a 2.4-fold increase in serum
levels of high mobility group box 1 (HMGB-1) (p<0.01), a
danger signaling molecule, indicating higher degree of
hepatocyte necrosis in KO mice. To clarify the mechanisms
of enhanced hepatocyte necrosis in KO mice, we next exam-
ined whether loss of Gab1 affected the mitochondrial function
during APAP-induced ALF. At 1.5 hours after APAP treatment,
KO mice showed enhanced mitochondrial translocation of JNK
compared with WT mice, accompanied by increased release
of mitochondrial enzymes such as Apoptosis-inducing factor
and Endonuclease G into the cytosol. These data suggested
that loss of Gab1 might cause hepatocyte necrosis through
mitochondrial dysfunction and subsequent nuclear DNA frag-
mentation. Finally, we examined compensatory proliferation in
hepatocytes surrounding necrotic areas after APAP treatment.
Ki67 stating demonstrated that KO mice had a 2-fold decrease
(p<0.05) in the number of proliferating hepatocytes. Consistent
with data of Ki67 staining, the mitogenic signals, such as ERK
and AKT were markedly reduced in KO mice, suggesting that
Gab1 might regulate both hepatocyte death and compensatory
proliferation during APAP-induced ALF. Conclusion: In a mouse
model of ALF, loss of Gab1 in hepatocytes resulted in higher
mortality with enhanced mitochondrial dysfunction and hepato-
cyte necrosis. Our data further suggested that Gab1 could be
a novel therapeutic target for the treatment of ALF
Disclosures:
Tetsuo Takehara - Grant/Research Support: Chugai Pharmaceutical Co., MSD
K.K.
The following people have nothing to disclose: Kunimaro Furuta, Yuichi Yoshida,
Takashi Kizu, Satoshi Ogura, Mayumi Egawa, Norihiro Chatani, Yoshihiro
Kamada, Shinichi Kiso
HEPATOLOGY, October, 2014
55
Antisteatotic Efficacy and Safety of the Liver X Receptor
alpha Inhibitor, Dithiolethione in Patients with Nonalco-
holic Fatty Liver Disease
Won Kim1, June Sung Lee2, Chun Kyon Lee3, Jong Eun Yeon4,
Byeong Gwan Kim1, Yoon Jun Kim5; 1Department of Internal Med-
icine and Liver Research Institute, Seoul Metropolitan Government
Seoul National University Boramae Medical Center, Seoul, Repub-
lic of Korea; 2Ilsan Paik Hospital, Inje University College of Med-
icine, Goyang, Republic of Korea; 3National Health Insurance
Corporation Ilsan Hospital, Goyang, Republic of Korea; 4Korea
University College of Medicine, Korea University Guro Hospital,
Seoul, Republic of Korea; 5Liver Research Institute, Seoul National
University College of Medicine, Seoul, Republic of Korea
Background & Aims: Oltipraz is a synthetic dithiolethione with
an antisteatotic effect by inhibiting the activity of liver X receptor
alpha (LXR-α). Recent experimental studies clearly demonstrated
the disruptive role of oltipraz on LXR-α-dependent lipogenesis in
hepatocytes and a high-fat diet mouse model. This study aimed
to evaluate the efficacy and safety of oltipraz for reducing liver
fat in subjects with non-alcoholic fatty liver disease (NAFLD).
Methods: We performed a multicenter, double-blind, place-
bo-controlled, phase II study. Subjects with liver fat content of
>20% and elevated aminotransferase levels were randomly
allocated to three groups given either placebo (n=22), 30 mg
(n=22), or 60 mg (n=24) oltipraz twice daily for 24 weeks.
The change of liver fat amount from baseline to 24 weeks was
quantified using magnetic resonance spectroscopy. We also
assessed changes of body mass index (BMI), liver enzymes, lip-
ids, insulin resistance, cytokines, NAFLD fibrosis scores (NFS),
and NAFLD activity scores (NAS). Results: Absolute changes in
liver fat content tended to increase in a dose-dependent man-
ner (-3.21±11.09% in a placebo group, -7.65±6.98% in a low
dose group, and -13.91±10.65% in a high dose group). Per-
cent reduction in liver fat content was also significantly greater
in a high dose group than in a placebo group. BMI and NFS
also significantly decreased in a high dose group compared
with in a placebo group. However, absolute changes of insulin
resistance, liver enzymes, lipids, NAS, and cytokines were not
significantly different among groups. The incidence of adverse
events was comparable among groups. Conclusions: 24-week
oltipraz treatment was well tolerated and significantly reduced
liver fat amount and BMI without worsening of liver fibrosis in
patients with NAFLD (NCT01373554).
Disclosures:
The following people have nothing to disclose: Won Kim, June Sung Lee, Chun
Kyon Lee, Jong Eun Yeon, Byeong Gwan Kim, Yoon Jun Kim
56
NASH Resolution is Associated with Improvements in
HDL and Triglycerides But Not in LDL or Non-HDL-C
Kathleen Corey1, Raj Vuppalanchi2, Laura Wilson3, Oscar Cum-
mings2, Naga P. Chalasani2; 1GI, Massachusetts General Hos-
pital, Boston, MA; 2Indiana University, Indianapolis, IN; 3John
Hopkins, Baltimore, MD
Nonalcoholic steatohepatitis (NASH) is associated with dys-
lipidemia and cardiovascular disease (CVD). However, the
impact of NASH resolution on dyslipidemia is unknown. Meth-
ods: Individuals in the Pioglitazone vs. Vitamin E vs. Placebo
for the Treatment of Nondiabetic Patients with NASH (PIVENS)
trial were included. In the PIVENS trial individuals were ran-
domized to pioglitazone, vitamin E or placebo daily. Change
in lipid levels was compared between those with and without
NASH resolution. Results: Dyslipidemia was frequent, with low
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
high-density lipoprotein (HDL) (<40mg/dL men, <50 mg/dL
women) in 63%, hypertriglyceridemia (≥150 mg/dL) in 46%,
hypercholesterolemia (≥200 mg/dL) in 47%, and triglycerides
(TG)/HDL>5.0 in 25%. Sixteen percent had LDL≥160 mg/dL
and 73% had elevated non-HDL cholesterol (non-HDL-C) (≥130
mg/dL). Among 222 individuals, 77 (35%) had NASH reso-
lution, including 33 (47%) on pioglitazone, 29 (36%) on vita-
min E and 15 (21%) on placebo. HDL increased with NASH
resolution but decreased in those without resolution (2.9mg/dL
vs. -2.5mg/dL, P<0.001, Table). Those with NASH resolution
had a significant decreases in TG and TG/HDL ratio compared
to those without resolution (TG -21.1 vs. -2.3mg/dL, P=0.03
and TG/HDL -0.7 vs 0.1, P=0.003). Non-HDL-C, LDL and cho-
lesterol decreased during the study in both groups but there
was no difference between those with or without NASH resolu-
tion. Lipid changes did not vary by treatment. Conclusions: In
the PIVENS trial, regardless of treatment group (pioglitazone,
vitamin E, or placebo), NASH resolution was associated with
improvements in TG and HDL but not in LDL and non-HDL-C.
Individuals whose NASH resolves after 96 weeks of follow-up
may still be at risk for CVD.
Changes in lipid profiles by NASH resolution
†Derived from multiple linear regression models, included treat-
ment group, BMI, ethnicity, statin use during study; for change
measures, baseline value of lipid.
Disclosures:
Kathleen Corey - Advisory Committees or Review Panels: Gilead
Naga P. Chalasani - Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-
rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin
The following people have nothing to disclose: Raj Vuppalanchi, Laura Wilson,
Oscar Cummings
225A
57
Early phase 1 clinical trial results of GR-MD-02, a galec-
tin-3 inhibitor, in patients having non-alcoholic steato-
hepatitis (NASH) with advanced fibrosis
Stephen A. Harrison1, Naga P. Chalasani2, Eric Lawitz3, Smitha
Marri2, Mazen Noureddin4, Arun J. Sanyal5, Thomas D. Schiano6,
Mohammad S. Siddiqui5, Brent A. Neuschwander-Tetri7, Peter G.
Traber8,9; 1Brooke Army Medical Center, San Antonio, TX; 2Indi-
ana University School of Medicine, Indianapolis, IN; 3The Texas
Liver Institute, University of Texas Health Science Center, San Anto-
nio, TX; 4University of Southern California, Los Angeles, CA; 5VCU
Medical Center, Richmond, VA; 6Icahn School of Medicine at
Mount Sinai, New York, NY; 7St. Louis University, St. Louis, MO;
8Galectin Therapeutics, Norcross, GA; 9Emory University School of
Medicine, Atlanta, GA
Introduction: NASH with fibrosis is a significant cause of liver
disease in which effective therapies are limited. Galectin-3
is a critical protein in the pathogenesis of liver fibrogenesis
and NASH. GR-MD-02, a galectin-3 inhibitor, has beneficial
therapeutic effects in rodent models of NASH and toxin-in-
duced cirrhosis. Methods: The phase 1 trial was designed as a
multi-center, partially blinded (patients, PI and staff), maximum
tolerated multiple dose escalation study in patients with biopsy
proven NASH having stage 3 fibrosis. In the first cohort, 8
patients were randomized to receive 4 doses of either placebo
(2 patients) or 2 mg/kg lean body weight (lbw) of GR-MD-02
(6 patients) by intravenous infusion on days 0, 28, 35 and
42. Drug levels were measured following the first and fourth
doses. Serum biomarkers associated with fibrosis (including
FibroTest® and the Enhanced Liver Fibrosis (ELF) score), with
inflammation (including IL-6, TNFα and IL8), serum levels of
aminotransferases, and keratin 18 (K-18, also known as CK-18)
were assessed at day -1 and day 56. Results: GR-MD 02 was
safe and well tolerated following 4 doses of 2 mg/kg lbw with
no treatment-associated adverse events. The pharmacokinet-
ics were consistent between individuals and after single and
multiple doses with no drug accumulation. FibroTest® scores
were significantly reduced in GR-MD-02 treated patients (-27%
± 5.8 (SEM)) compared to placebo patients (3.5% ± 20.5,
p=0.04, α<0.1). Although there was a tendency towards
reduction in ELF scores in treated patients (-3.8% ± 1.2) com-
pared to placebo (-2% ± 2), the difference did not reach sig-
nificance (p=0.2, α<0.1). Patients treated with GR-MD-02 also
had significant reductions in serum biomarkers associated with
inflammation when compared to patients treated with pla-
cebo, including IL-6 (-16% ± 4.7 vs. 6.5% ± 4.5, p=0.02,
α<0.1), TNFα (-16% ± 6.9 vs. 20% ± 30, p=0.06, α<0.1),
and IL-8 (-25.5% ± 3.6 vs. -3.5% ± 12.5, p=0.02, α<0.1).
Additionally, patients with greater evidence of liver cell injury,
as indicated by elevated serum aminotransferase levels, had a
marked decrease in serum K-18. Galectin-3 blood levels, which
do not correlate with tissue levels in animal models of NASH,
were not changed with treatment. Conclusions: This first human
study of the galectin-3 inhibitor GR-MD-02 achieved its primary
safety endpoint at a dose of 2 mg/kg. Additionally, this initial
dose showed improvement in serum biomarkers of fibrosis and
inflammation suggesting a potential beneficial disease effect.
The clinical trial is ongoing using a dose of 4 mg/kg of GR-MD-
02, which will be followed by an 8 mg/kg dose cohort.
Disclosures:
Stephen A. Harrison - Advisory Committees or Review Panels: Merck, Nimbus
Discovery; Grant/Research Support: Merck, Genentech; Speaking and Teach-
ing: Merck, Vertex
Naga P. Chalasani - Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-
rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin
226A AASLD ABSTRACTS
Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharma-
ceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck &
Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals;
Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingel-
heim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharma-
ceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio,
Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teach-
ing: Gilead, Kadmon, Merck, Vertex
Arun J. Sanyal - Advisory Committees or Review Panels: Bristol Myers, Gilead,
Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Nimbus, Genentech, Echo-
sens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept,
Ikaria, Takeda, GalMed, Novartis, Gilead; Independent Contractor: UpToDate,
Elsevier
Brent A. Neuschwander-Tetri - Advisory Committees or Review Panels: Boehring-
er-Ingelheim
Peter G. Traber - Management Position: Galectin Therapeutics
The following people have nothing to disclose: Smitha Marri, Mazen Noureddin,
Thomas D. Schiano, Mohammad S. Siddiqui
58
Novel MRI and MRE in ezetimibe versus placebo for
the treatment of nonalcoholic steatohepatitis: Random-
ized-controlled trial (MOZART Trial)
Rohit Loomba1,2, Claude B. Sirlin4, Brandon Ang2, Ricki Betten-
court1, Rashmi Jain2, Joanie Salotti1, Linda M. Soaft1, Jonathan
Hooker4, Yuko Kono1, Archana Bhatt2, Laura D. Hernandez2,
Phirum Nguyen2, Mazen Noureddin1, William Haufe4, Catherine
A. Hooker4, Meng Yin5, Richard Ehman5, Grace Y. Lin3, Mark A.
Valasek3, David A. Brenner1, Lisa Richards1; 1Division of Gastro-
enterology and Epidemiology, University of California, San Diego,
La Jolla, CA; 2NAFLD Translational Research Unit, Division of Gas-
troenterology, University of California, San Diego, La Jolla, CA;
3Department of Pathology, University of California, San Diego,
La Jolla, CA; 4Liver Imaging Group, Department of Radiology,
University of California, San Diego, La Jolla, CA; 5Department of
Radiology, Mayo Clinic, Rochester, MN
Background: Ezetimibe is an intestinal-blocker of dietary cho-
lesterol absorption and lowers low density lipoprotein (LDL)
cholesterol. Recent uncontrolled trials suggest that it may
reduce liver fat as estimated by computed tomography and
improve liver histology in nonalcoholic steatohepatitis (NASH).
Well-designed trials are needed to examine the efficacy of
ezetimibe versus (vs.) placebo. Aim: To examine the efficacy
of ezetimibe vs. placebo in reducing liver fat as measured by
magnetic-resonance-imaging derived proton-density-fat-fraction
(MRI-PDFF) in patients with biopsy-proven NASH. Methods:
In this randomized, double-blind, allocation-concealed, pla-
cebo-controlled trial, 50 patients with biopsy-proven NASH
were randomized (1:1) to either ezetimibe 10 mg orally daily
or identical placebo for 24 weeks. The primary outcome was
a change in liver fat as measured by MRI-PDFF in co-localized
regions of interest within each of the 9 liver segments. Second-
ary and exploratory endpoints included LDL reduction, histolo-
gy-determined 2-point reduction in NAFLD activity score, and
MRE-derived reduction in liver stiffness, respectively. Results:
Ezetimibe was not significantly better than placebo in reducing
liver fat content as measured by MRI-PDFF (Mean difference
between ezetimibe and placebo arms, -1.3%, p-value =0.4).
Compared to baseline, end-of-treatment MRI-PDFF was signifi-
cantly lower in the ezetimibe (15% to 11.6%, p-value <0.016)
but not in the placebo (18.5% to 16.4%, p-value =0.15) arm.
As expected, ezetimibe was significantly better than placebo
in reducing LDL levels, confirming the lipid-lowering effect of
ezetimibe in patients with NASH. There were no significant
decreases in serum ALT and AST between the ezetimibe and
the placebo arms. There were no significant differences in lon-
gitudinal changes in 2D and 3D MRE-derived stiffness between
the ezetimibe and the placebo arms. Among patients who
HEPATOLOGY, October, 2014
underwent end-of-treatment liver biopsy, 5/17 patients in eze-
timibe arm and 5/18 patients in placebo arm had a 2-point
reduction in NAS and were classified as histologic responders.
Compared to histologic non-responders (25/35), histologic
responders (10/35) had a significantly greater reduction in in
MRI-PDFF (-4.35% ± 4.9 vs. -0.30% ± 4.1, p-value <0.019).
Conclusions: Ezetimibe is not better than placebo in reducing
liver fat or improving liver histology in NASH. Ezetimibe lowers
liver fat by a small but clinically insignificant amount. Histologic
responder vs. non-responder comparative analyses and place-
bo-arm changes with MRI-PDFF and MRE may improve future
clinical trials by providing more comprehensive assessment of
treatment and placebo effects.
Disclosures:
Rohit Loomba - Consulting: Gilead Inc, Corgenix Inc, Janssen and Janssen Inc;
Grant/Research Support: Daiichi Sankyo Inc, AGA, Merck Inc
Claude B. Sirlin - Advisory Committees or Review Panels: Bayer; Grant/Research
Support: GE, Pfizer, Bayer; Speaking and Teaching: Bayer
Meng Yin - Patent Held/Filed: Mayo Clinic, Mayo Clinic, Mayo Clinic, Mayo
Clinic
Richard Ehman - Board Membership: Resoundant Inc; Management Position:
Resoundant Inc; Patent Held/Filed: Mayo Clinic / GE, Mayo Clinic / GE; Stock
Shareholder: Resoundant Inc.
Lisa Richards - Speaking and Teaching: Kadmon, BMS, Vertex, Merck
The following people have nothing to disclose: Brandon Ang, Ricki Bettencourt,
Rashmi Jain, Joanie Salotti, Linda M. Soaft, Jonathan Hooker, Yuko Kono, Arch-
ana Bhatt, Laura D. Hernandez, Phirum Nguyen, Mazen Noureddin, William
Haufe, Catherine A. Hooker, Grace Y. Lin, Mark A. Valasek, David A. Brenner
59
The prognostic relevance of liver histology features in
nonalcoholic fatty liver disease: the PRELHIN study
Paul Angulo1, David E. Kleiner2, Sanne Dam-Larsen3, Leon
Adams4, Bjornsson S. Einar5, Phunchai Charatcharoenwitthaya6,
Peter R. Mills7, Jill C. Keach8, Svanhildur Haflidadottir5, Flemming
Bendtsen3; 1Div. of Digestive Diseases & Nutrition, University of
Kentucky Medical Center, Lexington, KY; 2Laboratory of Pathol-
ogy, National Cancer Institute, Bethesda, MD; 3Department of
Gastroenterology, Hvidovre Hospital and Faculty of Health Sci-
ence,University of Copenhagen, Copenhagen, Denmark; 4School
of Medicine and Pharmacology, University of Western Australia,
Perth, WA, Australia; 5Section of Gastroenterology and Hepatol-
ogy, National University Hospital, Reykjavik, Iceland; 6Faculty of
Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand;
7Gartnavel General Hospital, Glasgow, United Kingdom; 8Div.
of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
Liver biopsy is often performed to confirm the diagnosis of non-
alcoholic fatty liver disease (NAFLD), but it remains uncertain
what prognostic information can be obtained from grading and
staging the disease. Aim: To determine the long-term prognostic
relevance of liver histological features in patients with NAFLD.
Methods: A cohort of 619 patients with NAFLD confirmed by
liver biopsy were included. Liver biopsies were scored by a sin-
gle liver pathologist (Dr. David Kleiner). The grade of steatosis,
inflammation and ballooning, and the NAFLD activity score
(NAS) were recorded. The diagnosis of NASH was recorded
and categorized as non-NASH, borderline/suspicious, or
definitive NASH. Fibrosis was staged on a 0-4 scale. Out-
comes analyzed were 1) overall mortality/liver transplantation,
and 2) liver-related events. Cumulative outcomes were calcu-
lated using Kaplan–Meier analysis and compared by log-rank
testing. Adjusted hazard ratio (HR) estimates were calculated
by Cox proportional hazard regression analysis including ste-
atosis, inflammation, ballooning, NAS, NASH, and fibrosis
stage, along with variables that may affect the outcomes such
as age, sex, race, BMI, diabetes, hypertension, use of statins,
site, and smoking. Time at risk (T0) was from the date of liver
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
biopsy to the date of outcome or last follow-up. Results Average
age was 49±15 years, and 62.5% were women. The average
NAS was 3.6±1.7; and 179 (29%) had definitive NASH. F0
was present in 322 (52%), and F3-4 in 71 (11.5%). The aver-
age follow-up was 152±88 months (range 4-551). A total of
192 patients died and 1 patient underwent liver transplanta-
tion. Variables independently associated with the outcome of
death/liver transplantation are described in the table below. A
total of 39 liver-related events occurred in 26 patients. Fibrosis
stage 3 (HR 14.2 [95% CI 3.38, 59.68] p<0.001) and stage
4 (HR 51.5 [95% CI 9.87, 269.2]; p<0.001) as compared to
stage 0 were the only variables independently associated with
the outcome of liver-related events. Conclusions: Fibrosis stage
but no other histological features or presence of NASH is inde-
pendently associated with overall death/liver transplantation
and liver related events in patients with NAFLD.
Disclosures:
The following people have nothing to disclose: Paul Angulo, David E. Kleiner,
Sanne Dam-Larsen, Leon Adams, Bjornsson S. Einar, Phunchai Charatcharoenwit-
thaya, Peter R. Mills, Jill C. Keach, Svanhildur Haflidadottir, Flemming Bendtsen
60
Metabolomic analysis identifies new biomarkers of liver
damage in NAFLD
Ester Vanni1, Chiara Rosso1, Lavinia Mezzabotta1, Chiara Sapon-
aro2, Melania Gaggini2, Roberto Gambino1, Ramy Ibrahim Kamal
Jouness1, Francesca Saba1, Emma Buzzigoli2, Fabrizia Carli2,
Gian Paolo Caviglia1, Maria Lorena Abate1, Antonina Smedile1,
Mario Rizzetto1, Maurizio Cassader1, Amalia Gastaldelli2, Elis-
abetta Bugianesi1; 1Medicale Science, University of Turin, Turin,
Italy; 2Cardiometabolic Risk Unit, Institute of Clinical Physiology,
CNR, Pisa, Italy
Background and aims: Mass spectrometry based metabolomics
is used to identify new biomarkers related to alteration in organ
metabolism. We have used this technique to analyse plasma
samples of subjects with NAFLD and identify possible markers of
severity of liver disease associated with metabolic dysfunction.
Methods: We studied 54 subjects, 45 NAFLD with liver biopsy
and 9 healthy control (CT) and measured plasma concentration
profile of amino acids (AA) and fatty acid (FA) by GCMS. Data
were correlated with NAS and fibrosis score, indexes of insulin
resistance (IR) measured by tracers, LFTs, beta–hydroxybutyrate
(BOH), ox-LDL, total antioxidative status (TAS), sRAGE, and
adiponectin. We calculated: a) using tracer infusion, hepatic
IR as endogenous glucose production x fasting insulin (HIR=EG-
PxFPI), adipose tissue insulin resistance (AT-IR) as fasting lip-
olysis x FPI; b) from fatty acid composition we calculated de
novo lipogenesis index (DNL=16:0/18:2) and SCD1 activity
as 16:1/16:0; c) from AA profile, the branched chain concen-
trations (BCAA) and the ratio of glutamate/(glycine +serine),
that is as an index of glutathione biosynthesis (GSH-I). Results:
Compared to controls, subjects with NAFLD had increased
H-IR (118±10 vs. 56±7) and AT-IR (34±3 vs. 13±2), GSH-I
(0.73±0.06 vs 0.33±0.09), DNL (1.17±0.05 vs 0.86±0.04)
and SCD1 (0.10±0.01vs 0.08±0.01) indices compared to
227A
controls. GSH_I was increased proportionally to the severity of
fibrosis (r=0.36 per trend, p<0.0001), ln(cholesterol) (r=0.39)
and negatively with ln(sRAGE) (r=0.30) but not with TG liver
content nor with NAS score, TAS, ox-LDL and adiponectin. DNL
was increased proportionally to circulating ln(TG) (r=0.53), fat
in biopsy (r=0.31) and both DNL and SCD-1 were increased
with high fibrosis Fib1/2 and Fib3/4 (p<0.05). GSH-I, DNL
and SCD1 were positively associated with the degree of
AT-IR (r=0.28; r=0.41; r=0.43) and of H-IR(r=0.39; r=0.28;
r=0.32). Conclusion: Metabolomic analysis allowed the iden-
tification of indexes (GSH-I, DNL and SCD1) associated with
increased hepatic and adipose tissue insulin resistance and
severity of fatty liver disease. Funded by FP7/2007-2013
under grant agreement n° HEALTH-F2-2009-241762 for the
project FLIP and PRIN 2009ARYX4T
Disclosures:
Mario Rizzetto - Advisory Committees or Review Panels: Merck, Janssen, BMS
The following people have nothing to disclose: Ester Vanni, Chiara Rosso, Lavinia
Mezzabotta, Chiara Saponaro, Melania Gaggini, Roberto Gambino, Ramy
Ibrahim Kamal Jouness, Francesca Saba, Emma Buzzigoli, Fabrizia Carli, Gian
Paolo Caviglia, Maria Lorena Abate, Antonina Smedile, Maurizio Cassader,
Amalia Gastaldelli, Elisabetta Bugianesi
61
HCV hijacks host exosomes for mediating alternative
active viral transmission and disease persistence
Terence N. Bukong, Fatemah Momen-Heravi, Karen Kodys, Shashi
Bala, Gyongyi Szabo; UMass Medical School, Worcester, MA
Background: While antiviral therapies offer significant treat-
ment advances, there is no vaccine against HCV and neu-
tralizing antibody therapies failed to block receptor–mediated
HCV transmission. This indicates that HCV infection involves
receptor-independent mechanisms. Exosomes are small cell-de-
rived vesicles that carry nucleic acids. Evidence suggests
that exosomes can mediate receptor-independent transfer of
genetic material between cells and their role in HCV infection
is uncertain. Aim: To evaluate the presence of HCV viral RNA
in exosomes and to determine mechanistic role of exosomes in
HCV transmission. Methods: For the first time, we established
a reliable immune-isolation method based on the exosomes
surface marker (CD63) to efficiently distinguish and purify cell
free virus and exosomes from patient serum and cell culture
supernatant. Using density particulate separation with immu-
nomagnetic separation, NanoSight, RT-qPCR, western blotting,
chromatin immuno-precipitation (ChIP) and ELISA we assessed
the role of exosomes to modulate HCV transmission and dis-
ease persistence in chronic HCV infected patients. Results: Our
exosome and virus isolation methods resulted in exosomes free
of virus contamination and vice versa. We determined that
exosomes, in contrast to viral-lipo proteins, contained APOB
and no APOE. We found replication competent HCV RNA in
exosomes from supernatants of HCV J6/JFH-1 infected Huh7.5
cells and from serum of HCV infected patients (some treat-
ment naïve and all IFN non-responders). These HCV exosomes
mediated HCV transmission to naïve Huh7.5 cells and primary
human hepatocytes even in the presence of HCV receptor
blocking antibody (anti-CD81, -ApoE and -SB-RI) pre-treatments.
HCV exosomes from most treatment-naïve and all treatment
non-responder patients resulted in effective virus transmission
and replication. Using RNA-ChIP analysis of exosomes iso-
lated from HCV J6/JFH-1 infected Huh 7.5 cells or from HCV
infected patients, we found that Ago2 which enhances HCV
replication, was associated with miR-122, positive sense HCV
RNA and, in some cases, negative sense HCV RNA. From
the therapeutic standpoint, vacuolar-type H+-ATPase inhibitor
and proton pump inhibitor could block exosome-mediated and
228A AASLD ABSTRACTS
even free virus mediated transmission of HCV to Huh 7.5 hep-
atoma cells. Conclusions: In summary, our novel findings pro-
vide mechanistic insights into how exosomes mediate cell-to-cell
viral transmission independent of HCV receptors. Furthermore,
our data suggest that circulating exosomes carry and transmit
replication competent HCV RNA in complex with miR-122 and
infect primary human hepatocytes.
Disclosures:
Gyongyi Szabo - Consulting: Idenix; Grant/Research Support: BMS, GSK, Cona-
tus, Idera, Johnson&Johnson, Novartis, Ocera, Roche, Shering - Plough, Wyeth,
Integrated Therapeutics, Idera
The following people have nothing to disclose: Terence N. Bukong, Fatemah
Momen-Heravi, Karen Kodys, Shashi Bala
62
Dynamic Association of DDX3X with Stress Granules
and Lipid Droplets in Hepatocytes Confers Multiple
Functions of DDX3X in Hepatitis C Virus Infection
Veronique Pene, Qisheng Li, Catherine Sodroski, Ching-Sheng
Hsu, T. Jake Liang; Liver Diseases Branch, NIDDK, NIH, Bethesda,
MD
The DExD/H-box helicase DDX3X is a ubiquitous ATP-depen-
dent RNA helicase with functions in innate immunity, mRNA
processing and translation initiation. Despite being implicated
in induction of IFN-β by RIG-I like helicases, DDX3 appears to
be a strong proviral host factor for HCV infection. Recently, we
showed that DDX3X, as a potential pattern recognition recep-
tor, specifically interacts with HCV 3’ UTR, leading to activa-
tion of IKK-α, which translocates to the nucleus and induces
lipogenesis and lipid droplet (LD) formation to facilitate viral
assembly (Li et al., Nat Med 2013). HCV core also binds to
and redistributes DDX3X to the viral assembly sites around LD;
however, this interaction seems to be dispensable for HCV
production and HCV-triggered activation of DDX3X–IKK-α path-
way. In this study, through extensive confocal microscopic,
biochemical and virologic approaches, we report dynamic
interactions of DDX3X with various cellular structures, viral ele-
ments and IKK-α that may confer multiple functions of DDX3X in
productive HCV infection. We show that upon HCV infection,
DDX3X redistributed to form speckle-like cytoplasmic structures
that partially co-localized with either core at the surface of
LD or IKK-α. Treatment of hepatocytes with HCV 3’UTR also
triggered DDX3X–IKK-α aggregation and association. These
DDX3X–IKK-α complexes colocalized closely with G3BP1, a
bona fide marker of stress granules (SGs), but not with LD,
mitochondria, peroxisome or autophagosome. During the time-
course of HCV infection, there was a dynamic shift in the asso-
ciations among DDX3X, IKK-α, SGs, and core/LD. Early after
infection, DDX3X–IKK-α puncta associated only with SGs. Later
when core was abundantly expressed, part of DDX3X puncta
appeared to interact with core around LD. Interestingly, SGs
were also seen to gradually translocate to LD late post-infection,
whereas IKK-α-associated SGs remained unbound to LD, prob-
ably representing the precursor step of nuclear translocation
of IKK-α to activate cellular lipogenesis and HCV assembly. In
HCV-infected cells, NS3 and 5A were also shown to colocalize
with DDX3X in close proximity to SGs and LD, consistent with
the tight juxtaposition of the replication complex and core-con-
taining LD during HCV replication and assembly. In addition,
siRNA-mediated silencing of DDX3X and various SG compo-
nents significantly inhibited HCV replication and production.
Our data suggest that DDX3X initiates a multifaceted cellular
program involving dynamic associations with HCV, IKK-α, SGs
and LD for its pivotal role in HCV replication and assembly.
Disclosures:
HEPATOLOGY, October, 2014
The following people have nothing to disclose: Veronique Pene, Qisheng Li,
Catherine Sodroski, Ching-Sheng Hsu, T. Jake Liang
63
Interleukin-17 favors progenitor cell proliferation and
differentiation in regenerating liver through IL-27/
WSX-1 axis
Adrien Guillot1,2, Nabila Hamdaoui1,2, Julien Calderaro1,2,
Jean-Michel Pawlotsky1,2, Sophie Lotersztajn1,2, Fouad Lafdil1,2;
1IMRB U955, INSERM, Créteil, France; 2UPEC University of Paris,
Créteil, France
Introduction. Liver Progenitor Cell (LPC) proliferation is fre-
quently observed, in chronic liver disease including cirrhosis,
hepatitis B and C infection, and referred to as ductular reac-
tion. LPC are bipotent cells that proliferate and differentiate
into hepatocyte and biliary cells, under the control of innate
and adaptive immune response, to achieve liver regeneration.
Gp130-mediated IL-6 signaling was identified as a key point
in supporting LPC proliferation. Interestingly, IL-27 cytokine,
produced by macrophages signals through a heterodimeric
receptor composed of gp130 and WSX-1 subunits but its role
in LPC driven hepatic regeneration is unknown. Furthermore,
T lymphocytes including Th1 and Th17 subpopulations were
identified in regenerating livers from LPC. Th1 cells directly
repress LPC development via IFN-g production, and the role of
Th17 cells producing both IL-22 and IL-17 cytokines is not fully
uncover. While IL-22 was shown to promote LPC proliferation,
the role of IL-17 is still unclear. Thus, we proposed to determine
the potent role of IL-17 in LPC proliferation and differentiation
in regenerating liver. Materials and methods. Liver samples
from patients with chronic liver disease were immunostained
with anti-CK19 and anti-IL-17 antibodies. Wild-type (WT), IL-17
(IL-17-/-) and WSX-1 (WSX-1-/-) deficient mice were subjected
to a model of liver regeneration from LPCs induced by a cho-
line deficient, and ethionine supplemented diet (CDE). Immune
response was analyzed by quantitative RT-PCR. LPC prolifera-
tion was assessed by anti-CK19 and anti-Ki67 immunostain-
ing. IL-17 effect on murine macrophage (RAW) phenotype was
analyzed by qRT-PCR. Murine LPC (BMOL) proliferation was
assessed by proliferation assay (MTS), and their differentiation
was studied by qRT-PCR and Western blot. Results. In liver sam-
ples from patients with ductular reaction, infiltrated IL-17+ cells
were localized close to CK19+ cells. In parallel, we showed
in CDE treated IL-17-/- mice, reduced CK19+Ki67+ proliferat-
ing LPC, and less hepatic inflammation including a significant
decrease in IL-27 expression, when compared with WT mice.
Besides, IL-17 could directly target macrophages to induce
IL-27 expression, and directly acted on LPC to promote their
proliferation. Interestingly, disrupted IL-27/WSX-1 signaling
in WSX-1-/- mice led also to a decrease in LPC number, and
reduced liver inflammation. IL-27 can directly target LPC and
favor their differentiation into hepatocytes. Conclusion. Taken
together, these data provide evidence of a collaborative role of
IL-17 and IL-27 in promoting liver regeneration. IL-27/WSX-1
axis promotes LPC differentiation into hepatocytes.
Disclosures:
Jean-Michel Pawlotsky - Consulting: Abbott, Achillion, Boehringer-Ingelheim, Bris-
tol-Myers Squibb, Idenix, Gilead, Janssen, Madaus-Rottapharm, Merck, Novartis,
Roche; Grant/Research Support: Gilead; Speaking and Teaching: Boehring-
er-Ingelheim, Bristol-Myers Squibb, Gilead, Madaus-Rottapharm, Merck, Jans-
sen-Cilag, Novartis, Abbott
The following people have nothing to disclose: Adrien Guillot, Nabila Hamd-
aoui, Julien Calderaro, Sophie Lotersztajn, Fouad Lafdil
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
64
Patients with alcoholic hepatitis present strong Th1 cellu-
lar immune responses to alcohol dehydrogenase, which
are related to impairment of the PD-1/PD-L1 pathway
Laura J. Blackmore1, Jennifer M. Ryan1, Godhev K. Manakkat
Vijay1, Xiaohong Huang1, Charalambos G. Antoniades2,1, Debbie
Shawcross1, Yun Ma1; 1Institute of Liver Studies & Transplantation,
King’s College London School of Medicine at King’s College Hos-
pital, London, United Kingdom; 2Hepatology Research Unit, St.
Mary’s Hospital, Imperial College, London, United Kingdom
Background: One third of people who drink to excess develop
alcoholic hepatitis (AH), characterised by florid hepatic inflam-
mation and death within 28 days in 35% of patients. We
recently reported that AH patients present strong cellular
immune responses to alcohol dehydrogenase (ADH), with a
predominant Th1 and a limited Th2 response. We have also
observed that AH patients have a reduced frequency of sup-
pressive PD-1 expressing CD4 T cells compared to healthy
controls. We postulate that the imbalanced cellular immune
response to ADH is related to a defect in the PD-1/PD-L1 path-
way, which negatively regulates T cells and is essential for
the maintenance of peripheral tolerance. Methods: Peripheral
blood mononuclear cells (PBMC) were collected from 7 patients
with AH (modified Maddrey’s DF ≥32; median age 48 years;
5 males). 25 overlapping peptides, spanning the human ADH
β1 subunit were constructed using fmoc solid phase chemistry.
1x105 cells/well were cultured with 2μl/ml CD3/CD28 T cell
stimulator and 50 units/ml IL-2, with and without 10μM of 8
ADH peptides, selected based on antigenicity and ability to
induce proliferation and IFNγ/IL-17 production from prelimi-
nary assays. Cells were cultured for 8 days in the presence or
absence of anti-PD-1, anti-PD-L1 or combined anti-PD-1/PD-L1
neutralizing antibodies. Cells were harvested and FACS was
used to determine T cell phenotype and the percentage of cyto-
kine producing T cells in each condition. Results: Both with and
without ADH peptides, CD4 T cells from AH patients secreted
more IFNγ (Th1) than Th2 cytokines IL-4 and TGF-β (p=0.01 to
p=0.046). In culture without ADH peptides, after adding com-
bined anti-PD-1 and anti-PD-L1, the changes in the frequency of
Th1 and Th2 cytokine producing CD4 T cells were not signifi-
cant. In culture with ADH peptides, the frequency of IFNγ pro-
ducing CD4 T cells remained at the same high level in cultures
with anti-PD-1, anti-PD-L1 and combined blockade. However,
the frequency of IL-4 and TGF-β producing CD4 T cells was
significantly decreased and this effect was strongest in the pres-
ence of combined blockade (IL-4 p=0.06; TGF-β p=0.017).
Conclusion: In this ex vivo culture simulating impairment of the
PD-1/PD-L1 pathway, we observed a significant decrease in
Th2 cytokine production after stimulation with antigenic ADH
peptides, which contributes to the imbalanced cellular immune
response in AH. Our results indicate that impairment of the reg-
ulatory PD-1/PD-L1 pathway may contribute to the pathogenic
Th1 immune response against ADH in AH. New AH therapies
should interrogate immunoregulatory mechanisms to limit this
inappropriate and damaging immune response.
Disclosures:
Debbie Shawcross - Advisory Committees or Review Panels: Norgine; Grant/
Research Support: Norgine; Speaking and Teaching: Norgine
The following people have nothing to disclose: Laura J. Blackmore, Jennifer M.
Ryan, Godhev K. Manakkat Vijay, Xiaohong Huang, Charalambos G. Antonia-
des, Yun Ma
229A
65
Blockage of CCL5/RANTES modifies immune infiltration
and the inflammatory milieu during chronic liver dis-
ease
Antje Mohs, Francisco Javier Cubero, Nadine Kuttkat, Christian
Trautwein; Department of Medicine III, University Hospital RWTH
Aachen, Aachen, Germany
Background: The inflammatory response during chronic liver
injury is a dynamic process with intrahepatic homing of T cells,
macrophages, and dendritic cells. During the migration of
immune cells, the CCL5/RANTES chemokine signaling path-
way has been shown to have detrimental effects during inflam-
matory disorders, including acute Con A–induced liver. In this
study, we aimed to evaluate the importance of CCL5/RANTES
in a novel experimental murine model of chronic liver injury.
Methods: Inactivation of CCL5-/- in hepatocyte-specific NEMO
knockout (NEMOΔhepa) mice was achieved by generation of
NEMOΔhepa/CCL5-/- double knockout mice. Characterization
of the progression of chronic inflammatory liver disease and
end-stage hepatocellular carcinoma (HCC) was investigated.
Additionally, we performed bone marrow transplantation (BMT)
to address the contribution of hematopoietic-derived CCL5/
RANTES to disease progression. Results: Genetic inactivation
of CCL5/RANTES ameliorated liver injury in NEMOΔhepa mice
as assessed by significant lower serum transaminases - ALT,
AST - and alkaline phosphatase (AP) levels. Concomitant with
these findings, 8 week-old NEMOΔhepa/CCL5-/- mice showed
reduced hepatic cell death (TUNEL, cleaved Caspase-3) and
decreased compensatory proliferation (Ki-67, PCNA). More-
over, liver fibrogenesis (Sirius red, Collagen IA1, TGF-β) were
significantly reduced in NEMOΔhepa/CCL5-/-. At 1 year of
age, NEMOΔhepa/CCL5-/- mice displayed smaller HCC nod-
ules and reduced vascularization. Next we aimed to under-
stand if the amelioration of liver inflammation and progression
of HCC observed in NEMOΔhepa/CCL5-/- was due to changes
in the pro-inflammatory cytokine milieu. We observed signifi-
cantly lower levels of TNFα, IL-1β and MCP-1, CD45+ Ly6G+
polymorphonuclear cells (PMN), CD45+ CD11b+ Gr1.1+
F4/80+ pro-inflammatory monocytes, and T-CD4+- and CD8+
cells in NEMOΔhepa/CCL5-/- mice. Moreover, BMT experi-
ments demonstrated that the hematopoietic-derived CCL5 is
crucial for immune cell infiltration and disease progression of
NEMOΔhepa. Conclusion: Hematopoietic cells-derived CCL5/
RANTES plays an important role for NEMOΔhepa-dependent
disease progression by activating pro-inflammatory cytokines
and immune cell infiltration. As a consequence CCL5/RANTES
drives apoptosis, proliferation, hepatitis, and HCC occurrence.
These results indicate that pharmacological modulation of
CCL5/RANTES might be of clinical relevance.
Disclosures:
Christian Trautwein - Grant/Research Support: BMS, Novartis, BMS, Novartis;
Speaking and Teaching: Roche, BMS, Roche, BMS
The following people have nothing to disclose: Antje Mohs, Francisco Javier
Cubero, Nadine Kuttkat
66
Inflammatory liver injury is associated with altered
alkaline phosphatase activity and hepatic asialoglyco-
protein receptor function
David P. Newton2, Dean J. Tuma2, Carol A. Casey1,2, Benita
L. McVicker1,2; 1Research Service, VA Nebraska-Western Iowa
Health Care System, Omaha, NE; 2Internal Medicine, University
of Nebraska Medical Center, Omaha, NE
Background: Alkaline phosphatase (AP) is a well-recognized
biomarker for liver diseases, especially those related to inflam-
230A AASLD ABSTRACTS
matory insults and the endotoxin lipopolysaccharide (LPS).
The AP enzyme is known to dephosphorylate LPS leading to
the attenuation of LPS-mediated liver damage. The asialogly-
coprotein receptor (ASGPR), a hepatic trafficking protein, is
known to bind and internalize AP resulting in proper AP reg-
ulation and LPS detoxification. We hypothesize that altered
ASGPR function leads to the loss of AP protective mechanisms
and enhanced liver injury. Methods: AP activity and expres-
sion were evaluated in comparison to liver injury in models
of known ASGPR dysfunction; ethanol-fed rats and ASGP
receptor-deficient (RD) mice. Results: Chronic ethanol feeding
resulted in elevated serum transaminases and a 2-fold increase
in inflammatory liver injury parameters (TNF-alpha, caspase-3,
triglycerides). Also, a significant 3-fold increase (p<0.02) in the
expression of pro-inflammatory liver macrophages (M1) was
detected in ethanol-fed rats whereas no change was observed
in the anti-inflammatory (M2) cells. Moreover, the binding and
internalization activity of the ASGPR was significantly reduced
(50-70%) in the ethanol-fed rats. Coincident with ethanol-in-
duced liver injury, liver AP mRNA levels were enhanced (30-
40%) which paralleled an increase in serum AP activity in the
alcohol-fed group. However, the activity of AP in the ethanol-in-
jured livers was found to be significantly reduced by 20-30%
(p<0.05). In another model, when animals devoid of ASGPRs
(RD mice) were treated with LPS, enhanced measures of liver
injury (TNF-alpha levels, serum enzymes) were detected com-
pared to saline or LPS-treated wild-type (WT) mice. It is known
that acute LPS challenge results in reduced serum AP levels
presumably due to AP uptake by hepatocyte ASGPRs. In agree-
ment, a 30% reduction in serum AP was seen in ASGPR-express-
ing WT mice 8 hours after LPS injection. In contrast, serum AP
levels in RD mice were not altered following the LPS challenge.
Moreover, hepatic AP activity in WT mice did not change, but
was reduced (25-30%) in the RD livers. Conclusions: Alter-
ations in AP uptake and activity in the liver is associated with
impaired hepatic ASGPR function and enhanced inflammatory
liver injury. We believe that the hepatic ASGPR plays a critical
role in liver inflammatory responses including the regulation of
the protective enzyme alkaline phosphatase. Further character-
ization of processes involved in ASGPRs control of AP activity
and LPS detoxification mechanisms could significantly enhance
treatment options for alcoholic liver disease.
Disclosures:
The following people have nothing to disclose: David P. Newton, Dean J. Tuma,
Carol A. Casey, Benita L. McVicker
67
Multiplex PCR Assay for Simultaneous Detection of
Genomes of Hepatitis A, B, C, D and E Viruses
Maja Kodani, Tonya Mixson-Hayden, Jan Drobeniuc, Saleem
Kamili; Division of Viral Hepatitis, Centers for Disease Control and
Prevention, Atlanta, GA
To date, five viruses, hepatitis A virus (HAV), hepatitis B virus
(HBV), hepatitis C virus (HCV), hepatitis delta virus (HDV) and
hepatitis E virus (HEV), have been etiologically associated with
hepatitis. These viruses vary widely in their natural history,
genome structure and composition, and mode of transmission.
HAV, HCV, HDV and HEV are RNA viruses while HBV is a DNA
virus. Since viral hepatitides are clinically indistinguishable,
various testing algorithms need to be employed to identify their
etiology. Nucleic acid testing (NAT) remains the gold standard
for diagnosis of active and viremic stages of infection. NAT
methodologies based on qualitative and quantitative PCR have
been developed for all five hepatitis viruses; however, a NAT-
based multiplex assay that can simultaneously detect all five
HEPATOLOGY, October, 2014
viruses is not available. We designed standardized TaqMan
assays for simultaneous detection of HAV RNA, HBV DNA,
HCV RNA, HDV RNA and HEV RNA. Individual PCR assays
for each virus were first optimized to run under identical exper-
imental conditions. The performances of these assays were then
evaluated on TaqMan Array Cards (TAC) for detecting five
viral genomes simultaneously. Sensitivity and specificity were
determined by testing 329 clinical specimens, which had been
tested for hepatitis viruses using laboratory-developed PCR tests
for detecting HAV, HBV, HCV, HDV and HEV. All samples for
HCV (n=32), HDV (n=28) and HEV (n=14) were found positive
in the TAC assay (sensitivity, 100%). 43 of 46 HAV-NAT pos-
itive samples were also positive in the TAC assay (sensitivity,
94%), while 36 of 39 HBV-NAT positive samples were positive
(sensitivity, 92%). No false-positives were detected for HBV
(n=32), HCV (n=36), HDV (n=30), and HEV (n=31) NAT-neg-
ative samples (specificity 100%), while 38 of 41 HAV-NAT
positive samples were positive by the TAC assay (specificity
93%). Overall, the TAC assay was concordant with individual
NATs for hepatitis A-E viral genomes and can be used for their
detection simultaneously in a multiplex format. The TAC assay
has potential for use in hepatitis surveillance and for screening
of clinical specimens in outbreak situations. Wider availability
of TAC-ready assays may allow for customized assays, for
improving acute jaundice surveillance and for other purposes
for which there is need to identify multiple pathogens rapidly.
Disclosures:
The following people have nothing to disclose: Maja Kodani, Tonya Mix-
son-Hayden, Jan Drobeniuc, Saleem Kamili
68
Serologic Testing Rates among US Veterans with Hepa-
titis B
Marina Serper2, Kimberly A. Forde2, David E. Kaplan1,2;
1Research and Gastroenterology, Philadelphia VA Medical Cen-
ter, Philadelphia, PA; 2Division of Gastroenterology, University of
Pennsylvania, Philadelphia, PA
OBJECTIVE: Hepatitis B Surface Antigen (HBsAg) is the ini-
tial screening test for detection of acute and chronic Hepatitis
B virus (HBV) infection. Chronic HBV treatment decisions are
based on additional serologic and biochemical testing rec-
ommended by the American Association for the Study of Liver
Diseases (AASLD). Few data exist on adherence to published
guidelines on testing and treating in HBV. METHODS: We
queried the Veterans Administration Corporate Data Ware-
house to identify adult patients with any positive HBsAg result
from 2002 to 2014. We determined if the following testing
was ever performed at any time following the positive HBsAg
result: HBeAg, HBeAb, HBcIgM, HDVAb, HDV RNA, HCVAb,
HIVAb. We queried whether the following testing was per-
formed within ± 180 days from the first HBsAg+ test: alanine
aminotransferase (ALT) and HBV DNA. We also assessed anti-
viral therapy treatment rates. RESULTS: A total of 2,643,089
Veterans underwent HBsAg screening of whom 50,109 (1.9%)
were positive. Of these 47622 (95.2%) were new diagno-
ses. The median age of new HBsAg+ individuals was 53 (IQR
44-61); 88.6% were male; 46.6% white, 31.4% black, 2.4%
Asian, 0.2% Hispanic, and 16% had unreported ethnicity. The
median ALT level for the 36969 (77.6%) of individuals with an
ALT drawn within 6 months of HBV testing was 43 (IQR 26-84)
and median serum bilirubin was 0.8 (IQR 0.6-1.1). Among
HBsAg+ individuals, 17.2% received testing for HBcIgM,
23.7% for HBeAg, 20.7% for HBeAb, 78.2% for HCV Ab,
33.2% for HIV Ab, 4.1% for HDVAb or HDV RNA, and 14.2%
had HBV DNA PCR testing. A total of 6605 of 47622 patients
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
(13.8%) received antiviral therapy. Of the 13144 patients with
ALT > 2x ULN (62 IU/ml), only 21.3% received antiviral ther-
apy; of the HBeAg+ patients with HBV DNA >20,000 IU/
ml, 72.2% received antiviral therapy. In patients with HBeAg-
hepatitis and HBV DNA > 2000IU/ml, only 34.7% received
antiviral therapy. CONCLUSIONS: Chronic HBV infection is
approximately 4 times more common in the Veteran popula-
tion than in the general US population. Among HBsAg+ Vet-
erans, the rates of serologic testing as recommended by the
AASLD for treatment stratification were suboptimal. Among
those tested, adherence to treatment guidelines was low, par-
ticularly for HBeAg-negative individuals. These data suggest
that significant provider education and improvement in clinical
processes are needed to improve provider adherence to testing
and treatment guidelines.
Disclosures:
David E. Kaplan - Grant/Research Support: Bayer Pharmaceuticals
The following people have nothing to disclose: Marina Serper, Kimberly A. Forde
69
Longitudinal serologic profiles up to 5 years in hepatitis
B surface antigen-negative chronic hepatitis B
Wai-Kay Seto1, Yasuhito Tanaka2, Danny Wong1, Noboru
Shinkai2, Ka-Shing Cheung1, Sze Hang Kevin Liu1, James Fung1,
Ching-Lung Lai1, Man-Fung Yuen1; 1Medicine, The University of
Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong;
2Virology and Liver Unit, Nagoya City University Graduate School
of Medical Sciences, Nagoya, Japan
Background: Hepatitis B virus (HBV) persists at low replicative
levels among chronic hepatitis B (CHB) patients after hepatitis
B surface antigen (HBsAg) seroclearance. The long-term sero-
logic profiles after HBsAg seroclearance in CHB have not been
well investigated. Methods: We used a highly-sensitive HBsAg
(hs-HBsAg) assay employing a semiautomated immune com-
plex transfer chemiluminescence enzyme technique (ICT-CLEIA,
Sysmex, Kobe, Japan) for the detection of HBsAg. The lower
limit of detection was 0.0005 IU/mL, 100 times more sensitive
than conventional HBsAg assays. We measured hs-HBsAg,
HBV DNA levels (Cobas Taqman, Roche Diagnostics, lower
limit of detection 20 IU/mL) and antibody to HBsAg (anti-HBs,
Abbott Laboratories, lower limit of detection 10 mIU/mL) in
CHB patients achieving HBsAg seroclearance, as documented
by Elecsys HBsAg II (Roche Diagnostics, lower limit of detection
0.05 IU/mL) at 3 time points: at the time of HBsAg seroclear-
ance, 6-12 months after HBsAg seroclearance and 3-5 years
after HBsAg seroclearance, if available. Results: 109 patients
(76.1% male, genotype B/C distribution 53.2%/47.8%) were
recruited. The mean age of HBsAg seroclearance was 49.5
(±10.9) years, with mean duration of documented HBsAg-pos-
itivity at our center before seroclearance 7.5 (±4.2) years. 25
patients (22.9%) were on nucleoside analogue therapy for a
mean duration of 5.5 (±3.2) years before HBsAg seroclear-
ance. 11 patients (10.1%) had detectable HBV DNA (median
level 37 IU/mL) at HBsAg seroclearance. Detectable hs-HBsAg
was noted in 88 (80.7%), 60 (55.0%) and 19 (20.2%) patients
at HBsAg seroclearance, 6-12 months after HBsAg seroclear-
ance and 3-5 years after HBsAg seroclearance respectively
(median detectable levels 0.0409, 0.0173 and 0.0102 IU/
mL respectively). Among patients with 3-5 years of follow-up
(n=94), hs-HBsAg positive patients at years 3-5, when com-
pared to hs-HBsAg negative patients, had a higher propor-
tion of anti-HBs negativity (90.0% and 36.5% respectively,
p=0.028). When considering all measurements together, anti-
HBs negativity, compared to anti-HBs positivity, was associated
with a higher rate of hs-HBsAg positivity (66.4% and 24.2%
231A
respectively, p<0.001). HBV genotype (B versus C) and pres-
ence of antiviral therapy had no association with hs-HBsAg pos-
itivity (p=0.803 and 0.283 respectively). Conclusion: Serum
hs-HBsAg achieved substantial rates of detectability during
HBsAg-negative phase of CHB. Anti-HBs negativity was associ-
ated with higher rates of hs-HBsAg detection. Serum hs-HBsAg
could potentially assist the differentiation of occult hepatitis B
patients from individuals with only past HBV exposure.
Disclosures:
Wai-Kay Seto - Advisory Committees or Review Panels: Gilead Science; Speak-
ing and Teaching: Gilead Science, Bristol-Myers Squibb
Yasuhito Tanaka - Grant/Research Support: Chugai Pharmaceutical CO., LTD.,
MSD, Mitsubishi Tanabe Pharma Corporation, Dainippon Sumitomo Pharma
Co., Ltd., DAIICHI SANKYO COMPANY, LIMITED, Bristol-Myers Squibb
Ching-Lung Lai - Advisory Committees or Review Panels: Bristol-Myers Squibb,
Gilead Sciences Inc; Consulting: Bristol-Myers Squibb, Gilead Sciences, Inc;
Speaking and Teaching: Bristol-Myers Squibb, Gilead Sciences, Inc
Man-Fung Yuen - Advisory Committees or Review Panels: GlaxoSmithKline,
Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer,
GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-My-
ers Squibb, Pfizer; Grant/Research Support: Roche, Bristol-Myers Squibb,
GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmith-
Kline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead
Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science
The following people have nothing to disclose: Danny Wong, Noboru Shinkai,
Ka-Shing Cheung, Sze Hang Kevin Liu, James Fung
70
Decades after recovery from acute hepatitis B virus
(HBV) infection the CD8+ T cell response against HBV
core is nearly undetectable
Helenie Kefalakes1,2, Christoph Jochum2, Gudrun Hilgard2, Alisan
Kahraman2, Anna M. Bohrer3, Nicolai El Hindy3, Guido Gerken2,
Michael Roggendorf4, Joerg Timm1; 1Virology, University of Duis-
burg-Essen, Essen, Germany; 2Gastreonterology, University of
Duisburg-Essen, Essen, Germany; 3Neurosurgery, University of
Duisburg-Essen, Essen, Germany; 4Virology, Technical University
of Munich, Munich, Germany
Introduction: Antiviral CD8+ T cells are a key component of
adaptive immune response and crucial for control of hepati-
tis B viral replication. Previous studies analyzing HLA-A*02
restricted epitopes have shown that patients with HBsAg
clearance after acute HBV infection have a strong CD8+ T
cell immune response, directed against HBV core protein,
however, the fate of CD8+ T cells after immune control was
achieved is unclear. Materials and Methods: We evaluated the
HBV-specific CD8+ T cell immune response upon antigen-spe-
cific expansion with overlapping peptides for the HBV core
protein in 67 patients with chronic (HBsAg positive, HBeAg
negative), 4 patients with acute and 16 patients after recov-
ery from acute HBV infection (HBsAg negative, anti-HBs and
anti-HBc positive). Patients who recovered from acute HBV
infection were further divided into those who cleared the virus
<10 years and >30 years ago. HBV-specific CD8+ T cells
were also analyzed directly ex vivo utilizing HLA-A*02-, HLA-
B*35-, HLA-B*51- and HLA-B*08-complexed peptide dextram-
ers. Results: Patients who had cleared the HBsAg >30 years
ago had significantly weaker CD8+ T cell immune responses
after antigen-specific expansion compared to patients who had
cleared the virus <10 years ago and patients with chronic
HBeAg negative infection (p<0.01). In patients <10 years after
HBsAg clearance there was a trend for a negative correla-
tion between the magnitude of the CD8+ T cell response and
the time elapsed after infection (p=0.0583, r= -0.8286). Also
directly ex vivo, patients who had cleared the HBsAg >30
years ago had less HBV-specific CD8+ T cells determined by
dextramer staining compared to patients with HBeAg negative
chronic infection (p=0.0005). Notably, the ability to expand
232A AASLD ABSTRACTS
HBV-specific CD8+ T cells upon peptide stimulation in vitro
(determined as fold expansion compared to ex vivo) was sig-
nificantly lower >30 years after HBsAg clearance compared
to chronic infection (p=0.0046). In patients with acute HBV
infection the CD8+ T cell immune response continued to decline
after HBsAg clearance even at a time when ALT levels had
already normalized (p=0.0313). Conclusions: In contrast to
HCV infection, decades after immune control of HBV infection,
specific CD8+ T cells become almost undetectable even upon
antigen-specific stimulation, whereas the anti-HBs titers remain
stable. There is evidence that HBV-specific CD8+ T cell immune
responses continuously decline after HBsAg clearance. In line
with clinical observations, this suggests that the humoral and
not the CD8+ T cell immune response contributes to prevention
of HBV reactivation decades after HBsAg clearance.
Disclosures:
Christoph Jochum - Advisory Committees or Review Panels: Gilead, Roche,
Norgine, Janssen-Cilag, Abbvie; Speaking and Teaching: BMS, Roche, Jans-
sen-Cilag, Gilead
Michael Roggendorf - Advisory Committees or Review Panels: gilead
The following people have nothing to disclose: Helenie Kefalakes, Gudrun Hil-
gard, Alisan Kahraman, Anna M. Bohrer, Nicolai El Hindy, Guido Gerken,
Joerg Timm
71
Primary resistance to HBV in a large population of treat-
ment-naive patients
Stephane Chevaliez1, Christophe Rodriguez1, Lila Poiteau1, Alex-
andre Soulier1, Philippe Chevallier2, Vincent Leroy3, Veronique
Brodard5, Cecile Brouard4, Christine Larsen4, Caroline Semaille4,
Jean-Michel Pawlotsky1; 1Virology & INSERM Unit U955, Henri
Mondor University Hospital, Creteil, France; 2Virology, Hospices
Civils de Lyon, Lyon, France; 3Hepatology, Hopital La Tronche,
Grenoble, France; 4Infectious diseases, National Institute for Pub-
lic Health Surveillance, Saint-Maurice, France; 5Virology, Hopital
Robert Debré, Reims, France
Background: Resistance to nucleos(t)ide analogues (NUC) is
the main cause of NUC treatment failures leading to disease
aggravation and complications. Objective: Our aim was to
assess the prevalence of primary resistance to NUCs in a
large cohort of treatment-naïve patients chronically infected
with HBV by means of a highly sensitive method for the detec-
tion of minority viral populations. Patients and Methods: More
than 250 patients were included. The HBV reverse transcrip-
tase domain (amino acid positions 66-271) was sequenced
by means of ultra-deep pyrosequencing (UDPS). Results are
available for the 183 first patients. More than 1,326,000
sequences were analyzed. Only substitution frequencies higher
than the mean maximal error rate for the corresponding amino
acid substitution plus 2 SDs were taken into account in the anal-
ysis. Results: At baseline, 75 patients (40.3%) harbored HBV
resistance-associated variants (RAV), generally in low propor-
tions (0.3%-20%). 26.9%, 9.7%, 1.6%, 1.6% of the patients
displayed RAVs representing less than 1%, 1%-5%, 5%-10%,
10%-20% of the viral quasispecies, respectively. 3 patients
harbored RAVs that represented more than 20% of the qua-
sispecies, including one A181V variant at 85%. None of the
patients were found to harbor variants with both resistance and
fitness mutations, which are generally selected on treatment at
the sensitivity level of the technique. In addition, UDPS analy-
sis revealed the presence of three hotspots of natural genetic
variability (up to 50% variability) spanning positions 121-131,
216-221 and 266-271, regardless of the HBV genotype. Con-
clusions: Primary HBV resistance to NUCs is frequent in treat-
ment-naïve patients. These results further emphasize the need
HEPATOLOGY, October, 2014
for using first-line therapies including NUCs with a high barrier
to resistance.
Disclosures:
Stephane Chevaliez - Advisory Committees or Review Panels: Janssen; Speaking
and Teaching: Gilead, BMS
Christophe Rodriguez - Grant/Research Support: Gilead, Roche
Vincent Leroy - Board Membership: roche, merck, gilead, bms, roche, merck,
gilead, bms, roche, merck, gilead, bms, roche, merck, gilead, bms; Consulting:
jansen, jansen, jansen, jansen; Grant/Research Support: roche, gilead, bms,
roche, gilead, bms, roche, gilead, bms, roche, gilead, bms; Speaking and Teach-
ing: bms, merck, gilead, roche, bms, merck, gilead, roche, bms, merck, gilead,
roche, bms, merck, gilead, roche
Jean-Michel Pawlotsky - Consulting: Abbott, Achillion, Boehringer-Ingelheim, Bris-
tol-Myers Squibb, Idenix, Gilead, Janssen, Madaus-Rottapharm, Merck, Novartis,
Roche; Grant/Research Support: Gilead; Speaking and Teaching: Boehring-
er-Ingelheim, Bristol-Myers Squibb, Gilead, Madaus-Rottapharm, Merck, Jans-
sen-Cilag, Novartis, Abbott
The following people have nothing to disclose: Lila Poiteau, Alexandre Soulier,
Philippe Chevallier, Veronique Brodard, Cecile Brouard, Christine Larsen, Car-
oline Semaille
72
Reactivation of Hepatitis B (HBV) in Patients Treated
with Anti-Tumor Necrosis Factor (anti-TNF) Agents
Mary Patricia Pauly1, Lue-Yen Tucker4, Jean-Luc Szpakowski3,
David Baer7, Joanna B. Ready2, Jessica P. Hwang5, Anna S. Lok6;
1Department of Gastroenterology/Hepatology, Kaiser Permanente,
Sacramento, CA; 2Gastroenterology, Kaiser Permanente, Santa
Clara, CA; 3Gastroenterology, Kaiser Permanente, Fremont, CA;
4Division of Research, Kaiser Permanente, Oakland, CA; 5Gen-
eral Internal Medicine, University of Texas MD Anderson Cancer
Center, Houston, TX; 6Gastroenterology, University of Michigan,
Ann Arbor, MI; 7Adult Hematology Oncology, Kaiser Permanente,
Oakland, CA
Background: Guidelines vary across specialties regarding HBV
screening and antiviral prophylaxis in patients receiving anti-
TNF. We sought to determine rate of HBV testing at baseline,
incidence of HBV reactivation and hepatotoxicity (HT) in a
large cohort of patients treated with anti-TNF. Methods: Retro-
spective study of patients age ≥18 enrolled in integrated health
care delivery system in Northern California who were started
on anti-TNF 2001-2010 and followed until 12/31/2012.
Baseline was defined as 01/1996 through 30 days post anti-
TNF initiation. Using the baseline HBV testing results, patients
were categorized into 3 groups (HBsAg+, HBsAg-/anti-HBc+,
and HBsAg-/anti-HBc-). Patients who never had any testing
before study entry and during follow-up period were cate-
gorized as ‘never tested’; the remaining patients were in the
group ‘others’. Grade 3-4 HT (HT>3) was calculated using
the National Cancer Institute Common Toxicity Criteria mod-
ified for those with baseline abnormal laboratory tests. HBV
reactivation was defined as 1 log increase in HBV DNA, or
HBV DNA >2000 if no baseline value available, or HBsAg+
when previously negative. Data on demographic, comorbid-
ities, laboratory tests, and medication history was extracted
from various electronic medical records. Cases with >3 HT and
HBV reactivation were validated by electronic chart review to
confirm accuracy. Results: Of 8887 patients who met the selec-
tion criteria, 62% were female, and the median age was 50
years (IQR 39-59). The racial/ethnic distribution of the cohort
was as follows: 59% Caucasian, 17% Hispanic, 11% Asian/
PI, 5% African American, and 8% other. 4883 (55%) had
baseline HBV testing; of those, 23 (0.5%) were HBsAg+, 440
(9%) were HBsAg-/anti-HBc+, and 3794 (78%) were HBsAg-/
anti-HBc-. During a median period of anti-TNF treatment of
41 months (IQR 21-74), reactivation of HBV occurred in 6
patients: 4 (17%) HBsAg+ group, 1 (0.03%) HBsAg-/anti-HBc-
group, and 1 (0.04%) never tested group. HT>3 was observed
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS 233A

in 247 (2.8%) patients, including 3 (13%) HBsAg+, 12 (3%)
HBsAg-/anti-HBc+, 112 (3%) HBsAg-/anti-HBc-, and 30 (1%)
never tested group. HT ≥3 was attributed to HBV reactivation
in 3 patients including 2 with baseline HBsAg+, 50 with other
causes of liver injury, and in the remaining patients the cause
was unclear. Antiviral prophylaxis was started in 5 HBsAg+
patients prior to anti–TNF. Conclusions: In this large cohort of
patients receiving anti-TNF, roughly half were tested for HBV
prior to initiation of therapy. Reactivation of HBV occurred in
17% of HBsAg+ pts. A few cases of HT>3 were attributed to
HBV reactivation but the cause of HT>3 was unclear in most
cases.
Disclosures:
Mary Patricia Pauly - Grant/Research Support: Merck, Gilead, Roche
Anna S. Lok - Advisory Committees or Review Panels: Gilead, Immune Targeting
System, MedImmune, Arrowhead, Bayer, GSK, Janssen, Novartis, ISIS, Tekmira;
Grant/Research Support: Abbott, BMS, Gilead, Merck, Roche, Boehringer
The following people have nothing to disclose: Lue-Yen Tucker, Jean-Luc Szpa-
kowski, David Baer, Joanna B. Ready, Jessica P. Hwang
from HCV within Medicare. Because of the large proportion of
Medicare patients that enter the program in advanced stages
of disease, treatment prior to Medicare entry is likely to be
more effective in mitigating the health consequences of HCV.
Disclosures:
David B. Rein - Grant/Research Support: Gilead Sciences, Inc.
The following people have nothing to disclose: John S. Wittenborn, Danielle
Liffmann, Joshua M. Borton
74
Minimum target prices for production of Direct Acting
Antivirals and associated diagnostics for developing
countries
Andrew M. Hill2, Nikolien S. van de Ven1, Bryony Simmons1,
Nathan Ford3, Saye H. Khoo2, Joseph M. Fortunak4; 1School of
Public Health, Imperial College London, London, United Kingdom;
2Molecular and Clinical Pharmacology, University of Liverpool,

Liverpool, United Kingdom; 3Centre for Infectious Disease Epide-

miology and Research, University of Cape Town, Cape Town,
73 South Africa; 4Chemistry and Pharmaceutical Sciences, Howard
Projected Health and Economic Impact of Hepatitis C on University, Washington, DC
the United States Medicare System From 2010 to 2024 Background: Several combinations of Direct Acting Antivirals
David B. Rein, John S. Wittenborn, Danielle Liffmann, Joshua M. (DAAs) can cure Hepatitis C (HCV) in the majority of treat-
Borton; NORC at the University of Chicago, Atlanta, GA ment-naïve patients, in a range of genotypes. Mass treatment
programmes to cure HCV in developing countries are only fea-
Over a million Americans with hepatitis C virus (HCV) will
sible if the costs of treatment and monitoring are very low. This
age into Medicare by 2024. Information on the clinical and
analysis aimed to estimate minimum costs of DAA treatment
economic burden of HCV in Medicare is limited. We used
and associated diagnostic monitoring. Methods: Clinical trials
primary data to estimate the clinical burden of HCV in Medi-
of HCV DAAs were reviewed to identify combinations with
care in 2009 and forecast this burden until 2024 assuming 3
consistently high rates of Sustained Virological Response (SVR)
treatment strategies. Our Medicare administrative claims data
in different genotypes. For each DAA, molecular structures,
contained 122,417 patient years of diagnosed HCV across
doses, treatment duration and components of retro-synthesis
the years 2002-2009. Using ICD-9-CM codes, we divided
were used to estimate costs of mass production. Manufacturing
HCV patients into 6 stages; chronic HCV, cirrhosis, decompen-
costs per gram of DAA were projected as formulated product
sated cirrhosis (DCC), hepatocellular carcinoma, transplant/
cost, based upon treating at least 5 million patients/year (to
post-transplant, and death occurring in a year with diagnosed
arrive at volume demand) and a 40% margin for formulation.
HCV. We estimated incremental annual costs of each stage
Costs of diagnostic support were estimated based on published
using a two-part health expenditure. We weighted the data
developing country prices of genotyping, HCV antigen tests
to estimate the Medicare population in each HCV stage as
(to confirm infection pre-treatment and identify relapse/re-in-
of 2009 and estimated new cases of HCV entering Medicare
fection post-treatment), plus full blood count/clinical chemis-
from 2010-2024 using NHANES. We used a simulation to
try. Results: Predicted minimum costs for 12-week courses of
forecast future HCV health outcomes in Medicare, assuming no
HCV DAAs (patent expiry dates) were: US$50 for ribavirin
treatment (NT), treatment with pegylated interferon, ribavirin,
1200mg/day (generic), US$20 for daclatasvir 60mg/day
and a protease inhibitor (PRPI), and an all-oral high efficacy
(2027), US$102 for sofosbuvir 400mg/day (2029), US$90
regimen (AO). We estimated 796,232 patients with HCV in
for ledipasvir 90mg/day (2030), US$44 for MK-8742 (2028),
Medicare in 2009, of whom 63.1% had chronic infection only,
and US$71 for MK-5172 (2030). Predicted minimum costs for
9.9% had cirrhosis, 14.7% had DCC, 2.5% had HCC, 2.6%
12 week courses of combination DAAs with the most consistent
transplant or post-transplant maintenance, and 7.2% died
efficacy results were: US$122 per person for sofosbuvir+da-
during 2009. We estimated that between 2010 and 2024,
clatasvir, US$152 for sofosbuvir+ribavirin (US$304 for 24
an additional 1,027,066 individuals with chronic HCV would
weeks), US$192 for sofosbuvir+ledipasvir and US$115 for
enter the Medicare system. Of the cumulative 1,823,298 indi-
MK-8742+MK-5172. Diagnostic testing costs were estimated
viduals with chronic HCV currently in or entering Medicare
at US$90 for genotyping (if treatment not pan-genotypic),
from 2010-2024, with NT we forecast that 661,060 (36.2%)
US$34 for two HCV antigen tests (lower detection limit 2000
would die from HCV or other causes while in a diagnosed state
IU/mL) and US$22 for two full blood count, ALT and creati-
of DCC, HCC, or transplant/post-transplant. Treatment with
nine tests (before and during treatment). Conclusions: Minimum
PRPI reduced deaths in these states by these states by 29,720,
costs of treatment and diagnostics to cure HCV were estimated
and increased undiscounted QALYs by 1,562,119. Treatment
at US$171-360 per-person, without genotyping or US$261-
with AO reduced deaths in these states by 126,163 and
450 per-person with genotyping. These cost estimates assume
increased undiscounted QALYs by 7,692,906. The incremen-
that similar large-scale treatment programmes for HIV/AIDS
tal costs of non-antiviral HCV treatment were higher in chronic
can be established for HCV. Treatments with proven pan-ge-
HCV and cirrhosis than values used in prior cost-effectiveness
notypic activity will be required to avoid expensive pre-treat-
models while costs for advanced stages were similar. Medi-
ment genotyping. Further reductions in price could be achieved
care contained more diagnoses for advanced disease in 2009
through shorter durations of treatment, if efficacy is shown in
Medicare population than predicted by previous simulation.
future trials.
Treatment, especially treatment with interferon free, all oral
Disclosures:
regimens could substantially reduce morbidity and mortality
234A AASLD ABSTRACTS
Andrew M. Hill - Consulting: Janssen
Saye H. Khoo - Grant/Research Support: Merck, Janssen, Gilead, ViiV
The following people have nothing to disclose: Nikolien S. van de Ven, Bryony
Simmons, Nathan Ford, Joseph M. Fortunak
75
Cost-Effectiveness of Novel Hepatitis C Drug Regimens
Among Treatment-Experienced U.S. Veterans
Alexis P. Chidi1,2, Shari S. Rogal3, Cindy L. Bryce4,5, Michael
J. Fine2,5, Chester B. Good2,6, Larissa Myaskovsky2,5, Vinod K.
Rustgi3,7, Allan Tsung7,8, Kenneth J. Smith5; 1School of Medicine,
University of Pittsburgh, Pittsburgh, PA; 2Center for Health Equity
Research & Promotion, VA Pittsburgh Healthcare System, Pitts-
burgh, PA; 3Division of GI, Hepatology, and Nutrition, University
of Pittsburgh, Pittsburgh, PA; 4Graduate School of Public Health,
University of Pittsburgh, Pittsburgh, PA; 5Division of General Inter-
nal Medicine, University of Pittsburgh, Pittsburgh, PA; 6Pharmacy
Benefits Management, Department of Veteran’s Affairs, Pittsburgh,
PA; 7Starzl Transplant Institute, University of Pittsburgh, Pittsburgh,
PA; 8Division of Hepatobiliary and Pancreatic Surgery, University
of Pittsburgh, Pittsburgh, PA
Background: It remains unclear whether treatment-experienced
patients (partial- or null-responders) with hepatitis C (HCV)
should begin treatment with current sofosbuvir (SOF)-based
regimens or wait for all-oral, interferon-free regimens expected
in 2015. Methods: We used a Markov model with one-year
cycle length for a cohort of 50-year old Veterans with geno-
type 1, 2, or 3 HCV to compare treating: (1) all with current
SOF regimens using American Association for the Study of
Liver Disease/Infectious Disease Society of America (AASLD)
recommendations; (2) METAVIR F3-4 disease with AASLD rec-
ommendations and F0-2 disease in one year with future all-oral
regimens; (3) all with SOF regimens using Veteran’s Health
Administration (VHA) guidelines [AASLD alternative recommen-
dation of SOF with pegylated-interferon/ribavirin (PEG/RBV)
for PEG-eligible genotypes 1 & 2, wait to treat F0-3 genotype
3]; (4) all with future all-oral regimens in one year; or (5) only
cirrhotic (F4) patients. For comparison, we included the previ-
ous standard of care (PEG/RBV ± telaprevir/boceprevir) and
no treatment. We modeled the natural history of HCV and
cirrhosis, assuming progression, morbidity, and mortality risks
were lower after sustained virologic response (SVR). Analyses
used a VHA perspective, with a 3% annual discount rate and
lifetime horizon. We varied model inputs in one-way sensitivity
analyses. Results: Preferred strategies included AASLD guide-
lines for genotypes 1 ($53,281/QALY) and 3 ($24,724/
QALY), and VHA guidelines for genotype 2 ($38,853/QALY)
[see Table], which were dominant (less costly, more effective)
compared to waiting for all-oral regimens or treating based on
fibrosis score. Results were sensitive to SVRs for SOF/PEG/
RBV, SOF/simeprevir ± RBV and SOF/RBV, costs of future
all-oral regimens, and strategies for treating genotype 3. Con-
clusion: For treatment-experienced U.S. Veterans, using current
SOF-based regimens cost less and was more effective than
waiting to treat with future all-oral therapies, regardless of gen-
otype or METAVIR fibrosis score.
HEPATOLOGY, October, 2014
Cost-Effectiveness of Treatment Strategies for Treatment-Experi-
enced Veterans with HCV
Disclosures:
Vinod K. Rustgi - Grant/Research Support: Abbvie, BMS, Gilead, Achillion
The following people have nothing to disclose: Alexis P. Chidi, Shari S. Rogal,
Cindy L. Bryce, Michael J. Fine, Chester B. Good, Larissa Myaskovsky, Allan
Tsung, Kenneth J. Smith
76
Clinical efficacy of highly effective interferon-free ther-
apy in patients with chronic HCV infection and compen-
sated advanced hepatic fibrosis
Adriaan J. van der Meer1, Raoel Maan1, Jordan J. Feld2, Heiner
Wedemeyer 3, Giovanna Fattovich 4, Jean-Francois Dufour 5,
Frank Lammert6, Andres Duarte-Rojo2, Michael P. Manns3, Ste-
fan Zeuzem7, Wolf P. Hofmann7, Donatella Ieluzzi8, Robert J. de
Knegt1, Bettina E. Hansen1, Bart J. Veldt1, Harry L. Janssen1,2;
1Gastroenterology & Hepatology, Erasmus MC, Rotterdam, Neth-
erlands; 2Liver Centre, Toronto Western Hospital, Toronto, ON,
Canada; 3Department of Gastroenterology, Hepatology, and
Endocrinology, Medical School Hannover, Hannover, Germany;
4Department of Medicine, University of Verona, Verona, Italy;
5Hepatology, Department of Clinical research, University of Bern,
Bern, Switzerland; 6Department of Medicine II, Saarland Univer-
sity Medical Center, Homburg, Germany; 7Medizinische Klinik 1,
Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am
Main, Germany; 8Department of Surgery, University of Verona,
Verona, Italy
INTRODUCTION Independent of host characteristics, 95%
of patients with chronic HCV infection attain SVR with inter-
feron-free therapy. We aimed to assess the clinical efficacy
of such therapies for the individual patient with compensated
advanced fibrosis. METHODS A multicenter cohort study
including all consecutively treated patients with chronic HCV
infection and advanced hepatic fibrosis was performed. Clini-
cal efficacy of therapy was assessed as the number needed to
treat (NNT) to prevent 1 death in 5 years, which was calcu-
lated with the adjusted hazard ratio (HR) of SVR for all-cause
mortality and the individual’s estimated 5-year survival based
on our externally validated mortality risk score (including solely
objective variables). [NNT=(1/(estimated 5y-survival without
SVR^(HR of SVR) – estimated 5y-survival without SVR))*(100/
SVR rate)] RESULTS In total, 530 patients were followed for
a median of 8.4 (IQR 6.4-11.4) years. Median age was 48
(IQR 42-56) years, 143 (27%) patients had bridging fibrosis
and 387 (63%) had cirrhosis. SVR was attained by 192 (36%)
patients. Cox analyses showed that SVR was independently
associated with reduced all-cause mortality (adjusted HR 0.25,
95%CI 0.12-0.53), without significant interactions with any
baseline variables. Among patients without SVR, the 5-year
mortality rate was 8.6 (95%CI 5.7-11.5). For calculating the
NNT, the HR of SVR was fixed at 0.25 and the SVR rate at
95%. The NNT to prevent 1 death in 5 years was 29, 15, 10
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
or 8 in case of a 5-year mortality risk of 5, 10, 15 or 20%,
respectively. The figure shows the estimated NNT and 5-year
mortality risk, according to the individual’s mortality risk score.
CONCLUSION These results indicate that the clinical efficacy
of interferon-free therapy varies extensively among patients
with advanced liver disease, which might provide guidance
when prioritizing patients for treatment with these costly reg-
imens.
Disclosures:
Adriaan J. van der Meer - Speaking and Teaching: MSD, Gilead
Raoel Maan - Consulting: AbbVie
Jordan J. Feld - Advisory Committees or Review Panels: Idenix, Merck, Janssen,
Gilead, AbbVie, Merck, Theravance, Bristol Meiers Squibb; Grant/Research
Support: AbbVie, Boehringer Ingelheim, Janssen, Gilead, Merck
Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD,
Roche, Gilead, Abbott, BMS, Falk, Abbvie, Novartis, GSK; Grant/Research
Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS,
MSD, Novartis, ITF, Abbvie, Gilead
Jean-Francois Dufour - Advisory Committees or Review Panels: Bayer, BMS, Gil-
ead, Janssen, Novartis, Roche, Jennerex, Merck; Speaking and Teaching: Bayer,
Boehringer-Ingelheim, Novartis, Roche
Andres Duarte-Rojo - Advisory Committees or Review Panels: Gilead Sciences;
Grant/Research Support: Vital Therapies
Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim,
Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/
Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim,
BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK,
Novartis
Stefan Zeuzem - Consulting: Abbvie, Boehringer Ingelheim GmbH, Bristol-Myers
Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen,
Roche Pharma AG, Vertex Pharmaceuticals
Robert J. de Knegt - Advisory Committees or Review Panels: MSD, Roche,
Norgine, Janssen Cilag; Grant/Research Support: Gilead, MSD, Roche, Janssen
Cilag, BMS; Speaking and Teaching: Gilead, MSD, Roche, Janssen Cilag
Bart J. Veldt - Board Membership: GSK, Janssen Therapeutics
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sci-
ences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support:
Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck,
Medtronic, Novartis, Roche, Santaris
The following people have nothing to disclose: Giovanna Fattovich, Frank Lam-
mert, Wolf P. Hofmann, Donatella Ieluzzi, Bettina E. Hansen
235A
77
Treatment with Interferon (IFN) and Ribavirin (RBV)-Free
Regimens with Ledipasvir (LDV) and Sofosbuvir (SOF)
Improves Patient-Reported Outcomes (PRO) for Patients
with Genotype 1 (GT1) Chronic Hepatitis C (CH-C):
Results from the ION-1,2 and 3 Clinical Trials
Zobair Younossi1,7, Maria Stepanova 2,7, Patrick Marcellin 3,
Nezam H. Afdhal4, Kris V. Kowdley5, Stefan Zeuzem6, Sharon L.
Hunt7; 1Center for Liver Disease, Department of Medicine, Inova
Fairfax Hospital, Falls Church, VA; 2CLDQ LLC, Washingtom, DC;
3Viral Hepatitis Research Unit, Hospital Beaujon, Clichy, France;
4Hepatology, Beth Israel Deaconess Medical Center, Boston,
MA; 5Digestive Diseases Institute, Virginia Mason Clinic, Seattle,
WA; 6Department of Medicine, J.W. Goethe University Hospital,
Frankfurt, Germany; 7Betty and Guy Beatty Center for Integrated
Research, Inova Health System, Falls Church, VA
IFN+RBV negatively impacts patient-reported outcomes (PROs)
in CH-C. AIM: To assess PROs in CH-C patients treated with
RBV-free SOF+LDV regimens. METHODS: PRO questionnaires
[Chronic Liver Disease Questionnaire-HCV (CLDQ-HCV), Short
Form-36 (SF-36), Functional Assessment of Chronic Illness
Therapy-Fatigue (FACIT-F), and Work Productivity and Activity
Index: Specific Health Problem (WPAI:SHP)] were administered
at baseline, during, and post-treatment to GT1 CH-C subjects
treated with SOF+LDV+RBV or SOF+LDV. RESULTS: 1,952 sub-
jects were enrolled: age 53.1±10.2, 60.2% males, 11.5%
with cirrhosis, 77.5% treatment-naïve. Duration of treatment
consisted of 8 (N=431), 12 (N=867) and 24 weeks (N=654).
Baseline demographics and psychiatric disorders were similar
between treatment arms (all p>0.05). During treatment with the
RBV-containing regimens, some PRO decrements (compared to
baselines) were observed (up to -6.7% on a normalized 0-100%
scale in 8 weeks, -6.3% in 12 weeks, -4.9% in 24 weeks; all
p<0.05). On the other hand, patients receiving SOF+LDV regi-
mens showed significant improvement of PRO during treatment
(up to +7.4%, +7.0% and +6.7%, respectively; all p<0.0001).
In fact, in the RBV-free arm, improvements in some of the PROs
were observed starting as early as 2 weeks and maximized
by the end of treatment. Throughout treatment, most of the
PRO (HRQL, vitality, fatigue, work productivity) were supe-
rior for RBV-free regimens: up to +10.3% (8 weeks), +10.3%
(12 weeks), and +7.4% (24 weeks) (p<0.0001). Receiving
RBV was also an independent predictor of PRO impairment
in multivariate analysis (beta up to -5.8%, p<0.005). Patients
who achieved sustained viral eradication showed significant
improvement of their PROs (up to +8.3%, p<0.0001). CON-
CLUSION: Ribavirin-free SOF+LDV regimen is associated with
both high efficacy and significant improvement of PROs during
treatment and after eradication of HCV.
236A AASLD ABSTRACTS
Disclosures:
Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen,
MSD, Abbvie, Alios BioPharma, Idenix, Akron; Grant/Research Support: Roche,
Gilead, BMS, Novartis, Janssen, MSD, Alios BioPharma; Speaking and Teach-
ing: Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Boehringer, Pfizer,
Abbvie
Nezam H. Afdhal - Consulting: Merck, Vertex, Idenix, GlaxoSmithKline, Spring-
bank, Gilead, Pharmasett, Abbott; Grant/Research Support: Merck, Vertex, Ide-
nix, GlaxoSmithKline, Springbank, Gilead, Pharmasett, Abbott
Kris V. Kowdley - Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research
Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria,
Janssen, Merck, Mochida, Vertex
Stefan Zeuzem - Consulting: Abbvie, Boehringer Ingelheim GmbH, Bristol-Myers
Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen,
Roche Pharma AG, Vertex Pharmaceuticals
The following people have nothing to disclose: Zobair Younossi, Maria Ste-
panova, Sharon L. Hunt
78
Direct Care Costs for Hepatocellular Carcinoma in
patients with Hepatitis C cirrhosis
Andreea M. Catana, Daniel Mansuri, Nidhi Sethi, Annie Vong,
Saurabh Sethi, Nezam H. Afdhal; Hepatology, Beth Israel Deacon-
ess Medical Center, Boston, MA
Hepatitis C is the commonest cause of hepatocellular cancer
(HCC) in the US and the incidence is expected to increase
further as the HCV population ages and develops more cirrho-
sis. Management of HCC is very heterogenous with multiple
non-surgical and surgical options. The true cost of care of the
HCV patient with HCC is unknown. AIMS: To evaluate the total
direct health care costs of different approaches to HCC care in
HCV patients in a major referral and transplant center. METH-
ODS: 101 patients were randomly selected by computer from a
list of all HCC patients with HCV between 2003 and 2013. All
patients were biopsy-proven HCC or met UNOS OPTN criteria.
Patients were categorized by the primary treatment modality
of TACE, Cyberknife radiotherapy, radiofrequency abalation
(RFA), chemotherapy or resection. Patients could have multiple
treatment modalities and also go on to liver transplant, which
is considered as a separate modality for cost determination.
The direct cost includes the cost of the procedure, imaging,
hospitalizations and all subsequent care of the HCC patient
until either death or transplant including cost of HCV treatment
and immunosuppression post-transplant. Costs were derived
from the Medicare fee schedule abstracted from the HCUP
NIS sample 2011. Medication costs used were wholesale
acquisition costs (Redbook 2014). RESULTS: 101 patients, 82
male mean age 59years (range 49-82) were included. All
had HCV cirrhosis at diagnosis with a median CTP score of
7 ( range 5-11) and a median MELD of 8. Genotype 1 (74%)
and genotype 3 (16%) were predominant. 31 patients were
HCV treatment naïve, 65 treatment failures and 4 had had a
prior SVR. Majority of HCC were detected through cross-sec-
tional radiological screening programs. Liver staging using the
Barcelona score was A1 20%; A2 18%; A3 16% and A4
27%; B 12% and C 7%. Tumor size was mean 2.8cms with a
range from 1 – 14cms. Mean follow up was 32 months with a
range from 4 – 118 and 37 patients have died. Initial primary
treatment modalities were RFA 53%; TACE 26%; Cyberknife
10%, resection 8% and chemotherapy 2%. 43 patients went
on to liver transplantation. Calculated overall cost of HCC care
for this group of patients was $22,030,108 for a mean cost
per patient of $218,120. The 43 patients who underwent
transplant accounted for $17,025,037 of the overall costs at
$395,000 per transplanted patient compared to $5,817,300
for the non transplant patients for a mean cost of $100,299
per patient. CONCLUSIONS: Pharmaco-economic studies of
HEPATOLOGY, October, 2014
HCV treatment need to model real life estimations of true direct
cost of HCC care.
Disclosures:
Daniel Mansuri - Stock Shareholder: Gilead Sciences
Nezam H. Afdhal - Consulting: Merck, Vertex, Idenix, GlaxoSmithKline, Spring-
bank, Gilead, Pharmasett, Abbott; Grant/Research Support: Merck, Vertex, Ide-
nix, GlaxoSmithKline, Springbank, Gilead, Pharmasett, Abbott
The following people have nothing to disclose: Andreea M. Catana, Nidhi Sethi,
Annie Vong, Saurabh Sethi
79
Once Daily Sofosbuvir with GS-5816 for 8 Weeks with
or without Ribavirin In Patients with HCV Genotype 3
without Cirrhosis Result in High Rates of SVR12: The
ELECTRON2 Study
Edward J. Gane1, Robert H. Hyland2, Di An2, John McNally2,
Diana M. Brainard2, William T. Symonds2, John G. McHutchison2,
Catherine A. Stedman3; 1Auckland Clinical Studies, Auckland,
New Zealand; 2Gilead Science, Inc, Foster City, CA; 3Christchurch
Clinical Studies Trust, Christchurch, New Zealand
Background: Sofosbuvir (SOF) is approved in combination
with other direct-acting antiviral agents for the treatment of
chronic HCV infection. GS-5816 is an investigational inhibi-
tor of the HCV NS5A protein with picomolar antiviral activity
across all HCV genotypes 1-6. In a phase 2 study, treatment
with SOF+GS-5816 at a dose of 25 or 100 mg/day with
or without ribavirin (RBV) was found to be safe and effective
when administered for 12 weeks. In this study, we evaluated
whether this regimen would also be effective for patients with
HCV genotype 3 when administered for a shorter, 8-week
duration. Methods: 104 treatment-naïve, non-cirrhotic patients
with chronic HCV genotype 3 infection were randomized to
receive SOF+GS-5816 25 mg, SOF+GS-5816 25 mg+RBV,
SOF+GS-5816 100 mg, or SOF+GS-5816 100 mg+RBV.
Results: The majority of subjects were male (63, 61%), Cauca-
sian (79, 76%), and had IL28B non-CC genotype (59, 57%).
The median BMI was 25.8 kg/m2, and the median HCV RNA
was 6.1 log10IU/ml. Two patients did not complete the study
treatment: one discontinued due to an adverse event, and one
withdrew consent. Both withdrew before completing two weeks
of treatment, prior to achieving undetectable HCV RNA, and
were lost to follow-up in the posttreatment phase. SVR12 rates
are included in the table below. SOF+GS-5816 with or with-
out RBV was well tolerated. Adverse events, which were more
common in the RBV arm, were generally mild, and Grade 3/4
laboratory abnormalities were infrequent and were consistent
with the safety profile of RBV. There was one SAE (seizure)
that occurred after treatment was completed in a patient with
a history of seizure disorder and suspected nonadherence to
seizure medication. No toxicity attributable to SOF+GS-5816
was identified. Conclusions: Treatment with SOF+GS-5816 25
mg or 100 mg for 8 weeks, with or without RBV, resulted
in high rates of SVR12 in GT3 HCV-infected patients. Treat-
ment was well tolerated with no identified safety signal due to
SOF or GS-5816. These data support further development of
SOF+GS-5816 without RBV for treatment of chronic HCV.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Disclosures:
Edward J. Gane - Advisory Committees or Review Panels: Novira, AbbVie,
Novartis, Gilead Sciences, Janssen Cilag, Vertex, Achillion, Tekmira, Merck, Ide-
nix; Speaking and Teaching: AbbVie, Novartis, Gilead Sciences, Janssen Cilag
Robert H. Hyland - Employment: Gilead Sciences, Inc; Stock Shareholder: Gilead
Sciences, Inc
John McNally - Employment: Gilead Sciences, Inc
Diana M. Brainard - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
William T. Symonds - Employment: Gilead
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Catherine A. Stedman - Advisory Committees or Review Panels: Jansen, MSD;
Speaking and Teaching: Gilead
The following people have nothing to disclose: Di An
80
Safety and Efficacy of Treatment with Sofosbu-
vir+GS-5816±Ribavirin for 8 or 12 Weeks in Treatment
Naïve Patients with Genotype 1-6 HCV Infection
Tram T. Tran1,
Timothy R. Morgan2,
Paul J. Thuluvath3,
Kyle Etz-
korn4, Federico Hinestrosa5, Myron Tong6, John McNally7, Diana
M. Brainard7, Lingling Han7, Brian Doehle7, Erik Mogalian7,
John G. McHutchison7, Raymond T. Chung8, Gregory T. Ever-
son9; 1Cedars-Sinai Medical Center, Los Angeles, CA; 2VA Long
Beach, Long Beach, CA; 3Mercy Medical Center, Baltimore, MD;
4Borland-Groover Clinic, Jacksonville, FL; 5Orlando Immunology
Center, Orlando, FL; 6Huntington Medical Research Institutes,
Pasadena, CA; 7Gilead Sciences, Inc., Foster City, CA; 8Mas-
sachusetts General Hospital, Boston, MA; 9University of Denver
Colorado, Aurora, CO
Introduction: The combination of sofosbuvir (SOF) and
GS-5816 for 12 weeks has demonstrated high efficacy in treat-
ment naïve patients without cirrhosis with chronic genotype
1-6 HCV infection. Here we report final results from a Phase
2 study including evaluation of SOF + GS-5816 ± RBV for 8
weeks in treatment naïve patients without cirrhosis with geno-
type 1-6 HCV infection. Methods: In Part A, treatment naïve
genotype 1-6 HCV-infected patients without cirrhosis were
randomized 1:1 to SOF+GS-5816 25mg or SOF+GS-5816
100mg for 12 weeks. In Part B, treatment naïve genotype 1
and 2 HCV-infected patients without cirrhosis were randomized
1:1:1:1 to SOF+ GS-5816 25mg, SOF+GS-5816 25mg+RBV,
SOF+GS-5816 100mg or SOF+GS-5816 100 mg+RBV for 8
weeks. The SOF dose was 400 mg. Ribavirin was administered
1000-1200mg in a divided daily dose. Results: 377 patients
(47% GT1, 33% GT2, 14% GT3, 4% GT4, < 1% GT5, and
2% GT6) were randomized and treated; 58% were male, 87%
were white, and 36% had IL28B CC genotype. HCV RNA
results at post-treatment week 12 (SVR12) are presented below
for all genotype 1 and genotype 2 HCV infected patients.
SVR rates ranged from 77-90% with 8 weeks of treatment and
91-100% with 12 weeks of treatment. RBV did not appear to
enhance SVR rates. Relapse accounted for all virologic failures
237A
with the majority of relapse occurring by post-treatment week
4. The most frequently reported adverse events (> 10%) were
fatigue, headache and nausea. One patient discontinued treat-
ment with SOF +GS-5816 after 7 days due to abdominal pain,
palpitations and dizziness. Seven patients reported 8 SAEs;
none were considered related to study drug. There was no
evidence of drug related changes in hematologic, chemistry
or urinalysis parameters. Conclusions: SOF+GS-5816 for 8 or
12 weeks was well tolerated with a low incidence of treatment
discontinuation and SAEs. High SVR12 rates were achieved
in patients with genotype 1-6 HCV infection administered SOF
+GS-5816 100mg for 12 weeks. This study demonstrates that
co-administration of SOF with GS-5816 100mg for 12 weeks
without RBV is an appropriate regimen for further evaluation in
Phase 3 studies.
SVR12 in Patients Treated with SOF + GS-5816 for 8 or 12
Weeks
Disclosures:
Tram T. Tran - Advisory Committees or Review Panels: Gilead, Bristol Myers
Squibb; Consulting: Gilead, AbbVie, Janssen; Grant/Research Support: Bristol
Myers Squibb; Speaking and Teaching: Bristol Myers Squibb, Gilead
Timothy R. Morgan - Grant/Research Support: Merck, Vertex, Genentech, Gil-
ead, Bristol Myers Squibb
Paul J. Thuluvath - Advisory Committees or Review Panels: Bayer, Gilead, Vertex;
Grant/Research Support: Gilead, Abbott, BMS, Isai, Salix; Speaking and Teach-
ing: Bayer/Onyx, Vertex, Gilead
Federico Hinestrosa - Advisory Committees or Review Panels: Gilead; Grant/
Research Support: Gilead, BMS, BI, Achillion, Janssen, Idenix; Speaking and
Teaching: Gilead, Abbvie, Genentech
John McNally - Employment: Gilead Sciences, Inc
Diana M. Brainard - Employment: Gilead Sciences, Inc.
Brian Doehle - Employment: Gilead Sciences
Erik Mogalian - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead
Sciences, Inc.
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Raymond T. Chung - Consulting: Abbvie; Grant/Research Support: Gilead, Mass
Biologics
Gregory T. Everson - Advisory Committees or Review Panels: Roche/Genen-
tech, Abbvie, Galectin, Boehringer-Ingelheim, Eisai, Bristol-Myers Squibb, HepC
Connection, BioTest, Gilead, Merck; Board Membership: HepQuant LLC, PSC
Partners, HepQuant LLC; Consulting: Abbvie, BMS, Gilead, Bristol-Myers Squibb;
Grant/Research Support: Roche/Genentech, Pharmassett, Vertex, Abbvie, Bris-
tol-Myers Squibb, Merck, Eisai, Conatus, PSC Partners, Vertex, Tibotec, GlobeIm-
mune, Pfizer, Gilead, Conatus, Zymogenetics; Management Position: HepQuant
LLC, HepQuant LLC; Patent Held/Filed: Univ of Colorado; Speaking and Teach-
ing: Abbvie, Gilead
The following people have nothing to disclose: Kyle Etzkorn, Myron Tong,
Lingling Han
238A AASLD ABSTRACTS HEPATOLOGY, October, 2014

81 Triange/square=SVR12 rate. Error bar=95% confidence interval.

TURQUOISE-II: Regimens of ABT-450/r/Ombitasvir and BMI=body-mass index.
Dasabuvir With Ribavirin Achieve High SVR12 Rates
in HCV Genotype 1-Infected Patients with Cirrhosis,
Regardless of Baseline Characteristics
Michael W. Fried1, Xavier Forns2, Nancy Reau3, Heiner Wede-
meyer4, Mitchell L. Shiffman5, Angeles Castro6, David J. Mutimer7,
Samuel S. Lee8, Roger Trinh9, Sandra S. Lovell9, Leticia Canizaro9,
Marcos Pedrosa9, Thomas Berg10; 1University of North Carolina at
Chapel Hill UNC Liver Center, Chapel Hill, NC; 2Liver Unit, Hospi-
tal Clinic, IDIBAPS and CIBEREHD, Barcelona, Barcelona, Spain;
3University of Chicago Medical Center, Chicago, IL; 4Mediz-

inische Hochschule Hannover, Hannover, Germany; 5Liver Institute

of Virginia, Newport News, VA; 6Complejo Hospitalario Univer-
sitario A Coruña (CHUAC), A Coruña, Spain; 7Queen Elizabeth
Hospital and NIHR Liver Biomedical Research Unit, Birmingham,
United Kingdom; 8University of Calgary, Calgary, AB, Canada;
9AbbVie Inc., North Chicago, IL; 10Universitätsklinikum Leipzig,

Leipzig, Germany
Purpose: Efficacy of interferon-containing therapies in HCV-in-
fected patients (pts) are affected by factors including more
advanced liver disease, as may be clinically evidenced by
hypoalbuminemia or thrombocytopenia. ABT-450 is an HCV
NS3/4A protease inhibitor (dosed with ritonavir, ABT-450/r)
identified by AbbVie and Enanta. Ombitasvir (ABT-333) is an
NS5A inhibitor; dasabuvir (ABT-267) is an NS5B RNA poly-
merase inhibitor. The phase 3 TURQUOISE-II trial examined
efficacy and safety of an all-oral regimen of co-formulated
ABT-450/r/ombitasvir+dasabuvir with ribavirin (3D+RBV) in
treatment (tx)-naïve and tx-experienced pts with HCV genotype
(GT) 1 infection and compensated (Child-Pugh A) cirrhosis.
We report efficacy by baseline pt and disease characteris-
tics. Methods: In this open-label trial, pts were randomized to
receive 3D+RBV for 12 or 24 weeks. SVR12 rates were calcu-
lated for all pts and for pt subgroups. SVR12 rates are reported
for select subgroups; rates for additional subgroups will be
presented. Results: 380 pts were randomized and received
study drug. Overall SVR12 rates were 91.8% and 95.9% for
the 12- and 24-week arms, respectively. SVR12 rates did not
differ substantially by sex, age, body-mass index, or HCV RNA
(Figure). SVR12 rates were 88.9-97.0% in pts with platelet
counts <100x109/L and 84.0-88.9% in pts with serum albu-
min <35g/L. Conclusions: Among pts with HCV GT1 infection
and cirrhosis, SVR12 rates with 3D+RBV were high across
a broad range of subgroups, including pts with evidence of
impaired hepatic synthetic function and/or evidence of portal
hypertension.
Disclosures:
Michael W. Fried - Consulting: Genentech, Merck, Abbvie, Vertex, Janssen, Bris-
tol Myers Squibb, Gilead; Grant/Research Support: Genentech, Merck, AbbVie,
Vertex, Janssen, Bristol Myers Squibb, Gilead; Patent Held/Filed: HCCPlex
Xavier Forns - Consulting: Jansen, MSD, Abbvie; Grant/Research Support:
Roche, MSD, Gilead
Nancy Reau - Advisory Committees or Review Panels: Kadmon, Jannsen, Vertex,
Idenix, AbbVie, Jannsen; Grant/Research Support: Vertex, Gilead, Genentech,
AbbVie, BMS, Jannsen, BI
Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD,
Roche, Gilead, Abbott, BMS, Falk, Abbvie, Novartis, GSK; Grant/Research
Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS,
MSD, Novartis, ITF, Abbvie, Gilead
Mitchell L. Shiffman - Advisory Committees or Review Panels: Merck, Gilead,
Boehringer-Ingelheim, Bristol-Myers-Squibb, Abbvie, Janssen; Consulting: Roche/
Genentech, Gen-Probe; Grant/Research Support: Merck, Gilead, Boehring-
er-Ingelheim, Bristol-Myers-Squibb, GSK, Abbvie, Beckman-Coulter, Achillion,
Lumena, Intercept, Novarit, Gen-Probe; Speaking and Teaching: Roche/Genen-
tech, Merck, Gilead, GSK, Janssen, Bayer
Samuel S. Lee - Consulting: Bristol Myers Squibb, Gilead, Roche, Janssen, Ver-
tex, Genentech, Merck, Abbvie; Grant/Research Support: BMS, Gilead, Roche,
Janssen, Merck, Vertex, Abbvie; Speaking and Teaching: BMS, Gilead, Roche,
Merck, Vertex
Sandra S. Lovell - Employment: AbbVie
Marcos Pedrosa - Employment: Abbvie
Thomas Berg - Advisory Committees or Review Panels: Gilead, BMS, Roche,
Tibotec, Vertex, Jannsen, Novartis, Abbott, Merck; Consulting: Gilead, BMS,
Roche, Tibotec; Vertex, Janssen; Grant/Research Support: Gilead, BMS, Roche,
Tibotec; Vertex, Jannssen, Merck/MSD, Boehringer Ingelheim, Novartis; Speak-
ing and Teaching: Gilead, BMS, Roche, Tibotec; Vertex, Janssen, Merck/MSD,
Novartis, Merck, Bayer
The following people have nothing to disclose: Angeles Castro, David J. Mutimer,
Roger Trinh, Leticia Canizaro
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
82
An Integrated Safety and Efficacy Analysis of >500
Patients with Compensated Cirrhosis Treated with Ledip-
asvir/Sofosbuvir with or without Ribavirin
Marc Bourlière1, Mark S. Sulkowski2, Masao Omata3, Stefan
Zeuzem4, Jordan J. Feld5, Eric Lawitz6, Patrick Marcellin7, Robert
H. Hyland8, Xiao Ding8, Jenny C. Yang8, Steven J. Knox8, Phil-
lip S. Pang8, Mani Subramanian8, William T. Symonds8, John
G. McHutchison8, Alessandra Mangia9, Edward J. Gane10, K.
Rajender Reddy11, Masashi Mizokami12, Stanislas Pol13, Nezam
H. Afdhal14; 1Hôpital Saint Joseph, Marseilles, France; 2Johns
Hopkins University, Baltimore, MD; 3Yamanashi Prefectural Hospi-
tal Organization, Yamanashi, Japan; 4Johann Wolfgang Goethe
University, Frankfurt am Main, Germany; 5Sandra Rotman Centre
for Global Health, University of Toronto, Toronto, ON, Canada;
6Texas Liver Institute, University of Texas Health Science Center, San
Antonio, TX; 7Hôpital Beaujon, University of Paris, Paris, France;
8Gilead Science, Inc, Foster City, CA; 9Liver Unit, Casa Sollievo
della Sofferenza Hospital, San Giovanni Rotondo, Italy; 10New
Zealand Liver Transplant Unit, Auckland City Hospital, Auckland,
New Zealand; 11University of Pennsylvania, Philadelphia, PA;
12Research Center for Hepatitis and Immunology, National Center
for Global Health and Medicine, Chiba, Japan; 13Department of
Hepatology, Université Paris-René Descartes, Paris, France; 14Beth
Israel Deaconess Medical Center, Boston, MA
Background and Aims: Patients with HCV and Cirrhosis rep-
resent a population in most need of treatment; however, with
interferon based therapy, such patients are difficult to cure
and consequently often underrepresented in clinical trials.
Ledipasvir/sofosbuvir (LDV/SOF) Phase 2 and Phase 3 studies
included >500 patients with compensated cirrhosis. We ana-
lyzed the safety and efficacy of the regimen in this population.
Methods: Treatment-naïve or treatment-experienced patients
with chronic HCV genotype 1 infection and compensated cir-
rhosis who had participated in Phase 2 or Phase 3 studies
receiving LDV/SOF+/-ribavirin (RBV) for 12 or 24 weeks were
included in this pooled analysis. Results: 514 subjects with
compensated cirrhosis were identified. The majority (91%) of
patients had cirrhosis diagnosed by biopsy or fibroscan (>12.5
kPa). Of the 293 patients on whom a fibroscan was performed,
137/293 (47%) had a value >20 kPa. The majority were
treatment-experienced (353, 69%), male (343, 67%), GT 1a
(307, 60%), and IL28B non-CC (405, 79%). 238 (67% of
the treatment-experienced patients) had previously received
a protease inhibitor-containing regimen. 91 (18%) initiated
therapy with a baseline platelet count of <90,000 cells/μL. 59
(11%) initiated therapy with a baseline albumin <3.5 g/dL.
The patients received one of four regimens: 12 weeks of LDV/
SOF (118, 23%), or LDV/SOF+RBV (206, 40%), or 24 weeks
of LDV/SOF (132, 26%) or LDV/SOF+RBV (58, 11%). Safety
in patients with cirrhosis was similar to that previously reported
in patients without cirrhosis. Adverse events including anemia
were more frequent in patients who received RBV. No other
trends in adverse events or serious adverse events were noted.
To date, 284 patients have available post-treatment week 12
data; of these, 269 (95%) have achieved SVR12. Safety and
efficacy for all 514 subjects will be presented. Conclusions:
Based on results from over 500 patients, LDV/SOF is effective,
safe, and well-tolerated for the treatment of compensated cir-
rhotic patients with HCV genotype 1.
Disclosures:
Marc Bourlière - Advisory Committees or Review Panels: Schering-Plough,
Bohringer inghelmein, Schering-Plough, Bohringer inghelmein; Board Member-
ship: Bristol-Myers Squibb, Gilead, Idenix; Consulting: Roche, Novartis, Tibotec,
Abott, glaxo smith kline, Merck, Bristol-Myers Squibb, Novartis, Tibotec, Abott,
glaxo smith kline; Speaking and Teaching: Gilead, Roche, Merck, Bristol-Myers
Squibb
239A
Mark S. Sulkowski - Advisory Committees or Review Panels: Merck, AbbVie,
Idenix, Janssen, Gilead, BMS, Pfizer; Grant/Research Support: Merck, AbbVie,
BIPI, Vertex, Janssen, Gilead, BMS
Masao Omata - Advisory Committees or Review Panels: Boehringer Ingelheim;
Speaking and Teaching: Otsuka Pharmaceutical, Bayer
Stefan Zeuzem - Consulting: Abbvie, Boehringer Ingelheim GmbH, Bristol-Myers
Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen,
Roche Pharma AG, Vertex Pharmaceuticals
Jordan J. Feld - Advisory Committees or Review Panels: Idenix, Merck, Janssen,
Gilead, AbbVie, Merck, Theravance, Bristol Meiers Squibb; Grant/Research
Support: AbbVie, Boehringer Ingelheim, Janssen, Gilead, Merck
Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharma-
ceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck &
Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals;
Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingel-
heim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharma-
ceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio,
Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teach-
ing: Gilead, Kadmon, Merck, Vertex
Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen,
MSD, Abbvie, Alios BioPharma, Idenix, Akron; Grant/Research Support: Roche,
Gilead, BMS, Novartis, Janssen, MSD, Alios BioPharma; Speaking and Teach-
ing: Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Boehringer, Pfizer,
Abbvie
Robert H. Hyland - Employment: Gilead Sciences, Inc; Stock Shareholder: Gilead
Sciences, Inc
Xiao Ding - Employment: Gilead Sciences
Jenny C. Yang - Employment: Gilead Sciences
Steven J. Knox - Employment: Gilead Sciences
Phillip S. Pang - Employment: Gilead Sciences
Mani Subramanian - Employment: Gilead Sciences
William T. Symonds - Employment: Gilead
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Alessandra Mangia - Advisory Committees or Review Panels: ROCHE, Janssen,
MSD, ROCHE, Janssen, MSD, Boheringer ; Consulting: Gilead; Grant/Research
Support: Shering-Plough, Shering-Plough
Edward J. Gane - Advisory Committees or Review Panels: Novira, AbbVie,
Novartis, Gilead Sciences, Janssen Cilag, Vertex, Achillion, Tekmira, Merck, Ide-
nix; Speaking and Teaching: AbbVie, Novartis, Gilead Sciences, Janssen Cilag
K. Rajender Reddy - Advisory Committees or Review Panels: Genentech-Roche,
Merck, Janssen, Vertex, Gilead, BMS, Novartis, Abbvie; Grant/Research Sup-
port: Merck, BMS, Ikaria, Gilead, Janssen, AbbVie
Stanislas Pol - Board Membership: Sanofi, Bristol-Myers-Squibb, Boehringer Ingel-
heim, Tibotec Janssen Cilag, Gilead, Glaxo Smith Kline, Roche, MSD, Novartis;
Grant/Research Support: Glaxo Smith Kline, Gilead, Roche, MSD; Speaking and
Teaching: Sanofi, Bristol-Myers-Squibb, Boehringer Ingelheim, Tibotec Janssen
Cilag, Gilead, Glaxo Smith Kline, Roche, MSD, Novartis
Nezam H. Afdhal - Consulting: Merck, Vertex, Idenix, GlaxoSmithKline, Spring-
bank, Gilead, Pharmasett, Abbott; Grant/Research Support: Merck, Vertex, Ide-
nix, GlaxoSmithKline, Springbank, Gilead, Pharmasett, Abbott
The following people have nothing to disclose: Masashi Mizokami
83
Integrated Efficacy Analysis of Four Phase 3 Studies in
HCV Genotype 1a-Infected Patients Treated with ABT-
450/r/Ombitasvir and Dasabuvir With or Without
Ribavirin
Gregory T. Everson1, Geoffrey Dusheiko2, Eoin Coakley3, Stephen
D. Shafran4, Fabien Zoulim5, Moises Diago6, Bradley Freilich7,
Ravi Ravinuthala8, Suzanne Norris9, Junyuan J. Xiong3, Roger
Trinh3, Tolga Baykal3, Yan Luo3, Mark S. Sulkowski10; 1Univer-
sity of Colorado Denver, Aurora, CO; 2The Royal Free Hospital,
London, United Kingdom; 3AbbVie Inc., North Chicago, IL; 4Uni-
versity of Alberta, Edmonton, AB, Canada; 5Hospices Civils de
Lyon, Lyon, France; 6Hospital Quirón de Valencia, Valenci, Spain;
7Kansas City Gastroenterology & Hepatology, Kansas City, MO;
8Consultants for Clinical Research, Cincinnati, OH; 9St. James’s
Hospital, Dublin, Ireland; 10Johns Hopkins University, Baltimore,
MD
Objective: The interferon-free, all-oral, 3 direct-acting antiviral
(3D) regimen of coformulated ABT-450 (an HCV NS3/4A pro-
240A AASLD ABSTRACTS
tease inhibitor identified by AbbVie and Enanta, dosed with
ritonavir [r]) and ombitasvir (an NS5A inhibitor) with dasabuvir
(a non-nucleoside NS5B RNA polymerase inhibitor) achieves
high rates of sustained virologic response (SVR) in patients (pts)
infected with HCV genotype (GT) 1. We report the pooled data
from four phase 3 clinical trials assessing the SVR12 rates of the
3D regimen with or without ribavirin (RBV) in treatment-naïve
and prior pegIFN/RBV (PR)-experienced pts with or without
cirrhosis infected with HCV GT1a. Methods: Patients infected
with HCV GT1a in the PEARL-IV, SAPPHIRE-I, SAPPHIRE-II, or
TURQUOISE-II trials received 12 weeks (including pts with cir-
rhosis) or 24 weeks (only pts with cirrhosis) of 3D with weight-
based RBV (including pts with cirrhosis) or without RBV (only
treatment-naïve pts without cirrhosis). SVR12 rates were based
on intent-to-treat population. Results: Among the 1060 HCV
GT1a-infected pts, 632 were from the United States, 295 from
Europe, and 133 from the rest of the world. In pts without cir-
rhosis, 12 weeks of 3D+RBV yielded similarly high SVR12 rates
in treatment naïve and PR-experienced groups (Table). SVR12
rates were higher in treatment-naïve pts without cirrhosis receiv-
ing 3D+RBV (95.7%) compared to 3D alone (90.2%). High
SVR12 rates were observed with both 12 and 24 week treat-
ments in pts with cirrhosis, however, in GT1a-infected pts with
cirrhosis and a prior PR null response a higher SVR12 rate was
observed with longer treatment duration. Among pts receiving
3D+RBV, the rates of on-treatment virologic failure and relapse
by post-treatment week 12 were low, 0.7% (6/856) and 2.9%
(24/830), respectively. In pts without cirrhosis receiving 3D
alone, 2.9% (6/204) had on-treatment virologic failure, and
5.2% (10/193) relapsed. Serious adverse events and discon-
tinuations due to adverse events occurred in 2.8% (30/1060)
and 1.2% (13/1060) of pts, respectively. Conclusions: In HCV
GT1a-infected pts, the 3D+RBV regimen achieved high SVR12
rates, including historically difficult to cure subgroups of pts
with prior PR null response and/or cirrhosis. In treatment-naïve
pts without cirrhosis the addition of RBV to 3D improved SVR12
rates. GT1a-infected pts with cirrhosis and a prior PR null
response may benefit from longer treatment duration.
Disclosures:
Gregory T. Everson - Advisory Committees or Review Panels: Roche/Genen-
tech, Abbvie, Galectin, Boehringer-Ingelheim, Eisai, Bristol-Myers Squibb, HepC
Connection, BioTest, Gilead, Merck; Board Membership: HepQuant LLC, PSC
Partners, HepQuant LLC; Consulting: Abbvie, BMS, Gilead, Bristol-Myers Squibb;
Grant/Research Support: Roche/Genentech, Pharmassett, Vertex, Abbvie, Bris-
tol-Myers Squibb, Merck, Eisai, Conatus, PSC Partners, Vertex, Tibotec, GlobeIm-
mune, Pfizer, Gilead, Conatus, Zymogenetics; Management Position: HepQuant
LLC, HepQuant LLC; Patent Held/Filed: Univ of Colorado; Speaking and Teach-
ing: Abbvie, Gilead
Eoin Coakley - Employment: AbbVie; Stock Shareholder: AbbVie
Stephen D. Shafran - Advisory Committees or Review Panels: Merck, Roche,
Bristol Myers Squibb, Vertex, Pfizer, Gilead, Boehringer Ingelheim, Janssen; Con-
sulting: AbbVie; Grant/Research Support: Merck, Roche, Bristol Myers Squibb,
Boehringer Ingelheim, Pfizer, Vertex, Gilead, AbbVie
Fabien Zoulim - Consulting: BMS, Gilead, Roche; Grant/Research Support: BMS,
Gilead, Roche; Speaking and Teaching: BMS, Gilead
Moises Diago - Grant/Research Support: BOHERINGER, ROCHE, MSD, GILEAD,
BMS, GSK, JANSEN, ABBVIE
Bradley Freilich - Grant/Research Support: schering plough, vertex, roche,
abbott, pharmaset, anadys, abbott, schering plough, vertex, roche, abbott,
pharmaset, anadys, abbott, schering plough, vertex, roche, abbott, pharmaset,
anadys, abbott, schering plough, vertex, roche, abbott, pharmaset, anadys,
abbott, connatus, bristol myers, jansen, gilead; Speaking and Teaching: onyx,
onyx, onyx, onyx, gilead, jansen, abbott
Suzanne Norris - Advisory Committees or Review Panels: AbbVie
Junyuan J. Xiong - Employment: AbbVie
Tolga Baykal - Employment: AbbVie
Yan Luo - Employment: AbbVie; Stock Shareholder: AbbVie
HEPATOLOGY, October, 2014
Mark S. Sulkowski - Advisory Committees or Review Panels: Merck, AbbVie,
Idenix, Janssen, Gilead, BMS, Pfizer; Grant/Research Support: Merck, AbbVie,
BIPI, Vertex, Janssen, Gilead, BMS
The following people have nothing to disclose: Geoffrey Dusheiko, Ravi Ravinut-
hala, Roger Trinh
84
High Efficacy of Sofosbuvir/Ledipasvir for the Treatment
of HCV Genotype 1 in Patients Coinfected With HIV on
or off Antiretroviral therapy: Results from The NIAID
ERADICATE Trial
Kerry S. Townsend1, Anu Osinusi1,2, Amy K. Nelson1, Anita
Kohli3,4, Chloe Gross3, Michael A. Polis1, Phillip S. Pang5,
Mohammad M. Sajadi2, Mani Subramanian5, John G. McHutchi-
son5, Henry Masur4, Shyam Kottilil1; 1Laboratory of Immunoregula-
tion, National Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, MD; 2Institute of Human Virology,
University of Maryland School of Medicine, Baltimore, MD; 3Clin-
ical Research Directorate/Clinical Monitoring Research Program,
Science Applications International Corp (SAIC), Frederick Inc,
Frederick National Laboratory for Cancer Research, Frederick,
MD; 4Critical Care Medicine Department, National Institutes of
Health Clinical Center, National Institutes of Health, Bethesda,
MD; 5Gilead Sciences, Foster City, CA
Background: HIV/HCV coinfected patients have been histori-
cally poor responders to IFN-based HCV treatment. Sofosbuvir,
an NS5B inhibitor, and ledipasvir, an NS5A inhibitor, are
being developed for the treatment of chronic Hepatitis C with
promising results in HCV monoinfected patients.We describe
the safety and efficacy regimen of sofosbuvir (SOF) and ledi-
pasvir (LDV) in HIV/HCV coinfected patients. Methods: Fifty
HCV, genotype-1, treatment naïve subjects received a fixed
dose combination (FDC) of SOF/LDV (400mg/90mg) once
daily for 12 weeks in two different groups (A: antiretroviral
therapy (ARV)-naïve, n=13 and B: patients on permitted ARV
combination comprised of the following: Truvada with Efa-
virenz, Rilpivirine or Raltegrevir with HIV viral suppression,
n=37). Serial measurements of safety parameters, virologic
and host correlates were performed. The HCV viral load (VL)
was measured using the Abbott Assay with a lower limit of
quantification (LLOQ) of 12 IU/ml. For all patients, mean log10
baseline HCV viral load was 5.9 log10IU/ml. Results: Baseline
demographics were similar between groups except for base-
line HIV viral load and CD4 count (p < 0.05). Patients were
primarily African American (84%), male (74%), mean age of
57 years with early disease HAI fibrosis score of <2 (78%) and
genotype 1a infection (74%). In ARV naïve subjects, SVR 12 is
100%. In ARV treated subjects, 97% (36/37) achieved SVR4
(SVR12 data from all subjects will be presented). There were
no changes in CD4 counts, HIV RNA levels or renal param-
eters observed. There were no serious adverse events (SAEs)
related to study drugs or discontinuations due to adverse events
(AEs). Conclusions: Treatment of chronic hepatitis C in HCV/
HIV co-infected patients with sofosbuvir/ledipasvir was effec-
tive and well-tolerated, suggesting HIV infection may not be
a major determinant of treatment outcome with sofosbuvir/
ledipasvir therapy.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Disclosures:
Phillip S. Pang - Employment: Gilead Sciences
Mani Subramanian - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
The following people have nothing to disclose: Kerry S. Townsend, Anu Osinusi,
Amy K. Nelson, Anita Kohli, Chloe Gross, Michael A. Polis, Mohammad M.
Sajadi, Henry Masur, Shyam Kottilil
85
Sub-normothermic machine perfusion preservation for
graft selection and therapy in a mouse liver transplan-
tation model
Masato Fujiyoshi, Akinobu Taketomi; Gastroenterological Surgery
I, Hokkaido University, Sapporo, Japan
To expand the donor pool safely, the development of new
methods to evaluate and furthermore improve the graft viability
during the preservation period is desirable. Under conventional
hypothermic preservation conditions, however, the biological
activities of liver grafts are suppressed to unmeasurable levels
and the uptake of therapeutic substances is inhibited. To over-
come these limitations, we established a new mouse model of
liver transplantation including a machine graft perfusion pro-
cess and achieved an extracorporeal non-hypothermic period
for evaluation and improvement of the graft viability in this
study. We developed a new organ perfusion machine in which
an oxygenated perfusion of the liver graft can be performed
at a wide range of temperatures. The liver graft was harvested
with the diaphragm, and the intra-thoracic IVC was clamped
to form a closed perfusion pathway. We adopted William
medium E as the perfusate, and oxygenated it with 100% oxy-
gen. After harvesting, a liver graft was connected to the perfu-
sion circuit and a graft perfusion was initiated at 4 degrees C.
Thereafter the temperature was raised to 25 degrees C and a
sub-normothermic graft perfusion was performed for 60 min.
The perfusion speed was at 2.5ml/min. After the sub-normo-
thermic perfusion, the temperature was lowered again, and
the graft was detached and prepared at 4 degrees C. Liver
transplantation was performed according to Qian’s method.
In this model (n=4), the mean oxygen consumption indicated
by the difference of the oxygen partial pressure between the
inflow and the outflow perfusate was 74.7 mmHg and the
mean carbon dioxide production indicated by the carbon diox-
ide partial pressure in the outflow perfusate was 0.0 mmHg at
4 degrees C. During sub-normothermic perfusion at 25 degrees
C, the mean oxygen consumption and the mean carbon diox-
ide production were increased to 290.8 mmHg and 5.6 mmHg
respectively. All recipient mice that had undergone liver trans-
241A
plantation using liver grafts after sub-normothermic machine
perfusion at 25 degrees C for 60 min survived more than 7
days (n=4). In conclusion, we confirmed that metabolic activi-
ties of liver grafts were kept at substantial levels and evaluable
during sub-normothermic machine perfusion, and succeeded in
liver transplantation after sub-normothermic machine perfusion
preservation.
Disclosures:
The following people have nothing to disclose: Masato Fujiyoshi, Akinobu Take-
tomi
86
A thyroid hormone receptor beta-selective T3 analog
promotes liver repopulation in apolipoprotein E-defi-
cient mice, correcting hypercholesterolemia
Wei Zhang1,3, Patrik Asp4, Bhavapria Vaitheesvaran2, Laibin Liu1,
Rafi Kabarriti1, Hillary Yaffe1, Rani Sellers5, Namita Roy-Chowd-
hury2,3, Jayanta Roy-Chowdhury2,3, Markus Grompe6,8, Thomas
Scanlan7, Chandan Guha1,3; 1Department of Radiation Oncology,
Albert Einstein College of Medicine, Bronx, NY; 2Department of
Medicine, Albert Einstein College of Medicine, Bronx, NY; 3Mar-
ion Bessin Liver Research Center, Albert Einstein College of Medi-
cine, Bronx, NY; 4Department of Surgery, Albert Einstein College
of Medicine, Bronx, NY; 5Department of Pathology, Albert Ein-
stein College of Medicine, Bronx, NY; 6Oregon Stem Cell Center,
Oregon Health & Science University, Portland, OR; 7Department
of Physiology and Pharmacology, Oregon Health & Science Uni-
versity, Portland, OR; 8Pape Family Pediatric Research Institute,
Oregon Health & Science University, Portland, OR
Background: We showed previously that preparative hepatic
X-irradiation (HIR) before hepatocyte transplantation (HT),
followed by mitotic stimulation with triiodothyronine (T3) per-
mits hepatic repopulation. Aim: To circumvent the cardiac
side effects of T3, we sought a substitute for repopulating the
liver of apolipoprotein-deficient (ApoE-/-) hypercholesterol-
emic mice. We tested the hypothesis that transplanting wild-
type hepatocytes in HIR-pretreated ApoE-/- mice, followed by
administration of GC-1 (a thyroid hormone receptor-b (TR-b)
selective agonist), should ameliorate hypercholesterolemia.
Methods: We determined the optimum HIR dose by transplant-
ing C57Bl/6 hepatocytes into DPPIV-/- mice that underwent
HIR 1 day before HT and GC-1 treatment (1mg/kg daily i.p.
for 3 weeks after HT). Based on these results, ApoE-/- mice
received 30Gy HIR in the median and left lobes 24 hr before
intrasplenic injection of 106 hepatocytes from congeneic b-ga-
lactosidase transgenic C57Bl/6 (ROSA-26) mice. Beginning
24 hr after HT, GC-1 was administered for 3 weeks. Other
groups received HT only, HIR+HT or HT+GC-1. Serum choles-
terol and ApoE levels were determined 2 days before, and 2,
4, 8 and 12 weeks after HT. Liver repopulation was assessed
by Immunofluorescence (IF) staining for ApoE+ donor cells and
western blot analysis of ApoE, 12 weeks after HT. Results: In
sham operated controls, cholesterol levels increased progres-
sively for 12 weeks. In HT only or HIR+HT groups, cholesterol
levels did not change significantly (P>0.5). In mice receiving
HT+GC-1, cholesterol levels declined during the 2 weeks of
GC-1 treatment (from 720+65 to 446+42 mg/dl, p<0.05), but
242A AASLD ABSTRACTS
increased after discontinuing GC-1 (674+121 mg/dl). In con-
trast, in the HIR+HT+GC-1 group, cholesterol levels declined by
79% from pretreatment levels of 629+40 to near normal levels
186+38 mg/dl (p<0.01) in 12 weeks. In this group, ApoE
was detectable by western blot in the HIR-preconditioned liver
lobes and IF staining showed massive (60-70%) repopulation
by the ApoE+ hepatocytes. The livers of the HT only, HIR+HT
or HT+GC-1 groups contained donor hepatocytes as single
cells or in small clusters. Conclusions: We show for the first
time that a TR-b agonist, GC-1, in combination with prepar-
ative HIR induces massive hepatic repopulation in mice with
transplanted hepatocytes, resulting in marked amelioration of
hypercholesterolemia in ApoE-deficient recipient mice. Unlike
T3, GC-1 did not exhibit cardiac side effects. Preparative HIR
in combination with GC-1, which is undergoing clinical trial for
other indications, may provide a novel effective regimen for
HT-based treatment of inherited metabolic liver diseases.
Disclosures:
Markus Grompe - Board Membership: Yecuris Corp.; Consulting: Yecuris Corp.;
Stock Shareholder: Yecuris Corp.
The following people have nothing to disclose: Wei Zhang, Patrik Asp, Bhavapria
Vaitheesvaran, Laibin Liu, Rafi Kabarriti, Hillary Yaffe, Rani Sellers, Namita
Roy-Chowdhury, Jayanta Roy-Chowdhury, Thomas Scanlan, Chandan Guha
87
Controlled processing of a full-size porcine liver to a
decellularized matrix for tissue engineering
Nicola Buehler, Martin Schenk; Experimental Medicine, University
of Tuebingen, Tuebingen, Germany
Background and aims: The shortage of donor organs asks
for new sources for transplantable bioengineered organs.
The generation of full-size humanized organs based on ani-
mal matrix scaffolds providing an intact vascular network is a
highly favourable solution. Recent decellularization methods
are mostly time consuming, associated with high rinsing vol-
umes and poorly standardized. In this study we describe a
recirculating decellularization method to obtain a porcine liver
matrix in only 24 hours under standardized processing. Meth-
ods: Full porcine livers (529±33g), harvested from minipigs
(n=15, 24±1kg), were decellularized by flushing with 3L of an
isotonic sodium chloride solution, freezing at -80°C and con-
trolled portal perfusion (20mmHg) with 2x10L of a 1% sodium
dodecyl sulphate (SDS) at 37°C and a final perfusion with
DNase in TrisHCl/MgCl2 (n=7), interrupted by washing steps
with phosphate buffered saline. Protein concentrations were
continuously monitored by optical density (280nm). DNA, gly-
cosaminoglycans (GAGs) and collagen contents were assessed
and a hematoxylin and eosin (H&E) staining was performed.
Results: After 24h the liver had a white and clear appearance
and protein levels didn’t rise anymore. DNA was significantly
decreased in the decellularized tissue (1.9% only SDS, 0.5%
SDS and DNase) while GAGs could be preserved. Collagen
levels decreased to 51% in SDS + DNase flushed liver and to
32.9% in SDS flushed livers respectively. H&E staining showed
an intact extra cellular matrix with no nuclear residuals (Figure).
Conclusion: This study shows that porcine livers can be success-
fully decellularized with low volumes of a 1% SDS solution and
DNase in a standardized process in only 24 hours, in order to
obtain an organ scaffold which can be used for tissue engineer-
ing and later on for transplantation. The loss of collagen might
be critical for recellularization attempts but needs to be tested
in further settings.
HEPATOLOGY, October, 2014
Portal trias of a decellularized liver, H&E staining
Disclosures:
The following people have nothing to disclose: Nicola Buehler, Martin Schenk
88
Transplantation of human fetal biliary tree stem/pro-
genitor cells into two patients with advanced liver cir-
rhosis
Vincenzo Cardinale1, Guido Carpino2, Raffaele Gentile1, Chi-
ara Napoletano3, Hassan Rahimi3, Antonio Franchitto4, Rossella
Semeraro1, Marianna Nuti3, Paolo Onori4, Pasquale Bartolomeo
Berloco5, Massimo Rossi5, Daniela Bosco3, Roberto Brunelli6,
Alice Fraveto1, Cristina Napoli1, Alessia Torrice1, Manuela
Gatto1, Rosanna Venere1, Carlo Bastianelli6, Camilla Aliberti6,
Filippo Maria Salvatori7, Adolfo F. Attili8, Lola M. Reid9, Eugenio
Gaudio4, Domenico Alvaro1; 1Department of Medico-Surgical Sci-
ences and Biotechnologies, Sapienza University of Rome, Rome,
Italy; 2Department of Health Sciences, University of Rome “Foro
Italico”, Rome, Italy; 3Department of Experimental Medicine, Sapi-
enza University of Rome, Rome, Italy; 4Department of Anatomical,
Histological, Forensic Medicine and Orthopedics Sciences, Sapi-
enza University of Rome, Rome, Italy; 5Department of General
Surgery and Organ Transplantation, Sapienza University of Rome,
Rome, Italy; 6Department of Gynecologic-Obstetric and Urologic
Sciences, Sapienza University of Rome, Rome, Italy; 7Department
of Radiological Sciences, Sapienza University of Rome, Rome,
Italy; 8Department of Clinical Medicine, Sapienza University of
Rome, Rome, Italy; 9Department of Cell Biology and Physiology,
Program in Molecular Biology and Biotechnology, Univesity of
North Carolina School of Medicine, Chapel Hill, NC
Aim: Efforts to identify cell sources and approaches for cell
therapy of liver diseases are ongoing. The aim of the present
study was to evaluate the feasibility, safety and the clinical
outcomes of the first procedure of transplantation of human
fetal biliary tree stem cells in patients with advanced liver cir-
rhosis. Methods: The cells were immune-sorted for EpCAM (Epi-
thelial Cell Adhesion Molecule) from human fetal biliary tree
(including the gallbladder) by protocols in accordance with
current good manufacturing practice (cGMP). Cell products
were evaluated by standard sterility tests for gram+, gram-,
aerobic and anaerobic bacteria, mycetes and with endotoxins
tests, and characterized immediately by Flow Cytometry (FC)
for EpCAM and Leucine-Rich Repeat-Containing G Protein-Cou-
pled Receptor 5 (LGR5) before transplantation. Two patients
with advanced cirrhosis (Child-Pugh C) have been submitted
to the procedure of via hepatic artery cell transplantation and
observed trough a 12 months follow-up. Patients were not can-
didates for liver transplantation because of their age being
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
greater than 70 years. Informed consent was obtained from
the patients. Results: In fetal tissues, most EpCAM-positive cells
co-expressed LGR5 and were located in the ductal plate, in
the surface epithelium and bud of peribiliary glands of larger
intrahepatic and extrahepatic bile ducts, and in gallbladder
epithelium. The sorting resulted in isolation of 42 million viable
cells from the first fetus and 60 million from the second one; the
FC analyses demonstrated that the immunomagnetic sorting
enriched the EpCAM+ population to a percentage of 73.9 and
51%, respectively. The via hepatic artery transplantation pro-
cedures were found absolutely safe. Immuno-suppressants were
not required, and the patients did not display any adverse
effects correlated with cell transplantation or suggestive of
immunological complications. From a clinical point of view,
both patients showed biochemical and clinical improvement
during the 6 month follow-up and the second patient main-
tained a stable improvement for 12 months (Child-Pugh score
from C-11 to B-8, MELD score from 21 to 16). Conclusions:
This report represents the proof of the concept that the human
fetal biliary tree stem cells are a suitable and large source for
cell therapy of liver cirrhosis. The isolation procedure can be
carried out under cGMP conditions and, finally, the infusion
procedure is easy and safe for the patients. This represents the
basis for forthcoming controlled clinical trials.
Disclosures:
Lola M. Reid - Consulting: PhoenixSongs Biologicals; Grant/Research Support:
Vesta Therapeutics, NIH, The Hamner Institute
The following people have nothing to disclose: Vincenzo Cardinale, Guido
Carpino, Raffaele Gentile, Chiara Napoletano, Hassan Rahimi, Antonio
Franchitto, Rossella Semeraro, Marianna Nuti, Paolo Onori, Pasquale Bar-
tolomeo Berloco, Massimo Rossi, Daniela Bosco, Roberto Brunelli, Alice Fraveto,
Cristina Napoli, Alessia Torrice, Manuela Gatto, Rosanna Venere, Carlo
Bastianelli, Camilla Aliberti, Filippo Maria Salvatori, Adolfo F. Attili, Eugenio
Gaudio, Domenico Alvaro
89
Decellularized Human Liver as a Natural 3D Scaffold for
Organ Engineering and 3D-Disease Modeling
Giuseppe Mazza1, Krista Rombouts1, Andrew R. Hall1, Luca
Urbani3, Lisa Longato1, Alan M. Holmes4, Panagiotis Maghsoud-
lou3, Robert Good4, Amar P. Dhillon1, Barry Fuller2, Brian David-
son2, Dipok K. Dhar1, Paolo De Coppi3, Massimo M. Malago’2,
Massimo Pinzani1; 1Institute for Liver and Digestive Helath, UCL,
London, United Kingdom; 2Division of Surgery, UCL, London,
United Kingdom; 3Institute for Child Health, UCL, London, United
Kingdom; 4Centre for Rheumatology and Connective Tissue Dis-
eases, UCL, London, United Kingdom
AIM: Human tissue engineering combines cells and scaffolds for
the development of 3D-structure in order to regenerate organs
and to recapitulate disease in vitro. Biological scaffolds com-
posed of extracellular matrix (ECM) can be derived by decel-
lularisation of a tissue wedge section up to the whole organ
with preservation of ECM integrity, bioactivity and three-dimen-
sional organisation. These scaffolds may be implanted, with
or without cell repopulation, to regenerate a complete organ
or to improve tissue repair, respectively. In this study we have
investigated the usage of human liver as a platform of 3D bios-
caffold with the repopulation of different cell types important in
liver development and diseases. METHODS: The decellulariza-
tion efficiency and quality of the resultant ECM scaffold were
determined by immunohistochemistry for ECM components and
DNA residues, and by Scanning Electron Microscopy. Five
mm3 cubes obtained from decellularized human liver were
subcutaneously transplanted in mice to evaluate sterility, bio-
compatibility and immune response. In addition, decellular-
ised human livers were repopulated by employing multifocal
injection of human parenchymal and non-parenchymal cell
243A
line such as LX2, SKHep, HepG2 and human Endothelial Pro-
genitor Cells (hEPC) and compared with the same cell types
grown under standard 2D condition for the same length of
time. RESULTS: The decellularisation of the whole human liver
left lobe was obtained after 2 weeks perfusion. This innovative
protocol resulted in scaffolds with a preserved 3D structure
and ECM composition, while DNA and cellular residues were
successfully removed. Biocompatibility was thoroughly demon-
strated in the xenotransplantation model. Human liver scaffolds
were progressively repopulated for up to 21 days with LX2,
SKHep and HepG2 cells and with hEPC for up to 6 days. These
3D-cultures showed remarkable viability, motility and prolifer-
ation associated with remodelling effects on the surrounding
ECM. Notably, the expression of some genes and proteins
involved in liver fibrosis and cancer was different between the
2D and the 3D system. CONCLUSION: For the first time to
our knowledge, we showed an efficient protocol to completely
decellularize human livers. The decellularization protocol was
demonstrated to be efficient in maintaining 3D structure and
ECM composition and all its cellular biological features inves-
tigated so far. This advancement is fundamental for the devel-
opment of 3D technologies leading to auxiliary transplantation
and for the study of human liver pathophysiology.
Disclosures:
Amar P. Dhillon - Independent Contractor: Echosens
Massimo Pinzani - Advisory Committees or Review Panels: Intercept Pharmaceu-
tical, Silence Therapeutic, Abbot; Consulting: UCB; Speaking and Teaching:
Gilead, BMS
The following people have nothing to disclose: Giuseppe Mazza, Krista Rom-
bouts, Andrew R. Hall, Luca Urbani, Lisa Longato, Alan M. Holmes, Panagiotis
Maghsoudlou, Robert Good, Barry Fuller, Brian Davidson, Dipok K. Dhar, Paolo
De Coppi, Massimo M. Malago’
90
Lymphocyte cell adhesion molecule L-selectin plays a
dynamic role in ischemia reperfusion injury of a ste-
atotic liver
Vasantha L. Kolachala1, Abramowsky Carlos2, Ming Shen1,
Alayna Feng1, Allan D. Kirk1, Nitika A. Gupta1; 1Department of
Pediatrics, Emory University School Of Medicine, Atlanta, GA;
2Department of Pathology, Emory University School of Medicine,
Atlanta, GA
Background: A steatotic liver is increasingly vulnerable to isch-
emia reperfusion injury (IRI), which is commonly encountered
during hepatic resection, shock, myocardial infarction and liver
transplantation. The underlying mechanisms of the resultant
cell death and hepatocellular dysfunction of the steatotic liver
undergoing IRI, are incompletely defined. Adhesion molecules
and T cell trafficking are an area of intense research in IRI and
pro-inflammatory states, but their significance in IRI of a ste-
atotic liver is largely unknown. Aim: The aim of this study was
to investigate the role of adhesion molecules, T cell trafficking
and cytokines in IRI of a steatotic liver. Methodology: Male
C57BL6 mice were fed a high fat diet (HFD) for 12 weeks.
Hepatic steatosis was determined by oil red O (ORO) staining.
The mice were subjected to 40 minutes of hepatic ischemia,
followed by 24 hours of reperfusion. Hepatocellular injury
was assessed by presence of liver necrosis and level of serum
ALT. Splenocytes were subjected to flow cytometry for T cell
markers such as CD3, CD4, CD8, PD1, CD69, CD62L, and
for adhesion molecules (P-selectin, E-selectin, L-selectin, ICAM-
1, VCAM-1) by immunofluorescence and RT-PCR. Cytokines
were assessed by a 20-Plex Luminex assay. L selectin was
blocked and hepatocellular damage after IRI was assessed
to mechanistically define the role of the adhesion molecule.
Results: Mice fed a HFD diet showed significant increase in
244A AASLD ABSTRACTS
body weight (42±1.2, vs. 24.6±0.6 grams; p<0.0001) and
presence of hepatic steatosis by ORO stain. Splenocytes from
HFD mice undergoing IRI demonstrated significant increase
in CD4+ T cell activation markers, such as PD1 (p<0.0009),
CD69(p<0.01), and CD62L(p<0.001), in addition to higher
levels of serum ALT and significant increase in hepatocellular
necrosis. The T cell proliferation marker Ki67 (p<0.0089), was
significantly higher in HFD IRI as compared to lean IRI. Expres-
sion levels of L-selectin (p<0.03) but not P or E-selectin were
elevated in HFD IRI. Increased cytokines such as IFNγ, IL-1a,
IL-10, IL-6 and IL-17, suggested a pro-inflammatory milieu in
HFD IRI. Blockade of L-selectin, lead to a significant attenuation
of hepatocellular injury. Conclusion: A steatotic liver undergo-
ing IRI is associated with elevation of adhesion molecule L-se-
lectin along with activation and proliferation of CD4+ T cells,
and a pro-inflammatory cytokine milieu. Blocking the adhesion
molecule L-selectin leads to mitigation of hepatocellular injury,
thus offering an important and clinically relevant therapeutic
intervention in the increasingly prevalent clinical condition of
IRI of fatty liver disease.
Disclosures:
The following people have nothing to disclose: Vasantha L. Kolachala,
Abramowsky Carlos, Ming Shen, Alayna Feng, Allan D. Kirk, Nitika A. Gupta
91
Benefit of Paracentesis on In-hospital Mortality Among
Adults Admitted with Cirrhosis and Ascites
John N. Gaetano, Dejan Micic, Archita P. Desai, Andrew Aron-
sohn, Nancy Reau, Helen S. Te, K. Gautham Reddy, Donald M.
Jensen; Gastroenterology, Hepatology and Nutrition, University of
Chicago Medicine, Chicago, IL
Background: The incidence of spontaneous bacterial perito-
nitis (SBP) in patients with cirrhosis complicated by ascites
has been reported to occur in up to one-third of hospitalized
patients. Consensus guidelines by the AASLD recommend that
all patients non-electively admitted to the hospital with asci-
tes should receive a diagnostic paracentesis upon admission
to exclude SBP. Little data exists regarding adherence to this
guideline and its associated outcomes. Methods: The 2011
Nationwide Inpatient Sample (NIS) was used to identify adults,
non-electively admitted (and not transferred to another acute
care facility) with diagnoses of cirrhosis and ascites. In-hos-
pital mortality was the primary outcome assessed between
individuals receiving a paracentesis and those who did not.
Subgroup analysis was performed for early vs. late paracen-
tesis (performed on day 0 or 1 of admission), as well as those
with signs of systemic infection or hepatic decompensation, i.e
hepatic encephalopathy, acute kidney injury, metabolic acido-
sis, leukocytosis, and fever. Risk factors for in-hospitality mor-
tality among patients diagnosed with SBP were also assessed.
Results: Out of 8,023,590 admissions captured in the 2011
NIS, 31,614 met inclusion criteria. Of these, only 51%
(16,133) underwent paracentesis, 59% of which occurred on
day 0 or day 1 of admission. The overall all-cause in-hospi-
tal mortality was 7.6%. Performance of a paracentesis was
associated with a 29% reduction in mortality (8.9% vs 6.3%;
adjusted odds ratio 0.55; 95% CI 0.54-0.65). Patients under-
going early paracentesis (Day 0 or day 1) showed a reduction
in mortality (7.4% vs. 5.5%), however, with multi-variate anal-
ysis, this association was not statistically significant. Additional
factors associated with in-hospital mortality were the presence
of acute kidney injury (adjusted OR 3.86; 95% CI 3.48-4.29),
metabolic acidosis (adjusted OR 3.38; 95% CI 3.01-3.79),
encephalopathy (adjusted OR 1.80; 95% CI 1.63-1.99), and
SBP (adjusted OR 2.15; 95% CI 1.83-2.51). Patients admitted
HEPATOLOGY, October, 2014
on a weekend had a higher mortality (OR 1.15; 95% CI 1.03-
1.29), and weekend admission was also associated with less
frequent early paracentesis (50% vs. 62%). Conclusion: While
the importance of its implementation is known amongst experts,
paracentesis appears to be overlooked as an essential com-
ponent of care for patients with cirrhosis and ascites. Future
studies to investigate the obstacles that prevent clinicians from
performing paracentesis on admission are needed. This data
also supports the use of diagnostic paracentesis as a key inpa-
tient quality measure for care of patients with cirrhosis.
Disclosures:
Nancy Reau - Advisory Committees or Review Panels: Kadmon, Jannsen, Vertex,
Idenix, AbbVie, Jannsen; Grant/Research Support: Vertex, Gilead, Genentech,
AbbVie, BMS, Jannsen, BI
Helen S. Te - Advisory Committees or Review Panels: Gilead Sciences, Jansenn
Pharmaceuticals; Grant/Research Support: Abbvie, BMS
K. Gautham Reddy - Advisory Committees or Review Panels: AASLD Transplant
Hepatology Pilot Steering Committee, ACG Training Committee, Program Direc-
tor’s Caucus Steering Committee; Grant/Research Support: Intercept, Ocera,
Merck, Lumena
Donald M. Jensen - Grant/Research Support: Abbvie, Boehringer, BMS, Genen-
tech/Roche, Janssen
The following people have nothing to disclose: John N. Gaetano, Dejan Micic,
Archita P. Desai, Andrew Aronsohn
92
Pathogenesis and clinical impact of relative adrenal
insufficiency in hospitalized patients with acute decom-
pensation of cirrhosis
Salvatore Piano1, Elisa Favaretto1, Silvano Fasolato1, Carla Sca-
roni1, Elisabetta Gola1, Alessandra Brocca1, Antonietta Sticca1,
Filippo Morando1, Marta Cavallin1, Antonietta Romano1, Gia-
como Zanus2, Angelo Gatta1, Umberto Cillo2, Paolo Angeli1,3;
1Department of Medicine DIMED, University of Padova, Padova,
Italy; 2Unit of Hepatobiliary Surgery and Liver Transpantation, Uni-
versity of Padova, Padova, Italy; 3Department of Medicine DIMED,
Unit of Medical Emergencies in Liver Transplantation, University of
Padova, Padova, Italy
Background and aims: Relative adrenal insufficiency (RAI) is
common in hospitalized patients with acute decompensation
of cirrhosis and recently has been associated with the develop-
ment of hepatorenal syndrome, sepsis, septic shock and poor
survival. Its pathogenesis has not yet been clearly defined. The
aim of our study was to explore factors associated with the
development of RAI and to further investigate clinical impact
of RAI in these patients. Methods: 94 patients admitted to the
hospital for an acute decompensation of cirrhosis were con-
secutively enrolled in the study and followed up for 90 days.
Adrenal function was assessed with short synacthen test (SST).
RAI was diagnosed when the increase in serum total cortisol
after SST was <9 mg/dL in patients with basal serum total cor-
tisol <35 mg/dL. Bacterial infections, markers of inflammations
(PCR and pro-inflammatory cytokines including: TNF α, IL-6,
IL-1β), ACTH and substrates for steroidogenesis such as choles-
terol, HDL cholesterol and apolipoprotein A1, which is required
for normal cholesteryl ester accumulation in steroidogenic cells,
were explored as possible pathogenetic factors involved in
the development of RAI. Results: RAI was diagnosed in 42.6
% of them. Patients with RAI were younger (57.0 vs 61.5
years; p=0.047), had higher MELD Na score (22 vs 18.4;
p=0.01), higher C-reactive protein, (15.0 vs 11.5 mg/L), and
lower total cholesterol (1.5 vs 2.1 mmol/L; p=0.028), HDL
(0.4 vs 0.6 mmol/L; p=0.034) and apolipoprotein A1 (0.6 vs
0.8; p=0.006) than patients without RAI. TNF α, IL6, IL1β and
ACTH were not significantly different between the two groups.
Apolipoprotein A1 was the only independent predictor of RAI
(OR=0.12; p=0.011). In our series the presence of RAI was
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
associated with an higher risk to develop bacterial infections
(65.1 vs 42.4%; p= 0.039), hyponatremia (46.0 vs 14.3%;
p=0.002), and with poorer 90-day transplant free survival
(70.7 vs 90.3%; p=0.013). In the multivariate Cox regression
analysis MELD-Na (HR=1.096, p=0.030), age (HR=1.059;
p=0.043) and RAI (HR=3.277; p=0.041) were found to be
independent predictors of mortality. Conclusions: RAI is fre-
quent in patients who are hospitalized for an acute decompen-
sation of cirrhosis. Low level of apolipoprotein A1 seems to
have a pivotal role in its pathogenesis. RAI is associated with a
high risk to develop bacterial infections and hyponatremia and
with a low probability of survival in these patients.
Disclosures:
Umberto Cillo - Grant/Research Support: Novartis, Bayer, Astellas
Paolo Angeli - Advisory Committees or Review Panels: Sequana Medical
The following people have nothing to disclose: Salvatore Piano, Elisa Favaretto,
Silvano Fasolato, Carla Scaroni, Elisabetta Gola, Alessandra Brocca, Antonietta
Sticca, Filippo Morando, Marta Cavallin, Antonietta Romano, Giacomo Zanus,
Angelo Gatta
93
Prediction of Subclinical Coronary Atherosclerosis Based
on Coronary Calcification in Cirrhotic Candidates for
Liver Transplantation
Jihyun An, Ju Hyun Shim, Young-Suk Lim, Kang Mo Kim, Han Chu
Lee, Jonggi Choi, Gi-Ae Kim, Hyung-Don Kim, Young Joo Yang,
Yeonjung Ha, Mi-Jung Jun, Jee Eun Yang, Young-Hwa Chung,
Yung Sang Lee, Dong Jin Suh; 1Department of Gastroenterology,
Liver Center, Asan Medical Center, University of Ulsan College of
Medicine, Seoul, Republic of Korea
Backgrounds/aims: Although coronary artery disease (CAD)
is the leading cause of non-graft-related complication in liver
transplant (LT) recipients, there is no consensus regarding the
preferred test for detecting occult CAD at the time of pre-LT
screening. Coronary artery calcium (CAC) scoring has been
extensively studied as a powerful, non-invasive tool for cardio-
vascular risk assessment in the general population. The aim
of this study is to investigate whether CAC scoring could pre-
dict obstructive CAD in asymptomatic LT candidates with liver
cirrhosis (LC). Methods: This study included 850 consecutive
cirrhotic patients who underwent computerized coronary angi-
ography with CAC measurement using the Agaston method
as a pre-LT workup. None of these patients had a previous
CAD history. Obstructive CAD was defined as ≥50% of lumi-
nal narrowing in any artery on computerized angiography.
The association between CAC score and obstructive CAD was
analyzed using the Pearson correlation method, logistic regres-
sion and area under the receiver operating characteristic curve
(AUROC) analyses. Results: The mean CAC score of all patients
was 90.0 (range, 0-4411.4). The CAC score was 0 for 535
patients (62.9%), 1-100 for 191 (22.5%), 101-400 for 74
(8.7%), and >400 for 50 (5.9%). Obstructive CAD was iden-
tified in 72 patients (8.5%). The mean CAC score significantly
differed between patients with and without obstructive CAD
(633.6 vs. 39.6; P<0.05). The prevalence of obstructive CAD
increased with the CAC score (1.7% for 0, 5.8% for 1-100,
25.7% for 101-400, and 66.0% for >400). The CAC score
was significantly correlated with the grade of coronary stenosis
(r=0.71; P<0.05). The CAC score showed excellent perfor-
mance for predicting obstructive CAD with an AUROC value of
0.88. The best cut-off CAC score was 38.8 for obstructive CAD
with a sensitivity of 83% and a specificity of 86%. In multivari-
ate analysis, a CAC score at a cut-off of 38.8 was an indepen-
dent predictor for obstructive CAD (adjusted odds ratio[OR],
23.9; P<0.05). Older age, male sex, a current smoker, hyper-
tension, diabetes, and alcoholic LC were significantly associ-
245A
ated with a CAC score above 38.8 (adjusted OR, 1.07, 3.27,
1.59, 1.54, 1.79, and 2.17; Ps<0.05), as were neither liver
function and coagulation parameters nor viral hepatitis affect
the score. Conclusion: Our data indicate that the CAC score
is an accurate tool for predicting subclinical obstructive CAD
in cirrhotic subjects. Traditional cardiovascular risk factors,
together with alcoholic LC, were closely associated with higher
CAC score. Based on our results, CAC scoring may be helpful
for coronary risk prediction in LT candidates with LC.
Disclosures:
Young-Suk Lim - Advisory Committees or Review Panels: Bayer Healthcare, Gil-
ead Sciences; Grant/Research Support: Bayer Healthcare, BMS, Gilead Sci-
ences, Novartis
Han Chu Lee - Grant/Research Support: Medigen Biotechnology Co., Novartis,
Roche, Bayer HealthCare, Bristol-Myers Squibb, INC research, Boehringer Ingel-
heim, Taiho Pharmaceutical Co., Yuhan Co.
The following people have nothing to disclose: Jihyun An, Ju Hyun Shim, Kang
Mo Kim, Jonggi Choi, Gi-Ae Kim, Hyung-Don Kim, Young Joo Yang, Yeonjung
Ha, Mi-Jung Jun, Jee Eun Yang, Young-Hwa Chung, Yung Sang Lee, Dong Jin Suh
94
Hepatic Encephalopathy is Associated with Persistent
Cognitive Deficits Despite Adequate Medical Treatment:
A Multi-center, International Study
Silvia Nardelli3, Sanath Allampati2, Nicole Noble1, Oliviero Rig-
gio3, Kevin D. Mullen2, Eugenia Onori3, Ravi Prakash2, Stefania
Gioia3, Ariel Unser1, Melanie White1, Edith A. Gavis1, Jasmohan
S. Bajaj1; 1Gastroenterology, Hepatology and Nutrition, VCU and
McGuire VAMC, Richmond, VA; 2Gastroenterology, Metrohealth
Medical Center, Case Western Reserve University, Cleveland, OH;
3Gastroenterology, La’Sapienza, University of Rome, Rome, Italy
Hepatic encephalopathy (HE) is considered reversible regard-
ing mental status but may not be from a cognitive standpoint.
This may have implications for brain recovery post-transplant
and needs evaluation with multi-center studies. Aim: evaluate
persistence of cognitive impairment in HE compared to no-HE
patients in a multi-center study. Methods: Outpatient cirrhotics
from 3 centers (Virginia, Rome & Ohio) underwent cognitive
testing including paper-pencil (psychometric hepatic enceph-
alopathy score:PHES) & inhibitory control test (ICT; outcomes
lures) ≥7 days apart without intervening disease changes. The
1st half of ICT is identical to the 2nd half. Therefore subjects
with intact learning ability should improve (have less lures) in
the 2nd compared to the 1st half. PHES has 6 tests (number
conn A/B:NC A/B, digit symbol: DS, serial dotting:SD & line
tracing errors/time:LTTe/t). Learning between test administra-
tions & ICT lure changes were compared in HE vs. no-HE pts.
Results: 187 pts (77 VA, 50 Rome, 30 OH, 59yrs, MELD 11,
12 yrs educ) were included. Italian pts were significantly older
& less educated than the rest but MELD was similar. 20% had
prior HE (24 VA, 9 Rome, 3 OH) controlled on meds (100%
lactulose,25% also on rifaximin). HE pts had a higher MELD
score (16 vs 10, p<0.0001). Baseline visit: HE pts had worse
performance on all tests compared to no-HE pts. While no-HE
pts significantly improved on ICT (1st half 7.1 vs. 6.2, 2nd
half,p<0.0001), HE pts did not show learning capability (1st
half 7.9 vs 7.8, p=0.1). Retesting visit: All pts were retested a
median of 20 days later without change in cirrhosis severity/
complications. Again HE pts did not show ICT learning (7.8 vs
6.9,p=0.37) while no-HE ones continued to improve (6.0 vs.
5.4, p<0.0001). Changes in tests over time: There was a sig-
nificant improvement in four PHES subtests in the second testing
compared to the first in no-HE pts (NC-A 42 vs 36, p=0.05,
NC-B 103 vs 93, p=0.007, DS 46 vs 49,p=0.002, SD: 68 vs
64, p=0.05) and ICT lures (13 vs 11, p=0.05) in no-HE pts.
In contrast there was only improvement in two of the 6 PHES
246A AASLD ABSTRACTS
subtests (NC-B 146 vs 131, p=0.34, SD: 90 vs 84, p=0.1,
LTTt 132 vs 125,p=0.4, LTTe 49 vs 51, p=0.72), apart from
DS (37 vs 41, p=0.001) & NC-A,( 56 vs 47, p=0.01) and no
improvement on ICT (total lures 14.8 vs 14.3, p=0.74) in HE
pts. Conclusion: In this multi-center study, patients with prior HE
showed persistent significant learning impairment compared to
those without prior HE, despite adequate medical therapy. This
persistent change should increase efforts to reduce the first HE
episode and potentially increase their transplant listing priority
for HE patients.
Disclosures:
Kevin D. Mullen - Advisory Committees or Review Panels: Salix, AASLD/EASL;
Speaking and Teaching: Salix, Abvie
Jasmohan S. Bajaj - Advisory Committees or Review Panels: Salix, Merz, otsuka,
ocera, grifols, american college of gastroenterology; Grant/Research Support:
salix, otsuka, grifols
The following people have nothing to disclose: Silvia Nardelli, Sanath Allampati,
Nicole Noble, Oliviero Riggio, Eugenia Onori, Ravi Prakash, Stefania Gioia,
Ariel Unser, Melanie White, Edith A. Gavis
95
Facility and patient level predictors of endoscopic vari-
ceal screening within the largest integrated healthcare
system in the United States
Varun Saxena1, Jennifer A. Flemming3, Hui Shen2,1, Norah Ter-
rault1, Alexander Monto2,1, Catherine Rongey2,1; 1Gastroenterol-
ogy, University of California San Francisco, San Francisco, CA;
2Gastroenterology, San Francisco Veterans Affairs Medical Cen-
ter, San Francisco, CA; 3Gastroenterology, Queen’s University,
Ontario, ON, Canada
Introduction: The American Association for the Study of Liver
Disease (AASLD) recommends screening for esophageal var-
ices (EV) by esophagoduodenoscopy (EGD) in patients with
cirrhosis within one year to guide decisions regarding pri-
mary prophylaxis for EV hemorrhage. Aim: To determine the
patient and facility factors associated with AASLD guideline
recommended EV screening in a cohort of veteran’s with hep-
atitis C (HCV) associated cirrhosis. Methods: We created a
national cohort of veterans, identified between 1/1/2004-
12/31/2005 and followed until 12/31/2011, with HCV
viremic-confirmed, newly diagnosed cirrhosis, who rely upon
the Veterans Health Administration for care. Patients with a
prior history of cirrhosis and history of gastrointestinal bleed
were excluded. Primary outcome variable was receipt of out-
patient screening EGD within one year of cirrhosis diagnosis.
Patient and facility level factors were examined in bi-variate
and multivariate logistic regression to identify predictors of EV
screening within AASLD guidelines. Results: A total of 4,230
patients with newly diagnosed HCV associated cirrhosis were
identified and followed for a median of 6.1 years (IQR: 4.0-
8.0). At cohort entry, median age of cirrhosis diagnosis was
54.4 years (IQR: 50.3-57.1), 98% were male, 66.2% were
non-hispanic white and 44.5% presented with decompensation
as their first diagnosis of cirrhosis. During the study period,
10.6% of patients developed a variceal bleed, 21.5% of
patients progressed towards decompensation and 38.3% died.
During follow-up, 54% of patients received a screening EGD;
33.8% of patients received a screening EGD within guidelines
with a median time from cirrhosis diagnosis to EGD of 26
days (IQR: 18 - 125). The majority (85.8%) of patients who
received a screening EGD per AASLD guidelines had been
seen previously in a gastroenterology (GI) or hepatology clinic.
In multivariate analysis, a decompensation event (OR 1.16, CI
1.01-1.32) and GI/hepatology clinic access (OR 2.1, CI 1.73-
2.46) were positively associated with receiving EV screening
per AASLD guidelines while cardiovascular and mental health
HEPATOLOGY, October, 2014
co-morbidities were negatively associated. Conclusions: The
majority of veterans are receiving EV screening, however only
one-third are receiving EV screening per AASLD guidelines.
Of these patients, the majority had been previously seen in
a gastroenterology and hepatology clinic and median time
from diagnosis to screening was a prompt 26 days. Our study
highlights the importance of specialty clinic access as providers
are otherwise relying on clinical cues (i.e. decompensation) to
prompt referral for endoscopy.
Disclosures:
Norah Terrault - Advisory Committees or Review Panels: Eisai, Biotest; Con-
sulting: BMS, Merck; Grant/Research Support: Eisai, Biotest, Vertex, Gilead,
AbbVie, Novartis, Merck
The following people have nothing to disclose: Varun Saxena, Jennifer A. Flem-
ming, Hui Shen, Alexander Monto, Catherine Rongey
96
Changes on hepatic venous pressure gradient induced
by a physical exercise program in cirrhotic patients: a
randomized open clinical trial
Ricardo Macías-Rodríguez1, Aldo Torre1, Hermes Ilarraza-Lo-
melí2, Astrid Ruiz-Margáin1, Octavio García-Flores1, Andres
Duarte-Rojo3; 1Gastroenterology, INCMNSZ, Mexico, Mexico;
2Cardiac Rehabilitation, Instituto Nacional de Cardiología “Igna-
cio Chávez”, Mexico City, Mexico; 3Division of Gastroenterology
and Hepatology, University of Arkansas for Medical Sciences,
Little Rock, AR
Background: Physical exercise (PE) in cirrhosis is restricted
due to sarcopenia, leg edema, ascites, and cardiopulmonary
complications. A major concern regarding PE is the increase
in hepatic venous pressure gradient (HVPG), as previously
observed in two studies evaluating acute changes in hepatic
hemodynamics. However, there are no studies evaluating the
effect of chronic PE on HVPG. Aim: To evaluate the changes
in HPVG in cirrhotic patients undergoing a supervised physical
training program. Material and methods: As part of a random-
ized, open label clinical trial, we included 23 cirrhotics (17
males), with 11 allocated to the exercise group (E= physical
exercise + nutritional therapy), and 12 to control (C= nutri-
tional therapy). Physical exercise program (PEP) consisted of
40-supervised sessions including stationary bicycle and kine-
siotherapy over 14 weeks, with a target heart rate of 60-80%
the maximum predicted. All patients with varices were on
beta-blockers. Clinical (leg cramps, hepatic encephalopathy)
and biochemical (blood ammonia) data, HPVG, and treadmill
stress test were assessed pre and post-intervention. Ammonias
were collected before each treadmill test, after its completion,
and at 11:00, 13:00, and 15:00 hrs.U Mann-Whitney and
X2 were used as appropriate.Friedman test was performed
for pre and post differences. Results:Main etiology of cirrhosis
was hepatitis C infection (30%). All patients were Child A/B
(15/8), mean MELD was10±2.9. There were no significant
differences in baseline demographic, clinical and biochemi-
cal characteristics between groups. Adherence to the PEP was
>80% in all patients. Baseline HVPG (mmHg) median values
were 14.5(11-18.5) and 11.5 (3.5-17.5); and final HVPG
values were 11.5 (8.5-16.75) and 14 (9-22) for the E and C
groups, respectively. This corresponded to a decrease in HVPG
of -2.5 (-5.25 to 2) for the E group, and an increase of 4 (0.25
to 8)for the C group (p=0.007).There was no difference in the
AUC for ammonia before and after the PEP, when E and C
groups were compared: initial treadmill test (426 ± 183 and
488 ± 255 for E group, p=0.3; 438 ± 58 and 487 ±56 for
C group, p=0.5; respectively). All patients in the E group had
improved leg cramps, and no episodes of hepatic encepha-
lopathy were precipitated by PE. There were no episodes of
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
variceal bleeding observed during the study. Conclusion: This
is the first study showing that a14-week supervised PEP is a
safe intervention, and in contrast to what has been described
after an acute bout of exercise, it does not increase the HPVG
in cirrhotic patients. Moreover, the PEP did not affect ammonia
levels or precipitated episodes of hepatic encephalopathy.
Disclosures:
Andres Duarte-Rojo - Advisory Committees or Review Panels: Gilead Sciences;
Grant/Research Support: Vital Therapies
The following people have nothing to disclose: Ricardo Macías-Rodríguez, Aldo
Torre, Hermes Ilarraza-Lomelí, Astrid Ruiz-Margáin, Octavio García-Flores
97
Compromised intestinal epithelial barrier function is a
major contributor in the progression of diet induced
non-alcoholic fatty liver disease (NAFLD) to steatohep-
atitis (NASH) and is driven primarily by innate immune
activation
Khalidur Rahman1,2, Natalie Thorn1, Pradeep Kumar1, Asma Nus-
rat3, Charles A. Parkos3, Frank A. Anania1,2; 1Department of Med-
icine, Division of Digestive Diseases, Emory University School of
Medicine, Atlanta, GA; 2Atlanta VA Medical Center, U.S. Dept.
of Veterans Affairs, Decatur, GA; 3Department of Pathology and
Laboratory Medicine, Emory University, Atlanta, GA
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD)
progresses to non-alcoholic steatohepatitis (NASH) in twenty
percent of NAFLD patients. The exact mechanisms for disease
progression are not entirely clear, although accumulating evi-
dence suggest a role for intestinal barrier dysfunction as per-
missive in enhancing translocation of microbial products that
drive hepatic inflammation and disease progression. The AIM
of the present study was to delineate the respective contribu-
tion of intestinal epithelial permeability to the pathogenesis of
diet-induced NASH in a mouse model of compromised intesti-
nal epithelial permeability due to deletion of the tight junction
protein, junctional adhesion molecule A (JAM-A-/-). METHODS:
Male C57BL/6j (WT) or JAM-A-/- mice were fed ad libitum
either normal diet (ND) or a high fat, high cholesterol diet with
2% fructose water (HFCD). Intestinal epithelial permeability
was assessed by in vivo FITC-Dextran permeability assay. Liver
tissue injury and inflammation were assessed by histological,
RT-qPCR, and flow cytometric analysis. RESULTS: Within 8 wks
of HFCD feeding, JAM-A-/- mice developed steatosis, lobular
inflammation, hepatocellular ballooning and fibrosis, which
correlated with increased intestinal permeability and serum
LPS levels. Only modest NASH-related histologic findings were
observed in the HFCD-fed WT mice. Liver injury in the HFCD-
fed JAM-A-/- mice was associated with a significant increase
in serum transaminases and cholesterol. Increased fibrosis in
HFCD-fed JAM-A-/- mice correlated with increased α-smooth
muscle actin (αSMA) expression as assessed by immunohis-
tochemistry. Markers of hepatic inflammation, toll like recep-
tors 4, 5, and 9; and inflammatory cytokines TNF-α, IL-6 and
IL-1β transcript levels were also significantly up regulated in the
HFCD-fed JAM-A-/- mice. Flow cytometric analysis revealed
increased intrahepatic macrophages, and recruitment of
inflammatory monocytes and neutrophils in HFCD-fed JAM-A-
/- mice compared with WT mice. Taken together, our data
indicate that rapid progression of liver injury in the HFCD-fed
JAM-A-/- mice can be attributed to increased intestinal perme-
ability resulting in enhanced translocation of bacterial products
that drive hepatic inflammation primarily via activation of the
innate immune system. CONCLUSION: These findings implicate
intestinal epithelial permeability as a major factor in NASH
severity. Therapies being studied in the lab to restore gut integ-
247A
rity in HFCD-fed JAM-A-/- mice may prove to be of clinical
value. Further, our data suggest that the HFCD JAM-A-/- model
may be a powerful new tool to study the role of host defenses
in NASH pathogenesis.
Disclosures:
The following people have nothing to disclose: Khalidur Rahman, Natalie Thorn,
Pradeep Kumar, Asma Nusrat, Charles A. Parkos, Frank A. Anania
98
Mmu-miR-615-3p REGULATES LIPOAPOPTOSIS BY
INHIBITING C/EBP HOMOLOGOUS PROTEIN
Yasuhiro Miyamoto, Amy S. Mauer, Harmeet Malhi; Gastroenter-
ology and Hepatology, Mayo Clinic, Rochester, MN
C/EBP homologous protein (CHOP) is normally undetectable
and induced under conditions of endoplasmic reticulum (ER)
stress. The saturated toxic free fatty acid, palmitate, induces
ER stress including CHOP expression and apoptosis, termed
lipoapoptosis. However, the pathways of palmitate-induced
CHOP-dependent lipoapoptosis are obscure. Recent studies
have shown that microRNAs can promote apoptosis under
conditions of ER stress. Therefore, we hypothesized that pal-
mitate-regulated microRNAs derepress CHOP expression, thus
promoting lipoapoptosis. Our aim was to identify and function-
ally characterize microRNAs repressed by palmitate, which in
turn might regulate CHOP expression. Methods: RNA sequenc-
ing was performed on microRNAs enriched from hepatocyte
cell lines treated with palmitate. Tunicamycin treated cell lines
were included as a control. Computational tools were used
to identify regulatory microRNAs of interest. Taqman assays
were used to confirm the expression of candidate microRNAs.
Gain-of-function, loss-of-function and a reporter gene assay
were used to confirm the microRNA binding and regulatory
functions. Results: Treatment of hepatocytes with palmitate or
tunicamycin results in a significant reduction in miR-615-3p
levels before the onset of significant apoptosis. There is a sin-
gle miR-615-3p binding site in the 3’ untranslated region of
the Chop mRNA. Luciferase reporter gene assay showed that
exogenously transfected miR-615-3p binds to and represses
the activity of the reporter gene. Using a precursor of miR-
615-3p to augment the levels of this microRNA, there is a
reduction of CHOP protein levels under palmitate and tunica-
mycin treatment conditions. Finally, a significant reduction in
palmitate- and tunicamycin-induced apoptosis was observed in
cells transfected with a precursor of miR-615-3p. Conclusions:
Our working model is that palmitate lowers miR-615-3p levels,
thus derepressing CHOP expression under conditions of ER
stress, consequently promoting lipoapoptosis. MicroRNAs are
druggable targets, and we propose that this approach may be
useful to inhibit hepatocyte lipoapoptosis.
Disclosures:
The following people have nothing to disclose: Yasuhiro Miyamoto, Amy S.
Mauer, Harmeet Malhi
99
Impaired macrophage autophagy triggers steatohepati-
tis in obese mice by promoting proinflammatory macro-
phage polarization
Kun Liu, Enpeng Zhao, Ghulam Ilyas, Gadi Lalazar, Yu Lin, Kath-
ryn Tanaka, Mark J. Czaja; Albert Einstein College of Medicine,
Bronx, NY
Recent findings that excessive lipid accumulation decreases
cellular levels of autophagy, and that autophagy modulates
immune responses, suggested that alterations in macrophage
248A AASLD ABSTRACTS
autophagy with obesity may regulate innate immunity in
NASH. We hypothesized that an obesity-induced impairment
of macrophage autophagy promotes NASH development by
altering proinflammatory M1 and anti-inflammatory M2 mac-
rophage polarization which leads to an overactive innate
immune response. Methods: Wild-type mice and mice with a
LysM-Cre-mediated macrophage knockout of the autophagy
gene Atg5 were fed a high fat diet (HFD) alone or together
with low-dose lipopolysaccharide (LPS; 0.25 mg/day). Results:
Primary bone marrow-derived macrophages (BMDM) and peri-
toneal macrophages from wild-type mice fed 16-20 weeks of
HFD had decreased levels of autophagic flux indicating an
impairment of macrophage autophagy in obesity. With 12
weeks of HFD combined with 2 weeks of LPS, macrophage
Atg5 knockout mice, but not littermate controls, developed sys-
temic and hepatic inflammation. Contrary to prior reports that
autophagy regulates only inflammasome-generated IL-1β, Atg5
null mice had increased serum protein and hepatic mRNA levels
for the inflammasome-independent proinflammatory cytokines
TNF and IL-6. This effect was liver specific as white adipose tis-
sue cytokine expression was equivalent in control and knockout
mice. Hepatic macrophage number was unchanged in knock-
out mice by F4/80 mRNA levels and CD68 immunofluores-
cence. The mechanism by which loss of autophagy promoted
inflammation was through effects on macrophage polarization.
BMDM and Kupffer cells from HFD-fed, LPS-treated knockout
mice stimulated with LPS/IFNγ or IL-4/IL-13 in vitro assumed a
more inflammatory phenotype with both increased proinflam-
matory M1 and decreased anti-inflammatory M2 polarization
as determined by measures of M1/M2 marker genes and pro-
teins. Loss of autophagy altered a number of cellular signaling
pathways that mediate M1/M2 polarization including STAT6,
JNK and Akt. The heightened inflammation in HFD-fed, LPS-
treated knockout mice triggered liver injury without affecting
steatosis. Knockout mice had statistically significant increases
in histological grade of liver injury (1.0 vs. 0.2), TUNEL stain-
ing (2.1 vs. 0.2 cells/HPF) and caspase 3 and 7 cleavage.
Conclusions: Autophagy has critical functions in both M1 and
M2 polarization that determine hepatic macrophage pheno-
type and down regulate liver inflammation. Obesity impairs
macrophage autophagy which promotes proinflammatory mac-
rophage activation leading to the progression of simple steato-
sis to liver inflammation and hepatocyte injury.
Disclosures:
Mark J. Czaja - Consulting: Oncozyme Pharma Inc.; Grant/Research Support:
Oncozyme Pharma Inc.
The following people have nothing to disclose: Kun Liu, Enpeng Zhao, Ghulam
Ilyas, Gadi Lalazar, Yu Lin, Kathryn Tanaka
100
Phosphatidylcholine Transfer Protein (PC-TP) and Thio-
esterase Superfamily Member 2 (Them2) Promote Endo-
plasmic Reticulum (ER) Stress by Increasing Acyl Chain
Saturation of Membrane Phospholipids and Depleting
Calcium
Baran A. Ersoy, Kristal M. Maner-Smith, Yingxia Li, Ipek Alper-
tunga, David E. Cohen; Department of Medicine, Brigham and
Women’s Hospital, Harvard Medical School, Boston, MA
Background: Non-alcoholic fatty liver disease (NAFLD) is
associated with increases in hepatic ER stress in the setting of
excessive nutritional intake. Within the ER, the incorporation
of saturated free fatty acids (FFA) into membrane phospho-
lipids results in the depletion of calcium and ER stress due to
protein misfolding. PC-TP is highly expressed in the liver and
activates Them2, an acyl-CoA thioesterase that converts fatty
HEPATOLOGY, October, 2014
acyl-CoAs to FFA. In cell culture systems, knockdown or genetic
ablation of PC-TP or Them2 protects against ER stress. Aim:
This study was designed to determine whether ER stress due
to PC-TP and Them2 expression is attributable to incorporation
of saturated FFA into ER membrane and calcium depletion.
Methods: ER stress was induced in Pctp−/−, Them2−/− and wild
type littermate mice by high fat diet feeding for 8 w or by
i.p. tunicamycin injection for 2 d (0.25 mg/kg body weight).
Hepatic FFA, triglyceride and cholesterol concentrations were
quantified by enzymatic assays. Fatty acyl chain saturation of
the ER membrane phospholipids was assessed by mass spec-
trometry. In primary hepatocytes, ER stress was induced by 6
h exposure to 0.5 mM palmitic acid, a saturated FFA, or 0.5
μM thapsigargin, which depletes ER calcium. Markers for ER
stress were assayed by immunoblot analysis. ER calcium deple-
tion following thapsigargin treatment (2 μM) was measured
in HEK 293E cells using Fluo-4 as a sensor after siRNA-me-
diated knockdown of PC-TP and Them2. Results: Pctp−/− and
Them2−/− mice were protected against high fat diet- or tunica-
mycin-mediated induction of ER stress as evidenced by reduc-
tions in hepatic markers of ER stress. Compared to wild type
mice, hepatic FFA, triglycerides and cholesterol concentrations
were reduced in Pctp−/− and Them2−/− mice following tunica-
mycin treatment. Supporting a role for PC-TP in FFA-induced
ER stress, high fat diet feeding led to increased fatty acyl chain
saturation in the hepatic ER membrane of wild type but not
Pctp−/− mice. In Pctp−/− and Them2−/− hepatocytes, palmitic
acid and thapsigargin failed to induce ER stress. Knockdown
of PC-TP and Them2 expression in HEK 293E cells reduced
thapsigargin-induced loss of ER calcium by 60% and 40%,
respectively. Conclusion: PC-TP and Them2 contribute to the
incorporation of saturated FFA into the ER membrane and to
the depletion of calcium upon high fat diet feeding. We spec-
ulate that, by promoting ER stress, PC-TP and Them2 play a
pathogenic role in the development of NAFLD.
Disclosures:
David E. Cohen - Advisory Committees or Review Panels: Merck, Genzyme; Con-
sulting: Novartis, Aegerion, Dignity Sciences, Intercept; Speaking and Teaching:
Merck
The following people have nothing to disclose: Baran A. Ersoy, Kristal M. Man-
er-Smith, Yingxia Li, Ipek Alpertunga
101
Fibroblast growth factor 21 treatment improves athero-
genic diet-induced liver injury and metabolic syndrome
in Ossabaw miniature swine
Samer Gawrieh1, Mouhamad Alloosh2, Rachel M. Sheridan3,
Tiebing Liang1, Howard C. Masuoka1, Naga P. Chalasani1,
Michael Sturek2; 1Division of Gastroenterology and Hepatology,
Indiana University School of Medicine, Indianapolis, IN; 2Cellu-
lar& Integrative Physiology, Indiana University, Indianapolis, IN;
3Pathology, Cincinnati Children’s Hospital, Cincinnati, OH
Background: Fibroblast growth factor 21 (FGF21) improves
insulin sensitivity, triglycerides and lipoprotein levels, while
reducing body weight in mice and monkeys. Ossabaw minia-
ture swine develop metabolic syndrome along with severe liver
injury and progressive fibrosis that resembles human non-alco-
holic steatohepatitis (NASH) when fed high-fat, high-fructose
atherogenic (NASH) diet. Aim: To test the effect of FGF21
therapy on liver histology and metabolic indices in Ossabaw
Swine with metabolic syndrome and NASH. Methods: Eight
Ossabaw swine were fed an average of 5000 kcal per day
of NASH diet and developed metabolic syndrome and NASH
after 30 weeks of feeding. The pigs were then treated with
FGF21 at 1mg/kg subcutaneously once daily for 16 weeks
while continuing on NASH diet. Pre- and post-treatment liver
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
biopsies were evaluated according to predefined histologi-
cal scoring system. Staging of fibrosis accounted for bridging
fibrous septa normally present in swine livers. Improvement in
histological features after FGF21 therapy was defined as a
reduction of ≥ 1 point, whereas worsening was defined as an
increase of ≥ 1 point compared to pre-therapy biopsy. Insulin
sensitivity was assessed with an oral glucose tolerance test.
Results: Mean body weight was 53.5, 88, and 90 kg at study
weeks 0, 30, and 46, respectively. Sixteen weeks of FGF21
therapy significantly reduced fasting total cholesterol (265 vs
173 mg/dL, p<0.05) and the peak post-prandial triglycerides
(142 vs 92.5 mg/dL, p <0.05). Although fasting glucose did
not significantly change, fasting insulin was significantly lower
following FGF21 therapy (25 vs 14 mU/ml, p< 0.05). All liver
biopsies prior to initiating FGF21 therapy showed significant
fibrosis and extensive hepatocyte ballooning. Following FGF21
therapy, improvement in fibrosis, ballooning, portal and lobu-
lar inflammation was noted in 62.5%, 87.5%, 50%, and 25%,
respectively. Electron microscopy showed markedly decreased
number of secondary lysosomes within hepatocytes and an
increased number of lipid-laden Kupffer cells after FGF21
therapy. Except for itching at the injection site, FGF21 was
well tolerated. Conclusions: FGF21 therapy results in improve-
ments in liver necroinflammation and fibrosis, insulin sensitivity,
and post-prandial lipidemia in Ossabaw miniature swine with
diet-induced NASH. These observations suggest that FGF21
should be further investigated as a potential treatment for
NASH.
Disclosures:
Naga P. Chalasani - Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-
rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin
The following people have nothing to disclose: Samer Gawrieh, Mouhamad
Alloosh, Rachel M. Sheridan, Tiebing Liang, Howard C. Masuoka, Michael
Sturek
102
Micro RNA 21 inhibition of SMAD 7 enhances fibrogen-
esis via leptin mediated NADPH oxidase in experimen-
tal nonalcoholic steatohepatitis
Diptadip Dattaroy1, Ratanesh K. Seth1, Suvarthi Das1, Sahar
Pourhoseini1, Mitzi Nagarkatti2, Gregory A. Michelotti3, Anna
Mae Diehl3, Saurabh Chatterjee1; 1Environmental Health Sci-
ences, University of South Carolina, Columbia, SC; 2Department
of Pathology, Microbiology and Immunology, University of South
Carolina, Columbia, SC; 3Division of Gastroenterology, Duke Uni-
versity, Durham, NC
Hepatic fibrosis in NASH is the common pathophysiologic pro-
cess resulting from chronic liver inflammation associated with
rise in proinflammatory cytokines and oxidative stress. Though
leptin has been found to play a distinct role in the stellate cell
activation and TGF β production, molecular mechanisms involv-
ing reactive oxygen species, especially the role of NADPH
oxidase were revealed recently. Though significant research
has been carried out on the leptin induced NADPH oxidase in
fibrogenesis, the molecular mechanisms that connect leptin-NA-
DPH oxidase axis in upregulation of TGF β signaling has been
unclear. Recently, there is an increased emphasis on non-cod-
ing RNAs in controlling NASH progression. For this we hypoth-
esized that leptin mediated upregulation of NADPH oxidase
and its subsequent induction of mir21 via NF-κB activation
causes increased TGF β signaling by inhibiting SMAD7. A
high fat (60% kCal) diet fed chronic mouse model was used for
inducing fatty liver and subsequent steatohepatitic lesions fol-
lowing administration of hepatotoxin bromodichloromethane.
To prove the role of Leptin-NADPH oxidase-miR21 axis, mouse
deficient in genes for leptin, p47 phox and mir21 were used.
249A
Results showed that wild type mice that had steatohepatiic
lesions, had increased oxidative stress, increased p47 phox
expression, augmented NF-κB activation and increased mir21
levels. These mice showed increased TGF β, SMAD2/3 phos-
phorylation, COL1A1 and α-SMA expression with a concom-
itant decrease in both miRNA and protein levels of SMAD7
(inhibitor of TGF β signaling pathway and a regulatory SMAD
that is a direct target of mir21). Mice that were deficient in
leptin, leptin receptor or p47 phox had decreased NF-κB and
mir21 levels suggesting the role of these proteins in inducing
NFkB mediated mir21. Further mir21 ko mice had decreased
TGF b signaling, increased SMAD7 levels and decreased
fibrogenesis as shown by a-SMA levels and picrosirius red
staining. The increased markers for stellate cell activation, col-
lagen deposition and fibrogenesis when compared to wild
type mice were decreased in mice that were deficient in leptin
and p47 phox genes, suggesting that leptin mediated NADPH
oxidase plays a direct role in fibrogenesis via mir21-induced
inhibition of SMAD7. Interestingly macrophage depletion by
GdCl3 didn’t decrease TGF β signaling or kinetics of SMAD7
expression. Taken together the studies show the novel role of
leptin-NADPH oxidase- mediated regulation of mir21 in NASH
and identifies mir21 as a potential therapeutic target of fibro-
genesis in NASH.
Disclosures:
Anna Mae Diehl - Consulting: Roche; Grant/Research Support: Gilead, Genfit
The following people have nothing to disclose: Diptadip Dattaroy, Ratanesh K.
Seth, Suvarthi Das, Sahar Pourhoseini, Mitzi Nagarkatti, Gregory A. Michelotti,
Saurabh Chatterjee
103
Engineering in vitro human hepatic organoids
Mohammad R Ebrahimkhani1, Patrick Guye1,2, Nathan Kipniss1,2,
Jeremy Velazquez1, Ron Weiss1,2, Linda Griffith1; 1Department
of Biological Engineering,, Massachusetts Institute of Technology
(MIT), Cambridge,, MA; 2Synthetic Biology Center, Massachusetts
Institute of Technology, Cambridge, MA
A central challenge in drug development is the divergence
between results obtained from animal studies and from human
trials. Thus, reliable in vitro human organoid models that can
capture the complexity of their in vivo counterparts are crucial
to gain mechanistic insights into human physiology and enable
the development of treatments that are effective across broad
patient populations. To reach this goal we used genetic engi-
neering and controlled heterotypic cell-cell interaction to gener-
ate human hepatic organoids. First we utilized mature adult liver
cells such as hepatocytes and kupffer cells to induce self-mor-
phogenesis of microscale 3D liver tissue in a ~300 um depth
scaffold and within a microfluidic device with programmed per-
fusion and semi-physiological media components. Our results
showed an immunocompetent 3D organotypic hepatic tissue
with physiologically relevant oxygen gradient across the tissue
and improved hepatic function, which could maintain robust
innate immune sensing and responsiveness. Next, to develop
complex liver organoid structures containing both parenchymal
and non-parenchymal cells we turned to embryogenesis as a
complex process that involves co-differentiation of multiple pro-
genitor cells through cell-cell/ cell-matrix interactions. Through
genetically engineering human induced pluripotent stem cells
(iPS) cells, we developed a novel approach for generating and
co-differentiating human iPSC-derived progenitors that results
in stepwise development of complex, organ-like tissues. As a
function of variations in the level of the introduced transcrip-
tion factor, we created a symmetry-breaking event in the cells,
which in turn initiated a gastrulation-like process, organization
250A AASLD ABSTRACTS
and co-differentiation of all three germ layers. Within 16 days,
we obtained vascularized hepatic-like tissue that contains hepa-
toblasts, cholangiocytes, hemogenic endothelium, stellate (-like)
cells and hematopoietic progenitors. Additionally, the gener-
ated hepatic environment induced and supported fetal hema-
topoiesis as occurs naturally in the fetal liver. Thus, for the first
time by recapitulating embryonic morphogenetic processes we
could drive complex hepatic tissue from human iPSCs, using
only autologous cell sources and generating stromal cells that
co-develop with the parenchymal cells. Our novel data and
integrated approaches taken, can pave a path toward engi-
neering human organoid systems for a range of applications
relevant to human health.
Disclosures:
Patrick Guye - Patent Held/Filed: MIT
The following people have nothing to disclose: Mohammad R Ebrahimkhani,
Nathan Kipniss, Jeremy Velazquez, Ron Weiss, Linda Griffith
104
A novel toxin responsible for outbreaks of biliary atre-
sia in livestock causes lumen obstruction in a cholangio-
cyte spheroid model
Orith Waisbourd-Zinman1, Christine Dang2, Kyung A. Koo2, John
R. Porter2, Michael Pack3, Rebecca G. Wells3; 1Department of
Gastroenterology, Hepatology and Nutrition, Children’s Hospi-
tal of Philadelpahia, Philadelpahi, PA; 2Department of Biological
Sciences, University of the Sciences, Philadelphia, PA; 3Division
of Gastroenterology, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, PA
Background: Biliary atresia (BA) is a rapidly progressive
fibro-inflammatory and obliterative disease of the extrahepatic
bile ducts that occurs in 1 in 8,000 to 15,000 patients. The
etiology is unknown although likely involves an environmen-
tal insult such as infection or toxic exposure combined with a
genetic predisposition. BA occurs naturally in newborn live-
stock after ingestion of a specific plant by pregnant animals,
suggesting a potential new model for the disease. We recently
isolated a novel toxin, biliatresone, from the implicated plant;
this toxin causes selective atresia of the extrahepatic biliary
tree in zebrafish. Additionally, we have shown that abnormal
cilia are associated with BA. We hypothesize that disruption
of the microtubule network is a key element of the pathophys-
iology of BA, resulting in loss of polarity and architectural dis-
ruption and ultimately leading to ductal obstruction. Methods:
We cultured cholangiocytes in 3-D mixtures of collagen and
Matrigel, in which cells formed spheroids,with external base-
ment membranes (marking the basolateral surface) and lumens
(apical surface). We treated cultures with the toxin and control
at a point when lumens were well-formed (seven days) and
stained for cell polarity markers; we then analyzed the results
by confocal microscopy. We carried out a microarray to inves-
tigate the molecular mechanism of toxin action, followed by
real-time PCR and silencing and overexpression strategies to
confirm pathways. We also stained human BA explant tissue
for expression and distribution of polarity markers. Results:
Treatment with toxin (biliatresone) but not vehicle or a toxin
congener resulted in a dose-dependent loss of spheroid lumens,
with redistribution of apical (F-actin) but not basal (beta1 inte-
grin) polarity markers. A toxin congener found in plants con-
sumed by humans causes narrowing of spheroid lumens, but
not loss of lumens. Loss or redistribution of polarity markers was
observed in human biliary atresia livers as well. Microarray
analysis showed abnormalities in Sox protein expression and
in Notch pathway components after toxin treatment. Discus-
sion: Our results suggest that biliatresone, which causes BA
HEPATOLOGY, October, 2014
in a zebrafish model and is likely responsible for outbreaks
of BA in livestock, acts by compromising cholangiocyte polar-
ity and therefore luminal integrity. In vivo, this is a potential
cause of lumen obstruction and may be an important part of the
pathophysiology of BA. The mechanism of action of the toxin
appears to involve Notch pathway members and Sox proteins.
Work is ongoing to further define the molecular pathway and
determine the reason for its specificity towards cholangiocytes.
Disclosures:
The following people have nothing to disclose: Orith Waisbourd-Zinman, Chris-
tine Dang, Kyung A. Koo, John R. Porter, Michael Pack, Rebecca G. Wells
105
Mitofusin-2 is a novel target of sirtuin 1 that enhances
autophagy and confers cytoprotection against isch-
emia/reperfusion injury in human and mouse livers
Thomas Biel1, Joseph A. Flores-Toro1, Joseph W. Dean1, Min-Ho
Lee1, William A. Dunn2, Ivan Zendejas1, Kevin E. Behrns1, Jae-
Sung Kim1; 1Surgery, University of Florida, Gainesville, FL; 2Anat-
omy and Cell Biology, University of Florida, Gainesville, FL
INTRODUCTION: Autophagy clears abnormal or surplus cel-
lular constituents and dysfunctional organelles. Impaired
autophagy and subsequent onset of the mitochondrial per-
meability transition (MPT) contributes to ischemia/reperfusion
(I/R) injury in the liver. Sirtuin 1 (SIRT1) is a deacetylase that
plays a pivotal role in cell survival and longevity. Despite its
extramitochondrial localization, SIRT1 regulates mitochondrial
biogenesis and oxidative phosphorylation, implying that mito-
chondrial proteins might be potential SIRT1 targets. The AIM
of this study is to identify mitochondrial targets of SIRT1 and
to elucidate their roles in I/R injury. METHODS: Human liver
biopsies were collected before and after 15 minutes of a single
episode of inflow occlusion during hepatectomy. Mouse livers
and hepatocytes were subjected to I/R. The changes in sirtuins
and autophagic flux, MPT onset, and hepatocyte death were
determined with biochemical and imaging analysis. SIRT1 was
overexpressed with adenoviral delivery. In some experiments,
pharmacological activators of SIRT1, resveratrol and SRT1720,
were treated. SIRT1 conditional knockout mice were also used
to further clarify the role of SIRT1. RESULTS: Ischemia alone
decreased human SIRT1 expression by 80%. Similarly, I/R
drastically decreased SIRT1 in mouse livers. SIRT1 expression
in isolated hepatocytes became undetectable after reperfusion
although its mRNA level remained unaltered during I/R. In
contrast to SIRT1, the expression of SIRT3 and SIRT5, mitochon-
drial sirtuins, did not decrease after I/R. Adenoviral overex-
pression or pharmacological activation of SIRT1 significantly
suppressed defective autophagy, MPT onset and hepatocyte
death after I/R, while SIRT1-null livers and hepatocytes exhib-
ited markedly heightened sensitivity to I/R injury. Biochemi-
cal and proteomic approach in both human and mouse livers
revealed that SIRT1 interacts directly with mitofusin-2 (MFN2),
a mitochondrial outer membrane protein. Furthermore, MFN2,
but not MFN1, was deacetylated by SIRT1. Noticeably, I/R
also depleted livers of MFN2, which was, however, reversed
by SIRT1 overexpression. Moreover, SIRT1 overexpression sub-
stantially increased autophagy in wild type cells, but failed to
enhance autophagy in MFN2-deficient cells. CONCLUSION:
The loss of SIRT1 causes a sequential chain of defective auto-
phagy, mitochondrial dysfunction, and hepatocyte death after
I/R. The deacetylation of MFN2 by SIRT1 may be a key event
underlying SIRT1-mediated cytoprotection. Enhancing SIRT1 or
modulating acetylation status of MFN2 could be a new thera-
peutic strategy to improve liver function after liver resection and
transplantation surgery.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Disclosures:
The following people have nothing to disclose: Thomas Biel, Joseph A. Flores-
Toro, Joseph W. Dean, Min-Ho Lee, William A. Dunn, Ivan Zendejas, Kevin E.
Behrns, Jae-Sung Kim
106
SQSTM1/p62-mediated Autophagic Removal of Acet-
aminophen-Protein Adducts and Damaged Mitochon-
dria Protects Against Acetaminophen-Induced Liver
Injury
Hong-Min Ni, Mitchell R. McGill, Hartmut Jaeschke, Wen-Xing
Ding; Pharmacology, Toxicology and Therapeutics, The University
of Kansas Medical Center, Kansas City, KS
Acetaminophen (APAP)-induced liver injury is the most fre-
quent cause of acute liver failure in the US and many other
countries. APAP produces liver cell death by a sequence of
events that requires the early formation of a reactive metab-
olite, N-acetyl-p-benzoquinone imine (NAPQI), a subsequent
phase where adducts of cellular and mitochondrial proteins
are formed, and a final phase where these adducts trigger
mitochondrial dysfunction and necrotic cell death. Whether
hepatocytes can remove the APAP-adducts (APAP-AD) and by
which mechanisms are not known. Our recent work has shown
that cell survival after APAP overdose is dependent on the auto-
phagy pathway. However, the mechanisms by which autoph-
agy protects against APAP-induced liver injury are not clear. In
the present study, using a specific antibody for APAP-AD, we
found APAP-AD increased after 1 hr treatment with APAP and
reached a maximum around 2 hrs, which started to decline
at 6 hrs and reached a relative low level at 24 hrs. These
results were also confirmed by HPLC-ED analysis for APAP-AD.
Moreover, similar time-dependent changes of APAP-AD were
also detected in APAP-treated primary mouse hepatocytes.
Interestingly, we found that APAP-AD displayed a punctate
pattern and were colocalized with GFP-LC3 positive auto-
phagosomes and LAMP1 positive lysosomes in APAP-treated
primary hepatocytes. Moreover, using nycodenz gradient
centrifugation approach, we isolated autophagosomes and
autolysosomes from control and APAP-treated mouse livers. We
found that only the autophagosomes and autolysosomes from
APAP-treated mouse livers contained APAP-AD and mitochon-
dria, suggesting autophagy may selectively remove APAP-AD
and damaged mitochondria. More importantly, pharmacologi-
cal inhibition of autophagy by chloroquine increased APAP-AD
and damaged mitochondria in APAP-treated mouse livers
resulting in increased liver injury. In contrast, pharmacological
induction of autophagy by rapamycin decreased APAP-AD and
damaged mitochondria and attenuated APAP-induced liver
injury. Furthermore, we also found that SQSTM1/p62 (here-
after referred to as p62), an autophagy receptor protein, was
also recruited to APAP-AD and damaged mitochondria. Ade-
novirus-mediated shRNA knockdown of p62 led to increased
APAP-AD and necrosis. Collectively, our data indicate for
the first time that the level of APAP-AD could be regulated by
p62-mediated selective autophagy. Modulating p62-mediated
selective autophagy for APAP-AD and damaged mitochondria
may be a novel promising approach for treating APAP-induced
liver injury.
Disclosures:
Hartmut Jaeschke - Grant/Research Support: McNeil Consumer Health
The following people have nothing to disclose: Hong-Min Ni, Mitchell R. McGill,
Wen-Xing Ding
251A
107
Commensal microbiota is hepatoprotective and sup-
presses liver fibrosis in mice
Magdalena Mazagova1, Lirui Wang1, Andrew T. Anfora2, Max
Wissmueller1, Scott A. Lesley2, Caroline Westwater3, David A.
Brenner1, Bernd Schnabl1; 1Medicine, University of California San
Diego, La Jolla, CA; 2Genomics Institute of the Novartis Research
Foundation, San Diego, CA; 3Department of Oral Health Sciences,
Medical University of South Carolina, Charleston, SC
Background: Translocation of bacteria and their products across
the intestinal barrier is common in patients with liver disease,
and there is strong evidence that experimental liver fibrosis
depends on bacterial translocation. The aim of our study was
to define the role of the microbiota in liver fibrosis using con-
ventional and germ-free C57BL/6 mice. Methods and Results:
Chronic liver injury was induced by administration of thioac-
etamide (TAA) in the drinking water for 21 weeks. Increased
liver fibrosis was observed in germ-free mice as compared with
conventional mice as assessed by qPCR for collagen α1(I) and
quantification of Sirius red positive area. Hepatocytes showed
more toxin-induced oxidative stress and cell death. This was
accompanied by increased activation of hepatic stellate cells
(HSCs), while hepatic mediators of inflammation were not dif-
ferent. To rule out the possibility that the microbiota metabo-
lizes orally administered TAA prior to absorption, a second
model of liver fibrosis was used. Repeated intraperitoneal
injections of carbon tetrachloride (CCl4; total of 12 times) con-
firmed that germ-free mice show more toxin-induced liver injury
and fibrosis. In particular, CCl4-induced liver injury was much
higher in germ-free mice than conventional mice as evidenced
by ALT levels. Similarly, a genetic model using Myd88/Trif
deficient mice (Myd88-/-/TrifLPS2/LPS2), which lack downstream
innate immunity signaling and mimic a germ-free state, had
more severe fibrosis and liver injury than wild type mice fol-
lowing CCl4 injections. Since cells cannot be maintained under
germ-free conditions in culture, we isolated parenchymal and
non-parenchymal cells from Myd88/Trif deficient mice. Activa-
tion of Myd88/Trif deficient and wild type HSCs was similar
in culture. Wild type Kupffer cells showed significantly higher
baseline, LPS- and poly (I:C)-induced expression of inflamma-
tory cytokines as compared with Myd88/Trif deficient Kupffer
cells, which did not explain our in vivo phenotype. However,
isolated Myd88/Trif deficient hepatocytes were more suscep-
tible to toxin-induced cell death in culture. Several cytochrome
p450 enzymes such as retinoid acid metabolizing Cyp26a1
are lower in Myd88/Trif deficient hepatocytes and livers of
germ-free mice. Hepatic Cyp2e1 protein, which is metaboliz-
ing TAA and CCl4, was similarly expressed in germ-free mice,
conventional and Myd88/Trif deficient mice. In conclusion,
the commensal microflora is hepatoprotective and suppresses
fibrosis upon chronic liver injury in mice. This is the first study
describing a beneficial role of the commensal microflora in
maintaining liver homeostasis and suppressing liver fibrosis.
Disclosures:
The following people have nothing to disclose: Magdalena Mazagova, Lirui
Wang, Andrew T. Anfora, Max Wissmueller, Scott A. Lesley, Caroline Westwa-
ter, David A. Brenner, Bernd Schnabl
252A AASLD ABSTRACTS
108
A hepatocyte-targeted RNAi-based treatment for liver
disease associated with alpha-1-antitrypsin deficiency
Christine I. Wooddell1, Keith S. Blomenkamp2, Steven Kanner1,
Qili Chu1, Holly L. Hamilton1, Darren H. Wakefield1, Lauren J.
Almeida1, Julia O. Hegge1, Jason J. Klein1, Vladimir M. Subbo-
tin1, Guofeng Zhang1, Ryan M. Peterson1, Dawn R. Christianson1,
James Hamilton1, Jeffrey Teckman2, David L. Lewis1; 1Arrowhead
Research Corporation, Pasadena, CA; 2Pediatrics, St. Louis Univer-
sity School of Medicine, St. Louis, MO
PURPOSE: Alpha-1 antitrypsin deficiency (AATD) is an autoso-
mal recessive genetic disorder that causes pulmonary disease
in adults and liver disease in children and adults. Wild type
alpha-1 antitrypsin (AAT) is a 52 kDa circulating glycopro-
tein produced primarily in liver hepatocytes (~90% of total).
The E342K substitution, known as the PiZ mutation, results in
improper AAT processing and impairs its secretion by hepato-
cytes. Individuals homozygous for the PiZ allele (PiZZ) have
very low serum concentrations of the Z mutant AAT (Z-AAT) and
accumulate Z-AAT aggregates in hepatocytes. These aggre-
gates lead to a recurrent cycle of hepatocyte injury and asso-
ciated fibrosis, which over time leads to liver disease including
cirrhosis and hepatocellular carcinoma. We are currently
developing a RNAi-based therapeutic to reduce Z-AAT aggre-
gates in liver, which we propose will prevent the progression
and development of AATD-associated liver disease in PiZZ
individuals. METHODS: A set of RNAi triggers targeting AAT
was designed using bioinformatic algorithms and screened for
activity in cells in culture. Highly active RNAi triggers were fur-
ther modified by incorporating unlocked nucleobase analogs
(UNAs). The most potent UNAs were tested in a transgenic
mouse model expressing the human PiZ mutant allele. In vivo
delivery was accomplished by conjugating the UNAs to choles-
terol (chol-UNA) to enhance liver uptake and co-injecting each
with a hepatocyte targeted and reversibly masked peptide
(MLP-(CDM-NAG) designed to enhance endosomal escape.
RESULTS: Intravenous injection of candidate chol-UNAs with
MLP-(CDM-NAG) led to dose-dependent inhibition of serum
Z-AAT of up to 98% in PiZ mice. Reduced levels of serum
Z-AAT (>90%) were sustained in PiZ mice given four biweekly
injections of the most potent chol-UNA with MLP-(CDM-NAG).
In the livers of these mice, greatly reduced levels of soluble and
Z-AAT aggregates were observed coincident with improved
liver histology. As an indicator of the potency and duration of
effect that might be expected in humans, a single co-injection of
chol-UNA and MLP-(CDM-NAG) was performed in cynomolgus
monkeys. This led to >90% KD of serum AAT with a duration
of effect of greater than one month. CONCLUSION: These
results demonstrate dramatic and long-lasting reduction of AAT
following co-injection of chol-UNA and MLP-(CDM-NAG) in the
PiZ mouse and in cynomolgus monkeys. Repeat dosing pre-
vented and even reversed accumulation of Z-AAT aggregates
in the PiZ mouse model, the cause of liver disease. This RNAi
therapeutic holds great promise for the treatment of patients
with AATD-associated liver disease.
Disclosures:
Christine I. Wooddell - Employment: Arrowhead Research Corporation
Steven Kanner - Employment: Arrowhead Research Corp.
Qili Chu - Employment: Arrowhead Madison
Darren H. Wakefield - Employment: Arrowhead Research
Lauren J. Almeida - Employment: Arrowhead Research Corporation
Julia O. Hegge - Employment: Arrowhead Madison
Vladimir M. Subbotin - Employment: Arrowhead Research Corporation
Ryan M. Peterson - Employment: Arrowhead Madison, Inc.
Dawn R. Christianson - Employment: Arrowhead Research Corporation; Stock
Shareholder: Arrowhead Research Corporation
HEPATOLOGY, October, 2014
James Hamilton - Employment: Arrowhead Research Corp
Jeffrey Teckman - Consulting: Dicerna, Isis Pharmaceuticals, Vertex, Proteostasis,
Genkyotex, The Alpha-1 Project; Grant/Research Support: Alnylam, Arrowhead,
Alpha-1 Foundation
David L. Lewis - Employment: Arrowhead Research Corporation
The following people have nothing to disclose: Keith S. Blomenkamp, Holly L.
Hamilton, Jason J. Klein, Guofeng Zhang
109
A Genome-wide Association Study Identifies THBS2 as a
Candidate Modifier of Liver Disease Severity in Alagille
Syndrome
Kathleen M. Loomes1,2, Ellen Tsai3, Lara A. Underkoffler1, Chris-
topher Grochowski3, Alexandra M. Falsey3, Binita M. Kamath4,5,
Henry C. Lin1,2, Kurt D. Hankenson6, Marcella Devoto3,2, Nancy
B. Spinner7,8; 1Division of Gastroenterology, Hepatology and
Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA;
2Department of Pediatrics, Perelman School of Medicine at the
University of Pennsylvania, Philadelphia, PA; 3Division of Human
Genetics, The Children’s Hospital of Philadelphia, Philadelphia,
PA; 4Division of Gastroenterology, Hepatology and Nutrition, Hos-
pital for Sick Children, Toronto, ON, Canada; 5Research Insti-
tute, University of Toronto, Toronto, ON, Canada; 6Department of
Orthopedic Surgery, University of Pennsylvania School of Veteri-
nary Medicine, Philadelphia, PA; 7Department of Pathology, The
Children’s Hospital of Philadelphia, Philadelphia, PA; 8Department
of Pathology, Perelman School of Medicine at the University of
Pennsylvania School of Medicine, Philadelphia, PA
Alagille syndrome (ALGS) is an autosomal dominant, multisys-
tem disorder characterized by bile duct paucity, cholestasis,
cardiac disease and other features. ALGS is primarily caused
by mutations in the JAG1 gene, which encodes a ligand in the
Notch signaling pathway. Liver disease severity in ALGS is
highly variable, even within families carrying the same JAG1
mutation. The factors that influence liver disease severity in
ALGS are unknown. We hypothesized that genetic modifiers
may contribute to the variable expressivity of this disorder. We
carried out a genome-wide association study (GWAS), com-
paring patients with mild versus severe liver disease. Methods:
We studied a well-characterized cohort of ALGS patients, who
were either enrolled into an IRB-approved protocol at The Chil-
dren’s Hospital of Philadelphia, or through the NIDDK-funded
Childhood Liver Disease Research and Education Network.
Liver disease severity was determined using strict criteria, tak-
ing into account both clinical and biochemical data, excluding
patients younger than 5 years of age, or those who died or
underwent liver transplantation before the age of 5. Results: In
our cohort of Caucasian subjects with known pathogenic JAG1
mutations, 103 had mild and 73 had severe liver disease. We
conducted a GWAS on these patients and identified two loci
that reached suggestive genome-level significance including
one in a gene desert and a second within chromosome band
6q27, 2 kb upstream of the THBS2 gene. The 6q27 signal
(SNP rs7382539) was associated at p<10-5 for samples of
European ancestry. Thrombospondin 2 (THBS2) codes for a
secreted matricellular protein that regulates cell proliferation,
apoptosis and angiogenesis, and has been shown to poten-
tiate Notch signaling. To determine the expression pattern of
THBS2 in the liver, we used a reporter mouse line expressing
green fluorescent protein (GFP) under the control of the THBS2
promoter. Co-staining with CK19 and GFP antibodies revealed
THBS2 expression in the bile ducts and periportal regions of the
mouse liver. Examination of THBS2 null mouse livers revealed
no fibrosis or hepatobiliary pathology, but staining with CD34
antibody demonstrated increased microvessels in the portal
regions in the adult null animals. Conclusion: Our GWAS has
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
identified a SNP upstream of THBS2 that correlates with liver
disease severity in ALGS. THBS2 is known to augment JAG1/
Notch interactions, and THBS2 is expressed in mouse bile
ducts. Therefore, THBS2 is the first plausible candidate to be
a genetic modifier of liver disease severity in ALGS. Further
studies will be required to determine the effect of the SNP on
THBS2 expression and function.
Disclosures:
The following people have nothing to disclose: Kathleen M. Loomes, Ellen Tsai,
Lara A. Underkoffler, Christopher Grochowski, Alexandra M. Falsey, Binita M.
Kamath, Henry C. Lin, Kurt D. Hankenson, Marcella Devoto, Nancy B. Spinner
110
Lifestyle intervention by a 16-week programme of
supervised diet and physical exercise ameliorates portal
hypertension in patients with cirrhosis and obesity: the
SportDiet study
Annalisa Berzigotti1,2,
Agustin Albillos3,2,
Càndid Villanueva4,2,
Joan Genescà5,2, Alba Ardevol4,2, Salvador Augustin5,2, Jose Luis
Calleja6,2, Rafael Bañares7,2, Juan Carlos Garcia-Pagan1,2, Fran-
cisco Mesonero3,2, Jaime Bosch1,2; 1Hospital Clinic i Provincial,
Barcelona, Spain; 2CIBERehd, Madrid, Spain; 3Hospital Universi-
tario Ramón y Cajal, Madrid, Spain; 4Hospital Santa Creu i Sant
Pau, Barcelona, Spain; 5Hospital Universitari Vall d’Hebron, Bar-
celona, Spain; 6Hospital Puerta de Hierro, Madrid, Spain; 7Hospi-
tal Universitario La Paz, Madrid, Spain
BACKGROUND. In patients with compensated cirrhosis and
portal hypertension, obesity increases the risk of clinical
decompensation possibly by increasing portal pressure. We
postulated that weight loss might safely reduce portal pressure
in obese cirrhotic patients with PH. METHODS. This prospec-
tive pilot, multicentric study tested whether a 16-week lifestyle
intervention aimed at reducing body weight (normoproteic
hypocaloric diet supervised by nutritionists+ 60 min/wk of
supervised physical activity) is safe and may reduce HVPG in
obese cirrhotics with HVPG≥ 6 mmHg (with or without esoph-
ageal varices, EV; receiving or not non-selective beta-blockers,
NSBB). Exclusion criteria: multinodular HCC, active alcohol-
ism, untreated large EV, previous ascites, Child-Pugh score >8,
TIPS, or contraindications to exercise. RESULTS. 60 patients
(pre-planned N) were included; 50 completed the study and
were included in the analysis (56±8 y/o; 62% male; etiology:
viral 36%, alcoholic 38%, NASH 26%; BMI 33.3±3.2 Kg/
m2; 92% Child A; 72% HVPG ≥10 mmHg; 30% with previous
variceal hemorrhage but currently compensated; EV in 62%;
60% on NSBB). Lifestyle intervention significantly decreased
body weight: mean −5.0±4.0 Kg; median −5.2% range −15.0-
+3.1% (p<0.0001 vs. baseline); this was associated with a
significant decrease in waist circumference and percentage
of body fat. Body weight decreased ≥ 5% in 52% and ≥10%
in 16%. HVPG also significantly decreased from 13.9±5.6
mmHg to 12.3±5.2 mmHg (p<0.0001 vs. baseline). Aver-
age reduction was −10.7±17.9%; HVPG decreased ≥10%
in 42% and ≥20% in 24% of pts. HVPG decreased below
10 mmHg in 4 patients, all with weight reduction ≥ 5%. Pts
showing weight reduction ≥10% had a greater decrease in
HVPG vs. pts with weight reduction <10% (−23.7±19.9% vs.
−8.2±16.6%p=0.024). Both weight and HVPG decrease were
less marked in pts with diabetes. Results were similar across
etiologies of cirrhosis, clinically significant portal hypertension
and EV, treatment with NSBB, history of variceal bleeding
and study Center. No episodes of clinical decompensation
occurred during the study; Child and MELD scores did not
change. Weight loss was maintained after 6 months (6 mo
weight: 84.8 Kg vs. 85.7 Kg at 16-wk, p=0.136). CON-
253A
CLUSIONS. In obese patients with cirrhosis and portal hyper-
tension, lifestyle intervention by means of diet and moderate
exercise for 16 weeks was safe, reduced body weight and
effectively reduced HVPG. HVPG decreased by ≥10% in ~40%
of cases and this occurred also in patients on NSBB therapy,
suggesting that weight reduction by lifestyle changes should be
recommended in this population. (Clinical Trials.gov identifier
NCT 01409356).
Disclosures:
Juan Carlos Garcia-Pagan - Grant/Research Support: GORE
Jaime Bosch - Consulting: Falk, Gilead Science, Norgine, ONO-USA, Intercept
pharma, Exalenz, Almirall, Conatus; Grant/Research Support: Gore
The following people have nothing to disclose: Annalisa Berzigotti, Agustin Albil-
los, Càndid Villanueva, Joan Genescà, Alba Ardevol, Salvador Augustin, Jose
Luis Calleja, Rafael Bañares, Francisco Mesonero
111
Multicenter Study of Down-staging of Hepatocellular
Carcinoma (HCC) to within Milan Criteria before Liver
Transplantation (LT)
Neil Mehta1, Jennifer Guy2, Catherine T. Frenette3, Monika
Sarkar1, Robert W. Osorio2, William B. Minteer3, John P. Rob-
erts4, Francis Y. Yao1,4; 1Medicine, University of California, San
Francisco, San Francisco, CA; 2Transplantation, California Pacific
Medical Center, San Francisco, CA; 3Organ and Cell Transplanta-
tion, Scripps Green Hospital, La Jolla, CA; 4Surgery, University of
California, San Francisco, San Francisco, CA
The University of California, San Francisco group has shown
excellent post-LT outcome for selected patients following suc-
cessful HCC down-staging to Milan criteria. Eligibility criteria
in this down-staging protocol include 1 lesion >5 cm and ≤ 8
cm, 2-3 lesions at least one >3 cm but ≤ 5 cm and total tumor
diameter ≤ 8 cm, or 4-5 tumors ≤ 3 cm with total tumor diam-
eter ≤ 8 cm. A minimum observation period of 3 months after
down-staging was required before LT. This protocol has since
been adopted by Region 5 although post-LT outcomes have
not yet been reported from other Region 5 centers. In this mul-
ticenter study, we aimed to assess post-LT and intention to treat
outcomes under this uniform down-staging protocol. Patients
from three Region 5 centers (n=187) were enrolled from March
2002 to December 2012. Median pre-treatment alpha-feto-
protein (AFP) was 24 ng/mL (IQR 8-154) and median Child-
Pugh score was 7 (IQR 5-8). Forty-eight patients (26%) had
a single down-staging treatment and 49 (26%) received >3
treatments. LT was performed after successful down-staging in
109 patients (58%). Dropout occurred in 68 patients (36%),
mostly from tumor progression or death; 10 were still await-
ing LT. Median time from first down-staging procedure to LT
or dropout was 12.6 and 7.8 months, respectively. Cumu-
lative probabilities of dropout by competing risks (CR) at 1
and 2 years from first down-staging procedure were 26% and
41%, respectively. Factors predicting dropout in multivariate
CR analysis were Child’s class B (HR 1.9, p=0.03) and C
(HR 3.2, p=0.006). Continuous and categorized pre-treatment
AFP levels predicted dropout on univariate but not multivariate
analysis. In the explant,15% exceeded Milan criteria; only 1
patient had poorly differentiated grade and 36% had com-
plete tumor necrosis. After a median post-LT follow-up of 4.3
years, the Kaplan-Meier 1- and 5-year post-LT survival was
95% and 80%, and recurrence-free probabilities were 95%
and 87%, respectively. Factors predicting HCC recurrence
on CR multivariate analysis were pre-treatment AFP >500 (HR
8.4, p=0.004) and microvascular invasion (HR 7.3, p=0.02).
Overall intention-to-treat survival at 1 and 5 years after first
down-staging procedure was 84% and 56%, respectively.
There were no center specific differences in cumulative proba-
254A AASLD ABSTRACTS
bility of dropout (p=0.95), post-LT survival (p=0.62), or HCC
recurrence (p=0.95). Conclusion: In this largest series to date
and first multicenter study on tumor down-staging under a uni-
form protocol, we observed excellent post-transplant outcomes
with no center specific differences. Our results support broader
application of this uniform down-staging protocol in LT.
Disclosures:
Catherine T. Frenette - Speaking and Teaching: Bayer, Salix, Gilead, Wako
The following people have nothing to disclose: Neil Mehta, Jennifer Guy, Monika
Sarkar, Robert W. Osorio, William B. Minteer, John P. Roberts, Francis Y. Yao
112
Salivary Microbiome shows Dysbiosis comparable to
Stool Microbiome in Cirrhotic Patients with Hepatic
Encephalopathy
Jasmohan S. Bajaj1, Naga Betrapally2, Phillip Hylemon1, Melanie
White1, Douglas M. Heuman1, Masoumeh Sikaroodi2, Kalyani
Daita1, Patrick M. Gillevet2; 1Gastroenterology, Hepatology and
Nutrition, VCU and McGuire VAMC, Richmond, VA; 2Microbiome
analysis center, George Mason University, Manassas, VA
Gut microbiota changes are seen in cirrhosis and hepatic
encephalopathy (HE) but the oral microbiome has not been
evaluated. Aim:evaluate the oral microbiome in cirrhosis and
compare it to stool microbiome. Methods: Cirrhotic outpatients
(with/without HE) and age-matched controls underwent stool
and saliva collection (after rinsing) for microbiome analysis on
the same day. 16S rRNA pyrosequencing was performed to
obtain relative abundance of microbiota which was compared
between and within groups in both stool and saliva. Compar-
ison was performed using metastats and principal component
analyses(PCO). Autochthonous, beneficial taxa <(Lachnospir-
aceae, Ruminococcae and Clostridiales XIV) were specifically
studied. Results: 103 cirrhotics (55 yrs, MELD 11, 46%HCV,42
HE) and 31 controls were included. On PCO, stool and saliva
microbiome clustered far apart showing differences between
the sites as a whole. However in both sites, controls and no-HE
patients clustered closer compared to HE patients.Salivary
microbiome: Streptococcaceae was the most abundant fam-
ily which was similar between groups. With progression and
HE, the relative autochthonous taxa abundance decreased
while potentially pathogenic ones (Enterobacteriaceae,Fuso-
bacteriaceae, Enterococcaceae, Prevotellaceae) increased in
saliva (Table 1). Stool microbiome: Bacteroidaceae,the most
abundant taxon, was similar between groups. As with saliva
and prior studies, relative abundance of autochthonous taxa
reduced with HE with increase in Enterobacteriaceae and
Enterococcaceae but not Prevotellaceae.Conclusions: Dysbiosis
represented by reduction in commensal, autochthonous bac-
terial abundance is also present in saliva in addition to stool
and worsens with progressive disease and HE in cirrhosis. This
could represent a global mucosal-immune interface change in
cirrhotic patients. Oral microbiome analysis could be an easier
alternative to stool to analyze dysbiosis in cirrhosis.
HEPATOLOGY, October, 2014
Microbial abundances between subjects in saliva and stool
† autochthonous families, * statistically significant differences
between groups
Disclosures:
Jasmohan S. Bajaj - Advisory Committees or Review Panels: Salix, Merz, otsuka,
ocera, grifols, american college of gastroenterology; Grant/Research Support:
salix, otsuka, grifols
Douglas M. Heuman - Consulting: Bayer, Grifols, Genzyme; Grant/Research
Support: Exilixis, Novartis, Bayer, Bristol Myers Squibb, Scynexis, Ocera, Mann-
kind, Salix, Globeimmune, Roche, SciClone, Wyeth, Otsuka, Ikaria, UCB, Cel-
gene, Centocor, Millenium, Osiris; Speaking and Teaching: Otsuka, Astellas
Patrick M. Gillevet - Management Position: BioSpherex LLC
The following people have nothing to disclose: Naga Betrapally, Phillip Hylemon,
Melanie White, Masoumeh Sikaroodi, Kalyani Daita
113
A prospective open label randomized noninferiority trial
to compare the efficacy and safety of monotherapy with
noradrenaline and terlipressin in patients of cirrhosis
with septic shock admitted to the Intensive care unit
(NCT01836224)
Ashok K. Choudhury, Chitranshu Vashishtha, Deepak Saini,
Sachin Kumar, Shiv K. Sarin; Hepatology, Institute of Liver and
Biliary Sciences New Delhi, India, NEW DELHI, India
Background and Aims: Cirrhosis and septic shock had changes
in the hemodynamics and microcirculation and terlipressin has
advantages of improving microcirculation, hepatorenal syn-
drome and likely prevention of variceal bleed when used as a
vasopressor in addition to supplementing relative vasopressin
deficiency. The present study is to compare the efficacy and
safety of monotherapy with noradrenaline or Terlipressin in
patients of cirrhosis with septic shock. Methods: Within 30
minutes of presentation, consecutive patients of decompen-
sated cirrhosis with septic shock were randomized in an open
label manner to receive either continuous infusion of terlip-
ressin (Group-A, 1.3-5,2mcg/min, n=38) or Noradrenaline
(Group-B, at 7.5-60mcg/min, n=40) with the aim to achieve
a target Mean Arterial Pressure (MAP) of >65mm Hg. The
standard medical care was equal in both the groups. Moni-
toring for perfusion, metabolic parameters and hemodynam-
ics were recorded and followed from admission till death or
28days follow up. Results: Seventy eight patients (Group A-38,
Group B-40) matched for age, sex and etiology of cirrhosis
with median CTP (12.5 vs. 13, p=0.25), MELD (34 vs 34,
p=0.63) and SOFA score (13 vs 15, p=0.42).At admission,
the major source of sepsis were spontaneous bacterial peritoni-
tis (SBP) followed by pneumonia, but the second hit sepsis was
predominantly due to pneumonia (93% vs. 64.7%, P=0.12)
with no SBP in terlipressin group (0% vs. 23.5% p<0.05). The
target MAP at 6 hours was achieved in both the groups (91
vs. 80% p=0.18). Use of terlipressin compared to noradren-
aline was associated with lower failure rate (25%, 62.5%,
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
p <0.05), better maintenance of MAP (93.8% vs. 72.5%,
p=0.02) with cessation of vasopressor requirement (50%
versus 25% p=0.03) at 48 hours, improved urine output at
24 hours (59% versus 36%, p=0.05) and no variceal bleed
(0% versus 15.45%, p=0.03) without significantly increased
adverse effects (40.6% vs. 22.5%, p=0.12). Terlipressin use
showed delayed resolution of Acute Kidney Injury on fifth day
(59.4% vs. 16.75, p=0.08) with improved lactate clearance,
Central Venus Oxygen saturation and CO2 gradient in Venous
– arterial blood gases (p=NS). An early survival advantage
was seen with the use of terlipressin (93.5% vs. 75%, p=0.02)
in the first 48 hours, but not at 28 days. Conclusion: Terlip-
ressin as a vasopressor is non-inferior to noradrenaline with
greater hemodynamic stability, early survival benefit, improved
urine output, reduced variceal bleed and decreased incidence
of nosocomial SBP with nonfatal and reversible adverse effects.
Its use is recommended in decompensated cirrhotics presenting
with septic shock.
Disclosures:
The following people have nothing to disclose: Ashok K. Choudhury, Chitranshu
Vashishtha, Deepak Saini, Sachin Kumar, Shiv K. Sarin
114
Initial Report of a Large, Randomized, Double Blind,
Placebo-controlled, Phase 3 Trial of Terlipressin plus
Albumin for the Treatment of Type 1Hepatorenal Syn-
drome (HRS-1): The REVERSE Study
Thomas D. Boyer1, Arun J. Sanyal2, Florence Wong3, R Todd Fred-
erick4, John R. Lake5, Jacqueline G. O’Leary6, Daniel Ganger7,
Terry D. Box8, Khurram Jamil9, Stephen Chris Pappas10; 1Univer-
sity of Arizona, Tucson, AZ; 2Virginia Commonwealth University,
Richmond, VA; 3University of Toronto, Toronto, ON, Canada;
4California Pacific Medical Center, San Francisco, CA; 5University
of Minnesota Medical School, Minneapolis, MN; 6Baylor Univer-
sity Medical Center, Dallas, TX; 7Northwestern University, Chi-
cago, IL; 8University of Utah, Salt Lake City, UT; 9Ikaria, Hampton,
NJ; 10Orphan Therapeutics, Lebanon, NJ
Background and Aims: HRS-1 is a reversible form of acute kid-
ney injury in cirrhotics with ascites. The aim of REVERSE was to
define the efficacy and safety of terlipressin plus albumin versus
albumin alone for the treatment of HRS-1. Methods: HRS-1 was
defined as rapidly deteriorating renal function (SCr ≥2.5 mg/
dL and actual or projected doubling of SCr within 2 weeks)
without improvement in renal function (<20% decrease in SCr
and SCr ≥2.5 mg/dL) 48 hours after both diuretic withdrawal
and albumin-fluid challenge in adult cirrhotics with ascites.
Subjects were randomized to terlipressin (1 mg IV every 6
hours) or placebo, plus albumin in both groups. Treatment was
continued to Day 14 unless the following occurred: confirmed
HRS reversal (CHRSR), renal replacement therapy (RRT), trans-
plantation or SCr at or above baseline at Day 4. CHRSR was
defined as 2 SCr values ≤1.5 mg/dL, at least 48 hours apart,
on treatment, without RRT or liver transplant; HRS reversal was
a decrease in SCr to ≤1.5 mg/dL. Results: 196 subjects were
enrolled; 97 were randomized to terlipressin, 99 to placebo.
Demographic and baseline clinical characteristics were simi-
lar between treatment groups. CHRSR, the primary endpoint,
was observed in 19/97 patients (19.6%) in the terlipressin
group vs. 13/99 patients (13.1%) in the placebo group (p
= 0.2214); a higher percentage of patients in the terlipres-
sin group achieved HRS reversal (23/97; 23.7%) compared
with placebo (15/99; 15.2%) (p=0.1296). The change from
baseline to end of treatment in SCr was significantly greater
for terlipressin vs. placebo (terlipressin -1.2, placebo -0.6, ter-
lipressin vs. placebo -0.6 mg/dL, p = 0.0003); there was sig-
255A
nificant correlation between improvement of SCr and survival
(r2 = 0.7274, p=0.0035). All subjects in the terlipressin group
who achieved CHRSR (n=19) were alive without RRT at Day
90 vs. 6/13 (46%) in the placebo group (p<0.0001). Overall
and transplant-free survival was similar between study groups;
CHRSR was associated with significantly improved survival at
Day 90 (p=0.0002). Adverse event (AE) incidence was similar
for the 2 groups; serious AEs were reported in 59/97 (63.4%)
subjects in the terlipressin group vs. 53/99 (55.8%) subjects in
the placebo group. No new or unexpected AEs were reported.
Summary: Terlipressin plus albumin treatment is associated with
improved renal function compared to albumin alone in patients
with HRS-1; the improvement in renal function correlates with
survival. Patients achieving CHRSR with terlipressin had a bet-
ter outcome compared to those who responded to albumin
alone. Conclusion: Terlipressin is effective in improving renal
function in HRS-1.
Disclosures:
Thomas D. Boyer - Consulting: Ikaria; Grant/Research Support: Abbvie, Gilead,
Merck
Arun J. Sanyal - Advisory Committees or Review Panels: Bristol Myers, Gilead,
Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Nimbus, Genentech, Echo-
sens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept,
Ikaria, Takeda, GalMed, Novartis, Gilead; Independent Contractor: UpToDate,
Elsevier
Florence Wong - Consulting: Gore Inc; Grant/Research Support: Grifols
R Todd Frederick - Advisory Committees or Review Panels: Vital Therapies; Con-
sulting: Salix, Gilead, Ocera, Hyperion
John R. Lake - Advisory Committees or Review Panels: BMS; Consulting: Vital
Therapies, Novartis, HepaHope; Grant/Research Support: Gilead, Salix, Ocera,
Essai
Jacqueline G. O’Leary - Consulting: Gilead, Jansen
Daniel Ganger - Grant/Research Support: merck, gilead, Ocera
Terry D. Box - Advisory Committees or Review Panels: Gilead, Genentech, Abb-
Vie, Salix, Janssen; Grant/Research Support: Gilead, Merck, BMS, AbbVie,
Idenix, Salix, Conatus, Cumberland, Boehringer Ingelheim, Genfit, Vital Ther-
apeutics, Sundise, ikaria; Speaking and Teaching: Gilead, Merck, Genentech,
Salix
Khurram Jamil - Employment: IKARIA; Stock Shareholder: IKARIA
Stephen Chris Pappas - Consulting: Orphan Therapeutics, Abbvie
115
The Economic Impact of Sofosbuvir- and Simepre-
vir-based HCV Treatment in the United States
Jagpreet Chhatwal1, Fasiha Kanwal2, Mark S. Roberts3, Michael
A. Dunn3; 1Health Services Research, MD Anderson Cancer
Center, Houston, TX; 2Houston Veterans Affairs Health Services
Research and Development Center of Excellence, Michael E.
DeBakey Veterans Affairs Medical Center, Houston, TX; 3University
of Pittsburgh, Pittsburgh, PA
Purpose: Sofosbuvir (SOF) and simeprevir (SMV) based ther-
apies for chronic hepatitis C virus (HCV) infection offer highly
efficacious, safer but substantially more expensive options than
the old standard-of-care (oSOC). The population-level economic
impact of the uptake of new treatments and resulting down-
stream cost savings remain unknown. Our objective was to
estimate the resources needed to treat all eligible HCV-patients
with new drugs in the next 5 years and resulting downstream
cost-savings. Method: We developed a validated Markov
microsimulation model that simulated the natural history of
HCV. We included both treatment-naive and treatment-expe-
rienced patients and defined baseline population based on
HCV genotype, age and fibrosis distribution of the HCV-in-
fected population in the United States. We simulated SOF/
SMV-based therapies as recommended by a recently published
AASLD-IDSA guideline, as well as the oSOC that consisted of
either first-generation protease inhibitors or peginterferon-riba-
256A AASLD ABSTRACTS
virin based therapies. We used published clinical trials data to
derive efficacy estimates for SOF, SMV, and the oSOC. Health-
state specific annual costs and treatment costs were estimated
from published sources. Using a validated prediction model
of HCV disease burden in the United States and NHANES
study, we estimated the number of people who will be eligible
for treatment in the next 5 years and the resources needed to
treat them. Results: In 2014, 1.32 million treatment-naive and
0.45 million treatment-experienced people would be aware
of their HCV disease. In addition, 0.51 million people would
be diagnosed in the next 5 years because of risk-based and
birth-cohort HCV screening. We estimated that a total of 1.60
million people with insurance coverage would be eligible for
treatment during the next 5 years. Payers would need $188
billion to cover drug costs of all treatment-eligible HCV patients
during the next 5 years. The resources needed by the type of
insurance coverage would be $104 billion by private pay-
ers, $54 billion by Medicare/Medicaid, and $30 billion by
military/state/government. Compared with the oSOC, new
drugs would cost an additional $113 billion; whereas, the
lifetime economic savings because of the use of SOF/SMV
would be $21 billion, i.e. only 19% of the additional spend-
ing on drugs. The results were highly dependent on drugs’
price. Conclusions: At the current price of SOF/SMV-based
therapies, resources needed to treat a large number of eligible
HCV patients would be immense and likely unsustainable. Price
reductions and value-based patient prioritization are needed to
manage HCV patients effectively.
Disclosures:
Jagpreet Chhatwal - Consulting: Merck & Co., Inc., Gilead; Grant/Research
Support: NIH/National Center for Advancing Translational Sciences
The following people have nothing to disclose: Fasiha Kanwal, Mark S. Roberts,
Michael A. Dunn
116
The Use of All Oral Regimens for Treatment of Chronic
Hepatitis C (CHC) Coupled with Birth Cohort Screening Is
Highly Cost Effective: The Health and Economic Impact
on the U.S. Population
Zobair Younossi1,3, Mendel Singer2, Linda Henry3, Sharon L.
Hunt1,3, Thomas Jeffers1,3, Spencer Frost1,3, Brian P. Lam1; 1Center
for Liver Disease, Department of Medicine, Inova Fairfax Hospital,
Falls Church, VA; 2Health Services Research and Policy, Case
Western University, Cleveland, OH; 3Betty and Guy Beatty Center
for Integrated Research, Inova Health System, Falls Church, VA
CHC is associated with significant health and economic bur-
den to the society. Although risk-based screening for HCV has
been recommended and CDC recently expanded screening
to those born between 1945-1965 (Birth Cohort Screening,
BCS), the vast majority HCV infected individuals remain undi-
agnosed and untreated. This is especially important in the con-
text of new anti-HCV therapy with greatly improved outcomes
(high SVR and PRO improvement). Aim: Determine the health
and economic impact of a one-time screening for HCV in the
era of highly effective anti-HCV regimens. Methods: A deci-
sion analytic Markov model that simulated patients until death
was used to compare four strategies for screening for CHC
in people born 1945-1965 without known CHC, excluding
2% ineligible for oral therapy: (1) Risk-based screening with
treatment based stage of liver disease (RBS), (2) Risk-based
screening and treat all without staging (RBA), (3) Birth Cohort
Screening with treatment based on the stage of liver disease
(BCSS), (4) Birth Cohort Screening and treat all without stag-
ing (BCSA). Treatment based on staging implied treatment for
fibrosis stages F2-F4 with subsequent staging every 5 years for
HEPATOLOGY, October, 2014
F0-F2. Parameters were taken from the literature. Treatment in
BCS was phased in over 5 years from initiation of screening
program. Oral therapy was assumed to have 98% SVR and
cost of $1,000/day for 12 weeks, with no disutility of treat-
ment since quality of life is better on treatment. Knowledge of
CHC had a disutility of .02. Drug costs were based on cost of
acquisition. Effectiveness was measured in quality-adjusted life
years (QALYs) and disease progression. Results were provided
per person with previously unknown CHC, and projections to
population screened. Results: About 100 million people would
be screened, 1.4 million with unknown CHC. BCSA was the
most cost effective strategy, with an ICER of $32,263/QALY.
Compared to RBS strategy, BCSA strategy cost an extra $123
billion and produced an additional 22.9 million QALYs. Con-
clusions: Availability of highly efficacious and well tolerated
all-oral regimens for CHC patients with excellent tolerability
makes BCS of the baby boomers highly cost-effective with great
health and economic benefits at the population level.
Disclosures:
Brian P. Lam - Advisory Committees or Review Panels: BMS; Speaking and Teach-
ing: Gilead; Stock Shareholder: Gilead
The following people have nothing to disclose: Zobair Younossi, Mendel Singer,
Linda Henry, Sharon L. Hunt, Thomas Jeffers, Spencer Frost
117
Alcoholic Liver Disease is the Primary Driver of
Increased Inpatient Charges Among Patients with Cir-
rhosis: A National Inpatient Survey Analysis 2002-2010
Monica Schmidt, Paul H. Hayashi, Ramon Bataller, Alfred S. Bar-
ritt; Medicine, University of North Carolina, Chapel Hill, NC
Background: Healthcare costs have precipitously increased
over the last decade and the economic burden of cirrhosis
is no exception. We aimed to examine trends in inpatient
charges amongst patients with different etiologies of cirrhosis
to determine the main drivers of cirrhosis related healthcare
expenditures. Methods: We identified patients >=18 years of
age, admitted with any diagnostic code containing “cirrho-
sis” in the HCUP NIS data from 2002-2010. Our primary
outcome was total inpatient charges. Patient and hospital
characteristics were analyzed for trends using ordinary least
squares regression modeling. Results: 781,700 patients with
cirrhosis were admitted to US hospitals participating in the
NIS between 2002-2010. Of these, 370,728 (47.4%) had a
diagnosis of alcoholic cirrhosis (AC). Admissions increased by
30% between 2002-2010 for patients with AC. Total charges
for AC increased 100% over the time period from $1 billion to
$2 billion, accounting for approximately 50% of all inpatient
cirrhosis related charges during the time period (Figure 1). Dis-
ease severity in AC patients has increased in recent years [Elix-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
hauser comorbidity index rose from 2.6 (95% CI 2.6-2.6) in
2002 to 3.6 (95% CI 3.5-3.6) in 2010], and the mean length
of stay has remained greater than that of other etiologies of cir-
rhosis [7.0 (95% CI 6.9-7.1) in 2002 dropping to 6.1 (95% CI
6.0-6.1) in 2010 (p<0.001). Summary: Alcohol misuse is the
main cause of cirrhosis among hospitalized patients and is the
main driver of increased healthcare expenditures among this
population. Higher number of admissions, declining length of
stay and fewer procedures done for alcoholic cirrhosis suggests
that the high total cost is driven primarily by volume. Strategies
aimed at early detection of alcoholic liver disease and improve-
ment in patient management may yield the greatest benefit in
reducing cirrhosis related healthcare expenditures.
Disclosures:
Monica Schmidt - Grant/Research Support: Merck & Co.; Patent Held/Filed:
HCCplex; Stock Shareholder: PleX Diagnostics
Ramon Bataller - Advisory Committees or Review Panels: Sandhill; Consulting: VTI
Alfred S. Barritt - Grant/Research Support: Salix Pharmaceuticals; Speaking and
Teaching: Abbott Molecular
The following people have nothing to disclose: Paul H. Hayashi
118
Early physician follow up and reduction in 60-day read-
mission in patients hospitalized for cirrhosis
Fasiha Kanwal1, Yumei Cao1, Sumeet K. Asrani2, Hashem El-Se-
rag1, Steven Asch3, Jennifer R. Kramer1; 1Michael E. DeBakey VA
Medical Center and Baylor College of Medicine, Houston, TX;
2Baylor University Medical Center, Baylor Scott and White, Dallas,
TX; 3Department of Medicine and Health Services Research, Palo
Alto VA Healthcare System, Palo Alto, CA
Background: Early outpatient follow-up after hospitalization
reduces the rate of readmission in other chronic conditions.
However, follow-up after cirrhosis hospitalization and its
association with readmission rates is unknown. Methods: We
conducted a retrospective cohort study using data from the
Veterans Affairs (VA) Corporate Data Warehouse of patients
with cirrhosis (defined by ICD-9 codes for cirrhosis or its com-
plications) who were hospitalized with a liver related diagnosis
and discharged to home from 125 hospitals (2010-2013). We
defined early follow-up as an outpatient visit with a physician
within 14 days after discharge from the index hospitalization.
The time to first readmission was the number of days between
index discharge date and subsequent readmission date cen-
soring at death or 60 days (post discharge). We used Cox
proportional hazards models to examine association between
early follow-up and 60-day all cause readmission after adjust-
ing for patients’ age, race, MELD score, medical co-morbidity,
liver-related complications, and length of stay of index hospi-
talization. Results: We identified 31,593 patients with cirrhosis
257A
(median age=62 years). A total of 19,303 patients (61.1%)
had a visit with a physician within 14 days (26.7% saw a
primary care physician; 9.4% saw a gastroenterologist; rest
saw other specialists) and 11,075 (35.1%) were readmitted
within 60 days of discharge. After adjusting for above factors
and clustering of patients within facilities, patients with early
follow-up were ~20% less likely to be readmitted than those
who did not have an early visit (Table). Conclusions: Despite
the high risk of readmission among patients hospitalized for
cirrhosis, 40% of patients did not visit a physician within 2
weeks of discharge, which reduced risk of readmission. These
data suggest that transitional care may be effective in reducing
readmissions in patients with cirrhosis.
Disclosures:
Hashem El-Serag - Consulting: Gilead
The following people have nothing to disclose: Fasiha Kanwal, Yumei Cao,
Sumeet K. Asrani, Steven Asch, Jennifer R. Kramer
119
Do liver transplant centers need different risk adjust-
ment of quality metrics of costs and early readmission
for managing hospitalized patients with cirrhosis?
Marwan Ghabril1, Samuel Hohmann2, Eric S. Orman1, Raj
Vuppalanchi1, A. Joseph Tector3, Paul Y. Kwo1, Naga P. Cha-
lasani1; 1Gastroenterology and Hepatology, Indiana University,
Indianapolis, IN; 2Comparative Data and Informatics, University
Healthsystem Consortium, Chicago, IL; 3Transplant Surgery, Indi-
ana University, Indianapolis, IN
Background: Cirrhosis is associated with increased hospital-
ization duration, costs, inpatient mortality and 30 day read-
mission (TDR) rates. Patients in need of liver transplant (LT)
reflect this most pointedly due to disease severity, and present
increased demand for resources and potentially poorer hospi-
talization outcomes for LT centers. Aim: To describe outcomes
of hospitalization in patients with cirrhosis at LT and non-LT cen-
ters. Methods: The University Healthsystem Consortium (UHC)
collates data from 120 academic centers and 300 affiliates,
captures same-center TDR, and provides regression modeling
of expected length-of-stay (LOS), cost, and inpatient mortality
for each admission (allowing for comparison of centers using
observed-to-expected (O/E) ratio of modeled metrics). A UHC
database query identified 68,397 admissions with a diagnosis
of cirrhosis from 2009-2012 at 101 centers (55 LT, 46 non-LT)
in non-transplanted patients. Admission volumes, observed,
258A AASLD ABSTRACTS
expected and O/E ratio of outcomes (LOS, costs, and inpatient
mortality), TDR rates, and LT volumes (per www.optn.org) were
determined for each center. Parameters were compared in LT
vs. non-LT centers, and high volume (>500 LT in 2009-2012)
vs. lower volume (≤500 LT) LT centers. Data were reported
as percentages, or mean±SD. Results: Patient and hospital-
ization parameters in LT and non-LT centers are described in
Table 1. LT centers had more extreme severity of illness, higher
admission volumes, resource utilization and mortality. TDR,
observed and O/E cost ratio were significantly higher for LT
centers. High volume (5) compared to lower volume (50) LT
centers had a mean of 1076±223 vs. 894±315 admissions,
p=0.1, frequency of specialized primary service 41±24% vs.
22±22%, p=0.06, O/E LOS ratio 1.17±0.16 vs. 1.04±.15,
p=0.05, O/E cost ratio1.37±0.336 vs. 1.12±0.27, p=0.04,
O/E mortality ratio 1.2±22 vs. 1±0.2, p=0.07, and TDR rate
26.4±2.9% vs. 25.7±4.4%,p=0.7, respectively. Conclusions:
LT centers provide high volume, specialized care for patients
with cirrhosis at higher costs and early readmissions. High
volume LT centers are especially at risk for relatively worse
outcomes without accurate risk adjustment for disease severity.
Establishing benchmarks for quality metrics for LT centers need
to take these observations into consideration.
Table 1
Disclosures:
Marwan Ghabril - Grant/Research Support: Salix
Paul Y. Kwo - Advisory Committees or Review Panels: Abbott, Novartis, Merck,
Gilead, BMS, Janssen; Consulting: Vertex; Grant/Research Support: Roche, Ver-
tex, GlaxoSmithKline, Merck, BMS, Abbott, Idenix, Vital Therapeutics, Gilead,
Vertex, Merck, Idenix; Speaking and Teaching: Merck, Merck
Naga P. Chalasani - Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-
rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin
The following people have nothing to disclose: Samuel Hohmann, Eric S. Orman,
Raj Vuppalanchi, A. Joseph Tector
120
Geographic differences in access to transplant care
among Medicaid enrollees with end-stage liver disease
David S. Goldberg1,3, Benjamin French2,3, James D. Lewis1,3, Scott
D. Halpern3,4; 1Division of Gastroenterology, Hospital of the Uni-
versity of Pennsylvania, Philadelphia, PA; 2Leonard Davis Institute
of Health Economics, University of Pennsylvania, Philadelphia, PA;
3Center for Clinical Epidemiology and Biostatistics, University of
Pennsylvania, Philadelphia, PA; 4Pulmonary, Allergy, and Critical
Care Division, University of Pennsylvania, Philadelphia, PA
Introduction: There are limited data on geographic differences
in access to liver transplantation (LT) in large cohorts of patients
due to the inability to identify the population with end-stage
liver disease (ESLD) in need of LT. Methods: We used 1999-
2009 Medicaid data from CA, FL, NY, OH, and PA (40% of
Medicaid population) to identify all patients 18-75 years of
HEPATOLOGY, October, 2014
age with ESLD (cirrhosis + hepatic decompensation and/or
hepatocellular carcinoma (HCC) using validated ICD-9 algo-
rithms). Medicaid data were linked with UNOS transplant
data. Results: Among 186,269 Medicaid enrollees with cirrho-
sis, 102,752 (55.2%) had ESLD, and 92,706 (90.2%) did not
have a malignancy precluding LT. The initial indication for list-
ing was decompensated cirrhosis in 83,483 (89.9%) patients
and HCC in 9345 (9.1%). Only 7,738 (8.4%) ESLD patients
were listed (77.3% with decompensated cirrhosis, 22.8% with
HCC), with significant between-state variability: 5.5% and
5.6% in FL and OH, versus 8.6%, 9.6%, and 9.9% in NY, PA,
and CA, respectively (P<0.001). In multivariable models that
accommodated clustering of patients within organ procurement
organization, statistically significant differences in waitlisting
rates across states persisted after adjustment for demographic
characteristics, diagnosis, and distance to LT center (Table 1).
Furthermore, increased distance to the closest LT center was
associated with decreased odds of waitlisting, as was black
race. Conclusions: There are marked geographic and racial
differences in access to transplant care in the Medicaid popula-
tion. These must be addressed to equitably care for the broader
population of patients with ESLD.
Multivariable model evaluating waitlisting
* Only variables with p<0.05 presented
Disclosures:
David S. Goldberg - Grant/Research Support: Bayer Healthcare
James D. Lewis - Grant/Research Support: Bayer
The following people have nothing to disclose: Benjamin French, Scott D. Halpern
121
Ohio Solid Organ Transplantation Consortium (OSOTC)
Exception Criteria for Early Liver Transplantation (LT) in
Severe Alcoholic Hepatitis
Ibrahim A. Hanouneh, Annette Humberson, Ariana L. Fiorita,
Arthur J. McCullough, Robert O’Shea, Catherine Rosenbaum,
Jamile Wakim-Fleming, Laura E. Nagy, Nizar N. Zein; Gastroen-
terology and Hepatology, Cleveland Clinic, Cleveland, OH
Patients with alcoholic hepatitis (AH) not responding to medical
therapy have a 6-month survival rate of ~30% and most deaths
occur within 2 months. While early LT can improve survival, a 3
to 6 month abstinence from alcohol with active participation in
recovery program is the standard usually required before these
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
patients are considered for LT. In 2009, Ohio Solid Organ
Transplantation Consortium (OSOTC) established the medically
urgent exception criteria for early LT in patients with AH. Aim:
to study the survival outcome in patients with AH who met the
medically urgent exception criteria as defined by OSOTC for
early LT. Methods: We identified all adult patients with AH who
met OSOTC exception criteria for early LT at our institution
between 2009-2013. Patients were approved for medically
urgent exception criteria since they met: confirmed abstinence,
signed sobriety contract, and commitment to begin or continue
a substance use treatment program. They also had supportive
family members, stable work history, demonstrated insight into
their past substance misuse and understanding of the impact on
their current health situation. A second group of patients with
AH considered for LT met the standard criteria requirements of
OSOTC was identified. The standard criteria requires at least
a 3 month abstinence and completion of 3 month active sub-
stance recovery program. Survival outcome and alcohol relapse
following LT were compared between standard and exception
criteria groups. Results: 57 patients with AH met OSOTC med-
ically urgent exception and 61 met the standard OSOTC cri-
teria. There was no difference in demographic characteristics
between the two groups. Both MELD and Maddrey’s scores
were significantly higher in exception criteria patients than
standard criteria patients [MELD 35+4 vs. 26+5, p=0.001;
Maddrey’s 110+54 vs. 52+22, p=0.001]. The dropping-off
the transplant list for exception criteria patients was 51% com-
pared to 34% for standard criteria patients (p=0.02). The
cumulative 6-month survival rate post-LT was similar among
patients with AH/exception OSOTC criteria and AH patients/
standard OSOTC criteria (87% vs. 85%, p=ns). This benefit of
LT was maintained through 2 years of follow-up in both groups.
Among patients with AH who underwent LT after meeting the
exception OSOTC criteria, four patients resumed drinking alco-
hol following LT. This rate of alcohol relapse was comparable
to patients who met the standard OSOTC criteria (7% vs. 11%,
p=0.08). Conclusions: Early LT can improve survival in patients
with severe AH. OSOTC medically urgent exception criteria
may identify selective patients with AH at low-rate of alcohol
relapse following LT.
Disclosures:
The following people have nothing to disclose: Ibrahim A. Hanouneh, Annette
Humberson, Ariana L. Fiorita, Arthur J. McCullough, Robert O’Shea, Catherine
Rosenbaum, Jamile Wakim-Fleming, Laura E. Nagy, Nizar N. Zein
122
Liver Transplantation for Neuroendocrine Tumors Is
Unlikely the Best Option
Nicholas Nissen, Edward M. Wolin, Trista Leong, James M. Miro-
cha, Run Yu, Ashley Wachsman, Marc L. Friedman, Steven D.
Colquhoun; Surgery, Cedars-Sinai, Los Angeles, CA
Purpose: The role of liver transplantation (OLT) in the treat-
ment of metastatic neuroendocrine tumors (mNET) continues
to evolve. Retrospective analysis of the UNOS database out-
comes report overall survivals for 1,3, & 5 years at 81%, 65%
& 49%, respectively. mNET-specific Milan criteria have been
proposed. Methods: In a retrospective, single-center, IRB-autho-
rized database review of 1,567 NET patients, 468 patients
were identified with liver involvement. The mean age was 58
(14-94) and genders were exactly even. Tumors were well dif-
ferentiated in 24.8%, moderate in 7.5%, poor/undifferentiated
in 10.7% with the remainder not classified. All patients were
treated with a multi-disciplinary, multi-modality approach, but
none with OLT. Results: Overall Kaplan-Meier survival for the
entire cohort at 1,3 & 5 years was 78%, 60% & 49.5%, with
259A
a median of 4.9 years. Fifty-one patients met the NET-Milan cri-
teria (well-differentiated, GI origin & age ≤ 55). For this group
1,3, & 5 year survivals were 100%, 92.2 % & 76.8% respec-
tively (see graph). Fifteen-year survival was 72%. Conclusions:
A multi-disciplinary, multi-modality treatment approach with-
out OLT can provide overall survivals almost identical to those
reported from UNOS data of patients treated with OLT. In
patients meeting the proposed NET-Milan criteria, survival with
this non-transplant approach was clearly superior to OLT. These
results strongly suggest that optimal outcomes for select patients
with mNET can be obtained without OLT. Future prospective
multi-center trials will be necessary to define best-practice ther-
apy for patients with mNET.
Disclosures:
The following people have nothing to disclose: Nicholas Nissen, Edward M.
Wolin, Trista Leong, James M. Mirocha, Run Yu, Ashley Wachsman, Marc L.
Friedman, Steven D. Colquhoun
123
Domino liver transplantation (DLT) using familial amy-
loid polyneuropathy (FAP) grafts: Report from the FAP
world transplant registry (FAPWTR) and call for an
international collaborative study to assess the risk of de
novo FAP in domino recipients
Arie Stangou1, Marie E. Larsson2, Ole Suhr3, Henryk E. Wilczek4,
Bo-Goran Ericzon5; 1Liver Unit, Queen Elizabeth Hospital, Birming-
ham, United Kingdom; 2Department of Transplantation, Karolinska
Institute, Stockholm, Sweden; 3Public Medicine, Umea University,
Umea, Sweden; 4Department of Transplantation, Karolinska Insti-
tute, Stockholm, Sweden; 5Department of Transplantation, Karo-
linska Institute, Stockholm, Sweden
Domino liver transplantation (DLT) using FAP grafts is an excel-
lent resource, however the Amyloid Society is aware of poten-
tial risks of FAP transmission to the domino recipients. Between
1995-2013 the FAPWTR received 1082 reports of DLT world-
wide, including Portugal (524 cases), France (167), Sweden
(69), USA (66), Spain (56), Germany (52), Brazil (48), Japan
(38), UK (20), Belgium (16), Switzerland 13. Mean age of
DLT recipients 55+/- 9.1 years (median 56), 75% male. Main
indications for DLT were liver cancer in 440 cases, HBV/
HCV cirrhosis 193, alcoholic cirrhosis 213. At median 7.2
years post DLT (0.6-17.6 years), 697 of the 1082 domino
recipients are alive. Overall survival 62%. Leading causes of
death were tumour recurrence (24%), sepsis(16%), cardiac
deaths (7%), periopeartive deaths (5%). Transmission of FAP
was initially only sporadically reported, however longer term
follow up reveals 5-10% risk of developing features of de novo
260A AASLD ABSTRACTS
FAP at 8-10 years after domino LT. Fifteen domino recipients
have received re-transplant for the indication of systemic de
novo FAP to date, with excellent results and prompt reversal
of FAP features within 1-2 years after LT. The long term risk of
FAP in the surviving 697 domino recipients remains unknown;
potential treatments include retransplantation or novel anti-
TTR agents. The FAPWTR advises that domino FAP remains
a valuable resource in liver transplantation and continues to
support the domino practice as mutually beneficial to FAP and
cirrhotic/HCC patients, but vigilant follow up is required for
possible developments of de novo amyloidosis in the domino
recipients. In view of novel anti-amyloid medication potentially
becoming available either as licensed agents or drug trials
in the near future, the FAPWTR invites participation from all
specialist centres involved in LT for FAP and DLT in a large col-
laborative study under the International Society of Amyloidosis
and FAPWTR to investigate the risk of FAP transmission in the
domino recipients, mode of presentation and disease course,
response to treatment with re-transplant, and future consider-
ation of drug trials/ medical treatment. Study outline: Aim: To
investigate the evolution of amyloid disease in the recipients
of FAP liver grafts. Primary end point: Histological confirma-
tion of amyloid deposition in abdominal fat specimens, cen-
trally collected and analysed at the Uppsala Amyloid Centre of
Excellence Secondary end points:1. Neurological disease,2.
Cardiac amyloid involvement,3. Systemic amyloid deposits.
Inclusion- exclusion criteria: All domino transplant recipients
6 months post DLT onwards are eligible for screening. Recruit-
ment period: 2-3 years.
Disclosures:
The following people have nothing to disclose: Arie Stangou, Marie E. Larsson,
Ole Suhr, Henryk E. Wilczek, Bo-Goran Ericzon
124
Predictors of Mortality in Patients with Low MELD on the
Liver Transplant Wait List
Swaytha Ganesh 1, Chandraprakash Umapathy 3, Abhinav
Humar2, Christopher B. Hughes2, Mark Sturdevant2, Elizabeth A.
Kallenborn2, Vinod K. Rustgi1, Shahid M. Malik1, Amit D. Tevar2;
1Gastroenterology, University of Pittsburgh Medical Center, Pitts-
burgh, PA; 2Transplant Surgery, University of Pittsburgh Medical
center, Pittsburgh, PA; 3Division of Internal Medicine, University of
Pittsburgh Medical Center, Pittsburgh, PA
Liver allocation within US centers is predicated by MELD score.
As MELD scores of those transplanted continue to rise, wait
time and wait list mortality will adversely impacted. A signif-
icant number of these wait list deaths occur at lower MELD
scores. Our primary aim is to assess the predictors of mortality
on the wait list, in patients with lower MELD scores (≤ 15)
We examined the baseline characteristics and predictors of
mortality on the wait list in patients with MELD scores ≤ 15. A
retrospective analysis was conducted of all adult patients on
the liver transplant wait list at a large single center from 2005
to current. We excluded patients with a MELD > 15, those
with HCC and those with a prior liver transplant 31.7% (446
of 1404) of patients in this period of time were listed with a
MELD ≤ 15. Mean age was 54.3 ± 11 years and 60.5% were
males (N = 269). Alcoholic liver disease and HCV accounted
for 20.2% and 28.5% respectively and 19.2% had NASH. The
mean MELD score in this group of patients was 12 ± 2.464.
The median follow up for the entire group was 366 days.
Overall mortality was 18.2% (81), 20% were removed from
the list and 41.9% were transplanted. 62 patients (14%) died
(n=37) or were removed (n=25) from the list at 1 year. 1/3 rd
of the patients were removed from the list due to improvement
HEPATOLOGY, October, 2014
in their clinical condition, and others due to deconditioning,
advancing age, and medical non-compliance, social and finan-
cial issues. The leading cause of death was infection (62.3%).
152 (34%) of the low MELD patients had ascites at the time of
listing; 16% of these patients were dead at one year follow-up.
Only one patient in this group underwent TIPS. In univariate
analysis, albumin (P< 0.05), and age (P< 0.05) at the time of
listing, correlated with mortality. The MELD, race, sex, and eti-
ology of liver disease were not independent risk factors for mor-
tality. In multivariate analysis, albumin (P< 0.02, OR=0.555),
age at listing (P< 0.04, OR= 1.024), were independent pre-
dictors of mortality. Subgroup analysis of patients who died
or were removed from the list at 1 year showed additionally,
that sodium at listing (P= 0.004, OR=0.83) was a predictor of
outcome Nearly 1/3rd of patients at our center over the last
10 years were listed with a MELD score of ≤ 15. Fewer than
50% of these patients were eventually transplanted. 37 patients
died at one year with a majority being secondary to infectious
causes. Elderly patients with hypoalbuminemia and hypona-
tremia seem to be at the highest risk. Increased utilization of
TIPS and early discussion of live donor transplant may provide
better outcomes for such patients.
Disclosures:
Vinod K. Rustgi - Grant/Research Support: Abbvie, BMS, Gilead, Achillion
The following people have nothing to disclose: Swaytha Ganesh, Chan-
draprakash Umapathy, Abhinav Humar, Christopher B. Hughes, Mark Stur-
devant, Elizabeth A. Kallenborn, Shahid M. Malik, Amit D. Tevar
125
A preliminary analysis of liver allocation based on the
“Share 35” policy in UNOS region 4
James F. Trotter1, Juan D. Arenas2, J. S. Bynon3, John Duffy9, Hany
A. Elbeshbeshy9, Preston F. Foster4, Rafik M. Ghobrial8, John A.
Goss10, Goran Klintmalm1, Vivek Kohli9, Marlon F. Levy5, Jorge A.
Marrero2, Natalie G. Murray5, Ken Washburn6, Jeff Weinstein7,
Harlan Wright11; 1Baylor University Medical Center at Dallas, Dal-
las, TX; 2UT-Southwestern, Dallas, TX; 3UT-Houston, Houston, TX;
4Methodist Healthcare System, San Antonio, TX; 5Baylor All Saints,
Fort Worth, TX; 6UT-San Antonio, San Antonio, TX; 7Methodist Hos-
pital, Dallas, TX; 8Methodist Hospital, Houston, TX; 9Zuhdi Trans-
plant Center, Oklahoma City, OK; 10Baylor College of Medicine,
Houston, TX; 11Oklahoma Transplant Center, Oklahoma City, OK
Background: Implementation of the new liver allocation policy
known as the “Share 35” was undertaken to “decrease wait list
deaths and minimize distance traveled” for donor organs. How-
ever, the actual impact of changes in organ allocation policy is
never certain until after implementation where unintended con-
sequences of the new policy and the clinical practice of trans-
plant centers may become apparent. We report the outcomes
of liver transplant candidates and recipients before and after
implementation of the “Share 35” policy in the United Network
of Organ Sharing (UNOS) Region 4 (Oklahoma and Texas).
Methods: We measured the outcomes of liver transplant candi-
dates on the waiting list, as well as organ placement and char-
acteristics of liver transplant candidates as provided by UNOS
for the 6 months preceding (12/17/2012 – 6/17/2013) and
after (6/18/2013 – 12/18/2013) implementation of “Share
35 “ policy. Results: The number of liver transplants increased
from before (256) to after (295) “Share 35.” As shown in the
Table, while the proportion of patients transplanted at higher
MELD scores, cold ischemic time, distance organ travelled, and
% procured organ discarded increased after implementation
of “Share 35,” those either dying on the list or removed as
“too sick to transplant” remain unchanged. Conclusion: This
preliminary analysis shows that in UNOS region 4, liver allo-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
cation under “Share 35” is associated with transplantation of
sicker patients without reducing patients lost on the waiting list
prior to transplant. Continued evaluation of patient and organ
outcomes are required to fully assess the impact of this change
in liver allocation policy.
* = p < 0.05
# = p = NS
Disclosures:
Goran Klintmalm - Advisory Committees or Review Panels: Novartis; Grant/
Research Support: Astellas, Novartis, Opsona, Quark
Jorge A. Marrero - Advisory Committees or Review Panels: Bayer, Onyx; Grant/
Research Support: Bayer, Blueprint Medicine
The following people have nothing to disclose: James F. Trotter, Juan D. Are-
nas, J. S. Bynon, John Duffy, Hany A. Elbeshbeshy, Preston F. Foster, Rafik M.
Ghobrial, John A. Goss, Vivek Kohli, Marlon F. Levy, Natalie G. Murray, Ken
Washburn, Jeff Weinstein, Harlan Wright
126
The impact of MELD score and hospitalization status
prior to liver transplantation on short-term post-trans-
plantation survival: a national study
Therese Bittermann, George A. Makar, David S. Goldberg; Gas-
troenterology, Hospital of the University of Pennsylvania, Philadel-
phia, PA
Introduction: Although the MELD score accurately predicts
short-term pre-transplant survival on the waitlist, it is weakly
correlated with long-term post-transplant survival. The United
Network for Organ Sharing (UNOS) has recently instituted
Share 35 as a means to more broadly share organs across
geographic regions to the sickest waitlist candidates. The
potential impact of this policy on post-transplant outcomes has
not been well established. Methods: UNOS data from 2002-
2013 was used to evaluate the association between laboratory
MELD score at transplantation and hospitalization status on
short-term post-transplant patient survival. Results: There were
50,847 single-organ liver transplant recipients included in the
analysis. Since 2002, an increasing proportion of transplant
recipients have been transplanted from the hospital (14.2%
in 2002 versus 20.5% in 2013) or the ICU (6.9% in 2002 to
9.7% in 2013). Unadjusted 3-, 6-, and 12-month post-trans-
plant patient survival was significantly lower with increasing
laboratory MELD score at transplant, and hospitalization or
ICU status (p<0.001). The proportion of transplant recipients
alive at 1 year was 90.0% if transplanted from home, com-
pared to 86.1%, and 80.3% if transplanted from the hospi-
tal or ICU, respectively. The unadjusted 1-year survival was
approximately 90% for those with a laboratory MELD score
<20, compared to 81.6% in those with a laboratory MELD
score ≥35 at transplant. In multivariable generalized estimating
equation (GEE) models that treated center as a random effect,
both increasing MELD score and hospitalized or ICU status
were associated with significantly increased short-term mor-
tality (Table 1). Conclusions: While policies such as Share 35
may decrease waitlist mortality by facilitating organ allocation
to patients with more advanced liver disease on the basis of
MELD score alone, they may also yield increased short-term
mortality post-transplantation. Future policy changes should
261A
take into consideration the downstream consequences of such
“urgency-based” allocation policies.
Table1: Short-term mortality OR (95% CI) in multivariable GEE
models
Disclosures:
David S. Goldberg - Grant/Research Support: Bayer Healthcare
The following people have nothing to disclose: Therese Bittermann, George A.
Makar
127
Molecular markers of progenitor cells define outcome
of HCC patients beyond Milan criteria undergoing liver
transplantation
Oriana Miltiadous1, Yujin Hoshida1, M. Isabel Fiel1, Daniela
Sia1,2, Swan N. Thung1, Andrew Harrington1, Poh Seng Tan1,3,
Hui Dong1,4, Monica Higuera1,5, Kate Revill1, Charissa Y. Chang1,
Jorge Rakela6, Thomas J. Byrne6, Myron Schwartz1, Sander S.
Florman1, Josep M. Llovet1,7; 1Mount Sinai Liver Cancer Program
(Division of Liver Diseases, Department of Medicine, Tisch Can-
cer Institute, Department of Pathology, Transplantation Institute,
Department of Surgical Oncology), Icahn School of Medicine at
Mount Sinai, New York, NY; 2Gastrointestinal Surgery and Liver
Transplantation, National Cancer Institute, Milan, Italy; 3Gastroen-
terology and Hepatology, University Medicine Cluster, National
University Health System, Singapore, Singapore; 4Eastern Hepa-
tobiliary Surgery Hospital, Second Military Medical University,
Shanghai, China; 5Barcelona - Clínic Liver Cancer Group (HCC
Translational Research Laboratory, Liver Unit, Pathology Dept),
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),
Liver Unit. Hospital Clínic, Universitat de Barcelona, Barcelona,
Spain; 6Division of Hepatology, Mayo Clinic, Phoenix, AZ; 7Insti-
tucio Catalana de Recerca I Estudis Avançats, Barcelona, Spain
Introduction: Since availability of donor organs is limited, bet-
ter predictors of hepatocellular carcinoma (HCC) recurrence
and overall survival (OS) are needed in the selection of candi-
dates for liver transplantation (LT). A subgroup of HCC patients
beyond Milan criteria achieve good outcome after transplanta-
tion, but no radiology-based selection has succeeded in identi-
fying them. Here we explore tumor biomarkers and genomics
of patients with extended indications as a first step to identify
good candidates for LT. Methods: A total of 132 HCC patients
transplanted from 1990 to 2013 beyond Milan criteria (based
on the explant pathology) with archived fixed tissue were
included from two institutions: Mount Sinai Hospital (n=94) and
Mayo Clinic (n=38). Extra-hepatic metastasis and macrovascu-
lar invasion at the time of transplant were excluded. We aimed
to define biomarkers, which predict HCC patients with good
outcome after transplantation by studying gene signatures
[whole-genome DASL HT beadarray (Illumina)] and immmu-
nohistological markers (CK19, EpCAM). Prognostic markers
were assessed by nearest template prediction and were ana-
lyzed for correlation with clinical variables. Results: Most of the
patients were males (79.5%) with a median age of 56, HCV
positive (71%) and HBV positive (14%). The median size of the
largest tumor was 4cm (range 1-9cm). Beyond-Milan staging
262A AASLD ABSTRACTS
was defined as having single tumor ≥5cm (4.5%), 2-3 tumors
with the larger>3cm (38.6%) or more than 3 tumors within
the liver (56.8%). Satellites were present in 18% patients and
microvascular invasion in 84%. After a median follow up of
88 months, the 5-year OS and recurrence rates were 57% and
34.5%, respectively. In the multivariable analysis CK19 signa-
ture1 (HR=2.95, p<0.001), size≥5cm (HR=3.37, p=0.023)
and satellites (HR=2.98, p=0.001) were independent predic-
tors of recurrence. For OS, S2 subclass2 (HR=3.18, p=0.001)
and size≥5 cm (HR=5.06, p<0.001) predicted outcome. Thus,
signatures of progenitor cell markers (CK19 and S2) predicted
clinical outcome. In fact, patients with no progenitor-cell signa-
tures (CK19 and S2 negative), had better survival (5-yr:67%;
HR=0.58, p=0.036) and recurrence rate (5-yr:19%; HR=0.32,
p<0.001). Results were consistent in the subgroup of patients
with pre-operative staging beyond Milan (n=94). Conclusions:
Gene signatures associated with progenitor markers (CK19
and S2) improve prognostic prediction in HCC patients beyond
Milan who undergo LT. Absence of these gene signatures may
assist the decision for extended indications of LT beyond Milan.
1Villanueva A et al. Gastroenterology 2011;140:1501-12.e2.
2Hoshida Y et al. Cancer Res 2009;69:7385-92.
Disclosures:
Charissa Y. Chang - Consulting: Gilead, Vertex, Onyx
Myron Schwartz - Consulting: Gilead, Inova
Josep M. Llovet - Advisory Committees or Review Panels: Nanostring, Blueprint
medicines; Consulting: Bayer Pharmaceutical, Bristol Myers Squibb, Imclone,
Biocompatibles, Novartis, GSK; Grant/Research Support: Bayer Pharmaceutical,
Bristol Myers Squibb, Boehringer-Ingelheim
The following people have nothing to disclose: Oriana Miltiadous, Yujin Hoshida,
M. Isabel Fiel, Daniela Sia, Swan N. Thung, Andrew Harrington, Poh Seng Tan,
Hui Dong, Monica Higuera, Kate Revill, Jorge Rakela, Thomas J. Byrne, Sander
S. Florman
128
Using HNF4α Target Gene Signature Obtained from
Combinatorial Bioinformatics as a Predictive Tool in
Hepatocellular Carcinoma (HCC) Pathogenesis
Chad M. Walesky1, Sumedha S. Gunewardena2, Byunggil Yoo3,
Genea T. Edwards1, Udayan Apte1; 1Pharmacology, Toxicology
and Therapeutics, University of Kansas Medical Center, Kansas
City, KS; 2Department of Biostatistics, University of Kansas Medical
Center, Kansas City, KS; 3Kansas Intellectual and Developmental
Disabilities Research Center, University of Kansas, Kansas City, KS
HNF4α is the master regulator of hepatic differentiation. Recent
studies have demonstrated that HNF4α can also actively inhibit
hepatocyte proliferation. Acute deletion of HNF4α in adult
mice results in spontaneous hepatocyte proliferation and
increased promotion of diethylnitrosamine-induced HCC. We
used a combinatorial bioinformatics approach consisting of
combined RNA sequencing-ChIP sequencing to identify global
changes in gene expression after HNF4α deletion. RNA seq
studies revealed that a total of 829 genes changed after acute
HNF4α deletion (515 up regulated vs 314 down regulated).
Further cross analysis of RNA seq data with HNF4α ChIP seq
data indicated that 45% of these genes have a putative HNF4α
binding site within 10 kb from the transcription start site (TSS)
indicating that those may be direct targets of HNF4α. Next.
we performed a RNA-seq analysis on liver tumors developed in
HNF4α-KO mice, which revealed 2152 unique gene changes.
Further bioinformatics analysis identified a set of 322 genes,
which changed in the same direction upon HNF4α deletion,
either acute or in the tumors obtained from HNF4α-KO mice
and had a putative HNF4α binding site within10 kb upstream.
Out of these 322 genes, 82 genes were up regulated upon
HNF4α deletion and are novel negative targets of HNF4α.
HEPATOLOGY, October, 2014
Majority of these genes play a significant role in cell prolifera-
tion and are repressed by HNF4α in mature quiescent hepato-
cytes. To determine the ability of HNF4α target gene signature
as a predictive tool in HCC pathogenesis, we further refined
the 322-gene signature to 44 genes considering human ortho-
log expression. This 44 gene HNF4α target gene signature
was used to determine changes in HNF4α activity in human
HCCs in an in silico analysis. Independent gene expression
data sets of 102 individual human samples available in public
domain (GEO) were used and samples were clustered using
HNF4α target gene expression. The HNF4α gene expression
signature was successful in distinguishing Cirrhotic-non-HCC
and cirrhotic-with HCC with >80% specificity. Furthermore,
HNF4α target gene signature was able to separate normal,
cirrhotic non-HCC, dysplastic nodules, early stage HCC and
advanced HCC from each other with >85% specificity. Finally,
HNF4α gene signature was able to separate HCC from paired
non-tumor tissues with 100% specificity. These data indicate
that loss of HNF4α is a critical factor in HCC and HNF4α func-
tion as measured by target gene expression is a potential pre-
dictive biomarker in HCC pathogenesis in humans. (This work
was supported by NIH P20 GM103549, P20 GM103418, 5
T32 ES007079-34 and R01 DK098414)
Disclosures:
The following people have nothing to disclose: Chad M. Walesky, Sumedha S.
Gunewardena, Byunggil Yoo, Genea T. Edwards, Udayan Apte
129
TERT promoter mutation is an early somatic genetic
alteration in the malignant transformation of cirrhotic
nodules in hepatocellular carcinoma
Jean-Charles Nault1,3, Julien Calderaro1,4, Luca Di Tomaso5,
Charles Balabaud6, Elie S. Zafrani4, Paulette Bioulac-Sage6,7,
Massimo Roncalli5, Jessica Zucman-Rossi1,2; 1Inserm U1162,
Paris, France; 2Université Paris Descartes, Paris, France; 3Service
d’hépatologie, hôpital Jean Verdier, APHP, Bondy, France; 4Ser-
vice d’anatomopathologie, hôpital Henri Mondor, APHP, Crétei,
France; 5Department of pathology, Istituto Clinico Humanita,
Milano, Italy; 6Inserm U1053, université de bordeaux, bordeaux,
France; 7CHU de bordeaux, Hôpital Pellegrin, Bordeaux, France
Recently, we identified somatic mutations of the TERT promoter
as the most frequent genetic alterations of hepatocellular car-
cinoma (HCC). Here, we aimed to evaluate the occurrence of
TERT promoter mutation in the malignant transformation of the
cirrhotic nodules in HCC. Methods: We screened a series of
96 nodules developed in 58 cirrhosis and also 114 additional
cirrhosis for TERT promoter mutations and 10 cancer genes
known as recurrently mutated in HCC in 31 nodules. Immu-
nohistochemistry were performed with Glypican 3, glutamine
synthase and HSP70 and all these samples were reviewed
collectively by 6 expert liver pathologists. Results: The 96 ana-
lyzed nodules were diagnosed as low grade dysplastic nodules
(LGDN, 32 cases), high grade dysplastic nodules (HGDN, 20
cases), early HCC (eHCC, 27 cases) or small and progressed
HCC in 17 cases. The agreement between the initial diagno-
sis from pathological report and the final expert consensus
was moderate (Weighted kappa=0.547) underlining the dif-
ficulties in the routine diagnostic assessment. TERT promoter
mutations were identified in 29/96 nodules (30%) in both
FFPE and frozen samples. In the overall series, TERT promoter
mutations were significantly associated with acinar formation
(P<0.0001), unpaired arteries (P=0.013), cytological atypia
(P=0.001) positive HSP70 immunostaining (P<0.0001) and
positive GPC3 immunostaining (P=0.014). TERT promoter
mutations were identified in 6% of LGDN, 20% of HGDN, 59%
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
of eHCC and 42% of small and progressed HCC. We didn’t
find any TERT promoter mutations in the cirrhotic matched tis-
sues, consequently all these mutations were somatic events. In
the same line, no mutations in TERT promoter mutations were
identified in 114 cirrhosis. TERT promoter mutation is also the
most frequent molecular defect in eHCC (59% of mutations)
since the established immunohistochemical criteria (at least two
positive markers among GPC3 3, glutamine synthase and HSP
70) for diagnosis of malignancy was found in only 37% of the
cases. In comparison, somatic mutations in 10 other cancer
genes were identified in 28% of the small and progressed
HCC but not in LGDN, HGDN and eHCC. Conclusion: TERT
promoter mutation is the earliest genetic event occurring during
the malignant transformation of cirrhotic nodules. Its frequency
increases during the different steps of carcinogenesis. In con-
trast, other cancer genes (as CTNNB1, TP53…) are late events
involved in tumor progression from early HCC to small and
progressed HCC. Consequently, we can propose somatic TERT
promoter mutation as a new biomarker predictive of the malig-
nant transformation of cirrhotic preneoplastic lesions in HCC.
Disclosures:
Jessica Zucman-Rossi - Advisory Committees or Review Panels: Astellas, Celgene;
Consulting: pfizer; Grant/Research Support: Integragen; Speaking and Teach-
ing: bayer, lilly
The following people have nothing to disclose: Jean-Charles Nault, Julien Calde-
raro, Luca Di Tomaso, Charles Balabaud, Elie S. Zafrani, Paulette Bioulac-Sage,
Massimo Roncalli
130
Gene alterations in β-catenin and p53/cell cycle control
pathway are closely associated with development and
prognosis of hepatocellular carcinoma: Comprehensive
analyses by next generation sequencing technology
Fukiko Kawai-Kitahata1, Yasuhiro Asahina1,
Syun Kaneko1,
Hiroko
Nagata1, Fumio Goto1, Satoshi Otani1, Miki Taniguchi1, Miyako
Murakawa1, Sayuri Nitta1, Takako Watanabe1, Megumi Tasa-
ka-Fujita1, Yasuhiro Itsui1, Mina Nakagawa1, Sei Kakinuma1,
Nobuyuki Enomoto 2, Mamoru Watanabe 1; 1Tokyo Medical
and Dental University, Tokyo, Japan; 2University of Yamanashi,
Yamanashi, Japan
Background/aim:Genetic alterations in specific genes lead to
disruption of cellular pathways and are thought to be critical
events in the hepatocarcinogenesis and progression of hepa-
tocellular carcinoma (HCC).However, such genetic alterations
responsible for tumor development and progression are still
unclear. To identify genetic alterations associated with hepa-
tocarcinogenesis and prognosis of HCC, we comprehensively
investigated genetic alterations in paired HCC and surround-
ing non-HCC tissues by next generation deep sequencing
technology.Methods:Next generation deep sequencing was
performed in paired HCC and surrounding non-HCC tissue
samples obtained from 83 HCC patients who were consecu-
tively treated by surgery. The male/female ratio was 63/20
and mean age was 67 ± 9.6 years.Tumor grading ranged
from well (n = 21) to moderately (n = 45) or poorly differenti-
ated HCC (n = 16). The Ion AmpliSeq cancer panel v2, which
targets 2790 mutational hotspot regions of the 50 cancer-asso-
ciated genes, was used to generate target amplicon libraries
from 10 ng of purified genomic DNA. Alignment to the hg19
human reference genome and variant calling was carried
out, and nucleotide variants that were detected in tumors and
absent in corresponding non-tumor tissue were determined as
somatic mutations. Association between gene mutation and
data on clinical outcomes were analyzed. Results:The mean
coverage depth was 2024 per sample, with 99.1% of targets
covered to a depth of 100X. In total, we identified 210 muta-
263A
tions with 14 genes. We found that CTNNB1, TP53, PTEN,
CDKN2A, HRAS, PIK3CA, and STK11were mutated in 29
(35%), 29 (35%), 2 (2.4%), 2 (2.4%), 1 (1.2%), 1 (1.2%), 1
(1.2), and 50 (60%) of 83 HCCs had mutations either in CTN-
NB1or TP53. Interestingly, 7 (8.4%) HCCs had both CTNNB1
and TP53 gene mutations, although mutation in these 2 genes
has been reported as a mutually exclusive event. Significantly
higher rate of TP53 mutations were found in hepatitis B virus
related HCC (72.2% versus 24.6%, p = 0.0008). Although
none of each mutated gene associated with tumor character-
istics including tumor size, pathological differentiation, and
vascular invasion, and presence of intra or extrahepatic metas-
tasis, mutations in both CTNNB1 and TP 53 were significantly
associated with shorter disease free survival (DFS) (median DFS;
195 versus 470 days, p = 0.02). Conclusions:Gene alterations
in β-catenin and p53/cell cycle control pathway are closely
associated with HCC development, and gene alterations in
both pathways are related to poor prognosis. Our observations
may have clinically important implications in diagnosis and
predicting outcomes for patients with HCC.
Disclosures:
Yasuhiro Asahina - Grant/Research Support: Chugai Pharceutical Co. Ltd., Toray
Industries, Inc., Dainippon-Sumitomo Pharma Co. Ltd, Merck Sharp and Dohme,
Bristol-Myers Squibb
The following people have nothing to disclose: Fukiko Kawai-Kitahata, Syun
Kaneko, Hiroko Nagata, Fumio Goto, Satoshi Otani, Miki Taniguchi, Miyako
Murakawa, Sayuri Nitta, Takako Watanabe, Megumi Tasaka-Fujita, Yasuhiro
Itsui, Mina Nakagawa, Sei Kakinuma, Nobuyuki Enomoto, Mamoru Watanabe
131
Aspartate β-hydroxylase is a Therapeutic Target for
Intrahepatic Cholangiocarcinoma
Chiung-Kuei Huang1, Arihiro Aihara1, Rolf I. Carlson1, Mark
Olsen2, Tunan Yu1, Jack R. Wands1; 1Liver Research Center, Rhode
Island Hospital and the Alpert Medical School of Brown Universi-
tyq, Providence, RI; 2Department of Medical Chemistry, College of
Pharmacy Glendale, Midwestern University, Glendale, AZ
Background: Cholangiocarcinoma (CCA) is a highly lethal dis-
ease due to early intrahepatic invasion and subsequent wide-
spread metastatic disease. Aspartate β-hydroxylase (ASPH) is
a ~86KD Type II transmembrane protein and a member of
the α-ketoglutarate-dependent dioxygenase family. It catalyzes
the hydroxylation of aspartyl and asparaginyl residues in epi-
dermal growth factor (EGF)-like domains of various proteins
such as Notch and Jagged (JAG) which play critical roles in
cell growth, differentiation, adhesion and migration. ASPH is
highly overexpressed (>95%) in CCA. However, little is known
regarding the molecular mechanisms by which ASPH may
mediate CCA development and growth. Previous studies have
suggested that ASPH is a major activator of Notch signaling
which is a known promoter of a malignant phenotype charac-
terized by increased cell migration, invasion, colony formation
and metastatic spread. Methods: In this study, we determined
whether ASPH could serve as a therapeutic target for CCA
and clarified the potential molecular mechanisms by which
ASPH mediates CCA progression. We demonstrated that the
enzymatic activity of ASPH was critical for CCA progression
using a mutant construct of the catalytic site which lacks enzy-
matic activity. In addition, we inhibited ASPH protein levels
using an shRNA construct to “knock down” expression and
determined effects on CCA growth in vivo and migration and
invasion in vitro. In addition, small molecule inhibitors (SMIs)
were developed by rational drug design based on the crystal
structure of the catalytic site of ASPH. The rat BDE-Neu intra-
hepatic cholangiocarcinoma model was employed to evaluate
the anti-tumor effects of these SMIs. Results: It was observed
264A AASLD ABSTRACTS
that the enzymatic activity of ASPH was critical for its biologic
function and low levels reduced CCA growth and progres-
sion as demonstrated by both a catalytic inactive point mutant
construct and SMI treatment of established intrahepatic CCA.
Mechanistically, overexpression of ASPH was found to modu-
late Notch activation by generating the transcriptionally active
C-terminal intracellular domain (ICD) fragment which trans-
locates to the nucleus to upregulate Notch responsive genes
involved in enhanced cell proliferation, migration, invasion
and metastases. Thus, inhibiting ASPH function was shown to
downregulate Notch activation and significantly inhibit CCA
growth. Conclusion: The enzymatic activity of ASPH was crit-
ical for CCA development and progression and targeting of
ASPH by an SMI may be a therapeutic approach for treatment
of this disease.
Disclosures:
The following people have nothing to disclose: Chiung-Kuei Huang, Arihiro
Aihara, Rolf I. Carlson, Mark Olsen, Tunan Yu, Jack R. Wands
132
Cohesins: Novel Markers for the Efficacy of Sorafenib in
Hepatocellular Carcinoma
Richard Kalman, Mart Dela Cruz, Ramesh Wali, Hemant Roy;
Gastroenterology, Boston Medical Center, Boston, MA
Background: Hepatocellular Carcinoma (HCC) is a leading
cause of cancer related death worldwide and on the rise in
Europe and the United States. Sorafenib has provided an
important advance in treatment of HCC although its efficacy
has been modest. Sorafenib inhibits Raf kinase, angiogenesis
and a myriad of other genes. Elucidating the precise mecha-
nism of action may be critical for designing better agents. In this
regard, HCC is a biologically heterogeneous disease. Recently
our group has noted that alterations in high order chromatin are
one of the earliest changes in carcinogenesis (Gastro 2011,
Clin Gastro Hep 2012). The molecular determinants of these
changes are unclear, but is chromatin looping controlled by the
cohesin family of proteins in several malignancies (Solomon et
al., Nature Gen 2013). SMC3, a key structural maintenance
protein of the cohesin multimer, has been recently implicated in
a number of non-hepatic cancers. We, therefore, hypothesized
that sorafenib’s effect may be mediated through alterations in
SMC3. Methods: For this study we chose a two-step approach,
assessing the immunohistochemical (IHC) expression of the pro-
teins with tissue microarrays, and then ascertaining whether
these candidate cohesion proteins are modulated by sorafenib
through immunoblot. To determine the expression of cohesins
in normal vs malignant tissue we performed IHC on a HCC
Tissue Array (Bio Max, Rockland, North Carolina). Arrays
were stained for anti-SMC antibody. For immunoblot studies,
human hepatocellular carcinoma cell line HepG2 cells (ATCC,
Manassas, VA) were plated in 60mm cell culture dishes. Cells
were treated with either 2uM of sorafenib (Santa Cruz Bio-
technology, Santa Cruz, CA) or DMSO for 24 hours. Protein
was harvested and processed for immunoblot studies. Results:
IHC revealed a large induction of SMC3 (5-fold increase, p
0.03) in malignant tissue as compared to normal liver. Immu-
noblot revealed the chemopreventive agent sorafenib was able
to markedly downregulate (~76%, p 0.04). Conclusions: We
demonstrated that the SMC3 was dramatically upregulated in
HCC, suggesting that this cohesin may be involved in the ple-
otropic alterations in gene expression. Importantly, the estab-
lished anti-neoplastic agent, sorafenib, was able to blunt this
overexpression. This suggests that SMC3 alterations in high
order chromatin may not only be an early event in HCC but
also a target for a chemopreventive/chemotherapeutic agent.
HEPATOLOGY, October, 2014
Disclosures:
The following people have nothing to disclose: Richard Kalman, Mart Dela Cruz,
Ramesh Wali, Hemant Roy
133
Genetic insights into primary biliary cirrhosis – an inter-
national collaborative meta-analysis and replication
study
Heather J. Cordell1, Younghun Han2, Yafang Li2, George F. Mells3,
Gideon Hirschfield4, Gang Xie5, Brian D. Juran6, M. Eric Gersh-
win7, Pietro Invernizzi8, Konstantinos Lazaridis6, Carl A. Ander-
son9, Michael F. Seldin10, Chris Amos2, Richard N. Sandford3,
Katherine Siminovitch5; 1Institute of Genetic Medicine, Newcastle
University, Newcastle-upon-Tyne, United Kingdom; 2Geisel School
of Medicine, Darmouth, Hanover, NH; 3Academic Department of
Medical Genetics, University of Cambridge, Cambridge, United
Kingdom; 4School of Immunity and Infection, University of Bir-
mingham, Birmingham, United Kingdom; 5Lunenfeld-Tanenbaum
Research Institute, Mount Sinai Hospital, Toronto, ON, Canada;
6Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN;
7Internal Medicine, UC Davis, Sacramento, CA; 8IRCCS Istituto
Clinico Humanitas, Milan, Italy; 9Wellcome Trust Sanger Institute,
Hinxton, Cambridge, United Kingdom; 10Biological Chemistry and
Molecular Medicine, UC Davis, Sacramento, CA
Primary biliary cirrhosis (PBC) results from an interaction of
genetic and environmental factors. To date, four genome-wide
association studies (GWAS) and two Illumina Immunoarray
studies of PBC have helped delineate the genetic architecture
of this disease. These studies confirmed associations at the
human leukocyte antigen (HLA)-region and identified 27 non-
HLA susceptibility loci. Candidate genes are notably involved
in the IL-12 signalling cascade. To identify additional risk loci
for PBC, we have undertaken genome-wide meta-analysis
(GWMA) of discovery datasets from the North American, the
Italian and the UK GWAS of PBC, with a combined, post-QC
sample size of 2,745 cases and 9,802 controls. Genome-wide
imputation of each discovery dataset was undertaken in MACH
using HapMap3 as reference panel; GWMA was undertaken
using ProbABEL and META. Following meta-analysis, the index
single nucleotide polymorphisms (SNPs) at loci with PDISCOV-
ERY<5×10-5 were genotyped in a validation cohort consisting
of 3,716 cases and 4,261 controls. To prioritise candidate
variants and genes at confirmed risk loci, we used the ENCODE
and the 1000Genomes datasets to identify SNPs within regula-
tory elements and non-synonymous (ns) SNPs in strong linkage
disequilibrium (LD) with the index variant (r2>0.8). Finally,
we performed pathway analysis of results from the GWMA
using i-GSEA4GWAS. We identified six previously unknown
risk loci for PBC, of which four overlap with risk loci for other
autoimmune conditions (Table 1). Candidate genes included
IL12B at 5q31. Functional annotation identified SNPs that are
strongly correlated to the index variant and predicted to affect
expression of CCL20 at 2q36 and DGKQ at 4p16. Pathway
analysis identified several highly-plausible gene sets associated
with PBC, including IL-12, JAK-STAT, IL-21, IL-23 and IFN-α,β
signalling pathways. Conclusion This uniquely powered inter-
national collaborative GWMA and replication study confirms
additional immunologically relevant loci and processes that are
associated with the risk of developing PBC.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Table 1. Results from discovery, validation and joint analyses
Disclosures:
Richard N. Sandford - Advisory Committees or Review Panels: Otsuka; Grant/
Research Support: Intercept
The following people have nothing to disclose: Heather J. Cordell, Younghun
Han, Yafang Li, George F. Mells, Gideon Hirschfield, Gang Xie, Brian D. Juran,
M. Eric Gershwin, Pietro Invernizzi, Konstantinos Lazaridis, Carl A. Anderson,
Michael F. Seldin, Chris Amos, Katherine Siminovitch
134
DNA Methylation Profiling of the X Chromosome in Pri-
mary Biliary Cirrhosis
Ana Lleo2, Ming Zhao3, Yixin Tan3, Francesca Bernuzzi2, Bochen
Zhu3, Qiqun Tan3, Tingting Jiang3, Lina Tan3, Wei Liao3, Maria F.
Donato4, Federica Malinverno4, Luca Valenti5, Edoardo A. Pulixi5,
Pietro Invernizzi2,5, Quiajin Lu3, M. Eric Gershwin1; 1Internal Medi-
cine, University of California, Davis, CA; 2Liver Unit and Center for
Autoimmune Liver Diseases, Humanitas Clinical and Research Cen-
ter, Rozzano, Italy; 3Department of Dermatology, The 2nd Xiangya
Hospital, Central South University, Chansha, China; 4Migliavacca
Center for the Study of Liver Disease, 1st Division of Gastroenterol-
ogy, Milan, Italy; 5Internal Medicine, Fondazione Istituto di Ricov-
ero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda - Ospedale
Maggiore Policlinico Milano, Milan, Italy
Although the etiology of primary biliary cirrhosis (PBC) remains
enigmatic, there are several pieces of data supporting a strong
genetic predisposition followed by environmental interactions
that lead to a selective loss of tolerance. Moreover, the basis
for the female predominance in PBC is unknown. However,
recent evidence suggests that aberrant epigenetic regulation
contributes to the genetic-environmental interactions as well as
to the female predisposition of PBC. In fact, there is pilot data
that further suggests that epigenetic alterations of the X chro-
mosome are at least partially responsible for the female bias
in PBC. In the study herein, we rigorously defined the X chro-
mosome methylation profile of CD4+, CD8+, and CD14+ cells
from 30 PBC patients and 30 controls using a genome-wide
approach. Each subject provided peripheral blood mononu-
clear cells and, thereafter, CD4, CD8, and CD14 subpopu-
lations were purified. Thence, genomic DNA was isolated,
sonicated, and immunoprecipitated for analysis of methylation.
Firstly, using groups of 10 PBC and 10 controls, the products
from the three lymphoid cell subpopulations were hybridized
to a custom tiled 4-plex array containing 27,728 CpG Islands
annotated by UCSC and 22,532 well-characterized RefSeq
promoter regions. Subsequently, using 20 additional patients
with PBC and 20 additional controls, bisulfite sequencing was
used for validation on this subsequent group of independent
samples. Finally, we also isolated RNA for detection of expres-
sion of selected genes (CXCR3, UBE2A and FUNDC2) by
RT-qPCR from all samples from the 30 patients with PBC and
the 30 controls. We report herein a striking demethylation of
265A
CXCR3 in CD4+ T cells in PBC. In addition, we note hyper-
methylation of UBE2A and FUNDC2 in CD8+ T cells, as well
as in the regulatory sequences on the X chromosome of the
CD4+ T cells in patients with PBC. These data reflect an intense
abnormal DNA methylation profiling on the X chromosome in
PBC lymphoid subpopulations. In conclusion, and including the
DNA demethylation of CXCR3, our results also emphasize a
potential role of CXCR3 in the natural history of PBC.
Disclosures:
The following people have nothing to disclose: Ana Lleo, Ming Zhao, Yixin Tan,
Francesca Bernuzzi, Bochen Zhu, Qiqun Tan, Tingting Jiang, Lina Tan, Wei Liao,
Maria F. Donato, Federica Malinverno, Luca Valenti, Edoardo A. Pulixi, Pietro
Invernizzi, Quiajin Lu, M. Eric Gershwin
135
Soluble adenylyl cyclase (sAC, ADCY10) regulates bile-
salt-induced apoptosis (BSIA) in human cholangiocytes:
a link to primary biliary cirrhosis (PBC)
Jung-Chin Chang, Simei Go, Coen C. Paulusma, Ulrich Beuers,
Ronald Oude Elferink; Tytgat Institute for Liver and Intestinal
Research, Academic Medical Center, Amsterdam, Netherlands
BACKGROUND AND AIM: The chloride/bicarbonate
exchanger (AE2, SLC4A2) generates a “bicarbonate
umbrella”, which maintains most bile salts in the deprotonated
state and minimizes the pro-apoptotic effect of their protonated,
hydrophobic counterpart. In primary biliary cirrhosis (PBC) AE2
is downregulated and we have previously demonstrated that
knockdown of AE2 sensitized the H69 cholangiocyte cell line
not only towards BSIA, but also to etoposide-induced apoptosis
(1). Hence, there might be yet another mechanism accounting
for the sensitization of Ae2-deficient cholangiocytes towards
pro-apoptotic agents. In fibroblasts from Ae2-/- mice we demon-
strated that intracellular bicarbonate accumulation increases
expression and activity of sAC, an evolutionarily conserved
enzyme that, in contrast to its transmembrane counterpart
(tmAC), is activated by bicarbonate and fine-tuned by calcium,
but not regulated by G-proteins or forskolin (2). On the basis
of these combined results we hypothesized that BSIA in the
H69 cholangiocyte cell line is regulated by sAC. METHODS:
The immortalized human cholangiocyte cell line H69 was used
to examine BSIA with caspase 3/7 activity as readout. Activ-
ity of sAC was inhibited with the specific inhibitors KH7 and
2-OH-estradiol. Knockdown was achieved with lentiviral vec-
tors harbouring short hairpin sequences. RESULTS: Apoptosis
induced with 750μM chenodeoxycholate (CDC) was inhibited
by sAC-inhibitors (by 74% and 84% for 50μM KH7 and 40μM
2-OH-estradiol, respectively). Apoptosis induced with 1mM
GCDC (sodium glycochenodeoxycholate) was similarly inhib-
ited by KH7. Chelating intracellular free calcium ([Ca2+]i) with
BAPTA reduced CDC-induced apoptosis by 80%, demonstrat-
ing that increased [Ca2+]i upon bile salt treatment is necessary
for apoptosis to take place. Knockdown of the mitochondrial
calcium uniporter, the principal transporter for mitochondrial
calcium buffering, sensitized H69 cholangiocytes to CDC- and
GCDC-induced apoptosis and this could be reversed by KH7
treatment, suggesting cytosolic sAC instead of mitochondrial
sAC is involved. Moreover, CDC-induced apoptosis was also
prevented by 88% and 52% when treated with forskolin or
dibutyryl-cAMP. CONCLUSION: BSIA in H69 cholangiocytes
is calcium-dependent. Inhibition of sAC prevents BSIA. Cyto-
solic sAC but not mitochondrial sAC is responsible for BSIA.
Our results suggest that cAMP from cytosolic sAC promotes
BSIA, whereas cAMP from tmAC protects against BSIA. These
results provide an important link between the observed down-
regulation of AE2 and increased apoptosis of cholangiocytes
266A AASLD ABSTRACTS
in PBC. (1)Hohenester et al. 2012 HEPATOLOGY 55:173 (2)
Mardones et al. 2008 JBC 283:12146
Disclosures:
Ulrich Beuers - Consulting: Intercept, Novartis; Grant/Research Support: Zam-
bon; Speaking and Teaching: Falk Foundation, Gilead, Roche, Scheringh, Zam-
bon
The following people have nothing to disclose: Jung-Chin Chang, Simei Go,
Coen C. Paulusma, Ronald Oude Elferink
136
New model to identify UDCA-treated primary biliary cir-
rhosis patients in need of additional therapy. Results of
an international follow-up study of 4119 patients
Willem J. Lammers1, Henk R. van Buuren1, Cyriel Y. Ponsioen2,
Harry L. Janssen3, Annarosa Floreani4, Gideon Hirschfield5,
Christophe Corpechot6, Marlyn J. Mayo7, Pietro Invernizzi8, Pier
Maria Battezzati9, Albert Pares10, Frederik Nevens11, Andrew K.
Burroughs12, Andrew Mason13, Kris V. Kowdley14, Mohamad
Imam15, Kirsten Boonstra2, Angela C. Cheung3, Teru Kumagi5,16,
Nora Cazzagon4, Irene Franceschet4, Palak J. Trivedi5, Raoul Pou-
pon6, Ana Lleo8, Llorenç Caballeria10, Giulia Pieri12, Keith D.
Lindor17, Bettina E. Hansen1; 1Erasmus University Medical Center,
Rotterdam, Netherlands; 2Dept of Gastroenterology and Hepatol-
ogy, Academic Medical Center, Amsterdam, Netherlands; 3Liver
Clinic, Toronto Western & General Hospital, University Health
Network, Toronto, ON, Canada; 4Department of Surgery, Oncol-
ogy and Gastroenterology, University of Padua, Padua, Italy;
5NIHR Biomedical Research Unit and Centre for Liver Research,
University of Birmingham, Birmingham, United Kingdom; 6Cen-
tre de Référence des Maladies Inflammatoires des VoiesBiliaires,
Hôpital Saint-Antoine, APHP, Paris, France; 7Digestive and Liver
diseases, UT Southwestern Medical Center, Dallas, TX; 8Liver Unit
and Center for Autoimmune Liver Diseases, Humanitas Clinical and
Research Center, Rozzano (MI), Italy; 9Department of Health Sci-
ences, Università degli Studi di Milano, Milan, Italy; 10Liver Unit,
Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Bar-
celona, Spain; 11Dept of Hepatology, University Hospitals Leuven,
KULeuven, Leuven, Belgium; 12The Sheila Sherlock Liver Centre,
The Royal Free Hospital, London, United Kingdom; 13Divison of
Gastroenterology and Hepatology, University of Alberta, Edmon-
ton, AB, Canada; 14Liver Center of Excellence, Digestive Disease
Institute, Virginia Mason Medical Center, Seattle, WA; 15Dept
Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN;
16Department of Gastroenterology and Metabology, Ehime Univer-
sity graduate School of Medicine, Ehime, Japan; 17Arizona State
University, Phoenix, AZ
Background Several biochemical criteria have been proposed
to assess the therapeutic response and long-term prognosis in
ursodeoxycholic acid (UDCA)-treated PBC. These criteria were
shown to have independent and additive predictive ability. This
study aimed to define a single, unifying criterion identifying
those patients at greatest need for second-line treatment. Meth-
ods Long-term follow-up data collected in 15 North American
and European centers were analysed using Cox proportional
hazard regression models to construct prediction models based
on numerous combinations of biochemical and clinical parame-
ters that were obtained after one year of treatment with UDCA.
The ability of these models to predict both liver transplanta-
tion-free survival and liver-related death or liver transplanta-
tion (LTx), was tested using c-statistic and Akaike Information
Criterion (AIC) and was compared with previously reported
response criteria. A predictive index (PI) was calculated based
on the beta coefficient of the final Cox regression model. Results
4119 UDCA-treated PBC patients were included. During a
mean follow-up time of 8.4 years 320 patients underwent liver
transplantation and 566 patients (269 liver related) died. In
HEPATOLOGY, October, 2014
the final multivariate model the following variables had the
best predictive performance: Age at entry (p=8.7*10-39), bili-
rubin (p=1.0*10-56), albumin (p=7.0*10-14) and AST/plate-
lets ratio (APRI) (p=1.8*10-20). Survival for patients with a PI
<50th percentile was comparable to that of an age-, sex- and
calendar time-matched Dutch population (5-yr: 98% vs 98%
and 10-yr: 94% vs 95% respectively, p=0.07). For patients
with a PI ≥50th percentile survival was worse compared to a
matched population (5-yr: 90% vs 94%, 10-yr: 75% vs 86%
respectively, p<8.0*10-16). The prognostic utility of this model
was superior to that of previously reported response criteria
and was satisfactory in specific subgroups (Table). Conclusion
This new composite model, based on age, bilirubin, albumin
and APRI, represents an improved clinical tool for identifying
patients with an insufficient therapeutic response after one year
of UDCA treatment. The prognosis of patients with a PI ≥50th
percentile deviates from that of a matched general Dutch pop-
ulation. Such patients may be candidates for additional treat-
ment.
Comparative performance of PBC predictive index
1. all-cause mortality and LTx 2. liver-related death and LTx
Disclosures:
Cyriel Y. Ponsioen - Consulting: AbbVIE; Grant/Research Support: AbbVIE, Sch-
ering Plough, Dr. Falk Pharma, Tramedico Netherlands
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sci-
ences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support:
Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck,
Medtronic, Novartis, Roche, Santaris
Marlyn J. Mayo - Grant/Research Support: Intercept, Salix, NGM, Lumena,
Gilead
Albert Pares - Consulting: Lumena Pharmaceuticals
Frederik Nevens - Consulting: CAF, Intercept, Gore, BMS, Abbvie, Novartis,
MSD, Eumedica, Janssen; Grant/Research Support: Ipsen, Roche, MSD, Astellas
Kris V. Kowdley - Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research
Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria,
Janssen, Merck, Mochida, Vertex
Palak J. Trivedi - Grant/Research Support: Wellcome Trust
The following people have nothing to disclose: Willem J. Lammers, Henk R. van
Buuren, Annarosa Floreani, Gideon Hirschfield, Christophe Corpechot, Pietro Inv-
ernizzi, Pier Maria Battezzati, Andrew K. Burroughs, Andrew Mason, Mohamad
Imam, Kirsten Boonstra, Angela C. Cheung, Teru Kumagi, Nora Cazzagon, Irene
Franceschet, Raoul Poupon, Ana Lleo, Llorenç Caballeria, Giulia Pieri, Keith D.
Lindor, Bettina E. Hansen
137
The Impact of Age at Presentation on Symptoms in Pri-
mary Biliary Cirrhosis
Jessica K. Dyson1, Laura Griffiths2, Samantha J. Ducker2, George
F. Mells3, Richard N. Sandford3, David Jones1,2; 1Liver Unit, Free-
man Hospital, Newcastle upon Tyne, United Kingdom; 2Institute of
Cellular Medicine, Newcastle University, Newcastle upon Tyne,
United Kingdom; 3Academic Department of Medical Genetics,
University of Cambridge, Cambridge, United Kingdom
Background Primary Biliary Cirrhosis (PBC) causes clinical
impact both through progression to advanced liver disease
and the impact of increasingly well characterised symptoms.
The UK-PBC Study has shown that a significant proportion of
patients present before age 50 (25% at 49 or younger) and
that disease characteristics appear to be different in younger
patients. Methods Observational study of patients recruited to
the UK-PBC Research Cohort consisting of prevalent patients
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS 267A

between January 2008-December 2011 with a diagnosis of taxonomic units using Uparse and analysed using Qiime and
PBC. Patients underwent comprehensive symptom assessment the Vegan package in R. Results: We identified little difference
measures: PBC-40 (disease-specific quality of life (QoL) mea- in richness and complexity (Simpson’s index) of the microbiota
sure), Epworth Sleepiness Scale (ESS), Orthostatic Grading between conditions. However an analysis of variance showed
Scale (OGS), Hospital Anxiety and Depression Scale (HADS), a significant difference in the composition of the microbiota
and Pruritus visual analogue scale (VAS). Results The study between conditions, irrespective of biopsy site (p = 0.001).
cohort includes 2353 patients with 90.6% females and median This was confirmed by constrained ordination, which resulted
age at diagnosis 55 years (range 16–86). For analysis, the in clear separation between the three groups (Fig 1). However
cohort was divided into younger (<50 years) and older (>60 there was no difference in microbiota between sites. Indeed
years) patients. Frequency of very poor or poor perceived over- sites from the same patient were highly similar and clustered
all QoL was significantly higher in younger than older present- together. PSC-IBD and IBD showed reduced levels of Prevotella
ing patients (41% vs 26%, Chi Square (CS) 54.2, p<0.0001). and Roseburia (a butyrate producer). PSC-IBD patients showed
All symptom severity scores were significantly higher in young a near complete absence of Bacteroides compared to IBD and
presenting patients. Younger patients with poor QoL had sig- controls and significant increases in Escherichia, Lachnospira-
nificantly more symptom domains showing clinically significant ceae and Megasphera. Conclusions: We demonstrate that the
abnormality (CS 18.1, p<0.0005). In terms of extreme symp- gut-adherent microbiota in patients with PSC-IBD, IBD and con-
tom load, 27% of <50 year old patients with poor QoL had trols are significantly different, independent of site of biopsy.
between 8 and 10 (the maximum possible) significant symptom This supports PSC-IBD as a distinct entity, and one for which
domain scores compared with 16% of the over 60s with poor further microbiota based studies are important.
QoL. In contrast to symptom load, UDCA non-response did not
Figure 1: PCA plot demonstrating differences in microbiota in dis-
predict poor QoL in either age group (>60 years: CS 2.4, OR
ease groups (p = 0.001)
1.68 (0.9-3.2), p=0.12; <50 years: CS 1.1, OR 1.3 (0.7-2.1),
p=0.3). Social dysfunction symptoms were a particularly dis-
criminating feature in young patients with poor QoL compared
to good QoL (OR for association between QoL status and social
symptom status 423 [95% CI 58-3078], p<0.0001). Amongst
younger patients with poor QoL, social dysfunction symptoms
correlated particularly strongly with depression, fatigue and
cognitive symptoms (r=0.67, 0.56, and 0.8 respectively, all
p<0.0001). Discussion The UK-PBC Study has shown that there
are marked phenotypic differences in PBC patients presenting
at a younger age with worse perceived QoL and significantly
increased symptom burden. Social dysfunction symptoms are a
specific feature of younger patients and associate strongly with
depression, fatigue and cognitive symptoms. Offering psycho-
logical support and targeting specific symptoms in young PBC
patients offer a potential approach to life quality improvement.
Disclosures:
Richard N. Sandford - Advisory Committees or Review Panels: Otsuka; Grant/
Research Support: Intercept
David Jones - Consulting: Intercept
The following people have nothing to disclose: Jessica K. Dyson, Laura Griffiths,
Samantha J. Ducker, George F. Mells

Disclosures:

138 Palak J. Trivedi - Grant/Research Support: Wellcome Trust

Probing the microbiota in PSC: the gut adherent micro- James W. Ferguson - Advisory Committees or Review Panels: Astellas, Novartis

biota of PSC-IBD is distinct to that of IBD and controls The following people have nothing to disclose: Mohammed Nabil Quraishi, Mar-
tin Sergeant, Gemma L. Kay, Tariq Iqbal, Chrystala Constantinidou, Jacqueline
Mohammed Nabil Quraishi1,2,
Martin Sergeant2,
Gemma L. Kay2, Z. Chan, David H. Adams, Mark J. Pallen, Gideon Hirschfield
Tariq Iqbal3, Chrystala Constantinidou2, Jacqueline Z. Chan2,
Palak J. Trivedi1, James W. Ferguson1, David H. Adams1, Mark J.
Pallen2, Gideon Hirschfield1; 1Centre for Liver Research and NIHR
Biomedical Research Unit, University of Birmingham, Birmingham,
United Kingdom; 2Division of Microbiology and Infection, Uni-
versity of Warwick, Coventry, United Kingdom; 3Department of
Gastroenterology, Queen Elizabeth Hospital Birmingham, Birming-
ham, United Kingdom
Background: The pathophysiology of PSC remains unclear, but
a close association with IBD is overt. We sought to document
changes in the gut microbiota in PSC and IBD by characteris-
ing gut adherent bacteria in patients with PSC and IBD, IBD
alone and healthy controls. Methods: We collected pan-co-
lonic biopsy samples from 9 controls, 10 IBD and 11 PSC-IBD
patients, undergoing colonoscopy. Gut microbiota were char-
acterised using 16s rRNA based analysis of the V3 - V4 region
(Illumina MiSeq). The sequences were clustered into operational
268A AASLD ABSTRACTS
139
Clinical characteristics and outcomes of acute alcoholic
hepatitis–early report from the Translational Research
and Evolving Alcoholic hepatitis Treatment (TREAT) con-
sortium
Suthat Liangpunsakul1, Vijay Shah2, Arun J. Sanyal3, Barry P.
Katz4, Patrick S. Kamath2, Puneet Puri3, Megan Comerford1,
Behnam Saberi2, Zhangsheng Yu4, Xiaowei Ren4, Naga P.
Chalasani1, David W. Crabb1, Svetlana Radaeva5; 1Division of
Gastroenterology/Hepatology, Department of Medicine, Indiana
University School of Medicine (IU), Indianapolis, IN; 2Division
of Gastroenterology and Hepatology, Department of Medicine,
Mayo Clinic, Rochester, MN; 3Division of Gastroenterology and
Hepatology, Department of Medicine, Virginia Commonwealth
University (VCU), Richmond, VA; 4Department of Biostatistics,
Indiana University, Indianapolis, IN; 5Division of Metabolism and
Health Effects, National Institute on Alcohol Abuse and Alcoholism,
NIH, Bethesda, MD
Background: The TREAT consortium, consisting of investigators
from IU, Mayo Clinic, and VCU, is funded by the NIAAA. One
of its objectives is to conduct a prospective study of patients
with acute alcoholic hepatitis (AH) and heavy drinkers without
liver disease to better characterize their clinical characteristics/
outcomes. Aim: To describe clinical characteristics and out-
comes of the cases with AH compared to controls. Methods:
AH cases were defined as those with average alcohol con-
sumption >40 g/d (women) and >60 g/d (men) for at least
6 Mos and <6 wks before enrollment, and labs showed total
bilirubin (TB)>2 mg/dL and AST>50 U/L. Controls were age,
gender, and race-matched heavy drinkers with the amount/
duration of drinking similar to those with AH, but with normal
TB, AST and ALT. Time Line Follow-Back was used to quan-
tify the amount of alcohol consumed over the 30-day period
before enrollment. Subjects were prospectively followed for
up to one year. The difference between groups was analyzed
using chi-square/Student’s t-test. Results: Between 5/2013 and
5/2014, 66 cases (age 47±18 yrs,58% men and 88% White)
and 40 controls (age 43±12 yrs,63% men and 80% White)
were enrolled. The median levels of alcohol consumption (g/
drinking day) in cases and controls were 100 (range 14-596)
and 218 (range 46-822), p < 0.001. Baseline lab values are
shown below. AH cases had higher MELD scores and WBC but
lower serum protein, albumin,and platelets. 33 AH cases had
baseline MELD score > 20. Ten AH cases (17%) died during
follow up from multi-organ failure(6), sepsis(2), fall(1), and
motor vehicle accident(1). All deaths were those with MELD
scores > 20. The overall mortality in cases with MELD > 20
was 30% with 1- and 3-month mortality at 9.3% and 24%,
respectively, despite standard of care including steroid and/
or pentoxifylline. Summary: Patients with AH carry significant
risk of mortality despite receiving treatment with steroids and/
or pentoxifylline but this risk appears to be exclusively limited
to those with MELD > 20.
Disclosures:
HEPATOLOGY, October, 2014
Arun J. Sanyal - Advisory Committees or Review Panels: Bristol Myers, Gilead,
Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Nimbus, Genentech, Echo-
sens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept,
Ikaria, Takeda, GalMed, Novartis, Gilead; Independent Contractor: UpToDate,
Elsevier
Patrick S. Kamath - Advisory Committees or Review Panels: Sequana Medical
Puneet Puri - Advisory Committees or Review Panels: Health Diagnostic Labora-
tory Inc.; Consulting: NPS Pharmaceuticals Inc.
Naga P. Chalasani - Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-
rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin
The following people have nothing to disclose: Suthat Liangpunsakul, Vijay Shah,
Barry P. Katz, Megan Comerford, Behnam Saberi, Zhangsheng Yu, Xiaowei Ren,
David W. Crabb, Svetlana Radaeva
140
Combinative use of baseline and dynamic models in
patients with severe alcoholic hepatitis: Prediction of
death as a continuum in risks of mortality
Alexandre Louvet1,2, Julien Labreuche3, Florent Artru1,2, Jerome
Boursier4, John G. O’Grady5, Robert L. Carithers6, Sylvie
Naveau7, Emmanuel Diaz8, Guillaume Lassailly1,2, Amélie Can-
nesson1,2, Valerie Canva-Delcambre1, Sébastien Dharancy1,2, Tim-
othy R. Morgan9, Alain Duhamel3, Philippe Mathurin1,2; 1Service
des maladies de l’appareil digestif, Hôpital Huriez, Lille, France;
2Unité 995, INSERM, Lille, France; 3Unité de Biostatistiques, CHRU
de Lille, Lille, France; 4Service d’hépato-gastroentérologie, CHU
d’Angers, Angers, France; 5Liver Unit, King’s College Hospital,
London, United Kingdom; 6Veterans Affairs, Puget Medical Cen-
tre, Seattle, WA; 7Service d’hépato-gastroentérologie, Hôpital
Antoine-Béclère, Clamart, France; 8Service d’hépato-gastroentérol-
ogie, Hôpital Germon et Gauthier, Béthune, France; 9Veterans
Affairs, Long Beach, CA
The classical prediction of prognosis of patients with severe
alcoholic hepatitis (AH) relies on the single use of baseline or
dynamic models. A new concept may consist in combining the
two types of models to assess outcome as a continuum in proba-
bilities of death. Methods: Using data from patients with severe
alcoholic hepatitis (Maddrey DF≥32) treated with steroids, we
combined baseline (DF or MELD score) and on-treatment (Lille
score) models. Results: 897 patients were included: age 50.6
years, 58.5% of males, bilirubin 156 mmol/l, prothrombin time
20.2 s, creatinin 8 mg/l, DF 55, MELD 25.2, Lille model 0.34.
Six-month survival was 64.1%. The relationship between Lille
score and 6-month survival was linear whereas it was nonlinear
between DF and survival with a threshold at a DF of 90. Using
a Cox regression model, we built-up contour lines, to assess
the probability of survival using DF at day 0 and Lille model
at day 7 (Figure, top). As an example, a patient admitted with
a DF at 100 with a Lille model at day 7 of 0.25 has a proba-
bility of survival of 73% at 6 months, which drops to 27.7% if
Lille model is 0.7. The likelihood of the joint-effect model was
improved in comparison to a model based only on Lille model
(p=0.016). We conducted a second analysis Lille-MELD on a
subgroup of 638 patients for whom MELD score was available
(Figure, bottom). The efficacy of the joint-effect model was also
better as compared to each model alone (p<0.001). As an
example, a patient admitted with a MELD score at 28 with a
Lille model of 0.25 has a probability of survival of 73% at 6
months, which drops to 30.3% if Lille model is 0.7. Conclusion:
The present study stratifies the risk of death in AH, based on
severity status at admission and evolution upon therapy. Such
approach results in a balanced evaluation instead of giving a
yes/no Manichean prediction of death aiming to define a new
therapeutic strategy.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Disclosures:
John G. O’Grady - Advisory Committees or Review Panels: Astellas, Novartis;
Speaking and Teaching: Astellas, Roche
Sébastien Dharancy - Board Membership: NOVARTIS; Speaking and Teaching:
ROCHE, ASTELLAS
Timothy R. Morgan - Grant/Research Support: Merck, Vertex, Genentech, Gil-
ead, Bristol Myers Squibb
Philippe Mathurin - Board Membership: Schering-Plough, Janssen-Cilag, BMS,
Gilead, Abvie; Consulting: Roche, Bayer, Boehringer
The following people have nothing to disclose: Alexandre Louvet, Julien
Labreuche, Florent Artru, Jerome Boursier, Robert L. Carithers, Sylvie Naveau,
Emmanuel Diaz, Guillaume Lassailly, Amélie Cannesson, Valerie Canva-Delcam-
bre, Alain Duhamel
269A
141
Impact of intensive enteral nutrition in association with
corticosteroids in the treatment of severe alcoholic hepa-
titis: a multicenter randomized controlled trial
Christophe Moreno1,2, Eric Trépo1,2, Alexandre Louvet3, Delphine
Degré1,2, Boris Bastens4, Axel Hittelet5, Marie-Astrid Piquet6,
Wim Laleman7, Hans Orlent8, Luc Lasser9, Thomas Sersté10,
Peter Starkel11, Xavier Dekoninck12, Sergio Negrin Dastis13,
Jean Delwaide14, Isabelle Colle15, Chantal de Galocsy16, Sven
M. Francque17, Philippe Langlet18, Virginie Putzeys19, Hendrik
Reynaert20, Thierry Gustot1,2, Pierre Deltenre21,22; 1Department of
Gastroenterology, Hepatopancreatology and Digestive oncology,
CUB Hôpital Erasme, Brussels, Belgium; 2Laboratory of Experi-
mental Gastroenterology, Université Libre de Bruxelles, Brussels,
Belgium; 3Service des maladies de l’appareil digestif, Hôpital
Huriez, Lille, France; 4Department of Gastroenterology, Hôpital
Saint-Joseph, Liège, Belgium; 5Department of Gastroenterology,
Hôpital Ambroise Paré, Mons, Belgium; 6Service d’Hépatogastro-
entérologie, CHU de Caen, Caen, France; 7Department of Liver
and Biliopancreatic disorders, University Hospitals Leuven, Leuven,
Belgium; 8Department of Gastroenterology and Hepatology, AZ
St Jan, Brugge, Belgium; 9Department of Hepatogastroenterology,
CHU Brugmann, Brussels, Belgium; 10Department of Hepatogas-
troenterology, CHU Saint-Pierre, Brussels, Belgium; 11Department
of Gastroenterology, Cliniques universitaires Saint-Luc, Brussels,
Belgium; 12Department of Gastroenterology, Hôpital Saint-Pierre,
Ottignies, Belgium; 13Department of Gastroenterology, Hôpital
Saint-Joseph, Warquignies, Belgium; 14Department of Hepatogas-
troenterology, CHU Sart Tilman, Liège, Belgium; 15Department of
Hepatogastroenterology, Ghent University Hospital, Ghent, Bel-
gium; 16Department of Gastroenterology, Hôpitaux Iris Sud, Brus-
sels, Belgium; 17Department of Gastroenterology and Hepatology,
University Hospital Antwerp, Edegem, Belgium; 18Department of
Gastroenterology, CHIREC, Brussels, Belgium; 19Department of
Gastroenterology, CHR La Citadelle, Liège, Belgium; 20Department
of Hepatogastroenterology, UZ Brussel, Brussels, Belgium; 21Ser-
vice d’Hépato-Gastroentérologie, Hôpital de Jolimont, Haine-Saint-
Paul, Belgium; 22Service de Gastroentérologie et d’Hépatologie,
Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Introduction. Severe alcoholic hepatitis (AH) is associated with
a high risk of short-term mortality. Although adequate nutritional
support is recommended in these patients, the recommended
protein-caloric intake is often difficult to achieve orally in this
population. Our objective was to evaluate the impact of inten-
sive enteral nutrition in addition to steroid therapy on 6-month
survival in patients with severe AH. Methods. This multicenter
randomized, controlled trial was performed in 18 Belgian and
2 French hospitals. Two groups were included: 1) intensive
enteral nutrition and methylprednisolone (intensive group)
or 2) conventional nutrition and methylprednisolone (control
group). In the intensive group, enteral nutrition was given using
a feeding tube for 14 days and patients received Fresubin HP
Energy® (1.5 kcal/ml, 7.5 g prot/100 ml) as it follows: 1L/
day if body weight (BW) < 60 kgs, 1.5L if BW between 60
and 90 kgs, 2L if BW>90 kgs. Nutrition intake was recorded
for 14 days in both groups. Results. A total of 136 patients
with a severe biopsy-proven AH (Maddrey discriminant func-
tion [mDF] ≥ 32) were randomized, 68 in each group. At
baseline, there were no significant difference between the two
groups (intensive vs. control) for age (49.5±8.7 vs. 51.5±8.6),
male gender (69.1 vs. 58.8%), bilirubin (13.3 [8.9-23.5] vs.
11.9 [6.9-21.5] mg/dL), INR (1.8 [1,6-2.1] vs. 1,8 [1.6-2.1]),
mDF (52.3 [40.9-70.2] vs. 54 [42-68.5]) and MELD score
(22.8 [21.4-26.3] vs. 22.4 [20.2-25.1]). Mean kcal intake
was 2206±754 vs. 1754±656 kcal/day (p=0.001) and mean
protein intake was 106±37 vs. 80±32 g/day (p<0.001). In
270A AASLD ABSTRACTS
intention-to-treat (ITT) analysis, 6-month survival was not sta-
tistically different between the two groups: 55.9 vs. 47.0%
(p=0.316). In the intensive group, 43/68 (63.2%) patients
received at least 80% of the planned kcal intake defined by
the protocol, and were considered in the per-protocol analysis.
In per-protocol analysis, 6-month survival was higher in the
intensive group: 69.8 vs. 46.8% (p=0.015). In addition, mean
kcal intake/kg/day > 26.4 (median value) was associated
with a higher 6-month survival (68.3 vs. 42.4%, p=0.002).
In ITT multivariable analysis, a mean kcal intake/kg/day >
26.4, baseline mDF, serum sodium, MELD and the Lille scores
remained independently associated with 6-month survival. Con-
clusions. Intensive enteral nutrition by feeding tube does not
improve 6-month survival in patients with severe AH. However,
adequate nutritional support is associated with a better short-
term prognosis. Adequate nutritional intake should be targeted
in AH patients treated with corticosteroids.
Disclosures:
Christophe Moreno - Consulting: Abbvie, Janssen, Gilead, MSD, Novartis, BMS;
Grant/Research Support: Janssen, Gilead, Roche, MSD, Novartis, Astellas
Isabelle Colle - Advisory Committees or Review Panels: MSD, Janssen, MSD, Gil-
ead; Grant/Research Support: Bayer; Patent Held/Filed: Trombogenics; Speak-
ing and Teaching: BMS, Janssen
Hendrik Reynaert - Advisory Committees or Review Panels: MSD, Gillead, Jans-
sen, BMS, Abbvie; Grant/Research Support: Roche
Pierre Deltenre - Consulting: Janssen, Gilead, BMS
The following people have nothing to disclose: Eric Trépo, Alexandre Louvet,
Delphine Degré, Boris Bastens, Axel Hittelet, Marie-Astrid Piquet, Wim Laleman,
Hans Orlent, Luc Lasser, Thomas Sersté, Peter Starkel, Xavier Dekoninck, Sergio
Negrin Dastis, Jean Delwaide, Chantal de Galocsy, Sven M. Francque, Philippe
Langlet, Virginie Putzeys, Thierry Gustot
142
The soluble mannose receptor (sCD206) is highly
elevated in alcoholic liver disease, predicts clinical
endpoints and correlates with macrophage activation
marker sCD163
Thomas D. Sandahl, Sidsel Støy, Sidsel Rødgaard-Hansen, Holger
J. Møller, Henning Grønbæk, Hendrik V. Vilstrup; Medicine V
(Hepatology and Gastroenterology), Aarhus University Hospital,
Aarhus, Denmark
Background: Macrophage activation plays and important role
in alcoholic liver disease (ALD). The mannose receptor (CD206,
MR, MRC1), expressed primarily by subsets of macrophages
and dendritic cells, is known to mediate endocytosis, antigen
presentation, and induction of immune responses. A soluble
form (sCD206, sMR,) has recently been identified in human
serum. Aim: To study blood sCD206 and its correlation with
clinical endpoints and macrophage activation marker sCD163
in patients with alcoholic liver disease. Methods: We included
49 patients with alcoholic hepatitis (AH), 80 alcoholic cirrhosis
(AC) patients (Child-Pugh CP-A:n=26, CP-B:n=28, CP-C:n=26)
and 21 healthy controls (HC). The liver status was described by
the Child-Pugh, MELD & GAHS -scores. In the cirrhosis patients
we conducted liver vein catheterisations with measurement of
the hepatic venous pressure gradient (HVPG) and at the same
time measured blood concentrations of sCD206, sCD163.
Short term survival data (84-days) was collected for AH patients
and long term (4 years) for AC patients. The Kaplan Meier
method was used for survival analysis. Results: The sCD206
concentration was markedly increased in ALD (AH 1.32, AC
0.44, HC 0.20 mg/L; p<0.002). sCD206 increased in a step-
wise manner with the CP-score (p<0.001). sCD206 correlated
positively with sCD163 in both cirrhosis (p>0.0001, r=0.6)
and AH patients (p>0.0001, r=0.6). In AC, Receiver Operator
Characteristics (ROC) analysis showed sCD206 were able to
predict portal hypertension (HVPG ≥ 10 mmHg) with an area
HEPATOLOGY, October, 2014
under the ROC curve of 0.87. In AC, patients with a high
level of sCD206 (>0.43 mg/l) had a higher mortality rate than
patients with a low level of sCD206 (p=0.02). Conclusion:
The soluble mannose receptor sCD206 is highly elevated in
alcoholic liver disease, especially in patients with alcoholic
hepatitis, and correlates strongly with the macrophage acti-
vation marker sCD163. sCD206 predicts portal hypertension
and long term mortality in cirrhosis patients but not short term
AH mortality.
Disclosures:
Holger J. Møller - Grant/Research Support: Danish Council for Strategic
Research; Independent Contractor: IQ-Products, NL; Patent Held/Filed: Aarhus
University; Stock Shareholder: Affinicon Aps
Henning Grønbæk - Advisory Committees or Review Panels: Novartis; Grant/
Research Support: NOVO Nordisk; Speaking and Teaching: Eli Lilly, Ipsen
The following people have nothing to disclose: Thomas D. Sandahl, Sidsel Støy,
Sidsel Rødgaard-Hansen, Hendrik V. Vilstrup
143
High-mobility group box-1 participates in the pathogen-
esis of alcoholic liver disease
Xiaodong Ge1, Daniel J. Antoine2, Yongke Lu1, Elena Arriazu1,
Tung Ming Leung1, Arielle L. Klepper1, Andrea D. Branch1, M. Isa-
bel Fiel3, Natalia Nieto1; 1Division of Liver Diseases, Icahn School
of Medicine at Mount Sinai, New York, NY; 2MRC Centre for
Drug Safety Science, Molecular and Clinical Pharmacology, the
University of Liverpool, Liverpool, United Kingdom; 3Department of
Pathology, Icahn School of Medicine at Mount Sinai, New York,
NY
Background & Aim: Growing clinical and experimental evi-
dence suggests that sterile inflammation contributes to alcoholic
liver disease. High-mobility group box-1 (HMGB1) is highly
induced during liver injury; yet, a link between this alarmin
and alcoholic liver disease has not been established. Thus,
the aim of this work was to determine whether HMGB1 con-
tributes to the pathogenesis of alcoholic liver disease. Results:
Liver biopsies from patients with alcoholic liver disease showed
a robust increase in HMGB1 expression and translocation,
which correlated with disease stage, compared to healthy
explants. Similar findings were observed in three mouse mod-
els of alcoholic liver disease. Using primary cell culture, we
validated the ability of hepatocytes from ethanol-fed mice or of
hepatocytes treated with ethanol to secrete a large amount of
HMGB1. Secretion was time- and dose-dependent under etha-
nol treatment and responsive to prooxidants and antioxidants.
Selective ablation of Hmgb1 in hepatocytes protected from
alcohol-induced liver injury in mice due to increased carnitine
palmitoyltransferase-1, phosphorylated 5’AMP-activated pro-
tein kinase-α and phosphorylated peroxisome proliferator-ac-
tivated receptor-α expression along with elevated low-density
lipoprotein and very low-density lipoprotein export. Native and
post-translationally modified HMGB1 were detected in human
and in mice with alcoholic liver disease. In liver and in serum
from control mice and in serum from healthy volunteers, the
lysine residues within the peptides containing nuclear localiza-
tion signals-1 and 2 were non-acetylated and all cysteine resi-
dues were reduced. However, in livers from ethanol-fed mice,
in addition to all thiol/non-acetylated isoforms of HMGB1, we
observed acetylated nuclear localization signals-1 and 2, a
unique phosphorylation site in serine 35 and an increase in
oxidation of HMGB1 to the disulfide isoform. In serum from
ethanol-fed mice and from patients with alcoholic liver dis-
ease there was disulphide bonded hyper-acetylated-HMGB1,
disulphide bonded non-acetylated-HMGB1 and HMGB1 phos-
phorylated in serine 35. Hepatocytes appeared to be a major
source of these HMGB1 isoforms. Conclusion: Hepatocyte
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
HMGB1 participates in the pathogenesis of alcoholic liver dis-
ease and undergoes post-translational modifications that could
condition its toxic effects.
Disclosures:
Andrea D. Branch - Grant/Research Support: Kadmon, Gilead, Janssen
The following people have nothing to disclose: Xiaodong Ge, Daniel J. Antoine,
Yongke Lu, Elena Arriazu, Tung Ming Leung, Arielle L. Klepper, M. Isabel Fiel,
Natalia Nieto
144
Nogo-B (Reticulon B) in Kupffer cells promotes alco-
hol-induced hepatic steatosis
Jin-Kyu Park, Teruo Utsumi, Yirang Jung, Yasuko Iwakiri; Internal
Medicine, Section of Digestive Diseases, Yale University School of
Medicine, New Haven, CT
Background: Chronic alcohol consumption leads to hepatic ste-
atosis. The molecular mechanisms of lipid accumulation have
been primarily investigated in hepatocytes, while the roles
of neighboring cells in this process have been less explored.
Nogo-B (a.k.a., Reticulon 4B) is an endoplasmic reticulum res-
ident protein and plays important roles in pathological con-
ditions in various tissues. In the liver, Nogo-B is expressed
in non-parenchymal cells including Kupffer cells, but not in
hepatocytes, and promotes liver fibrosis. Given that Kupffer
cells play a role in hepatic steatosis in a paracrine manner,
we hypothesize that Nogo-B may contribute to ethanol-in-
duced steatosis by modulating Kupffer cell function. Methods:
Wild-type (WT) or Nogo-B knockout (KO) mice were fed with
control or Lieber-DeCarli ethanol liquid diets (5% ethanol) for
6 weeks. Lipopolysaccharide (LPS) was injected intraperito-
neally 9 hours before sample collection. For in vitro studies,
Kupffer cells were isolated from WT and KO mice and treated
with 0 or 100 mM ethanol in the presence or absence of
LPS. Results: Lipid accumulation was significantly reduced in
livers of Nogo-B KO mice fed with ethanol diet, compared
to WT mice (hepatic triglyceride levels: 10+/-2 vs. 28+/-4
mg/g liver, p<0.01; steatosis score: 0.8+/-0.1 vs. 2.0+/-0.3,
p<0.05). A histological score showed a trend toward reduced
inflammation in KO livers, compared to WT livers (p=0.07),
and was associated with decreased infiltration of neutrophils
(p<0.05) and lower tumor necrosis factor alpha (TNFα) expres-
sion (p=0.05) in KO livers. Consistently, in Nogo-B KO mice
fed ethanol, expression of M2-type macrophage markers, such
as MRC2, CD163 and IL10, was significantly up-regulated
(p<0.05), compared to WT mice. In vitro, Kupffer cells isolated
from Nogo-B KO mice demonstrated significantly decreased
inducible nitric oxide (iNOS), interleukin 1beta (IL1β) and TNFα
expression in response to ethanol/LPS (p<0.05), all of which
are known as NFkB response genes. Interestingly, KO Kupffer
cells decreased translocation of p65 protein (an active form
of NFkB) to the nucleus, compared to WT Kupffer cells, sug-
gesting that Nogo-B may regulate NFkB activity in response
to ethanol. Conclusion: These results indicate that Nogo-B pro-
motes alcohol-induced hepatic steatosis by modulating Kupffer
cell function. Given that iNOS, IL1β and TNFα are known to
enhance hepatic lipid accumulation, Nogo-B might exert this
role by increasing release of these cytokines from Kupffer cells
through its regulation of NFkB activity. Specific deletion of
Nogo-B in Kupffer cells may be a therapeutic potential for alco-
hol-induced steatosis/steatohepatitis.
Disclosures:
The following people have nothing to disclose: Jin-Kyu Park, Teruo Utsumi, Yirang
Jung, Yasuko Iwakiri
271A
145
Development and Characterization of Induced Pluripo-
tent Stem Cell-Derived Cholangiocytes
Thiago de Assuncao1, Yan Sun1, Bing Q. Huang1, Yasuhiro
Ikeda2, Robert C. Huebert1; 1Gastroenterology and Hepatology,
Mayo Clinic, Rochester, MN; 2Biochemistry and Molecular Biol-
ogy, Mayo Clinic, Rochester, MN
Background. Cholangiocytes, the specialized epithelial cells
that line the intra- and extra-hepatic bile ducts, are the target
of a heterogeneous group of liver diseases, known as the chol-
angiopathies. While hepatocyte transplantation is being exten-
sively studied in the context of liver failure and metabolic liver
disease, cell-based therapy for biliary disease has not been
explored. A new understanding of the mechanisms driving bil-
iary development has provided the theoretical underpinnings
for the rational development of induced pluripotent stem cell
(iPSC)-derived cholangiocytes (iDCs). Therefore, the purpose
of this study was to develop an approach to generate iDCs
and to fully characterize the cells in vitro and in vivo. Meth-
ods and Results. Normal human iPSC lines were generated
by forced expression of the Yamanaka pluripotency factors
OCT4, SOX2, KLF4, and c-MYC. We then pursued a step-wise
differentiation strategy toward iDCs using a process of precise
temporal exposure to key biliary morphogens (including Activin
A, Wnt3A, fibroblast growth factor 2, bone morphogenic
protein 2, sonic hedgehog, Notch ligands, and transforming
growth factor beta). Morphologic analysis of the cells shows
a stepwise phenotypic change toward an epithelial monolayer
and scanning electron microscopy demonstrates the presence
of primary cilia, known to be present on cholangiocytes but
not hepatocytes. Molecular analysis at various stages of differ-
entiation shows appropriate enrichment in markers of iPSCs,
definitive endoderm, hepatic specification, hepatic progenitor
cells, and ultimately cholangiocytes. Immunostaining for the bil-
iary-specific cytokeratins, CK7 and CK19, shows uniform and
strong staining. RT-PCR shows robust mRNA expression of mul-
tiple biliary markers including AE2, EPCAM, and PKD2. iDCs
also have low expression of progenitor and hepatocyte mark-
ers such as HNF4, ABCB4, albumin, and alpha-fetoprotein.
Western blotting demonstrates robust enrichment of multiple
functionally relevant biliary proteins in iDCs including α-tubu-
lin, AQP1, ASBT, and SSTR2. In 3-dimensional culture, iDCs
self-assemble into duct-like structures within a collagen matrix.
In vivo, the cells engraft within existing mouse bile ducts follow-
ing retrograde intrabiliary infusion. Conclusion. In summary,
we have developed a novel approach to generate cholangio-
cytes from iPSCs. In addition to providing mechanistic insights
about biliary differentiation, iDCs provide a platform for in
vitro disease modelling as well as individualized, cell-based,
regenerative therapies for the cholangiopathies.
Disclosures:
The following people have nothing to disclose: Thiago de Assuncao, Yan Sun,
Bing Q. Huang, Yasuhiro Ikeda, Robert C. Huebert
272A AASLD ABSTRACTS
146
Liver progenitor cells are derived from mature hepato-
cytes
Branden Tarlow2,1, Carl Pelz2, Leslie A. Wakefield2, Willscott E.
Naugler3, Milton Finegold4, Markus Grompe2; 1Cell & Develop-
mental Biology, Oregon Health & Science Univ, Portland, OR;
2Pediatrics, Oregon Health & Sciences University, Portland, OR;
3Hepatology & GI, Oregon Health & Sciences University, Portland,
OR; 4Baylor College Of Medicine, Houston, TX
Background: Liver stem/progenitor cells, or hepatic oval cells,
appear and undergo a massive expansion in chronic human
liver disease. A long-standing debate in the field has centered
on whether progenitors are derived from biliary-like cells that
acquire hepatocyte functions or from hepatocytes that lose
hepatocyte functions. Recently, we showed that clonally-traced
cholangiocyte-derived Sox9+ progenitors rarely contribute to
regeneration of the hepatocyte pool in several mouse injury
models. Methods: Here, we generated hepatocyte-chimeras by
transplanting fluorescent-marked mouse hepatocytes or human
hepatocytes into Fah-mutant mice to specifically track the prog-
eny of mature hepatocytes. Oval cell injury was induced by
feeding 0.1% DDC for 4-8 weeks. Hepatocyte-derived pro-
genitor cells were FACS-isolated for RNAseq profiling, in vitro
progenitor assays, histologic and ultrastructural analysis, and
transplantation assays. To track the fate of hepatocyte-derived
progenitors upon recovery from liver injury, we generated
chimeric mice by transplanting Sox9-CreERT2 ROSA-mTmG
hepatocytes in Fah-mutant mice. To assess the plasticity of
human hepatocytes in chimeric livers, we utilized species-spe-
cific immunohistochemistry and RNAseq mRNA quantification.
Results: After inducing liver injury and progenitor activation,
mouse hepatocytes were a significant source (10-30%) of
Sox9+ Opn+ cells, or hepatocyte-derived liver progenitor
cells (hLPCs). RNAseq expression profiling showed that hLPCs
downregulated hepatocyte genes and specifically induced
expression of genes associated with epithelial-to-mesenchymal
transition. Remarkably, hLPCs assembled in ductal cords and
were indistinguishable from cholangiocytes by light microscopy
or in terms of Hnf1b, Spp1 or Sox9 expression levels. hLPCs,
however, were ultrastructurally distinct and functionally distinct
from cholangiocytes in vitro. In vivo lineage tracing and serial
transplantation assays indicated that hLPCs retained a mem-
ory of their cell of origin. hLPCs could differentiate back into
hepatocytes following a 4-8 week recovery period. Addition-
ally, we show that human hepatocytes have the capacity to
induce hKRT19 expression and give rise to cords of EpCAM+
progenitor-like biliary cells following chronic injury in human-
ized mouse livers. Conclusions: Human and mouse hepatocytes
can undergo metaplasia and reversibly acquire many features
of ductal cells as a response to injury. Further promoting the
differentiation of hepatocyte-derived progenitors back into
hepatocytes may represent a therapeutic strategy in decom-
pensated liver failure.
Disclosures:
Markus Grompe - Board Membership: Yecuris Corp.; Consulting: Yecuris Corp.;
Stock Shareholder: Yecuris Corp.
The following people have nothing to disclose: Branden Tarlow, Carl Pelz, Leslie
A. Wakefield, Willscott E. Naugler, Milton Finegold
HEPATOLOGY, October, 2014
147
Gender Influence Liver Regeneration During Acute
Hepatic Injury
Francesco P. Russo1, Rosa Di Liddo2, Debora Bizzaro1, Thomas
Bertalot2, Giacomo C. Sturniolo1, Maria Teresa Conconi2, Patrizia
Burra1; 1Department of Surgery, Oncology and Gastroenterology,
Gastroenterology Section, Padova, Italy; 2Department of Phar-
maceutical and Pharmacological Sciences, University of Padova,
Padova, Italy
Background and aims: Several lines of evidence have emerged
indicating sexual dimorphism in the immune response of the
acute phase of the inflammatory process. The aim of this study
was to evaluate the role of gender disparity, inflammatory
microenvironment and molecular mechanisms involved during
liver regeneration after acute liver damage. Methods: acute
liver damage was induced in both male and female BALB/c
mice aging 8 weeks by a single CCl4 administration (i.p.)
(0,75 ml/kg in olive oil). Animals were sacrificed at different
time point (2, 5, 8 and 12 days) after the injury. In a second
set of experiments, an injection of flutamide (i.p 50mg/Kg
in olive oil) per day was performed on Balb/c mice aging 8
weeks following a single CCl4 administration (i.p 0.75 ml/
Kg in olive oil). The livers were excised, and then analysed by
immunohistochemistry, RT- PCR, western blotting, FACS and
HPLC chromatography analyses. Results:. Female livers after 8
days appeared almost normal in size and morphology, while
male’s maintained an altered aspect. Immunohistochemistry
showed a massive inflammatory infiltrated in both gender, but
a predominant macrophage component in male tissue up to
12 days. RT-PCR analysis showed a significant TNF-α and IL-6
mRNA up-regulation in CCl4 treated mice, mainly in male vs.
female mice (9 n-fold vs. 3 n-fold). A significant up-regulation
of mRNA androgen receptor was detected in male animals
compared to females. Macrophages sorted by FACS from liv-
ers of CCl4 treated mice, confirmed the up-regulation for the
androgen receptor by RT-PCR. FACS analysis showed a dif-
ferent basal expression of androgen receptor in female and
male mouse during liver populations. After acute liver damage,
the animal response started at 5 days in females involving
CD11b+ Gr1+AR- populations while in males at 8 days with
CD11b+ Gr1+ AR+ cells. A different modulation of inflamma-
tory Gr1 positive cells was observed in animals after treatment
with flutamide. In females, the infiltrating Gr1+ cells showed
an increased expression of AR at 5 days. In contrast, flutamide
seemed to control the recruitment of migratory monocytes in
males at 8 days. In parallel, an altered response of CD4+
and CD8+ cells was detected in male mice in comparison
to females. Conclusions: In conclusion, It appears that male
mice respond to acute liver damage in a different way respect
to females, by recruiting inflammatory monocytes expressing
androgen receptor and lymphocytes.
Disclosures:
The following people have nothing to disclose: Francesco P. Russo, Rosa Di
Liddo, Debora Bizzaro, Thomas Bertalot, Giacomo C. Sturniolo, Maria Teresa
Conconi, Patrizia Burra
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
148
Hepatic Growth Regulation and Tumorigenesis is linked
to Autophagy via the Hippo Tumor Suppressor Pathway
Youngmin A. Lee1, Luke A. Noon1, Tingfang Lee1, Kemal M. Akat2,
Marie-Luise Berres3, Hsin I Chou1, Cathie Pfleger3, Elisabeth G.
Kramer4, Gareth John4, M. Isabel Fiel5, Ronald E. Gordon5, Yujin
Hoshida1, Mark J. Czaja6, Scott L. Friedman1; 1Division of Liver
Diseases, Icahn School of Medicine at Mount Sinai, New York,
NY; 2Laboratory of RNA Molecular Biology, Rockefeller Univer-
sity, New York, NY; 3Department of Oncological Sciences, Icahn
School of Medicine at Mount Sinai, New York, NY; 4Institute of
Neurosciences, Icahn School of Medicine at Mount Sinai, New
York, NY; 5Department of Pathology, Icahn School of Medicine
at Mount Sinai, New York, NY; 6Department of Medicine, Albert
Einstein College of Medicine, New York, NY
Background: Genetic models in which autophagic genes (Atg5,
Atg7, Vps45) have been inactivated develop the common fea-
tures of marked hepatomegaly and tumorigenesis by unknown
mechanism(s). The Hippo tumor suppressor pathway plays a
critical role in organ size and growth control, since liver-spe-
cific deletions of its components (e.g. Mst1/2, Sav1, Mer) or
overexpression of Yap (the Hippo pathway effector) lead to
prominent hepatomegaly and tumorigenesis. Moreover, Hippo
pathway dysregulation has been implicated in HCC. Methods:
Olig1Cre:Atg7f/f mice were generated and the specificity of
the Olig1 promoter determined by crossing Olig1Cre mice
with a reporter mouse line. The livers of Atg7-deficient mice
were analyzed by qRT-PCR, microarray, immunoblotting and
immunohistochemistry. AML12-shAtg7 and AML12-scrambled
cells served as an in vitro model. Results: We exploited a new
hepatocyte-specific promoter, Olig1, to drive Cre recombinase
expression in the livers of mice with floxed alleles of Atg7.
OligCRE/Rosa26 reporter mice showed cre recombination in
hepatocytes, but not endothelial cells, cholangiocytes or stellate
cells. Olig1Cre:Atg7f/f conditional knock out mice displayed
dramatic hepatomegaly with a 3-fold increase in liver-to-body
weight ratio and highly increased serum AST/ALT levels (2800
U/ml and 2200 U/ml respectively). Hepatocytes also had
increased proliferative activity (Ki67) (12.8 vs. 76.5 Ki67+
cells /field, n=3) at 3 months of age. There was significantly
increased nuclear staining of hepatocyte Yap/Taz, consistent
with Yap/Taz activation and decreased Yap inactivation by
the core components of the Hippo Pathway. These findings
were complemented by findings of: (1) increased protein lev-
els of Yap/Taz; (2) decreases in Yap/Taz inactivating Hippo
pathway members (Mer, Sav1, pLats, pMob) in whole liver
lysates; (3) significantly increased mRNA expression of Yap/
Taz targets (Ctgf, Birc5, Itgb2, Afp and Areg) by qRT-PCR and
gene arrays; (4) significantly increased nuclear Yap in AML12-
shAtg7 cells by staining and immunoblotting, and increased
proliferation by [3H]-thymidine incorporation, which could be
inhibited by the Yap/Tead inhibitor verteporfin; (5) significant
inhibition of hepatocyte proliferation in vivo by verteporfin in
Olig1Cre:Atg7f/f as assessed by Ki67 staining; and (6) devel-
opment of multinodular HCCs in Olig1CRE:Atg7f/f and Alb-
CRE:Atg7f/f mice at 8 months. Conclusion: We describe a new
hepatocyte-specific promoter in the liver and have uncovered a
novel link between autophagy and the Hippo tumor suppressor
pathway. These findings have implications for illuminating the
basis of hepatic growth regulation and tumorigenesis.
Disclosures:
Mark J. Czaja - Consulting: Oncozyme Pharma Inc.; Grant/Research Support:
Oncozyme Pharma Inc.
273A
Scott L. Friedman - Advisory Committees or Review Panels: Pfizer Pharmaceutical,
Sanofi-Aventis; Consulting: Conatus Pharm, Exalenz, Genenetch, Glaxo Smith
Kline, Hoffman-La Roche, Intercept Pharma, Isis Pharmaceuticals, Melior Dis-
covery, Nitto Denko Corp., Debio Pharm, Synageva, Gilead Pharm., Ironwood
Pharma, Alnylam Pharm, Tokai Pharmaceuticals, Bristol Myers Squibb, Takeda
Pharmaceuticals, Nimbus Discovery, Bristol Myers Squibb, Intermune, Astra Zen-
eca, Abbvie, Intermune; Grant/Research Support: Galectin Therapeutics, Tobira
Pharm, Vaccinex Therapeutics, Tobira; Stock Shareholder: Angion Biomedica
The following people have nothing to disclose: Youngmin A. Lee, Luke A. Noon,
Tingfang Lee, Kemal M. Akat, Marie-Luise Berres, Hsin I Chou, Cathie Pfleger,
Elisabeth G. Kramer, Gareth John, M. Isabel Fiel, Ronald E. Gordon, Yujin
Hoshida
149
Controlled repopulation of normal rat liver by WT
hepatocytes expressing a tamoxifen regulated liver
growth gene, YapERT2
Mladen Yovchev1, Fadi L. Jaber1, Zhonglei Lu2, Shachi Patel1,
Joseph Locker3, Leslie E. Rogler1, John W. Murray1, Mariana D.
Dabeva1, Liang Zhu2,1, David A. Shafritz1; 1Medicine, Albert
Einstein College of Medicine, Bronx, NY; 2Developmental and
Molecular Biology, Albert Einstein College of Medicine, Bronx,
NY; 3Pathology, Albert Einstein College of Medicine, Bronx, NY
Background and Aims. Adult hepatocytes extensively repopu-
late a massively injured or mitoinhibited liver but they barely
double after transplantation into normal liver. We previously
reported extensive repopulation of normal adult liver by fetal
liver stem/progenitor cells (FLSPC), which have higher prolifer-
ative potential than adult hepatocytes. However, it is unlikely
that FLSPC will be used for liver cell therapy, because of high
numbers of cells required for repopulation and ethical con-
cerns. Using microarrays, we determined that Yap, a prolif-
erative and liver growth control gene, is hyperexpressed in
FLSPC compared to adult hepatocytes and hypothesized that
introducing Yap into adult hepatocytes would allow these
cells to repopulate the normal adult liver. Because continuous
Yap expression in the liver of transgenic mice leads to hepa-
tocarcinogenesis and Yap is hyperexpressed in many tumors
including the liver, we linked Yap to the estrogen receptor
(ERT2) to control its subcellular location/function by tamoxifen
administration. Results. Expression/function of our lenti vector
was validated in cultured YapERT2 transduced HeLa cells by
inducing a shift from cytoplasmic to nuclear expression upon
addition of 0.1 uM 4 OH-tamoxifen to the medium (immuno-
histochemistry), which correlated with increased expression
of Yap and Yap target genes, CTGF, cyclin D1, and survivin
(an anti-apoptotic gene) by qRT PCR. Repopulation of DPPIV-
Fischer (F) 344 rat liver with lenti YapERT2 transduced DPPIV+
F344 rat hepatocytes was 8.9 ± 2.64% SEM at 6 mo. after
cell transplantation on continuous tamoxifen feeding (500 mg/
kg in chow), was nil off tamoxifen and was 0.27% ± 0.09%
SEM with lenti-GFP on tamoxifen (P = 0.01, Student T test).
Transplanted lenti YapERT2 transduced hepatocytes expanded
≈100 fold during repopulation, were totally integrated into the
parenchymal plates without distortion of host tissue, appeared
normal morphologically and exhibited normal hepatic gene
expression without evidence of dedifferentiation, cellular dys-
plasia or expression of liver progenitor or cancer stem cell
genes (i.e., AFP, OV6, CK19, Sox9, CD133 or CD44) by
immunohistochemistry. Conclusions. Lenti YapERT2 transduced
hepatocytes repopulate normal adult rat liver to ≈10% in 6
mo. without evidence for tumorigenicity. Ongoing studies con-
tinue to monitor tumorigenesis. These findings, unprecedented
to our knowledge, suggest that our single vector approach
with upregulated proliferation of transplanted hepatocytes to
increase liver repopulation will provide the basis for successful
274A AASLD ABSTRACTS
treatment of a wide variety of inherited metabolic liver disor-
ders and potentially other liver diseases.
Disclosures:
The following people have nothing to disclose: Mladen Yovchev, Fadi L. Jaber,
Zhonglei Lu, Shachi Patel, Joseph Locker, Leslie E. Rogler, John W. Murray, Mar-
iana D. Dabeva, Liang Zhu, David A. Shafritz
150
Genome-wide identification of miRNA binding-sites in
primary human hepatic stellate cells
Kemal M. Akat1, Youngmin A. Lee2, Feng Hong2, Marie-Luise
Berres4, Swan N. Thung3, Meena B. Bansal2, Thomas Tuschl1,
Scott L. Friedman2; 1Laboratory of RNA Molecular Biology, Rocke-
feller University, New York, NY; 2Division of Liver Diseases, Icahn
School of Medicine at Mount Sinai, New York, NY; 3Department
of Pathology, Icahn School of Medicine at Mount Sinai, New York,
NY; 4Department of Oncological Sciences, Icahn School of Medi-
cine at Mount Sinai, New York, NY
Background: MiRNAs are abundant ~22-nt non-coding RNAs
that regulate hundreds of gene targets in a sequence- and con-
text-specific manner. While miRNAs have been described in
hepatic stellate cells (HSCs), only relative changes in miRNA
expression have been reported and there is no genome wide-
map of miRNA targets. Theoretical algorithms to predict miRNA
binding-sites, while helpful, do not reflect context-dependent,
real-time miRNA binding to target sites. In contrast, miRNA
binding-sites in living cells can be directly analyzed using the
PAR-CLIP method (photoactivatable ribonucleoside-enhanced
cross-linking and immunoprecipitation) (Hafner et al, 2010,
Cell). Our aim was to identify miRNAs targets and target-sites
on a genome-wide scale in HSCs by Ago2 PAR-CLIP. Methods:
Primary HSCs were isolated from human livers, culture acti-
vated by expanding on polystyrene cell culture dishes, and the
purity confirmed by FACS. A barcoded small RNA-sequencing
(miRNAseq) protocol developed in our laboratory was used
to quantify HSC miRNA expression, which was combined
with RNAseq of polyA-RNA using the Illumina TruSeq platform
to analyze target gene expression. PAR-CLIP was performed
using a mouse monoclonal human anti-Ago2 antibody (clone
9E8.2). Results: There was a consistent miRNA profile across
5 biological replicates of primary HSCs, clearly distinct from
primary human hepatocytes, which dominated whole liver
miRNA expression. 55 unique miRNAs organized in 21 cis-
trons, and representing 28 miRNA families constituted 90% of
the sequencing reads. The top 5 most abundant miRNA cistrons
were mir-21(1), mir-98(13), mir-23a(6), mir-29a(4), and mir-
22(1), respectively. We obtained 30,000 Ago2 binding-re-
gions (clusters) by PAR-CLIP representing 8000 unique genes.
The clusters were almost evenly distributed over the coding
sequences and 3’ UTRs, and they were enriched in motifs com-
plementary to the seed-sequence of almost all highly expressed
miRNA families identified by miRNAseq. 8000 clusters con-
tained canonical 6mer, 7mer-A1, 7mer-m8, and 8mer miRNA
binding-sites for these highly expressed miRNAs. Among oth-
ers, we identified over hundred miR-21 binding-sites, including,
but not limited to genes involved in TGF-β1 signaling or tissue
fibrosis. Conclusion: Using RNAseq and PAR-CLIP we have
identified thousands of bona fide miRNA binding sites in pri-
mary human HSCs at single-nucleotide resolution, uncovering
both known and novel miRNA targets. This comprehensive cat-
alogue of HSC miRNAs provides fertile directions for clarifying
regulatory events and identifying novel therapeutic targets.
Disclosures:
Thomas Tuschl - Advisory Committees or Review Panels: Alnylam Pharmaceuti-
cals, Regulus Therapeutics
HEPATOLOGY, October, 2014
Scott L. Friedman - Advisory Committees or Review Panels: Pfizer Pharmaceutical,
Sanofi-Aventis; Consulting: Conatus Pharm, Exalenz, Genenetch, Glaxo Smith
Kline, Hoffman-La Roche, Intercept Pharma, Isis Pharmaceuticals, Melior Dis-
covery, Nitto Denko Corp., Debio Pharm, Synageva, Gilead Pharm., Ironwood
Pharma, Alnylam Pharm, Tokai Pharmaceuticals, Bristol Myers Squibb, Takeda
Pharmaceuticals, Nimbus Discovery, Bristol Myers Squibb, Intermune, Astra Zen-
eca, Abbvie, Intermune; Grant/Research Support: Galectin Therapeutics, Tobira
Pharm, Vaccinex Therapeutics, Tobira; Stock Shareholder: Angion Biomedica
The following people have nothing to disclose: Kemal M. Akat, Youngmin A. Lee,
Feng Hong, Marie-Luise Berres, Swan N. Thung, Meena B. Bansal
151
IL-1 signaling regulates bile duct injury and obstruction
in biliary atresia
Tatsuki Mizuochi1, Pranavkumar Shivakumar1, Reena Mourya1,
Stephanie Walters1, Bryan Donnelly2, Shiva K. Shanmukhappa3,
Jorge A. Bezerra1; 1Gastroenterology, Hepatology, and Nutrition,
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH;
2Pediatric Surgery, Cincinnati Children’s Hospital Medical Center,
Cincinnati, OH; 3Pathology and Laboratory Medicine, Cincinnati
Children’s Hospital Medical Center, Cincinnati, OH
Purpose: We have reported human and experimental data
pointing to key roles of the innate immune system in pathogen-
esis of biliary atresia. Here, we aimed at exploring whether
activation of the inflammasome is a mechanism used by innate
immunity to target the bile duct epithelium. Methods and
Results: First, we quantified mRNA for key inflammasome mol-
ecules in liver biopsies obtained at diagnosis of biliary atresia
and at different stages of bile duct injury in the rhesus rotavirus
(RRV) model of disease. The expression of the genes encoding
NLRP3, CASPASE-1, IL-18 and IL-1β increased in patients’ livers
~1.5-fold above age-matched controls, and in extrahepatic bile
ducts (EHBDs) of newborn mice 2.0-132.0-fold above saline-in-
jected controls. Based on these findings, we hypothesized that
the disruption of inflammasome signaling decreases biliary
injury and obstruction. Testing this hypothesis, we subjected
IL-1 receptor 1-deficient (IL-1R1–/–) and wild-type (WT) mice to
RRV challenge. We found that the loss of IL-1R1 suppressed the
experimental atresia phenotype as shown by decreased serum
total bilirubin (IL-1R1–/–: 5.8±1.5 vs WT: 9.0±1.3 mg/dL;
P<0.01), serum ALT (IL-1R1–/–: 79±11 vs WT: 130±13 U/L;
P<0.001), and milder hepatocyte necrosis and portal inflam-
mation (compared to the typical severe findings in WT livers).
EHBDs at 10 days of age showed epithelial injury and obstruc-
tion in WT mice; in contrast, EHBDs from IL-1R1–/– mice had
intact epithelium and decreased inflammation. Further, IL-1R1–
/– mice showed decreased hepatic mRNA expression of the
inflammation-related genes Ifn-γ, Tnf-α, Il-6, Cxcl9, Cxcl10, Mcp-
1, Il-1α and Il-1β. Exploring the mechanisms at the cellular level,
flow-cytometry experiments found that loss of IL-1R1 diminished
the number of plasmacytoid dendritic cells (pDCs) expressing
Rae-1 (IL-1R1–/–: 1.1±0.2x103 vs WT: 8.7±2.8x103 cells/
liver; P<0.001) and of Nkg2d-expressing NK cells (IL-1R1–/–:
0.9±0.3x103 vs WT: 5.4±0.9x103 cells/liver; P<0.001).
Most notably, hepatic DCs from RRV-challenged IL1R1–/–
failed to activate RRV-naive NK lymphocytes from livers of new-
born mice in co-culture experiments, as shown by a low number
of CD69+ (IL-1R1–/–: 9±1 vs WT: 31±2 %; P<0.001) and
Nkg2d+ NK cells (IL-1R1–/–: 4±0.4 vs WT: 6±1 %; P<0.01).
Conclusions: Disruption of the inflammasome by the loss of
IL-1R1 signaling suppressed the activation of DCs and their
ability to activate NK cells, and prevented obstruction of bile
ducts in experimental biliary atresia. These data identify a reg-
ulatory role of IL-1R1 in pathogenesis of bile duct injury, and
as a potential novel therapeutic approach to treat the disease.
Disclosures:
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Jorge A. Bezerra - Grant/Research Support: Molecular Genetics Laboratory,
CHMC
The following people have nothing to disclose: Tatsuki Mizuochi, Pranavkumar
Shivakumar, Reena Mourya, Stephanie Walters, Bryan Donnelly, Shiva K. Shan-
mukhappa
152
IL-1β is a Critical Mediator of Parenteral Nutrition Asso-
ciated Cholestasis in Mice
Karim C. El Kasmi, Padade Vue, Aimee Anderson, Michael W.
Devereaux, Natarajan Balasubramaniyan, Frederick J. Suchy, Ron-
ald J. Sokol; Pediatrics, UC Denver, Aurora, CO
Background: Hepatic macrophage activation by endotoxin
(LPS) absorbed from injured intestine promotes Parenteral
Nutrition Associated Cholestasis (PNAC) in mice (Hepatol-
ogy. 2012;55:1518-28). Furthermore, intestinal microbiota
and TLR4 signaling promote transcriptional suppression of
hepatic bile salt export pump Abcb11/BSEP, bilirubin exporter
Abcc2/MRP2 and sterol exporter Abcg5/8, which is associ-
ated with accumulation of cholestatic PN-derived phytosterols
(Sci. Transl. Med. 2013 Oct 9;5(206):206ra137). However,
the signaling pathways regulating these alterations in gene
expression in mice with PNAC remain undefined. The aim
of this study was to elucidate the role of cytokine signaling
pathways as mediators in PNAC. Methods and Results: Wild
type (WT) C57/B6 mice that were exposed to dextran sulfate
sodium (DSS) (to induce intestinal injury) for 4 days followed
by infusion of phytosterol-containing (soy lipid) PN solution
through a central venous catheter for 14 days (DSS-PN mice)
developed cholestasis (increased serum bile acids and bili-
rubin) and hepatocyte injury (increased AST and ALT) com-
pared to controls (including mice treated with DSS only, PN
only, or untreated chow fed). Compared to controls, DSS-PN
mice displayed significantly reduced hepatic mRNA amounts
of Abcb11, Abcc2, Abcg5/8, paralleled by increased mRNA
for Il1b while mRNA for Tnfα and Il6 were not increased. To
further elucidate the role of IL-1β signaling in these pathways,
mice with genetic deletion of the receptor for IL-1 (IL-1Rko) and
syngeneic wild type mice were exposed to DSS-PN for 14 days
or control treatments. Compared to DSS-PN wild type mice,
DSS-PN treated IL-1Rko mice had significantly reduced serum
AST, ALT, bile acids, and bilirubin. Moreover, hepatic gene
expression of Abcb11, Abcc2, and Abcg5/8 was not reduced
in DSS-PN IL1R-ko mice. To determine if IL-1β had a direct effect
on hepatocytes, wild type mice were injected with recombinant
IL-1β and sampled after 4 hrs, and HuH7 and HepG2 cells
(human hepatocyte cell lines) were incubated with IL-1β for 4
hrs and gene expression was measured. Compared to con-
trols, IL-1β treatment significantly suppressed gene expression
of Abcb11, Abcc2, and Abcg5/8 both in the mice and in the
two hepatocyte cell lines. Conclusions: Hepatic IL-1β signaling
is a critical mediator in the pathogenesis of PNAC and pro-
motes cholestasis and phytosterol accumulation through direct
suppression of hepatocyte gene expression of Abcb11, Abcc2,
Abcg5/8. Pharmacologic targeting of IL-1 signaling (e.g. IL-1
receptor antagonists) as a therapeutic strategy for PNAC and
other cholestatic liver injuries thus deserves further investiga-
tion.
Disclosures:
Ronald J. Sokol - Advisory Committees or Review Panels: Yasoo Health, Inc.,
Ikaria, Yasoo Health, Inc., Ikaria; Consulting: Roche, Roche; Grant/Research
Support: Lumena
The following people have nothing to disclose: Karim C. El Kasmi, Padade
Vue, Aimee Anderson, Michael W. Devereaux, Natarajan Balasubramaniyan,
Frederick J. Suchy
275A
153
Treatment with the LXR agonist T0901317 ameliorates
liver disease in Atp7b-/- (Wilson Disease) mice
James P. Hamilton1, Lahari Koganti1, James J. Potter1, Abigael
Muchenditsi2, David L. Huso2, Esteban Mezey1, Svetlana Lut-
senko2; 1Department of Medicine, Johns Hopkins University School
of Medicine, Baltimore, MD; 2Department of Physiology, Johns
Hopkins University School of Medicine, Baltimore, MD
Background and Aim: Wilson’s disease (WD) is caused by
mutations in ATP7B and results in Cu accumulation in tissues.
Recent studies have identified lipid metabolism/cholesterol bio-
synthesis as an early target of hepatic copper toxicity. We
hypothesized that activation of liver X receptor (LXR) signalling
with the agonist, T0901317, would increase lipid metabolism
and alter the disease phenotype in Atp7b-/- mice. Methods: 6
week old Atp7b-/- (KO) and Atp7b+/- (Het) mice were treated
with 50 mg/kg/day of T0901317 (T0) for 8 weeks. Serum
biochemistries and lipid profiles were performed at the end of
treatment. Livers were sectioned for RNA isolation, Hematoxy-
lin and Eosin staining, copper measurements, and procedures
were performed by standardized protocols. Results: Compared
to untreated KO mice, the liver morphology and function were
dramatically improved in the treated animals. Histologic scores
of inflammation were significantly improved in the treated
KO mice. AST was reduced by 65% and ALT was reduced
by 47%. Treatment significantly reduced serum bilirubin and
increased albumin in KO mice. Treatment resulted in a 30-fold
reduction in Collagen1a mRNA and 10-fold reduction in Timp1
mRNA in the KOs. Compared to Het mice, KO mice had a
10-fold increase in TNFa, a 2-fold increase IL-1B, and a 25-fold
increase in iNOs expression. Treatment with the LXR agonist
significantly reduced the expression of these three genes in the
KO mice. Total cholesterol, LDL, and HDL more than doubled
in the treated KO mice compared to the untreated mice. These
levels were similar to treated and untreated Het mice. Serum
triglycerides were significantly reduced in the KO mice but
normal in treated animals. Histology showed no hepatic ste-
atosis or steatohepatitis in any of the mice. Fatty acid synthase
(FASN) mRNA was inhibited in the KO and significantly upreg-
ulated in these mice after the treatment. Interestingly, RT-PCR for
several other LXR target genes, such as ABC1, Cyp7a1, HMG-
CoA1, LXRα, LXRβ, SREBP1, and FXR were unchanged by the
drug. Finally, the levels of hepatic Cu in treated and untreated
KO mice were nearly identical and 38-fold higher than those
in the Het mice. The drug had no significant adverse effect
on Het animals. Conclusions: Treatment with an LXR agonist
improved liver histology, liver enzymes and liver function in a
mouse model of WD. The improvements were associated with
a decrease in genetic markers of liver fibrosis and a decrease
in inflammatory cytokines. There was no change in hepatic
copper. These findings suggest alterations in LXR activation
may contribute to the pathogenesis of liver disease in WD.
Disclosures:
The following people have nothing to disclose: James P. Hamilton, Lahari
Koganti, James J. Potter, Abigael Muchenditsi, David L. Huso, Esteban Mezey,
Svetlana Lutsenko
154
LUM001, an Inhibitor of ASBT, Improves Liver Function
and Tissue Pathology in a Rat Cholestasis Model
Bradley T. Keller, Svetlana Nikoulina, Nicolaus Nazarenkov, Bro-
nislava Gedulin; Research, Lumena Pharmaceuticals, San Diego,
CA
Elevated hepatic and serum bile acids (SBA) play a role in pro-
gression of cholestatic liver disorders. Blocking BA recycling by
276A AASLD ABSTRACTS
inhibiting the apical sodium-dependent BA transporter (ASBT)
is an attractive pharmacological approach to lower SBA and
may offer a new treatment for several human cholestatic dis-
eases. We describe the effect of LUM001, a potent, minimal-
ly-absorbed ASBT inhibitor (ASBTi), on SBA and liver function
in a rat partial bile duct ligation (pBDL) model of cholestasis.
We adapted a mouse pBDL model (Heinrich et al., Surgery,
2011) to HSD rats and observed similar characteristics of
human cholestatic liver disease - significantly elevated SBA
and abnormal liver function markers. Rats (n=4-6/group) were
anesthetized with isoflurane, the common bile duct exposed
by midline laparotomy and a short length of PE-10 tubing was
placed parallel to the bile duct. A ligature of 4-0 silk suture
was tied tightly around the duct and tubing after which the
tubing was removed resulting in constriction of the duct lumen
without complete obstruction. Three days after pBDL surgery,
serum levels of alkaline phosphatase (ALP), aspartate amino-
transferase (AST), alanine aminotransferase (ALT), γ-glutamyl
transferase (GGT) and total bilirubin (TBil) increased from base-
line by 37-, 6-, 12-, 14- and 73-fold, respectively. By 7 days,
AST and ALT levels had begun to normalize (4-fold vs. sham)
while ALP, GGT and TBil values remained high at 19-, 19- and
51-fold vs. sham, respectively. This profile was sustained at 14
days with elevations of 80-, 47- and 34-fold for ALP, GGT and
TBil, respectively. SBA levels were also dramatically increased
by 29-, 14- and 13-fold at 3, 7 and 14 days after surgery.
LUM001 was administered once daily by oral gavage (10
mg/kg/day) starting 6 hours after surgery. At 7 days post-sur-
gery, ASBTi treatment significantly reduced SBA 92% (59 μM),
ALP 19% (603 IU/L), GGT 69% (10.2 IU/L) and TBil 61%
(2.0 mg/dL) compared to vehicle control. By 14 days, SBA
was reduced 87% (80 μM), ALP 37% (536 IU/L), GGT 93%
(3.4 IU/L) and TBil 91% (0.3 mg/dL) compared to vehicle.
Similar effects were seen with 1 mg/kg/day LUM001. Liver
histopathology analysis confirmed less tissue damage in the
LUM001 groups. These data show that the rat pBDL model
results in significant elevation of SBA and serum liver markers
from 3-14 days, characteristic of cholestasis and liver injury.
Blocking BA recycling with LUM001 attenuates these increases
and improves tissue morphology suggesting that an ASBTi
may provide a novel treatment for cholestatic liver disease that
decreases the accumulation of toxic bile acids and reduces the
severity of cholestatic liver injury.
Disclosures:
Bradley T. Keller - Consulting: Shire Human Genetic Therapies Inc; Employment:
Lumena Pharmaceuticals, Rivervest Venture Partners
Svetlana Nikoulina - Consulting: Lumena Pharmaceuticals
Bronislava Gedulin - Employment: Lumena Pharmaceuticals
The following people have nothing to disclose: Nicolaus Nazarenkov
155
Pharmacological inhibition of intestinal bile acid re-up-
take blocks inflammatory liver injury and fibrosis in a
murine model of sclerosing cholangitis
Julia Simmons1, Amy Taylor1, Shiva K. Shanmukhappa2, Brad-
ley T. Keller3, Alexander G. Miethke1; 1Department of Gastroen-
terology, Cincinnati Children&apos;s Hospital Medical Center,
Cincinnati, OH; 2Pathology, Cincinnati Children&apos;s Hospital
Medical Center, Cincinnati, OH; 3Lumena Pharmaceutical Inc,,
San Diego, CA
Although the etiology of primary sclerosing cholangitis (PSC) is
unknown and multifactorial, retained bile acids (BA) are likely
key drivers of liver injury and fibrosis. Mice deficient in mdr2,
a canalicular phospholipid floppase, excrete low phospholipid
“toxic” bile causing rapid progression of cholestasis and biliary
HEPATOLOGY, October, 2014
fibrosis resembling small duct PSC. Here we hypothesize that
pharmacological inhibition of the ileal apical sodium co-de-
pendent bile acid transporter (ASBT) blocks progression of liver
disease in mdr2-/- mice. 30-day-old mdr2-/- mice were fed
with high-fat chow containing 0.006% of SC-435, a minimally
absorbed, potent inhibitor of ASBT, providing on average 11
mg/kg/day of the compound. 14 days later serum BA and
plasma total bilirubin/ ALT levels were determined using enzy-
matic and colorimetric assays, respectively. Liver histology was
assessed blinded on H&E and Sirius Red stained liver sections
applying a validated sclerosing cholangitis score. SYBR green
and Taqman-based real time RT-PCR was employed to quanti-
tate whole liver mRNA expression. Age and gender matched
mdr2-/- mice on the same diet without the compound served
as controls. Treatment with SC-435 improved animal growth
rates (mean±SEM of weight change: +4.3±0.5 vs -0.2±0.7
g in SC-435 vs controls; n=6-7 per group, p<0.001) and
dramatically reduced plasma biomarkers of cholestasis (total
bilirubin: 0.5±0.04 vs 6.8±0.6 mg/dL; p<0.001) and of hepa-
tocellular injury (ALT: 187±22 vs 1358±350 IU/L; p=0.002).
On a 1 to 4 scale, liver injury was greatly diminished in the
SC-435 treated compared with control mice (grade of inflam-
mation: 1.6±0.3 vs 2.8±0.4, of ductal proliferation 1.4±0.2
vs 3.3±0.2, of necrosis: 1.3±0.2 vs 2.3±0.2, and of fibrosis
1.6±0.2 vs 3.3±0.3; p<0.05 for all parameters). Searching for
mechanisms we found that SC-435 caused intestinal bile acid
losses, as determined after 7 days of treatment (fecal BA con-
tent: 0.35±0.06 vs 0.1±0.03 μmol/day in SC-435 vs controls;
p=0.01) while dramatically reducing serum BA levels after 14
days (14±2 vs 298±7 μM; p<0.001). Concomitantly, mRNA
expression for TNFα, a signature pro-inflammatory cytokine
of murine sclerosing cholangitis, was decreased (fold-change
over mdr2+/+ mice: 7.1±3.6 vs 40±7.2, p=0.02). Further-
more, expression levels of the pro-fibrotic genes Col1A2, SMA
and Timp1 were significantly down-regulated by 3.1-, 2.9- and
2.6-fold, respectively, in SC-435 treated vs mdr2-/- control
mice. Conclusion: Inhibition of ASBT dramatically reduces BA
pool size and blocks progression of inflammatory liver injury
and fibrosis in mdr2-/- mice. Thus, inhibition of ASBT may be a
promising target for pharmacotherapy of PSC.
Disclosures:
Bradley T. Keller - Consulting: Shire Human Genetic Therapies Inc; Employment:
Lumena Pharmaceuticals, Rivervest Venture Partners
Alexander G. Miethke - Grant/Research Support: Lumena, Pharmaceutical Inc.
The following people have nothing to disclose: Julia Simmons, Amy Taylor, Shiva
K. Shanmukhappa
156
The zebrafish ductbend mutation is a sensitizer to tox-
in-induced biliary atresia and a potential homologue of
a human biliary atresia modifier
Xiao Zhao1, Kristin Lorent1, Weilong Gong1, Kyung A. Koo2, Steve
Whittaker3, John R. Porter2, Rebecca G. Wells1,4, Michael Pack1,5;
1Department of Medicine, Perelman School of Medicine, Univer-
sity of Pennsylvania, Philadelphia, PA; 2Department of Biological
Sciences, University of the Sciences, Philadelphia, PA; 3Hume Live-
stock Health and Pest Authority, Albury, NSW, Australia; 4Depart-
ments of Pathology and Laboratory Medicine, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, PA; 5Cell and
Developmental Biology, Perelman School of Medicine, University
of Pennsylvania, Philadlephia, PA
Biliary atresia (BA) is a progressive fibro-inflammatory disease
affecting the extrahepatic biliary tree and is the most common
cause of neonatal cholestasis as well as the leading indication
for liver transplantation in the pediatric population. Although
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
the etiology of BA remains obscure, there is increasing evi-
dence that environmental factors might initiate biliary injury
in genetically susceptible patients. Supporting the role of an
environmental toxin as a BA trigger has been the occurrence
of epidemic BA-like syndrome in newborn Australian livestock.
Coincident with each epidemic was maternal consumption of
Dysphania plant species that were not part of the animal’s nor-
mal diet (owing to drought conditions). We imported and frac-
tionated two species of Dysphania plants from pastures grazed
on during the most recent outbreak, and used a zebrafish bili-
ary secretion assay to isolate a novel extrahepatic biliary toxin
that we named biliatresone. Confocal immunofluorescence
microscopy and histological analyses showed that exposure
to biliatresone caused selective destruction of the extrahepatic
bile ducts in zebrafish larvae in a dose- and time-dependent
manner. To identify genetic modifiers of biliatresone and to
elucidate its mechanism of action, we examined its activity in
mutant larvae with intrahepatic biliary defects. One mutant,
ductbend, showed heightened sensitivity to the toxin. 5 day
post-fertilization mutant larvae treated with the toxin at a dose
that did not affect their wild type siblings and other biliary
mutants had typical toxin-induced extrahepatic defects. Genetic
mapping experiments localized the ductbend locus to a region
within zebrafish chromosome 22 that has conserved synteny to
two independent BA susceptibility loci (10q24.2, 16p13.3),
thus linking biliatresone-induced toxicity to the pathogenesis of
human BA. The close proximity of the zebrafish homologs of
the non-linked human BA susceptibility loci suggests that genes
within this large chromosomal segment could be co-regulated
in biliary cells. These results have allowed us to establish a new
animal model to study BA and genetic susceptibility to BA, and
provided us with important insights into the sequence of events
underlying the development of this enigmatic disease.
Disclosures:
The following people have nothing to disclose: Xiao Zhao, Kristin Lorent, Wei-
long Gong, Kyung A. Koo, Steve Whittaker, John R. Porter, Rebecca G. Wells,
Michael Pack
157
Increased Natriuretic Effects of α2- vs. α1-adrener-
gic Agonists, Alone or in Combination with Standard
Diuretics, in Rats with Experimental Cirrhosis and Asci-
tes
Giovanni Sansoe1, Manuela Aragno2, Raffaella Mastrocola2,
Maurizio Parola2; 1Gastroenterology Unit, Gradenigo Hospital,
Torino, Italy; 2Department of Clinical and Biological Sciences, Uni-
versity of Torino, Torino, Italy
Background. Sympathetic nervous system (SNS) activation of
ascitic crrhosis reduces fluid delivery to the Henle’s loop and
makes responses to diuretics negligible. Sympatholytic α2-ad-
renoceptor agonists, associated with diuretics, may therefore
improve natriuresis in advanced cirrhosis. Paradoxically, also
α1-adrenergic agonists may improve systemic hemodynamics
and sodium excretion in advanced cirrhosis. Aims & Meth-
ods. Renal effects of clonidine (α2-agonist) and midodrine
(α1-agonist), alone or associated with diuretics, were assessed
in five groups of rats with ascitic cirrhosis due to 13-week
CCl4 administration (groups G1-G5) and compared, through
evaluation of renal function and hormonal status, to rats with
ascitic cirrhosis (G6) and ascitic cirrhotic rats receiving daily
diuretics (0.5 mg/kg furosemide plus 2 mg/kg K+-canrenoate
during the 11th-13th weeks of CCl4) (G7). G1-G5 cirrhotic rats
received daily, during the 11th-13th weeks of CCl4: clonidine
0.3 mcg alone (G1), diuretics + clonidine 0.2 (G2), 0.5 (G3),
or 1 mcg (G4), diuretics + midodrine 1 mg/kg b.w. (G5).
277A
Results. In group G1 (clonidine alone) and G2 (diuretics +
clonidine 0.2 mcg) sodium excretions were higher than in the
cirrhotic group treated with diuretics alone (G7) (all P<0.03).
Glomerular filtration rate and renal plasma flow were higher
in cirrhotic rats treated with clonidine alone (G1) than in cir-
rhotic rats receiving diuretics (G7) (all P<0.03). The addition
of clonidine (0.2 mcg) in G2 to diuretics (G7) reduced tubular
free-water reabsorption from 48 ± 12 to 30 ± 8 microL/min
(P<0.01), serum norepinephrine from 423 ± 122 to 169 ± 90
ng/L (P<0.01) and plasma renin activity from 25 ± 12 to 12 ±
7 ng/mL/h (P<0.03). The addition of midodrine to diuretics did
not improve the renal performance measured in ascites treated
with diuretics only. Conclusions. α2- but not α1-agonists reduce
SNS function and hyper-aldosteronism and improve natriuresis
in cirrhotic ascites, treated or not with standard diuretics.
Disclosures:
Giovanni Sansoe - Consulting: Shire Pharmaceuticals Ltd., Basingstoke, Hamp-
shire, UK.
Manuela Aragno - Grant/Research Support: Shire Pharmaceutical
Raffaella Mastrocola - Grant/Research Support: Shire Pharmaceutical
Maurizio Parola - Independent Contractor: Shire Pharmaceutical Ltd, Basingstoke,
UK
158
The effect of long-term use of non-selective beta-blocker
on the development of acute kidney injury in patients
with liver cirrhosis
Sang Gyune Kim1, W. Ray Kim2, Joseph J. Larson3, Walter K.
Kremers3, Patrick S. Kamath3; 1gastroenterology and hepatology,
soonchunhyang university Bucheon hospital, Bucheon si, Republic
of Korea; 2gastroenterology and hepatology, Stanford university
medical school, Palo Alto, CA; 3Mayo clinic, Rochester, MN
Background: Non-selective beta-blockers (NSBBs) have played
a key role in the prevention of portal hypertensive bleeding
in patients with cirrhosis. However, recent studies have sug-
gested that NSBB use is associated with decreased survival
in patients with refractory ascites. Our hypothesis was that
NSBBs may reduce perfusion of vital organs, such as the kid-
neys, in susceptible cirrhotic patients. The aim of this study is
to evaluate any association between NSBB use and the inci-
dence of acute kidney injury (AKI). Methods: We used a nested
case-control design from the cohort of liver transplant waitlist
registrants at Mayo clinic, Rochester, USA. Cases consisted of
patients who developed AKI ≥ stage 2, defined by a 2-3 fold
increase in serum creatinine compared to baseline. Each AKI
patient was matched to a control, based on MELD-Na score,
age at registration, baseline creatinine, and follow-up duration.
Results: Out of the total cohort of 2250 waitlist registrants, 202
patients met the criteria of AKI. The most common etiology of
liver cirrhosis was hepatitis C (24%), followed by alcoholic and
non-alcoholic steatohepatitis (21%), primay sclerosing cholan-
gitis (21%), and primary biliary cirrhosis (7%). The median
follow-up duration was 20.3 (range: 3~201) months. When
compared to matched controls without AKI, ascites (78.7%
versus (vs.) 52.0%), non-white race (16.3% vs. 7.9%) and
absence of malignancy (89.6% vs. 82.7%) were more com-
monly seen among the cases. In the overall comparison with
the controls, the frequency of NSBB use was higher among the
cases, albeit insignificantly (46.0% vs. 37.6%, p=0.09). In
the univariate proportional hazard regression analysis, female
sex, non-caucasian, malignancy, autoimmune etiology, high
MELD and MELD-Na at baseline, and ascites were significantly
associated with development of AKI. In multivariable analyses,
the impact of NSBB on AKI incidence was different according
to the presence of ascites: NSBB use in patients with ascites
278A AASLD ABSTRACTS
was significantly associated with development of AKI (hazard
ratio [HR], 2.79; 95% confidence interval [CI], 1.40-5.54),
while in patients without ascites, NSBB was protective (HR,
0.19; 95% CI, 0.06-0.60), after adjusting for MELD-Na at
baseline, sex, race, etiology of cirrhosis and presence of liver
cancer. Conclusions: The use of NSBB increased the risk of
AKI in cirrhotic patients with ascites, which likely contributes to
increased mortality.
Disclosures:
W. Ray Kim - Consulting: Bristol Myers Squibb, Gilead Sciences
Patrick S. Kamath - Advisory Committees or Review Panels: Sequana Medical
The following people have nothing to disclose: Sang Gyune Kim, Joseph J. Lar-
son, Walter K. Kremers
159
Efficacy and safety of a probiotic preparation in the
secondary prophylaxis of hepatic encephalopathy in
cirrhotic patients: Final results of a double blind, ran-
domized, placebo controlled study
Radha K. Dhiman1, Baldev S. Rana1, Swastik Agrawal1, Ash-
ish Garg1, Madhu Chopra1, Kiran K. Thumburu1, Amit Khattri1,
Samir Malhotra2, Ajay K. Duseja1, Yogesh K. Chawla1; 1Hepa-
tology, Postgraduate Institute of Medical Education and Research
(PGIMER), Chandigarh, India; 2Clinical Pharmacology, Postgradu-
ate Institute of Medical Education and Research (PGIMER), Chan-
digarh, India
Probiotics may not be efficacious in altering clinically relevant
outcomes in cirrhotic patients with hepatic encephalopathy
(HE). This study assessed the efficacy of a probiotic prepa-
ration in the prevention of HE recurrence (primary outcome),
and reduction in hospitalizations, improvement in the severity
of liver disease and in proinflammatory markers, and improve-
ment in health-related quality of life (HRQOL) (secondary
outcomes) in patients with liver cirrhosis. In a randomized,
double-blind, placebo-controlled trial using computer gener-
ated number allocation, conducted at a tertiary care hospital
in India, patients with liver cirrhosis who had recovered from
an episode of HE during the previous month were assigned to
receive either a probiotic preparation (VSL#3®; CD Pharma
India Pvt. Ltd, New Delhi, India) at a dose of 900 billion bac-
teria daily (n=66), or placebo (n=64) for 6 months. There was
a trend toward reduction in the mean-time to HE recurrence
[123 (95% confidence interval [CI], 108–138) vs 105 (89–
120) days] in probiotic-treated versus placebo-treated patients
(P=0.10). The hazard ratio (HR) for the risk of a breakthrough
episode in the probiotic group was 0.65 (95% CI, 0.38-1.11;
P=0.10) versus the placebo group. Hospitalizations were sig-
nificantly less common in the probiotic group versus placebo
group for overall complications of liver cirrhosis [24.2% vs
45.3%, HR 0.52 (95% CI, 0.28–0.95); respectively; P=0.034]
and for those involving HE [19.7% vs 42.2%, respectively;
HR 0.45 (95% CI, 0.23–0.87; P=0.02)]. Child–Turcotte–Pugh
score (P=0.001), indoles (0.001), plasma interleukin (IL)-1β
(P=0.048), IL-6 (P=0.002), tumor necrosis factor-α (P=0.032),
renin (P=0.003), aldosterone (P=0.021), and brain-type natri-
uretic peptide (P=0.016) levels improved significantly from
baseline to 6 months in the probiotic group but not the placebo
group. There was a significant improvement in the physical
function (P=0.005) and role physical (P=0.019) domains and
in the physical component summary (P=0.030) of the Medical
Outcomes Study Short-Form (SF)-36 after 24 weeks of treatment
in the probiotic group while there was no change in any of
the SF-36 domain in placebo group. There were no adverse
events related to the study drug. Conclusions: Over a 6-month
period, treatment with probiotic significantly reduced the risk
HEPATOLOGY, October, 2014
of hospitalization involving overall complications of cirrhosis
including HE and significantly improved liver disease severity,
systemic inflammation and HRQOL. (ClinicalTrials.gov number,
NCT01110447) Interim results of this study were presented in
AASLD 2012 as oral presentation (Hepatology 2012;56(Suppl
255A)
Disclosures:
The following people have nothing to disclose: Radha K. Dhiman, Baldev S.
Rana, Swastik Agrawal, Ashish Garg, Madhu Chopra, Kiran K. Thumburu, Amit
Khattri, Samir Malhotra, Ajay K. Duseja, Yogesh K. Chawla
160
A prospective, open labeled, randomized controlled trial
comparing Carvedilol + VSL#3 versus EVL for primary
prophylaxis of esophageal variceal bleeding in cirrhotic
patients non-responder to carvedilol (NCT01196481)
Ankit Bhardwaj1, Avinash Kumar2, Devraj Rangegowda2, Chan-
dan K. Kedarisetty2, Manoj Kumar2, Chitranshu Vashishtha2, Ajeet
S. Bhadoria1, Shiv K. Sarin2; 1Research, Institute of Liver and Bili-
ary Sciences, New Delhi, India; 2Hepatology, Institute of Liver and
Biliary Sciences, New Delhi, India
Background & Aim: Gastro-esophageal variceal bleeding (VB)
is an important complication of portal hypertension (PHT) with
mortality of 30-50% within 6 weeks. The recommended ther-
apy for primary prophylaxis of large varices is beta-blocker
therapy (BB) or endoscopic variceal ligation (EVL). However,
there are limited options for BB non-responders. VSL#3 is
hypothesized to reduce gut translocation and endotoxemia
with consequent reduction of portal pressure. We investigated
the efficacy of combination of VSL#3 and carvedilol compared
to EVL as primary prophylaxis for non-responders to BB for
large varices. Patients and Methods: It was a randomized open
labeled active controlled trial.Consecutive cirrhotics with large
varices were prospectively enrolled from December 2012.
After informed consent, patients were given maximum toler-
ated dose of carvedilol till heart rate reduced to 55 bpm or
adverse-effects developed. After 2 months, repeat HVPG was
performed and non-responders (≤ 20% reduction in HVPG)
were randomized into carvedilol +VSL#3(Group A) or EVL
(Group B) in 1:1 ratio.The primary end-point was onset of first
variceal bleed. Secondary end-points were time to bleed and
safety profile of drugs. Results: Out of 119 patients, 76 patients
underwent repeat HVPG. 42 (55.26 %) were responders and
excluded from the study. 34 non- responders were randomized
into Groups A (n=17) or B (n=17). The mean CTP and MELD
in Group A (6.75 ± 0.856 and 8.20 ± 3.028) and B (7.33 ±
1.496 and 9.85 ± 4.981) were comparable (p> 0.05). The
mean carvedilol dose was 11.92 ± 2.05 mg/day and target
heart rate achieved in Group A was 58±3 beats per minute.
Baseline HVPG in Group A 15.88 ± 2.956 while in Group B
was 16.78 ± 5.559 and respectively. A significantly higher
proportion of variceal bleeds were seen in Group A (6 of 17,
35.3%) compared to Group B (1 of 17, 5.8%) at 12 months
(p=0.03). The onset of first variceal bleed was at 9.2 ± 0.96
weeks in Group A and 11.8 ± 0.21 weeks in Group B which
was statistically significant (p- 0.02) (Fig.1). No mortality and
adverse events were reported in either group. Conclusions:
This is the first RCT (NCT01196481) showing that carvedilol
is effective in about 50% patients with large varices. However,
in BB non-responders, combining VSL#3 with carvedilol is not
effective and EVL remains the first choice for primary prophy-
laxis for large esophageal varices.
Disclosures:
The following people have nothing to disclose: Ankit Bhardwaj, Avinash Kumar,
Devraj Rangegowda, Chandan K. Kedarisetty, Manoj Kumar, Chitranshu Vash-
ishtha, Ajeet S. Bhadoria, Shiv K. Sarin
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
161
Effects of Non-Selective β-Blockers on Hemodynamics
and Paracentesis Induced Circulatory Dysfunction in
Patients with Cirrhosis Undergoing Large Volume Para-
centesis: a Preliminary Report
Alberto Ferrarese1, Alberto Zanetto1, Paolo Angeli2, Edoardo
Casiglia2, Silvano Fasolato2, Giovanni Boschetti2, Kryssia I. Rodri-
guez1, Elena Nadal1, Ilaria Bortoluzzi1, Francesco P. Russo1, Gia-
como Germani1, Patrizia Burra1, Marco Senzolo1; 1Multivisceral
Transplant Unit, Department of Surgery, Oncology and Gastroen-
terology, Padua University Hospital, Padua, Italy; 2Department of
Medicine, Padua University Hospital, Padua, Italy
Background and aims: Non-Selective β-Blockers (NSBBs) have
been associated with increased incidence of Paracentesis
Induced Circulatory Dysfunction (PICD) and reduced survival in
patients with cirrhosis and refractory ascites; however, causes
of death were not related to worsening haemodynamics. We
have prospectively evaluated intra-individual central and
peripheral hemodynamic effects produced by NSBBs introduc-
tion and the incidence of PICD in patients undergoing large
volume paracentesis (LVP). Methods: Patients with cirrhosis and
refractory ascites, having indication to initiate or discontinue
NSBBs were enrolled. During two consecutive LVP (while been
respectively on and off NSBBs therapy), for each patient car-
diac output (CO), systemic vascular resistances (SVR), periph-
eral vascular resistances (PVR), and Plasma Renin Activity (PRA)
before and 60’ after LVP were recorded, using impedance
cardiography and plethysmography. Results: Eleven patients
were enrolled, 6 completed the study; all the patients did have
diuretic intractable refractory ascites and new indication to
introduce propranolol (mean dose±SD 60±21.9 mg/day).
Before NSBBs initiation, SVR (1808±358.3 vs 1398±332.4
dyn.s.cm−5; p= .02) and PVR (45.9±7.0 vs 27.7±5.9 mmHg.
min.dl.ml-1; p= .04) significantly decreased 60’ after LVP than
pre-paracentesis; CO consequently showed an increasing trend
(3.8±0.67 vs 4.4±1.14 l/min; p= .06). PICD was diagnosed
in 2/6 patients. While on NSBBs therapy, CO did not increase
after LVP (3.3±0.9 vs 3.6±1.0 l/min; p= .1), but this was coun-
terbalanced by a smaller decrease of SVR (1981.12±314.2 vs
1763.29±555.05 dyn.s.cm−5; p= .1) and PVR (44.17±12.2
vs 32.1±7.86 mmHg.min.dl.ml-1; p= .2). Three of six patients
showed an increase in PRA values post-LVP, consistent with
PICD. Conclusions: In patients with cirrhosis undergoing LVP,
the inotropic negative effect of NSBBs seems to be counterbal-
anced by smaller decrease of vascular resistances, probably
due to splanchnic β2-blockade. Therefore, the incidence of
PICD was not increase by introduction of NSBBs, which may
be void of detrimental effects in patients with cirrhosis under-
going LVP.
Disclosures:
Paolo Angeli - Advisory Committees or Review Panels: Sequana Medical
The following people have nothing to disclose: Alberto Ferrarese, Alberto
Zanetto, Edoardo Casiglia, Silvano Fasolato, Giovanni Boschetti, Kryssia I. Rodri-
guez, Elena Nadal, Ilaria Bortoluzzi, Francesco P. Russo, Giacomo Germani,
Patrizia Burra, Marco Senzolo
162
A randomized trial of ‘Imipenem versus Cefepime’ in
difficult to treat spontaneous bacterial peritonitis (SBP)
and to evaluate the risk factors for treatment failure
Ankur Jindal, Shiv K. Sarin; Hepatology, Institute of Liver and Bili-
ary sciences, New Delhi, India, New Delhi, India
BACKGROUND In presence of bacterial resistance and/or
failure of first-line antibiotic therapy, ceftriaxone, has poor
outcome in patients with SBP. Carbepenems, are often used
279A
emperically and may lead to unwarranted drug resistance. The
comparative efficacy & safety of Cefepime, compared to car-
bepenems is not known in such difficult to treat SBP (DTT-SBP)
patients. Such data may prevent emergence of carbanemase
resistant strains and develop practice guidelines. PATIENTS
& METHODS This open label randomized trial (Septem-
ber 2012-December 2013) [Clinical trials- NCT01852630]
included decompensated cirrhotics with DTT-SBP, defined as
i). hospital acquired SBP (> 48 h of admission), ii). microbial
resistance or inadequate response to first-line antibiotic (reduc-
tion in ANC by < 25% at 48 h), or iii). recurrence of SBP.
These patients were randomized to Cefepime IV 1g t.i.d (Gr
A) or Imipenem IV 1g t.i.d (Gr. B). Diagnostic paracentesis
was done at baseline and response tap at 48 h & 5 days for
early response (reduction in ANC by > 25% and negative
cultures at 48 h) or resolution of SBP (< 250 cu/mm. ANC at
day 5) [primary end point]. Persistence of SBP at day 5 consti-
tuted treatment failure. Secondary end-point was survival at 3
month. RESULTS Of 957 diagnostic paracentesis among 1200
admitted decompensated cirrhotics, 253 (26.4%) had SBP.
175 (69.2%) with DTT-SBP received Cefepime (Gr..A;n-88)
or Imipenem (Gr. B;n-87). Their baseline demographics, etiol-
ogy, clinical, disease severity and ascitic fluid parameters were
comparable. Main cause of DTT-SBP was resistance to first-line
antibiotics (39% Gr.A and 48% Gr.B). Both early response
(58.6% Gr. A vs. 51.7% Gr. B; p-0.36) and SBP resolution
rates (65.5% vs. 60.9%; p-0.53) were comparable, no differ-
ence in mortality at week 2, month 1 & 3 (38.6% vs. 37.9%;
p-0.92). Early response at 48 h (associated with absence of
AKI & septic shock) was only independent predictor of SBP
resolution(Odd’s ratio-18.95). Progression of HE & progressive
/persistant AKI predicted high mortality & treatment failure.
Hospital acquired DTT-SBP had higher mortality than others
(39.7% vs.17.3%;p<0.01). Septic shock was main pretermi-
nal event (32.3% Gr.A vs.35.6% Gr.B). Patients who died
had higher MELD (28 vs 24) and lower SBP resolution rate
(p-0.001). Baseline AKI (OR-5.3), pneumonia(OR-7.1),septic
shock (OR-6.4) and failure of SBP resolution (OR-14.3) were
independent predictors of 3 month mortality. CONCLUSIONS
Difficult to treat SBP is a major clinical problem with limited
options. Cefepime may be an effective alternative to Imipenem.
Failure to achieve SBP response at 48 hours is the strongest
predictor of treatment failure.
Disclosures:
The following people have nothing to disclose: Ankur Jindal, Shiv K. Sarin
163
Outcomes of Liver Transplantation in Patients with Hep-
atitis C and Hepatocellular Carcinoma (HCC): The U.S.
Transplant Registry Data
Zobair Younossi1,4, Maria Stepanova1,4, Sammy Saab2, Kameron
Tavakolian1, Brian P. Lam1, Manirath Srishord1, Chapy Venkate-
san1,4, James N. Cooper3, Homan Wai1,4, Linda Henry1; 1Center
for Liver Disease, Department of Medicine, Inova Fairfax Hospi-
tal, Falls Church, VA; 2Departments of Medicine and Surgery,
David Geffen School of Medicine at University of California at
Los Angeles, Los Angeles, CA; 3College of Life Sciences, George
Mason University, Fairfax, VA; 4Betty and Guy Beatty Center for
Integrated Research, Inova Health System, Falls Church, VA
BACKGROUND AND AIM: Hepatocellular carcinoma (HCC)
is an important complication of cirrhosis with an increasing
incidence in the U.S. most likely due to hepatitis C virus (HCV).
The only potentially curative treatment option for HCC is liver
transplantation. METHODS: All adults (18+) who underwent
liver transplantation for HCC were included from the Scien-
280A AASLD ABSTRACTS
tific Registry of Transplant Recipients (1992-2013). Etiology
of liver disease (LD) was grouped into HCV (anti-HCV-posi-
tive), hepatitis B (HBV, HBsAg-positive), and other LD (negative
viral hepatitis serology). RESULTS: Total 8,625 liver transplant
recipients with HCC were included; 5,471 had HCV, 604
HBV, and 2,387 had other causes of LD. In comparison to
hepatitis C, patients with hepatitis B were predominantly Asian
(60.3%) and male (83.0%), had lower rates of pre-transplant
obesity (HBV 11.4% vs. 30.1% in hepatitis C, 37.9% in other
LD, p<0.0001), diabetes (HBV 14.2% vs. HCV 17.5% and
other LD 30.5%, respectively, p<0.0001). Important comorbid-
ities were equally prevalent regardless of etiology (coronary
artery disease, stroke, peripheral vascular disease, pulmonary
embolism, cancer) (all p>0.05). In follow-up (43±38 months),
7.9% of HCC patients had graft failure and 27.8% died. HCV
patients with HCC had highest average rate of graft failure:
HBV 5.5% vs. HCV 8.9% vs. 6.4% in other LD (p<0.0001).
After 1 year of follow-up, graft failure rates were similar in
all HCC patients (4.8%-5.4%, p=0.55). Despite this, starting
year 3 post-transplant, the cumulative risk of graft failure in
HCV patients became significantly higher (HCV 11.4% vs.
HBV 6.6% vs. other LD 8.0%, p=0.0003) and remained high
by follow-up year 5 (HCV 14.5% vs. HBV 8.1% vs. other LD
9.9%, 0.0007). The lowest post-transplant mortality rate was
observed in HBV patients (HBV: 19.9% vs. HCV 29.1% and
other LD 26.9%, p<0.0001). In fact, this difference was border-
line significant starting as early as 1 year post-transplant (HBV
8.5% vs. HCV 12.0%, other LD 11.4%, p=0.0596), became
highly significant by year 3 (HBV 15.5% vs. HCV 27.0% and
other LD 22.7%, p<0.0001). In multivariate analysis of HCC
patients, having hepatitis C was independently associated with
an increased risk of both graft failure (aHR (95% CI) = 1.73
(1.35-2.21), p<0.0001) and mortality (1.34 (1.20-1.49),
p<0.0001). CONCLUSIONS: Patients with HCV-associated
HCC are at higher risk of adverse post-transplant outcomes.
Given that HCV is the main driver of HCC in the U.S., better
screening strategies and aggressive treatment of HCV patients
with the newly developed highly effective interferon- and riba-
virin-free regimens must be considered.
Disclosures:
Sammy Saab - Advisory Committees or Review Panels: BMS, Gilead, Merck,
Genentech; Grant/Research Support: Merck, Gilead; Speaking and Teaching:
BMS, Gilead, Merck, Genentech, Salix, Onyx, Bayer, Janssen; Stock Share-
holder: Salix, Johnson and Johnson, BMS, Gilead
Brian P. Lam - Advisory Committees or Review Panels: BMS; Speaking and Teach-
ing: Gilead; Stock Shareholder: Gilead
The following people have nothing to disclose: Zobair Younossi, Maria Ste-
panova, Kameron Tavakolian, Manirath Srishord, Chapy Venkatesan, James N.
Cooper, Homan Wai, Linda Henry
HEPATOLOGY, October, 2014
164
Real world risk score for hepatocellular carcinoma
(RWS-HCC): development and external validation of a
clinically practical predictive score to identify low risk
individuals
Zhongxian Poh1, Liang Shen2, Hwai-I Yang3, Wai-Kay Seto4,
Vincent W. Wong5, Clement Y. Lin1, Boon-Bee George Goh1,
Jason Chang1,6, Henry Lik-Yuen Chan5, Man-Fung Yuen4, Chien-
Jen Chen3, Chee-Kiat Tan1,6; 1Gastroenterology & Hepatology,
Singapore General Hospital, Singapore, Singapore; 2Biostatis-
tics Unit, Yong Loo Lin School of Medicine, National University
of Singapore, Singapore, Singapore; 3Genomics Research Cen-
ter, Academia Sinica, Taipei, Taiwan; 4Department of Medicine,
The University of Hong Kong, Queen Mary Hospital, Hong Kong,
Hong Kong; 5Department of Medicine and Therapeutics and Insti-
tute of Digestive Disease, The Chinese University of Hong Kong,
Hong Kong, Hong Kong; 6Duke-NUS Graduate Medical School,
Singapore, Singapore
Background: Current HCC predictive risk scores in chronic hep-
atitis B (CHB) patients require HBV-DNA quantification which
is a costly test not available in all parts of the world. Globally,
the majority of CHB patients are seen in healthcare settings
where only simple liver biochemistries (LBC) and ultrasound are
available, thus limiting the applicability of such scores. Aim:
This study aims to develop and externally validate a clinically
practical HBV-DNA-free scoring system to predict HCC in CHB
patients. Methods: The development cohort comprised 673
CHB patients from our department’s outpatient clinics enrolled
in a physician driven HCC surveillance program comprising
3-6 monthly LBC and AFP and 6-12 monthly imaging. They
were followed up over 10 years (2003-2013). Cirrhosis was
diagnosed on histology or imaging with supportive clinical
evidence. HCC was diagnosed on dynamic CT/MRI scan or
histology. The validation cohorts included 2586, 449 and 318
patients from the REVEAL-HBV, Queen Mary Hospital (QMH),
Hong Kong and Prince of Wales Hospital (PWH), Hong Kong
respectively. Risk factors at baseline evaluated for HCC devel-
opment included gender, age, presence of cirrhosis, HBeAg
status, albumin, bilirubin, alkaline phosphatase, ALT, AST and
AFP. Independent variables were gender, age, AFP level and
cirrhosis. Multiple logistic regression was used to predict risk
of HCC at 10 years. Results: 673 patients were enrolled with
545 (81%) still on follow-up after 10 years. Over 10 years,
43 developed HCC in the development cohort and 217 in the
validation cohorts (REVEAL-134; QMH-30; PWH-53). Using
a cutoff value of ≥4.5 (see table), AUROC was 0.915 (95%
CI 0.880-0.949) with 88.1% sensitivity, 83% specificity and
98.8% negative predictive value (NPV) in the development
cohort. AUROC were 0.767 (95% CI 0.725-0.810), 0.902
(95% CI 0.856-0.948) and 0.830 (95% CI 0.747-0.913) in
the REVEAL, QMH and PWH validation cohorts respectively.
Specificity and sensitivity ranged between 79.2%-95.8% and
48.5-76.7% respectively for the 3 validation cohorts and NPV
varied between 93.0-97.9%. Conclusion: We have developed
and validated a risk score utilising simple baseline variables
without HBV-DNA quantification to accurately identify CHB
patients with low 10-year risk of HCC development. It can be
used to assess HCC risk and make informed decisions regard-
ing surveillance and management of CHB patients.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS 281A

Disclosures: tive cohort study, DM was associated with an increased risk

Wai-Kay Seto - Advisory Committees or Review Panels: Gilead Science; Speak- of HCC over 30 years of follow-up. The association was inde-
ing and Teaching: Gilead Science, Bristol-Myers Squibb
pendent of duration of diabetes and did not appear to be
Vincent W. Wong - Advisory Committees or Review Panels: Abbvie, Gilead; mediated by BMI.
Consulting: Merck, NovaMedica; Speaking and Teaching: Gilead, Echosens
Disclosures:
Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, MSD,
Bristol-Myers Squibb, Roche, Novartis Pharmaceutical; Speaking and Teaching: Raymond T. Chung - Consulting: Abbvie; Grant/Research Support: Gilead, Mass
Echosens, Abbvie Biologics
Man-Fung Yuen - Advisory Committees or Review Panels: GlaxoSmithKline, Andrew T. Chan - Consulting: Pfizer Inc, Bayer Healthcare, Pozen Inc, Millennium
Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, Pharmaceuticals
GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-My- The following people have nothing to disclose: Lindsay Y. King, Hamed Khalili,
ers Squibb, Pfizer; Grant/Research Support: Roche, Bristol-Myers Squibb, Edward S. Huang
GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmith-
Kline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead
Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science
Chee-Kiat Tan - Advisory Committees or Review Panels: Gilead Sciences, MSD; 166
Grant/Research Support: Bristol-Myers Squibb Hepatocellular Carcinoma (HCC) Surveillance Among
The following people have nothing to disclose: Zhongxian Poh, Liang Shen, Cirrhotic Patients with Commercial Health Insurance:
Hwai-I Yang, Clement Y. Lin, Boon-Bee George Goh, Jason Chang, Chien-Jen
Chen National Rates and Determinants of Surveillance
David S. Goldberg1,2, Adriana Valderama3, Rajesh Kamalakar3,
Sujit S. Sansgiry4, Svetlana Babajanyan3, James D. Lewis1,2; 1Divi-
165 sion of Gastroenterology, Hospital of the University of Pennsyl-
Diabetes mellitus is associated with an increased risk vania, Philadelphia, PA; 2Center for Clinical Epidemiology and
of HCC in a large prospective cohort with long term fol- Biostatistics, University of Pennsylvania, Philadelphia, PA; 3Bayer
low-up HealthCare, Whippany, NJ; 4University of Houston College of
Pharmacy, Houston, TX
Lindsay Y. King1, Hamed Khalili1, Edward S. Huang3, Raymond
T. Chung1, Andrew T. Chan1,2; 1Gastroenterology, Massachusetts Purpose: AASLD guidelines recommend biannual HCC screen-
General Hospital, Boston, MA; 2Channing Division of Network ing for cirrhotic patients. Previous data from government spon-
Medicine, Brigham and Women’s Hospital, Boston, MA; 3Gas- sored health plans suggests adherence to these guidelines is
troenterology, Palo Alto Medical Foundation, Mountain View, CA suboptimal. The objective of this study was to evaluate HCC
surveillance rates in a nationally representative cohort of com-
Purpose: There are few established lifestyle risk factors for
mercially insured cirrhotic patients. Methods: We used the
hepatocellular carcinoma (HCC). Some studies have suggested
Truven Health Analytics databases from 2006-2010, using
an association between diabetes mellitus (DM), obesity and
1/1/2006 as the anchor date for evaluating outcomes given
HCC. However, these data are largely based on retrospective
the publication of AASLD screening guidelines in 11/2005.
case-control studies or cohorts in which diagnoses are based
Surveillance patterns were characterized using categorical and
on claims data. In addition, few studies have been able to
continuous outcomes. The categorical outcome was: 1) com-
account for the influence of body mass index (BMI) or the dura-
plete (one ultrasound every 6-month interval after 1/1/2006);
tion of DM in relation to risk. Thus, we prospectively exam-
2) incomplete (≥1ultrasound); or 3) none. The continuous
ined the association between DM and risk of HCC within two
measure was defined as the proportion of time “up-to-date”
large cohorts of US men and women that have also provided
with surveillance (PUTDS), with the six months immediately fol-
detailed information on other lifestyle risk factors. Methods: We
lowing each ultrasound categorized as “up-to-date.” Results:
conducted a prospective study of 49,432 men enrolled in the
During a median follow-up of 22.9 (IQR: 16.3-33.9) months
Health Professionals Follow-up Study since 1986 and 116,146
among 8,916 cirrhotic patients, only 785 (8.8%) patients had
women enrolled in the Nurses’ Health Study since 1980 with-
complete surveillance, 4,943 (55.4%) incomplete, and 3,188
out a prior history of cancer. Biennially, with greater than 90%
(35.8%) none. During follow-up, the mean PUDTS was 0.34
follow-up, we collected updated data on DM, other lifestyle risk
(SD: 0.29), and the median was 0.31 (IQR: 0.03-0.52). Mul-
factors, and diagnoses of cancer and other chronic diseases.
tinomial logistic regression models identified two significant
We documented cases of HCC (ICD9 155) identified through
access to care factors, insurance type (p=0.03) and provider
participant reports or follow-up of deaths through physician
subtype (p<0.001). Patients with consumer-directed, high-de-
review of medical records. We used Cox proportional hazards
ductible, capitated point-of-service, or equivalent premium
models to estimate hazard ratios (HR) and 95% confidence
income health insurance were significantly more likely to have
intervals (CI) for HCC, adjusting for known and putative risk
incomplete or no surveillance (p=0.007) compared to those
factors. To account for changes in risk factors over time, we
with preferred provider organization or point of service insur-
used time-varying exposure variables. For alcohol intake and
ance (PPO/POS), and cirrhotic patients diagnosed by non-GI
body mass index, we used baseline measures to minimize the
physicians had 1.8 to 2.5 times increased odds of having
influence of preclinical disease on these exposures. Results:
no surveillance. Patients with complete surveillance had a sig-
Over 30 years of follow-up, we documented 163 incident
nificantly (p<0.05) greater number of physician visits during
cases of HCC over 3,891,069 person years in both cohorts.
follow-up when stratified by hepatic decompensation status:
Compared with non-diabetics, diabetics had a multivariable
1) no hepatic decompensation: mean-1.8 visits (complete sur-
HR for HCC of 3.52 (95%CI 2.44-5.08, p<0.0001) after
veillance), 1.1 (incomplete), and 0.6 (none); 2) prior hepatic
adjustment for age, sex, BMI, aspirin use, smoking status, and
decompensation: mean-2.8 visits (complete), 1.5 (incomplete),
alcohol intake. The association of DM and HCC appeared
and 1.1 (none). In linear regression models, non-GI provider,
similar in women and men. Compared to those without DM,
non-PPO/POS health insurance, and increasing age were
the multivariable HRs for HCC were 3.09 (95%CI 1.60-5.98)
associated with decreased PUTDS, while a history of a hepatic
for those with diabetes for 1-4 years; 3.85 (95%CI 2.04-7.29)
decompensation, presence of any component of the metabolic
for 5-8 years; 3.67 (95%CI 1.81-7.42) for 9-12 years, and
syndrome, and diagnosis of hepatitis B or C were associated
3.57 (95%CI 2.07-6.15) for more than 12 years (P linear trend
with increased PUTDS. Conclusions: HCC surveillance rates
among diabetics=0.65). Conclusions: In this large US prospec-
in commercially insured at-risk patients remain poor despite
282A AASLD ABSTRACTS HEPATOLOGY, October, 2014

formalized guidelines. Improving access to appropriate spe- tive evidence of liver dysfunction (MELD) and tumor aggressive-
cialized care should be targeted for quality improvement inter- ness (AFP) to prioritize the listing of HCC pts for LT. This has the
ventions. potential to improve organ allocation.
Disclosures: Disclosures:
David S. Goldberg - Grant/Research Support: Bayer Healthcare The following people have nothing to disclose: Mohannad Dugum, Nizar N.
Adriana Valderama - Employment: Bayer Zein, Rocio Lopez, Carlos J. Romero-Marrero, Federico N. Aucejo, Bijan Eghte-
sad, Bradley Confer, Ibrahim A. Hanouneh
Sujit S. Sansgiry - Consulting: Bayer Pharmaceuticals
James D. Lewis - Grant/Research Support: Bayer
The following people have nothing to disclose: Rajesh Kamalakar, Svetlana
Babajanyan 168
A Multicenter Randomized Controlled Trial of Percutane-
ous Cryoablation Versus Radiofrequency Ablation Ther-
167 apy in Patients with Hepatocellular Carcinoma
Achieving Equity among Patients With and Without Chunping Wang1, Huaming Wang2, Wuwei Yang3, Kaiwen Hu4,
Hepatocellular Carcinoma (HCC) Who Are Listed for Hui Xie2, Wenlin Bai1, Zheng Dong1, Yinying Lu1, Zhen Zeng1,
Liver Transplantation (LT): A Scoring System Utilizing Min Lou1, Hong Wang1, Xudong Gao1, Xiujuan Chang1, Linjing
MELD and Alpha Fetoprotein (AFP) An1, Jianhui Qu1, Jin Li5, Ke-Qin Hu6, Yongping Yang1; 1Center of
Therapeutic Research for Hepatocellular Carcinoma, 302nd Hos-
Mohannad Dugum1, Nizar N. Zein2, Rocio Lopez4, Carlos J. Rome-
pital, Beijing, Beijing, China; 2Center of Interventional Radiology
ro-Marrero2, Federico N. Aucejo3, Bijan Eghtesad3, Bradley Con-
for Oncology, the 302nd Hospital, Beijing, China; 3Center of Inter-
fer2, Ibrahim A. Hanouneh2; 1Internal Medicine, Cleveland Clinic
ventional Radiology for Oncology, the 307nd Affiliated Hospital of
Foundation, Cleveland, OH; 2Gastroenterology and Hepatology,
Military Acaemy of Science, Beijing, China; 4Center of Oncology,
Cleveland Clinic Foundation, Cleveland, OH; 3Transplantation
Orient Affiliated Hospital of Beijing Traditional Chinese Medicine
Center, Cleveland Clinic Foundation, Cleveland, OH; 4Quantita-
University, Beijing, China; 5Medical Center, the 302nd Hospital,
tive Health Sciences, Cleveland Clinic Foundation, Cleveland, OH
Beijing, China; 6Division of GI/Hepatology, University of Cali-
Background: The United Network for Organ Sharing (UNOS) frnia, Irvine, School of Medicine, Orange, CA, USA, Irvine, CA
provides patients (pts) with HCC who are listed for LT with
Background & Aims: Radiofrequency ablation (RFA) is con-
exemption MELD points that can place them at an advantage
sidered a major one of curative treatment options for hepato-
for earlier LT compared to pts listed for non-malignant indi-
cellular carcinoma (HCC). Growing data have demonstrated
cations. Aim: Identify a scoring system that achieves survival
that cryoablation represents a safe and effective alternative
benefit equity among pts with and without HCC who are listed
therapy for HCC, but no randomization controlled trial (RCT)
for LT. Methods: We defined LT survival benefit as the differ-
has been reported to compare cryoablation with RFA in HCC
ence between life expectancy if transplanted and life expec-
treatment. The present study was a multicenter RCT aimed to
tancy if the subject remains on the waiting list (WL). Adult pts
compare the outcomes of percutaneous cryoablation with RFA
listed for LT in the United States between 2003 and 2012
for the treatment of HCC. Methods: Three hundred and sixty
were identified from the UNOS database, including HCC pts
patients with Child class A or B cirrhosis and 1-2 HCC lesions
meeting exemption policy 3.6.4.4 (stage T2). A univariable
≤ 4 cm, treatment naïve, without metastasis were randomly
analysis was performed to assess differences between HCC
assigned at 1:1 ratio to receive cryoablation (n=180) or RFA
and non-HCC pts; this was done for WL and LT populations.
(n=180) treatment. The baseline characteristics, including age,
Pre-LT survival was modeled using competing risks analysis and
gender,Child-Pugh class, α-fetoprotein, tumor size, HBV DNA
post-LT survival was assessed using Cox regression. Using these
load,platelet count,ECOG score, alanine aminotransferase,
models, life expectancy on WL and after LT was estimated for
albumin, and bilirubin level, were comparable in both groups,
each patient by calculating the area under the survival curve
except the number of patients with two tumors (cryoablation
up to 5 years using the trapezoidal rule. Linear regression was
vs RFA group : 10.56% vs 5%, P = 0.049). The primary end-
used to obtain a regression model defining 5-year LT survival
points were local tumor recurrence in 3 years after the treat-
benefit based on MELD score for non-HCC pts and based on
ment and safety. Results: The local tumor recurrent rates at 1, 2,
MELD and AFP for HCC pts. These 2 models were equated
and 3 years were 3%, 7%, and 7% for cryoablation and 9%,
to obtain an adjusted HCC-MELD score which matches the LT
11%, and 11% for RFA, respectively (P = 0.043). For lesions
survival benefit of HCC pts to non-HCC pts having the same
>3 cm in diameter, there was a significantly lower local tumor
biochemical MELD. Results: 101,458 pts were included in the
recurrent rate in cryoablation group vs. RFA group (7.7% ver-
analysis. Average age at time of listing was 53 ± 10 years,
sus 18.2%, P = 0.041). The 1-, 3-, and 5-year overall survival
65% were male and 13% had HCC. 69% of HCC pts under-
rates were 97%, 67% and 40%, for cryoablation and 97%,
went LT compared to 47% of non-HCC pts. Median LT survival
66%, and 38% for RFA, respectively (P = 0.747). The 1-, 3-,
benefit was higher for non-HCC pts compared to HCC pts.
and 5-year tumor-free survival rates were 89%, 54%, and 35%
Mean time on WL was 13.9 ± 20.3 months for non-HCC pts
in the cryoablation group and 84%, 50%, and 34% in the RFA
compared to 9.1 ± 14.1 months for HCC pts; p<0.001. LT sur-
group, respectively (P = 0.628). Multivariate analysis showed
vival benefit in non-HCC pts increased with increasing MELD
that Child-Pugh B and distant or intrahepatic recurrence were
[= -14.35 + 1.22*MELD; p<0.001]. LT survival benefit in HCC
significant negative predictors to overall survival. Major com-
pts increased with increasing MELD and decreasing AFP [=
plications occurred in 7 patients (3.9%,including 2 peritoneal
-11.83 + 0.95*MELD – (0.83*logAFP); p<0.001]. Equating
hemorrhage, 1 symptomatic pleural effusion, 1 septicemia, 1
these 2 regressions we obtained an adjusted HCC-MELD score:
hemopneumothorax, 1 pneumothorax and 1 worsened jaun-
2.06 + (0.78*MELD) – (0.67*logAFP) that predicts an equal
dice ) following cryoablation and in 6 patients (3.3%, including
survival benefit following LT for HCC pts compared to non-
2 septicemia, 1 peritoneal hemorrhage, 1 symptomatic pleural
HCC pts having the same biochemical MELD. Conclusion: We
effusion, 1 intrahepatic abscess and 1 worsened ascites ) fol-
describe a scoring system that equilibrates the survival benefit
lowing RFA (P = 0.776). Conclusions: Our data demonstrated
among pts with and without HCC who are on a common LT list.
the cryoablation resulted in a significantly lower HCC recurrent
Rather than arbitrary exemption points, this score uses objec-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
rate, although both cryoablation and RFA were equally safe
and effective with similar 5-year survival rates. (This was a
registered clinical trial in China, listed at Clinicaltrial.gov, ID
number, 20071203T) Key words: Hepatocellular carcinoma;
Cryoablation; Radiofrequency ablation
Disclosures:
Ke-Qin Hu - Grant/Research Support: BMS, Gilead, Merck, Vertex, Genentech;
Speaking and Teaching: BMS, Gilead, Merck, Vertex, Genentech
The following people have nothing to disclose: Chunping Wang, Huaming
Wang, Wuwei Yang, Kaiwen Hu, Hui Xie, Wenlin Bai, Zheng Dong, Yinying
Lu, Zhen Zeng, Min Lou, Hong Wang, Xudong Gao, Xiujuan Chang, Linjing An,
Jianhui Qu, Jin Li, Yongping Yang
169
Molecular sequencing and phylogenetics as enhanced
surveillance tools for monitoring Hepatitis C virus trans-
mission dynamics in British Columbia
Andrea Olmstead1,2, Vincent Montoya1,2, Jeffrey Joy3, Iris Luo2,
Naveed Z. Janjua1, Art Poon3, Brendan Jacka4, Francois Lam-
oury4, Tanya L. Applegate4, Jason Grebely4, Richard Harrigan3,
Mel Krajden1,2; 1British Columbia Centre for Disease Control, Van-
couver, BC, Canada; 2University of British Columbia, Vancouver,
BC, Canada; 3BC Centre for Excellence in HIV/AIDS, Vancouver,
BC, Canada; 4The Kirby Institute, UNSW, Sydney, NSW, Austra-
lia
Background: Improved surveillance methods are needed to
understand and monitor the impact of prevention and treatment
interventions on population level HCV transmission dynamics.
Next-generation sequencing (NGS), Sanger sequencing and
viral phylogenetics were used to differentiate acute versus
chronic Hepatitis C virus (HCV) infections and for identifying
transmission networks. Methods: Maximum-likelihood phylo-
genetics was applied to 647 Sanger sequences (HCV NS5B
and Core-HVR1 regions) from 618 individuals diagnosed in
British Columbia in 2011. This included 25 individuals with
2 or 3 serial specimens sampled < 1 year apart. Recent trans-
mission clusters were identified using a cutoff based on the
genetic distance between serial samples. Factors associated
with clustering were analyzed using logistic regression. Deep
sequencing of an HCV NS5B amplicon was used to measure
HCV intra-host sequence diversity in a subset of 77 individuals
with acute (n=13) and chronic (n=64) infection. HCV diversi-
fication was quantified with a single nucleotide variant (SNV)
analysis and Shannon’s entropy. The relationship between
acute versus chronic infection and HCV diversity was explored
by constructing receiver operating characteristic (ROC) plots.
Results: In the NS5B and Core-HVR1 phylogenies, 103 individ-
uals (16.7%) belonged to recent transmission clusters. Individu-
als in clusters were more likely to be seroconverters (OR 2.29,
95%CI 1.49-3.54), genotype 1a and 3a (OR 5.74, 95%CI
2.33-19.1), and <45 years old (OR 1.85, 95%CI 1.21-2.84)
compared to those not in clusters. Acute and chronic HCV
infections could be differentiated using both SNV and Shan-
non’s entropy analysis (p <0.001), with the latter producing the
highest area under the curve value (0.86) by the ROC analysis.
A significantly greater number of synonymous mutations were
associated with chronic versus acute infections, accounting for
much of the difference in sequence diversity observed between
those acutely and chronically infected. Conclusion: Sequenc-
ing and molecular phylogenetics are powerful tools that can
be applied to differentiate acute from chronic infection and to
understand HCV transmission dynamics at a population level.
Systematic application of these methods can be used to monitor
the effectiveness of transmission reduction interventions and to
target public health resources to populations at risk of onward
transmission.
283A
Disclosures:
Jason Grebely - Advisory Committees or Review Panels: Merck, Gilead; Grant/
Research Support: Merck, Gilead, Abbvie, BMS
Mel Krajden - Grant/Research Support: Roche, Merck, Siemens, Boerhinger
Ingelheim, Hologic
The following people have nothing to disclose: Andrea Olmstead, Vincent Mon-
toya, Jeffrey Joy, Iris Luo, Naveed Z. Janjua, Art Poon, Brendan Jacka, Francois
Lamoury, Tanya L. Applegate, Richard Harrigan
170
HCV infection in opiod-using (OU) pregnant women.
Krans E, Rustgi V, Department of Obstetrics and Gyne-
cology, Magee-Womens Research Institute and the
Thomas Starzl Transplant Institute, University of Pitts-
burgh
Elizabeth E. Krans, Vinod K. Rustgi; the thomas starzl transplant
institute, university of pittsburgh medical center, Pittsburgh, PA
Objective: Hepatitis C Virus (HCV) infection is prevalent among
a growing population of opioid-using (OU) pregnant women.
Prenatal care providers often serve as the primary care provid-
ers for these women. Illicit drug use and specifically, opioid
use during pregnancy has increased dramatically over the last
decade from 1.19 to 5.77 per 1,000 hospital births. Due to
high rates of intravenous opioid use, 40-75% of OU pregnant
women are HCV positive and over 4% are HIV positive. Auto-
matic eligibility for Medicaid during pregnancy and the post-
partum period also facilitates accessibility and affordability of
HCV screening, testing and postpartum treatment options for
many otherwise uninsured high-risk women. Our objective was
to evaluate prenatal care delivery for opioid dependent (OD)
pregnant patients with Hepatitis C Virus. Methods: We stud-
ied a retrospective cohort of 702 opioid dependent pregnant
women from 2009 to 2012 at the University of Pittsburgh. HCV
was defined as a positive anti-HCV antibody test. Descriptive
statistics were used to report prenatal care delivery charac-
teristics regarding the evaluation of HCV for the population.
All analyses were conducted with STATA® 12 (StataCorp,
College Station, TX). Results: Of 702 OD pregnant women,
309 (44%) had a diagnosis of HCV and approximately 28% of
HCV infections were newly diagnosed in pregnancy. Liver func-
tion was evaluated in 90% of patients and 37% had abnormal
results. Fewer than 25% of patients had viral load (HCV-RNA)
testing, fewer than 16% had genotype testing and fewer than
16% had an immunization for either Hepatitis A or B. While
74% of patients were referred to hepatology, fewer than 20%
attended the consultation. Finally, fewer than 2% of OD preg-
nant women received HCV treatment within 1 year following
delivery Conclusions: Recent improvements in the effectiveness
and tolerability of HCV treatment regimens underscore the
importance of identifying HCV in high-risk populations such
as OD pregnant women, and engaging these patients in treat-
ment. Prenatal care delivery to pregnant women with HCV is
currently suboptimal and efforts to improve HCV education
and counseling for patient and providers, care coordination
between prenatal care providers and hepatologists to facilitate
HCV treatment for high-risk, substance-using pregnant women
is warranted.
Disclosures:
Vinod K. Rustgi - Grant/Research Support: Abbvie, BMS, Gilead, Achillion
The following people have nothing to disclose: Elizabeth E. Krans
284A AASLD ABSTRACTS
171
Opioid agonist therapy is associated with lower inci-
dence of hepatitis C virus infection in young adult per-
sons who inject drugs
Judith I. Tsui1,
Jennifer Evans2,
Paula J. Lum3,
Judith A.
Kimberly Page2; 1Medicine, Boston University School of Medicine,
Boston, MA; 2Epidemiology and Biostatistics, University of Califor-
nia San Francisco, San Francisco, CA; 3Medicine, University of
California San Francisco, San Francisco, CA
Background: Injection drug use is the primary mode of trans-
mission for hepatitis C virus (HCV) infection. Prior studies sug-
gest opioid agonist therapy (OAT) may reduce incidence of
HCV among people who inject drugs (PWID), however, little
is known about its effects in younger PWID. This study evalu-
ated whether OAT was associated with a lower incidence of
HCV in a cohort of young adult PWID. Methods: Prospective,
observational cohort study of young adult PWID (<30 years
old) in San Francisco who were anti-HCV negative at baseline.
The study was conducted January 2000 through September
2012 with quarterly interviews and blood samples. The pre-
dictor of interest was recent (within past 3 month) substance
use treatment: no treatment, non-OAT treatment, or OAT (meth-
adone or buprenorphine) detoxification or maintenance. The
outcome was incident HCV infection documented with a new
positive HCV RNA result and/or a positive anti-HCV result.
Cumulative HCV incidence rates and 95% confidence intervals
were calculated assuming a Poisson distribution. Cox Propor-
tional Hazards models were fit adjusting for age, gender, race,
years of injection drug use, homelessness and incarceration.
Results: Baseline characteristics of the sample (n=552) were:
median age 23 (IQR: 20-26), 32% female, 73% Caucasian,
40% did not graduate high school, and 69% were homeless.
The median years injecting was 3.6 (IQR: 1.5-6.6); 34% were
daily injectors and the majority (82%) reported no recent treat-
ment for substance use disorders. Over the observation period
of 680 person-years (py), there were 171 incident cases of
HCV (incidence rate=25.1/100 py; 95% CI: 21.6-29.2). The
rate ratio was significantly lower for participants who reported
recent maintenance OAT (0.31; 95% CI: 0.14-0.65), but not
for those who reported recent non-OAT treatment (0.63; 95%
CI: 0.37-1.08), or OAT detoxification (1.45; 95% CI: 0.80-
2.69). After adjustment for other covariates, maintenance
OAT was associated with lower relative hazards for becoming
infected with HCV over time (AHR=0.40; 95% CI: 0.19-0.88).
Conclusions: In this cohort of young adult PWID, recent main-
tenance OAT was associated with lower incidence of HCV.
Medication assisted treatment for opioid use disorders may be
one strategy to prevent spread of HCV among young PWID.
Disclosures:
The following people have nothing to disclose: Judith I. Tsui, Jennifer Evans, Paula
J. Lum, Judith A. Hahn, Kimberly Page
HEPATOLOGY, October, 2014
172
Hepatitis C Virus Infection Increases Risk of Chronic Kid-
ney Disease: REVEAL-HCV Study
Tai-Shuan Lai1,2, Mei-Hsuan Lee3, Hwai-I Yang4, Yong Yuan5, Gil-
Hahn2,3, bert LItalien5,6, Kuo-Liong Chien2, Chien-Jen Chen4; 1Department
of Internal Medicine, National Taiwan University Hospital, Bei-Hu
Branch, Taipei, Taiwan; 2Institute of Epidemiology and Preventive
Medicine, National Taiwan University, Taipei, Taiwan; 3Institute of
Clinical Medicine, National Yang-Ming University, Taipei, Taiwan;
4Genomics Research Center, Academia Sinica, Taipei, Taiwan;
5Global Health Economics and Outcomes Research, Bristol-Myers
Squibb, Princeton, NJ; 6Yale University School of Medicine, New
Haven, CT
Introduction This community-based prospective study aimed to
compare the prevalence and mortality of chronic kidney dis-
eases between participants with and without chronic hepatitis
C virus (HCV) infection. Methods A total of 23,785 partici-
pants aged 30-65 years were enrolled in 1991-1992. Serum
HCV RNA levels were tested for participants seropositive for
antibodies against HCV (anti-HCV). Deaths from renal causes
were ascertained through computerized linkage with National
Death Certification profiles until December 31, 2008. Results
There were 1,313 participants seropositive for anti-HCV and
2,751 had chronic kidney diseases at study entry. The multivar-
iate-adjusted prevalence odds ratio (95% confidence interval,
p value) was 1.34 (1.13-1.59, p<0.001) for chronic kidney
disease and 1.34 (1.17-1.55, p<0.001) for proteinuria in
anti-HCV seropositives compared with seronegatives. A total
of 17,455 participants (including 826 anti-seropositives) with-
out chronic kidney disease at study entry were followed for a
median period of 16.1 years. A total of 85 deaths from renal
causes occurred during 281,502 person-years of follow-up.
Mortality rates per 100,000 person-years from renal causes
were 26.4 and 109.3 for anti-HCV seronegatives and sero-
positives, respectively. Comparing with participants seronega-
tive for anti-HCV, the multivariate-adjusted hazard ratio (95%
confidence interval, p value) of dying from renal causes was
3.94 (2.22-7.01, p<0.001) for all anti-HCV-seropositive par-
ticipants, 2.50 (1.08-5.76) for those with low HCV RNA levels,
and 6.93 (3.33-14.42) for those with high HCV RNA levels.
Conclusion Chronic HCV infection is significantly associated
with an increased risk of proteinuria and chronic kidney dis-
ease. Serum HCV RNA level is a major risk predictor of deaths
from renal diseases in a dose-response relation.
Cumulative Risk of Deaths From Renal Causes by Serum HCV
RNA Level
Disclosures:
Yong Yuan - Employment: Bristol Myers Squibb Company
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Gilbert LItalien - Employment: Bristol Myers Squibb; Stock Shareholder: Bristol
Myers Squibb
The following people have nothing to disclose: Tai-Shuan Lai, Mei-Hsuan Lee,
Hwai-I Yang, Kuo-Liong Chien, Chien-Jen Chen
173
Patients with chronic hepatitis C virus infection have an
increased risk of non-Hodgkin’s lymphoma
Tung-Hung Su1,2, Chun-Jen Liu1,2, Chi-Ling Chen2, Tai-Chung
Tseng3, Chen-Hua Liu1,2, Hung-Chih Yang1, Pei-Jer Chen1,2,
Ding-Shinn Chen1,2, Jia-Horng Kao1,2; 1Department of Internal
Medicine, National Taiwan University Hospital, Taipei, Taiwan;
2Graduate Institute of Clinical Medicine, National Taiwan Univer-
sity College of Medicine, Taipei, Taiwan; 3Division of Gastroenter-
ology, Department of Internal Medicine, Buddhist Tzu Chi General
Hospital, Taipei Branch, Taipei, Taiwan
Background and Aims Chronic hepatitis C virus (HCV) infec-
tion is associated with extra-hepatic manifestations, including
non-Hodgkin’s lymphoma (NHL). However, large-scale studies
with long-term follow-up in Asian population are still lacking.
We thus investigated the association of chronic HCV infection
with lymphoma by using a population-based cohort. Mate-
rials and Methods Chronic hepatitis C (CHC) patients were
retrieved from the Taiwan National Health Insurance Research
Database during 2001-2005 and those with prior malignancy
or co-infected with hepatitis B or human immunodeficiency
virus were excluded. Their comorbidities were matched by
propensity score with another age- and sex-matched con-
trol population without HCV infection. The CHC and control
groups were followed longitudinally until the end of 2009 for
the newly development of lymphoma. Results A total of 12,228
CHC and 48,912 control patients were included and well
matched for comorbidities of hypertension, diabetes mellitus,
peptic ulcer disease, pulmonary disease, coronary artery dis-
ease, cerebrovascular disease and hyperlipidemia. After an
average follow-up of 6 and 8 years in the CHC and control
groups, respectively, there were 29 all lymphoma and 24 NHL
developed in the CHC group; whereas there were 108 all
lymphoma and 80 NHL developed in the control group. Using
Kaplan-Meier survival analysis, the CHC group had signifi-
cantly greater cumulative incidence rates of all lymphoma and
NHL than the control group (logrank tests, all P<.05). By Cox-re-
gression analysis and adjustment for other comorbidities, older
age and HCV infection were associated with an increased
risk of either all lymphoma (HR: 1.77, 95% CI: 1.19-2.63) or
NHL (HR: 1.98, 95%CI: 1.28-3.06) development. Conclusion
Asian patients with chronic HCV infection is associated with an
increased risk of all lymphoma and NHL development.
Disclosures:
Pei-Jer Chen - Advisory Committees or Review Panels: BMS, GSK, BMS, GSK,
Medigene; Independent Contractor: J & J; Speaking and Teaching: Roche, Roche
Ding-Shinn Chen - Consulting: BMS, GSK, Gilead, Roche, Merck, BMS, GSK,
Gilead, Roche, Merck
The following people have nothing to disclose: Tung-Hung Su, Chun-Jen Liu,
Chi-Ling Chen, Tai-Chung Tseng, Chen-Hua Liu, Hung-Chih Yang, Jia-Horng Kao
285A
174
Mortality and progression to decompensated cirrhosis
in chronic hepatitis C (CHC) patients with liver biopsy
confirmed fibrosis in the Chronic Hepatitis Cohort Study
(CHeCS)
Anne C. Moorman1, Fujie Xu1, Xin Tong1, Stuart C. Gordon2,
Loralee B. Rupp2, Mei Lu2, Philip R. Spradling1, Eyasu H. Teshale1,
Joseph A. Boscarino3, Vinutha Vijayadeva4, Mark A. Schmidt5,
Scott D. Holmberg1; 1Division of Viral Hepatitis, Centers for Dis-
ease Control and Prevention, Atlanta, GA; 2Henry Ford Health Sys-
tem, Detroit, MI; 3Geisinger Health System, Danville, PA; 4Kaiser
Permanente Hawaii, Honolulu, HI; 5Kaiser Permanente Northwest,
Portland, OR
Background: CHC patients are at risk for progressive hepatic
fibrosis and cirrhosis, leading to hepatocellular carcinoma
(HCC) or decompensated cirrhosis (DC); deaths from CHC
are increasing in the U.S. Using data from CHeCS, an ongo-
ing observational cohort study among patients of 4 U.S. inte-
grated healthcare systems, we sought to describe all-cause
mortality and progression to DC/ HCC among CHC patients
following biopsy-confirmed fibrosis in the era prior to direct
acting antivirals (DAAs). Methods: For patients with liver biop-
sies performed during 2004-2011 and before onset of DC,
HCC, or HCV therapy, fibrosis scores from different systems
were mapped to a F0–F4 equivalency scale. Onset of DC was
defined as first occurrence in the following group of conditions
identified by ICD9 diagnosis/procedure codes validated as
associated with DC in CHeCS: liver transplant, hepatic enceph-
alopathy, portal hypertension, esophageal varices or ascites.
HCC was based on validated tumor registry reports. We exam-
ined patient demographic and clinical characteristics and used
a proportional-hazard model with treatment as time-dependent
covariate to estimate risk of developing DC. Results: Among
14,256 patients eligible for the CHeCS HCV cohort during
2004-2011, 2,110 had qualifying biopsies and of these 616
(29%) had F2 fibrosis, 336 (16%) F3, and 300 (14%) F4.
The proportions of DC, HCC and death were observed over
mean/median 4 years in each group (range 3.7-4.2 years):
for F2 3.6% developed DC, 1.0% HCC, and 4.9% died; for
F3 these were 10.1%/2.7%/10.4% and for F4 were 27.7%
/8.3%/23.7%. Ever-receipt of anti-HCV therapy was 64%
among F3, 52% among F4, and 41% among F2 patients.
Among those treated, SVR was achieved by 46% of F2, 26%
of F3, and 23% of F4 patients. In a proportional hazards
model, after adjusting for demographic and clinical covari-
ates, factors independently associated with progression to DC
included black vs white race (aHR 1.8), initial biopsy stage F3
(aHR 2.4) or F4 (aHR 3.9) vs F2, higher Charlson comorbidity
score at any time after biopsy (compared with score of 0, score
≥3 aHR= 3.0, score 2 aHR=2.8, score 1 aHR=1.8), or platelet
count <normal (aHR 4.6) or serum bilirubin >normal (aHR 3.4)
at the time of biopsy. Receipt of any anti-HCV treatment was
protective (aHR 0.7). Conclusions: In a large cohort of CHC
patients during 2004-2011 prior to the prevalent use of triple
therapy, we observed substantial progression to DC, HCC, and
mortality among those at higher fibrosis levels despite avail-
ability of standard therapy. These findings can help providers
in determining the risks of disease progression without DAA-
based anti-HCV therapy.
Disclosures:
Stuart C. Gordon - Advisory Committees or Review Panels: Tibotec; Consulting:
Merck, CVS Caremark, Gilead Sciences, BMS, Abbvie; Grant/Research Sup-
port: Roche/Genentech, Merck, Vertex Pharmaceuticals, Gilead Sciences, BMS,
Abbott, Intercept Pharmaceuticals, Exalenz Sciences, Inc.
The following people have nothing to disclose: Anne C. Moorman, Fujie Xu, Xin
Tong, Loralee B. Rupp, Mei Lu, Philip R. Spradling, Eyasu H. Teshale, Joseph A.
Boscarino, Vinutha Vijayadeva, Mark A. Schmidt, Scott D. Holmberg
286A AASLD ABSTRACTS
175
Liver Stiffness Measurement Predicts Posthepatectomy
Liver Failure
Gen Yamamoto1, Kojiro Taura1, Yukinori Koyama2, Kazutaka
Tanabe1, Takahiro Nishio1, Yukihiro Okuda1, Etsuro Hatano1,
Shinji Uemoto1; 1Department of Surgery, Graduate School of Med-
icine, Kyoto University, Kyoto, Japan; 2Department of Medicine,
University of California San Diego, San Diego, CA
Posthepatectomy liver failure (PHLF) is a fatal complication after
partial hepatectomy. Prediction of PHLF based on preoperative
liver function test and the functional liver volume to be resected
is crucial. Chronic liver injury results in liver fibrosis that is
directly associated with liver dysfunction. Recently liver stiff-
ness measurement (LSM) is gaining popularity as a noninvasive
assessment for liver fibrosis. In this study we aimed to eval-
uate the usefulness of LSM for predicting PHLF. We enrolled
two hundreds and thirty-four patients (152 primary liver tumors
and 81 metastatic liver tumors) undergoing partial hepatec-
tomy between August 2011 and April 2014. Liver stiffness
was measured with ACUSON model S2000 ultrasound system
(Siemens Medical Solutions) equipped with Acoustic Radia-
tion Force Impulse (ARFI) system and was expressed as shear
wave velocity (SWV) (m/s). Remnant of the liver (REM) (%)
was calculated by CT volumetry and the weight of resected
specimens. In addition to general blood test, ICG elimination
rate (ICG K) was measured preoperatively. PHLF was defined
according to the criteria proposed by International Study
Group of Liver Surgery (Surgery. 2011 May;149(5):713-24.)
and gradad as A, B, or C. Liver fibrosis was graded as F0
to F4 by METAVIR score. The ability of SWV, ICG K, and
general hematological/biochemical factors for the prediction
of PHLF was compared by receiver operating characteristic
(ROC) analysis. The mean SWV was 1.31, 1.40, 1.60, 1.80,
and 2.80 for F0 to F4, respectively. Grade A PHLF occurred
in 21 patients (9%) whereas grade B in 16 patients (7%) and
grade C in 4 patients (2%). The area under the curve (AUC)
of the ROC curve (AUROC) for the prediction of PHLF was
(in descending order) 0.704 for SWV, 0.698 for hyaluronic
acid (HA), 0.674 for PT-INR, 0.673 for platelet count (PLT),
0.664 for T-bil and 0.619 for ICG K. AUROC for grade B or
C PHLF was 0.783 for SWV, 0.754 for HA, 0.722 for PLT,
0.676 for ICG K, 0.636 for PT-INR and 0.621 for T-Bil. The
stepwise variable selection with minimum BIC’s method identi-
fied 3 significant factors associated with PHLF. They were 1/
SWV, 1/REM and T-Bil. By logistic regression analysis, we
established a risk index for PHLF as (-2.23521458260909)
+ (-4.49647423960785) * 1/SWV + 1.24494777087502
* 1/REM + 1.91138407348298 * T-Bil. AUROC of the risk
index for PHLF was 0.799 for all grade and 0.835 for grade
B or C, which were better than AUROC of any single preoper-
ative factors. In conclusion, risk assessment incorporating LSM
is useful for the prediction of PHLF.
Disclosures:
The following people have nothing to disclose: Gen Yamamoto, Kojiro Taura,
Yukinori Koyama, Kazutaka Tanabe, Takahiro Nishio, Yukihiro Okuda, Etsuro
Hatano, Shinji Uemoto
176
The Differential Impact of Donor-Specific Antibodies in
Living vs. Deceased Donor Liver Transplantation
Josh Levitsky1, Anat R. Tambur1, R Carlin Walsh1, Chunfa Jie1,
Joseph Kang1, Hugo Kaneku2, Michael M. Abecassis1; 1North-
western University, Chicago, IL; 2UCLA, Los Angeles, CA
Background: Recent attention has focused on the impact of
donor-specific HLA antibodies (DSA) in deceased donor liver
HEPATOLOGY, October, 2014
transplantation (DDLT). With less ischemia, improved donor
selection and more controlled procedures, living donor liver
transplantation (LDLT) may speculatively lead to less DSA for-
mation and/or impact on patient and graft outcomes. Aim: To
compare the incidence and impact of DSA in LDLT vs. DDLT
Methods: The A2ALL biorepository was probed for primary
LDLT and DDLT recipients with available serum samples pre-
(immediately prior to implantation) and post-LT (~3 months).
Samples positive for panel reactive antibodies were tested for
DSA (class, titer) using the Luminex platform. We compared
the incidence of pre- (preformed) and post- (de novo) LT DSA
between LDLT and DDLT and correlated DSA with the follow-
ing time-dependent endpoints: patient and graft survival, rejec-
tion, biliary/vascular complications, HCV recurrence. Results:
129 LDLT and 66 DDLT recipients were identified. There were
more HCV+ recipients (51.5% vs. 34.7%, p=0.03) in the DDLT
group, but no differences in other demographics, rejection,
graft failure or death. The prevalence of +DSA pre/post-LT
(p=0.93, Table) was not different between DDLT and LDLT.
There was also no association between patient survival and
the timing (pre/post), class (I vs. II), and titer of DSA between
the groups. However, pre-LT DSA+ was associated with higher
graft failure only in DDLT (p=0.01). Post-LT DSA+ was asso-
ciated with graft failure regardless of LT type (p=0.005) but
with rejection only in DDLT (p=0.0001). Biliary complications
were higher in LDLT vs. DDLT (p<0.001) but independent of
DSA. There was no difference in HCV recurrence or vascular
complications in both ± DSA. Conclusion: Although preformed
or de novo DSA have a similar prevalence in DDLT vs. LDLT,
they are associated with adverse graft outcomes (graft survival,
rejection), mainly in DDLT. While our findings need further
validation, future research should focus on mechanisms of DSA
graft injury and strategies to mitigate the impact of DSA, partic-
ularly in the DDLT setting.
Prevalence of Pre/Post-LT DSA (DDLT vs. LDLT)
Disclosures:
Josh Levitsky - Consulting: Transplant Genomics Inc; Grant/Research Support:
Novartis; Speaking and Teaching: Gilead, Salix
The following people have nothing to disclose: Anat R. Tambur, R Carlin Walsh,
Chunfa Jie, Joseph Kang, Hugo Kaneku, Michael M. Abecassis
177
Liver Resection for Cholangiocarcinoma: Biological and
Surgical Predictors of Outcome, Status Quo in Additive
Therapy
Arash Nickkholgh1, Arianeb Mehrabi1, Thomas Bruckner2, Ben-
jamin Goeppert3, Peter Schemmer1; 1Dept. of General, Visceral
and Transplant Surgery, Ruprecht-Karls University of Heidelberg,
Heidelberg, Germany; 2Institute of Medical Biometry and Infor-
matics (IMBI), Ruprecht-Karls University of Heidelberg, Heidelberg,
Germany; 3Institute of Pathology, Ruprecht-Karls University of Hei-
delberg, Heidelberg, Germany
Background: Liver resection constitutes the only curative option
for intrahepatic and hilar Cholangiocarcinoma (CCA). The aim
of this work was to analyze the outcome of patients undergo-
ing liver resection for CCA, and to revisit the biological and
surgical determinants of outcome, and the role of neoadjuvant
and additive therapeutic modalities in our single-center cohort
of patients during the last decade. Methods: Using a prospec-
tively filled database of all consecutive patients undergoing
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
surgery due to a preoperative diagnosis of hepatobiliary malig-
nancy between December 2001 and May 2011 (n=936) at
the Department of General, Visceral, and Transplant Surgery
at the University of Heidelberg, demographic, anatomical, clin-
ical, operative, surgical pathologic and follow-up data of all
patients with a final diagnosis of CCA was analyzed. Results: A
final surgical pathologic diagnosis of CCA was made for 236
patients. CCA was found to be intrahepatic (IHCCA, n=117,
50%), proximal extrahepatic -hilar or Klatskin’s tumor- (HCCA,
n=77, 32%), or distal extrahepatic (n=42, 18%). One hundred
and seventy patients (50%) underwent liver resection, including
4 patients (3.4%), who had undergone neoadjuvant chemo-
therapy, and 6 (5%) patients, who had undergone emboli-
zation of the right portal vein. Local R0-status was achieved
in 78 patients (67%). Biliary complications occurred in 31
patients (26.5%). Death within the same admission occurred
in 14 cases (12%). The 1-, 3-, and 5-year overall survival were
68%, 40%, and 28%, respectively; the mean survival time of
all patients underwent liver resection was 32 ± 3 months. By
the end of the study, recurrence was documented in 51 patients
(44%) (mean time to recurrence: 23 ± 3 months, mean survival
time after recurrence: 12 ± 2 months). Surgical margins (R-Sit-
uation) and performance of locoregional lymphadenectomy
were the only independent variables to improve overall sur-
vival in a multivariate regression analysis. An abnormal CA
19-9 (≥ 37 u/mL), AJCC/UICC T3-4 vs. T1-2, and R1-2 vs. R0
were the independent predictors of recurrence. Neoadjuvant
or adjuvant therapies did not yield a survival benefit in patients
undergoing liver resection. Conclusion: Surgery remains the
only curative treatment for patients with CCA. Extended resec-
tion in order to achieve histologically free margins and the per-
formance of locoregional lymphadenectomy improve survival.
Additive therapeutic strategies to prolong disease-free survival
are still ineffective.
Disclosures:
The following people have nothing to disclose: Arash Nickkholgh, Arianeb Meh-
rabi, Thomas Bruckner, Benjamin Goeppert, Peter Schemmer
178
Non-invasive biomarkers are superior to clinical mea-
sures in predicting hepatic decompensation after liver
resection
James A. Thomas1,2, Ashok S. Raj1,2, Uthayanan Chelvaratnam1,
Marrianne Black1, Caroline Tallis1, Linda Fletcher1, Gerald Holt-
mann1,2, Jonathan Fawcett1, Katherine Stuart1; 1Hepatology, Prin-
cess Alexandra Hospital, Brisbane, QLD, Australia; 2School of
Medicine, University of Queensland, Brisbane, QLD, Australia
Background/Aim: Novel, non-invasive biomarkers to assess
liver function and predict clinical outcomes are urgently
needed. Hepatocellular carcinoma (HCC) is the fifth most com-
mon malignancy worldwide and often occurs in cirrhosis. Surgi-
cal resection of HCC is a potentially curative treatment option,
however it has the capacity to cause hepatic decompensation.
No single test currently in clinical use offers reliable risk strati-
fication. This study aims to assess the clinical utility of the 13C
methacetin breath test (13CMBT, measure of hepatocyte mic-
rosomal function), transient elastography using FibroScan and
indocyanine green (ICG) clearance (measure of liver perfusion
and excretory function) in predicting hepatic decompensation
in patients undergoing liver resection. Methods: 13CMBT,
FibroScan and ICG clearance were prospectively measured in
105 patients being assessed for liver resection. Patient demo-
graphics, clinical and laboratory data were recorded includ-
ing Child-Pugh-Turcotte (CPT) and Model for End-Stage Liver
Disease (MELD) scores. 23 patients had surgery. Post-operative
287A
hepatic decompensation was determined by biochemical (ele-
vation in bilirubin or INR) and clinical (ascites, encephalopa-
thy) parameters. 2 tailed P values <0.05* or <0.01** were
considered statistically significant. Results: There was signif-
icant correlation of 13CMBT, FibroScan and ICG clearance
with serum bilirubin (R=-0.43**, 0.21*, 0.42**) and albumin
levels (R=0.37**,-0.41**, -0.72**), respectively. Only ICG
clearance was associated with INR (R=0.26*). Both CPT (R=-
0.44**, 0.46**, 0.68**) and MELD scores (R=-0.2 [p=0.08],
0.28*, 0.38**) correlated with these biomarkers. ICG clear-
ance correlated with FibroScan (R=0.5**) and 13CMBT (R=-
0.55**) as did FibroScan with 13CMBT (R=-0.38**). Receiver
operating characteristic (ROC) curve plots were used to assess
the performance of these tests in predicting post-operative liver
decompensation. The areas under the curve (AUROC) for CPT
score (0.46) and MELD (0.55) offered limited clinical utility
compared to ICG clearance (0.78). Multivariate analysis was
used to control for duration of surgery and weight of resected
liver; 13CMBT was strongly associated with post-operative
decompensation (R=0.68*). Conclusions: 13CMBT, FibroScan
and ICG clearance correlated with laboratory measures of
liver function. ICG clearance and 13CMBT were superior to
routine blood tests, CPT and MELD scores in predicting hepatic
decompensation after liver resection. This result justifies further
evaluation in other cohorts and clinical settings.
Disclosures:
The following people have nothing to disclose: James A. Thomas, Ashok S. Raj,
Uthayanan Chelvaratnam, Marrianne Black, Caroline Tallis, Linda Fletcher, Ger-
ald Holtmann, Jonathan Fawcett, Katherine Stuart
179
Higher MELD scores at time of transplant are not asso-
ciated with lower survival following living donor liver
transplantation among patients with MELD <25
Ryan B. Perumpail1, Robert Wong1, Andrew M. Su1, Clark A.
Bonham2, Carlos O. Esquivel2, Aijaz Ahmed1; 1Division of Gastro-
enterology and Hepatology, Stanford University Medical Center,
Stanford, CA; 2Department of Surgery, Stanford University Medi-
cal Center, Stanford, CA
Background: Although the Model for End-stage Liver Disease
(MELD) score predicts liver transplantation waitlist survival,
there is uncertainty surrounding what upper limit MELD score
should be used to disqualify patients as too sick for living
donor liver transplantation (LDLT). This uncertainty stems from
the paucity of large studies evaluating the effect of MELD score
on survival following LDLT. Aim: To evaluate the association
between MELD score and survival following LDLT in the U.S.
population. Methods: All U.S. adult LDLT recipients with MELD
<25 were evaluated using the 2003-2012 United Network for
Organ Sharing registry. Survival following LDLT was stratified
into three MELD categories (MELD<15 vs. MELD 15-19 vs.
MELD 20-24) and evaluated using Kaplan Meier methods and
multivariate Cox proportional hazards models. Results: Over-
all, 2,258 patients underwent LDLT, including 1,210 patients
with MELD <15 (53.6%), 732 with MELD 15-19 (32.4%), and
316 with MELD 20-24 (14.0%). Compared to patients with
MELD <15, there was a significantly greater prevalence of
ascites among those with MELD 15-19 (79.8% vs. 63.0%,
p<0.001) and MELD 20-24 (82.0% vs. 63.0%, p<0.001).
The same trend was seen for hepatic encephalopathy: MELD
15-19 (60.5% vs. 50.4%, p<0.001) and MELD 20-24 (63.9%
vs. 50.4%, p<0.001). Compared to patients with MELD <15,
overall 5-year survival following LDLT was similar among
patients with MELD 15-19 (80.9% vs. 80.3%, p=0.77) and
MELD 20-24 (81.2% vs. 80.3%, p=0.73) (Figure). When com-
288A AASLD ABSTRACTS
pared to patients with MELD <15, there was no significant
difference in long-term post-LDLT survival among those with
MELD 15-19 (HR 1.11, 95% CI, 0.85 – 1.45, p=0.45) and
a non-significant trend towards lower survival in patients with
MELD 20-24 (HR 1.28, 95% CI, 0.91 – 1.81, p=0.16). Con-
clusions: Among adult patients with chronic liver disease and
MELD <25, higher MELD scores are not associated with signifi-
cantly lower survival following LDLT.
Disclosures:
Aijaz Ahmed - Consulting: Bristol-Myers Squibb, Gilead Sciences Inc., Roche,
AbbVie, Salix Pharmaceuticals, Janssen pharmaceuticals, Vertex Pharmaceuti-
cals, Three Rivers Pharmaceuticals; Grant/Research Support: Gilead Sciences
Inc.
The following people have nothing to disclose: Ryan B. Perumpail, Robert Wong,
Andrew M. Su, Clark A. Bonham, Carlos O. Esquivel
180
Outcomes and Complications of Right versus Left Lobe
Liver Donation
Hillary Braun, Jennifer L. Dodge, Chris Freise, Nancy L. Ascher,
John P. Roberts; University of California, San Francisco, San Fran-
cisco, CA
Purpose: Minimizing risk to donors in living donor liver trans-
plantation (LDLT) remains a paramount concern. Right lobe (RL)
donation appears to be associated with increased morbidity.
The purpose of this study was to assess the differences in out-
comes and complications for left lobe (LL) versus right lobe (RL)
donors and their recipients. Methods: The medical records of
donors and recipients who underwent LDLT at our institution
between 2003-2013 were reviewed for basic demographic
information. For donors, we also assessed graft size, length of
initial hospital stay (LOS), wound complications, GI symptoms,
MSK symptoms, ED visits, and return to the OR. For recipients,
we evaluated survival, return to the OR, and variables related
to intraoperative modification of portal inflow. We compared
these variables between LL and RL donors and recipients using
Fisher’s exact and Wilcoxon rank sum tests. Correlations were
evaluated using Spearman’s rank correlation coefficients.
Post-transplant survival was estimated using the Kaplan-Meier
method. Significance was set at p<0.05. Results: Between
2003 and 2013, 107 LDLTs were performed at our institution,
with 62 RL and 45 LL grafts. The average LL graft was 436.7
cc versus an average RL graft of 828.5 cc. Compared with
RL counterparts, LL donors were significantly younger (median
30 (IQR 25-38) vs. 37 (30-46) years, p=0.001) and had a
shorter median (IQR) LOS (7 (6-7) vs. 7 (7-8) days, p=0.001).
LL recipients were also younger compared with RL recipients
(53 (44-60) vs. 57 (50-65), p=0.04) and had a longer LOS
(13 (9-16) vs. 10 (8-14) days, p=0.004). Donor LOS increased
with graft volume (rho= 0.38, p<0.001) while recipient LOS
HEPATOLOGY, October, 2014
decreased with graft volume (rho= -0.29, p=0.004). LLs were
more frequently transplanted into male recipients (67vs.45%,
p=0.03) and the splenic artery was ligated more frequently in
LL recipients (40vs.10%, p<0.001). LL transplants resulted in
fewer recipient reoperations (30vs.60%, p=0.004), and fewer
donor readmissions (11vs.27%, p=0.05). One and 3 year
patient survival for LL was 93% and 90% versus 92% and 86%
for RL recipients (p=0.81 and p=0.74, respectively). One and
3 year graft survival for LL was 89% and 89% versus 90% and
85% for RL recipients (p=0.79 and p=0.82, respectively). Con-
clusions: LL donation was associated with fewer donor hospital
admissions, and LL recipients had fewer return trips to the OR.
Graft volume was positively correlated with LOS for the donor
and inversely correlated with recipient LOS. Survival at one
and three years did not differ significantly between RL and LL.
Disclosures:
The following people have nothing to disclose: Hillary Braun, Jennifer L. Dodge,
Chris Freise, Nancy L. Ascher, John P. Roberts
181
High Levels of Circulating Alpha-1-AT Mutant Z Polymer
Protein May Serve as the First Described Disease-Spe-
cific Biomarker for Liver Disease in Alpha-1-AT Defi-
ciency
Jeffrey Teckman1,2, Paula Buchanan5, Lu Tan3, David A. Lomas4;
1Pediatrics and Biochemistry, Saint Louis University, Saint Louis,
MO; 2Cardinal Glennon Children’s Medical Center, Saint Louis,
MO; 3University of Cambridge, Cambridge, United Kingdom;
4University College London, London, United Kingdom; 5Saint Louis
University Center for Outcomes Research, Saint Louis University,
Saint Louis, MO
Background: Homozygous ZZ alpha-1-antitrypsin (A1AT) defi-
ciency is an important cause of pediatric liver disease, and
causes chronic hepatitis, cirrhosis and hepatocellular carci-
noma in adults. A1AT ZZ homozygotes synthesize an abnor-
mal form of the A1AT protein. 85% of the mutant Z protein
molecules are retained in hepatocytes instead of secreted.
Intracellular retention of the mutant Z protein triggers liver
injury. Some of the mutant Z protein retained in hepatocytes
attains a unique, “polymerized” conformation in which multi-
ple Z protein molecules aggregate in a highly stable quater-
nary structure. A1AT mutant Z protein polymers can also be
detected as small, soluble oligomers in serum, representing a
small fraction of the total A1AT level. The polymer conforma-
tion of mutant Z protein is thought to be highly toxic to cells.
The clinical course of A1AT deficiency is highly variable, and
the factors which determine disease progression in an individ-
ual and the predictive markers are still unknown. Objective:
We hypothesized that the magnitude of circulating mutant Z
polymers would correlate with the degree of liver injury and
might be developed as a clinical biomarker of disease severity.
Methods: We examined serum samples obtained at enrollment
from ZZ subjects with liver disease participating in the Child-
hood Liver Disease Research and Education Network (ChiL-
DREN). This prospective, longitudinal, multi-center NIH study
includes nearly 400 A1AT subjects. Detailed history, physical
exam, imaging and laboratory data are collected to identify
subjects with native liver and no portal hypertension (PHT), or
native liver with PHT (29% have PHT). Total circulating A1AT
level was measured in the clinical lab, and published assays
using polymer specific antibodies were used to quantify the cir-
culating mutant Z polymer levels. Results: The mean circulating
polymer level in the cohort was 8.35ug/ml (+/- 7.34 S.D.).
Significantly higher polymer levels were found in the patients
with PHT (p=0.004), and each 1ug/ml increase in polymer
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
level increased the likelihood of PHT 6.7%. The mean total
A1AT level in the cohort was 35.0mg/dl (+/- 11.6 S.D.) and
there was no significant correlation of total A1AT level to PHT
(p=0.84). Continued study will follow the change in polymer
level over time, the relationship of polymer to progression from
no PHT to with PHT, and examine mechanistic links to other
clinical, laboratory, environmental and genetic modifiers. Con-
clusion: Circulating A1AT mutant Z protein polymer level is the
first disease-specific biomarker associated with liver disease
severity reported in A1AT deficiency.
Disclosures:
Jeffrey Teckman - Consulting: Dicerna, Isis Pharmaceuticals, Vertex, Proteostasis,
Genkyotex, The Alpha-1 Project; Grant/Research Support: Alnylam, Arrowhead,
Alpha-1 Foundation
David A. Lomas - Advisory Committees or Review Panels: GSK; Board Member-
ship: GSK; Consulting: GSK; Grant/Research Support: GSK, MRC
The following people have nothing to disclose: Paula Buchanan, Lu Tan
182
Dysregulation of Cholesterol 7 alpha-hydroxylase
(CYP7A1) is involved in the abnormal bile acid synthesis
in livers from biliary atresia children
Yasuhiro Hasegawa1, Hiroki Kondou1,
Kazuhiko Masa-Bessho1,
nobu Kawai2, Kie Nakao1, Takehisa Ueno3, Yoshinori Satomura1,
Akiko Konishi1, Takeshi Kimura1, Kayo Ikeda1, Makiko Tachibna1,
Yoko Miyoshi1, Toshimi Michigami2, Keiichi Ozono1; 1Pediatrics,
Graduate School of Medicine, Osaka University, Suita, Japan;
2Bone and Mineral Research, Research Institute, Osaka Medical
Center for Maternal and Child Health, Izumi, Japan; 3Pediatric
Surgery, Graduate School of Medicine, Osaka University, Suita,
Japan
Backgrounds: Bile acid biosynthesis is strictly regulated by neg-
ative feedback mechanisms under physiological state. Along
with the classical pathway, in which bile acids directly bind
to nuclear receptor farnesoid X receptor (FXR) in hepatocytes
and inhibit the transcription of CYP7A1, recently, bile acids
have been found to induce synthesis of fibroblast growth factor
(FGF)19 via FXR in small intestinal epithelium. FGF19 is then
secreted into portal vein and binds to FGFR4/β klotho (KLB)
complex on hepatocyte plasma membrane, resulting in tran-
scriptional suppression of CYP7A1 through the ERK pathway.
However, it is not clear how the FGF19 signaling pathways
are regulated under chronic cholestasis. Here we studied the
regulation of the signaling pathways under chronic cholesta-
sis using serum and liver tissue from biliary atresia (BA) chil-
dren. Methods: Tissues and serum were obtained from 8 BA
children and 4 non-cholestatic control (NC; hepatoblastoma,
hepatic hemanigoma, urea cycle disorder). Serum FGF19
level was measured by ELISA. Total RNA was extracted from
hepatocytes dissected using laser micro-dissection system and
expression levels of CYP7A1, FXR, small heterodimer partner
(SHP), FGF19, FGFR4, KLB and sprouty homolog 2 (SPRY2)
were examined by qPCR. Phosphorylation of FGFR4, Src
homology 2 (SHP2), c-Raf and ERK were detected by immu-
noprecipitation and Western blotting. Permission to perform
this study was given by the Ethics Committee in our institute,
and written informed consent was obtained from parents of
all of the patients. Results: Expression of CYP7A1 mRNA was
not suppressed in the isolated hepatocytes from BA children
despite high concentration of serum bile acids. To Investigate
mechanisms of this dysregulation, we found the expression of
FXR and SHP were upregulated in BA hepatocytes. Regarding
the FGF19 signaling pathway, both serum and tissue levels of
FGF19 were significantly increased and FGF19 was aberrantly
synthesized in hepatocytes from BA children. Expression of
both FGFR4 and KLB mRNA were increased in BA hepatocytes
289A
and FGFR4 was phosphorylated in both BA and NC livers,
but phosphorylation of SHP2, c-Raf and ERK was significantly
decreased in BA livers. To investigate the down regulation
mechanisms of MAP kinase, we studied SPRY2 which inhibits
ERK pathway at downstream of FGFR. Expression of SPRY2
mRNA was significantly increased in BA hepatocytes. Conclu-
sion: Bile acids biosynthesis was not properly suppressed by
FGF19/FGFR4 as well as classical pathways in BA hepato-
cytes. SPRY2 may be involved in the dysregulation and this
might be one of the mechanisms which deteriorates cholestatic
cirrhosis in BA children.
Disclosures:
The following people have nothing to disclose: Yasuhiro Hasegawa, Hiroki Kon-
dou, Kazuhiko Bessho, Masanobu Kawai, Kie Nakao, Takehisa Ueno, Yoshinori
Satomura, Akiko Konishi, Takeshi Kimura, Kayo Ikeda, Makiko Tachibna, Yoko
Miyoshi, Toshimi Michigami, Keiichi Ozono
183
Progression to high-risk gastroesophageal varices in
biliary atresia children with low-risk signs at first endos-
copy
Oanez Ackermann1, Mathieu Duché1, Beatrice Ducot3,4, Emman-
uel Jacquemin1,2, Olivier Bernard1; 1Hépatologie Pédiatrique,
Assistance Publique des Hôpitaux de Paris, Le Kremlin Bicêtre,
France; 2Inserm U 757, université Paris Sud 11, le kremlin bice-
tre, France; 3santé publique et épidémiologie, assistance publique
hopitaux de paris, Le Kremlin Bicêtre, France; 4Inserm, CESP Cen-
tre for research in Epidemiology and Population Health, U1018,
Epidemiology of Reproduction and Children Development Team,
assistance publique hopitaux de paris, Le Kremlin Bicêtre, France
Background & Aims. Biliary atresia, the most frequent cause of
cirrhosis in children, carries a risk of gastrointestinal bleeding
due to portal hypertension. Our goal was to define the factors
associated with the emergence of endoscopic signs carrying
a high risk of bleeding in children who did not display these
signs at the first upper gastrointestinal endoscopy. Methods.
From 1989 to 2013, 242 children with low-risk signs at first
endoscopic examination underwent > 2 upper gastrointestinal
endoscopic examinations. The emergence of high-risk gastro-
esophageal varices was observed in 82 children (median age,
60 months; range, 9–309 months). A survival study using the
occurrence of high-risk varices as event was performed to iden-
tify factors related to the emergence of these varices and to
describe the probability of their emergence at intervals varying
from six to 36 months according to these factors. Results. The
total serum bilirubin concentration (p<0.003), age (p<0.0001),
and number/grade of esophageal varices (p<0.0001) at the
previous endoscopy were significantly related to the emer-
gence of high-risk varices. The probability of the emergence of
high-risk signs was higher and these signs appeared faster in
infants younger than 12 months, with bilirubin > 100 mmol/l
and/or when the previous endoscopic examination displayed
> 1 grade 1 or grade 2 varices. Progression to high-risk varices
was also related to the serum bilirubin concentration variation
between two endoscopies among the youngest infants. Con-
clusion. The results allow to define a program of repeat endos-
copies to detect high-risk varices and to proceed with primary
prophylaxis of bleeding with endoscopic treatment or hasten
liver transplantation when these signs were found.
Disclosures:
The following people have nothing to disclose: Oanez Ackermann, Mathieu
Duché, Beatrice Ducot, Emmanuel Jacquemin, Olivier Bernard
290A AASLD ABSTRACTS
184
Hepatic inflammation may influence liver stiffness mea-
surements by transient elastography in children and
young adults
Aileen Raizner1, Nick M. Shillingford2, Paul D. Mitchell3, Sarah
Harney1, Roshan Raza1, Jessica Serino1, Maureen M. Jonas1,
Christine K. Lee1; 1Gastroenterology, Hepatology and Nutrition,
Boston Children’s Hospital, Harvard School of Medicine, Boston,
MA; 2Pathology and Laboratory Medicine, Children’s Hospital Los
Angeles and University of Southern California, Los Angeles, CA;
3Clinical Research Center, Boston Children’s Hospital, Boston, MA
Background/Aim: Transient elastography (TE) (FibroScan®,
Echosens, Paris, France), used to measure liver stiffness, is used
to assess fibrosis. In adults, hepatic inflammation has been
shown to contribute to liver stiffness resulting in overestimation
of fibrosis. We aim to investigate the contribution of inflam-
mation to liver stiffness, as measured by TE, in a pediatric
cohort. Methods: This was a cohort analysis of children and
young adults who underwent TE within 1 year of a liver biopsy.
TE probe selection was based on thoracic perimeter (TP); the
M (medium) probe if TP >75cm and the S (small) probe if ≤
75cm. ALT was obtained within 30±7 days of the TE. Fibrosis
was assessed by METAVIR stage and inflammation by ALT and
Ishak score. Data were stratified by METAVIR stage (F0-F2
vs. F3-F4) and analyzed with rank sums and general linear
models. A previous study in this cohort demonstrated that liver
stiffness measurement (LSM) >8.6kPa was highly associated
with F3-F4 (Lee et al. J Pediatr 2013). Results: 198 patients
(55% male) age 3 weeks to 24 years (15% <3 years, 9 % ≥18
years) were enrolled. Diagnoses included autoimmune hepatitis
(N=42, 21%), viral hepatitis (N=40, 20%), cholestasis (N=
19, 10%), fatty liver (N=18, 9%, 14/18 had nonalcoholic
steatohepatitis), biliary atresia (N=9, 5%), metabolic disease
(N=8, 4%), allograft rejection (N=4, 2%) and other (N=58,
29%). 31% of patients had F3-F4 fibrosis. The median interval
between biopsy and LSM was 1.8 (IQR 0.7-5.0) months. In
patients with F0-F2, the proportion of subjects with LSM>8.6kPa
increased with increasing ALT (P=0.0003; Table). In patients
with F3-F4, there was no association between ALT and LSM
(P=0.27). Abnormal ALT was independently associated with
greater LSM (>8.6kPa) after adjusting for dichotomized META-
VIR score (OR 3.8, P= 0.007). Ishak inflammation score was
not associated with LSM after adjusting for METAVIR score
(P=0.28). Conclusions: In patients with mild fibrosis, elevated
ALT was associated with higher LSM, sometimes in the range
seen with significant fibrosis. With more severe fibrosis, there
is little contribution to LSM by inflammation. Ishak score cor-
relates poorly with ALT as a determinant of inflammation. Care
must be taken when interpreting TE values for fibrosis in the
presence of inflammation.
Disclosures:
Maureen M. Jonas - Advisory Committees or Review Panels: Gilead Sciences;
Consulting: Eisai; Grant/Research Support: Bristol Myers Squibb, Roche, Merck
Schering Plough
HEPATOLOGY, October, 2014
The following people have nothing to disclose: Aileen Raizner, Nick M. Shill-
ingford, Paul D. Mitchell, Sarah Harney, Roshan Raza, Jessica Serino, Christine
K. Lee
185
Pediatric Nonalcoholic Fatty Liver Disease (NAFLD): His-
tological Feature Changes Over Time in Paired Biopsies
from the NASH CRN
Elizabeth M. Brunt1, David E. Kleiner2, Patricia H. Belt3, Jean P.
Molleston4, Jeffrey B. Schwimmer5, Joel E. Lavine6, Brent A. Neus-
chwander-Tetri7; 1Pathology and Immunology, Washington Univer-
sity School of Medicine, St Louis, MO; 2Laboratories of Pathology,
National Cancer Institute, Bethesda, MD; 3Bloomberg School of
Public Health, Johns Hopkins Univerisity, Baltimore, MD; 4Pediat-
rics, Indiana University, Indianapolis, IN; 5Pediatrics, University of
California, San Diego, San Diego, CA; 6Pediatrics, Nutrition and
Gastroenterology, Columbia University, New York, NY; 7Internal
Medicine, Saint Louis University School of Medicine, St. Louis, MO
Background and Aim: Little is known about changes in liver
histology over time in children with NAFLD. The NASH Clinical
Research Network (NASH CRN) has provided a unique oppor-
tunity to study such changes. Methods: Children (n=102) with
two sets of biopsies separated by 1-11 years (median 2.2y)
from either the NASH CRN TONIC trial placebo group (Lavine
et al, JAMA, 2011) or the NAFLD Database were included.
Biopsies were reviewed centrally in a masked fashion by the
NASH CRN Pathology Committee. The histological features
of the first and last biopsies were compared using Fisher’s
exact tests. Results: There were 73 boys, 69 Hispanics, and
68 children were older (11-17 y) at the first biopsy. The diag-
nosis patterns shifted significantly over time: zone 1, (border-
line 1b) pattern decreased from 27.5% to 9.8%, while the
zone 3 (borderline 1a) pattern, and definite steatohepatitis
patterns both increased from 14.7% and 28.4% to 18.6% and
29.4%, respectively (p=0.001). In parallel, fibrosis patterns
changed. The portal predominant (1c) fibrosis in 30.4% in
the first biopsy decreased to 15.7% in the last; “no fibrosis”
increased from 28.4% to 40.2% and a smaller increase was
seen in bridging fibrosis from 12.8% to 17.7% (p=0.001).
Significant decreases in steatosis (p=0.02) and increases in
ballooning (p=0.0003) were also noted. In subgroup analyses,
girls showed more overall feature changes than boys, as did
children who were older at first biopsy than those who were
younger at first biopsy. Conclusions: With age, features asso-
ciated with “adult” NAFLD were significantly more common:
fibrosis patterns shifted to include less “portal only” to patterns
with zone 3 fibrosis. Girls showed more feature changes than
boys, and older children at first biopsy showed more changes
than children who were younger at first biopsy. The grade of
steatosis commonly decreased with age, as grades of other
features increased. The changes in fibrosis and diagnostic cat-
egories represent changes in patterns of injury, from those of
“pediatric” to those of “adult” NASH. These findings have
implications for patient care, clinical trials and studies of pedi-
atric and adult NAFLD pathogenesis.
Disclosures:
Elizabeth M. Brunt - Consulting: Synageva; Independent Contractor: Rottapharm,
Kadmon; Speaking and Teaching: Geneva Foundation
Jean P. Molleston - Grant/Research Support: scherring, roche, vertex
Jeffrey B. Schwimmer - Speaking and Teaching: Daiichi Sankyo, Inc.
Joel E. Lavine - Consulting: Merck, Crosscare, Gilead, Takeda Millenium; Grant/
Research Support: Janssen
Brent A. Neuschwander-Tetri - Advisory Committees or Review Panels: Boehring-
er-Ingelheim
The following people have nothing to disclose: David E. Kleiner, Patricia H. Belt
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
186
Magnetic Resonance Imaging and Liver Histology as
Biomarkers of Hepatic Steatosis in Children with Nonal-
coholic Fatty Liver Disease
Jeffrey B. Schwimmer1,2, Michael S. Middleton6, Cynthia A. Beh-
ling3,1, Kimberly P. Newton1,2, Hannah Awai1,2, Melissa N. Paiz1,
Jonathan Hooker6, Gavin Hamilton6, John Fontanesi4,5, Claude B.
Sirlin6; 1Pediatrics, UC San Diego, San Diego, CA; 2Gastroenterol-
ogy, Rady Children’s Hospital, San Diego, CA; 3Pathology, Sharp
Medical Center, San Diego, CA; 4Medicine, UC San Diego, San
Diego, CA; 5Family and Preventive Medicine, UC San Diego, San
Diego, CA; 6Radiology, UC San Diego, San Diego, CA
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is
the most common chronic liver disease in children. In order to
advance the field of NAFLD, noninvasive imaging methods for
measuring liver fat are needed. Advanced magnetic resonance
imaging (MRI) has shown great promise for the quantitative
assessment of hepatic steatosis but has not been validated in
children. AIM: To evaluate the correlation and diagnostic accu-
racy of MRI-estimated liver proton density fat fraction (PDFF),
a biomarker for hepatic steatosis, compared to the histologic
steatosis grade in children with NAFLD. RESULTS: The study
included 174 children with a mean age of 14.0 years. MRI-es-
timated liver PDFF was significantly (p < 0.01) correlated
(0.725) with steatosis grade. Correlation of MRI-estimated liver
PDFF and steatosis grade was confounded by both sex and
fibrosis stage. The correlation was significantly (p<0.01) stron-
ger in girls (0.86) than in boys (0.70). The correlation was sig-
nificantly (p<0.01) weaker in children with stage 2-4 fibrosis
(0.61) than children with no fibrosis (0.76) or stage 1 fibrosis
(0.78). The diagnostic accuracy of commonly used threshold
values to distinguish between no steatosis and mild steatosis
ranged from 0.69 to 0.82. The overall accuracy of predicting
the histologic steatosis grade from MRI-estimated liver PDFF
was 56%. CONCLUSION: Advanced magnitude-based MRI
can be used to estimate liver PDFF in children, and those PDFF
values correlate well with liver histology. Thus magnitude-based
MRI has the potential for clinical utility in the evaluation of
NAFLD, but at this time no single threshold value has sufficient
accuracy to be considered diagnostic for an individual child.
Disclosures:
Jeffrey B. Schwimmer - Speaking and Teaching: Daiichi Sankyo, Inc.
Michael S. Middleton - Consulting: Gilead, Pfizer, Synageva, Merck, Bracco;
Grant/Research Support: Isis, Genzyme, Siemens, Bayer; Stock Shareholder:
General Electric
Cynthia A. Behling - Grant/Research Support: NASH CRN
Hannah Awai - Grant/Research Support: NIH
Gavin Hamilton - Grant/Research Support: GE Healthcare
Claude B. Sirlin - Advisory Committees or Review Panels: Bayer; Grant/Research
Support: GE, Pfizer, Bayer; Speaking and Teaching: Bayer
The following people have nothing to disclose: Kimberly P. Newton, Melissa N.
Paiz, Jonathan Hooker, John Fontanesi
187
Stimulation of PPAR-γ reduces NFkB-dependent inflam-
mation in cystic fibrosis biliary epithelium
Roberto Scirpo1,2, Romina Fiorotto2, Ambra Villani2, Luca Fab-
ris2,3, Mario Strazzabosco1,2; 1University of Milan-Bicocca, Milan,
Italy; 2Yale University, Section of Digestive Diseases, New Haven,
CT; 3University of Padua, Padova, Italy
Cystic Fibrosis-associated liver disease (CFLD) is a chronic
cholangiopathy that negatively impacts the quality of life
and survival of CF patients. Our recent studies show that in
CFTR-defective cholangiocytes, TLR/NF-kB-dependent innate
immune responses are increased and may contribute to the
291A
pathogenesis of CFLD. Our studies imply that a correct ther-
apeutic approach to CFLD should aim at controlling inflam-
mation in biliary epithelial cells. Emerging evidence support
a role of the nuclear receptor (NR) PPAR-γ as negative regula-
tor of TLR-mediated inflammation. In this study, we tested the
hypothesis that pharmacological activation of PPAR-γ would
limit the altered innate immune response in CFTR-defective
biliary epithelium. Primary cholangiocytes were isolated from
C57BL/6J-Cftrtm1Unc mice (Cftr-KO) and their WT littermates.
The gene expression profile of several NRs confirmed that bil-
iary epithelial cells express: PPAR isoforms α, β/δ and γ, FXR,
LXR-β, and Vitamin D Receptor. Interestingly, PPAR-γ was highly
expressed in CF cholangiocytes, but the expression of specific
PPAR-γ target genes, was not increased, indicating that the
receptor was not properly activated. On the other hand, stimu-
lation with the synthetic agonist pioglitazone (PIO) significantly
increased PPAR-γ transcriptional activity in CF cells. To under-
stand if decreased availability of endogenous PPAR-γ activators
might impair PPAR-γ function in CF, we performed a lipidomic
analysis of the major ω-3 and ω-6 polyunsaturated fatty acids.
CF cells presented an increased amount of arachidonic acid
(AA), the main source of pro-inflammatory mediators, over the
amount of the anti-inflammatory docosahexaenoic acid, pre-
cursor of PPAR-γ ligands. Treatment with LPS causes a higher
NF-κB activation and cytokine secretion in Cftr-KO cells, as
compared to WT cholangiocytes. We found that in Cftr-KO
cells, PIO significantly inhibited activation of NF-κB and the
production of pro-inflammatory cytokines such as LIX (CXCL5),
MCP-1 (CCL2), MIP-2 (CXCL2), G-CSF (CSF3) and KC (CXCL1)
at baseline and after stimulation with LPS, by directly activat-
ing PPAR-γ, as shown by the use of the antagonist GW9662.
Finally, we show that the anti-inflammatory effect of PIO in CF
biliary epithelium results from the upregulation of the NF-κB
negative regulator IκBα. In conclusion, our study suggests
that the chronic inflammatory state of Cftr-defective cholangio-
cytes may depend in part on decreased availability of PPAR-γ
endogenous ligands and that stimulation of PPAR-γ signaling
by synthetic agonists may represent a novel strategy to limit
inflammation in CFLD.
Disclosures:
The following people have nothing to disclose: Roberto Scirpo, Romina Fiorotto,
Ambra Villani, Luca Fabris, Mario Strazzabosco
188
PD-L1+ MDSCs are likely to become a new biomarker in
hepatocellular carcinoma patients
Tomoaki Iwata, Yasuteru Kondo, Osamu Kimura, Takayuki
Kogure, Tatsuki Morosawa, Yasuyuki Fujisaka, Tooru Shimose-
gawa; Tohoku University, Gastroenterology, Sendai, Japan
Background: Various types of immunosuppressive networks exist
in the microenvironment of hepatocelluar carcinoma (HCC).
Recently, it has been reported that myeloid-derived suppressor
cells (MDSCs) suppress the function of NK cells and tumor-spe-
cific T cells in the tumor-bearing host. In patients with HCC,
MDSCs are described as CD33+HLA-DRlowCD11b+CD14+
cells. We showed that MDSCs express surface PD-L1 molecules
in peripheral blood mononuclear cells (PBMCs) from patients
with HCC. The aim of this study is to determine PD-L1+ MDSCs
are likely to become a new biomarker in hepatocellular carci-
noma patients. Material and method: Patients: Permission for
the study was obtained from the Ethics Committee at our Uni-
versity. (i) We collected blood samples from 30 healthy donors
and 120 patients with various stages of HCC who were hos-
pitalized in our institute and subjected them to multicolor flow
cytometric analysis (FACS) for PD-L1+ MDSCs percentages. (ii)
292A AASLD ABSTRACTS
We used a transwell coculture system with PBMCs and several
different liver cancer cell lines such as HepG2, Huh7, Hep3B,
Li7, PLC. After 72 hours coincubation, multicolor FACS analy-
sis was performed. RNA from these cell lines was extracted,
and PCR amplification was done using primers for human
CSF-1, CSF-2, CSF-3, IL-1β, IL-6, CCL2, VEGFA, S100A8 and
S100A9. Results: (i) PBMCs from HCC patients contained sig-
nificantly higher percentages of PD-L1+ MDSCs in comparison
to those from healthy subjects (p < 0.001). PBMCs from TNM
IV HCC patients had significantly higher percentages of PD-L1+
MDSCs in comparison to those of TNM I, II and III patients (p
< 0.001). However, this increase was not correlated with the
Child-Pugh grade, serum concentrations of cancer biomarkers
(AFP and PIVKA-II). The percentages of PD-L1+ MDSCs were
reduced by treatment for HCC. (ii) After 72 hours coincubation
with the liver cell lines, the percentages of PD-L1+ MDSCs were
significantly increased compared with control. By cocultured
with Hep3B, Li7 and PLC, the percentages of PD-L1+ MDSCs
were higher than in those cocultured with other cell lines (Hep-
G2:p<0.05, Huh7:p<0.005, Hep3B, Li7, PLC: p<0.001). The
expression of CSF-1 and VEGFA was higher in the cell lines
that strongly induced PD-L1+ MDSCs. Conclusion: The differen-
tiation of PD-L1+ MDSCs was induced by soluble factors from
hepatocellular carcinoma, and peripheral blood from HCC
patients had significantly higher percentages of PD-L1+ MDSCs
in comparison to those of healthy subjects. The percentages of
PD-L1+ MDSCs were reduced by HCC treatment, suggesting
that we might use PD-L1+ MDSCs as a new biomarker and a
new target of treatment in hepatocellular carcinoma.
Disclosures:
The following people have nothing to disclose: Tomoaki Iwata, Yasuteru Kondo,
Osamu Kimura, Takayuki Kogure, Tatsuki Morosawa, Yasuyuki Fujisaka, Tooru
Shimosegawa
189
Unraveling of multilevel inhibition of interferon (IFN)-β
production, signaling and target-gene induction in
PAMPs-activated immune cells from patients with alco-
holic cirrhosis
Emmanuel Weiss1,4, Rakhi Maiwall2, Pierre-Emmanuel Rautou3,
Magali Fasseu1, Mikhael Giabicani1, Catherine Paugam-Burtz1,4,
Francois Durand1,3, Dominique Valla1,3, Didier Lebrec1,3, Sophie
Lotersztajn1, Pierre de la Grange5, Richard Moreau1,3; 1UMR_
S1149 Center for Research in Inflammation (CRI), Inserm and Paris
Diderot University, Paris, France; 2Liver unit, Institute of Liver &
Biliary Sciences, New Delhi, India; 3DHU Unity, Liver unit, Beau-
jon hospital, APHP, Clichy, France; 4Anesthesiology and intensive
care, Beaujon hospital, APHP, Clichy, France; 5GenoSplice tech-
nology, St Louis hospital, Paris, France
Background: The pathogen-associated molecular pattern
(PAMP) lipopolysaccharide (LPS) is known to induce IFN-β
pathways via TLR4 activation. In murine models of alcoholic
liver disease the engagement of IFN-β pathways is known to
protect against liver inflammation. Although patients with alco-
holic cirrhosis have bacterial translocation and LPS release,
their ability to activate IFN-β is unknown. We hypothesized
that LPS induction of IFN-β and IFN-stimulated genes (ISGs)
might be defective in immune cells from patients with alcoholic
cirrhosis. Aims: To assess IFN-β pathways in immune cells from
patients with alcoholic cirrhosis and healthy subjects as well as
the effects of other PAMPs and the influence of the etiology of
cirrhosis. Methods: 75 patients with cirrhosis (64 alcoholic, 11
HCV) and 33 healthy subjects were included. Peripheral blood
mononuclear cells (PBMCs) were obtained and cells were
stimulated or not with PAMPs or increasing concentrations of
HEPATOLOGY, October, 2014
“exogenous” IFN-β. PAMPs included LPS, polyIC alone (TLR3
agonist) or combined with lipofectamine (RIG-I-like receptors
agonist). Cell production of IFN-β was measured in the super-
natant by ELISA. RT-qPCR monitored expression of 47 bona
fide ISGs. Results: LPS-induced IFN-β production was found to
be significantly lower (-64%) in cells from patients with alco-
holic cirrhosis than in “healthy” cells. Even if the 47 ISGs were
induced (>2-fold) in both groups, 68% of LPS-induced ISGs had
a significantly lower expression in “alcoholic” than “healthy”
cells. Similar differences in IFN-β production and ISG induction
were found in alcoholic and healthy cells when the 2 other
PAMPs were used. Compared to healthy cells, alcoholic cells
had a significant rightward shift in the concentration-response
curve to IFN-β for each ISG induction, indicating that defective
IFN-β signaling played a role in ISG under-expression in alco-
holic cirrhosis. Finally, during LPS stimulation, while 32 ISGs
were under-expressed in alcoholic cells, the expression of only
9 ISGs was significantly decreased in “HCV” cells indicating
that defective ISG induction is a hallmark of alcoholic cirrhosis.
Multivariate analysis showed that low basal ISG expression in
alcoholic cells played a major role in decreased PAMP-induced
ISG induction, which is another mechanism of inhibition. Con-
clusions: This study shows that inhibition of IFN-β production,
signaling and ISGs induction is a multilevel process that is spe-
cific for PAMP-activated immune cells in patients with alcoholic
cirrhosis. These results suggest that defective IFN-β pathways
may be an important factor of susceptibility to liver inflamma-
tion in alcoholic cirrhosis.
Disclosures:
Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis;
Speaking and Teaching: Gilead
Dominique Valla - Advisory Committees or Review Panels: Sequana medical;
Consulting: IRIS; Speaking and Teaching: MSD, Gilead
Pierre de la Grange - Management Position: GenoSplice
The following people have nothing to disclose: Emmanuel Weiss, Rakhi Maiwall,
Pierre-Emmanuel Rautou, Magali Fasseu, Mikhael Giabicani, Catherine Pau-
gam-Burtz, Didier Lebrec, Sophie Lotersztajn, Richard Moreau
190
Arginine methylation of TRAF6 regulates TLR signaling
and susceptibility to spontaneous bacterial peritonitis in
cirrhosis
Irina Tikhanovich 1,3 , Sudhakiranmayi Kuravi 1,3 , Antonio
Artigues2,3, Maria T. Villar 2,3, Kenneth Dorko 5,3, Atta M.
Nawabi4,3, Benjamin R. Roberts3, Steven A. Weinman1,3; 1Inter-
nal Medicine, University of Kansas Medical Center, Kansas City,
KS; 2Biochemistry, University of Kansas Medical Center, Kansas
City, KS; 3The Liver Center, University of Kansas Medical Center,
Kansas City, KS; 4Surgery, University of Kansas Medical Center,
Kansas City, KS; 5Pharmacology, Toxicology and Therapeutics,
University of Kansas Medical Center, Kansas City, KS
We have previously shown that hepatitis C and alcohol cause
a loss of hepatic activity of the protein arginine methyltransfer-
ase, PRMT1 and a decrease in hepatic arginine methylation.
To determine possible consequences of PRMT1 inhibition, we
performed a bioinformatics search and identified the E3-ubiq-
uitin ligase, TRAF6, a key component of antibacterial TLR sig-
naling, as a possible methylation target of PRMT1. Patients
with cirrhosis have a well-known defect in the clearance of
bacterial infections and are at high risk for spontaneous bacte-
rial peritonitis (SBP). The AIMS of this study were to determine
whether TRAF6 is regulated by arginine methylation and if this
mechanism contributes to susceptibility to SBP in patients with
cirrhosis. METHODS: TRAF6 methylation was measured by
IP and immunoblotting as well as MS/MS proteomics. NF-κB
responses were measured by luciferase reporters, mRNA
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
expression and p65 nuclear translocation. Liver samples were
obtained from transplant explants of cirrhotic patients with
ascites with or without a history of SBP. Cell culture studies
were performed in Huh7 hepatoma cells and THP monocytes.
RESULTS: Under basal conditions TRAF6 was arginine methyl-
ated at R88 and R125 in a PRMT1-dependent fashion. Meth-
ylation inhibited TRAF6 ubiquitin ligase activity and kept the
TLR pathway inactive under basal conditions. In response to
TLR ligands, TRAF6 was rapidly demethylated. Ligand-induced
demethylation required the activity of the jumonji domain pro-
tein JMJD6, a histone arginine demethylase, and was neces-
sary for maximal activation of NF-κB. Loss of PRMT1 led to a
decrease in TRAF6 methylation, partial pre-activation of the
TLR pathway in the absence of ligand, and failure to gener-
ate a robust NF-κB response to TLR ligands. We defined a
“methylation potential” in human liver as the ratio of PRMT1/
JMJD6. In normal liver PRMT1/JMJD6 ratio was 2.24±1.09
(n=20) whereas the ratio was 0.92±0.48 (n=11) in cirrho-
sis without SBP and 0.43±0.16 (n=11) in cirrhosis with SBP
(P<0.001). Low PRMT1/JMJD6 ratio correlated with elevated
pathway pre-activation as measured by the level of nuclear
p65. CONCLUSION: Arginine methylation is a novel mecha-
nism that regulates TLR signaling by inhibiting TRAF6. It serves
to keep the pathway inactive at baseline, a condition that is
necessary for optimal TLR responses. Patients with cirrhosis
have decreased hepatic PRMT1 leading to pathway pre-activa-
tion and impaired ligand responses. This defect is significantly
worse in patients with a documented history of SBP. Defective
arginine methylation is therefore a newly described mechanism
for the infection susceptibility of cirrhosis.
Disclosures:
Steven A. Weinman - Consulting: MSD Japan
The following people have nothing to disclose: Irina Tikhanovich, Sudhakiran-
mayi Kuravi, Antonio Artigues, Maria T. Villar, Kenneth Dorko, Atta M. Nawabi,
Benjamin R. Roberts
191
Increased prevalence of deficient polymorphisms of
innate immune system in cirrhotic patients with ascites
and spontaneous bacterial infections
Veronica Prado1, Anibal Silva1, Miriam Castro1,4, Francisco
Lozano2, Ausgusto Villanueva3,4, Juan Acevedo1, Pere Gines1,3,
Vicente Arroyo3,4, Javier Fernandez1,3; 1Liver Unit, Hospital Clinic
Barcelona, Barcelona, Spain; 2Immunology Laboratory, Hospi-
tal Clinic Barcelona, Barcelona, Spain; 3Institut d’Investigacions
Biomèdiques August-Pi-Sunyer (IDIBAPS), Barcelona, Spain; 4Cen-
tro de Investigación Biomédica en Red de Enfermedades Hepáti-
cas y Digestivas (CIBEREHED), Barcelona, Spain
TRL2 and NOD-2 polymorphisms have been implicated in the
pathogenesis of SBP in cirrhosis. However, a global assess-
ment of cell membrane receptor polymorphisms has not been
performed until now. This study was aimed at determining the
impact of deficient polymorphisms of the innate immune system
(toll like receptor 2 and 4, surfactant protein D, mannose-bind-
ing lectin and MBL associated serine protease) on the risk of
developing spontaneous bacterial infections in patients with
advanced cirrhosis. Methods: Case control study including
166 cirrhotic patients with ascites with (cases; n=77; 90%
SBP) and without history of spontaneous infections (control
group; n=89). The presence of deficient genotypes of MBL2
(0/0, XA/0, 0/XA), MASP2 (D105G), TLR2 (R677R753Q),
TLR4 (D299GT399I) and SFTPD (TT) and serum levels of man-
nose- binding lectin (MBL; n=83) were analysed at enrolment.
Results: Age (59±9 years in both groups), sex (66% male in
both groups) and main cause of liver disease (alcoholic cirrho-
293A
sis: 42% in cases and 49% in controls) were similar between
cases and controls. As expected, cases showed poorer liver
function than controls (MELD score 21±8 vs. 17±6 points,
respectively; p<0.0001). Platelet count and ascitic fluid protein
levels were similar between groups. Prevalence of deficient
polymorphisms of the innate immune system in the whole series
was 32.9% (54/166). The prevalence of any polymorphism of
the innate immune system was significantly higher in cases than
in controls (43% vs. 24%; p=0.01). Fourteen cases (18%) and
6 controls (7%) had TLR4 cosegregated mutations (p=0.04).
MBL2 deficient polymorphisms were also more prevalent in
cases than controls (21% vs. 9%; p=0.05). Prevalence of other
polymorphisms was not significantly different between groups
(SFTPD: 16% vs. 9%; TLR2: 3% vs. 2%; MASP-2: 1% vs. 6%, in
cases and controls respectively). Mean serum MBL levels were
significantly lower in patients with MBL2 deficient polymor-
phisms (140 ±231 vs. 1202±875 ng/ml; p=0.0001). Conclu-
sions: TLR4 and MBL2 deficient polymorphisms of the innate
immune system are more prevalent in cirrhotic patients with
ascites who develop spontaneous bacterial infections. These
genetic variants could increase the risk of developing SBP and
other spontaneous infections in cirrhosis. The role of exogenous
MBL administration in the prevention of spontaneous infections
in patients with advanced cirrhosis and MBL deficient polymor-
phisms should be investigated in future RCT.
Disclosures:
Pere Gines - Advisory Committees or Review Panels: Ferring ; Grant/Research
Support: Sequana Medical, Grifols
Vicente Arroyo - Speaking and Teaching: GRIFOLS
The following people have nothing to disclose: Veronica Prado, Anibal Silva,
Miriam Castro, Francisco Lozano, Ausgusto Villanueva, Juan Acevedo, Javier
Fernandez
192
Negative regulation of the interferon response by an
interferon-induced long non-coding RNA
Hiroto Kambara1, Farshad Niazi1,7, Lenche Kostadinova2, Dilip
Moonka3, Christopher T. Siegel4, Anthony B. Post5, Elena Car-
nero6, Marina Barriocanal6, Puri Fortes6, Donald D. Anthony2,
Saba Valadkhan1; 1Biochemistry, Case Western Reserve Univer-
sity, Cleveland, OH; 2Medicine, Case Western Reserve University,
Cleveland, OH; 3Division of Gastroenterology, Henry Ford Health
System, Detroit, MI; 4Medicine, University Hospitals Case Medical
Center, Cleveland, OH; 5Surgery, University Hospitals Case Medi-
cal Center, Cleveland, OH; 6Hepatology and Gene Therapy, Cen-
ter for Applied Medical Research (CIMA), University of Navarra,
Pamplona, Spain; 7Genomic Medicine Institute, Lerner Research
Institute, Cleveland Clinic, Cleveland, OH
Long non-coding RNAs (lncRNAs) play critical roles in diverse
cellular processes; however, their involvement in many criti-
cal aspects of the immune response including the interferon
(IFN) response remains poorly understood. To address this
gap, we compared the global gene expression pattern of pri-
mary human hepatocytes before and at three time points after
treatment with IFN-α. Among ~200 IFN-induced lncRNAs,
one transcript showed ~100 fold induction. This RNA, which
we named lncRNA-CMPK2, was a spliced, polyadenylated
nuclear transcript that was induced by IFN in diverse cell types
from human and mouse. Similar to protein-coding IFN-stimu-
lated genes (ISGs), its induction was dependent on JAK-STAT
signalling. Intriguingly, knockdown of lncRNA-CMPK2 resulted
in a marked reduction in HCV replication in hepatocytes, sug-
gesting that it could affect the antiviral role of IFN. We could
show that lncRNA-CMPK2 knockdown resulted in upregulation
of several protein-coding antiviral ISGs. The observed upregu-
lation was caused by an increase in both basal and IFN-stim-
294A AASLD ABSTRACTS
ulated transcription, consistent with loss of transcriptional
inhibition in knockdown cells. These results indicate that the
IFN response involves a lncRNA-mediated negative regulatory
mechanism. Interestingly, lncRNA-CMPK2 was strongly upreg-
ulated in a subset of HCV-infected human livers, suggesting a
role in modulation of the IFN response in vivo.
Disclosures:
Dilip Moonka - Advisory Committees or Review Panels: Gilead; Grant/Research
Support: Bristol-Myers Squibb, Genentech; Speaking and Teaching: Merck,
Genentech, Gilead
Anthony B. Post - Advisory Committees or Review Panels, Schering Plough, onyx,
Gilead, Schering Plough, onyx, Gilead, Schering Plough, onyx, Gilead, Schering
Plough, onyx; Speaking and Teaching: Gilead, Roche, vertex, Roche, vertex,
Roche, vertex, Roche, vertex; Stock Shareholder: amgen, amgen, amgen, amgen
The following people have nothing to disclose: Hiroto Kambara, Farshad Niazi,
Lenche Kostadinova, Christopher T. Siegel, Elena Carnero, Marina Barriocanal,
Puri Fortes, Donald D. Anthony, Saba Valadkhan
193
HBsAg Loss with Tenofovir Disoproxil Fumarate (TDF)
plus Peginterferon alfa-2a (PEG) in Chronic Hepatitis B
(CHB): Results of a Global Randomized Controlled Trial
Patrick Marcellin1, Sang Hoon Ahn2, Xiaoli Ma3, Florin A. Caruntu4,
Won Young Tak5, Magdy Elkashab6, Wan-Long Chuang7, Fehmi
Tabak8, Rajiv Mehta9, Joerg Petersen10, Eduardo B. Martins11,
Phillip Dinh11, Amoreena C. Corsa11, Prista Charuworn11, Mani
Subramanian11, John G. McHutchison11, Maria Buti12, Giovanni
B. Gaeta13, George V. Papatheodoridis14, Robert Flisiak15, Henry
Lik-Yuen Chan16; 1Hopital Beaujon, University Paris-Diderot, Cli-
chy, France; 2Division of Gastroenterology, Yonsei University Col-
lege of Medicine, Seoul, Republic of Korea; 3Drexel University
College of Medicine, Philadelphia, PA; 4National Institute for Infec-
tious Diseases “ Matei Bals”, Bucharest, Romania; 5Kyungpook
National University Hospital, Daegu, Republic of Korea; 6Toronto
Liver Center, Toronto, ON, Canada; 7Kaohsiung Medical Univer-
sity Chung-Ho Memorial Hospital, Kaohsiung City, Taiwan; 8Uni-
versity of Istanbul, Istanbul, Turkey; 9Liver Clinic, Surat, India; 10IFI
Institute for Interdisciplinary Medicine at the Asklepios Klinik St.
George, University of Hamburg, Hamburg, Germany; 11Gilead
Sciences, Foster City, CA; 12Hepatology Unit, Hospital Universitari
Vall d’Hebron, Barcelona, Spain; 13Viral Hepatitis Unit, Depart-
ment of Infectious Diseases, Second University of Naples, Naples,
Italy; 14Athens University Medical School, “Hippokration” General
Hospital of Athens, Athens, Greece; 15Medical University of Bialys-
tok, Bialystok, Poland; 16Department of Medicine and Therapeutics
and Institute of Digestive Disease, The Chinese University of Hong
Kong, Hong Kong SAR, Hong Kong
Background: Rates of HBsAg loss in CHB patients treated with
nucleos(t)ide analogues (NA) or PEG therapy are relatively
low. Studies comparing PEG+NA combination therapy versus
PEG alone are inconclusive. Here we present the Week 48
analysis of an ongoing trial evaluating TDF+PEG as combina-
tion therapy. Methods: 740 patients with non-cirrhotic CHB
were randomized 1:1:1:1 to receive TDF+PEG x48 weeks
(Arm A); TDF+PEG x16 weeks followed by TDF x32 weeks
(Arm B); continuous TDF (Arm C); PEG x48 weeks (Arm D).
The primary hypotheses compared the rates of HBsAg loss,
estimated by Kaplan-Meier method, at Week 72 for arms A
vs C, A vs D, B vs C, and B vs D. The Week 48 analysis was
pre-specified. Results: Of the 740 patients randomized and
treated, 58.4% were HBeAg(+), mean age 37 years, 74.9%
Asians and HBV genotype distribution (A, B, C, D, E-H) was
8.2%, 27.3%, 42.3%, 20.8% and 1.1%, respectively. At week
48, patients receiving PEG+TDF for 48 weeks had significantly
higher rates of HBsAg loss than either TDF or PEG alone (fig-
ure). Arm A had higher rates of HBs seroconversion (5.9%)
HEPATOLOGY, October, 2014
than Arms B (0.6%), C (0%) or D (1.8%). Of the subjects with
HBsAg loss, 73% were HBeAg(+) at baseline and had the
following genotype distribution: 31.8% A, 36.4% B, 18.2%
C, and 13.6% D. Rates of HBeAg loss were also higher in
arms receiving PEG+TDF(Arm A 24.3%, Arm B 20.2%, Arm C
8.3%, Arm D 12.5%). HBV DNA suppression (HBV DNA < 15
IU/ml) was higher in the TDF-containing arms (Arm A 69.2%,
Arm B 71.2%, Arm C 60.5%, Arm D 20.8%). No unexpected
AEs were observed in the combination arms. Conclusion: CHB
patients treated with TDF and PEG combination therapy for 48
weeks achieved significantly higher rates of HBsAg loss than
either therapy given alone.
Figure: Proportion of Subjects with HBsAg Loss (p-values compar-
ing HBsAg loss rates based on stratified log-ranked test adjusted
for multiple testing)
Disclosures:
Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen,
MSD, Abbvie, Alios BioPharma, Idenix, Akron; Grant/Research Support: Roche,
Gilead, BMS, Novartis, Janssen, MSD, Alios BioPharma; Speaking and Teach-
ing: Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Boehringer, Pfizer,
Abbvie
Xiaoli Ma - Consulting: Gilead Sciemces, Inc, Bristol-Myers Squibb, Inc
Florin A. Caruntu - Advisory Committees or Review Panels: MSD, Abbvie, Jans-
sen, BMS, Roche
Won Young Tak - Advisory Committees or Review Panels: Gilead Korea; Grant/
Research Support: SAMIL Pharma; Speaking and Teaching: Bayer Korea
Magdy Elkashab - Advisory Committees or Review Panels: GSK INC, GILEAD
SCIENCES INC, Roche Canada; Speaking and Teaching: GILEAD SCIENCES
INC
Wan-Long Chuang - Advisory Committees or Review Panels: Gilead, Roche,
Abbvie, MSD; Speaking and Teaching: BMS
Joerg Petersen - Advisory Committees or Review Panels: Bristol-Myers Squibb,
Gilead, Novartis, Merck, Bristol-Myers Squibb, Gilead, Novartis, Merck; Grant/
Research Support: Roche, GlaxoSmithKline, Roche, GlaxoSmithKline; Speaking
and Teaching: Abbott, Tibotec, Merck, Abbott, Tibotec, Merck
Eduardo B. Martins - Employment: Gilead Sciences, Inc.; Stock Shareholder:
Gilead Sciences, Inc.
Phillip Dinh - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences
Amoreena C. Corsa - Employment: Gilead Sciences Inc.; Stock Shareholder:
Gilead Sciences Inc.
Prista Charuworn - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Mani Subramanian - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Maria Buti - Advisory Committees or Review Panels: Gilead, Janssen, Vertex,
MSD; Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gil-
ead, Janssen, Vertex, Novartis
Giovanni B. Gaeta - Advisory Committees or Review Panels: Janssen, Merck,
Abbvie, Roche; Speaking and Teaching: BMS, Gilead
George V. Papatheodoridis - Advisory Committees or Review Panels: Janssen,
Abbvie, Boehringer Ingelheim, Novartis, BMS, Gilead, Roche, MSD; Consulting:
Roche; Grant/Research Support: BMS, Gilead, Roche, Abbvie, Janssen; Speak-
ing and Teaching: Janssen, Novartis, BMS, Gilead, Roche, MSD, Abbvie
Robert Flisiak - Advisory Committees or Review Panels: Gilead, Merck, Roche,
Bristol Myers Squibb, Janssen, Novartis, Abbvie; Grant/Research Support:
Roche, Bristol Myers Squibb, Janssen, Novartis, Gilead, Vertex, Merck; Speak-
ing and Teaching: Janssen, Merck, Roche, Bristol Myers Squibb, Gilead, Abbvie
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, MSD,
Bristol-Myers Squibb, Roche, Novartis Pharmaceutical; Speaking and Teaching:
Echosens, Abbvie
The following people have nothing to disclose: Sang Hoon Ahn, Fehmi Tabak,
Rajiv Mehta
194
Effectiveness of Hepatitis C Virus (HCV) Testing for Per-
sons Born during 1945-1965 – Summary Results from
Three Randomized Controlled Trials
Bryce D. Smith1, Anthony K. Yartel2, Kimberly Ann Brown3, Kath-
erine Krauskopf4, Omar I. Massoud5, Cynthia E. Jordan5, Natalie
Kil4, Alex D. Federman4, David R. Nerenz3, Danielle Liffmann6,
David B. Rein6; 1Centers for Disease Control and Prevention,
Atlanta, GA; 2CDC Foundation, Atlanta, GA; 3Henry Ford Hospi-
tal, Detroit, MI; 4Icahn School of Medicine at Mount Sinai, New
York, NY; 5University of Alabama at Birmingham, Birmingham, AL;
6NORC at the University of Chicago, Atlanta, GA
PURPOSE: CDC and the U.S. Preventive Services Taskforce
recommend 1-time HCV testing for persons born during 1945-
1965 (birth cohort). We present summary results from 3 inde-
pendent trials to determine the relative probability of identifying
HCV infections using birth cohort (BC) testing versus current
screening protocol. METHODS: From December 2012 to Feb-
ruary 2014, we conducted HCV (BC) testing trials at 3 large
primary care healthcare centers using variations of the ran-
domized controlled trial design. Across centers, patients born
during 1945-1965 with no clinical documentation of prior
HCV test or infection were randomly assigned (individually or
in defined clusters) to receive a 1-time HCV test (intervention)
or the prevailing screening protocol (control). In trial #1, we
individually assigned patients to receive letters with invitations
for BC testing. For trial #2, we assigned clinics to implement
BC testing with provider Best Practice Alert. In trial #3, we
assigned clinics to perform BC testing with trained recruiters;
mid-trial, intervention and control arms were switched such that
each clinic served as its own control. Analysis was by inten-
tion-to-treat with patient as the unit of inference. We estimated
the risk ratio (RR) of identifying patients with HCV antibody or
RNA positive results (HCV+) using BC testing versus control for
each trial, with adjustment for correlated data. We applied
meta-analysis to summarize individual risk ratios into a pooled
effect estimate. RESULTS: In trial #1, 9,000 patients were allo-
cated to BC (n=3,000) or control (n=6,000) in a 1:2 ratio,
and 8,992 patients (BC=2,996; control=5,996) were included
in the analysis. The RR of identifying HCV+ patients using BC
testing versus control was 8.0 (95%CI 1.7–37.7). In trial #2,
10 clinics were assigned to BC (n=5) or control (n=5) in a 1:1
ratio; data from 13,481 patients (BC=8,313 control=5,168)
were analyzed. HCV+ patients were 3 times more likely to be
identified using BC testing versus control (RR 3.1, 95%CI 1.2–
8.2). In trial #3, 4 clinics were assigned to both BC (n=4) and
control (n=4) over 2 different time periods (crossover); data for
14,966 patients (BC=4,608; control=10,358) were analyzed.
BC testing was 5 times more likely to identify HCV+ patients
compared with control (RR 5.2, 95%CI 2.8–9.5); period had
no significant effect on outcome (p=0.20). Pooled RR of iden-
tifying HCV+ patients using BC testing versus control was 4.8
(95%CI 2.9–7.8). CONCLUSIONS: HCV testing of persons
born during 1945-1965 without prior ascertainment of HCV
risk was 5 times more effective in identifying persons with pre-
vious or current HCV infection compared with standard of care.
Disclosures:
295A
Kimberly Ann Brown - Advisory Committees or Review Panels: CLDF, Merck,
Salix, Gilead, Vertex, Novartis, Genentech, Gilead, Janssen, Novartis, Salix;
Consulting: Blue Cross Transplant Centers, Salix; Grant/Research Support: CLDF,
Gilead, Exalenz, CDC, BMS, Bayer-Onyx, Ikaria, Hyperion, Merck; Speaking
and Teaching: Salix, Merck, Genentech, Gilead, CLDF, Vertex
David B. Rein - Grant/Research Support: Gilead Sciences, Inc.
The following people have nothing to disclose: Bryce D. Smith, Anthony K. Yartel,
Katherine Krauskopf, Omar I. Massoud, Cynthia E. Jordan, Natalie Kil, Alex D.
Federman, David R. Nerenz, Danielle Liffmann
195
Sofosbuvir and Ribavirin therapy for the Treatment of
HIV/HCV coinfected patients with HCV GT1-4 Infection:
The PHOTON-1 and -2 Trials
Juergen K. Rockstroh1, Massimo Puoti2, Maribel Rodriguez-Tor-
res3, Douglas Dieterich4, Anuj Gaggar5, Liyun Ni5, Benedetta
Massetto5, Evguenia S. Svarovskaia5, Diana M. Brainard5, Mani
Subramanian5, John G. McHutchison5, Susanna Naggie6, Chloe
Orkin7, Jean-Michel Molina8, Mark S. Sulkowski9; 1Department
of General Internal Medicine I, University Hospital of Bonn,
Bonn, Germany; 2Division of Infectious Diseases, AO Ospedale
Niguarda Ca&apos; Granda, Milano, Italy; 3Fundacion De Inves-
tigacion, SJB School of Medicine, San Juan; 4Mount Sinai School
of Medicine, New York, NY; 5Gilead Sciences, Inc., Foster City,
CA; 6Duke Clinical Research Institute, Durham, NC; 7Barts Health
NHS Trust, London, United Kingdom; 8University of Paris Diderot,
Paris 7 and Department of Infectious Diseases, Saint-Louis Hospital,
Paris, France; 9Johns Hopkins University, Baltimore, MD
Background and Aim: Interferon-free treatments for HCV that
can be safely administered with antiretroviral therapy (ART)
are needed for HIV/HCV co-infected patients. These two stud-
ies evaluated the safety and efficacy of sofosbuvir (SOF), a
pan-genotypic HCV NS5B inhibitor, with ribavirin (RBV) in
individuals coinfected with HIV and HCV genotype (GT) 1-4.
Methodology: 497 HCV-HIV coinfected patients, were enrolled
in the PHOTON-1 or PHOTON-2 Phase 3 studies to receive
SOF 400 mg QD and RBV 1000-1200 mg/day for 12 or 24
weeks, based on HCV genotype and prior treatment status.
Multiple ART regimens were permitted as were patients with
compensated cirrhosis. The primary efficacy endpoint was sus-
tained virologic response 12 weeks after treatment (SVR12);
safety assessments included HIV RNA and CD4 cell levels.
Results: Baseline demographics and virologic responses are
shown in the table. SVR12 rates were 80-91% with the excep-
tion of GT3 HCV patients treated with 12 weeks of SOF+RBV
(67%). Among 76 patients with cirrhosis, 59 (77%) achieved
SVR12. Multivariate analyses of baseline characteristics asso-
ciated with SVR, by HCV genotype, showed that significant
predictors for SVR12 were non-black race and absence of cir-
rhosis for GT1 patients, and lower HCV RNA level at baseline
and a longer treatment duration for GT3 patients. 445 subjects
(89.5%) experienced any AE but only 8% had a Grade 3 or
4 AE and 2.5% had an AE resulting in early SOF discontinu-
ation. There was no change in CD4 T-cell percentage during
treatment. Among patients suppressed on ART, 1% had HIV
virologic breakthrough though none of these subjects required
a change in ART. Conclusions: HCV GT 1-4 patients coinfected
with HIV achieved high rates of SVR12 with an interferon-free,
all-oral regimen of SOF+RBV. This pooled analysis from two
Phase 3 studies further demonstrates that SOF+RBV treatment
was well-tolerated and safely co-administered with multiple ART
regimens, and suggest that concurrent HIV-1 infection does not
reduce SVR12 rates with sofosbuvir-based regimens.
296A AASLD ABSTRACTS
Disclosures:
Juergen K. Rockstroh - Advisory Committees or Review Panels: Boehringer
Ingelheim, Bristol-Myers Squibb, Gilead, Merck, Abbott, ViiV, Vertex, Tibotec,
Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck, Pfizer, Abbott, ViiV,
Vertex, Tibotec; Board Membership: Human Genome Sciences; Consulting:
Bionor, Abbvie, Novartis, Abbott, Novartis; Grant/Research Support: Abbott,
Merck, Abbott, Merck; Speaking and Teaching: Abbott, Gilead, GlaxoSmith-
Kline, Abbvie, Roche, Merck, ViiV, Abbott, Gilead, GlaxoSmithKline, Roche,
Merck, ViiV
Massimo Puoti - Advisory Committees or Review Panels: GSK, Abbott, Janssen,
MSD, Roche, Gilead Sciences, Novartis, GSK, Abbott, Janssen, MSD, Roche,
Gilead Sciences, Novartis, GSK, Abbott, Janssen, MSD, Roche, Gilead Sciences,
Novartis, GSK, Abbott, Janssen, MSD, Roche, Gilead Sciences, Novartis; Speak-
ing and Teaching: BMS, BMS, BMS, BMS
Maribel Rodriguez-Torres - Advisory Committees or Review Panels: Hoffman La
Roche, Pharmasset, Bristol-Myers Squibb, Inhibitex, Vertex, Janssen R&D Ire-
land; Consulting: Abbott Labs, Akros, Glaxo Smith Kline, Genentech, Janssen
R&D Ireland, Santaris, Scynexis, Theravance; Grant/Research Support: Anadys,
Novartis, Merck, Vertex, Hoffman-LaRoche, Inhibitex, Bristol-Myers Squibb,
Idera, Pharmasset, Sanofi-Aventis, Merck, Abbott, Pfizer, Human Genome Sci-
ences, Gilead, Johnson & Johnson, Zymogenetics, AKROS, Scynexis, Santaris,
Boehringher, Idenix, Genentech, Beckman Coulter, Mochida Pharmaceutical,
Theravance
Douglas Dieterich - Advisory Committees or Review Panels: merck, Idenix, Jans-
sen ; Consulting: Gilead, BMS
Anuj Gaggar - Employment: Gilead Sciences
Benedetta Massetto - Employment: Gilead Sciences, Inc.; Stock Shareholder:
Gilead Sciences, Inc
Evguenia S. Svarovskaia - Employment: Gilead Sciences Inc.; Stock Shareholder:
Gilead Sciences Inc.
Diana M. Brainard - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Mani Subramanian - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Susanna Naggie - Advisory Committees or Review Panels: Vertex Pharmaceuti-
cals, Boehinger Ingelheim, Gilead, Abbott, Merck; Consulting: Achillion; Grant/
Research Support: Vertex Pharmaceuticals, Anandys, Scynexis, Medtronic, Gil-
ead, AbbVie, BMS, Jenssen, Merck, Achillion
Chloe Orkin - Advisory Committees or Review Panels: Viiv, gilead, bms, boeh-
ringer ingelgeim; Grant/Research Support: johnson and johnson, abbvie
Jean-Michel Molina - Board Membership: Gilead, BMS, Janssen, merck, Abbott,
boehringer; Grant/Research Support: merck; Speaking and Teaching: merck,
gilead, BMS
Mark S. Sulkowski - Advisory Committees or Review Panels: Merck, AbbVie,
Idenix, Janssen, Gilead, BMS, Pfizer; Grant/Research Support: Merck, AbbVie,
BIPI, Vertex, Janssen, Gilead, BMS
The following people have nothing to disclose: Liyun Ni
HEPATOLOGY, October, 2014
196
Efficacy and safety of MK-5172 and MK-8742 ± rib-
avirin in hepatitis C genotype 1 infected patients with
cirrhosis or previous null response: Final results of the
C-WORTHY Study (Parts A and B)
Eric Lawitz1, Edward J. Gane2, Brian Pearlman3, Edward Tam4,
Wayne Ghesquiere5, Dominique Guyader6, Laurent Alric7, Jean-
Pierre Bronowicki8, Lorenzo Rossaro9, William Sievert10, Reem
H. Ghalib11, Luis A. Balart12, Fredrik Sund13, Martin Lagging14,
Frank Dutko15, Anita Y. Howe15, Melissa Shaughnessy15, Peggy
Hwang15, Janice Wahl15, Michael Robertson15, Barbara A.
Haber15; 1The Texas Liver Institute, University of Texas Health Sci-
ence Center, San Antonio, TX; 2Aukland Clinical Studies, Grafton,
Auckland, New Zealand; 3Atlanta Medical Center, Atlanta, GA;
4LAIR Centre, Vancouver, BC, Canada; 5Vancouver Island Health
Authority, Victoria, BC, Canada; 6Department of Hepatology,
Rennes University Hospital, Rennes 1 University, Rennes, France;
7CHU Purpan, Digest Dept., UMR 152, Toulouse 3 University,
Toulouse, France; 8INSERM U954, Centre Hospitalier Universitaire
de Nancy, Université de Lorraine, Vandoeuvre-les-Nancy, France;
9Univeristy of California, Davis Medical Center, Sacramento, CA;
10Monash University and Monash Health, Melbourne, VIC, Aus-
tralia; 11Texas Clinical Research Institute, Arlington, TX; 12Tulane
University School of Medicine, New Orleans, LA; 13Infectious Dis-
eases, Uppsala University, Uppsala, Sweden; 14Institute of Biomed-
icine, University of Gothenburg, Gothenburg, Sweden; 15Merck &
Co., Inc., Whitehouse Station, NJ
Purpose: The purpose of this study was to assess the efficacy,
safety and effective treatment duration of MK-5172 (hepati-
tis C virus [HCV] NS3/4A protease inhibitor) in combination
with MK-8742 (an HCV NS5A replication complex inhibitor)
± ribavirin in patients with HCV genotype (GT)1 infection with
baseline characteristics of poor response, including either cir-
rhosis or prior null response to peginterferon /ribavirin (PR
null). Methods: Patients with a prior PR null response ± cirrhosis
or treatment-naive patients with cirrhosis were randomized to
receive MK-5172 (100 mg QD) and MK-8742 (50 mg QD) ±
ribavirin (weight-based) for 12 or 18 weeks. Primary endpoint
was the proportion of patients achieving HCV RNA<25 IU/mL
12 weeks after end of treatment (SVR12) assessed by COBAS
TaqMan v2.0 (lower limit of quantitation <25 IU/mL). The study
is ongoing, and all patients will have received 24 weeks of fol-
low-up by November 2014. Results:253 patients were enrolled
(male, 58%; African American, 6%; GT1a, 65%). Among
patients treated for 12 weeks with MK-5172 + MK-8742 with-
out RBV, 94% (28/29) of treatment-naive patients with cirrhosis
and 91% (30/33) of prior PR null responders achieved SVR12
(Table). High SVR12 rates were achieved regardless of the
use of ribavirin or extending the treatment duration from 12
to 18 weeks (results as of May 1, 2014). Among prior PR
null patients with cirrhosis treated for 12 or 18 weeks with
MK-5172 + MK-8742 ± RBV, 95% (41/43) achieved SVR12.
Final SVR12 and SVR24 results will be presented. Adverse
events reported in >10% of patients were fatigue (25%), head-
ache (24%) and asthenia (14%). Conclusions: Treatment with
MK-5172 + MK-8742 ± RBV demonstrated high rates of effi-
cacy in treatment-naïve patients with cirrhosis and prior PR null
responders. Neither RBV nor extension of treatment duration
from 12 to 18 weeks was needed to achieve SVR12 in a high
proportion of patients. These results support the ongoing Phase
3 development of MK-5172 + MK-8742 ± ribavirin for 12
weeks.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
* Duration of treatment with MK-5172 + MK-8742 ± RBV in
weeks
‡ Some patients have not yet reached the SVR12 time point
§ One non-cirrhotic patient was randomized into this arm
Disclosures:
Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharma-
ceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck &
Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals;
Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingel-
heim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharma-
ceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio,
Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teach-
ing: Gilead, Kadmon, Merck, Vertex
Edward J. Gane - Advisory Committees or Review Panels: Novira, AbbVie,
Novartis, Gilead Sciences, Janssen Cilag, Vertex, Achillion, Tekmira, Merck, Ide-
nix; Speaking and Teaching: AbbVie, Novartis, Gilead Sciences, Janssen Cilag
Brian Pearlman - Grant/Research Support: BI, BMS, J&J, Abbott, Gilead, Merck;
Speaking and Teaching: Merck, Kadmon Pharmaceuticals, Vertex
Edward Tam - Advisory Committees or Review Panels: BMS, ABBVIE, GILEAD,
MERCK, ROCHE, VERTEX, JANSSEN
Dominique Guyader - Advisory Committees or Review Panels: ROCHE, GILEAD,
IRIS, ABBVIE; Board Membership: MERCK; Grant/Research Support: JANSSEN;
Speaking and Teaching: BMS
Laurent Alric - Grant/Research Support: Roche, MSD, BMS, Gilead
Jean-Pierre Bronowicki - Consulting: Merck, Janssen, Boehringer Ingelheim, Gil-
ead, BMS, Bayer, Novartis, GSK, Merck, Janssen, Boehringer Ingelheim, Gilead,
BMS, Bayer, Novartis, GSK, ABBVIE; Speaking and Teaching: Roche, Merck,
Janssen, BMS, Bayer, Roche, Merck, Janssen, BMS, Bayer
Lorenzo Rossaro - Consulting: Merck, Genentec; Grant/Research Support: Gil-
ead, Novartis, Vertex, BMS, AbbVie, Jannsen; Speaking and Teaching: Salix,
Onix/Bayer
William Sievert - Speaking and Teaching: Gilead Sciences, Bristol Myers Squibb,
Merck, Gilead Sciences, Bristol Myers Squibb, Merck, Gilead Sciences, Bristol
Myers Squibb, Merck, Gilead Sciences, Bristol Myers Squibb, Merck
Reem H. Ghalib - Grant/Research Support: Bristol Myers Squibb Pharmaceuti-
cals, Vertex Pharmaceuticals, Janssen, Merck, Genentech, Idenix, Zymogenetics,
Pharmasset, Anadys, Duke Clinical Research Institute, Achillion, Boehringer Ingel-
heim, Gilead Pharmaceuticals, Virochem Pharmaceuticals, Abbott, Medtronic
Inc, Novartitis, Roche, Schering Plough, Salix, tibotec, Inhibitex, Takeda, Abbvie
Luis A. Balart - Advisory Committees or Review Panels: Genentech; Grant/
Research Support: Merck, Genentech, Bayer, conatus, Ocera, Hyperion, Gil-
ead Sciences, Bristol Myers Squibb, Mochida, Eisai, Vertex, Merck, Genen-
tech, Bayer, Conatus, Ocera, Hyperion, Gilead Sciences, Bristol Myers Squibb,
Mochida, Eisai, Vertex, takeda, GI Dynamics; Speaking and Teaching: Merck,
Merck, Merck, Merck
Martin Lagging - Advisory Committees or Review Panels: Roche, MSD, Janssen,
Gilead, Medivir; Speaking and Teaching: Roche, MSD, Janssen, Abbott, Gilead
Frank Dutko - Employment: Merck & Co., Inc.; Stock Shareholder: Merck & Co.,
Inc.
Anita Y. Howe - Employment: Merck Research Laboratory
Peggy Hwang - Employment: Merck, Merck
Janice Wahl - Employment: Merck & Co,
Michael Robertson - Employment: Merck; Stock Shareholder: Merck
Barbara A. Haber - Employment: Merck
The following people have nothing to disclose: Wayne Ghesquiere, Fredrik Sund,
Melissa Shaughnessy
297A
197
High Efficacy of Treatment with Sofosbuvir+GS-5816
±Ribavirin for 12 Weeks in Treatment Experienced
Patients with Genotype 1 or 3 HCV Infection
Stephen Pianko1, Steven L. Flamm2, Mitchell L. Shiffman3, Sonal
Kumar4, Simone I. Strasser5, Gregory J. Dore6, John McNally7,
Diana M. Brainard7, Lingling Han7, Brian Doehle7, Erik Mogalian7,
John G. McHutchison7, K. Rajender Reddy8, Stuart K. Roberts9;
1Monash Medical Centre, Clayton, VIC, Australia; 2Northwestern
University, Chicago, IL; 3Liver Institute of Virginia, Richmond, VA;
4Weill Cornell Medical College, New York, NY; 5Royal Prince
Alfred Hospital, Camperdown, NSW, Australia; 6St. Vincents Hos-
pital, Darlinghurst, NSW, Australia; 7Gilead Sciences, Inc., Fos-
ter City, CA; 8University of Pennsylvania, Philadelphia, PA; 9The
Alfred, Melbourne, VIC, Australia
Introduction: The combination of sofosbuvir (SOF) and
GS-5816 for 12 weeks has demonstrated high efficacy in treat-
ment naïve patients without cirrhosis with chronic genotype 1-6
HCV infection. This Phase 2 study evaluated SOF + GS-5816 ±
RBV for 12 weeks in treatment experienced patients with gen-
otype 1 or 3 HCV infection with or without cirrhosis. Methods:
Three cohorts of treatment experienced patients were evalu-
ated: patients with genotype 3 HCV infection without cirrhosis,
patients with genotype 3 HCV infection with cirrhosis, and
patients with genotype 1 HCV infection with and without cirrho-
sis who had failed treatment with a protease-inhibitor contain-
ing regimen. Within each cohort, patients were randomized
1:1:1:1 to SOF+GS-5816 25mg, SOF+GS-5816 25mg+RBV,
SOF+GS-5816 100mg or SOF+GS-5816 100 mg+RBV. The
SOF dose was 400 mg. Ribavirin was administered 1000-
1200mg in a divided daily dose. Results: 321 patients were
randomized and treated; 65% had genotype 3 HCV infection,
69% were male, 89% were white, 27% had IL28B CC gen-
otype and 43% had cirrhosis. The SVR12 rates in treatment
experienced genotype 3 infected patients with and without
cirrhosis administered SOF +GS-5816 100mg were 88% and
100%, respectively. The SVR12 rate was 100% in genotype 1
HCV infected patients administered SOF +GS-5816 100mg.
Relapse accounted for all virologic failures. The most frequently
reported adverse events (> 10%) in patients were fatigue,
headache, nausea and insomnia. Patients administered RBV
containing regimens also commonly reported pruritus and rash.
One patient discontinued treatment with SOF +GS-5816 25mg
+RBV after 81 days of treatment due to elevated ALT and GGT.
Nine patients reported 10 SAEs; none were considered related
to study treatment. Anemia was only observed in patients
receiving RBV. Conclusions: High SVR12 rates were achieved
in treatment experienced patients with genotype 1 or genotype
3 HCV infection administered SOF +GS-5816 100 mg for 12
weeks. SOF+GS-5816 for 12 weeks was well tolerated with
a low incidence of treatment discontinuation and SAEs. This
study demonstrates that co-administration of SOF 400mg with
GS-5816 100mg for 12 weeks without RBV is an effective and
safe regimen for treatment of HCV infection.
298A AASLD ABSTRACTS
SVR12 in Treatment-Experienced Patients Administered SOF +
GS-5816 ±RBV for 12 Weeks
a one subject has not returned for posttreatment assessments
Disclosures:
Stephen Pianko - Advisory Committees or Review Panels: Roche, Novartis, GIL-
EAD, Roche, Novartis; Consulting: GILEAD; Speaking and Teaching: JANSSEN
Steven L. Flamm - Advisory Committees or Review Panels: Gilead, Bristol Myers
Squibb, AbbVie, Janssen, Salix; Consulting: Merck, Janseen, Bristol Myers
Squibb, AbbVie, Salix, Gilead; Grant/Research Support: Janssen, Bristol Myers
Squibb, Merck, Vertex, Gilead, AbbVie, Boehringer Ingelheim; Speaking and
Teaching: Salix
Mitchell L. Shiffman - Advisory Committees or Review Panels: Merck, Gilead,
Boehringer-Ingelheim, Bristol-Myers-Squibb, Abbvie, Janssen; Consulting: Roche/
Genentech, Gen-Probe; Grant/Research Support: Merck, Gilead, Boehring-
er-Ingelheim, Bristol-Myers-Squibb, GSK, Abbvie, Beckman-Coulter, Achillion,
Lumena, Intercept, Novarit, Gen-Probe; Speaking and Teaching: Roche/Genen-
tech, Merck, Gilead, GSK, Janssen, Bayer
Sonal Kumar - Advisory Committees or Review Panels: Gilead
Simone I. Strasser - Advisory Committees or Review Panels: Janssen, AbbVie,
Roche Products Australia, MSD, Bristol-Myers Squibb, Gilead, Norgine, Bayer
Healthcare; Speaking and Teaching: Bayer Healthcare, Bristol-Myers Squibb,
MSD, Roche Products Australia, Gilead, Janssen
Gregory J. Dore - Board Membership: Bristol-Myers Squibb, Roche, Gilead,
Merck, Janssen, Abbvie; Grant/Research Support: Janssen, Bristol-Myers Squibb,
Vertex, Roche, Gilead, Merck, Abbvie; Speaking and Teaching: Roche, Merck,
Janssen
John McNally - Employment: Gilead Sciences, Inc
Diana M. Brainard - Employment: Gilead Sciences, Inc.
Brian Doehle - Employment: Gilead Sciences
Erik Mogalian - Employment: Gilead Sciences, Inc; Stock Shareholder: Gilead
Sciences, Inc
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
K. Rajender Reddy - Advisory Committees or Review Panels: Genentech-Roche,
Merck, Janssen, Vertex, Gilead, BMS, Novartis, Abbvie; Grant/Research Sup-
port: Merck, BMS, Ikaria, Gilead, Janssen, AbbVie
Stuart K. Roberts - Board Membership: Jannsen, Roche, Gilead, BMS
The following people have nothing to disclose: Lingling Han
HEPATOLOGY, October, 2014
198
High Sustained Virologic Response Rates in Liver Trans-
plant Recipients With Recurrent HCV Genotype 1 Infec-
tion Receiving ABT-450/r/Ombitasvir+Dasabuvir Plus
Ribavirin
Parvez S. Mantry1, Paul Y. Kwo2, Eoin Coakley3, Helen S. Te4,
Hugo E. Vargas5, Robert S. Brown6, Fredric D. Gordon7, Josh Lev-
itsky8, Norah Terrault9, James R. Burton10, Wangang Xie3, Caro-
lyn Setze3, Prajakta Badri3, Regis A. Vilchez3, Xavier Forns11; 1The
Liver Institute at Methodist Dallas, Dallas, TX; 2Indiana University,
Indianapolis, IN; 3AbbVie Inc., North Chicago, IL; 4University of
Chicago Medicine, Chicago, IL; 5Mayo Clinic, Arizona, Phoenix,
AZ; 6Columbia University Medical Center, Center for Liver Disease
and Transplantation, New York, NY; 7Lahey Hospital & Medical
Center, Burlington, MA; 8Northwestern University Comprehensive
Transplant Center, Chicago, IL; 9University of California, San
Francisco, San Francisco, CA; 10University of Colorado, Denver,
Aurora, CO; 11Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD,
Barcelona, Barcelona, Spain
Purpose:HCV infection is the most common indication for liver
transplantation(LT). HCV recurrence after LT is universal, lead-
ing to premature graft failure in 30-50% of patients(pts). Inter-
feron-based HCV therapies are limited by toxicity and poor
efficacy. ABT-450 is an HCV NS3/4A protease inhibitor(dosed
with ritonavir, ABT-450/r) identified by AbbVie and Enanta.
Ombitasvir is an NS5A inhibitor; dasabuvir is an NS5B RNA
polymerase inhibitor. We examined safety and efficacy of
ABT-450/r/ombitasvir and dasabuvir plus ribavirin(3D+RBV)
in non-cirrhotic LT recipients with recurrent HCV genotype(GT)
1 infection. Methods:In this ongoing open-label phase 2 trial,
pts received 24 weeks of co-formulated ABT-450/r/ombitas-
vir(150mg/100mg/25mg QD) and dasabuvir(250mg BID)
plus RBV(dosed at investigator discretion). Eligibility criteria
included LT≥12 months before screening, HCV treatment-na-
ive since LT, and screening biopsy Metavir score≤F2. Due
to interactions between calcineurin inhibitors(CNIs) and
study regimen, modified CNI dosing was advised(tacroli-
mus: 0.5mg once weekly or 0.2mg every 3 days; cyclospo-
rine: 1/5 the daily pre-study dose once daily). RVR, EOTR,
SVR4, SVR12, and SVR24 rates are reported. Updated SVR
rates will be presented. Results:All 34 enrolled pts achieved
RVR and EOTR(Table). SVR4, SVR12, and SVR24 rates are
97.1%(33/34), 97.0%(32/33), and 93.3%(14/15). No pt
had breakthrough on treatment; 1 relapsed. Advised lower
CNI dosing resulted in stable CNI levels. The most common
treatment-emergent adverse events(AEs) were fatigue(50.0%)
and headache(44.1%). One pt discontinued treatment after
week 18 due to AEs(moderate rash, memory impairment, anx-
iety); this pt achieved SVR12. Five pts with grade 2(N=4) or
grade 3(N=1) hemoglobin decreases received erythropoietin
at investigator discretion. No pt was transfused or had an epi-
sode of acute rejection. Conclusions:LT recipients with recurrent
HCV GT1 infection achieved high SVR rates with the interfer-
on-free 3D+RBV regimen. The regimen was generally well-toler-
ated and drug-drug interactions were manageable.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Disclosures:
Parvez S. Mantry - Consulting: Salix, Gilead, Janssen, Abbvie; Grant/Research
Support: Salix, Merck, Gilead, Boehringer-Ingelheim, Mass Biologics, Vital Ther-
apies, Santaris, Vertex, Bristol-Myers Squibb, Abbive, Bayer-Onyx; Speaking
and Teaching: Gilead, Janssen, Salix, Bayer-Onyx
Paul Y. Kwo - Advisory Committees or Review Panels: Abbott, Novartis, Merck,
Gilead, BMS, Janssen; Consulting: Vertex; Grant/Research Support: Roche, Ver-
tex, GlaxoSmithKline, Merck, BMS, Abbott, Idenix, Vital Therapeutics, Gilead,
Vertex, Merck, Idenix; Speaking and Teaching: Merck, Merck
Eoin Coakley - Employment: AbbVie; Stock Shareholder: AbbVie
Helen S. Te - Advisory Committees or Review Panels: Gilead Sciences, Jansenn
Pharmaceuticals; Grant/Research Support: Abbvie, BMS
Hugo E. Vargas - Advisory Committees or Review Panels: Eisai; Grant/Research
Support: Merck, Gilead, Idenix, Novartis, Vertex, Janssen, Bristol Myers, Ikaria,
AbbVie
Robert S. Brown - Advisory Committees or Review Panels: Vital Therapies; Con-
sulting: Genentech, Gilead, Merck, Abbvie, Janssen; Grant/Research Support:
Gilead, Merck, Vertex, AbbVie, Salix, Janssen, Vital Therapies
Fredric D. Gordon - Advisory Committees or Review Panels: Gilead, AbbVie;
Grant/Research Support: BMS, Vertex, Gilead, AbbVie
Josh Levitsky - Consulting: Transplant Genomics Inc; Grant/Research Support:
Novartis; Speaking and Teaching: Gilead, Salix
Norah Terrault - Advisory Committees or Review Panels: Eisai, Biotest; Con-
sulting: BMS, Merck; Grant/Research Support: Eisai, Biotest, Vertex, Gilead,
AbbVie, Novartis, Merck
James R. Burton - Grant/Research Support: Vertex pharaceuticals, Abbvie phar-
maceuticals, Gilead pharmaceuticals, Janssen pharmaceuticals
Wangang Xie - Employment: AbbVie
Carolyn Setze - Employment: AbbVie; Stock Shareholder: AbbVie
Prajakta Badri - Employment: Abbvie; Stock Shareholder: Abbvie
Regis A. Vilchez - Employment: AbbVie Inc.
Xavier Forns - Consulting: Jansen, MSD, Abbvie; Grant/Research Support:
Roche, MSD, Gilead
199
The lipid flippase ATP11C-CDC50A heterodimer is
essential for basolateral localization of the hepatic bile
salt transporters OATP1B2 and NTCP in central hepato-
cytes
Jyoti Naik1, Dirk R. de Waart1, Karina S. Utsunomiya1,2, Kam
Ho-Mok1, Suzanne Duijst1, Ronald Oude Elferink1, Piter J. Bosma1,
Coen C. Paulusma1; 1Tytgat Institute, Academic Medical Center,
Amsterdam, Netherlands; 2Department of Biochemistry, University
of Maringá, Paraná, Brazil
Introduction: P4 ATPases are lipid flippases involved in trans-
port of phospholipids from the exoplasmic to the cytosolic leaflet
of biological membranes. Deficiency of the P4 ATPase ATP8B1
causes progressive familial intrahepatic cholestasis type 1 in
men. We have previously shown that the cholestasis in ATP8B1
deficiency originates at the canalicular membrane. Recently it
was shown that loss of the P4 ATPase ATP11C in mice leads
to unconjugated hypercholanemia (Siggs et al, 2011). Aim: To
299A
study whether ATP11C deficiency in mouse liver interferes with
the activity of the basolateral uptake transporter for unconju-
gated bile salts, OATP1B2. Methods: ATP11C deficient mice
were generated by chemical mutagenesis (Siggs et al, 2011).
OATP1B2 and NTCP (transporter of conjugated bile salts)
mediated transport was analysed by single-pass liver perfusion
after bolus injection of cholyl-L-lysyl-fluorescein (CLF) and tauro-
cholate (TC) via tail vein. Bile was sampled and output of CLF
and TC was quantified. TC infusions were performed to ana-
lyze canalicular bile formation. Bile samples were analyzed
for bile salts, alkaline phosphatase and cholesterol. Localiza-
tion of hepatic transporters were studied by immunofluorescent
staining. Results: Biliary output of CLF was 104±12% of the
applied dose in littermates and 22±13% in ATP11C-deficient
mice. Biliary TC, cholesterol and alkaline phosphatase output
were unaffected, demonstrating that NTCP-mediated transport
and canalicular membrane function were unaffected. ATP11C,
OATP1B2 and CDC50A (the β-subunit for ATP11C) localized
at the basolateral membrane of central hepatocytes in con-
trol liver, but were virtually absent in ATP11C-deficient liver.
While NTCP was homogenously distributed in control liver,
expression was completely lost from the central hepatocytes
in ATP11C-deficient liver. Hepatic over-expression of human
ATP11C by Adeno-associated virus (AAV8) mediated deliv-
ery corrected expression of OATP1B2, NTCP and CDC50A
in ATP11C-deficient mice. AAV8 mediated knockdown of
hepatic CDC50A in wild type mice resulted in 80% knock-
down of CDC50A mRNA levels and phenocopied ATP11C-de-
ficient mice. Conclusion: ATP11C-deficient mice suffer from an
unconjugated hypercholanemia that originates in the central
hepatocytes of the liver and is caused by impaired basolateral
expression of OATP1B2. Surprisingly, canalicular membrane
function was not affected. ATP11C and CDC50A heterodi-
merization is essential for basolateral targeting of OATP1B2
and NTCP in central hepatocytes. AAV8-mediated delivery of
shRNAs is a powerful approach to clarify the role of hepato-
cyte-specific proteins in liver function.
Disclosures:
The following people have nothing to disclose: Jyoti Naik, Dirk R. de Waart,
Karina S. Utsunomiya, Kam Ho-Mok, Suzanne Duijst, Ronald Oude Elferink, Piter
J. Bosma, Coen C. Paulusma
200
The Cystic Fibrosis Conductance Regulator (CFTR) con-
trols c-Src tyrosine kinase signaling and regulates
innate immunity and epithelial polarity in cholangio-
cytes
Romina Fiorotto1, Ambra Villani1, Antonis Kourtidis3, Roberto
Scirpo1,2, Carlo Spirli1, Panos Z. Anastasiadis3, Mario Strazza-
bosco1,2; 1Yale University, Section of Digestive Diseases, New
Haven, CT; 2University of Milan-Bicocca, Milan, Italy; 3Cancer
Biology, Mayo Clinic, Jacksonville, FL
CFTR is expressed at the apical membrane of cholangiocytes
where it regulates Cl- and HCO3- secretion. CFTR also modu-
lates innate immune responses in the biliary epithelium. In fact,
TLR4-mediated responses to LPS are increased in cholangio-
cytes from Cftrtm1Unc (Cftr-KO) mice along with the activity
of c-Src, a non-receptorial tyrosine kinase. Aim of this study,
was to understand how CFTR deficiency leads to up-regulation
of c-Src activity in cholangiocytes. Results: Primary cholangio-
cytes were isolated from Cftr-KO mice and their WT littermates.
Y416 phosphorylation of c-Src was increased in Cftr-defective
cells, but not in WT cells exposed to Cftr-inh-177 to inhibit CFTR
function, suggesting that lack of CFTR protein at the membrane,
rather than lack of its channel activity causes c-Src activation.
300A AASLD ABSTRACTS
In WT cells, CFTR co-immunoprecipitated with proteins involved
in the negative regulation of c-Src (EBP-50, Csk and CBP);
confocal imaging confirmed their co-localization at the apical
membrane in WT cells. In Cftr-KO cells co-localization was lost
and the amount of EBP-50 and Csk in lipid rafts was signifi-
cantly reduced as compared to WT cells. Since c-Src is import-
ant for maintaining the integrity of epithelial cell-cell junctions,
we investigated the distribution of ZO-1 (tight junction), afadin
(adherens junction) and subcortical F-actin fibers. In Cftr-KO
cells ZO-1 and afadin lost their junctional restriction and also
appeared diffusely distributed in the cytoplasm; also the cor-
tical actin ring failed to form properly, suggesting a polarity
defect. Increased Y228 phosphorylation of p120, a substrate
of c-Src and a marker of junction destabilization, was also
observed in Cftr-KO cells. Treatment with PP2, an inhibitor of
c-Src, significantly decreased TLR4-mediated NF-kB activation
and cytokine secretion and rescued the polarity phenotype,
as shown by ZO-1 and F-actin distribution. Inhibition of c-Src
in vivo significantly attenuated biliary damage and inflamma-
tion in a Cftr-KO mouse model. In conclusion these findings
suggest a novel role of CFTR as regulator of c-Src activation.
Expression of CFTR facilitates the assembly of a protein com-
plex located in lipid rafts able to negatively regulate c-Src. Lack
of CFTR perturbs this complex. Consequently c-Src self-activates
promoting an increase in TLR4 responses, the destabilization
of cell-cell junctions and an impairment in cell polarity. The
protective effects of c-Src inhibition in vivo demonstrate the
pathogenetic relevance of this mechanism and suggest that
c-Src is a potential therapeutic target for CF-liver disease and
other cholangiopathies.
Disclosures:
The following people have nothing to disclose: Romina Fiorotto, Ambra Villani,
Antonis Kourtidis, Roberto Scirpo, Carlo Spirli, Panos Z. Anastasiadis, Mario
Strazzabosco
201
Interleukin-33 induces cholangiocyte proliferation via
IL13/IL-4R/STAT6 pathway
Jun Li, Reena Mourya, Stephanie Walters, Karis Kosar, Pranavku-
mar Shivakumar, Stacey S. Huppert, Jorge A. Bezerra; Division
of Gastroenterology, Hepatology and Nutrition and the Pediatric
Liver Care Center, Cincinnati Children&apos;s Hospital Medical
Center, Cincinnati, OH
Background: We recently uncovered a novel cholangiocyte
growth-promoting circuit involving Interleukin-33 (IL33), type
2 innate lymphoid cells (ILC2s), and IL13, which we directly
linked to tissue repair and carcinogenesis. Here, we aimed
to investigate the role of signaling events downstream of IL33
in cholangiocyte proliferation. Methods/Results: To identify
molecular pathways activated by IL33, we performed whole
RNA sequencing of extrahepatic bile ducts 1 and 4 days after
IL33 administration into adult mice. IL33 triggered the activa-
tion of 30 genes in the cell cycle signaling pathway ≥2-fold
above controls at day 1, including regulators of G1-S transi-
tion, DNA replication, G2-M transition, and cell cycle check-
point. We also found a >2-fold increase in IL4ra, a member of
heterodimer receptor for IL13 at days 1 and 4. Based on these
data, we hypothesized that signaling events downstream of
IL-4Ra are required for cholangiocyte proliferation. Testing this
hypothesis, we determined proliferation of primary cholangio-
cytes from extrahepatic bile ducts cultured with IL13 (0.5 μg/
mL), and found a significant increase in proliferation above
controls after 24 hours (P=0.03). To precisely determine if the
IL13/IL-4Ra axis is a secondary downstream signal regulator
of IL33, we injected 1 μg of IL33 daily to adult mice carry-
HEPATOLOGY, October, 2014
ing the genetic inactivation of IL4ra (IL4ra-/- mice). We found
that loss of functional IL-4R receptor significantly decreased
Brdu uptake in CK19+ extrahepatic cholangiocytes compared
to wild-type (WT) controls (4.0±1.4% vs 12.5±1.2%, respec-
tively; P<0.001). The reduced proliferation was not dependent
on the expansion of hepatic ILC2 cells, as demonstrated by
similar numbers of cells by flow cytometry (Il4ra-/-=36.6±1.9%
vs WT= 36.8±2.8%, respectively; P=0.92). Additionally, ILC2
cells from Il4ra-/- mice respond normally to IL33 in vitro, with
similar production of IL-4 and IL13 upon treatment with PMA-ion-
omycin. Based on the role of STAT6 as a signal transducer for
IL-4Ra, we subjected Stat6-/- mice to similar stimulation with
IL33. Cholangiocytes from Stat6-/- mice had reduced prolif-
eration when compared to WT cholangiocytes (4.8±2.7% vs
15.6±4.5%, respectively; P<0.001) and, like in Il4ra-/- mice,
had no difference in the number and IL13 production by ILC2
cells. Conclusions: Cholangiocyte proliferation triggered by
IL33 is linked to rapid transcriptional expression of numerous
cell cycle genes and dependent on a molecular axis contain-
ing IL13/IL-4R/STAT6 signaling. The IL-4R/STAT6 pathway,
independent of ILC2 cells, regulates cell proliferation and may
targetable to promote epithelial repair or block carcinogenesis.
Disclosures:
Jorge A. Bezerra - Grant/Research Support: Molecular Genetics Laboratory,
CHMC
The following people have nothing to disclose: Jun Li, Reena Mourya, Stephanie
Walters, Karis Kosar, Pranavkumar Shivakumar, Stacey S. Huppert
202
Ccl2-deficiency protects mice from cholestatic liver injury
by blocking hepatic leukocyte infiltration
Shi-Ying Cai, Xinshou Ouyang, Albert Mennone, Matthew R.
Smith, Carol J. Soroka, Wajahat Z. Mehal, James L. Boyer; Yale
Univ, New Haven, CT
Background: The role of leukocytes and the inflammatory
response in the pathogenesis of bile acid (BA) induced liver
injury remains controversial. Submillimolar levels of toxic BA
can damage cultured cells in vitro, but serum levels in choles-
tatic patients and animals never reach these levels in vivo.
Instead, elevated hepatic CCL2 (monocyte chemotactic pro-
tein 1) expression was detected in these patients and animals,
suggesting that the immune response plays an important role
in cholestatic liver injury. Aim: To determine the pathophysio-
logical role of the inflammatory response in BA induced liver
injury. Methods: Ccl2-/- and wild-type (WT) mice ( n=6-8 in
each treatment group) were subjected to 1% cholic acid (CA)
feeding or bile duct ligation (BDL) for 7 days. Plasma biochem-
istry and liver gene expression were analyzed. Liver histology
was examined blindly and scored 0-4+. Leukocyte profiles in
blood, liver and spleen were assessed using FACS and/or
immunohistochemistry. Results: CA-fed WT mice developed ele-
vated plasma levels of BA (59±11 mM) and ALT (166±99 U/L)
compared to CA-fed Ccl2-/- mice where lower plasma levels
of BA (27±20 mM, p<0.01) and ALT (61±24 U/L, p<0.05)
were detected. Induction of liver inflammatory chemokines and
cytokines was also abolished in CA-fed Ccl2-/- mice. After
BDL, hepatic necrosis was nearly absent (histology scores:
WT, 2.8±0.9 vs Ccl2-/-, 0.6±0.8) and plasma ALT was min-
imally elevated in Ccl2-/- BDL mice (WT: 796±358 vs Ccl2-
/-: 267±80 U/L, p<0.01) despite similar levels of plasma BA
in WT BDL mice. Furthermore, there were no differences in
plasma ALP, liver [BA], bile duct proliferation and liver fibrosis
between the two groups after BDL. FACS and immunohisto-
chemistry revealed significantly less neutrophil and monocyte
infiltration, specifically in the livers from Ccl2-/- BDL mice (GR-1
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
positive cells: WT, 67.7% vs Ccl2-/-, 30.1%), despite higher
mRNA expression of Cxcl2, Tnfα and Il-1β in Ccl2-/- livers
than in their WT controls. Despite these findings, there were
no substantial differences in liver expression of BA transport-
ers between Ccl2-/- and its corresponding WT controls. Sum-
mary: At pathophysiological concentrations of BA that induced
hepatocyte necrosis, liver injury correlated positively with liver
neutrophil infiltration but not plasma or hepatic bile acid levels.
Conclusion: Liver injury in these two cholestatic models is medi-
ated by the inflammatory response, rather than direct detergent
effects of bile acids. Reduction of the immune inflammatory
response may moderate cholestatic liver injury.
Disclosures:
Wajahat Z. Mehal - Management Position: Gloabl BioReserach Partners
The following people have nothing to disclose: Shi-Ying Cai, Xinshou Ouyang,
Albert Mennone, Matthew R. Smith, Carol J. Soroka, James L. Boyer
203
Identification and characterization of membrane Syn-
taxins in mouse biliary epithelial cells: role in regulated
ATP release and bile formation
Razan Bader1, Qin Li1, Charles Kresge1, Abhijit Bugde3, Matthew
A. Lewis2, Andrew P. Feranchak1; 1Pediatric Gastroenterology, UT
Southwestern, Dallas, TX; 2Radiology, UT southwestern, Dallas, TX;
3Live cell imaging, UT southwestern, dallas, TN
Background: Exocytic release of ATP into bile is an import-
ant mechanism to regulate bile formation through a pathway
known as purinergic signaling. In this pathway, released ATP
binds membrane P2 receptors on biliary epithelial cells (BECs),
increases [Ca2+]i, and stimulates Cl- and HCO3- efflux which
drives secretion. While a population of ATP-enriched vesicles
(ATP-V) has been identified in BECs, the mechanism by which
these vesicles fuse with the plasma membrane and undergo
exocytosis is unknown. Vesicle exocytosis is mediated by the
SNARE (Soluble N-ethylmaleimide (NEM)-sensitive Attachment
protein REceptor) complex, consisting of vesicular-associated
proteins and membrane-associated targets, known as syntaxins
(STX). The expression and function of STXs in BECs is unknown.
Aim: to identify the expression of STX proteins in mouse BECs
and determine their potential role in the exocytosis of ATP-V.
Methods: Studies were performed in mouse BECs. In individ-
ual cells, the rate of exocytosis was assessed by membrane
fluorescence of FM1-43 and trafficking and release of ATP-V
by dynamic live-cell imaging. In confluent BEC monolayers,
real-time ATP release was measured by i) luciferin-luciferase
assay, and ii) mesoscopic bioluminescence imaging utilizing a
highly sensitive CCD camera to capture “point-source bursts”
of released ATP. STX expression was determined by RT-PCR,
Western, and immunostaining. Knock-down of specific syn-
taxins was accomplished by transfection with specific siRNA.
Results: In response to hypotonic stimulation (30%), control
mouse BECs exhibited bulk ATP release and point-source
release from confluent monolayers; and, in individual cells,
an increase in the rate of exocytosis, trafficking and release of
ATP-V as expected. In contrast, interruption of SNARE complex
formation by NEM blocked both bulk ATP release and point-
source ATP bursts from monolayers, as well as decreased the
rate of exocytosis and exocytosis of ATP-V in individual cells.
Mouse BECs expressed STX -1A, -2, and -3A. STX -1B and -3B
were not expressed. Immunostaining revealed strong STX-1A
and -3A signal on the apical BEC membrane. In individual stud-
ies, transfection with specific siRNAs significantly decreased
protein expression of each STX, though only the STX -1A and
-3A knock-down was associated with inhibition of ATP release.
Conclusion: Together, the findings demonstrate that syntax-
301A
in-1A and -3A play an important role in ATP-V exocytosis and
release of ATP by BECs. Targeting STXs may represent a novel
therapeutic option to augment release of ATP into bile, increase
biliary secretion, and promote bile formation for the treatment
of cholestatic liver diseases.
Disclosures:
The following people have nothing to disclose: Razan Bader, Qin Li, Charles
Kresge, Abhijit Bugde, Matthew A. Lewis, Andrew P. Feranchak
204
Hepatic transport of conjugated bile acids in humans
quantitated by 11C-cholylsarcosine PET/CT
Nikolaj W. Ørntoft1, Kim Frisch1, Peter Ott2, Susanne Keiding1,2,
Michael Sørensen2; 1Dept. of Nuclear Medicine & PET Centre,
Aarhus University Hospital, Aarhus C, Denmark; 2Dept. of Hepa-
tology and Gastroenterology, Aarhus University Hospital, Aarhus
C, Denmark
Introduction: Hepatobiliary excretion of bile acids is an essential
liver function which is not accessible by conventional means of
measurements. We examined whether PET/CT using the radio-
labeled conjugated bile acid analogue [N-methyl-11C]cholyl-
sarcosine (11C-CSar) as tracer allowed quantitative assessment
of this function in human subjects. Methods: Ten healthy sub-
jects and ten patients with varying degrees of cholestasis each
underwent two 60 minutes dynamic PET/CT recordings of the
liver using intravenous bolus injection and continuous infusion
of 11C-CSar. Blood concentrations of 11C-CSar were measured
in samples collected from a radial artery and a hepatic vein.
Concentrations of 11C-CSar in the liver tissue and common
hepatic bile ducts were recorded by PET. Hepatic blood flow
was measured using intravenous infusion of indocyanine green
and Fick’s principle. Hepatic extraction fraction of 11C-CSar
was calculated from the arterial and hepatic venous concen-
tration measurements. Fractional biliary excretion at a given
time point was calculated as the ratio between 11C-CSar
excreted into bile and 11C-CSar supplied to the liver. Results:
The 11C-CSar concentration in liver tissue showed an initial
rapid rise, which was similar in patients and healthy subjects.
The subsequent elimination of 11C-CSar from liver tissue to
bile was significantly reduced in patients with cholestasis. In
the common hepatic bile duct, the arrival of 11C-CSar was
delayed and reached a lower peak concentration in the
patients than in the healthy subjects. The hepatic extraction
fraction was constant 90% (range 85 – 94%) throughout 60
min PET recordings in healthy subjects, while in the patients it
decreased with time from initially 86% (77 – 93%; p=0.09)
to 50% (28 – 59%; p<0.0001). This demonstrates a normal
uptake of 11C-CSar from blood to hepatocytes, combined with
a significant backflux of 11C-CSar from hepatocyte to blood in
patients with cholestasis, and essentially no backflux in healthy
subjects. Median fractional biliary excretion (time point 50
min) of 11C-CSar was 73% (55 – 80%) in healthy subjects and
38% (17 – 70%) in patients with cholestasis (p<0.001). This
demonstrates reduced secretion of 11C-CSar from hepatocyte
to bile in patients with cholestasis. Conclusions: 11C-CSar PET/
CT enables quantitation of the hepatobiliary excretion of con-
jugated bile acids. In patients with cholestasis, hepatic uptake
of 11C-CSar from blood was normal while there was backflux
of 11C-CSar to blood and the secretion from liver to bile was
reduced. These results show potential for investigation of the
hepatobiliary function using 11C-CSar PET/CT.
Disclosures:
The following people have nothing to disclose: Nikolaj W. Ørntoft, Kim Frisch,
Peter Ott, Susanne Keiding, Michael Sørensen
302A AASLD ABSTRACTS
205
Leucine mediated rescue of hyperammonemia mediated
impaired skeletal muscle protein synthesis in cirrhosis
Dawid Krokowski2, Ashok Runkana3, Samjhana Thapaliya3, Cyn-
thia Tsien4, Gangarao Davuluri3, Maria Hatzoglou2, Srinivasan
Dasarathy1,3; 1Gastroenterology, Cleveland Clinic, Cleveland,
OH; 2Pharmacology, Case Western Reserve University, Cleveland,
OH; 3Pathobiology, Cleveland Clinic, Cleveland, OH; 4Hepatol-
ogy, Toronto General Hospital, Toronto, ON, Canada
Backgound. Skeletal muscle ammonia uptake and concen-
trations of ammonia are increased in cirrhosis and result in
sarcopenia. In the skeletal muscle, ammonia is converted to
glutamine and exported extracellularly. Cirrhosis and hyper-
ammonemia are accompanied by reduced plasma and muscle
concentrations of leucine and increased plasma concentration
of glutamine. Since leucine directly activates mTOR and its
downstream signaling, promoting muscle protein synthesis, we
determined if leucine transport is maintained and permits res-
cue of the impaired protein synthesis of hyperammonemia.
Methods. Studies were performed in the skeletal muscle from
patients with cirrhosis and controls and in differentiated murine
C2C12 myotubes during hyperammonemia using protocols
established by us. Myotubes were exposed to either ammo-
nium acetate (10mM) or leucine (5mM) or a combination of
leucine and ammonium acetate and were compared with
control cells. mTOR and p70s6k phosphorylation and GCN2
expression were quantified by immunoblots and system L leu-
cine transporter (LAT1) was quantified by real time PCR. Rate
of protein synthesis was quantified using 3H phenylalanine
incorporation. Amino acid uptake was quantified using 3H
leucine uptake and amino acids quantified using HPLC. Results.
We show that low plasma concentrations of leucine in cirrhosis
was accompanied by increased expression of GCN2, a sensor
of intracellular amino acid starvation in the skeletal muscle of
cirrhotic compared to control subjects. Additionally, phosphor-
ylation of mTOR and its downstream target p70s6k were lower
in cirrhotic muscle compared to controls. In-vitro studies in dif-
ferentiated C2C12 myotubes showed that hyperammonemia
impaired protein synthesis and reduced cell diameter that are
reversed by 5mM leucine. We also show that skeletal mus-
cle leucine uptake and glutamine export are elevated during
hyperammonemia in C2C12 myotubes. Cellular concentrations
of aromatic amino acids that are not catabolized in the skele-
tal muscle are not altered. Conclusions. These data show that
hyperammonemia induces metabolic alterations in the skeletal
muscle characterized by increased leucine uptake via system
L amino acid transporter, LAT1. Even though intracellular con-
centrations of leucine were not elevated by supplementation
in the medium, reduced muscle protein synthesis and diame-
ter during hyperammonemia are reversed by leucine. These
data suggest increased utilization of leucine into the recently
described leucine-glutamate pathway of ammonia detoxifica-
tion and provide the basis for using leucine as a therapeutic
nutriceutical to reverse hyperammonemia and sarcopenia of
cirrhosis.
Disclosures:
The following people have nothing to disclose: Dawid Krokowski, Ashok Runk-
ana, Samjhana Thapaliya, Cynthia Tsien, Gangarao Davuluri, Maria Hatzoglou,
Srinivasan Dasarathy
HEPATOLOGY, October, 2014
206
Jak2/Arhgef1 signaling correlates with severity of liver
disease and represents a target for therapy of portal
hypertension
Sabine Klein1, Johanna Rick1, Robert Schierwagen1, Frank E.
Uschner1, Christian P. Strassburg1, Wim Laleman2, Tilman Sauer-
bruch1, Jonel Trebicka1; 1Internal Medicine I, University of Bonn,
Bonn, Germany; 2Department of Hepatology, University of Leuven,
Leuven, Belgium
Background: In cirrhosis, intrahepatic vasoconstriction and
hepatic stellate cell (HSC) contraction contribute to genera-
tion of portal hypertesnion. Angiotensin II (AngII) contracts
peripheral vessels via AT1-receptor (AT1R) stimulation which
induces activation of the Janus-kinase 2 (Jak2)/Arhgef1 path-
way and subsequent RhoA/Rho-kinase (ROCK) upregulation.
(Nat. Med., 2010). We could show that the AT1R mediated
Jak2 activation in HSC induces experimental and human liver
fibrosis (Hepatology 2014). Here we investigated whether
JAK2 inhibition decreases portal pressure in rodents with liver
cirrhosis and correlated transcription of the signaling mole-
cules JAK2/Arhgef1 to severity of liver disease in man. Meth-
ods: The mRNA levels of Jak2/Arhgef1 signaling components
were analyzed in 49 human liver explants and correlated to
clinical parameters of these patients before transplantation.
In two different cirrhosis models (BDL, CCl4) in rats the hemo-
dynamic effect of Jak2 inhibition, using AG490, were ana-
lyzed in vivo with help of the microsphere technique. Isolated
in situ liver perfusion experiments analyzed the AG490 effect
on the contractility of hepatic vascular bed. Primary rat HSC
were incubated with different AG490 doses (0.05mM, 0.5mM,
5mM, 25mM) and their contraction was measured in vitro. Jak2
conditional knock out mice with SM22 promotor (SM22Cre+;-
Jak2f/f) were subjected to liver injury (BDL, CCl4). The extent
of liver fibrosis and portal pressure was measured in these
mice using standard methods. Results: Hepatic mRNA levels
of Jak2 and Arhgef1 correlated significantly with the MELD
score in pre-transplant patients. Furthermore, Angiotensinogen,
Renin and ROCK were correlated to the levels of γGT and
hepatic INR. In cirrhotic rats AG490 decreased hepatic vas-
cular resistance and consequently the portal pressure in vivo
and in situ. AG490 relaxed dose dependently activated HSC
in vitro. Similarly, the SM22Cre+;Jak2f/f mice developed less
fibrosis and showed lower portal pressure upon liver injury
compared to their respective controls. Discussion: The extent of
hepatic Jak2/Arhgef1/ROCK expression correlates to severity
of liver disease in humans. In animals, Jak2 inhibition or knock
out, not only decreased fibrosis but also ameliorated portal
hypertension by relaxation of activated HSC. Thus, inhibition of
Jak2 in HSC might be an effective approach not only to reduce
hepatic fibrosis, but also to lower portal hypertension.
Disclosures:
Christian P. Strassburg - Advisory Committees or Review Panels: Novartis, Roche;
Speaking and Teaching: Novartis, Merz, MSD, Falk Pharma, BMS, Abbvie
The following people have nothing to disclose: Sabine Klein, Johanna Rick,
Robert Schierwagen, Frank E. Uschner, Wim Laleman, Tilman Sauerbruch, Jonel
Trebicka
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
207
Serum Cystatin C is a Powerful Prognostic Indicator in
Patients with Cirrhotic Ascites: A Multicenter Prospective
Observational Study
Yeon Seok Seo1, Soo Young Park2, Moon Young Kim3, Sang
Gyune Kim4, Jun Yong Park7, Hyung Joon Yim1, Byoung Kuk
Jang5, Seung Ha Park6, Ji Hoon Kim1, Ki Tae Suk8, Jin Dong
Kim9, Tae Yeob Kim10, June Sung Lee7, Soung Won Jeong4, Jae
Young Jang4, Hyonggin An11, Won Young Tak2, Soon Koo Baik3,
Jaeseok Hwang5, Young Seok Kim4, Joo Hyun Sohn10, Soon Ho
Um1; 1Internal Medicine, Korea University College of Medicine,
Seoul, Republic of Korea; 2Internal Medicine, Kyungpook National
University School of Medicine, Daegu, Republic of Korea; 3Internal
Medicine, Yonsei University Wonju College of Medicine, Seoul,
Republic of Korea; 4Internal Medicine, Soonchunhyang University
College of Medicine, Asan, Republic of Korea; 5Internal Medi-
cine, Keimyung University College of Medicine, Daegu, Republic
of Korea; 6Internal Medicine, Inje University College of Medicine,
Pusan, Republic of Korea; 7Internal Medicine, Yonsei University
Wonju College of Medicine, Wonju, Republic of Korea; 8Internal
Medicine, Hallym University College of Medicine, Chuncheon,
Republic of Korea; 9Internal Medicine, Cheju Halla General Hospi-
tal, Jeju, Republic of Korea; 10Internal Medicine, Hanyang Univer-
sity College of Medicine, Seoul, Republic of Korea; 11Department
of Biostatistics, Korea University College of Medicine, Seoul,
Republic of Korea
Background: Because renal dysfunction is often accompanied
by progression of liver dysfunction and hepatorenal syndrome
(HRS) is one of the major causes of mortality, accurate assess-
ment of renal function is very important for the assessment of
patients with cirrhotic ascites. Although several studies sug-
gested that cystatin C (CysC) level is more reliable than creati-
nine level, it is still unclear whether CysC could be useful as a
prognostic marker in these patients. This study was performed
to evaluate the clinical significance of CysC in patients with
cirrhotic ascites. Methods: Patients with cirrhotic ascites were
prospectively enrolled between Sep 2009 and Mar 2013 at
14 hospitals. Patients with hepatocellular carcinoma or paren-
chymal kidney disease or those taking diuretics were excluded.
Laboratory tests including serum creatinine and CysC were
performed at the time of enrollment. Results: Three-hundred
forty-six patients were enrolled. Age was 55.3+/-11.0 years
and 262 patients (75.7%) were male. The most frequent cause
of liver disease was alcoholic liver disease (56.6%), followed
by chronic hepatitis B (31.2%). Serum creatinine and CysC
levels were 1.0+/-0.5 mg/dL and 1.1+/-0.5 mg/L, respec-
tively. During 36.7+/-1.5 months of follow-up, 88 patients
died. Causes of mortality were as follows: HRS, 27 (7.8%),
liver failure, 26 (7.5%); variceal bleeding, 13 (3.8%); sep-
sis, 9 (2.6%); others, 9 (2.6%). Survival time was 36.7+/-1.5
months and 6- and 12-month survival rates were 86.7% and
80.8%, respectively. INR, bilirubin, albumin, glucose, creati-
nine, sodium, and CysC levels were significant factors on uni-
variate analysis, while sodium and CysC levels and INR were
independently associated factors with survival on multivariate
analysis. INR (1.9+/-0.7 vs 1.4+/-0.4), bilirubin (9.0+/-9.0
mg/dL vs 3.7+/-4.5 mg/dL), albumin (2.7+/-0.4 g/dL vs
2.9+/-0.6 g/dL), creatinine (1.2+/-0.6 mg/dL vs 0.9+/-0.4
mg/dL), sodium (132.4+/-6.1 mEq/L vs 136.7+/-4.2 mEq/L),
and CysC (1.5+/-0.6 mg/L vs 1.0+/-0.4 mg/L) levels were
significantly between patients with 1-year mortality and 1-year
survivors. On binary logistic regression analysis, sodium and
CysC levels and INR were independent predictors for 1-year
mortality. The incidences of HRS at 6 and 12 months were
5.4% and 7.6%, respectively. Similarly, sodium and CysC lev-
els and INR were independent factors for predicting develop-
303A
ment of HRS. Conclusions: Serum CysC level was a powerful
indicator for mortality and development of HRS in patients with
cirrhotic ascites.
Disclosures:
Won Young Tak - Advisory Committees or Review Panels: Gilead Korea; Grant/
Research Support: SAMIL Pharma; Speaking and Teaching: Bayer Korea
The following people have nothing to disclose: Yeon Seok Seo, Soo Young Park,
Moon Young Kim, Sang Gyune Kim, Jun Yong Park, Hyung Joon Yim, Byoung
Kuk Jang, Seung Ha Park, Ji Hoon Kim, Ki Tae Suk, Jin Dong Kim, Tae Yeob Kim,
June Sung Lee, Soung Won Jeong, Jae Young Jang, Hyonggin An, Soon Koo
Baik, Jaeseok Hwang, Young Seok Kim, Joo Hyun Sohn, Soon Ho Um
208
A low-cost, user-friendly EEG recording set for Hepatic
Encephalopathy assessment: a proof of concept, prelim-
inary study
Sami Schiff, Mariella Casa, Valeria Di Caro, Daniele Aprile,
Giuseppe Spinelli, Michele De Rui, Piero Amodio, Sara Montag-
nese; Department of Medicine, University of Padova, Padova, Italy
Electroencephalography (EEG) is useful to objectively diag-
nose/grade HE across its spectrum of severity. In addition,
the EEG has recently been shown to improve the prognostic
value of MELD. However, it requires expensive equipment, it
is time-consuming, and hepato-gastroenterologists are gener-
ally unfamiliar with its use/interpretation. Recent technological
advances have lead to the development of low-cost, user-
friendly EEG recording systems, allowing EEG acquisition in
limited neurophysiological experience settings. The aim of this
study was to assess the relationship between EEG parameters
obtained from a Standard-EEG system and from a commercial,
low-cost wireless headset (Light-EEG) in a group of well-char-
acterized patients with cirrhosis. Forty patients with cirrhosis
(32 males; 60±10 years) underwent EEG recording with both
types of equipment, within 20 minutes. Standard spectral
EEG parameters [i.e. Mean Dominant Frequency (MDF) and
the relative power of the theta band (theta%)] were obtained
from a bi-parietal derivation on both EEGs. Spearman’s rank
correlation coefficient and the Bland-Altman method were
utilized to evaluate correlation and agreement, respectively,
between measures obtained from the two EEG recording tools.
In addition, correlations between clinical parameters (MELD
and ammonia) and Light-EEG spectral parameters were com-
puted. Strong correlations were observed between spectral
parameters obtained from the two EEG systems (MDF: r=0.52;
p<0.001; theta%: r=0.83; p<0.0001). Bland-Altman analy-
sis indicated that spectral parameters obtained from the Stan-
dard- and Light-EEG systems were comparable, with clinically
acceptable ranges of oscillation and no systematic variation
of the differences across the range of measurement. Spectral
parameters obtained from the Light-EEG correlated significantly
with both the MELD score (MDF: r=-0.49, p=0.036; theta%:
r=0.61, p=0.007) and fasting, venous ammonia levels (MDF:
r=-0.47, p=0.018; theta%: r=-0.47, p=0.016). In conclusion,
reliable EEG parameters for purposes of HE evaluation can be
obtained from a commercial wireless headset. This may lead
to more widespread use of this operator-/patient-independent
tool for HE assessment in routine hepatological practice and in
the research setting.
Disclosures:
The following people have nothing to disclose: Sami Schiff, Mariella Casa, Vale-
ria Di Caro, Daniele Aprile, Giuseppe Spinelli, Michele De Rui, Piero Amodio,
Sara Montagnese
304A AASLD ABSTRACTS
209
Total 25(OH) Vitamin D is Not an Accurate Marker of
Vitamin D Status in Patients with Cirrhosis and Synthetic
Dysfunction
Jennifer C. Lai, Norah Terrault, Daniel Bikle, Blanca C. Lizaola,
Janice B. Schwartz; University of California, San Francisco, San
Francisco, CA
Background: Multiple studies have linked total 25(OH)D lev-
els with clinically important outcomes, such as risk of hepatic
decompensation, HCV treatment response rates, and mortal-
ity, in patients with cirrhosis. Current clinical assays for total
25(OH)D measure vitamin D bound to vitamin D binding pro-
tein (DBP) and albumin as well as unbound (“free”) D. We
hypothesized that cirrhotics with low albumin would have low
DBP, thus altering the ratios of total to free 25(OH)D and the
expected relationships between total 25(OH)D and markers
of bone metabolism. Methods: Outpatients ≥18y with cirrho-
sis with serum creatinine <1.5 mg/dL underwent one single
measurement of free and total 25(OH)D by immunoassay,
albumin, and a marker of bone metabolism [intact parathy-
roid hormone (iPTH)]. The cohort was categorized by serum
albumin (g/dL): ≥3.5 = normal, <3.5 = low. %Free 25(OH)
D=free / total 25(OH)D. Student’s t tests compared differences
between groups. Linear regression compared associations
between free D, total D, and iPTH. Results: Included were 91
cirrhotics; 69% had serum albumin ≤3.5 g/dL. Subjects with
low vs. normal albumin were similar (p>0.05) in mean age
(59 vs. 57y), %women (35 vs. 50%), body mass index (30
vs. 28 kg/m2), %HCV (59 vs. 54%), but differed by %non-
White race (71 vs. 44%; p=0.02). Mean MELD was higher in
those with low vs. normal albumin (15 vs.10; p<0.01). Rates
of total 25(OH)D deficiency (≤20 ng/mL) were significantly
higher in low vs. normal patients (82 vs. 43%). Cirrhotics with
low vs. normal albumin had significantly lower DBP (100 vs.
159 mg/mL), and free 25(OH)D (7 vs. 9 pg/mL), but higher
%free 25(OH)D (0.05 vs. 0.04%) [p<0.05 for each]. iPTH was
similar in low and normal albumin groups (35 vs. 30 pg/mL;
p=0.19). There was a strong association between iPTH and
both total (coef, -0.43; 95%CI, -0.75 to -0.11; p=0.01) and
free 25(OH)D (coef, -0.10; 95%CI, -0.18 to -0.02; p=0.01)
for normal but not low albumin patients [total 25(OH)D coef,
0.01; 95%CI, -0.12 to 0.14; p=0.86; free 25(OH)D coef,
-0.01; 95%CI, -0.05 to 0.04; p=0.84]. Conclusions: Cirrhotics
with low albumin have lower levels of DBP, total 25(OH)D
and free 25(OH)D compared to cirrhotics with normal albu-
min, despite higher %free 25(OH)D. The expected relationship
between total 25(OH)D and iPTH was observed in cirrhotics
with normal but not low albumin. These results demonstrate that
total 25(OH)D is not an accurate marker of bioactive vitamin D
status in cirrhotics with low albumin and call into question our
current practices of measuring and repleting vitamin D in this
population.
Disclosures:
Norah Terrault - Advisory Committees or Review Panels: Eisai, Biotest; Con-
sulting: BMS, Merck; Grant/Research Support: Eisai, Biotest, Vertex, Gilead,
AbbVie, Novartis, Merck
The following people have nothing to disclose: Jennifer C. Lai, Daniel Bikle,
Blanca C. Lizaola, Janice B. Schwartz
HEPATOLOGY, October, 2014
210
Optimizing muscle mass: therapeutic target to prevent
experimental hepatic encephalopathy
Sara Ghezzal1,2, Marc-André Clément2, Cristina R. Bosoi2, Rox-
anne Beauchamp2, Mélanie Tremblay2, Christopher F. Rose2,
Chantal Bemeur2,3; 1Université Pierre et Marie Curie, Paris,
France; 2Neuroscience Res. Unit, CRCHUM, Montreal, QC, Can-
ada; 3Département de nutrition, Université de Montréal, Montréal,
QC, Canada
Background: Malnutrition is an important prognostic factor
potentially influencing clinical outcome of patients suffering
from chronic liver disease (cirrhosis; CLD). Malnutrition, con-
sidered a consequence of metabolic disturbances (hyper-
metabolism), exacerbates severe muscle loss and hepatic
encephalopathy (HE) (complex neuropsychiatric disorder) in
cirrhotic patients. New management strategies focussing on
improving nutritional status and attenuating CLD-related com-
plications are an unmet clinical need. We hypothesize supple-
mentation with branched-chain amino acid leucine (LEU) and
exercise training (EX) could possibly attenuate muscle mass
loss and prevent HE (characterized by brain edema as well as
cognitive and psychomotor impairments) in CLD. Methods: CLD
was induced in rats following 6-week bile-duct ligation (BDL).
Five experimental groups were tested; 1) BDL; 2) BDL + LEU;
3) BDL + EX; 4) BDL + LEU + EX; 5) Sham-operated rats. One
week following BDL, rats were gavaged with LEU (1.35 mg/
kg) daily and submitted to 15 min EX (10 cm/s) every other
day for 5 weeks. Body weight, muscle (gastrocnemius) mass,
metabolic state (calculation of energy expenditure indepen-
dent of food intake and fecal mass), cerebral edema (specific
gravity method) and cognitive/psychomotor function (open-
field test; anxiety-like behavior assessment and novel object
recognition test; memory testing) were measured. Results: BDL
rats gained less body weight compared to sham-operated rats
(125.0g ± 24.9 vs 226.0g ± 38.5; p<0.05). LEU-treated BDL
rats display an improvement in brain edema (78.50% ± 0.03
vs 80.27% ± 0.14; p<0.05), muscle mass (5.48g/kg ± 0.90
vs 4.83g/kg ± 0.11; p<0.05) and circumference (15.6cm/
kg ± 0.8 vs 13.1cm/kg ± 0.7; p<0.05) and metabolic activity
(27.48 ± 1.15 vs 32.99 ± 2.35; p<0.05), which was further
ameliorated with EX, compared to BDL animals. In addition,
BDL rats receiving LEU and EX exhibited less anxiety-like behav-
ior (4.9s ± 1.2 vs 2.2s ± 0.9 passed in the center; p<0.01) as
well as better novel object recognition memory (69.6 ± 15.2%
vs 25.4 ± 9.6%; p<0.01), in comparison with BDL rats. Conclu-
sion: Our results demonstrate that supplemental LEU along with
EX recovers body weight loss, increases muscle mass, improves
metabolic activity, attenuates brain edema and improves cog-
nitive and psychomotor function. These findings suggest that
strategies aiming at improving nutritional status will attenuate
muscle mass loss and reduce the risk of developing HE. This in
turn will improve quality of life, decrease mortality and enhance
outcome post-liver transplantation. LEU supplementation and EX
could rapidly be translated into clinical practice.
Disclosures:
The following people have nothing to disclose: Sara Ghezzal, Marc-André Clé-
ment, Cristina R. Bosoi, Roxanne Beauchamp, Mélanie Tremblay, Christopher F.
Rose, Chantal Bemeur
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
211
The Severity of Steatosis Overestimates Liver Fibrosis
Diagnosis by liver Stiffness Measurement in Patients
with Nonalcoholic Fatty Liver Disease
Salvatore Petta1, Vito Di Marco1, Calogero Cammà1, Daniela
Cabibi2, Antonio Craxì1; 1Cattedra ed U.O.C. di Gastroenterolo-
gia ed Epatologia, Palermo, Italy; 2Cattedra di Anatomia Patolog-
ica, University of Palermo, Italy, Palermo, Italy
Background and aims: In Nonalcoholic Fatty Liver Disease
(NAFLD), the influence of steatosis on liver stiffness measure-
ment (LSM) is still debated. We assessed the impact of the
severity of steatosis on LSM values and on Transient Elastogra-
phy (TE) accuracy for the diagnosis of liver fibrosis, in a cohort
of consecutive patients with NAFLD. Methods: Two hundred
fifty-three patients with reliable LSM were assessed by clinical,
ultrasonographic and histological (Kleiner score) features. TE
was performed using the M probe. Results: Most patients were
males (70%), mean age and BMI were respectively 45 years
and 29.1 Kg/m2. Diabetes and hypertension were observed
in 20% and 24% of patients, respectively. Twenty-eight per-
cent of patients had grade 3 steatosis, one patient on two
had F2-F4 fibrosis, and 21% of patients had F3-F4 fibrosis.
Among patients with F0-F2 fibrosis, and with F0-F1 fibrosis,
mean LSM values, expressed in kPa, were significantly higher
in subjects with severe steatosis (≥ 66% at liver biopsy) com-
pared with those without (8.0±3.1 vs 6.5±2.6, p=0.002 for
F0-F2; 7.2±6.4 vs 6.2±2.2, p=0.04 for F0-F1). Instead no
differences were found in patients with F3-F4 and with F2-F4
fibrosis according to the presence of severe steatosis. Accord-
ingly, in subjects without severe fibrosis (F0-F2) and without
significant fibrosis (F0-F1), a higher rate of false-positive LSM
results was observed in patients with steatosis ≥ 66% compared
with those without (F0-F2: 33.3% vs. 13.2%; F0-F1: 23.6% vs.
14.9%). Conclusions: In patients with NAFLD, the presence of
severe steatosis lead to an overestimation of liver fibrosis by
LSM. In this clinical setting, noninvasive methods correcting
LSM values for severity of liver steatosis could improve the per-
formance of TE in predicting fibrosis.
Disclosures:
The following people have nothing to disclose: Salvatore Petta, Vito Di Marco,
Calogero Cammà, Daniela Cabibi, Antonio Craxì
212
Variants in Long non-Coding RNAs (lncRNAs)-Genomic
Regions may Contribute to Nonalcoholic Fatty Liver Dis-
ease Severity
Carlos J. Pirola2, Tomas Fernández Gianotti2, Hernán Dopazo3,
Cristian Rohr3, Gustavo O. Castaño4, Silvia Sookoian1,4; 1Clinical
and Molecular Hepatology, IDIM-CONICET, Ciudad Autonoma
de Buenos Aires, Argentina; 2Molecular Genetics and Biology of
Complex Diseases, IDIM-CONICET, Buenos Aires, Argentina; 3Bio-
medical Genomics and Evolution Laboratory, CONICET, Buenos
Aires, Argentina; 4Medicine and Surgery, Liver Unit, Hospital Abel
Zubizarreta, Buenos Aires, Argentina
Background: The human transcriptome is composed by a myr-
iad of non-protein-coding RNA species, including lncRNAs,
which are located at intergenic and intronic regions and even
in the antisense strand of protein-coding genes. LncRNAs have
a remarkable role in transcriptional and epigenetic regula-
tion, and disease. Notably, a large number (>90%) of genetic
variants related to diseases/traits from genome-wide associa-
tion studies map to intergenic or intronic regions and reside
in non-coding protein genes. Hence, we hypothesized that
variants in lncRNAs can affect the NAFLD phenotype and dis-
305A
ease susceptibility. We took advantage of deep-sequencing
techniques to comprehensively characterize human lncRNA
genomic regions in 96 subjects, including 64 patients with
NAFLD confirmed by liver biopsy (32 simple steatosis and 32
NASH), and 32 matched healthy controls. Methods: As a proof
of principle, we performed a global survey of genetic variation
associated with randomly selected lncRNA-genomic regions by
next generation sequencing technology undertaken by a Ion
Torrent Personal Genome Machine using 316 chips and bar-
coding (>50 x coverage). Results: We sequenced >240 Mb at
>Q20, in a total of 2,027,565 reads of 140 bp fragments on
average, including >60 lncRNAs encompassing 50 kb. Based
on the analysis of single nucleotide polymorphisms (SNPs), we
identified the rs11171490 located at the ENST00000554049
gene -a lncRNA (transcript ID: NONHSAT028661) spanning
555 kb (Chr12:55,828,539-55,979,255), reverse strand.
This SNP, which also localizes to an intron of OR6C2 locus,
was significantly associated with the histological progression of
NAFLD (chi2 test 10.8, regression analysis for an ordinal mul-
tinomial distribution p<0.005), OR: 3.23 per risk allele, 95%
CI 1.06-9.85, p<0.03. In addition, the rs41284980, which
resides in the lncRNA NONHSAT080697 (chr20: 60528524-
60573243, negative strand) was significantly associated with
increased gamma-glutamyl-transferase (p<0.0006) and CK-18
levels (p<0.002) in NASH patients; this variant also localizes
at an intron of the TAF4 gene, which encodes a RNA poly-
merase II. Finally, the intergenic rs2829145, which resides
in a novel lncRNA NONHSAT081453 (chr21: 25801094-
25920256, positive strand) was significantly associated
with ballooning degeneration (OR 2.89, 95% CI 1.06-7.86,
p<0.03). Conclusions: Our observations suggest that variation
in lncRNAs may contribute to disease progression and depict
the complexity of the genetic component of NAFLD. In addition,
they could provide insights in understanding the role of genetic
variation at intergenic (LincRNAs) and antisense transcription
of the genome.
Disclosures:
Carlos J. Pirola - Grant/Research Support: Merck Sharp and Dohme
The following people have nothing to disclose: Tomas Fernández Gianotti,
Hernán Dopazo, Cristian Rohr, Gustavo O. Castaño, Silvia Sookoian
213
Effects of bariatric surgery on severe liver injury in mor-
bid obese patients with proven NASH: a prospective
study
Guillaume Lassailly1,4, Robert Caiazzo2,5, David Buob3, Marie Pig-
eyre2, Helene Verkindt2, Violetta Raverdy2, Emmanuelle Leteurtre3,
Sebastien Dharancy1,4, Alexandre Louvet1,4, Francois Pattou2,5,
Philippe Mathurin1,4; 1Hepatology, CHRU lille, Lille, France; 2Bar-
itric Surgery, CHRU Lille, Lille, France; 3Pathology, CHRU Lille,
Lille, France; 4U995, INSERM, Lille, France; 5U1011, INSERM,
Lille, France
Non Alcoholic Steatohepatitis (NASH) is observed in around
10% of severe obese patients and leads to cirrhosis and hepa-
tocarcinoma. AASLD recommends lifestyle intervention as the
first line treatment for NASH, but failure is common and med-
ications are disappointing. Therefore, bariatric surgery could
be of interest to treat NASH in patient that failed lifestyle ther-
apy as it reduces weight and liver injury as steatosis. However,
prospective data are warranted to confirm the positive effect
of bariatric surgery on NASH due to its debated impact on
necroinflammation and fibrosis. METHODS: In the Lille bar-
iatric cohort, between 1994 and 2013, 109 morbidly obese
patients with biopsy proven NASH performed bariatric surgery.
Data were prospectively collected before and one year after
306A AASLD ABSTRACTS
surgery: BMI (kg/m2), insulin resistance (IR=1/QUICKI), fast-
ing glucose (mg/dL), HbA1c(%), ALT(UI/L), GGT(UI/L), steato-
sis (%), ballooning, necroinflammatory lesions, Nafld Activity
score (NAS), NASH grade (Brunt scoring) and fibrosis (Kleiner
and METAVIR staging). RESULTS: The main surgical procedures
in 109 NASH patients were 70 (64.2%) gastric bypass and
32 (29.4%) gastric band. Before surgery, patients with bridg-
ing fibrosis (33%) (≥F3 in Kleiner staging) had higher GGT
(101.5±15.9 vs 71.6±10.2), AST (50.3±3.7 vs 37.6±2.3),
IR index (3.8±0.1 vs 3.5±0.1), glycemia (179.3±10.5 vs
137.9±6.6), HbA1c (8.4±0.4 vs 7.4±0.3%), NAS (5.3±0.2 vs
4._±0.1), NASH grade (1.9±0.1 vs 1.3±0.1) (for all, p<0.05).
At 1 year, 82/109 patients had paired liver biopsies. Patients
were significantly improved in terms of: BMI (49.3±8.2 to
37.4±7), ALT (52.1±25.7 to 25.1±20), GGT (74.2±61.8
to 41.5±81.7), and IR index (3.6±0.5 to 2.9±0.5) HbA1c
(7.6±2 to 6±1%), (for all, p<0.01). NASH disappeared in
85% of cases and all histological features improved: steatosis
(58.5±22 to 17.2±20%), ballooning (1.4±0.5 to 0.3±0.6),
inflammation (1.3±0.5 to 0.5±0.6), NASH grading (1.5±0.7
to 0.2±0.6), NAS (4.9±1 to 1.6±1.5) and fibrosis (1.2±1.1 to
0.9±1.1) (for all: p<0.001). The probability of NASH disap-
pearance was higher in patients with mild NASH compared to
severe NASH (94% vs 70%, p<0.05). Patients with persistent
NASH had higher baseline IR index (4±0.6 vs 3.5±0.5), NASH
grade (2±0.7 vs 1.4±0.7) and fibrosis (2.1±1 vs 1.1±1) (for
all, p<0.05). At 1 year, they had less weight loss (-BMI: 8±6 vs
13±6, p=0.006), higher IR (4±1 vs 3.5±0.5), steatosis (44±24
vs 13±15), NAS (4.2±1.3 vs 1.2±1), and fibrosis (METAVIR:
1.9±1.3 vs 0.7±1) (for all, p<0.05). CONCLUSION: Bariatric
surgery should be considered as the first line therapy after life-
style intervention therapy failure in morbid obese with biopsy
proven-NASH.
Disclosures:
Emmanuelle Leteurtre - Speaking and Teaching: NOVARTIS
Sebastien Dharancy - Board Membership: NOVARTIS; Speaking and Teaching:
ASTELLAS, ROCHE
Philippe Mathurin - Board Membership: Schering-Plough, Janssen-Cilag, BMS,
Gilead, Abvie; Consulting: Roche, Bayer, Boehringer
The following people have nothing to disclose: Guillaume Lassailly, Robert
Caiazzo, David Buob, Marie Pigeyre, Helene Verkindt, Violetta Raverdy, Alex-
andre Louvet, Francois Pattou
214
The association of vascular function and non-alcoholic
fatty liver disease: the Framingham Heart Study
Michelle T. Long1,2, Na Wang6, Martin G. Larson2,6, Gary F.
Mitchell7, Joseph N. Palmisano8, Vasan S. Ramachandran2,9, Udo
Hoffmann5, Elizabeth K. Speliotes10, Joseph A. Vita3, Emelia J.
Benjamin2,3, Caroline S. Fox2,4, Naomi Hamburg2,3; 1Gastroen-
terology, Boston Medical Center, Boston, MA; 2National Heart,
Lung, and Blood Institute’s Framingham Heart Study, Framingham,
MA; 3Whitaker Cardiovascular Institute and Cardiology Section,
Boston University School of Medicine, Boston, MA; 4Division of
Endocrinology, Hypertension, and Metabolism, Brigham and
Women’s Hospital, Boston, MA; 5Radiology, Massachusetts Gen-
eral Hospital, Boston, MA; 6Mathematics and Statistics, Boston
University School of Public Health, Boston, MA; 7Cardiovascular
Engineering, Inc, Waltham, MA; 8Data Corrdinating Center, Bos-
ton University School of Public Health, Boston, MA; 9Section of Pre-
ventive Medicine, Boston University School of Medicine, Boston,
MA; 10Gastroenterology, University of Michigan, Ann Arbor, MI
Background & Aims: Patients with non-alcoholic fatty liver dis-
ease (NAFLD) have an increased risk of cardiovascular disease
(CVD); however, it is not known if NAFLD contributes to CVD
independent of known risk factors. Vascular dysfunction is a
HEPATOLOGY, October, 2014
marker of subclinical atherosclerosis that predicts future CVD
events. We examined the association between liver attenuation
on computed tomography (CT) and several indices of vascu-
lar function, including brachial artery flow-mediated dilation
(FMD; large arteries), peripheral arterial tonometry (PAT; small
vessels) and arterial tonometry (arterial stiffness). Methods:
We conducted a cross-sectional study of 2,320 Framingham
Heart Study participants in the Offspring and Third-Generation
Cohorts who participated in the multi-detector CT sub-study
and who participated in measurements of vascular function
and covariates and were free of overt CVD and had no his-
tory of excess alcohol intake. NAFLD was estimated by liver
attenuation and defined by a liver phantom ratio of ≤ 0.33.
We evaluated the association between NAFLD and vascular
function using multivariable partial correlations adjusting for
age, sex, cohort, cardiovascular risk factors (including smok-
ing, diabetes, hyperlipidemia and hypertension), body mass
index (BMI) and visceral adipose tissue (VAT). Results: The
prevalence of NAFLD in our sample (mean age 50 ± 10 years,
51% women) was 16.3%. In age-, sex- and cohort-adjusted
analyses, lower liver attenuation (more liver fat) was associ-
ated with lower FMD (r = -0.053, P=0.016), lower PAT ratio
(r = -0.199, P<0.0001), higher -1000/carotid-femoral pulse
wave velocity (r = 0.131, P<0.0001) and a higher mean
arterial pressure (MAP) (r = 0.105, P<0.0001). In multivari-
able-adjusted models, NAFLD was directly associated with
MAP (r=0.059, P=0.005) and inversely associated with PAT
ratio (r= -0.122, P<0.0001). After BMI was added to the mul-
tivariable model, the correlation between NAFLD and MAP
was no longer statistically significant (r=0.027, P=0.2); how-
ever, NAFLD remained correlated with PAT ratio (r= -0.093,
P=0.0005) even after VAT was added to the model (r= -0.078,
P=0.004). Conclusions: Lower liver attenuation (more liver fat)
is correlated with most measures of vascular dysfunction; how-
ever, most of these associations are attenuated and no longer
significant after adjusting for CVD risk factors. In multivariable
models, NAFLD is correlated with a lower PAT ratio which is
a measure of microvascular dysfunction. These findings are
consistent with a potential association between NAFLD and
microvascular dysfunction.
Disclosures:
Gary F. Mitchell - Advisory Committees or Review Panels: Novartis; Consulting:
Merck; Employment: Cardiovascular Engineering, Inc.; Stock Shareholder: Car-
diovascular Engineering, Inc.
The following people have nothing to disclose: Michelle T. Long, Na Wang,
Martin G. Larson, Joseph N. Palmisano, Vasan S. Ramachandran, Udo Hoff-
mann, Elizabeth K. Speliotes, Joseph A. Vita, Emelia J. Benjamin, Caroline S.
Fox, Naomi Hamburg
215
A Novel Epigenetic Landscape in the Biology of Nonal-
coholic Fatty Liver Disease: The role of 5-Hydroxymeth-
ylcytosine and Sequence Variation in Ten-Eleven
Translocation Family of Proteins
Carlos J. Pirola2, Tomas Fernández Gianotti2, Hernán Dopazo4,
Cristian Rohr4, Gustavo O. Castaño3, Silvia Sookoian1; 1Clinical
and Molecular Hepatology, IDIM-CONICET, Ciudad Autonoma
de Buenos Aires, Argentina; 2Molecular Genetics and Biology
of Complex Diseases, IDIM-CONICET, Ciudad Autonoma de
Buenos Aires, Argentina; 3Medicine and Surgery, Hospital Abel
Zubizarreta, Ciudad Autonoma de Buenos Aires, Argentina;
4Biomedical Genomics and Evolution, UBA-CONICET, Ciudad
Autonoma de Buenos Aires, Argentina
Background: 5-hydroxymethylcytosine (5-hmC) is a new epi-
genetic mark that modulates gene transcription by influenc-
ing DNA demethylation and chromatin structure remodeling;
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
non-CG hydroxymethylation appears to be prevalent in the
mitochondrial genome. The Ten-Eleven-Translocation (TET 1, 2
and 3) family of proteins is responsible for catalyzing the con-
version of 5-methylcytosine (5-mC) to 5-hmC. Because nonal-
coholic steatohepatitis (NASH) is associated with altered DNA
methylation profiles, changes in mitochondrial DNA (mtDNA)
content and PPARGC1A expression, we hypothesized that
epigenetic editing by 5-hmC might be a novel mechanism to
explain the NAFLD phenotype. Hence, we explored the global
levels of 5-hmC in the liver of NAFLD patients at different stages
of disease severity (n=67) and controls (n=23). In addition, we
screened for genetic variation in TET 1-3 loci by targeted deep
sequencing to explore its contribution to the disease biology;
for this purpose, we included simple steatosis (SS) n=32, NASH
n=32 and controls n=32. Methods: Global 5-hmC quantifica-
tion in liver genomic DNA was performed by Quest 5-hmC
DNA ELISA. Sequencing of TET1 (9.7 kb, 12 exons), TET2 (19
kb, 13 exons) and TET3 (11 kb, 9 exons) was performed by
next generation sequencing (Ion Personal Genome Machine)
using 316 chips and barcoding (>100 x coverage); liver
mtDNA was evaluated by real-time PCR. Results: Examination
of liver 5-hmC levels showed significant and positive correla-
tion with liver mtDNA content (Spearman R: 0.50, p<0.0003)
and negative correlation with TGO (R: -0.28 p<0.01), TGP (R:
-0.24 p<0.02) and liver mRNA-PPARGC1a (R: -0.57 p<0.006)
levels. TET1 protein expression in the nucleus of hepatocytes
assessed by immunohistochemistry showed reduced levels in
NASH in comparison with SS and controls. Deep sequencing
of TET genes revealed a total of 505 (TET1), 323 (TET2) and
178 (TET3) single-nucleotide polymorphisms (SNPs), includ-
ing 22 novel SNPs. Clinical associations focused on nonsyn-
onymous SNPs showed that TET1-rs3998860 (I123M) was
associated with lobular inflammation scores (p<0.03) and
CK18 levels (p<0.004), and TET2-rs2454206 (I1762V) was
associated with NAFLD severity (p<0.04) and liver methyla-
tion status of PPARGC1a (p<0.01); a low-frequency variant,
TET2-rs62621450 (H1778R), was found in 3 patients with
NAFLD. Conclusions: Our results suggest that the NAFLD phe-
notype is modulated by epigenetic mechanisms, particularly
the hydroxymethylation pathway, and confirm the susceptibility
of liver mitochondrial DNA to dynamic modifications regulated
by oxidative changes. Genetic diversity in TET1 and TET2 loci
might be involved in the pathogenesis of NAFLD
Disclosures:
Carlos J. Pirola - Grant/Research Support: Merck Sharp and Dohme
The following people have nothing to disclose: Tomas Fernández Gianotti,
Hernán Dopazo, Cristian Rohr, Gustavo O. Castaño, Silvia Sookoian
216
The macrophage activation marker soluble CD163 is
independently associated with liver inflammation and
fibrosis in patients with non-alcoholic fatty liver disease
Konstantin Kazankov1,
Francisco Barrera2,
Holger J. Møller3,
Elis-
abetta Bugianesi4, Chiara Rosso4, Saeed Esmaili2, Hendrik V.
Vilstrup1, Jacob George2, Henning Gronbaek1; 1Department of
Hepatology and Gastroenterology, Aarhus University Hospital,
Aarhus, Denmark; 2The Storr Liver Unit, University of Sydney and
Westmead Hospital, Westmead, NSW, Australia; 3Department
of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Den-
mark; 4Division of Gastroenterology and Hepatology, Department
of Medical Sciences, University of Torino, Torino, Italy
Background and aims: Macrophages play an important role in
the pathogenesis of non-alcoholic fatty liver disease (NAFLD)
and may contribute to the transition to steatohepatitis (NASH).
Soluble (s)CD163 is a specific macrophage activation marker
307A
and we hypothesized elevated sCD163 levels in association
with disease severity. We aimed to assess macrophage acti-
vation in NAFLD by sCD163 levels and relate it to the sever-
ity of disease. Methods: Associations between sCD163 and
biochemical and histological parameters of liver inflammation
and fibrosis were investigated in 171 and validated in 174
NAFLD/NASH patients. Demographic, clinical, biochemical,
and metabolic parameters were recorded at the time of liver
biopsy and sCD163 was measured by enzyme-linked immuno-
sorbent assay (ELISA). Results: Increased sCD163 levels were
closely associated with the severity of liver injury assessed by
the NAFLD Activity Score (NAS) and Kleiner fibrosis score in
both the estimation and the validation cohorts. In both cohorts,
patients with NAS≥5 had higher sCD163 compared to those
with NAS<5 (Estimation: 3.8 (2.8–5.3) vs. 2.5 (1.9–3.4)
mg/L, p<0.001; Validation: 2.3 (1.7–2.7) vs. 1.5 (1.1–2.1)
mg/L, p<0.001). In addition, sCD163 was associated with
biochemical parameters of liver injury and insulin resistance.
Multivariate regression analysis demonstrated independent
associations of sCD163 with the NAS and the fibrosis score
in both the estimation and the validation cohorts, adjusted for
the known risk factors and parameters associated with disease
severity. Moreover, sCD163 was a good predictor of severe
necroinflammation (NAS≥5) with an area under the Receiver
Operating Characteristics curve (AUROC) for the estimation
cohort of 0.78 (95% CI: 0.69–0.86), and 0.71 (95% CI:
0.62–0.81) for the validation cohort. In addition, sCD163 was
a predictor of advanced fibrosis and cirrhosis in both cohorts.
Conclusion: Soluble CD163, a specific macrophage activation
marker, is increased in association with liver disease severity
in NAFLD/NASH patients, and independently associated with
liver inflammation and fibrosis. Thus sCD163 may serve as a
potential biomarker for NAFLD severity.
Disclosures:
Holger J. Møller - Grant/Research Support: Danish Council for Strategic
Research; Independent Contractor: IQ-Products, NL; Patent Held/Filed: Aarhus
University; Stock Shareholder: Affinicon Aps
Jacob George - Advisory Committees or Review Panels: Roche, BMS, MSD,
Gilead, Janssen
Henning Gronbaek - Grant/Research Support: Novartis, Ipsen
The following people have nothing to disclose: Konstantin Kazankov, Francisco
Barrera, Elisabetta Bugianesi, Chiara Rosso, Saeed Esmaili, Hendrik V. Vilstrup
217
Intrahepatic Transcriptional Signature of Exhausted T
Cells in Chimpanzees Chronically Infected with HBV
Li Li1, Peng Yue1, Robert E. Lanford2, Congrong Niu1, Stephane
Daffis1, Daniel Tumas1, Abigail Fosdick1, William E. Delaney1,
Simon P. Fletcher1; 1Gilead Sciences, Foster City, CA; 2Depart-
ment of Virology and Immunology, Texas Biomedical Research
Institute, San Antonio, TX
Background & Aims: Prior studies in chimpanzees have pro-
vided important insights into the immunological mechanisms
that contribute to the resolution of acute HBV infection. In
contrast, chronic hepatitis B (CHB) in chimpanzees has not
been extensively studied. To provide insight into the state of
the immune system during chronic infection, we conducted a
retrospective analysis of liver biopsy samples from previous
chimpanzee studies. Methods: Whole transcriptome profiling
of liver biopsies taken in previous studies from chimpanzees
chronically infected with either HBV (CHB, n=3) or HCV (CHC,
n=4), as well as from uninfected animals (n=4) was performed
by RNA-Seq. The intrahepatic transcriptional response was
characterized by gene set enrichment analysis (GSEA), Inge-
nuity Pathway Analysis (IPA) and a gene module approach.
Results: Principal component analysis revealed that chronic
308A AASLD ABSTRACTS
HBV infection had only a modest effect on intrahepatic gene
expression, while chronic HCV infection substantially altered
the liver transcriptome. This was reflected in the low number
of differentially expressed genes (DEGs) associated with CHB
(n=144 vs. uninfected animals) relative to CHC (n=1,696).
IPA and module analysis revealed that chronic HBV infection is
associated with up-regulation of intrahepatic T and B cell gene
signatures, whereas type I interferon (IFN) and antigen pre-
sentation pathways were preferentially up-regulated in CHC.
Interestingly, GSEA identified significant enrichment of the
PD-1 signaling pathway in CHB. These intrahepatic expression
patterns are consistent with the limited information available
regarding immune responses in the liver of CHB patients. Like-
wise, the induction of T cell, B cell and PD-1 pathway gene
signatures in the liver of chronically infected chimpanzees
are consistent with the intrahepatic expression patterns in the
woodchuck model of CHB. The elevated expression of CXCL9
and ubiquitin D in the liver of chimpanzees with CHB also
indicates that an intrahepatic type II IFN response is character-
istic of persistent hepadnavirus infection in both woodchucks
and chimpanzees. In contrast, the absence of a neutrophil
transcriptional signature in chronically infected chimpanzees
may represent an important difference between these animal
models, and suggests they might reflect different stages of HBV
natural history in man. Conclusion: Chronic HBV infection in
chimpanzees shares key features with CHB in man as well as
woodchucks. Notably, this includes intrahepatic induction of
the PD-1 pathway, which suggests that T cell exhaustion is a
common feature of chronic hepadnavirus infection and likely
contributes to viral persistence.
Disclosures:
Li Li - Employment: Gilead Sciences
Peng Yue - Employment: Gilead Sciences
Robert E. Lanford - Grant/Research Support: Arrowhead Research
Congrong Niu - Employment: Gilead Science
Stephane Daffis - Employment: Gilead Sciences
Daniel Tumas - Employment: Gilead Sciences, Inc
Abigail Fosdick - Employment: Gilead Sciences
William E. Delaney - Employment: Gilead Sciences; Patent Held/Filed: Gilead
Sciences; Stock Shareholder: Gilead Sciences
Simon P. Fletcher - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
218
Combined Gene and MicroRNA Expression Profiling of
Hepatitis B Virus (HBV)-Associated Acute Liver Failure
(ALF) Reveals a Dominant B-Cell-Driven Disease Signa-
ture
Patrizia Farci1, Fausto Zamboni2, Ashley B. Tice1, Zhaochun
Chen1, Ronald E. Engle1, Giacomo Diaz3; 1Hepatic Pathogenesis
Section, Laboratory of Infectious Diseases, National Inst of Health,
Bethesda, MD; 2Liver Transplantation Center, Brotzu Hospital,
Cagliari, Italy; 3Department of Biomedical Sciences, University of
Cagliari, Cagliari, Italy
The dramatic clinical course of ALF has hampered molecular
pathogenesis studies. While in classic acute hepatitis B liver
damage is believed to be T-cell mediated, the pathogenesis
of HBV-associated ALF is unknown. By gene expression pro-
filing, we previously demonstrated that ALF is characterized
by a prominent intrahepatic B-cell gene signature associated
with overexpression of negative regulators of T-cell activation,
including CTLA-4. The availability of 13 liver specimens from
4 well-characterized patients with HBV ALF who underwent
liver transplant within 1 week of admission gave us the unique
opportunity to study the whole set of 2226 human miRNAs
HEPATOLOGY, October, 2014
(Affymetrix) in ALF and in individual specimens from 17 nor-
mal livers as controls. Our aim was to investigate the correla-
tion between mRNA and miRNA expression, as well as serum
cytokine profiles. A multivariate permutation F-test with a false
discovery rate of 1% identified 111 miRNAs differentially
expressed in ALF livers. To investigate the functional correla-
tions between miRNAs and mRNAs, first we performed two
independent analyses using Ingenuity. Seven major disease
categories were significantly associated with both mRNA and
miRNA expression in ALF, with inflammatory and immunolog-
ical diseases among the most prominent, demonstrating that
mRNAs and miRNAs are strongly correlated. Next, we inves-
tigated whether ALF-expressed immune genes could be targets
of differentially expressed miRNA. The analysis was conducted
on 54 of 111 miRNAs for which information on target mRNA
was available in mirBase. Strikingly, we found that the major-
ity of ALF-specific miRNAs (74%) target B-lineage-associated
genes, including: i) several Ig genes; ii) TNFRSF17/BCMA
and FCRL5, which promote B-cell maturation and proliferation,
respectively; iii) POU2AF1 and PRDM1, two master regulators
of germinal center formation and terminal B-cell differentiation.
Moreover, we found that most B-cell genes are simultaneously
targeted by several miRNAs, including miR-150, 155, 146a,
182 and 181b, which are known to regulate germinal centers,
B-cell differentiation and activation. Several miRNAs expressed
in ALF are upregulated in B-cell lymphomas. In contrast, only a
very small number of miRNA were identified that target T-cell
genes, in agreement with the limited T-cell signature detected in
ALF and with the absence of IFN-γ and its inducible chemokines
both amongst liver mRNAs and serum proteins. Conclusions:
This is the first genome-wide integrated analysis of mRNA and
miRNA expression in HBV ALF. Our results reveal a dominant
B-cell-driven disease signature consistent with a major role of
B-cell immunity in the pathogenesis of ALF.
Disclosures:
The following people have nothing to disclose: Patrizia Farci, Fausto Zamboni,
Ashley B. Tice, Zhaochun Chen, Ronald E. Engle, Giacomo Diaz
219
Analysis of innate and adaptive host immunity during
combination therapy with peginterferon Lambda-1a
and Entecavir in patients with HBeAg(+) chronic hepati-
tis B
Sandra Phillips1, Sameer Mistry1, Antonio Riva1, Helen Cooksley1,
Stefan Zeuzem2, Clive Woffendin3, Pei-Jer Chen4, Cheng-Yuan
Peng5, Ting-Tsung Chang6, Stefan Lueth7, Robert J. de Knegt8,
Moon Seok Choi9, Heiner Wedemeyer10, Michael Dao11, Chang
Wook Kim12, Heng C. Chu13, Megan Wind-Rotolo14, Roger Wil-
liams1, Elizabeth L. Cooney14, Shilpa Chokshi1; 1Institute of Hepa-
tology, Foundation for Liver Research, London, United Kingdom;
2Johann Wolfgang Goethe University Medical Center, Frankfurt,
Germany; 3Oregon Clinical and Translational Research Institute,
Portland, OR; 4National Taiwan University Hospital, Taipei, Tai-
wan; 5China Medical University Hospital, Taichung, Taiwan;
6National Chen Kung University Hospital, Tainan, Taiwan; 7Uni-
versity of Hamburg, Hamburg, Germany; 8Erasmus University, Rot-
terdam, Netherlands; 9Sungkyunkwan University, Seoul, Republic
of Korea; 10Hannover Medical School, Hannover, Germany; 11Pre-
cision Diagnostic Laboratory, Santa Ana, CA; 12The Catholic Uni-
versity of Korea, Seoul, Republic of Korea; 13Tri-Service General
Hospital, Taipei, Taiwan; 14Research and Development, Bristol-My-
ers Squibb, Wallingford, CT
Background/Aims: Multiple in vitro studies have been con-
ducted characterizing the innate antiviral effects of IFNλ. How-
ever to date there are limited data regarding the impact of
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
peginterferon Lambda-1a (Lambda), which has shown anti-HBV
activity both in vitro and in vivo, on host immune responses
in vivo. In this study we aimed to longitudinally assess the
effect of Lambda on innate and adaptive immunity when
administered in combination with Entecavir (ETV) employing
a sequential dosing approach in treatment-naive HBeAg(+)
chronic hepatitis B (CHB) patients. Methods: NK-cell frequency,
phenotype, expression of inhibitory/activating signatures and
function by IFNγ production and cytotoxicity were measured by
FACS. Expression of immunoinhibitory receptors on HBV-spe-
cific CD4+/CD8+ T-cells were measured by FACS. Ex-vivo
frequency of HBV-specific CD4+/CD8+ T-cells producing
IFNγ and IL-10 to genotype-specific HBcAg/HBsAg peptide
pools were quantified by Elispot assays and intracellular cyto-
kine staining. Levels of circulating T-regulatory cells were also
assessed. Immunological analyses were performed at 9 time-
points(TP) through the study period including Baseline, TW4,
TW8, TW12 TW16,TW24,TW36 and 2 subsequent follow
up visits (TW60, TW84). Virological and clinical parameters
were also measured at each TP and correlated with immuno-
logical assessments. Results: In this study, a total of 13 subjects
received combination Lambda plus ETV. The population was of
mean age 31.2 years, 77% male and 92% Asian. At baseline,
mean laboratory values showed: HBV DNA 8.3 log10 IU/mL,
qHBsAg 4.6 IU/mL and ALT 88 U/L. The addition of Lambda
to ETV was not associated with recovery of HBV-specific CD4/
CD8+ T-cells producing IFNγ. From baseline and through the
study there was a predominance of HBV-specific IL-10 pro-
duction and an increasing expression of PD1 particularly on
CD4+ T-cells. In contrast, addition of Lambda induced potent
activation of NK-cell functionality with marked augmentation of
IFNγ production, degranulation and ability to kill target cells.
This was associated with upregulation of activating receptor
NKG2D on CD56brightNK-cells but no changes in expres-
sion of PD1 or apoptosis-inducing TRAIL were observed. The
frequency of T-regulatory cells was low (<2%) throughout the
study. Conclusions: The use of Lambda in combination with
ETV in HBeAg(+) CHB patients impacts the innate and adaptive
immune responses differentially. Similar to the immunological
studies conducted in pegIFNα-treated CHB patients, Lambda
does not seem to reconstitute the impaired virus-specific T-cell
response but does induce potent antiviral NK-cell activation
and functionality in vivo.
Disclosures:
Stefan Zeuzem - Consulting: Abbvie, Boehringer Ingelheim GmbH, Bristol-Myers
Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen,
Roche Pharma AG, Vertex Pharmaceuticals
Pei-Jer Chen - Advisory Committees or Review Panels: BMS, GSK, BMS, GSK,
Medigene; Independent Contractor: J & J; Speaking and Teaching: Roche, Roche
Ting-Tsung Chang - Advisory Committees or Review Panels: Bristol-Myers Squibb;
Speaking and Teaching: Bristol-Myers Squibb
Stefan Lueth - Advisory Committees or Review Panels: BMS, Gilead, MSD, Jans-
sen
Robert J. de Knegt - Advisory Committees or Review Panels: MSD, Roche,
Norgine, Janssen Cilag; Grant/Research Support: Gilead, MSD, Roche, Janssen
Cilag, BMS; Speaking and Teaching: Gilead, MSD, Roche, Janssen Cilag
Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD,
Roche, Gilead, Abbott, BMS, Falk, Abbvie, Novartis, GSK; Grant/Research
Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS,
MSD, Novartis, ITF, Abbvie, Gilead
Chang Wook Kim - Consulting: Gilead, MSD; Grant/Research Support: BMS,
Handok, Pharmicell, Pharmaking; Speaking and Teaching: BMS, Donga, Dae-
woong
Megan Wind-Rotolo - Employment: Bristol-Myers Squibb; Stock Shareholder:
Bristol-Myers Squibb
Elizabeth L. Cooney - Employment: Bristol-Myers Squibb Inc; Stock Shareholder:
Bristol-Myers Squibb Inc
The following people have nothing to disclose: Sandra Phillips, Sameer Mistry,
Antonio Riva, Helen Cooksley, Clive Woffendin, Cheng-Yuan Peng, Moon Seok
Choi, Michael Dao, Heng C. Chu, Roger Williams, Shilpa Chokshi
309A
220
Silencing HBV transcription by targeting cccDNA-bound
chromatin modifiers
Gianna Aurora Palumbo1, Laura Belloni1,2, Sergio Valente4, Dante
Rotili4, Natalia Pediconi2,3, Antonello Mai4, Massimo Levrero1,2;
1Dept of Internal Medicine - DMISM, Sapienza University, Rome,
Italy; 2IIT-Sapienza center for life nanoscience, Rome, Italy;
3Department of Molecular Medicine, Sapienza University, Rome,
Italy; 4Dipartimento di Chimica e Tecnologia del Farmaco, Sapi-
enza University, Rome, Italy
Background and Aims: The HBV cccDNA is organized into
mini-chromosomes by histone and non-histone proteins and
HBV replication is regulated by the acetylation status of cccD-
NA-bound H3/H4 histones. We have previously shown that:
a) interferon-α inhibits HBV transcription/replication by favor-
ing the recruitment to the minichromosome of class III Histone
Deacetylase hSirt1 and histone methyltransferase Ezh2; b)
small compounds modulating these enzymatic activities may
in part mimic IFNa-induced cccDNA silencing. Here we fur-
ther characterize the activity on cccDNA transcription of small
compounds active on different classes of chromatin modifying
enzymes. Methods: Capsid-associated HBV-DNA, cccDNA
and pgRNA levels were assessed in HepG2 replicating HBV
or in the inducible HepAD38 stable HBV cell line, left untreated
or treated with: a) a p300 and PCAF histone acetyltransferases
(HAT) inhibitor, b) a hSirt1 activator and c) a JMJD3 histone
demethylase inhibitor. Recruitment of transcriptional cofactors
and cccDNA bound histones modifications were assessed
using the cccDNA ChIP assay. Results: The inhibition of PCAF/
p300 HATs, stimulation of hSirt1/2 activity or inhibition of
JMJD3 (i.e. potentiation of Ezh2 demthylase activity) affect to a
different extent pgRNA transcription and result in reduced HBV
replication. HATs inhibitors reduce cccDNA-bound H4 acetila-
tion and inhibit PCAF/p300 binding on the viral minichromo-
some, suggesting an autoregulatory loop involving p300- and
PCAF- dependent histones acetylation and their binding to the
cccDNA. The hSirt1/2 activator also induces a decrease in
cccDNA bound H4 acetylation levels and modulates Sirt1 and
Sirt2 binding to the minichromosome. Inhibition of JMJD3 enzy-
matic activity is mirrored by an increased recruitment of Ezh2
to the cccDNA. Conclusions: These results support the concept
of an epigenetic approach with small molecules to modulate
HBV transcription and replication
Disclosures:
Massimo Levrero - Advisory Committees or Review Panels: Gilead, Jansen Cilag;
Speaking and Teaching: Roche, BMS, MSD
The following people have nothing to disclose: Gianna Aurora Palumbo, Laura
Belloni, Sergio Valente, Dante Rotili, Natalia Pediconi, Antonello Mai
221
Long-term persistence of patient-derived hepatitis B
virus infection in 3D microfluidic primary hepatocyte
cultures
Sann Nu Wai2, Emma M. Large3, David Hughes3, Emma Sceats3,
Marion Lussignol4, Maria Teresa Catanese4, Mark R. Thursz2,
Marcus Dorner1,2; 1Virology, Imperial College London, London,
United Kingdom; 2Hepatology, Imperial College London, London,
United Kingdom; 3CN Bio Innovations Ltd., Oxford, United King-
dom; 4Infectious Diseases, King’s College London, London, United
Kingdom
Hepatitis B virus (HBV) is a global health concern, affecting
over 350 million people worldwide despite the availability of
a protective vaccine. Although direct-acting antivirals are avail-
able, therapy does not constitute a cure and drug resistance
has been described for most inhibitors. The inability to recapit-
310A AASLD ABSTRACTS
ulate all steps of the HBV life cycle in metabolically competent
adult hepatocytes has thus far hampered efforts to devise novel
treatment strategies. Despite the recent description of NTCP as
HBV receptor on hepatocytes, models relying on NTCP over-
expression and non-polarized culture of hepatoma cells do not
accurately reflect HBV infection. Here we describe a novel HBV
primary cell culture model utilizing 3D microfluidic cell culture
technology of human adult hepatocytes. Hepatocytes form a
physiological liver microarchitecture, as determined by electron
microscopy, including the formation of tight junctions and bile
canaliculi. Longitudinal genomic, proteomic and functional cell
assays confirm the ability to culture primary hepatocyte micro-
tissues for at least 21 days without dedifferentiation or cell mor-
tality. Persistent in vitro infection is established upon inoculation
with Hepatitis B virus derived from primary patient isolates
or recombinant sources, without requirement for pre-treatment
of the cultures with cytotoxic solvents such as dimethyl sulf-
oxide. Accumulation of covalently closed circular (ccc)DNA,
replication intermediates, pregenomic RNA as well as de novo
production of significant titres of infectious virus progeny, as
determined by HBsAg secretion and reinfection of naïve cells,
confirms that the complete HBV life cycle is supported in vitro.
In addition to HBeAg-positive isolates, infection is successfully
launched in liver microtissues using HBeAg-negative patient
isolates, and viral replication is inhibited upon treatment with
direct acting antiviral drugs. This HBV cell culture model offers
a new means for conducting target validation, drug discovery
and development of novel therapeutic candidates against HBV
in a physiological hepatocyte background.
Disclosures:
Mark R. Thursz - Advisory Committees or Review Panels: Gilead, BMS, Abbott
Laboratories
Marcus Dorner - Grant/Research Support: CN Bio Innovations, Ltd
The following people have nothing to disclose: Sann Nu Wai, Emma M. Large,
David Hughes, Emma Sceats, Marion Lussignol, Maria Teresa Catanese
222
Modeling hepatitis B virus infection in primary and in
inducible pluripotent stem cell-derived human hepato-
cytes to study virus-host interactions
Robert E. Schwartz1,2, Amir Shlomai3, Vyas Ramanan2,4, Ankit
Bhatta3, Ype P. De Jong1,3, Sangeeta Bhatia2,4, Charles M. Rice3;
1Department of Medicine, Weill Cornell Medical College, New
York, NY; 2Health Sciences and Technology, Massachusetts Insti-
tute of Technology, Cambridge, MA; 3Center for the Study of
Hepatitis C, Laboratory of Virology and Infectious Disease, The
Rockefeller University, New York, NY; 4Howard Hughes Medical
Institute, Koch Institute, Cambridge, MA
Hepatitis B virus (HBV) chronically infects 400 million people
worldwide and is a leading driver of end-stage liver disease
and liver cancer. Research into the biology and treatment of
HBV requires an in vitro cell culture system that supports the
HEPATOLOGY, October, 2014
infection of human hepatocytes, and accurately recapitulates
virus-host interactions. Here, we report that micro-patterned
co-cultures of primary human hepatocytes with stromal cells
(MPCCs) reliably support productive HBV infection, and infec-
tion can be enhanced by blocking elements of the hepatocyte
innate immune response associated with the induction of inter-
feron-stimulated genes. MPCCs maintain prolonged, productive
infection and represent a facile platform for studying virus-host
interactions and for developing antiviral interventions. Hepato-
cytes obtained from different human donors vary dramatically
in their permissiveness to HBV infection, suggesting that fac-
tors such as divergence in genetic susceptibility to infection
may influence infection in vitro. To establish a complementary,
renewable system on an isogenic background in which can-
didate genetics can be interrogated, we show that inducible
pluripotent stem cells (iPSCs) differentiated into hepatocyte-like
cells (iHeps) support HBV infection that can also be enhanced
by blocking ISG induction. Notably, the emergence of the
capacity to support HBV transcriptional activity and initial per-
missiveness for infection are marked by distinct stages of iHep
differentiation, suggesting that infection of iHeps can be used
both to study HBV and conversely to assess the degree of iHep
differentiation. Our work demonstrates the utility of these infec-
tious systems for studying HBV biology and the virus’ interac-
tions with host hepatocyte genetics and physiology.
Disclosures:
The following people have nothing to disclose: Robert E. Schwartz, Amir Shlo-
mai, Vyas Ramanan, Ankit Bhatta, Ype P. De Jong, Sangeeta Bhatia, Charles
M. Rice
223
Long-term therapy-induced viral clearance in chronic
HCV does not lead to normalization of the intrahepatic T
cell compartment
Michelle Spaan1, Mark Claassen2, Harry L. Janssen1,3, Robert
J. de Knegt1, Andre Boonstra1; 1Dept. of Gastroenterology and
Hepatology, ErasmusMC, Rotterdam, Netherlands; 2Dept. of Inter-
nal Medicine, ErasmusMC, Rotterdam, Netherlands; 3Dept. of
Gastroenterology and Hepatology, University of Toronto, Toronto,
ON, Canada
Although treatment-induced HCV eradication leads to normal-
ization of ALT levels, we previously showed that 4 weeks after
cessation of therapy, T cell infiltrates in the liver were still not
normalized. We now investigate the phenotype and activity of
intrahepatic and blood T cells in a follow up study in individ-
uals with undetectable HCV RNA for over 4 years following
successful antiviral treatment (SVR). Peripheral blood and multi-
ple aspirate biopsies from the liver were collected from chronic
HCV patients before and after IFN-based therapy (wk4-follow
up, wk24-follow up and year4-follow up). PBMC were stim-
ulated with HCV peptide pools to induce T cell proliferative
responses, which were assessed in the presence or absence
of neutralizing antibodies to the IL-10 receptor, TGF-beta or
after depletion of CD25+ Treg. Liver aspirate biopsies were
evaluated by flow cytometry for CD3+ T cells, CD4+ T cells
and Treg (CD4+CD25+FoxP3+ cells) as well as T cell mem-
ory markers. From a cohort of 13 patients that obtained SVR
after therapy, 4 individuals agreed with additional sampling
of the liver. By flowcytometry, we found that intrahepatic Treg
frequencies remained increased not only at 4 weeks after ther-
apy as we previously reported, but also at week 24 (Treg/
CD4: 9.4%) and, importantly, even at 4 years after success-
ful completion of therapy (Treg/CD4: 5.7%). In contrast, in
healthy liver samples, obtained from individuals never exposed
to HCV antigens, hardly any Treg were detected. On the basis
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
of expression of CD45RO and CD62L, the majority of Treg in
the livers sampled at 4 years after clearance of HCV were iden-
tified as central memory Treg (73.2% CD45RO+CD62L- cells).
In contrast to the liver, the frequency of blood Treg did not dif-
fer between individuals during short-term and long-term follow
up and those who had never been exposed to HCV. Function-
ally, however, 2 out of 5 patients displayed potent regulation
in PBMC of HCV-specific T cell proliferation by TGF-beta and
Treg (maximum increase 4-fold and 8-fold up to 8,000 cpm,
respectively) but no regulation by IL-10 was observed. Our
findings, gathered by multiple sampling of the liver and periph-
eral blood, demonstrate that the local immune response does
not revert to a resting state comparable to healthy livers after
successful HCV eradication, even after 4 years of follow up .
The persisting presence of high numbers of Treg with relatively
weak suppressive activity, based on their phenotype, suggests
ongoing residual regulation of immunopathology.
Disclosures:
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sci-
ences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support:
Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck,
Medtronic, Novartis, Roche, Santaris
Robert J. de Knegt - Advisory Committees or Review Panels: MSD, Roche,
Norgine, Janssen Cilag; Grant/Research Support: Gilead, MSD, Roche, Janssen
Cilag, BMS; Speaking and Teaching: Gilead, MSD, Roche, Janssen Cilag
Andre Boonstra - Grant/Research Support: BMS, Janssen Pharmaceutics, Merck,
Roche
The following people have nothing to disclose: Michelle Spaan, Mark Claassen
224
Reversal of T cell exhaustion in chronic HCV-infected
patients receiving direct-acting antivirals
Matthew A. Burchill, Lucy Golden-Mason, Hugo R. Rosen; GI-Hepa-
tology, University of Colorado-Denver, Aurora, CO
In most individuals acutely infected with HCV, the innate and
adaptive antiviral response is not sufficient to induce viral
clearance, which results in a state of long-term chronic infec-
tion. It is well documented that chronic infection with HCV
results in T cell exhaustion and impaired T cell immunity. An
as yet unanswered question in the field of T cell exhaustion is
how sterile viral clearance effects the phenotype and function
of previously exhausted T cells. Recently, novel therapies of
direct acting antivirals (DAA) regimens were developed which
induce rapid and sustained clearance of HCV. These DAAs
have provided the unique opportunity to determine whether
successful treatment-induced eradication of viral antigen leads
to a reversal of T cell exhaustion and reconstitution T cell effec-
tor function. As such, using a cohort of 20 patients receiving
DAAs we determined that a regimen of daclatasvir (NS5A
inhibitor), asunaprevir (NS3 protease inhibitor), and BMS-
791325 (non-nucleoside NS5B inhibitor) leads to rapid viral
clearance, a reversal of the exhausted phenotype on bulk CD8
T cells and induction of anti-viral CD8 T cell responses. Specif-
ically, we observed that following treatment with DAAs, PD1
expression was significantly (p<0.05, MWU) reduced on bulk
CD8 T cells in a majority of patients. Treatment with DAAs
also induced the down modulation of the co-inhibitory T cell
immunoglobulin and ITIM domain (TIGIT) on the bulk popula-
tion of CD8 T cells (p<0.001, MWU). The down modulation
of TIGIT was unique to DAA treatment, as this effect was not
observed when patients were treated with standard pegylated
IFN and ribavirin therapy. In addition, we observed that treat-
ment with DAAs resulted in the expansion of HCV specific
T cells through the use of MHC Class I tetramers specific to
HCV-NS3 (1406) or HCV-NS5a (2594) –reactive T cells, and
in some cases, decreases in PD-1 and Tim-1 on HCV-specific
311A
T cells. Collectively, our data demonstrate that the rapid viral
clearance following treatment with DAA results in the reversal
of the exhausted phenotype in CD8 T cells and the subsequent
expansion of HCV-specific CD8 T cells and thus the restoration
of antiviral T cell immunity.
Disclosures:
The following people have nothing to disclose: Matthew A. Burchill, Lucy Gold-
en-Mason, Hugo R. Rosen
225
Rapid Decrease in Hepatitis C Virus Viremia by Direct
Acting Antivirals Improves the Innate Immune Response
to IFNα
Elisavet Serti, Heiyoung Park, T. Jake Liang, Marc G. Ghany, Bar-
bara Rehermann; Liver Diseases Branch, NIDDK, NIH, Bethesda,
MD
Innate immune cells are activated in HCV infection as exempli-
fied by natural killer (NK) cells, which display increased levels
of TRAIL expression and cytotoxicity. These levels increase fur-
ther in response to IFNα-based therapy and mirror induction
of interferon stimulated genes (ISGs) in the liver. Here, we
asked whether a rapid reduction in viremia by direct acting
antivirals (DAAs) affects the NK cell response to IFNα. Twen-
ty-one HCV genotype 1a-infected nonresponders to previous
PegIFN/ribavirin therapy were treated with a regimen of Asu-
naprevir, Daclatasvir, PegIFN and ribavirin. All patients expe-
rienced a 1.7-4.3 log10 decline in HCV titer within 24 hours
with viremia <43 IU/ml by week 4. The first phase virological
response at 24h correlated in a linear regression analysis with
innate responsiveness to PegIFN, i.e. with the increase in NK
cell STAT1 and TRAIL expression in the first 24h of treatment.
Increased STAT1 and TRAIL expression were maintained until
at least week 4 of therapy, and were associated with NK cell
refractoriness to further in vitro stimulation with IFNα. Accord-
ingly, no increase in intrahepatic ISG expression was observed
6 hours after PegIFN injection at week 4 of therapy. To confirm
whether NK cell responsiveness to IFNα was influenced by
viremia, we compared NK cell responses in the current therapy
in a subset of 6 patients to NK cell responses during the past
PegIFN/ribavirin therapy, to which they were nonresponders.
This comparison showed a significantly greater increase in NK
cell STAT1, pSTAT1 and TRAIL expression in the first 24 hours
of during Asunaprevir, Daclatasvir, PegIFN and ribavirin ther-
apy, which resulted in rapid reduction in HCV titer, than during
the past PegIFN and ribavirin therapy, which did not reduce
HCV titer. In conclusion, this study shows that DAA-mediated
rapid reduction in HCV viremia improves NK cell responsive-
ness. Whether improved IFN responsiveness correlates with
clinical outcome needs to be determined.
Disclosures:
The following people have nothing to disclose: Elisavet Serti, Heiyoung Park, T.
Jake Liang, Marc G. Ghany, Barbara Rehermann
312A AASLD ABSTRACTS
226
A P70S Variant of the IFNλ4 Protein Displaying
Decreased Activity is Associated with Improved Hepati-
tis C Virus Clearance and Reduced Hepatic Expression
of Interferon-Stimulated Genes
Ewa Terczynska-Dyla1, Stephanie Bibert2, Francois H. Duong3,
Ilona Krol3, Emilie Collinet2, Zoltan Kutalik5,6, Vincent Aubert7,
Andreas Cerny8, Laurent Kaiser9, Raffaele Malinverni10, Alessan-
dra Mangia11, Darius Moradpour12, Beat Mullhaupt13, Francesco
Negro9, Rosanna Santoro11, David Semela14, Nasser Semmo15,
Markus H. Heim3,4, Pierre-Yves Bochud2, Rune Hartmann1;
1Department of Molecular Biology and Genetics, Aarhus University,
Aarhus, Denmark; 2Infectious Disease Service, Department of Med-
icine, University Hospital and University of Lausanne, Lausanne,
Switzerland; 3Department of Biomedicine, University of Basel,
Basel, Switzerland; 4Department of Gastroenterology and Hepa-
tology, University Hospital Basel, Basel, Switzerland; 5Institute of
Social and Preventive Medicine, University Hospital and University
of Lausanne, Lausanne, Switzerland; 6Swiss Institute of Bioinformat-
ics, Lausanne, Switzerland; 7Service of Immunology and Allergol-
ogy, Department of Medicine, University Hospital and University
of Lausanne, Lausanne, Switzerland; 8Fondazione Epatocentro
Ticino, Lugano, Switzerland; 9Division of Gastroenterology and
Hepatology, Geneva University Hospitals, Geneva, Switzerland;
10Pourtalès Hospital, Neuchatel, Switzerland; 11Scientific Research
Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo,
Italy; 12Division of Gastroenterology and Hepatology, University
Hospital and University of Lausanne, Lausannee, Switzerland;
13Division of Gastroenterology and Hepatology, University Hospi-
tal of Zurich, Zurich, Switzerland; 14Division of Gastroenterology
and Hepatology, Canton Hospital, St.Gallen, Switzerland; 15Ser-
vice of Hepatology, Department of Clinical Research, University of
Bern, Bern, Switzerland
Background: Genetic variants of the IFNλ3(IL28B)/IFNλ4 locus
are strongly associated with spontaneous clearance of hepatitis
C virus (HCV) and with response to treatments with pegylated
IFNα and ribavirin, but until now, the molecular mechanism
remains unknown. The recent discovery that the rs368234815
dG allele codes for a new member of the IFNλ family, IFNλ4,
provides a potential molecular link. Paradoxically, despite the
fact that IFNλ4 is potently antiviral, the dG allele is associated
reduced spontaneous and treatment induced clearance rates.
Furthermore, IFNλ4 protein has not yet been detected in cell
culture lysates, cell culture supernatants, or liver biopsies. In
the present work we further analyzed genetic variants of the
IFNλ4 locus. Methods: Wildtype IFNλ4 and a variant with an
amino acid substitution in the IFNλ4 protein changing a proline
at position 70 to a serine (P70S) were expressed in bacteria
and purified. Their potency to induce IFN stimulated genes
(ISG) was tested in HepG2 cells. Their antiviral activity was
assayed in EMCV infected HepG2 cells. The association of
these genetic variants of IFNλ4 with ISG expression was ana-
lyzed in 104 liver biopsies from patients with chronic hepatitis
C (CHC). The association of IFNλ4 variants with spontaneous
and treatment induced clearance of HCV was tested in 2 large
patient cohorts. Results: The P70S amino acid substitution in the
IFNλ4 protein significantly lowers its activity. IFNλ4-P70 is a
fully active IFNλ family member with even slightly higher induc-
tion of ISGs compared to IFNλ3, whereas IFNλ4-S70 is 5 times
less potent. The antiviral activity of IFNλ4-S70 was seven times
weaker compared to IFNλ4-P70. Importantly, the single amino
acid substitution in the IFNλ4 protein had a major effect on
the expression level of ISGs in the liver of patients with CHC.
Patients harboring the impaired IFNλ4-S70 variant display
a significant lower median expression level of ISGs. Patients
with the IFNλ4-S70 variant had significantly better treatment
HEPATOLOGY, October, 2014
response rates and better spontaneous clearance rates, com-
pared to patients coding for the fully active IFNλ4-P70 variant.
Conclusions: Altogether, these data provide compelling evi-
dence that the active IFNλ4 protein is the driver of high hepatic
ISG expression and causally linked to decreased spontaneous
HCV clearance and reduced response rates of treatments with
pegylated IFNα and ribavirin.
Disclosures:
Beat Mullhaupt - Consulting: MSD, Novartis, MSD, Janssen; Grant/Research
Support: Bayer, Gillead
Francesco Negro - Advisory Committees or Review Panels: Roche, MSD, Gilead,
Boehringer Ingelheim, Bristol-Myers Squibb, Novartis; Grant/Research Support:
Roche, Gilead
Pierre-Yves Bochud - Speaking and Teaching: MSD, Gilead
The following people have nothing to disclose: Ewa Terczynska-Dyla, Stephanie
Bibert, Francois H. Duong, Ilona Krol, Emilie Collinet, Zoltan Kutalik, Vincent
Aubert, Andreas Cerny, Laurent Kaiser, Raffaele Malinverni, Alessandra Mangia,
Darius Moradpour, Rosanna Santoro, David Semela, Nasser Semmo, Markus H.
Heim, Rune Hartmann
227
Epigenetic Analysis of the IFNλ3 Gene Identifies a Novel
Marker for Response to Therapy in HCV-infected Sub-
jects
Jeffrey F. Waring1, Emily Dumas2, Eoin Coakley2, Daniel E.
Cohen2, Kenneth B. Idler1, Ujjwal Das1, Thomas Podsadecki2,
Sandeep Dutta1; 1Clinical Pharmacology, AbbVie, North Chicago,
IL; 2Infectious Disease Clinical Development, AbbVie, North Chi-
cago, IL
Chronic HCV infection is characterized by high inter-individual
variability in terms of response to currently approved treat-
ments. Extensive GWAS analysis has identified that carriers of
the C/C allele for the polymorphism rs12979860 within the
5’ intergenic region of the IFNλ3 gene are more likely to dis-
play spontaneous clearance of HCV and achieve SVR follow-
ing treatment with pegylated interferon and ribavirin (pIFN/
RBV) relative to non-C/C carriers. Because rs12979860 is
not located in the coding region of IFNλ3, the mechanism
underlying how this variant affects response to HCV therapies
is not clear. Studies have shown that DNA methylation levels
are influenced by environmental factors and can affect gene
expression. We conducted epigenetic analysis on in the IFNλ3
promoter, in order to investigate whether DNA methylation is
associated with response to HCV therapy. Methods: DNA sam-
ples from HCV-infected subjects (genotypes 1-3) receiving an
IFN-free ABT-450-containing combination regimen (N=540) or
pIFN/RBV (N=18) and from HCV-uninfected, healthy controls
(N=127) were analyzed for IFNλ3 methylation levels using
bisulfite conversion. Results: Analysis of the IFNλ3 promoter
indicated that methylation levels were strongly associated with
rs12979860 allele status. As a group, carriers of the C/C
allele had significantly lower methylation levels relative to carri-
ers of the C/T or T/T alleles (average 27% methylation for C/C
vs 44% for T/T carriers). Methylation levels were associated
with response to pIFN/RBV treatment, as subjects with lower
methylation levels showed a greater mean reduction in HCV
RNA within the first 9 days of treatment relative to subjects with
higher levels (-1.8 vs -0.5 log, respectively). Methylation levels
did not affect response to DAAs with treatment durations of 12
or 24 weeks. However, non-C/C subjects with higher methyla-
tion levels showed a greater likelihood of relapsing with an 8
week treatment duration. Discussion: Epigenetic analysis of the
IFNλ3 promoter has identified that methylation levels strongly
associate with rs12979860 allele status. For subjects treated
with a DAA regimen for 12 or 24 weeks, methylation levels
did not affect treatment response. However, in subjects treated
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
with pIFN/RBV or with a DAA regimen for only 8 weeks, sub-
jects with lower methylation levels showed a more favorable
response to treatment relative to subjects with higher methyla-
tion levels. This analysis identifies a new parameter for iden-
tifying difficult-to-treat subjects, and may provide mechanistic
insight into the role of IFNλ3 genetic variants in HCV treatment
response.
Disclosures:
Jeffrey F. Waring - Employment: AbbVie
Emily Dumas - Employment: AbbVie; Patent Held/Filed: AbbVie; Stock Share-
holder: AbbVie
Eoin Coakley - Employment: AbbVie; Stock Shareholder: AbbVie
Daniel E. Cohen - Employment: AbbVie; Stock Shareholder: AbbVie
Kenneth B. Idler - Employment: AbbVie, Inc.; Stock Shareholder: AbbVie, Inc.
Thomas Podsadecki - Employment: AbbVie; Stock Shareholder: AbbVie
Sandeep Dutta - Employment: AbbVie; Stock Shareholder: AbbVie
The following people have nothing to disclose: Ujjwal Das
228
Hepatitis C Virus Eludes IFN-mediated Antiviral
Responses by Producing a Genomic Reservoir Protected
in Double-stranded RNA; Ribavirin Blocks this Escape
Strategy
Arielle L. Klepper1, Francis J. Eng1, Adeeb Rahman1, Brannon
Weeks1, Ahmed El-Shamy1, Erin H. Doyle1, M. Isabel Fiel1, Gon-
zalo Carrasco-Avino1, Sasan Roayaie1, Meena B. Bansal1, Mar-
garet R. MacDonald2, Thomas D. Schiano1, Andrea D. Branch1;
1Mount Sinai School of Medicine, New York, NY; 2Rockefeller
University, New York, NY
Introduction: HCV establishes persistent infection despite trig-
gering a robust interferon-induced anti-viral response. Inter-
feron-based regimens as well as direct-acting antiviral (DAA)
drugs are used to treat HCV. Regardless of the regimen,
HCV RNA can be undetectable in blood for months only to
reappear after treatment ends, causing relapse. Ribavirin is
a broad-spectrum antiviral drug that reduces relapse when
used in combination with interferon and/or with DAAs such
as sofosbuvir/ledipasvir. Methods: HCV RNAs were quanti-
fied in extracts of human liver and cultured cells. Huh-7.5 cells
replicating Con1/JFH virus were treated with HCV inhibitors,
interferon α-2b (IFN; 3 IU/mL, 9 IU/mL), ribavirin (25 or 100
mM), and 2’-C-methyl adenosine (2’CMA; 0.22 to 2.2 μM). To
allow HCV double-stranded (ds)RNA detection, RNA duplexes
were denatured prior to qPCR. RNA was also studied using
RNase III (cuts dsRNA), RNase A and RNase T1 (cuts ssRNA),
and Northern blotting. Bead array (Illumina) and Western blot-
ting were used to study pathways differentially regulated by
IFN compared to IFN/ribavirin. Results: Because relapse is an
important clinical problem and ribavirin reduces relapse, we
investigated pathways altered by the addition of ribavirin to
HCV-infected Huh-7.5 cells treated with IFN. Microarray anal-
ysis revealed that IFN-treated cells had elevated levels of acti-
vated PKR, an antiviral protein that binds to and is activated by
dsRNA. Ribavirin blocked PKR activation, suggesting that IFN
caused an increase in viral dsRNA (activating PKR) and ribavi-
rin prevented this shift in the viral RNA population. To explore
this possibility, RNA from various sources was heated to 106
°C to denature long dsRNA prior to reverse transcription. Using
this approach we found that HCV dsRNA is the predominant
form of viral RNA in the liver of HCV-infected patients. The
abundance of HCV dsRNA correlates with interferon-stimulated
gene induction. Northern blotting and ribonuclease digestion
showed that IFN increased production of genome-length HCV
dsRNA in HCV-infected Huh-7.5 cells and dramatically altered
the ratio of HCV plus and minus strands, reducing the level of
313A
plus strands while maintaining or increasing the level of minus
strands thereby preserving the capacity for progeny plus strand
synthesis. This process required de novo production of viral
RNA and dsRNA synthesis and was blocked by ribavirin. Con-
clusions: Our findings demonstrate that HCV can respond to
IFN by producing a genome-length viral dsRNA. This dsRNA is
a key target of ribavirin. The development of DAAs that target
viral dsRNA might improve treatment for HCV and other viruses
(DA031095, DK090317).
Disclosures:
Andrea D. Branch - Grant/Research Support: Kadmon, Gilead, Janssen
The following people have nothing to disclose: Arielle L. Klepper, Francis J. Eng,
Adeeb Rahman, Brannon Weeks, Ahmed El-Shamy, Erin H. Doyle, M. Isabel
Fiel, Gonzalo Carrasco-Avino, Sasan Roayaie, Meena B. Bansal, Margaret R.
MacDonald, Thomas D. Schiano
229
Long Term Treatment with Tenofovir Disoproxil Fuma-
rate for Chronic Hepatitis B Infection is Safe and Well
Tolerated and Associated with Durable Virologic
Response with no Detectable Resistance: 8 Year Results
from Two Phase 3 Trials
Patrick Marcellin1, Edward J. Gane2, Robert Flisiak3, Huy N.
Trinh4, Joerg Petersen5, Selim Gurel6, Kelly D. Kaita7, Iskren A.
Kotzev8, Naoky Tsai9, John F. Flaherty10, Raul E. Aguilar Schall10,
Kathryn M. Kitrinos10, Mani Subramanian10, John G. McHutchi-
son10, Jacob George11, Harry L. Janssen12, Maria Buti13; 1Hopital
Beaujon, Clichy, France; 2Auckland City Hospital, Auckland, New
Zealand; 3Medical University of Bialystok, Bialystok, Poland; 4San
Jose Gastroenterology, San Jose, CA; 5Asklepiosklinik St. Georg,
University of Hamburg, Hamburg, Germany; 6Uludag Universitesi
Tip Fakultesi, Bursa, Turkey; 7University of Manitoba, Winnipeg,
MB, Canada; 8University Hospital Sveta Marina, Varna, Bulgaria;
9Queens Medical Center, University of Hawaii, Honolulu, HI;
10Gilead Sciences, Foster City, CA; 11Storr Liver Unit, Westmead
Millennium Institute, Westmead Hospital, Sydney, NSW, Australia;
12University of Toronto, Toronto, ON, Canada; 13Universitari Vall
d’Hebron and Ciberehd, Barcelona, Spain
Background: Through 5 years of treatment with tenofovir diso-
proxil fumarate (TDF) in mostly naïve patients, we reported
sustained viral suppression with regression of fibrosis, and
reversal of cirrhosis in 74% of patients (Lancet 2013;381:468-
75). Further, no evidence of resistance to TDF was seen through
Year 6 (J Hepatol. 2014;59:434-42). Here we present Year 8
results, the initially pre-specified end of study period, for two
Phase 3 studies in HBeAg- and HBeAg+ chronic hepatitis B
patients. Methods: After 48 weeks of double-blind comparison
of TDF to adefovir dipivoxil, all patients were eligible to con-
tinue open-label TDF. Patients were assessed every 3 months
for efficacy and safety; resistance surveillance was performed
annually, and annual bone mineral density (BMD) assessments
by DXA were included starting at Year 4. Results: A total of 641
patients were randomized and treated; 585 (91%) entered the
TDF extension phase at Year 1, and 412 (64%) remained on
study at Year 8. Efficacy results are summarized in the table.
Durable viral suppression was maintained, and 7 additional
patients (5 HBeAg+ and 2 HBeAg- ) experienced loss of HBsAg
(5 patients with seroconversion to anti-HBs) between Years 5-8.
No resistance to TDF was detected through Year 8. Through
Year 8, a confirmed renal event (either ≥0.5 mg/dL increase in
serum creatinine, or serum phosphorus <2 mg/dL, or creatinine
clearance <50 mL/min) was observed in 2.2% of patients, and
BMD (T scores) of hip and spine were stable between Years
4-8. Conclusions: Long term results from these two studies show
314A AASLD ABSTRACTS
TDF to be safe and effective with no evidence of resistance
through 8 years.
aMissing=Failure (LTE-TDF analysis); bMissing=excluded (On-treat-
ment analysis); cNA=not applicable; dKaplan-Meier-ITT%
Disclosures:
Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen,
MSD, Abbvie, Alios BioPharma, Idenix, Akron; Grant/Research Support: Roche,
Gilead, BMS, Novartis, Janssen, MSD, Alios BioPharma; Speaking and Teach-
ing: Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Boehringer, Pfizer,
Abbvie
Edward J. Gane - Advisory Committees or Review Panels: Novira, AbbVie,
Novartis, Gilead Sciences, Janssen Cilag, Vertex, Achillion, Tekmira, Merck, Ide-
nix; Speaking and Teaching: AbbVie, Novartis, Gilead Sciences, Janssen Cilag
Robert Flisiak - Advisory Committees or Review Panels: Gilead, Merck, Roche,
Bristol Myers Squibb, Janssen, Novartis, Abbvie; Grant/Research Support:
Roche, Bristol Myers Squibb, Janssen, Novartis, Gilead, Vertex, Merck; Speak-
ing and Teaching: Janssen, Merck, Roche, Bristol Myers Squibb, Gilead, Abbvie
Huy N. Trinh - Advisory Committees or Review Panels: BMS, Gilead; Grant/
Research Support: BMS, Gilead; Speaking and Teaching: BMS, Gilead, vertex;
Stock Shareholder: Gilead
Joerg Petersen - Advisory Committees or Review Panels: Bristol-Myers Squibb,
Gilead, Novartis, Merck, Bristol-Myers Squibb, Gilead, Novartis, Merck; Grant/
Research Support: Roche, GlaxoSmithKline, Roche, GlaxoSmithKline; Speaking
and Teaching: Abbott, Tibotec, Merck, Abbott, Tibotec, Merck
Selim Gurel - Speaking and Teaching: Glead, BMS, Roche, MSD, Glead, BMS,
Roche, MSD, Janssen
Kelly D. Kaita - Advisory Committees or Review Panels: Gilead, Merck, Roche,
Janssen, Boehringer, BMS, GSK, Vertex, Abbvie; Grant/Research Support: Gil-
ead, Merck, Roche
Naoky Tsai - Advisory Committees or Review Panels: BMS, Gilead, AbbVie;
Grant/Research Support: BMS, Gilead, AbbVie, Janssen, Beckman; Speaking
and Teaching: BMS, Gilead, AbbVie, Janssen, Roche, Merck
John F. Flaherty - Employment: Gilead Sciences; Stock Shareholder: Gilead Sci-
ences
Raul E. Aguilar Schall - Employment: Gilead Sciences, Inc.
Kathryn M. Kitrinos - Employment: Gilead Sciences, Gilead Sciences; Stock
Shareholder: Gilead Sciences, Gilead Sciences
Mani Subramanian - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Jacob George - Advisory Committees or Review Panels: Roche, BMS, MSD,
Gilead, Janssen
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sci-
ences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support:
Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck,
Medtronic, Novartis, Roche, Santaris
Maria Buti - Advisory Committees or Review Panels: Gilead, Janssen, Vertex,
MSD; Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gil-
ead, Janssen, Vertex, Novartis
The following people have nothing to disclose: Iskren A. Kotzev
HEPATOLOGY, October, 2014
230
The Safety and Efficacy of Entecavir and Tenofovir
Combination Therapy for Chronic Hepatitis B in Patients
with Previous Nucleos(t)ide Treatment Failure: Week 96
Results of the ENTEBE study
Fabien Zoulim1, Maciej S. Jablkowski2, Mircea. Diculescu3, Joerg
Petersen4, Patrick Marcellin5,6, Soumaya Bendahmane7, Aleksan-
dra Kedzierska8, Krzysztof. Simon9, Harry L. Janssen10,11; 1Hepa-
tology Department, Hospices Civils de Lyon, INSERM U1052,
Lyon University, Lyon, France; 2Department of Infectious and Liver
Diseases, Medical University of Lodz, Lodz, Poland; 3Centre of
Gastroenterology and Hepatology, Fundeni Clinical Institute,
Bucharest, Romania; 4IFI Institute for Interdisciplinary Medicine,
Asklepios Klinik St Georg, Hamburg, Germany; 5Hôpital Beau-
jon, Assistance Publique Hôpitaux de Paris, University of Paris 7,
Paris, France; 6INSERM Unité 773, Centre de Recherches Claude
Bernard sur les Hepatites Virales, Clichy, France; 7Bristol-Myers
Squibb, Braine-I’Alleud, Belgium; 8Bristol-Myers Squibb, Rueil-Mal-
maison, France; 9Division of Infectious Diseases and Hepatology,
Wroclaw University of Medicine, Wroclaw, Poland; 10Department
of Gastroenterology & Hepatology, Erasmus Medical Center, Uni-
versity Medical Center Rotterdam, Rotterdam, Netherlands; 11Liver
Clinic, Toronto Western & General Hospital, University Health
Network, Toronto, ON, Canada
Introduction: In patients with chronic hepatitis B (CHB) who
failed on prior nucleos(t)ide (NUC) therapy, rescue therapy
should involve an effective antiviral regimen that is active
against any existing drug-resistant hepatitis B virus (HBV) vari-
ants. Combination therapy with entecavir (ETV) and tenofovir
disoproxil fumarate (TDF), two potent agents with non-over-
lapping resistance profiles, may provide a single regimen
suitable for all patients who failed on other NUC regimens.
Here we present Week 96 results of the ENTEBE study assess-
ing ETV+TDF for patients with prior failure on NUC therapy.
Methods: In this single-arm, open-label, multicenter study, CHB
patients with prior non-response, partial response, or virologic
breakthrough on NUC therapy were treated with ETV (1 mg)
plus TDF (300 mg) for 96 weeks. The primary endpoint was
the proportion of patients with HBV DNA <50 IU/mL (Roche
COBAS TaqMan-HPS Assay) at Week 48 (non-completer=-
failure). Secondary endpoints included proportions of patients
with antiviral responses at Week 96, safety, and resistance
to ETV or adefovir (ADV). Results: Overall, 92 patients were
treated; 6 patients discontinued prior to Week 96. At baseline,
65% of patients were HBeAg(+), median HBV DNA was 3.7
log10 IU/mL. Prior NUC treatment included monotherapy with
ETV (53%), lamivudine (LVD; 22%), TDF (12%), (ADV; 4%), or
telbivudine (LdT; 2%), or combinations of these agents (7%);
58% of patients had evidence of single- or multidrug resistance
mutations (LVD: 52%, ETV: 26%; ADV: 7%). At Week 48, 76%
(70/92) of patients achieved the primary endpoint (HBV DNA
<50 IU/mL). By Week 96, 85% (78/92) of patients had HBV
DNA <50 IU/mL, including 80% (16/20) with prior failure on
LVD, 100% (4/4) on ADV, 88% (42/48) on ETV, 82% (9/11)
on TDF, 100% (2/2) on LdT, and 83% (5/6) on combination
therapy. No treatment-emergent resistance to ETV or ADV was
observed. Six patients had on-treatment serious adverse events,
none of which were considered related to study treatment. One
patient died from hepatocellular carcinoma. Conclusions: In
patients who failed prior NUC therapy, 96 weeks of ETV+TDF
combination therapy was well tolerated and achieved virologic
suppression in the majority (85%) of patients, irrespective of the
type of prior NUC, with no new resistance development.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Disclosures:
Fabien Zoulim - Advisory Committees or Review Panels: Janssen, Gilead, Novira,
Abbvie, Tykmera, Transgene; Consulting: Roche; Grant/Research Support:
Novartis, Gilead, Scynexis, Roche, Novira; Speaking and Teaching: Bristol
Myers Squibb, Gilead
Maciej S. Jablkowski - Advisory Committees or Review Panels: Gilead, Abbvie;
Consulting: BMS, Gilead, Roche, MSD; Speaking and Teaching: BMS, Roche,
MSD, Janssen-Cilag, Novartis
Joerg Petersen - Advisory Committees or Review Panels: Bristol-Myers Squibb,
Gilead, Novartis, Merck, Bristol-Myers Squibb, Gilead, Novartis, Merck; Grant/
Research Support: Roche, GlaxoSmithKline, Roche, GlaxoSmithKline; Speaking
and Teaching: Abbott, Tibotec, Merck, Abbott, Tibotec, Merck
Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen,
MSD, Abbvie, Alios BioPharma, Idenix, Akron; Grant/Research Support: Roche,
Gilead, BMS, Novartis, Janssen, MSD, Alios BioPharma; Speaking and Teach-
ing: Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Boehringer, Pfizer,
Abbvie
Aleksandra Kedzierska - Employment: Bristol-Myers Squibb
Krzysztof. Simon - Advisory Committees or Review Panels: BMS, MSD, Roche,
GIlead
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sci-
ences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support:
Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck,
Medtronic, Novartis, Roche, Santaris
The following people have nothing to disclose: Mircea. Diculescu, Soumaya
Bendahmane
231
Tenofovir Disoproxil Fumarate Alone or in Combina-
tion With Entecavir in Patients With Entecavir-Resistant
Chronic Hepatitis B: Multicenter Randomized Trial
Young-Suk Lim1, Kwan Soo Byun2, Geum-Youn Gwak3, Byung
Chul Yoo3, So Young Kwon4, Yoon Jun Kim5, Jihyun An1, Han
Chu Lee1, Yung Sang Lee1; 1Gastroenterology, Asan Medical Cen-
ter, University of Ulsan College of Medicine, Seoul, Republic of
Korea; 2Internal Medicine, Korea University College of Medicine,
Seoul, Republic of Korea; 3Medicine, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Republic of
Korea; 4Internal Medicine, Konkuk University School of Medicine,
Seoul, Republic of Korea; 5Internal Medicine, Seoul National Uni-
versity College of Medicine, Seoul, Republic of Korea
Background/Aims: It is not clear whether tenofovir disoproxil
fumarate (TDF) and entecavir (ETV) combination therapy
shows superior antiviral efficacy over tenofovir monotherapy
in patients who harbor ETV-resistant hepatitis B virus (HBV).
Methods: In this multicenter open-label trial, patients who had
HBV with genotypic resistance mutations to ETV and serum
HBV DNA concentration >60 IU/mL were randomized to TDF
(300 mg/day) monotherapy (TDF group, n = 45) or to TDF
and ETV (1 mg/day) combination therapy (TDF+ETV group,
n = 45), and were included in the intention-to-treat analyses.
Patients who had adefovir-resistant HBV (rtA181V/T and/or
rtN236T) were excluded. Results: At baseline, mean HBV DNA
level was 4.28 +/- 1.60 log10 IU/mL. All 90 patients had at
least one ETV-resistance mutations; rtT184 (n = 49), rtS202 (n
= 43), or rtM250 (n = 7). All also had rtM204V/I +/- rtL180M
mutations. One patient in the TDF group withdrew the con-
sent at week 2. At week 48, the number of patients with HBV
DNA <15 IU/mL, the primary efficacy endpoint, was 32 (71%)
and 33 (73%) in the TDF and TDF+ETV groups, respectively
(P=0.81). Mean reduction in HBV DNA levels from baseline
315A
was -3.65 +/- 1.64 log10 IU/mL and -3.77 +/- 1.30 log10
IU/mL in the TDF and TDF+ETV groups, respectively (P=0.69).
Virological breakthrough was observed in a patient in the
TDF group at 48 weeks, which was attributed to documented
non-adherence to study drug. Only 7 and 5 patients in the TDF
and TDF+ETV groups, respectively, had HBV DNA >60 IU/mL
at 48 weeks, and were qualified for HBV resistance tests. Resis-
tance mutations to lamivudine and/or ETV was detected only in
3 and 2 patients in the TDF and TDF+ETV groups, respectively,
at 48 weeks. None developed additional resistance mutations.
None in the TDF group required protocol-defined switch over of
treatment. Both treatments were well tolerated, and safety and
adverse event profiles were similar in the two groups. Conclu-
sions: TDF monotherapy showed similarly high antiviral effi-
cacy and safety as TDF and ETV combination therapy during
48 weeks of treatment in patients with ETV-resistant HBV. None
developed additional resistance mutations. KEY WORDS: Lami-
vudine, Monotherapy, Resistance, Virologic response
Disclosures:
Young-Suk Lim - Advisory Committees or Review Panels: Gilead Science, Bayer;
Grant/Research Support: Gilead Science, Novartis, Bayer; Speaking and Teach-
ing: BMS
Kwan Soo Byun - Advisory Committees or Review Panels: Gilead; Grant/
Research Support: Gilead, BMS, Taiho, Jassen; Speaking and Teaching: BMS
Han Chu Lee - Grant/Research Support: Medigen Biotechnology Co., Novartis,
Roche, Bayer HealthCare, Bristol-Myers Squibb, INC research, Boehringer Ingel-
heim, Taiho Pharmaceutical Co., Yuhan Co.
The following people have nothing to disclose: Geum-Youn Gwak, Byung Chul
Yoo, So Young Kwon, Yoon Jun Kim, Jihyun An, Yung Sang Lee
232
Incidence of Hepatocellular Carcinoma (HCC) in a US
Cohort of Chronic Hepatitis B (CHB) Patients by Age,
Gender, Cirrhosis and Antiviral Treatment Status
Derek Lin1, Nghia H. Nguyen2, Joseph Hoang3, Vinh D. Vu3,
Huy N. Trinh4, Jiayi Li5, Jian Q. Zhang6, Huy A. Nguyen4, Khanh
Nguyen4, Mindie H. Nguyen3; 1Internal Medicine, Stanford
University Medical Center, Palo Alto, CA; 2School of Medicine,
University of California San Diego, San Diego, CA; 3Division of
Gastroenterology and Hepatology, Stanford University Medical
Center, Palo Alto, CA; 4San Jose Gastroenterology, San Jose, CA;
5Gastroenterology, Palo Alto Medical Foundation, Mountain View,
CA; 6Primary Care, Chinese Hospital, San Francisco, CA
Background: Antiviral therapy may reduce HCC risk but it is
unclear what the residual risk would be in treated patients. Our
aim is to characterize HCC incidence in treated and untreated
patients by cirrhosis status, age (< 45 or ≥45), and gender.
Methods: In this retrospective cohort study, 3933 consecutive
CHB patients were identified at 3 US centers from 1991-2014.
Patients were included if they had at least one year of follow-up
and treatment-naïve. Exclusion criteria included HCC at ini-
tial presentation and the development of HCC within the first
year of follow-up. Diagnosis was based on AASLD criteria for
HCC and histology or clinical or imaging data for cirrhosis.
Annual incidence was calculated in cases per 1000 person
years. Results: We included a total of 3220 patients with 102
incident HCC cases over a median time of follow-up of 4.1
(1-17) years. In multivariate analysis, antiviral therapy was an
independent predictor for reduced HCC risk (HR 0.43, 95%
CI 0.23-0.79) following adjustment for age, gender, cirrhosis,
HBeAg, ALT, and HBV DNA. In cirrhotic men, regardless of
age, the treated group had a lower incidence of HCC (Figure
1). For the non-cirrhotic cohort, the effects of antivirals, while
beneficial were modest with the exception of men ≥45 years
of age. HCC incidence in treated non-cirrhotic patients ranged
from 0 to 1.2 cases per 1000 person years among the vari-
316A AASLD ABSTRACTS
ous age and gender groups compared to 0 to 6.4 per 1000
person years if untreated. HCC incidence in cirrhotic patients
still ranged 16.5 to 37.1 cases per 1000 person years in men
and 0 to 12.1 cases per 1000 person years in women in the
treated group. Conclusion: Antiviral therapy was associated
with lower HCC risk; however, HCC incidence was still signifi-
cantly high in treated patients especially in older men and in
those with cirrhosis. Adherence to HCC surveillance continues
to be needed regardless of treatment status.
Disclosures:
Huy N. Trinh - Advisory Committees or Review Panels: BMS, Gilead; Grant/
Research Support: BMS, Gilead; Speaking and Teaching: BMS, Gilead, vertex;
Stock Shareholder: Gilead
Huy A. Nguyen - Advisory Committees or Review Panels: Gilead, BMS; Speaking
and Teaching: Gilead
Mindie H. Nguyen - Advisory Committees or Review Panels: Bristol-Myers
Squibb, Bayer AG, Gilead, Novartis, Onyx; Consulting: Gilead Sciences, Inc.;
Grant/Research Support: Gilead Sciences, Inc., Bristol-Myers Squibb, Novartis
Pharmaceuticals, Roche Pharma AG, Idenix, Hologic, ISIS
The following people have nothing to disclose: Derek Lin, Nghia H. Nguyen,
Joseph Hoang, Vinh D. Vu, Jiayi Li, Jian Q. Zhang, Khanh Nguyen
HEPATOLOGY, October, 2014
233
Timing of hepatocellular carcinoma (HCC) development
and predictability of a modified PAGE-B risk score in
caucasian chronic hepatitis B (CHB) patients treated with
entecavir (ETV) or tenofovir (TDF)
George V. Papatheodoridis1, George N. Dalekos2, Vana Sypsa3,
Cihan Yurdaydin4, Maria Buti5, Ioannis Goulis6, Heng Chi7,
Spilios Manolakopoulos8, Giampaolo Mangia9, Nikolaos Gatse-
lis2, Onur Keskin4, Savvoula Savvidou6, Bettina E. Hansen7, Jiannis
Vlachogiannakos1, Kostas Galanis2, Ramazan Idilman4, Massimo
Colombo9, Rafael Esteban5, Harry L. Janssen7,10, Pietro Lamper-
tico9; 1Academic Department of Gastroenterology, Laiko General
Hospital, Athens, Greece; 2Department of Internal Medicine, Thes-
salia University Medical School, Larissa, Greece; 3Department
of Hygiene, Epidemiology & Medical Statistics, Athens Univer-
sity Medical School, Athens, Greece; 4Department of Gastroen-
terology, University of Ankara Medical School, Ankara, Turkey;
5Hospital General Universitario Valle Hebron and Ciberehd,
Barcelona, Spain; 64th Department of Internal Medicine, Αristotle
University of Thessaloniki Medical School, Thessaloniki, Greece;
7Department of Gastroenterology & Hepatology, ErasmusMC,
Rotterdam, Netherlands; 82nd Department of Internal Medicine,
Athens University Medical School, Athens, Greece; 91st Division
of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale
Maggiore Policlinico, Università degli Studi di Milano, Milano,
Italy; 10Liver Clinic, Toronto Western & General Hospital, Univer-
sity Health Network, Toronto, ON, Canada
Background/Aims: We recently reported that HCC risk
scores developed in Asians have poor-moderate predictability
in Caucasian CHB patients for whom we suggested a new
score based on platelets, age and gender (PAGE-B) (Papa-
theodoridis et al, EASL 2014). In this 7-center, large ongoing
cohort study, we evaluated the timing of HCC development
in Caucasian CHB patients receiving ETV/TDF and assessed
the predictability of a modified PAGE-B risk score based on
clinically more reasonable platelet cut-offs. Methods: 1671
adult Caucasians with CHB±compensated cirrhosis and no
HCC at baseline (mean age:53 years, males:71%, naive
to antivirals:61%, cirrhosis:30%) who received ETV/TDF for
≥12 months were included. The cumulative incidence rates
of HCC derived from Kaplan-Meier estimates. PAGE-B score
was tested in our updated derivation dataset (6 centers’ data)
with Harrell’s c-index being used as discrimination measure.
Bootstrap was used for internal as well as external validation
in the data from the 7th largest center. Results: During a mean
follow-up of 50 months, the 1-, 3-, 5-year cumulative HCC
incidence rates were 0.5%, 1.6%, 2.7% for non-cirrhotic and
2.5%, 7.5%, 15.2% for cirrhotic patients (p<0.001). How-
ever, only 1 new HCC case has been diagnosed after year
5 (at 65 months) in 553 patients (31% cirrhotics) who had
been followed for a mean of 12 months beyond year 5. In the
derivation dataset (1,142 patients/45 HCCs), age (p<0.001),
gender (p=0.009) and platelets (p<0.001) were independently
associated with HCC. The modified PAGE-B risk score was con-
structed by applying -4/-2/0/2/4/6 points for age <30/30-
39/40-49/50-59/60-69/≥70 years, 0/5 points for females/
males (the same with the original PAGE-B) and 0/4/5 points
for platelets >150,000/100,000-150,00/<100,000/mm3
(c-index=0.81; 0.80 after bootstrap validation). In the external
validation dataset (484 patients/34 HCCs), the discrimination
was similar (c-index=0.82). There was very good agreement
between the modified and the original PAGE-B score (weighted
kappa for risk estimates comparisons: 0.93). Patients with mod-
ified PAGE-B score <4, 4-7, >7 had 5-year cumulative HCC
incidence rates of 1%, 2%, 16% in derivation and 0%, 2%,
17% in validation dataset. Conclusions: The HCC risk in CHB
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
patients might decrease with continuation of ETV/TDF therapy
beyond 5 years, but more data are required to confirm this
finding. The modified PAGE-B score represents a simple and
reliable predictor of HCC for Caucasian CHB patients under
ETV/TDF.
Disclosures:
George V. Papatheodoridis - Advisory Committees or Review Panels: Merck,
Novartis, Abbvie, Boerhinger, Bristol-Meyer Squibb, Gilead, Roche, Janssen,
GlaxoSmith Kleine; Grant/Research Support: Roche, Gilead, Bristol-Meyer
Squibb, Abbvie, Janssen; Speaking and Teaching: Merck, Bristol-Meyer Squibb,
Gilead, Roche, Janssen, Abbvie
Cihan Yurdaydin - Advisory Committees or Review Panels: Janssen, Roche,
Merck, Gilead, AbbVie; Speaking and Teaching: BMS
Maria Buti - Advisory Committees or Review Panels: Gilead, Janssen, Vertex,
MSD; Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gil-
ead, Janssen, Vertex, Novartis
Ioannis Goulis - Consulting: MSD, Gilead Sciences, Abbvie, Janssen-Cilag, Jans-
sen-Cilag, BMS; Grant/Research Support: BMS, Roche; Speaking and Teaching:
BMS, MSD, Gilead Sciences, Janssen-Cilag
Spilios Manolakopoulos - Advisory Committees or Review Panels: NOVARTIS,
ROCHE, MSD, BMS, GILEAD; Consulting: ROCHE, GILEAD, BMS; Speaking and
Teaching: MSD, GILEAD, BMS
Massimo Colombo - Advisory Committees or Review Panels: BRISTOL-MEY-
ERS-SQUIBB, SCHERING-PLOUGH, ROCHE, GILEAD, BRISTOL-MEYERS-SQUIBB,
SCHERING-PLOUGH, ROCHE, GILEAD, Janssen Cilag, Achillion; Grant/
Research Support: BRISTOL-MEYERS-SQUIBB, ROCHE, GILEAD, BRISTOL-MEY-
ERS-SQUIBB, ROCHE, GILEAD; Speaking and Teaching: Glaxo Smith-Kline,
BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, NOVARTIS, GILEAD,
VERTEX, Glaxo Smith-Kline, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH,
ROCHE, NOVARTIS, GILEAD, VERTEX, Sanofi
Rafael Esteban - Speaking and Teaching: MSD, BMS, Novartis, Gilead, Glaxo,
MSD, BMS, Novartis, Gilead, Glaxo, Janssen
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sci-
ences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support:
Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck,
Medtronic, Novartis, Roche, Santaris
Pietro Lampertico - Advisory Committees or Review Panels: Bayer, Bayer; Speak-
ing and Teaching: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gil-
ead, Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gilead
The following people have nothing to disclose: George N. Dalekos, Vana Sypsa,
Heng Chi, Giampaolo Mangia, Nikolaos Gatselis, Onur Keskin, Savvoula Sav-
vidou, Bettina E. Hansen, Jiannis Vlachogiannakos, Kostas Galanis, Ramazan
Idilman
234
Understanding hepatitis delta virus dynamics and anti-
viral efficacy of the prenylation inhibitor lonafarnib
Laetitia Canini1,Christopher Koh2,
Scott Cotler3,
Cihan Yurday-
din4, Stewart Cooper5, David Cory6, Vanessa Haynes-Williams2,
Mark A. Winters6, Ingrid C. Choong6, Jay H. Hoofnagle2, Jeffrey
Glenn7, Theo Heller2, Harel Dahari1,3; 1Theoretical Biology and
Biophysics, Los Alamos National Laboratory, Los Alamos, NM;
2Liver Diseases Branch, NIDDK, NIH, Bethesda, MD; 3The Program
for Experimental & Theoretical Modeling, Department of Medicine,
Division of Hepatology, Loyola University Medical Center, May-
wood, IL; 4Department of Gastroenterology, Ankara University,
Ankara, Turkey; 5Division of Gastroenterology, California Pacific
Medical Center, San Francisco, CA; 6Eiger Biopharmaceuticals,
San Carlos, CA; 7Division of Gastroenterology and Hepatology,
Stanford School of Medicine, Stanford, CA
Background/Aim: Understanding hepatitis delta virus (HDV)
dynamics is in its infancy due to limited studies with frequent
kinetic data and the availability of only one medication
(pegylated interferon-peg-IFN) with activity against HDV. The
new prenylation inhibitor lonafarnib (LNF) is a potent antiviral
agent that provides a breakthrough for the treatment of HDV
and an opportunity to further characterize HDV dynamics and
the antiviral effect of LNF. Methods: HDV kinetic data were
obtained from a Phase 2a study in which 12 patients were
treated with 100 mg twice daily (n=6; termed group 1) or 200
mg twice daily for 28 days of LNF (termed group 2). Blood
317A
samples were collected frequently during the first 72 hr, and
then weekly until day 28. The estimation of HDV clearance
rate (c) and LNF effectiveness in blocking production (eps), was
performed by a biphasic mathematical model with a lag time
(t0) using a population approach. Results: Baseline HDV RNA
was similar between dosing groups with median 6.0 log10
IU/ml (interquartile range IQR:[0.8]. After a delay of approx-
imately 1 day in which HDV remained at baseline levels, a
biphasic viral decline was observed. The 1st phase lasted for
7 to 21 days with greater (p=0.04) viral decline from baseline
in group 2 (median 0.95 IQR:[0.69] log IU/ml) compared to
group 1 (median 0.57 IQR:[0.49] log IU/ml). Because the
1st phase was long and the 2nd phase could not be ade-
quately characterized, the death/loss rate constant, delta, of
productive HDV-infected cells was set to 0.03/day. Model fits
indicate that t0=0.99 (standard error (se)=0.24 day), with an
HDV half-life (t1/2=LN(2)/c) of 1.4 day (se=0.16). A higher
LNF effectiveness in group 2, eps=0.87 (se=0.08) than in
group 1, eps=0.67 (se=0.07) was found [p=0.06]. Conclu-
sions: The analysis suggests a dose dependent effect of LNF
in blocking HDV release with efficacies of 67% and 87% in
the 100 mg and 200 mg LNF dosing groups, respectively.
The 87% effectiveness of the 200 mg LNF dose is somewhat
lower than previously estimated in patients treated with pegIFN
(eps=96%). A striking shorter delay was observed with LNF
(t0=1.0 day) compared to HDV-infected patients treated with
pegIFN (t0=8.5 day). Frequent measurements under LNF ther-
apy allowed for a refined estimate of HDV t1/2=1.4 day that
was about 2-fold shorter than under pegIFN (t1/2=2.9 day),
may suggest higher HDV production rate than recently esti-
mated (Hepatology 2013;Suppl.58(4):688A). The short t0 and
the refined HDV t1/2 support previous studies that the mech-
anism of action of LNF is blocking HDV assembly/secretion.
Disclosures:
Cihan Yurdaydin - Advisory Committees or Review Panels: Janssen, Roche,
Merck, Gilead, AbbVie; Speaking and Teaching: BMS
David Cory - Management Position: Eiger BioPharmaceuticals
Ingrid C. Choong - Management Position: Eiger BioPharmaceuticals
Jeffrey Glenn - Board Membership: Eiger Biopharmaceuticals; Consulting: Gil-
ead, Romark Laboratories; Grant/Research Support: Roche, Sundise; Stock
Shareholder: Riboscience LLC, Eiger Biopharmaceuticals, Eiger Group Interna-
tional
Harel Dahari - Consulting: Abbive; Speaking and Teaching: Rottapharm|Madaus
The following people have nothing to disclose: Laetitia Canini, Christopher Koh,
Scott Cotler, Stewart Cooper, Vanessa Haynes-Williams, Mark A. Winters, Jay
H. Hoofnagle, Theo Heller
235
Retreatment of Patients Who Failed Prior Sofosbu-
vir-Based Regimens with All Oral Fixed-Dose Combina-
tion Ledipasvir/Sofosbuvir Plus Ribavirin for 12 Weeks
David L. Wyles1, Paul J. Pockros2, Jenny C. Yang3, Yanni Zhu3,
Phillip S. Pang3, John G. McHutchison3, Steven L. Flamm4, Eric
Lawitz5; 1University of California, San Diego, La Jolla, CA;
2Scripps Translational Science Institute, La Jolla, CA; 3Gilead Sci-
ences, Inc, Foster City, CA; 4Northwestern University, Chicago, IL;
5The Texas Liver Institute, San Antonio, TX
Background: The approved treatment for genotype 1 HCV-in-
fected patients is Sovaldi (sofosbuvir, SOF) plus pegylat-
ed-interferon (PEG-IFN) and ribavirin (RBV) for 12 weeks or
Sovaldi plus RBV for 24 weeks in interferon-ineligible patients.
For patients who have failed such SOF-based therapies, we
evaluated the efficacy of 12 weeks of LDV/SOF+RBV. Meth-
ods: Genotype 1 HCV infected patients who participated in
a prior SOF Phase 2/3 study and failed to achieve SVR12,
were enrolled. The primary endpoint was SVR12. Results: 51
318A AASLD ABSTRACTS
patients who previously failed the following regimens: SOF+
PEG-IFN/RBV (n=25); SOF±RBV (n=21); or SOF-placebo+
PEG-IFN/RBV (n=5) were enrolled. The mean age was 54
years, 61% male, 16% African-American, 29% had cirrhosis,
92% IL28B CT/TT genotype, 59% GT1a, and mean HCV RNA
was 6.2 log10 IU/mL. SVR4 was 98% (50/51); the 1 patient
who relapsed had GT3a-infection and was enrolled in error.
Table 1 presents the SVR rates by prior treatment. Frequent
reported AEs (>10%) were fatigue, headache, diarrhea, and
rash. Two patients (4%) had treatment-emergent SAEs, one
patient discontinued treatment due to the SAE of bipolar disor-
der. Hemoglobin <10g/dL occurred in 2 patients (4%). Con-
clusions: Ledipasvir/sofosbuvir plus RBV for 12 week was well
tolerated and effective for retreatment of genotype 1 patients
who previously failed SOF-based regimens. Complete SVR12
rates will be presented.
Table 1. Overall SVR According to Prior Treatment
*1 relapse occurred in GT3a-infected patient
Disclosures:
David L. Wyles - Advisory Committees or Review Panels: Bristol Myers Squibb,
Merck, AbbVie, Janssen, Gilead; Grant/Research Support: Gilead, Merck, Ver-
tex, Pharmassett, AbbVie
Paul J. Pockros - Advisory Committees or Review Panels: Janssen, Merck, Genen-
tech, BMS, Gilead, Boehinger Ingelheim, AbbVioe; Consulting: Genentech,
Lumena, Regulus, Beckman Coulter, RMS; Grant/Research Support: Novartis,
Intercept, Janssen, Genentech, BMS, Gilead, Vertex, Boehinger Ingelheim,
Lumena, Beckman Coulter, AbbVie, RMS, Novartis, Merck; Speaking and Teach-
ing: Genentech, BMS, Gilead
Jenny C. Yang - Employment: Gilead Sciences
Yanni Zhu - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead Sci-
ences, Inc.
Phillip S. Pang - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Steven L. Flamm - Advisory Committees or Review Panels: Gilead, Bristol Myers
Squibb, AbbVie, Janssen, Salix; Consulting: Merck, Janseen, Bristol Myers
Squibb, AbbVie, Salix, Gilead; Grant/Research Support: Janssen, Bristol Myers
Squibb, Merck, Vertex, Gilead, AbbVie, Boehringer Ingelheim; Speaking and
Teaching: Salix
Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharma-
ceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck &
Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals;
Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingel-
heim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharma-
ceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio,
Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teach-
ing: Gilead, Kadmon, Merck, Vertex
HEPATOLOGY, October, 2014
236
Efficacy and safety of MK-5172 + MK-8742 ± riba-
virin in HCV mono-infected and HIV/HCV co-infected
treatment-naïve, non-cirrhotic patients with hepatitis C
virus genotype 1 infection: The C-WORTHY study (Final
results, Parts A and B)
Mark S. Sulkowski1, Christophe Hezode2, Jan Gerstoft3, John M.
Vierling4, Josep Mallolas5, Stanislas Pol6, Marcelo Kugelmas7,
Abel Murillo8, Nina Weis9, Ronald Nahass10, Oren Shibolet11,
Lawrence Serfaty12, Marc Bourlière13, Edwin DeJesus14, Eli.
Zuckerman15, Frank Dutko16, Anita Y. Howe16, Melissa Shaugh-
nessy16, Peggy Hwang16, Janice Wahl16, Michael Robertson16,
Barbara A. Haber16; 1John Hopkins University School of Medicine,
Baltimore, MD; 2Henri Mondor Hospital, University of Paris-Est,
Creteil, France; 3Department of Infectious Diseases, Rigshospitalet,
Copenhagen, Denmark; 4Baylor College of Medicine, Houston,
TX; 5Infectious Diseases Service, Hospital Clinic, Barcelona, Spain;
6University of Paris, Hospital Cochin, APHP and INSERM, Unite
Hepatol, Paris, France; 7South Denver Gastroenterology, Engle-
wood, CO; 8Advanced Medical & Pain Management Reserach
Clinic, Miami, FL; 9Department of Infectious Diseases, Copenha-
gen University Hospital, Hvidovre, Copenhagen, Denmark; 10ID
Care, Hilllsborough, NJ; 11Liver Unit, Department of Gastroenter-
ology, Tel-Aviv Medical Center, Tel-Aviv, Israel; 12Hôpital Saint
Antoine, APHP and INSERM UMR_938, Université Pierre & Marie
Curie, Paris, France; 13Service d’hépato-gastroentérologie, Hôpital
Saint-Joseph, Marseille, France; 14Orlando Immunology Center,
Orlando, FL; 15Liver Unit, Carmel Medical Center, Technion Fac-
ulty of Medicine, Haifa, Israel; 16Merck & Co. Inc., Whitehouse
Station, NJ
Purpose: Assess the efficacy, safety and durability of response
of MK-5172 (HCV NS3/4A protease inhibitor) and MK-8742
(HCV NS5A replication complex inhibitor) ± ribavirin (RBV)
in treatment-naive (TN), non-cirrhotic genotype (GT) 1 HCV
mono-infected and HIV/HCV co-infected patients (pts). Meth-
ods:C-WORTHY enrolled 159 mono-infected and 59 co-in-
fected pts. Mono-infected pts received 8 or 12 weeks of
MK-5172 (100 mg QD) + MK-8742 (20 or 50 mg QD) ±
RBV. Co-infected pts received 12 weeks ± RBV; all were on sta-
ble anti-retroviral regimens (raltegravir + tenofovir or abacavir
with 3TC or FTC). Primary endpoint was the proportion of pts
achieving HCV RNA<25 IU/mL assessed by COBAS TaqMan
v2.0 12 weeks after end of treatment (SVR12). In this ongoing
study, all pts will have 24 weeks of follow-up by November,
2014. Results: SVR12 rates by treatment arm are in the table.
SVR12 for mono- and co-infected pts treated for 12 weeks ±
RBV were 95% (123/129) and 93% (50/54), respectively.
Among mono-infected pts with GT1a infection treated with 8
or 12 weeks of MK-5172 + MK-8742 + RBV, the SVR12 rates
were 80% (24/30) or 94% (49/52), respectively, and 96%
(23/24) for co-infected pts treated for 12 weeks. Overall, the
12 week regimens of MK-5172 + MK-8742 ± RBV provided a
high antiviral response rate (SVR12=95% [173/183]) with a
low rate of virologic failure (3.3% [6/183]). All 5/5 pts who
discontinued early had HCV RNA <25 IU/mL at last visit on
record. Resistance-associated variants were analyzed in all
virologic failures. The safety profile of MK-5172 + MK-8742
±RBV was similar in mono- and co-infected pts. No patient
discontinued due to an adverse event (AE) or laboratory abnor-
mality. The most common AEs were fatigue, headache, nau-
sea, insomnia and asthenia. Co-infected pts maintained HIV
suppression during therapy except for 1 who discontinued HIV
medications. Conclusion: Once daily MK-5172 + MK-8742 ±
RBV for 12 weeks in TN, non-cirrhotic mono- and coinfected
pts achieved SVR12 rates of 89-98%. These results support the
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
ongoing Phase 3 development of MK-5172 + MK-8742 ± RBV
for 12 weeks.
*Proportion of pts with HCV RNA<25 IU/mL
†Some patients have not yet reached the SVR12 time point
‡Patient with HCV GT2 infection at time of breakthrough
Disclosures:
Mark S. Sulkowski - Advisory Committees or Review Panels: Merck, AbbVie,
Idenix, Janssen, Gilead, BMS, Pfizer; Grant/Research Support: Merck, AbbVie,
BIPI, Vertex, Janssen, Gilead, BMS
Christophe Hezode - Speaking and Teaching: Roche, BMS, MSD, Janssen, abb-
vie, Gilead
John M. Vierling - Advisory Committees or Review Panels: Abbvie, Bristol-Mey-
ers-Squibb, Gilead, Hyperion, Intercept, Janssen, Novartis, Merck, Sundise,
HepQuant, Salix; Grant/Research Support: Abbvie, Bristol-Meyers-Squibb,
Eisai, Gilead, Hyperion, Intercept, Janssen, Novartis, Merck, Sundise, Ocera,
Mochida; Speaking and Teaching: GALA, Chronic Liver Disease Foundation,
ViralEd
Josep Mallolas - Board Membership: Boehringer, Merck
Stanislas Pol - Board Membership: Sanofi, Bristol-Myers-Squibb, Boehringer Ingel-
heim, Tibotec Janssen Cilag, Gilead, Glaxo Smith Kline, Roche, MSD, Novartis;
Grant/Research Support: Glaxo Smith Kline, Gilead, Roche, MSD; Speaking and
Teaching: Sanofi, Bristol-Myers-Squibb, Boehringer Ingelheim, Tibotec Janssen
Cilag, Gilead, Glaxo Smith Kline, Roche, MSD, Novartis
Marcelo Kugelmas - Advisory Committees or Review Panels: Merck, Vertex,
Genentech; Consulting: Vertex, Merck, Gilead; Grant/Research Support: Vertex,
Bristol Myers Squibb, Boehringer-Ingelheim, Gilead, Janssen, Roche, Anadys,
Merck; Speaking and Teaching: Vertex, Gilead, Merck, Genentech
Nina Weis - Advisory Committees or Review Panels: Bristol-Myers Squibb, Glaxo
Smith Kline, Gilead, Janssen, Merck Sharp Dohme; Grant/Research Support:
The Dansih Council for Independent Research; Medical Sciences; Speaking and
Teaching: Janssen
Ronald Nahass - Advisory Committees or Review Panels: Gilead, MErck, Janssen,
BMS; Grant/Research Support: Gilead, Merck, Janssen, BMS; Speaking and
Teaching: Gilead, Merck, Janssen
Oren Shibolet - Advisory Committees or Review Panels: MSD, Abbvie, Novartis;
Grant/Research Support: MSD
Lawrence Serfaty - Advisory Committees or Review Panels: MSD, Janssen, Roche,
Gilead, BMS, Abbvie; Speaking and Teaching: Aptalis
Marc Bourlière - Advisory Committees or Review Panels: Schering-Plough,
Bohringer inghelmein, Schering-Plough, Bohringer inghelmein; Board Member-
ship: Bristol-Myers Squibb, Gilead, Idenix; Consulting: Roche, Novartis, Tibotec,
Abott, glaxo smith kline, Merck, Bristol-Myers Squibb, Novartis, Tibotec, Abott,
glaxo smith kline; Speaking and Teaching: Gilead, Roche, Merck, Bristol-Myers
Squibb
Edwin DeJesus - Consulting: Gilead, Janssen; Grant/Research Support: Abbott
Laboratories, Achillion, Avexa, Boehringer Ingelheim, Bristol Myers Squibb, Gil-
ead Sciences, GlaxoSmithKline, Hoffman LaRoche Laboratories, Merck, Pfizer,
Taimed, Tobira, Tibotec, Janssen; Speaking and Teaching: Gilead, Janssen
Frank Dutko - Employment: Merck & Co., Inc.; Stock Shareholder: Merck & Co.,
Inc.
Anita Y. Howe - Employment: Merck Research Laboratory
Peggy Hwang - Employment: Merck, Merck
Janice Wahl - Employment: Merck & Co,
Michael Robertson - Employment: Merck; Stock Shareholder: Merck
Barbara A. Haber - Employment: Merck
The following people have nothing to disclose: Jan Gerstoft, Abel Murillo, Eli.
Zuckerman, Melissa Shaughnessy
319A
237
Safety and Efficacy of Ledipasvir/Sofosbuvir Single-Tab-
let-Regimen in African Americans with Genotype 1
Chronic Hepatitis C Virus: A Retrospective Analysis of
Phase 3 Studies
Lennox J. Jeffers1, Julius M. Wilder2, Andrew J. Muir2, Charles
Howell3, Yanni Zhu4, Star Seyedkazemi4, Jenny C. Yang4, Phillip
S. Pang4, John G. McHutchison4, K. Rajender Reddy5; 1Miami
VA Medical Center, Miami, FL; 2Duke Clinical Research Institute,
Durham, NC; 3Howard University, Washington, DC; 4Gilead Sci-
ences, Inc., Foster City, CA; 5University of Pennsylvania School of
Medicine, Philadelphia, PA
Background: SVR rates among African Americans with gen-
otype 1 (GT 1) chronic hepatitis C virus (HCV) have histori-
cally been lower than other races or ethnicities. In the phase
3 ION program, the single-tablet-regimen (STR) of Ledipasvir
(LDV), an NS5A inhibitor, and sofosbuvir (SOF), an NS5B
nucleotide polymerase inhibitor, was shown to be safe and
effective (SVR12>90%) in treatment-naïve and –experienced
subjects. The aim of this analysis is to retrospectively evaluate
the safety and efficacy of LDV/SOF STR in African Americans.
Methods: Three open-label phase 3 clinical trials evaluated the
safety and efficacy of 8, 12 and 24 weeks of LDV/SOF with
or without ribavirin (RBV) for treatment of GT 1 chronic HCV.
There was no upper limit to age or body mass index (BMI). The
primary endpoint was SVR at 12 weeks after the end of ther-
apy (SVR12). SVR12, treatment-emergent adverse events, and
graded laboratory abnormalities were analyzed in Black vs.
non-Black subjects. Results: Of the 1952 patients randomized
and treated in these three phase 3 studies, 308 (16%) were
Black, 224 (12%) had compensated cirrhosis, 591 (26%) had
a BMI ≥ 30 kg/m2, 1597 (82%) had a high HCV viral load ≥
800,000 IU/mL, and 440 (23%) were treatment-experienced.
Black subjects were older, had higher BMIs, and were more
likely to be IL28B non-CC and to have lower ALT at baseline.
Overall, 95% of Black and 97% of non-Black patients achieved
SVR12. The intent-to-treat SVR12 rates in all treatment arms
are shown in Figure 1. The most common adverse events (AEs)
included fatigue, headache, nausea, and insomnia. The major-
ity of AEs occurred more frequently in the RBV-containing arms
of the studies. No differences were observed in overall safety
by race. Conclusions: Over 300 subjects who self-identified as
Black were included in the phase 3 ION program. LDV/SOF
STR, given once-daily, was highly effective in Black and non-
Black patients with GT 1 HCV infection, including those with
compensated cirrhosis and those who had previously failed
triple therapy with an HCV protease inhibitor + PegIFN + RBV.
Addition of RBV did not increase SVR rates but led to higher
rates of AEs. Efficacy and safety were similar in Black and non-
Black patients.
Figure 1
Disclosures:
Andrew J. Muir - Advisory Committees or Review Panels: Merck, Vertex, Gilead,
BMS, Abbvie, Achillion; Consulting: Profectus, GSK; Grant/Research Support:
Merck, Vertex, Roche, BMS, Gilead, Achillion, Abbvie, Pfizer, Salix, GSK, Inter-
cept, Lumena
320A AASLD ABSTRACTS
Charles Howell - Advisory Committees or Review Panels: Janssen, Inc,, Abb-
Vie; Grant/Research Support: Gilead Sciences, Bristol Myer Squibb, Boehringer
Ingelheim
Yanni Zhu - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead Sci-
ences, Inc.
Star Seyedkazemi - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gil-
ead Sciences, Inc.
Jenny C. Yang - Employment: Gilead Sciences, Inc
Phillip S. Pang - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
K. Rajender Reddy - Advisory Committees or Review Panels: Genentech-Roche,
Merck, Janssen, Vertex, Gilead, BMS, Novartis, Abbvie; Grant/Research Sup-
port: Merck, BMS, Ikaria, Gilead, Janssen, AbbVie
The following people have nothing to disclose: Lennox J. Jeffers, Julius M. Wilder
238
The Pharmacokinetics and Safety of the Direct Acting
Antiviral Regimen of ABT-450/r, Ombitasvir with/
without Dasabuvir in Subjects with Mild, Moderate and
Severe Renal Impairment Compared to Subjects with
Normal Renal Function
Amit Khatri1, Sandeep Dutta1, Thomas C. Marbury2, Richard A.
Preston3, Lino Rodrigues-Jr1, Haoyu Wang1, Walid Awni1, Rajeev
Menon1; 1AbbVie, Inc, North Chicago, IL; 2Orlando Clinical
Research Center, Orlando, FL; 3Clinical Pharmacology Research
Unit, Division of Clinical Pharmacology, Department of Medicine,
Miller School of Medicine, University of Miami, Miami, FL
Background: The 3 direct acting antiviral (DAA) regimen (3D)
of coformulated ABT-450/r (protease inhibitor identified by
AbbVie and Enanta dosed with ritonavir (RTV)) with ombitasvir
(NS5A inhibitor) plus dasabuvir (polymerase inhibitor) ± riba-
virin has completed Phase 3 clinical trials in HCV genotype 1
infected subjects. This study evaluated the pharmacokinetic (PK)
and safety profiles of the single dose of 3D regimen and the
2D regimen (ABT-450/r + ombitasvir) in subjects with various
degrees of renal impairment characterized using estimated cre-
atinine clearance (CLcr) by Cockroft-Gault equation. Methods:
This Phase 1, 2-period, open-label, non-fasting study enrolled
subjects not infected with HIV or HCV into 4 groups: normal
(NORM, CLcr: >90 mL/min), mild (MiRI, CLcr: 60 – 89 mL/
min), moderate (MoRI, CLcr: 30 – 59 mL/min) and severe
(SeRI, CLcr: 15 – 29 mL/min) renal impairment. Subjects with
SeRI were matched with NORM subjects based on age (±10
years), weight (±10 %), sex, tobacco use and ethnicity/race.
All subjects received single doses of the 3D regimen in Period
1 and the 2D regimen in Period 2 after a washout of 14 days.
Doses of ABT-450/r, ombitasvir and dasabuvir were 150/100
mg, 25 mg and 400 mg, respectively. Intensive PK assess-
ment was performed. Regression analyses were performed to
assess the effect of renal impairment on PK. Safety was eval-
uated through assessment of adverse events, vital signs, ECG
and clinical laboratory tests. Results: The slope parameters in
the regression analyses of AUC (area under the concentra-
tion-time curve from time 0 to infinity) versus CLcr were not
statistically significant for DAAs. The AUC of ombitasvir, ABT-
450, dasabuvir and RTV were less than 2%, 45%, 50% and
114% higher in subjects with renal impairment compared to
NORM subjects following administration of 3D and 2D regi-
mens. These changes in AUC of DAAs are not considered clin-
ically important. The t1/2 of the DAAs and RTV were similar
among subjects with renal impairment and healthy subjects.
Unchanged drug (%) excreted in urine was very low (≤ 1.56%)
for all drugs in all groups and not clinically relevant. The safety
of the DAA regimens was similar in NORM subjects and those
with renal impairment. Conclusions: No dose adjustment for
HEPATOLOGY, October, 2014
ABT-450, ritonavir, ombitasvir and dasabuvir are necessary in
subjects with mild, moderate or severe renal impairment.
Disclosures:
Amit Khatri - Employment: AbbVie, Inc; Patent Held/Filed: AbbVie, Inc; Stock
Shareholder: AbbVie, Inc
Sandeep Dutta - Employment: AbbVie; Stock Shareholder: AbbVie
Thomas C. Marbury - Employment: Orlando Clinical Research Center
Richard A. Preston - Grant/Research Support: Abbvie, Celerion, Chiasma, Cel-
gene, Conatus, Forest, Pfizer, Parexel, PPD, Takeda, Novartis, Exelixis, Idenix,
PPD, Akros, ApoPharma, Merck, Fujifilm, Reata, Watson
Lino Rodrigues-Jr - Employment: Abbvie
Haoyu Wang - Employment: AbbVie; Stock Shareholder: AbbVie
Walid Awni - Employment: AbbVie
Rajeev Menon - Employment: AbbVie; Stock Shareholder: AbbVie
239
Ledipasvir/Sofosbuvir with Ribavirin for the Treatment
of HCV in Patients with Decompensated Cirrhosis: Pre-
liminary Results of a Prospective, Multicenter Study
Steven L. Flamm1, Gregory T. Everson2, Michael Charlton3, Jill M.
Denning4, Sarah Arterburn4, Theo Brandt-Sarif4, Phillip S. Pang4,
John G. McHutchison4, K. Rajender Reddy5, Nezam H. Afdhal6;
1Northwestern Feinberg School of Medicine, Chicago, IL; 2Uni-
versity of Colorado Denver, Aurora, CO; 3Intermountain Medical
Center, Murray, UT; 4Gilead Sciences, Raleigh, NC; 5University
of Pennsylvania School of Medicine, Philadelphia, PA; 6Beth Israel
Deaconess Medical Center, Boston, MA
Background: In subjects with decompensated cirrhosis due to
HCV, therapeutic options are limited due to lack of efficacy and
the potential for more severe adverse events. We evaluated the
safety and efficacy of ledipasvir/sofosbuvir (LDV/SOF) with
ribavirin in this population. Methods: GT 1 and 4, naïve and
treatment-experienced patients with HCV infection, with CPT B
(N=55) or CPT C (N=53) clinically decompensated cirrhosis,
received 12 or 24 weeks of LDV/SOF with RBV (escalating
doses starting at 600 mg/day). Patients were ≥18 years of age
and had not undergone liver transplantation. The protocol-de-
fined efficacy endpoints were SVR (HCV RNA <15 IU/mL) 12
weeks after completion of treatment, safety, and tolerability.
Results: To date, 108 patients have been randomized and
treated. Most were male (67%), Caucasian (93%), and had
prior HCV treatment (65%). Mean baseline HCV RNA was 5.8
log10 IU/mL [range 3.2-7.1 log10 IU/mL]. 28 patients (26%)
had a MELD score > 15. Three patients discontinued study
treatment in the CPT class B group (2 underwent liver transplan-
tation and 1 subject died) and 7 patients discontinued study
treatment in the CPT class C group (2 underwent liver transplan-
tation, 3 discontinued due to adverse events and 2 died). 28
patients (26%) experienced treatment-emergent serious adverse
events (SAEs). Four SAEs in 4 patients (4%) were considered
related to study treatment; anemia, hepatic encephalopathy,
peritoneal hemorrhage, and an hemoglobin decreased. The
most common adverse events were fatigue, nausea and head-
ache, the same adverse events most frequently observed in sub-
jects with compensated cirrhosis. On-treatment Week 4 HCV
RNA < LLOQ and SVR4 by CPT B and C score are presented
in Table 1. Conclusions: Administration of LDV/SOF+RBV in
patients with decompensated cirrhosis has been well tolerated
and resulted in high SVR4 rates in this very difficult to treat
population. SVR 12 results will be presented.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS 321A

Table 1. Interim Observed On-treatment Week 4 HCV RNA < correlates were performed. Results: Of the patients enrolled,
LLOQ and SVR4 Results 40% were treatment experienced, and 40% had advanced
fibrosis. 35% of patients were of Egyptian origin and 35%
were of African origin. For this interim analysis, 17 patients
were evaluable for response at week 4, 13 patients for end of
treatment response, 6 patients for sustained virologic response
(SVR) at week 4 post-treatment (SVR4), and 4 patients for
SVR12. One patient was identified as non-compliant at week
4 and dropped out of the study but is included in the intention
Disclosures:
to treat analysis. All other patients achieved complete viral
Steven L. Flamm - Advisory Committees or Review Panels: Gilead, Bristol Myers
suppression on therapy and at follow up time points (Figure 1).
Squibb, AbbVie, Janssen, Salix; Consulting: Merck, Janseen, Bristol Myers Final SVR12 results will be presented. No grade 3/4 adverse
Squibb, AbbVie, Salix, Gilead; Grant/Research Support: Janssen, Bristol Myers events related to study drug were noted. Conclusions: Sofosbu-
Squibb, Merck, Vertex, Gilead, AbbVie, Boehringer Ingelheim; Speaking and vir and ledipasvir for 12 weeks in HCV GT4 patients were well
Teaching: Salix
tolerated and resulted in high viral suppression rates regardless
Gregory T. Everson - Advisory Committees or Review Panels: Roche/Genen-
tech, Abbvie, Galectin, Boehringer-Ingelheim, Eisai, Bristol-Myers Squibb, HepC of previous treatment status and underlying liver fibrosis. This
Connection, BioTest, Gilead, Merck; Board Membership: HepQuant LLC, PSC is the first report of an interferon and ribavirin free therapy
Partners, HepQuant LLC; Consulting: Abbvie, BMS, Gilead, Bristol-Myers Squibb; for patients with HCV GT4. Interim data suggests that this sin-
Grant/Research Support: Roche/Genentech, Pharmassett, Vertex, Abbvie, Bris-
tol-Myers Squibb, Merck, Eisai, Conatus, PSC Partners, Vertex, Tibotec, GlobeIm- gle-pill combination therapy may be an effective regimen for
mune, Pfizer, Gilead, Conatus, Zymogenetics; Management Position: HepQuant this patient population.
LLC, HepQuant LLC; Patent Held/Filed: Univ of Colorado; Speaking and Teach-
ing: Abbvie, Gilead Figure-1
Jill M. Denning - Employment: Gilead Sciences, Inc.
Sarah Arterburn - Employment: Gilead Sciences Inc.; Stock Shareholder: Gilead
Sciences Inc.
Phillip S. Pang - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
K. Rajender Reddy - Advisory Committees or Review Panels: Genentech-Roche,
Merck, Janssen, Vertex, Gilead, BMS, Novartis, Abbvie; Grant/Research Sup-
port: Merck, BMS, Ikaria, Gilead, Janssen, AbbVie
Nezam H. Afdhal - Consulting: Merck, Vertex, Idenix, GlaxoSmithKline, Spring-
bank, Gilead, Pharmasett, Abbott; Grant/Research Support: Merck, Vertex, Ide-
nix, GlaxoSmithKline, Springbank, Gilead, Pharmasett, Abbott
The following people have nothing to disclose: Michael Charlton, Theo Brandt-Sa-
rif

240
All Oral Treatment for Genotype 4 Chronic Hepatitis C
Infection with Sofosbuvir and Ledipasvir: Interim Results
from the NIAID SYNERGY Trial
Rama Kapoor1, Anita Kohli1, Sreetha Sidharthan2, Zayani Sims2,
Tess L. Petersen2, Anu Osinusi3, Amy K. Nelson3, Rachel Silk1, Col-
leen Kotb1, Kate Sugarman4, Brian P. Lam5, Phillip S. Pang6, Mani
Subramanian6, John G. McHutchison6, Henry Masur2, Shyam Kot-
tilil3, Vinod K. Rustgi7; 1Leidos Biomedical Research, Inc. (formerly
SAIC–Frederick, Inc.), Frederick National Laboratory for Cancer
Research, Frederick, MD; 2Critical Care Medicine Department,
National Institutes of Health Clinical Center, National Institutes of
Health, Bethesda, MD; 3Laboratory of Immunoregulation, National
Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD; 4Unity Health Care, Inc., Washington, DC;
5Center for Liver Diseases, Inova Fairfax Medical Campus, Falls
Disclosures:
Brian P. Lam - Advisory Committees or Review Panels: BMS; Speaking and Teach-
ing: Gilead; Stock Shareholder: Gilead
Phillip S. Pang - Employment: Gilead Sciences
Mani Subramanian - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Vinod K. Rustgi - Grant/Research Support: Abbvie, BMS, Gilead, Achillion
The following people have nothing to disclose: Rama Kapoor, Anita Kohli, Sree-
tha Sidharthan, Zayani Sims, Tess L. Petersen, Anu Osinusi, Amy K. Nelson,
Rachel Silk, Colleen Kotb, Kate Sugarman, Henry Masur, Shyam Kottilil

Church, VA; 6Gilead Sciences Inc., Foster City, CA; 7University of

Pittsburgh Medical Center, Pittsburgh, PA
Background: Chronic hepatitis C (HCV) Genotype 4 (GT4)
is the most common subtype in the Middle East and Africa.
In HCV GT-1 patients, use of directly acting antivirals have
shown high cure rates with excellent tolerability, but this has
not been reported in HCV GT4. We evaluated the safety, effi-
cacy, and tolerability of 12 weeks combination therapy with
sofosbuvir and ledipasvir in treatment naïve and experienced
patients infected with HCV GT4. Methods: Twenty patients
with GT4 HCV mono-infection were enrolled in a single center,
open-label, phase 2a trial, to receive sofosbuvir (400 mg) and
ledipasvir (90 mg) given as one tablet once daily for 12 weeks.
Serial measurements of safety parameters, virologic and host
322A AASLD ABSTRACTS
241
Reversal of Hepatorenal Syndrome Type 1 (HRS-1) with
Terlipressin plus Albumin versus Placebo plus Albumin
- Not All Responses Are Created Equal - An Analysis of
the REVERSE and OT-0401 Trials
Arun J. Sanyal1, Thomas D. Boyer2, R Todd Frederick3, Fredric
Regenstein4, Lorenzo Rossaro5, Victor Araya6, Hugo E. Vargas7,
K. Rajender Reddy8, Khurram Jamil9, Stephen Chris Pappas10;
1Virginia Commonwealth University, Richmond, VA; 2University
of Arizona, Tucson, AZ; 3California Pacific Medical Center, San
Francisco, CA; 4St. Luke’s Hospital, Kansas City, MO; 5University
of California, Davis Medical Center, Sacramento, CA; 6Albert
Einstein Medical Center, Philadelphia, PA; 7Mayo Clinic, Scotts-
dale, AZ; 8University of Pennsylvania, Philadelphia, PA; 9Ikaria,
Hampton, NJ; 10Orphan Therapeutics, Lebanon, NJ
Background and Aims: Renal function affects outcomes in
patients with HRS-1. Terlipressin plus albumin has been shown
to improve renal function in HRS-1 to a greater degree than
placebo plus albumin. However, it is unclear whether out-
comes following reversal of HRS-1 are the same when reversal
is achieved by terlipressin plus albumin vs. albumin alone. The
aim of this study was to review data from two pivotal, Phase
3 trials in HRS-1 and evaluate outcomes of those patients who
achieved reversal of HRS-1. Methods: Serum creatinine (SCr),
renal replacement therapy (RRT), and survival data from the
REVERSE and OT-0401 trials, both randomized, placebo-con-
trolled trials of terlipressin and albumin versus placebo plus
albumin with similar designs and patients enrolled, were pooled
to analyze: incidence of confirmed HRS reversal (CHRSR), use
of RRT, overall survival, and survival at Day 90 without RRT.
CHRSR was defined as 2 SCr values ≤1.5 mg/dL, at least
48 hours apart, on treatment, without RRT or liver transplant.
Results: Data from 308 patients were analyzed; 153 were ran-
domized to terlipressin, 155 to placebo. Baseline characteris-
tics were similar across the two studies and between treatment
groups. CHRSR was achieved in 37/153 patients (24.2%)
in the terlipressin group vs. 20/155 patients (12.9%) in the
placebo group (p = 0.0108). Survival was significantly higher
in patients with CHRSR vs. those without CHRSR (p<0.0001).
Patients with CHRSR received RRT significantly less often com-
pared to patients without CHRSR (4/57 (7%) vs. 109/251
(43%), p<0.0001). While Day 90 survival in patients with
CHRSR was similar, 27/37 (73%) in the terlipressin group
who achieved CHRSR were alive without RRT at Day 90 vs.
9/20 (45%) in the placebo group (p<0.05). No patient with
CHRSR in the terlipressin group received RRT; 4/16 (25%) of
patients with CHRSR in the placebo group received RRT. Sum-
mary: Pooled data from two large trials show that terlipressin
plus albumin treatment was associated with an increased fre-
quency of CHRSR compared to placebo and albumin. Survival
in patients with CHRSR was significantly higher, and use of RRT
significantly lower, than in patients without CHRSR. There were
significantly more patients in the terlipressin group with CHRSR
alive at Day 90 without RRT compared to placebo. Conclusion:
Reversal of HRS-1 occurs following treatment with terlipressin
plus albumin more frequently than with placebo plus albumin.
Achieving CHRSR reduces the need for RRT and improves sur-
vival. Furthermore, patients treated with terlipressin and albu-
min who achieve CHRSR have a better outcome at Day 90
compared to patients achieving CHRSR with albumin alone.
Disclosures:
Arun J. Sanyal - Advisory Committees or Review Panels: Bristol Myers, Gilead,
Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Nimbus, Genentech, Echo-
sens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept,
Ikaria, Takeda, GalMed, Novartis, Gilead; Independent Contractor: UpToDate,
Elsevier
HEPATOLOGY, October, 2014
Thomas D. Boyer - Consulting: Ikaria; Grant/Research Support: Abbvie, Gilead,
Merck
R Todd Frederick - Advisory Committees or Review Panels: Vital Therapies; Con-
sulting: Salix, Gilead, Ocera, Hyperion
Fredric Regenstein - Advisory Committees or Review Panels: Gilead, Janssen;
Grant/Research Support: Bristol-Myers Squibb, Roche/Genentech, Janssen,
Ikaria, Merck; Speaking and Teaching: Salix, Gilead; Stock Shareholder: John-
son & Johnson
Lorenzo Rossaro - Consulting: Merck, Genentec; Grant/Research Support: Gil-
ead, Novartis, Vertex, BMS, AbbVie, Jannsen; Speaking and Teaching: Salix,
Onix/Bayer
Victor Araya - Advisory Committees or Review Panels: Gilead, AbbVie; Grant/
Research Support: Vertex, Abbvie, Merck, Orphan Therapeautics, Johnson &
Johnson, Bristol Myers Squibb; Speaking and Teaching: AbbVie, Gilead, Bristol
Myers Squib, Onyx
Hugo E. Vargas - Advisory Committees or Review Panels: Eisai; Grant/Research
Support: Merck, Gilead, Idenix, Novartis, Vertex, Janssen, Bristol Myers, Ikaria,
AbbVie
K. Rajender Reddy - Advisory Committees or Review Panels: Genentech-Roche,
Merck, Janssen, Vertex, Gilead, BMS, Novartis, Abbvie; Grant/Research Sup-
port: Merck, BMS, Ikaria, Gilead, Janssen, AbbVie
Khurram Jamil - Employment: IKARIA; Stock Shareholder: IKARIA
Stephen Chris Pappas - Consulting: Orphan Therapeutics, Abbvie
242
New Multivariate Models to Predict Glomerular Filtra-
tion Rate in Patients with Cirrhosis
Ayse L. Mindikoglu1, Thomas C. Dowling4, Laurence S. Magder3,
Robert H. Christenson5, Matthew R. Weir2, Stephen L. Seliger2,
William R. Hutson1, Charles Howell6; 1Department of Medicine,
Division of Gastroenterology and Hepatology, University of Mary-
land School of Medicine, Baltimore, MD; 2Department of Medi-
cine, Division of Nephrology, University of Maryland School of
Medicine, Baltimore, MD; 3Department of Epidemiology and Pub-
lic Health, Division of Biostatistics and Bioinformatics, University
of Maryland School of Medicine, Baltimore, MD; 4University of
Maryland School of Pharmacy, Baltimore, MD; 5Department of
Pathology, University of Maryland School of Medicine, Baltimore,
MD; 6Department of Medicine, Howard University College of Med-
icine, Washington, DC
Background: It is well established that conventional glomerular
filtration rate (GFR) equations underestimate the extent of kid-
ney dysfunction in patients with cirrhosis. The objective of our
study was to assess the performance of novel GFR-estimating
equations in subjects with cirrhosis. Methods: Between 2010
and 2014, we measured GFR in 91 subjects with cirrhosis
by iothalamate plasma clearance simultaneously with serum
Cr, cystatin C, beta-trace protein, and beta-2 microglobu-
lin. Multivariate linear regression analysis was performed to
develop GFR-estimating models. Performance of the novel pre-
diction models, CrCl, estimated CrCl (eCrCl), and conventional
GFR-estimating equations was quantified as the percentage
of GFR estimates that differed by greater than 30% (1-P30) or
20% of measured GFR (mGFR) (1-P20) or the root mean square
error (RMSE). Results: Among 91 subjects with cirrhosis, female
gender was an independent predictor of serum Cr (β=-0.19,
P=0.0003) controlling for age and mGFR, but gender did not
predict cystatin C (β=-0.04, P=0.553), beta-trace protein (β=-
0.10, P=0.173) and beta-2 microglobulin (β=-0.30, P=0.344)
levels. Models that included Cr, cystatin C, age and gender
(Model 1) and Cr, cystatin C, beta-2 microglobulin, age and
gender (Model 2) resulted in the best fit to predict mGFR.
Among 59 subjects with cirrhosis and ascites, the accuracy
of Models 1 and 2 was significantly superior to conventional
GFR-estimating equations (Table 1). Conclusions: Alternative
renal function biomarkers, cystatin C, beta-2 microglobulin and
beta-trace protein were not dependent on gender in patients
with cirrhosis; whereas gender influenced serum Cr indepen-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
dent of mGFR. Models developed from subjects with cirrhosis
that included serum Cr, cystatin C and beta-2 microglobulin
were more accurate predictors of mGFR than CrCl, eCrCl and
conventional GFR equations among patients with ascites.
Disclosures:
Ayse L. Mindikoglu - Grant/Research Support: NIH/NIDD K5 K23 DK089008-
04, Living Legacy Foundation of Maryland
Charles Howell - Advisory Committees or Review Panels: Janssen, Inc,, Abb-
Vie; Grant/Research Support: Gilead Sciences, Bristol Myer Squibb, Boehringer
Ingelheim
The following people have nothing to disclose: Thomas C. Dowling, Laurence S.
Magder, Robert H. Christenson, Matthew R. Weir, Stephen L. Seliger, William
R. Hutson
243
No evidence of reduced mortality due to albumin
substitution in HCC-free cirrhotic patients undergoing
large volume paracentesis: a systematic review and
meta-analysis
Fabian Kütting1, Jens Schubert1, Jeremy Franklin2, Agnes Pelc1,
Andrea Bowe1, Vera Hoffmann1, Münevver Demir1, Dirk Nier-
hoff1, Ulrich Toex1, Hans-Michael Steffen1; 1Department of Gas-
troenterology and Hepatology, University Hospital of Cologne,
Cologne, Germany; 2Institute of Medical Statistics, Informatics and
Epidemiology, University of Cologne, Cologne, Germany
Objectives: Cirrhosis of the liver is a disease that occurs world-
wide. Current guidelines for clinical practice recommend the
infusion of human albumin after large volume paracentesis.
After inspecting the actual evidence behind this recommenda-
tion, we decided to conduct a systematic review and meta-anal-
ysis to address whether or not, albumin infusion has an effect
on mortality and morbidity in the context of large volume para-
centesis. Methods: We performed a comprehensive search of
large databases and abstract books of conference proceed-
ings up to Dec. 31st 2013. We were finally able to include
21 randomized controlled trials, testing the infusion of human
albumin against alternatives (vs. no treatment, vs. plasma
expanders; vs. vasoconstrictors) in HCC-free patients suffer-
ing from cirrhosis, totaling 1108 patients. We then analyzed
them with regard to mortality, changes in plasma renin activity
(PRA), hyponatremia, renal impairment, recurrence of ascites
with consequential re-admission into hospital and “additional
complications” (bleeding from esophageal varices, infections,
sepsis and multiple-organ dysfunction-syndrome). Additionally,
we employed trial sequential analysis in order to calculate the
number of patients required in controlled trials in order to be
able to determine a statistically significant advantage of the
administration of one agent over another with regard to mor-
tality. Results: While the administration of albumin effectively
prevents a rise in PRA as well as hyponatremia, strong clinical
endpoints, especially mortality are not significantly improved.
323A
Trial sequential analysis showed that at least 1337 additional
patients need to be recruited into RCTs and analyzed with
regard to this question in order to detect or disprove a 25%
mortality effect. Conclusions: There is no evidence that the infu-
sion of albumin after large-volume paracentesis significantly
lowers mortality in HCC-free patients with advanced liver dis-
ease.
Number of trials that registered events for each endpoint out of
the 22 total trials included, patients with HCC included in analy-
sis as indicated
Disclosures:
The following people have nothing to disclose: Fabian Kütting, Jens Schubert,
Jeremy Franklin, Agnes Pelc, Andrea Bowe, Vera Hoffmann, Münevver Demir,
Dirk Nierhoff, Ulrich Toex, Hans-Michael Steffen
244
Serum creatinine within 48 hours after hospitalization
is a strong predictor of mortality in patients with cirrho-
sis with complications provided the peak creatinine is
above 1.2 mg/dl
Anantha Nuthalapati3, Nicholas Schluterman2, Deborah Green-
berg2, Anuj Khanna3, Paul J. Thuluvath1; 1Medicine, Mercy
Medical Center & University of Maryland School of Mediicine,
Baltimore, MD; 2Epidemiology & Public Health, University of Mary-
land School of Medicine, Baltimore, MD; 3Medicine, Mercy Medi-
cal Center, Baltimore, MD
Recently, it has been suggested that acute kidney injury (AKI)
is an independent predictor of mortality in patients with cir-
rhosis. In this study, we examined the impact of AKI in 636
consecutive admissions in 339 patients who were admitted
to the hospital (Jan 2009-Dec 2013) for a complication(s) of
cirrhosis (patients admitted for elective procedures or surgery
excluded). Methods: The data from Jan 2013 to Dec 2013
were prospectively entered and the rest were entered retro-
spectively using electronic medical records. Serum creatinine
levels were recorded at baseline, defined as the average of all
creatinine measurements within 90 days prior to admission, on
admission, peak within 48 hours, peak during admission and
at discharge. Mortality data after discharge from the hospital
were obtained from social security database. Data were ana-
lyzed for in-hospital, 30-day, 90-day and overall mortality. The
Cox regression analysis combined all admissions and allowed
adjustment for covariates. Results: In-hospital, 30 day and
90-day mortality rates were 6%, 15% and 23%, respectively,
for patients’ first admission. 90-day survival in those with AKI
was 67% versus 91% without AKI. Increment in peak creatinine
within 48 hours from admission creatinine (peak 48 hours –
admission creatinine) was a very strong predictor of mortality,
but only if peak creatinine reached above 1.2 mg/dl. If peak
creatinine levels were below 1.2 mg/dl, there was no impact
on survival due to increment in peak creatinine. In admissions
with peak creatinine above 1.2 mg/dl, every 0.1 mg/dl incre-
324A AASLD ABSTRACTS
ment was associated with a higher mortality, and with 0.4mg/
dl increment, 90-day survival was only 58% versus 75% with
those with less than 0.4 mg/dl increment (p=0.03). Cox regres-
sion analysis showed that 48-hour peak creatinine of 1.2 mg/
dl or more had 1.7 higher hazard of death (CI 1.2-2.5), and
0.4 mg/dl increment had the worst outcome (HR 5.2, CI 2.9-
9.4). Reason for admission persisted as a predictor of survival,
but etiology of cirrhosis, or the use of PPI, beta blockers or
rifaxamin did not predict mortality. Other independent predic-
tors of mortality were white race, age, MAP less than 70mm/
Hg, hyponatremia, INR and bilirubin. Conclusion: Increments
in serum creatinine within 48 hours from hospitalization pre-
dict the survival provided the peak serum creatinine within 48
hours is above 1.2mg/dl. Increase in serum creatinine did not
have an impact if peak creatinine did not reach 1.2 mg/dl
or more. Early renal protection strategies after hospitalization
may improve the outcome of patients with cirrhosis admitted
with complications.
Disclosures:
Paul J. Thuluvath - Advisory Committees or Review Panels: Gilead, Abbvie;
Grant/Research Support: Vertex, Gilead, BMS, Isai, Salix, Abbvie; Speaking
and Teaching: Gilead, Onyx, Abbvie
The following people have nothing to disclose: Anantha Nuthalapati, Nicholas
Schluterman, Deborah Greenberg, Anuj Khanna
245
Unprecipitated acute kidney injury can occur amongst
stable patients with cirrhosis and ascites but no other
complications
Florence Wong1, Peter Jepsen2, Hugh R. Watson3, Hendrik V.
Vilstrup2; 1Medicine, University of Toronto, Toronto, ON, Canada;
2Hepatology and Gastroenterology, Aarhus University Hospital,
Aarhus, Denmark; 3Internal Medicine, Sanofi-Aventis, Chilly-Maza-
rin, France
Acute kidney injury (AKI) occurs frequently in decompensated
cirrhosis both in an ambulatory (Tsien et al, Gut 2013) and in
a hospital setting (Garcia-Tsao et al, Hepatology 2008). Most
AKI episodes are functional renal disorders, precipitated by
an acute event such as infection that perturbs the hemodynam-
ics. Because the background abnormal hemodynamics and
compromised renal circulation in decompensated cirrhosis can
further deteriorate, it is possible that AKI can occur without
any precipitant. Aim: to determine the prevalence of unprec-
ipitated AKI (acute É in serum creatinine (SCr) by ≥0.3mg/
dL (26.4mmol/L) in ≤48 hours or É by 50% from baseline)
(Wong et al, Gut, 2011) in a large cohort of ambulatory &
hospitalized decompensated cirrhotic patients. Methods: Data-
base containing 1115 stable decompensated cirrhotics with
ascites and no other complications (early ascites or Gp A:
n=434, diuretic responsive ascites or Gp B: n=451, refractory
ascites or Gp C: n=230) from several randomized controlled
vaptan trials was assessed. Two SCr readings ≤7 days apart
taken at screening and at randomization into the vaptan stud-
ies were used to determine AKI prevalence. No precipitating
event was reported between the 2 SCr readings. Results: AKI
had a prevalence of 1.8% in the entire cohort. The prevalence
of unprecipitated AKI increases with worsening ascites severity
(Gp A: 4/434 or 0.9%; Gp B: 7/451 or 1.6%; Gp C: 9/230
or 3.9%; p=0.019). AKI patients had a mean screening SCr of
89±24mmol/L (±SD), increased to 130±31mmol/L (p<0.001)
at AKI diagnosis. All patients except one had stage 1 AKI
defined as É in SCr by ≥26.4mmol/L or by 1.5-1.9X from
screening. One patient had stage 2 AKI (2.0-2.9X É in SCr
from screening). Within a 7-day period, the AKI in 3 stage 1
patients progressed, two to stage 2, and 1 to stage 3 (>3.0 X
É in SCr from screening). There was no significant difference
HEPATOLOGY, October, 2014
in terms of age, gender, liver cirrhosis etiology, history of dia-
betes or systemic hypertension, screening mean arterial pres-
sure, heart rate, blood work or Child-Pugh and MELD scores,
between those who developed AKI versus those who did not.
However, there was a significant negative correlation between
the screening serum Na and SCr (p=0.0008). Summary: AKI,
unprecipitated by any acute event, still occurs in 1.8% of stable
decompensated cirrhotic patients. Those with more severe asci-
tes, especially refractory ascites are at a higher risk for devel-
oping unprecipitated AKI, Conclusion: Patients with cirrhosis
and refractory ascites need to be monitored more closely for
the development of unprecipitated AKI, since AKI has a nega-
tive impact on the outcome of these patients.
Disclosures:
Florence Wong - Consulting: Gore Inc; Grant/Research Support: Grifols
Hugh R. Watson - Employment: Sanofi-aventis R&D; Stock Shareholder: Sano-
fi-aventis R&D
The following people have nothing to disclose: Peter Jepsen, Hendrik V. Vilstrup
246
Evaluation of serum cystatin C as a marker of early
renal impairment in patients with liver cirrhosis
Mahmoud S. Omar1, Wael Abdel-Razek1, Gamal Abo-Raia2,
Medhat Assem1, Gasser El-Azab1; 1Hepatology, National Liver
Institute, Shebeen El-Kom, Egypt; 2Clinical Pathology, National
Liver Institute, Shebeen El-Kom, Egypt
Background: Early detection of renal impairment (RI), one of the
major complications of liver cirrhosis, using the current markers
and equations could be challenging. Serum cystatin C (CysC)
was proposed as an effective reflection of the glomerular filtra-
tion rate (GFR). However, its role in patients with liver cirrhosis
has not been extensively verified especially in the detection of
early RI. Patients and Methods: Seventy consecutive potential
candidates for living donor liver transplantation were included
in this prospective study as they fulfilled: age 18-80 years,
serum creatinine (Cr) <1.5 mg/dL and no dehydration, sepsis
or GI bleeding during the month before enrollment. CysC, Cr
and estimated GFR [creatinine clearance (CCr), Cockcroft-Gault
formula (C-G) and MDRD equations with 4 and 6 variables]
were all correlated to isotopic GFR. Early RI was defined as
GFR of 60-89 mL/min/1.73 m2. Results: Patients included 61
(87.1%) males, and had a mean age of 47.4±9.3 years and
mean body weight of 78.2±14.7 kg. Liver cirrhosis was mostly
due to chronic viral hepatitis, HCV in 51 (72.9%) and HBV in
12 (17.1%) patients, and 20 (28.6%) patients had hepatocel-
lular carcinoma. The mean MELD was 16.2 (range 8-31); 18
(25.7%) and 52 (74.3%) patients were Child-Pugh class B and
C, respectively. GFR was ≥90, 60-89 and 30-59 mL/min/1.73
m2 in 22 (31.4%), 45 (64.3%), and 3 (4.3%) patients, respec-
tively. The mean Cr was 0.8±0.3 mg/dL and mean CysC was
1.9±1 mg/L. The GFR (mL/min/1.73 m2) was measured isoto-
pically as 84.5±16.6, and estimated as: C-G 132.9±65, CCr
82.4±31.3, MDRD4 119.2±63.5 and MDRD6 97.4±50.4.
All markers and equations, except C-G (p=0.100), were sig-
nificantly correlated to GFR: 1/CysC (r=0.437, p<0.0001),
CCr (r=0.367, p=0.002), 1/Cr (r=0.287, p=0.016), MDRD4
(r=0.260, p=0.030) and MDRD6 (r=0.286, p=0.017). The
table shows the area under the curve (AUC) for discriminating
early RI. At a cutoff value of 1.2 mg/L, CysC was 89.6%
sensitive and 63.6% specific in detecting early RI. Conclusion:
In patients with liver cirrhosis, CysC showed the highest signifi-
cant correlation to GFR and was the test that best discriminated
early RI especially at a cutoff of 1.2 mg/L.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Disclosures:
The following people have nothing to disclose: Mahmoud S. Omar, Wael Abdel-
Razek, Gamal Abo-Raia, Medhat Assem, Gasser El-Azab
247
Chronic Kidney Disease Epidemiology Collaboration
Equation combining Creatinine and Cystatin C is supe-
rior to other Creatine- and Cystatin C-based Equations
in Assessing Renal Function in Patients with Cirrhosis
Elisabeth Krones1,
Sabine Zitta2,
Stefan Neunherz1,Katharina
Artinger2, Tatjana Stojakovic3, Gilbert Reibnegger4, Franziska
Durchschein1, Juliana Buchgrabner2, Vanessa Stadlbauer1, Peter
Fickert1, Alexander R. Rosenkranz2; 1Division of Gastroenterol-
ogy and Hepatology, Department of Internal Medicine, Medical
University of Graz, Graz, Austria; 2Clinical Division of Nephrol-
ogy, Department of Internal Medicine, Medical University of Graz,
Graz, Austria; 3Clinical Institute of Medical and Chemical Lab-
oratory Diagnostics, Medical University of Graz, Graz, Austria;
4Institute for Physiological Chemistry, Medical University of Graz,
Graz, Austria
Background: The prognostic value of renal function in cirrhosis
is reflected by the inclusion of serum creatinine (SCr) levels in
the model for end-stage liver disease (MELD) a predictor of
3-month mortality. Accurate measurement of renal function in
cirrhotics however remains a clinical challenge. Although SCr
is easily measurable and available, it has numerous limita-
tions in patients with cirrhosis (e.g. reduced hepatic synthesis,
increased tubular secretion, negative correlation with muscle
mass) and may consequently be of limited value in determining
GFR. Measurement of GFR using inulin clearance (IC) as the
currently accepted gold standard is cost-intensive, time-con-
suming and of inferior role in daily clinical practice. Aim: To
compare IC to SCr- and cystatin C (CysC)-based equations
for GFR in patients at different stages of cirrhosis. Material
and Methods: We determined IC in 50 patients with cirrhosis
[divided by Child-Pugh A(18),B(18) and C(14)] and 24 age-
matched healthy living kidney donors using the bolus method,
which is superior over continuous inulin infusion since neither
urine samples nor steady state conditions are required. There-
fore, a bolus of 2500 mg sinistrin, an inulin-like polyfructosan,
was administered over 3 minutes and GFR was calculated on
the basis of sinistrin concentrations at different time points using
a two compartment model. GFR determined by IC was further-
more compared to different SCr- and/or CysC-based equations
(Cockcroft-Gault, MDRD, Hoek, Larson, CKD-EPI equations
using SCr, CysC and/or both) using bias, precision, and “Root
Mean Square Error” (RMSE). Results: Compared to IC, SCr-
based equations generally overestimated GFR in patients with
liver cirrhosis (e.g. bias 11.5, precision 21.8, RMSE 24.7 for
MDRD and bias 9.4, precision 20.5, RMSE 22.5 for CKD-EPI).
SCr-based overestimation of GFR correlated with progression
of liver disease and was not observed in healthy living kidney
donors. CysC-based equations showed better results but rather
underestimated GFR compared to IC, especially in patients
with Child Pugh C (e.g. bias -8.2, precision 17.5, RMSE 19.3
for CKD-EPI). Conclusion: All equations used for estimating GFR
showed a high bias. Amongst all, CKD-EPI equation combining
325A
SCr and CysC was superior to all other equations in assessing
GFR in cirrhosis (bias -0.12, precision 16.1, RMSE 16.1, accu-
racy 10%: 49%, accuracy 30%: 84%). Our results show the
critical importance of cross validation of different tests to accu-
rately determine GFR in cirrhotics. Determination of IC seems to
be reasonable in patients with cirrhosis, especially those being
evaluated for liver transplantation. Disclosures: none.
Disclosures:
Peter Fickert - Consulting: Falk Foundation, Falk Foundation, Falk Foundation,
Falk Foundation; Speaking and Teaching: Roche Austria, Gilead Austria, MSD
Austria, MERCK Austria, Roche Austria, Gilead Austria, MSD Austria, MERCK
Austria, Roche Austria, Gilead Austria, MSD Austria, MERCK Austria, Roche
Austria, Gilead Austria, MSD Austria, MERCK Austria
The following people have nothing to disclose: Elisabeth Krones, Sabine Zitta,
Stefan Neunherz, Katharina Artinger, Tatjana Stojakovic, Gilbert Reibnegger,
Franziska Durchschein, Juliana Buchgrabner, Vanessa Stadlbauer, Alexander
R. Rosenkranz
248
Bile pigment nephropathy and acute tubular necrosis
in decompensated cirrhotics and acute on chronic liver
failure
Suman Nayak 1, Rajendra P. Mathur 1, Sivaramakrishnan
Ramanarayanan1, Gyan Prakash1, Shiv K. Sarin2, Chitranshu
Vashishtha2, Manoj Kumar2, Rakhi Maiwall2, Ajeet S. Bhadoria2;
1nephrology, institute of liver and biliary science, New Delhi, India;
2hepatology, Institute of liver and biliary science, New Delhi, India
Background While functional renal dysfunction is assessed by
using Acute Kidney Injury Network (AKIN) criteria, the true
spectrum of kidney injury remains speculative. Since majority
of patients are very sick and coagulopathic, there is paucity
of data on renal biopsies and structural renal pathologies in
patients with cirrhosis and acute on chronic liver failure (ACLF).
Patients and Methods: We reviewed the post-mortem kidney
biopsy reports of patients with severe liver dysfunction who died
with acute kidney injury (AKI). Biopsy tissues were processed
and subjected to light microscopy and immunofluorescence.
In patients with pigment casts in tubules, additional special
stains for iron (Pearl’s stain) and bile (Fouchet’s) were used to
characterise the pigments. Results: Total of 43 renal biopsies of
patients with complete clinical details and death with AKI were
included; 18 patients had ACLF and 25 were decompensated
cirrhotics. Mean age of study population was 43.26±11.44
years. All 43 (100%) patients had renal structural anomalies.
Bile pigment nephropathy was found in 20/43 (46.51%) and
acute tubular necrosis (ATN) in 23/43 (53.49%) patients.
ACLF patients had significantly more number of bile pigment
nephropathy as compared to cirrhotics (72%vs 27.8%, p value
= 0.004). The mean urea (98.80±55.78 vs 90±44.68 mg/
dl, p value = 0.294) and creatinine (4.02±2.3 vs 3.42±1.5
mg/dl, p value = 0.081) were higher in bile pigment nephrop-
athy group compared to ATN group. The Mean CTP score
was higher in bile pigment nephropathy group compared to
ATN group (12.6±1.1 vs. 11.9±1.2, p value = 0.046). The
Mean MELD score (39.3±7.9 and 31.35±7.7) and bilirubin
(26.06±9.3 and 9.2±5.2 mg/dl) were higher in bile pigment
nephropathy group as compared to ATN group (p value =
0.002 and <0.001 respectively). On multivariate logistic
regression analysis, high bilirubin was found to be an inde-
pendent predictor of bile pigment nephropathy. Conclusion:
Patients with decompensated cirrhosis and ACLF, who develop
severe AKI, do have renal structural anomalies. Bile pigment
nephropathy is a common pathological finding; more so in
ACLF patients with high serum bilirubin. ATN should be sus-
pected early enough in decompensated cirrhotics.
Disclosures:
326A AASLD ABSTRACTS
The following people have nothing to disclose: Suman Nayak, Rajendra P.
Mathur, Sivaramakrishnan Ramanarayanan, Gyan Prakash, Shiv K. Sarin, Chi-
transhu Vashishtha, Manoj Kumar, Rakhi Maiwall, Ajeet S. Bhadoria
249
Plasma Renin concentration is associated with portal
hypertension, liver dysfunction, ascites and hyponatre-
mia and may predict mortality in cirrhosis
Rafael Paternostro1,2,Simona Bota1,2,
Philipp Schwabl1,2,
Remy
Schwarzer1,2, Thomas Reiberger1,2, Mattias Mandorfer1,2, Monika
Ferlitsch2, Michael Trauner2, Markus Peck-Radosavljevic1,2, Arnulf
Ferlitsch1,2; 1Vienna Hepatic Hemodynamic Laboratory, Divison of
Gastroenterology and Hepatology, Department of Internal Medi-
cine III, Medical University of Vienna, Vienna, Austria; 2Division of
Gastroenterology and Hepatology, Department of Internal Medi-
cine III, Medical University of Vienna, Vienna, Austria
Background & Aims: Plasma renin concentration (PRC) has
been reported to be elevated in patients with liver cirrhosis.
It remains to be established if PRC is associated with portal
hypertension (PHT), degree of liver dysfunction, and mortal-
ity in cirrhosis. Methods: PRC (in mIE/mL) was measured in
116 patients with liver cirrhosis undergoing measurement of
hepatic venous pressure gradient (HVPG) when Child-Pugh-
Score (CPS), MELD score, and grade of ascites were evalu-
ated. Mortality was recorded during follow-up. Results: Main
patient characteristics were as following; age: 56+-10years;
gender:75% male; CPS-A:37%, CPS-B:40%, CPS-C: 23%,
MELD: 8.9+-5.5, HVPG: 16+-6.6 mmHg, Ascites: absent/
grade1: 73%, Grade2: 15%, Grade3: 12%. Median PRC for
CPS-A was: 16.6mIE/mL (IQR:8.6-29), for CPS-B 41mIE/mL
(IQR:11.9-198.1) and in C 175.2mIE/mL (IQR:705-1855.4)
(A vs. B p=0.003, A vs. C p<0.0001, B vs. C p=0.01).In
patients with clinical significant portal hypertension (CSPH,
defined as a HVPG ≥10mmHg), median PRC was 43.7mIE/
mL (IQR: 14.6-219.9) as compared to 10.1mIE/mL (IQR: 5.02-
31.5; p=0.001) in patients without CSPH. The median PRC sig-
nificantly increased (p<0.001) with the degree of ascites: no
ascites 19.5mIE/mL (IQR:2.2-50.1), grade 1 ascites: 40.6mIE/
mL (IQR:2.69-149.5), grade 2 106mIE/mL (IQR:38.2-316.6),
and grade 3 ascites: 248.3mIE/mL (IQR:151.7-2021).PRC
significantly correlated with absolute CPS values (p<0.0001,
r=0.414), MELD score (p<0.0001, r=0.422), grade of asci-
tes (p<0.0001, r=0.476), and HVPG (p=0.0001, r=0.358).
In addition, PRC correlated with serum sodium (p<0.0001,
r=-0.574) and creatinine levels (p=0.002, r=0.283).Median
transient elastography values were 41+-22 and were avail-
able in 74 patients, significant correlation with PRC was found
(p<0.0001, r=0.400). Multivariate analysis found independent
correlations of PRC and sodium-levels (p<0.0001), MELD score
(p=0.008), CPS (p=0.009), and grade of ascites (p=0.02).
20 patients (17.2%) died during follow-up (median 519 days
(IQR:26.6-844.2)) . Median PRC was higher in patients who
died during follow-up: 112.4mIE/m (IQR:31.8-270.3) vs.
28.4mIE/m (IQR:9.3-110.9;p=0.02).Logrank test showed sig-
nificant difference in survival between those patients with ele-
vated PRC (>39.9 mIE/mL )and those with normal PRC levels
(p=0.022). Conclusions: PRC correlates with portal hyperten-
sion, severity of liver dysfunction (CPS and MELD), the degree
of ascites, and lower serum sodium levels in patients with liver
cirrhosis. It seems that higher PRC is also associated with mor-
tality, but prospective studies are needed if dynamic changes
of PRC are of independent prognostic value in liver cirrhosis.
Disclosures:
Simona Bota - Speaking and Teaching: Janssen Pharmaceutica, Boehringer Ingel-
heim, Bristol-Myers Squibb
HEPATOLOGY, October, 2014
Thomas Reiberger - Grant/Research Support: Roche, Gilead, MSD, Phenex;
Speaking and Teaching: Roche, Gilead, MSD
Mattias Mandorfer - Consulting: Janssen ; Grant/Research Support: Roche, MSD;
Speaking and Teaching: Boehringer Ingelheim, Roche, Bristol-Myers Squibb,
Janssen
Michael Trauner - Advisory Committees or Review Panels: MSD, Janssen, Gilead,
Abbvie; Consulting: Phenex; Grant/Research Support: Intercept, Falk Pharma,
Albireo; Patent Held/Filed: Med Uni Graz (norUDCA); Speaking and Teaching:
Falk Foundation, Roche, Gilead
Markus Peck-Radosavljevic - Advisory Committees or Review Panels: Bayer, Gil-
ead, Janssen, BMS, AbbVie; Consulting: Bayer, Boehringer-Ingelheim, Jennerex,
Eli Lilly, AbbVie; Grant/Research Support: Bayer, Roche, Gilead, MSD; Speak-
ing and Teaching: Bayer, Roche, Gilead, MSD, Eli Lilly
The following people have nothing to disclose: Rafael Paternostro, Philipp
Schwabl, Remy Schwarzer, Monika Ferlitsch, Arnulf Ferlitsch
250
Alpha-2a Adrenoceptor Subtype Stimulation by Guan-
facine Restores Diuretic Efficiency in Experimental
Cirrhosis and Refractory Ascites: Comparison with Clon-
idine Effects
Giovanni Sansoe1, Manuela Aragno2, Raffaella Mastrocola2,
Maurizio Parola2; 1Gastroenterology Unit, Gradenigo Hospital,
Torino, Italy; 2Department of Clinical and Biological Sciences, Uni-
versity of Torino, Torino, Italy
Background. In liver cirrhosis, adrenergic hyperfunction causes
proximal tubular fluid retention and reduces the response to
diuretics, leading to refractory ascites. Clonidine, a sympatho-
lytic drug, plus diuretics improve natriuresis in refractory asci-
tes. Aim. To compare diuretic efficiency of clonidine (aspecific
α2-adrenoceptor agonist) and SSP-002021R (specific α2A-re-
ceptor agonist and prodrug of guanfacine) when associated
with diuretics in experimental cirrhotic refractory ascites. Meth-
ods. Eight groups of rats were studied: controls (group G1);
controls receiving furosemide and potassium canrenoate (G2);
rats with ascitic cirrhosis due to 14 CCl4 weeks (G3); cirrhotic
rats treated with furosemide and canrenoate over the 11th-14th
CCl4 weeks (G4); cirrhotic rats treated with canrenoate and
clonidine (0.5 mcg three times a week) over the 11th-14th
CCl4 weeks (G5); cirrhotic rats treated with furosemide, canre-
noate and clonidine (0.5 mcg) (G6); cirrhotic rats treated with
diuretics and low-dose clonidine (0.3 mcg) (G7); cirrhotic rats
treated with diuretics and SSP002021R (5 mg/kg b.w. three
times a week) (G8).Three rats in each group, before sacrifice,
had their hormonal status and renal function assessed at the
end of 11th, 12th, 13th, and 14th CCl4 weeks. Results. Cir-
rhotic rats in G3 and G4 gained weight over the 11th-14th
CCl4 weeks. In G4, after a brief increase in sodium excretion
due to diuretics (11th week), rapid worsening of inulin clear-
ance (GFR) and natriuresis occurred in the 12th-14th CCl4
weeks (diuretic resistance). The addition of low-dose clonidine
(G7) or guanfacine (G8) to diuretics increased, respectively,
electrolytes excretion over the 11th-12th CCl4 weeks, or GFR
and urinary excretion of electrolytes over the 13th-14th CCl4
weeks. Natriuretic responses in G7 and G8 were ushered by
reduced catecholamine serum levels. Conclusions. Clonidine
reduces adrenergic function and potentiates diuretics-depen-
dent natriuresis before occurrence of refractory ascites. Specific
α2A-receptor agonists preserve GFR, increase natriuresis, and
prevent refractory ascites in this model.
Disclosures:
Giovanni Sansoe - Consulting: Shire Pharmaceuticals Ltd., Basingstoke, Hamp-
shire, UK.
Manuela Aragno - Grant/Research Support: Shire Pharmaceutical
Raffaella Mastrocola - Grant/Research Support: Shire Pharmaceutical
Maurizio Parola - Independent Contractor: Shire Pharmaceutical Ltd, Basingstoke,
UK
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
251
Albumin Infusions in Patients with Cirrhosis who Present
with Acute Kidney Injury and its Effect on Renal Function
Derek J. Feussner, Amy P. Myers, James C. Slaughter, Andrew
Scanga; Vanderbilt University, Nashville, TN
During an admission for AKI in patients with cirrhosis, individ-
uals at Vanderbilt University Hospital are given an albumin
challenge to improve their intravascular volume in hopes of
increasing blood flow delivered to the kidneys and improving
their renal function. There is limited evidence to guide albumin
dosing in this clinical scenario. Current recommendations are
to give 1gm/kg/day of albumin up to 100gm/day. Our goal
in performing this retrospective chart review is to identify differ-
ences in outcomes among patients with cirrhosis who present
with AKI and who receive differing daily doses of albumin.
Using Vanderbilt University Hospitals EMR, 1,124 charts were
reviewed from all patients admitted to the Hepatology service
from 2010–2013 with 149 subjects identified. Patients with
an admission diagnosis of AKI were included if their admis-
sion serum creatinine was >2.0mg/dL and had increased from
their prior baseline by ≥0.3mg/dL, or their admission serum
creatinine was 1.5 times their baseline value. Subjects who
met these criteria were excluded if they were diagnosed with
spontaneous bacterial peritonitis during their hospital stay. We
then looked at the admission creatinine, and creatinine after a
48hour albumin challenge to assess for improvement in renal
function. Our results show no evidence that increasing doses
of albumin are associated with increasing degree of change in
creatinine from pre-to-post intervention (p=0.49). In a multivari-
able model including MELD scores, PRBC administration and
urine sodium; there is no evidence that MELD scores, PRBCs,
urine sodium or albumin are associated with changes in creat-
inine. For subjects receiving less than or equal to 0.5 g/kg of
albumin BID, creatinine decreased by 0.44 units from pre to
post intervention; in subjects receiving more than 0.5 g/kg of
albumin, creatinine decrease by 0.42 units. This is a difference
of 0.02 units (95% CI: [-0.24 to 0.28]) due to albumin dosing.
While we were unable to show that increasing albumin dose
had a greater effect on improving renal function, in general
there was an improvement. This study shows no association
between albumin dose and effect on improving kidney function,
glomerular filtration rate or hospital length of stay in patients
with known cirrhosis. These results allowed us to develop a
hypothesis that larger doses of albumin are no more effective
than low dose albumin regimens in effecting change in overall
kidney function. Moving forward it is our goal to create a pro-
spective study with the aim of more effectively using albumin as
a hospital resource given Vanderbilt University Hospital as a
whole spent 4.6 million dollars on albumin from 2010–2013.
Disclosures:
The following people have nothing to disclose: Derek J. Feussner, Amy P. Myers,
James C. Slaughter, Andrew Scanga
252
Nosocomial spontaneous bacterial peritonitis is asso-
ciated with increased mortality compared to communi-
ty-acquired spontaneous bacterial peritonitis
Nicolas M. Intagliata, Zachary Henry, Nitin K. Ahuja, Neeral L.
Shah, Curtis K. Argo, Stephen H. Caldwell, Patrick G. Northup;
Gastroenterology and Hepatology, University of Virginia, Char-
lottesville, VA
Introduction: Hospital-acquired infections in cirrhosis patients
are associated with significant morbidity and mortality. We
aimed to examine the relative impact of nosocomial versus
327A
community-acquired spontaneous bacterial peritonitis (SBP)
among patients hospitalized at a tertiary liver transplant center.
Methods: Adult cirrhosis patients with SBP admitted over four
years (2009-2012) were identified through a clinical data-
base. SBP was defined as ascites fluid with >250 PMN/mm3.
Nosocomial cases were defined as SBP occurring greater than
48 hours after hospitalization. Patients with non-neutrocytic
bacterascites, SBP diagnosed prior to transfer, and secondary
peritonitis were excluded. Results: Of 341 patients with cirrho-
sis and peritonitis, 99 patients met criteria for SBP; 23 cases
(23%) were identified as nosocomial (NA-SBP) and 76 cases
(77%) as community-acquired (CA-SBP). Patients with NA-SBP
had significantly higher admission MELD scores (NA-SBP
28, 95% CI 22.9-32.8, vs. CA-SBP 22, 95% CI 19.6-23.9,
p=0.02), driven primarily by higher bilirubin levels (NA-SBP
13.0 mg/dL, 95% CI 7.4-18.6, vs. CA-SBP 5.9 mg/dL, 95%
CI 4.3-7.5, p=0.01). Exposure to antibiotics prior to paracen-
tesis was more common among patients with NA-SBP than
those with CA-SBP (91.3% vs. 56.2%, p=0.002). Patients with
NA-SBP had significantly longer hospitalizations (NA-SBP 16.9
days, 95% CI 12.1-21.7, vs. CA-SBP 8.4 days, 95% CI 6.4-
10.3, p =0.0001) with longer intervals preceding diagnostic
paracentesis (NA-SBP 6.2 days, 95% CI 4.3-8.0, vs. CA-SBP
0.5 days, 95% CI 0.4-0.7, p= 0.0001). Ascites culture yield
was low in this cohort (21/99, 21%), with a large proportion
of culture-positive ascites growing multi-drug resistant organ-
isms (9/21, 43%). Among NA-SBP patients, only 2/23 (9.5%)
yielded positive ascites cultures. 12/23 (52%) of NA-SBP
patients had a separate infection noted prior to SBP diagno-
sis. Kaplan-Meier survival analysis revealed 30-day mortality
was significantly higher in patients with NA-SBP (p=0.004,
Figure 1). A multivariate Cox proportional hazards model indi-
cated NA-SBP (HR 3.2, p=0.002) was a significant predic-
tor of mortality. Conclusions: NA-SBP carries a high 30-day
risk of mortality relative to CA-SBP. After controlling for other
important mortality correlates, NA-SBP was found to be an
independently significant predictor for death. As hospitalized
cirrhotic patients are prone to systemic infections, it is unclear
if elevated ascites neutrophils represent true SBP; rather, these
counts may be a surrogate marker for overall systemic infection
and consequently a higher risk of death. Further prospective
study is now needed to better characterize NA-SBP.
Disclosures:
Neeral L. Shah - Grant/Research Support: Boehringer Ingelheim
Curtis K. Argo - Consulting: Wellstat Diagnostics; Independent Contractor:
Genentech/Roche
Stephen H. Caldwell - Advisory Committees or Review Panels: Vital Therapy;
Consulting: Wellstat diagnostics; Grant/Research Support: Genfit, Gilead Sci-
ences
Patrick G. Northup - Grant/Research Support: Hemosonics, Bristol Meyer Squibb
The following people have nothing to disclose: Nicolas M. Intagliata, Zachary
Henry, Nitin K. Ahuja
328A AASLD ABSTRACTS
253
Microscopic Urinanalysis May Represent a Sensitive Test
for Kidney Injury in Cirrhotic and Cholestatic Patients
with Preserved Kidney Function
Elisabeth Krones1,Julia Fritz1,
Christoph Schwarz2,
Franziska
Durchschein1, Kathrin Eller2, Gernot Zollner1, Werner Ribitsch2,
Tatjana Stojakovic3, Sabine Zitta2, Juliana Buchgrabner2, Alexan-
der R. Rosenkranz2, Peter Fickert1; 1Division of Gastroenterology
and Hepatology, Department of Internal Medicine, Medical Univer-
sity of Graz, Graz, Austria; 2Division of Nephrology, Department
of Internal Medicine, Medical University of Graz, Graz, Austria;
3Clinical Institute of Medical and Chemical Laboratory Diagnostics,
Medical University of Graz, Graz, Austria
Background: Acute kidney injury (AKI) in cirrhosis represents
a high-risk situation. It is increasingly recognized that cir-
rhotic or cholestatic patients show abnormal renal histology
with glomerular and tubulointerstitial lesions that may not be
noted by routine renal function tests. Microscopic urinanalysis
is readily available, inexpensive and noninvasive, and cur-
rently considered to be a well-suited surrogate parameter for
structural kidney damage. We hypothesized that cirrhotic or
cholestatic patients with preserved renal function (eGFR >60
ml/min) upon routine laboratory evaluation frequently show
structural renal injury reflected by a pathologic urine cytology.
This may represent a herald of subsequent impaired renal func-
tion. Aim: To find a useful non-invasive clinical test to identify
early structural kidney injury in liver patients. Material and
Methods: We collected blood and urine samples from a total
of 150 patients [liver cirrhosis Child Pugh score class A (n=41),
B (n=38), C (n=28), obstructive cholestasis (n=19), and age-
matched healthy living kidney donors (n=24]. Patients with
diabetes, insufficiently treated arterial hypertension or pre-
existing kidney disease were excluded. Freshly voided urine
samples were analyzed by automatic flow cytometry (Sysmex
UF 1000) and microscopic urinanalysis after Papanicolaou
staining of a smear preparation of the urine sedimentation.
The specimens were analyzed for presence and number of
renal tubular epithelial cells (RTEC) and granular casts (GC).
Results: Serum creatinine (SCr) concentrations (in mg/dL) and
GFR determined by the CKD-EPI equation (in ml/h/1.73m2)
were normal amongst all groups (0.76±0.16 and 102±15 in
Childs A group, 0.78±0.17 and 101±12 in Childs B group,
0.84±0.23 and 95±19 in Childs C group, 0.85±0.2 and
93±21 in cholestasis group, 0.78±0.11 and 93.6±12.4 in
living kidney donors). RTEC and GC as sensitive markers of
tubular epithelial kidney injury were frequently found in liver
cirrhosis (RTEC in 15%, GC in 8%) and cholestasis (RTEC in
33%, GC in 20%), whereas none of the healthy living kidney
donors showed RTEC or GC upon urine cytology. Presence
of RTEC significantly correlated with serum bile acid levels
(correlation coefficient 0.207; p 0.015) Conclusions: Patients
with cirrhosis or cholestasis and normal kidney function show
RTEC and GC at increased numbers compared to controls.
Microscopic urinanalysis may represent a useful, noninvasive
and cheap diagnostic test to identify patients at high risk for
AKI or subclinical kidney injury which needs to be evaluated in
prospective clinical trials. Disclosures: none.
Disclosures:
Peter Fickert - Consulting: Falk Foundation, Falk Foundation, Falk Foundation,
Falk Foundation; Speaking and Teaching: Roche Austria, Gilead Austria, MSD
Austria, MERCK Austria, Roche Austria, Gilead Austria, MSD Austria, MERCK
Austria, Roche Austria, Gilead Austria, MSD Austria, MERCK Austria, Roche
Austria, Gilead Austria, MSD Austria, MERCK Austria
The following people have nothing to disclose: Elisabeth Krones, Julia Fritz,
Christoph Schwarz, Franziska Durchschein, Kathrin Eller, Gernot Zollner, Werner
Ribitsch, Tatjana Stojakovic, Sabine Zitta, Juliana Buchgrabner, Alexander R.
Rosenkranz
HEPATOLOGY, October, 2014
254
Relative Adrenal Insufficiency in Cirrhotic Patients with
Ascites
Virendra Singh1, Rajiv R. Singh1, Rama Walia2, Naresh Sach-
deva2, Ashish Bhalla3, Navneet Sharma3, Yogesh K. Chawla1;
1Hepatology, Postgraduate Institute of Medical Education and
Research, Chandigarh, India; 2Endocrinology, Postgraduate Insti-
tute of Medical Education and Research, Chandigarh, India; 3Inter-
nal Medicine, Postgraduate Institute of Medical Education and
Research, Chandigarh, India
Background : Relative adrenal insufficiency (RAI) has been
reported in critically ill patients with cirrhosis and is associated
with poor outcome. Its prevalence and impact on survival in
non-critically ill cirrhosis patients is largely unknown. We evalu-
ated the prevalence of RAI and its relationship to clinical course
in non-septic cirrhosis patients with ascites. Methods:The study
included 66 consecutive hemodynamically stable, non-septic
cirrhosis patients admitted with ascites. A 250-mg adrenocor-
ticotropic hormone stimulation test was performed within 24
hours of admission to detect RAI. Transcortin, calculated free
cortisol (cFC), and free cortisol index (FCI) were assessed in
all patients, with FCI >12 representing normal adrenal func-
tion. Patients were followed up for 3 months. Results: Sixty six
patients (56 males and 10 females) with cirrhosis and ascites
participated in the study. The mean Child-Pugh(CTP) and model
for end stage liver disease (MELD) scores were 10.6 ± 1.9 and
21.5 ± 7.3, respectively. Hepatorenal syndrome (HRS) was
present in 9 (13.6%) patients. The prevalence of RAI in patients
with cirrhosis and ascites was 47% (31/66). The prevalence
of RAI in patients with and without spontaneous bacterial peri-
tonitis (SBP), renal failure and type 1 HRS was comparable.
Hyponatremia at inclusion was present in significantly greater
number of patients with RAI (42% versus 17%, p=0.026).
Patients with RAI had lower serum levels of total cholesterol,
high density cholesterol (HDL) and low density cholesterol (LDL)
than patients without RAI. There was a significant correlation of
prevalence of RAI with the severity of liver disease with signifi-
cantly higher prothrombin time, international normalized ratio
(INR), MELD scores and CTP class in patients with RAI than
those without RAI. During follow up, there was no association
between RAI and the risk to develop new infections, severe
sepsis, type 1 HRS and death. Conclusions: RAI is common in
non-septic cirrhotic patients with ascites. It is likely to be a fea-
ture of liver disease per se which increases in prevalence with
increasing severity of liver disease. However, it does not affect
the short term outcome in these patients.
Disclosures:
The following people have nothing to disclose: Virendra Singh, Rajiv R. Singh,
Rama Walia, Naresh Sachdeva, Ashish Bhalla, Navneet Sharma, Yogesh K.
Chawla
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
255
Urinary NGAL Levels Reflect the Therapeutic Effects of
norUDCA in Mice with Cholemic Nephropathy
Elisabeth Krones1, Dietmar Glaenzer1, Franziska Durchschein1,
Alexander Kirsch2, Kathrin Eller2, Michael Trauner3, Alexander R.
Rosenkranz2, Peter Fickert1,4; 1Division of Gastroenterology and
Hepatology, Department of Internal Medicine, Medical University
of Graz, Graz, Austria; 2Clinical Division of Nephrology, Depart-
ment of Internal Medicine, Medical University of Graz, Graz,
Austria; 3Hans Popper Laboratory, Division of Gastroenterology
and Hepatology, Department of Internal Medicine III, Medical
University of Vienna, Vienna, Austria; 4Department of Pathology,
Medical University Graz, Graz, Austria
Background & Aims: Long-term common bile duct ligation
(CBDL) in mice models cholemic nephropathy with renal tubu-
lar cast formation, tubular epithelial cell injury and impaired
renal function (Fickert et al. Hepatology 2013). Interestingly,
renally excreted norursodeoxycholic acid (norUDCA) protects
CBDL mice from cholemic nephropathy, suggesting a pivotal
pathogenetic role for urinary excreted bile acids (BA). Neu-
trophil-gelatinase associated lipocalin (NGAL) is an iron-trans-
porting protein with increased renal excretion in nephrotoxic
or ischemic kidney injury. We aimed to test the hypothesis that
urinary NGAL measurement is useful to monitor acute kidney
injury in cholemic nephropathy. Methods: Chow-fed (controls)
or norUDCA (0.125% w/w)-treated CL57/BL6 mice were sub-
jected to CBDL for 8 weeks. Urinary NGAL levels were deter-
mined at time of harvesting using a commercially available
ELISA kit (Lipocalin-2/NGAL DuoSet Mouse, R&D Systems,
DY1857). In brief, samples were incubated with detection
antibody, labeled with streptavidin-HRP and subsequently
measured at 450 nm. Results: Chow-fed CBDL mice exhibited
significantly elevated urinary NGAL levels (29.6 ± 4.2 ng/
ml) compared to norUDCA-treated CBDL mice (9.4 ± 1.8 ng/
ml, p<0.05). NorUDCA treatment significantly ameliorated the
degree of nephritis and kidney fibrosis and consequently to a
significantly reduced renal hydroxyproline content (466 ± 107
μg/g vs. 797 ± 160 mg/g in controls, p<0.05). Conclusions:
Urinary NGAL measurement represents a suitable readout for
monitoring the degree of cholemic nephropathy in CBDL mice
and reflects the therapeutic effects of norUDCA. Future studies
should determine urinary NGAL levels in patients with cholemic
nephropathy. Disclosures: The Medical University of Graz has
filed a patent for the use of norUDCA in the treatment of liver
diseases, and P.F. and M.T. are listed as co-inventors (publica-
tion number WO2006119803) and P.F. received a research
grant and norUDCA from Dr. Falk Pharma GmbH for this proj-
ect.
Disclosures:
Michael Trauner - Advisory Committees or Review Panels: MSD, Janssen, Gilead,
Abbvie; Consulting: Phenex; Grant/Research Support: Intercept, Falk Pharma,
Albireo; Patent Held/Filed: Med Uni Graz (norUDCA); Speaking and Teaching:
Falk Foundation, Roche, Gilead
Peter Fickert - Consulting: Falk Foundation, Falk Foundation, Falk Foundation,
Falk Foundation; Speaking and Teaching: Roche Austria, Gilead Austria, MSD
Austria, MERCK Austria, Roche Austria, Gilead Austria, MSD Austria, MERCK
Austria, Roche Austria, Gilead Austria, MSD Austria, MERCK Austria, Roche
Austria, Gilead Austria, MSD Austria, MERCK Austria
The following people have nothing to disclose: Elisabeth Krones, Dietmar
Glaenzer, Franziska Durchschein, Alexander Kirsch, Kathrin Eller, Alexander
R. Rosenkranz
329A
256
Prevalence of hyperdynamic circulation in cirrhosis: lack
of association to presence and severity of ascites
Cristina Ripoll, Phillip Hohaus, Marcus Hollenbach, Robin A.
Greinert, Alexander Zipprich; Innere Medizin I, Martin-Luther-Uni-
versität Halle-Wittenberg, Halle (Saale), Germany
Patients with cirrhosis develop hyperdynamic circulation with
an increase in cardiac output (CO) and a decrease in systemic
vascular resistance (SVR). Patients with hyperdynamic circula-
tion can develop circulatory dysfunction(CD) when this com-
pensatory mechanism is insufficient. Although this takes place
theoretically in decompensated patients, namely in patients with
ascites, its prevalence has never been specifically analysed.
The aim was to evaluate the prevalence of hyperdynamic circu-
lation in patients with compensated and decompensated cirrho-
sis and it association to liver function, portal hypertension and
CD. Methods: Secondary analysis of a prospectively collected
dataset of patients with cirrhosis who underwent a hepatic
hemodynamic study and right heart catheterization. SVR and
CO were categorized according to the presence of abnormal
values (below 800 dyn.cm.s5 and above 8 l/m, respectively).
Hyperdynamic circulation was defined when both parameters
were abnormal. CD was defined by the presence of creatinin
>1.5 mg/dL and/or hyponatremia <130 mmol/L. Variables
are reported as percentages or medians(IQR). Comparison
were performed by means of U-mann Whitney and ANOVA.
Kaplan-Meyer curves were constructed and compared with
the log rank test. Results: 437 patients were included (65%
male, 71% had alcohol related disease, Child A 102 (23%), B
182 (42%), and C 130 (30%), 57% with ascites (n=249) and
30% with refractory ascites (n=130). 22% had hyperdynamic
circulation, interestingly 18% of patients without ascites and
25 % of patients with ascites had hyperdynamic circulation.
Patients with hyperdynamic circulation had greater HVPG [18
(13-20) mmHg vs. 16 (11-19) mmHg](p=0.007) although no
difference in creatinin and serum sodium were observed com-
pared to patients without hyperdynamic circulation. Among
patients with ascites, no difference in the prevalence of hyper-
dynamic circulation was observed according to the presence
of diuretic responsive (26%) or refractory ascites (23%). CD
was observed in 20% of patients, most frequently in patients
with refractory ascites (61%). No association was observed
between the presence of hyperdynamic circulation and CD.
Patients with CD had greater HVPG [19 (16-21) mmHg vs 15
(11-19) mmHg](p<0.001) and lower SVR [834 (683-1057)
dyn.cm.s-5 vs. 938 (751-1182) dyn.cm.s-5] (p=0.006), nev-
ertheless no differences in CO [6.9 (5.6-8.4) l/min vs. 6.7
(5.7-8.3) l/min] were observed. Conclusions: Approximately
25% of patients with cirrhosis have hyperdynamic circulation,
irrespective of ascites. CD is associated to refractory ascites.
Patients with CD have lower SVR, without differences in CO.
Disclosures:
The following people have nothing to disclose: Cristina Ripoll, Phillip Hohaus,
Marcus Hollenbach, Robin A. Greinert, Alexander Zipprich
330A AASLD ABSTRACTS
257
Outcomes in Patients Receiving Rifaximin along with
Systemic Antibiotics for the Inpatient Treatment of Spon-
taneous Bacterial Peritonitis
Jennifer D. Twilla1,
Anuj Sharma3,
Satheesh Nair2,
Emily H.
Wong2, Sanjaya K. Satapathy2; 1Department of Clinical Phar-
macy, University of Tennessee Health Sciences Center, Memphis,
TN; 2Department of Surgery, Methodist Transplant Institute, Univer-
sity of Tennessee Health Sciences Center, Memphis, TN; 3Depart-
ment of Gastroenterology, University of Tennessee Health Sciences
Center, Memphis, TN
Background: Spontaneous bacterial peritonitis (SBP) is the most
frequent infection in patients with cirrhosis causing significant
mortality which requires rapid recognition and treatment with
systemic antibiotic therapy. The purpose of our study was to
investigate whether the addition of non-absorbable oral anti-
biotic rifaximin for selective intestinal decontamination with
aim to reduce bacterial translocation from the gut in patients
admitted with SBP reduced mortality as well as other second-
ary outcomes. Methodology: A retrospective review of patients
admitted to Methodist LeBonheur Healthcare adult hospitals
between 4/09-4/14 with an ICD-9 diagnosis code of 567.23
(SBP) was conducted. These patients were reviewed for admin-
istration of systemic antibiotics +/- rifaximin during their
inpatient stay and divided into two groups: systemic antibi-
otics alone (SA) and systemic antibiotics + rifaximin (SA+R).
Inclusion criteria: ≥ 18 years of age, diagnosis of cirrhosis
or chronic liver disease, diagnosis of SBP, and received ≥ 5
days of systemic antibiotics. Patients groups were compared
to determine length of stay (LOS), development of hepatorenal
syndrome (HRS), bleeding, hepatic encephalopathy (HE), and
mortality. Results:Eighty patients were included with 44 patients
in the SA group and 36 patients in the SA+R group. Overall
mortality rate was 36%, with no statistically significant differ-
ences between the SA vs SA+R group (38% vs 34%; p=NS).
Average LOS was similar between the two groups (SA group
12.3±10.8 days vs SA+R group 14.8±13.7 days; p=NS).
Comparison of the SA group vs SA+R group for differences in
number of patients that developed HRS, bleeding, or HE did
not reveal any statistically significant differences. However, 18
patients had documentation of rifaximin as a home medication
prior to admission. Upon review of patients receiving rifaximin
prior to admission vs those who did not, there was a statisti-
cally significant difference in the development of HRS (11% vs
40%; p=0.02). Conclusion:The addition of rifaximin to systemic
antibiotics for inpatient treatment of SBP did not affect LOS nor
did it alter the development of HRS, bleeding, HE, or mortality.
Conversely, receiving rifaximin prior to admission significantly
reduced the progression to HRS. Larger prospective studies are
needed to validate these results.
Disclosures:
Satheesh Nair - Advisory Committees or Review Panels: Jansen; Speaking and
Teaching: Gilead
Sanjaya K. Satapathy - Advisory Committees or Review Panels: Gilead
The following people have nothing to disclose: Jennifer D. Twilla, Anuj Sharma,
Emily H. Wong
HEPATOLOGY, October, 2014
258
Clinical Predictors of Morbidity and Mortality in Hospi-
talized Children with Ascites
Grace Felix1, Thammasin Ingviya2, Ann O. Scheimann1, Pavis
Laengvejkal1, Alexandra Vasilescu1, Hejab Imteyaz1, Eric C. Sea-
berg2, Wikrom Karnsakul1; 1Pediatrics, Johns Hopkins School of
Medicine, Baltimore, MD; 2Johns Hopkins Bloomberg School of
Public Health, Baltimore, MD
BACKGROUND: Ascites is a common diagnosis in hospital-
ized children due to its association with a myriad of etiologies.
Little is known about factors predictive of morbidity and mortal-
ity in this population. METHODS: IRB approved retrospective
cross-sectional chart review was performed on children aged
0-21 hospitalized at Johns Hopkins Hospital between 1983-
2010 with an ICD-9 diagnosis of ascites (789.5, 789.51,
789.59). Multiple regression analysis was used to identify
demographic, laboratory, and clinical features as potential
predictors of morbidity and mortality. Study outcomes included
hospital length of stay (LOS) as a proxy for morbidity and
mortality (defined as death at hospital discharge). Predictors
analyzed included demographic data, ascites etiology and
grade (I, II or III), co-morbidities (hepatic encephalopathy (HE),
hepatorenal syndrome (HRS), portal vein thrombosis, hydrotho-
rax, etc.) and lab markers (thrombocytopenia, anemia, hypo-
natremia, and leukopenia). RESULTS: A total of 518 children
were studied. The average LOS of the population was 23.6
days. Children aged 0-5 had the longest LOS at 27.8 days
(p= 0.02), followed by the 6-12 age group and the 13-21
age group, respectively. Grade of ascites did not predict LOS.
Children with hepatic venous outflow obstruction had the lon-
gest LOS (41 days) while those with nephrotic syndrome had
the shortest LOS (10 days) with a p< 0.001. The presence
of hydrothorax was the only comorbidity associated with a
prolonged LOS, p= 0.016. Thrombocytopenia was the only
laboratory feature associated with longer LOS (p= 0.007).
Children aged 0-5 had the highest mortality rate (59.2%
p=0.003). Regarding etiologies, hepatic venous obstruction,
particularly veno-occlusive disease (VOD) had the highest mor-
tality (Adjusted OR = 33.1; 95% CI: (4.9-677.8)) while cancer
had the lowest (0.19%). The presence of HE (p=0.004), HRS
(p=0.009), thrombocytopenia (p<0.001) and hyponatremia
(p=0.035) were also associated with higher mortality. CON-
CLUSION: Among hospitalized children with ascites, age ≤5,
presence of VOD, hyponatremia, thrombocytopenia and leu-
kopenia were associated with greater morbidity and mortality
warranting further investigation.
Disclosures:
The following people have nothing to disclose: Grace Felix, Thammasin Ingviya,
Ann O. Scheimann, Pavis Laengvejkal, Alexandra Vasilescu, Hejab Imteyaz, Eric
C. Seaberg, Wikrom Karnsakul
259
Beyond Dr. Google: Early results of a personalized
weight-tracking smartphone application and alert sys-
tem for patients with ascites
Chanda Ho1, Neil Shah1, Nabil Alshurafa2, Behnam Shahbazi2,
Hassan Ghasemzadeh3, Norah Terrault1; 1Hepatology, UCSF,
San Francisco, CA; 2Computer Science, UCLA, Los Angeles, CA;
3Computer Science, Washington State University, Pullam, OR
Background: Medical management of ascites is currently lim-
ited to dietary sodium restriction, diuretics, and large-volume
paracentesis (LVP) with few interventions in place to prevent
ascites-related complications. We hypothesize close monitor-
ing of weights can prevent ascites complications related to
under or overdiuresis and propose utilizing smartphone appli-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
cations to test this hypothesis. Smartphone applications have
been shown to improve patient outcomes in chronic disease but
have not been tested in cirrhotic patients with ascites. Aim: To
develop and implement a patient-centered smartphone appli-
cation in cirrhotic patients with ascites. Methods: We designed
an application with the following features: 1) wireless scale
connectivity to record weights 2) patient reminders to weigh in
3) provider alerts if the patient had not weighed in at 72 hours
and/or if the patient exceeded a pre-defined, personalized
target weight range (TWR). Inclusion criteria were as follows:
patients with Child class B/C cirrhosis on at least 2 diuretics
with an ascites-related complication in the preceding 6 months
defined as fluid overload requiring LVP, renal (Cr ≥ 2.0 mg/
dL) or electrolyte (Na <128 mEq/L or K> 5.0 mEq/L) dysfunc-
tion, or a hospitalization/emergency department (ED) visit for
an ascites-related complication. To date, we have recruited
10 subjects in this ongoing study. We report initial results for
6 subjects along with feedback from qualitative interviews.
Results: The mean age of the subjects was 53 years (4 male,
2 female) with an average MELD score of 14 (range 9-24). All
but one subject used the application. Three subjects remained
in their TWR. Two subjects exceeded their TWR and gener-
ated provider alerts. These subjects required several episodes
of diuretic titration and ultimately underwent scheduled pro-
cedures. None of the participating subjects had a hospital/
ED visit during the study. From qualitative interviews, subjects
identified that the application facilitated their communication
with providers and aided in self-empowerment over their med-
ical care. Conclusions: Our experience shows that subjects
maintained their weight or successfully used the alerting system
to communicate with their provider regarding management.
Close, non-invasive monitoring of patient weights provided
an opportunity for an early intervention (uptitrating diuretics,
scheduling LVP) in this complex patient population and may
play a role in the prevention of ascites-related complications
such as a hospitalization/ED visit. Further studies are needed
to determine the impact of weight monitoring on patient quality
of life, longer-term outcomes, and health-care costs.
Disclosures:
Norah Terrault - Advisory Committees or Review Panels: Eisai, Biotest; Con-
sulting: BMS, Merck; Grant/Research Support: Eisai, Biotest, Vertex, Gilead,
AbbVie, Novartis, Merck
The following people have nothing to disclose: Chanda Ho, Neil Shah, Nabil
Alshurafa, Behnam Shahbazi, Hassan Ghasemzadeh
260
Determination of renal function through creatinine
and cystatin C-dependent formulas in comparison to
DTPA-Tc-99 clearance in Mexican cirrhotic patients
Jonathan Aguirre-Valadez 1, Haydee Verduzco-Aguirre 1, Ari-
adna K. Flores-Balbuena1, Octavio R. García-Flores1, Ricardo
Macías-Rodríguez1, Cristino Cruz-Rivera2, Jose A. Niño-Cruz2,
Ignacio Garcia1, Aldo Torre1; 1Gastroenterology, Instituto Nacio-
nal de Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico
DF, Mexico; 2Nephrology, Instituto Nacional de Ciencias Médicas
y Nutrición “Salvador Zubirán”, Mexico DF, Mexico
We studied 95 patients with liver cirrhosis of different eti-
ologies. GFR (glomerular filtration rate) was estimated by
Cockroft-Gault (CG), MDRD-4 (Modification of Diet in Renal
Disease), MDRD-6, Hoek’s CysC formula and CKD-EPI (Chronic
Kidney Disease Epidemiology Collaboration) based on serum
creatinine (sCr), CysC and sCr plus CysC. We used as stan-
dard GFR measured by DTPA-Tc99 (diethylene-triamine-penta-
acetate technetium) renal clearance. We divided patients in 3
groups according to MELD (Model for End-Stage Liver Disease)
score: <10, 11-14 and >15. Nutritional status was assessed
331A
with the Royal Free Hospital Subjective Global Assessment
(RFH-SGA) and bioelectrical impedance analysis (malnutrition
= phase angle <4.9°). Data was analyzed with SPSS ver.
21. Results: 44 men and 51 women were evaluated. 36.8%
of patients had a MELD score <10, 32.6% between 11-14
and 30.5% >15. Mean sCr was 0.74 ± 0.26 mg/dL, with
no difference between groups. Mean CysC was 1.19 ± 0.37
mg/L in all patients; in MELD <10 it was 1.02 ± 0.27, MELD
11-14 it was 1.17 ± 0.30, MELD >15 was 1.42 ± 0.42 (p =
0.004). Mean GFR by DTPA-Tc99 for all groups was 67.7 ±
30.14 ml/min/1.73m2. For MELD <10: 78.57 ± 25.6; MELD
11-14: 68.49 ±29.57; MELD >15: 53.66 ± 31.03. SCr for-
mulas overestimated GFR for all groups. Mean GFR by CG
was 110.6±50.63. CysC formulas showed a better perfor-
mance. Mean GFR by Hoek’s CysC formula was 68.7 ±21.44,
and by CKD-EPI CysC 69.3±25.89. In the MELD >15 group,
DTPA-Tc-99 detected a GFR <60 in 65% of patients and a
GFR <30 in 27%. CG detected a GFR <60 in 14% and none
<30. Similar results occured for all sCr formulas. Hoek’s CysC
formula detected 58% of GFRs <60 (concordance with DTPA
73%, underdiagnosis 26%) and 3% <30 (concordance 14%).
CKD-EPI CysC showed the best performance, detecting 66%
of GFRs <60 (concordance 79%, underdiagnosis 21%) and
25% of GFRs <30 (concordance 25%). Severe malnutrition
increased with MELD score. By RFH-SGA: 5.7% in MELD <10,
12.9% in MELD 11-14, 24.1% in MELD >15 were malnour-
ished, and by BIA 26%, 29% and 38% respectively. This could
contribute to the overestimation of renal function in this popu-
lation when sCr is used. Conclusion: Estimated GFR by CysC
formulas overestimated GFR by DTPA-Tc99 in a lesser degree
than sCr formulas. SCr may not be an adequate measure of
renal function in this population. Nutritional status could be
used to weigh parameters of renal function in malnourished
cirrhotic patients. The most benefited group could be patients
with MELD >15, candidates for liver transplantation, since an
impaired renal function affects postransplant outcomes, and
some of them could require liver-kidney transplant.
Disclosures:
The following people have nothing to disclose: Jonathan Aguirre-Valadez,
Haydee Verduzco-Aguirre, Ariadna K. Flores-Balbuena, Octavio R. García-
Flores, Ricardo Macías-Rodríguez, Cristino Cruz-Rivera, Jose A. Niño-Cruz, Igna-
cio Garcia, Aldo Torre
261
Predictors for the Development of Cardiac Ascites in
Patients Referred for Cardiac Transplantation
Brian Kim1, Amy Tan2, Berkeley N. Limketkai3, Sean Pinney4,
Thomas D. Schiano1; 1Hepatology, Mount Sinai, New York, NY;
2Medicine, Mount Sinai, New York, NY; 3Gastroenterology and
Hepatology, Johns Hopkins, Baltimore, MD; 4Cardiology, Mount
Sinai, New York, NY
Background: Cardiac ascites, while frequently diagnosed, has
no clear mechanism described in the literature. A portal pres-
sure greater than 10 mmHg is often cited as a requirement
for cirrhosis-related ascites. However, there is no minimum
right atrial (RA) pressure required for cardiac ascites formation
found in the literature. In a group of heart failure (HF) patients
referred for cardiac transplantation (CT), we attempted to iden-
tify patient characteristics and predictors associated with the
development of cardiac ascites. Methods: All adult patients with
HF referred to Mount Sinai Medical Center for CT from January
2010 to August 2013 were retrospectively assessed. Patients
were divided into two groups based on abdominal imaging:
those with and without clinically significant ascites, which was
defined as having “moderate” to “large” ascites. Demographic
information, serum laboratory values, and results of transtho-
332A AASLD ABSTRACTS
racic echocardiograms (TTE) and right heart catheterizations
(RHC) were compared between the groups. Results: Of the
225 patients assessed, 29 patients were excluded due to lack
of abdominal imaging. Of the 196 study patients, 29 (14.8%)
patients had clinically significant ascites. There were no signif-
icant differences in age, gender, ethnicity/race, and etiology
of heart disease in the two groups. However, the ascites group
had higher creatinine (2.3 vs 1.6 mg/dL, p=0.03), higher
BUN (50.1 vs 32.6 mg/dL, p<0.01), higher brain natriuretic
peptide (1611 vs 1103 pg/mL, p=0.04), and lower albumin
(3.3 vs 3.6 g/dL, p=0.03). On TTE, the ascites group had
more severe right ventricular (RV) dilatation (p=0.03) and more
tricuspid valve regurgitation (p<0.01). However, this group
had a higher left ventricular ejection fraction (33.0 vs 19.9%,
p<0.01). On RHC, the ascites group had a higher mean RA
pressure (17.1 vs 13.1 mmHg, p=0.01) and a higher RV end
diastolic pressure (18.4 vs 12.9 mmHg, p<0.01). There was
no difference in pulmonary capillary wedge pressure between
the groups (21.8 vs 22.9 mmHg, p=0.57). No clear threshold
value of RA pressure was identified for the development of car-
diac ascites. Conclusion: Clinically significant ascites was seen
in 14.8% of our HF patients referred for CT. Right-sided HF was
more commonly seen in the ascites group. In contrast, left-sided
HF did not correlate with the presence of ascites. Unlike in
cirrhosis, no minimum RA pressure elevation was required for
cardiac ascites formation. This is possibly due to other contrib-
uting factors in the formation of cardiac ascites, such as worse
renal function and lower serum albumin.
Disclosures:
Thomas D. Schiano - Consulting: vertex, merck, gilead, salix, idenix; Grant/
Research Support: mass biologics, itherx, galectin; Speaking and Teaching:
novartis, medhelp
The following people have nothing to disclose: Brian Kim, Amy Tan, Berkeley N.
Limketkai, Sean Pinney
262
Computer-assisted image analysis of fibrosis on liver
biopsy : relationship with portal pressure, histology and
clinical data
Nicolas Goossens1, Sophie Restellini1, Sophie Clément2, Laura
Rubbia-Brandt2, Laurent Spahr1; 1Hepatology, Univ. Hospitals of
Geneva, Geneva, Switzerland; 2Clinical Pathology, Univ. Hospi-
tals of Geneva, Geneva, Switzerland
Background : Liver fibrosis (Fib) participates to the development
of portal hypertension (PHT). Assessment of Fib is important
in the diagnosis and prognosis of patients with chronic liver
disease. Hepatic venous pressure gradient (HVPG) evaluates
PHT in clinical practice. We aimed to generate a simple cut-off
value of liver fibrosis density that would be associated with
several clinical, biological and histological endpoints. We
quantified liver fibrosis in transjugular biopsies (TJL-101-ET
needle set Cook) and determined the relationship with HVPG,
elastometry (FS), a non invasive marker of fibrosis/PHT, and
other parameters in a large cohort of chronic liver disease.
Methods : 86 patients (cirrhosis 67%, MELD 15.4 ± 6, alco-
holics (ALD)=61%, HCV=25%, HVPG 19 ± 5.4 mmHg, ascites
45%) and 9 healthy subjects candidates for living donation
were included. We used a computer-assisted method to assess
the relative proportion of fibrosis (% fibrosis/total biopsy spec-
imen) on Sirius red stained liver sections. The examiner was
blinded to patients’ characteristics. Results : Fibrosis was higher
in patients vs controls (7.8% vs 1%, p<0.001), and in ALD vs
HCV (9 vs 4.9%, p<0.01). Table: correlation of fibrosis with
variables. On multivariate analysis, only HVPG was associated
with fibrosis density (OR 1.3 per unit increase in HVPG, 95%
CI [1.1-1.7], p=0.009). Conclusion : In patients with advanced
HEPATOLOGY, October, 2014
chronic liver disease, density of fibrosis measured on Sirius red
stained liver biopsy correlates with PHT, elastometry, and fea-
tures of liver injury. We determined a threshold useful to iden-
tify patients with particular clinical, biological and histological
parameters that are commonly measured in clinical practice.
Disclosures:
The following people have nothing to disclose: Nicolas Goossens, Sophie Restel-
lini, Sophie Clément, Laura Rubbia-Brandt, Laurent Spahr
263
Non-invasive measurement of acute hemodynamic
changes using inert gas rebreathing during routine ther-
apeutic paracentesis in tense ascites
Christoph Antoni1, Joachim Saur2, Thomas Zimmerer1, Nenad
Suvajac2, Julia D. Michels2, Matthias Ebert1, Frederik Trinkmann2;
1Dept. of Internal Medicine II, University Hospital, Mannheim,
Germany., Mannheim, Germany; 2Dept. of Internal Medicine I,
University Hospital, Mannheim, Germany., Mannheim, Germany
Background: In cirrhosis with portal hypertension a decrease in
cardiac afterload leads to characteristic hyperdynamic circula-
tion and splanchnic arterial vasodilation. With disease progres-
sion, cardiac output (CO) cannot be further increased resulting
in arterial hypotension, stimulation of the sympathetic nervous
and renin-angiotensin system as well as ascites. Tense ascites
decreases venous return and thus CO due to compression of
the inferior vena cava and right atrium. Finally, hepatorenal
syndrome (HRS) is the extreme expression of this hemodynamic
dysfunction. Therapeutic paracentesis acutely increases CO
which has been previously identified to be an independent risk
factor for the development of HRS. However, the determination
of CO is difficult in clinical routine due to invasive, operator
dependent or time-consuming standard procedures such as
right heart catheterization, echocardiography or cardiac mag-
netic resonance imaging. The aim of our study was to evaluate
hemodynamic changes during paracentesis using non-invasive
inert gas rebreathing (IGR). Methods: Routine therapeutic para-
centesis was performed in the supine position using ultrasound
guidance in 28 patients with tense ascites refractory to therapy.
In patients with a volume of ascites removed (VA) > 5 liters albu-
min was administered. Hemodynamic parameters including
CO, stroke volume (SV), heart rate (HR), systolic and diastolic
blood pressure (SBP, DBP) were assessed immediately prior to
and after the procedure using IGR. Results: The collective (19
men) aged from 42 to 76 years. Mean MELD score was 13
with 15 patients in Child-Pugh class B (CPC) and 13 in C. Most
frequent causes of cirrhosis were alcohol (16) and HCV (4) or
HBV (3). Mean VA was 4400±1500 ml (range 1900 to 8000
ml). CO significantly increased from 5.7±1.7 to 7.0±2.0 l/min
after paracentesis (p<0.001). SV accordingly increased from
81±26 ml to 97±33 ml (p<0.001). Both SBP and DBP signifi-
cantly dropped from 122±19 to 117±18 mmHg (p=0.04) and
69±12 to 63±13 mmHg (p<0.001). HR remained unchanged
at 73±14 and 74±15 mmHg (p=0.69).There was a moderate
correlation between VA and change in CO (r=0.36, p=0.12).
We neither found differences between change in CO and CPC
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS 333A

(p=0.31) nor the cause of cirrhosis (p=0.25). Conclusion: IGR 266

is safe and feasible in tracking hemodynamic changes non-in- Response guided ascitic tap in spontaneous bacterial
vasively induced by therapeutic paracentesis. Hyperdynamic peritonitis predicts outcome
circulation further increases acutely showing a moderate asso-
Ashok K. Choudhury, Ankur Jindal, Chandan K. Kedarisetty, Tan-
ciation with VA. Further studies are warranted as knowledge
may S. Vyas, Ajeet S. Bhadoria, Shiv K. Sarin; Hepatology, Insti-
of hemodynamics may be beneficial in evaluating patients at
tute of Liver and Biliary Sciences New Delhi, India, NEW DELHI,
risk for e.g. HRS, portopulmonary hypertension or hepatopul-
India
monary syndrome.
Disclosures: Background and Aims: - Spontaneous bacterial peritonitis (SBP)
Christoph Antoni - Speaking and Teaching: Roche, MSD, BMS, Janssen, Gilead,
is the commonest and life-threatening infection in liver cirrhosis.
Falk Foundation Identification of risk factors, choice and timing of antibiotic in
The following people have nothing to disclose: Joachim Saur, Thomas Zimmerer, relation to response can improve outcome.We investigated the
Nenad Suvajac, Julia D. Michels, Matthias Ebert, Frederik Trinkmann role of serial ascitic tap for antibiotic response to predict the
outcome. Patients and Methods: - Patients of decompensated
cirrhosis diagnosed with spontaneous bacterial peritonitis (as
264 per definition) were analyzed retrospectively. As per proto-
PTFE-covered TIPS position relative to the hepatocaval col, the patient underwent ascitic tap after 48hr in all cases
junction and impact on shunt patency and on 5th and 7th day depending upon the clinical param-
eters. Results:- Total 161 patient of decompensated cirrhosis,
Charles N. Weber, Gregory J. Nadolski, Michael C. Soulen;
mean age 50.8yrs(±11.8SD, ) 82% male, with mean CTP
Radiology, Hospital of the University of Pennsylvania, Philadel-
=12.3±1.47 and median MELD = 22.7 (range=16-28) were
phia, PA
analyzed. Ethanol was the commonest etiology (n=64, 40%),
Purpose Distance from the hepatocaval junction (HCJ) to the followed by cryptogenic (n=32, 20%) and NASH (n=21,
hepatic venous (HV) end of transjugular intrahepatic porto- 13%). SBP was associated with hepatic encephalopathy (HE)
systemic shunt (TIPS) created with bare metal stents (BMS) has in 93(57.7%), Variceal bleed (VB) in 16(9.9%), septic shock
been shown to impact patency. Now, most TIPS are created in 60(37.2%) requiring ventilator support in 47(29.2%) with
with polytetrafluoroethylene (PTFE)-covered stent-grafts. Our median hospital stay of 7(range 4-14) days with a high mor-
study investigates the impact of distance from the HCJ on long- tality (n=43, 26.7%); predominantly due to sepsis (83.7%),
term patency of PTFE-covered TIPS. Methods PTFE-covered Variceal bleed (11.7%). The predictors of poor survival were
TIPS placed between 2002 and 2013 were retrospectively presence of HE, Child-C status, MELD >24, persistence of
reviewed. Clinical and imaging data were collected from the SBP on D3 and D7, low ascitic fluid glucose <92mg/dl%,
electronic medical record and radiology imaging archive. Dis- culture positivity for ascitic fluid (p<0.05). Reduction in ascitic
tance from HV end to the HCJ was recorded. Primary patency fluid neutrophil count by 13% on D3, was the only predictor
rates were calculated. Differences between groups based on associated with improved survival (p<0.05). Conclusions:- The
distance from HV end to HCJ were compared using Kaplan- clinical presentation, advanced liver disease, low ascitic fluid
Meier and Cox regression analyses. Results 300 PTFE-covered glucose with culture positivity at the baseline and the neutrophil
TIPS were included in the study. 201 were placed with a single count reduction but not the base line ascitic fluid TLC or reduc-
stent-graft while 99 were extended at the HV end with addi- tion at 48hr predict the resolution of SBP and overall outcome.
tional BMS(N=70) or stent-grafts(N=29). No threshold distance
between HV end of the TIPS and HCJ was found to impact long- The response tap at 48 hr showing neutrophil count reduction by
term patency (p-values at thresholds of 0, 5, 10, 15, and 20 13% is associated with better outcome
mm were 0.92, 0.79, 0.43, 0.36 and 0.24 respectively). Pri-
mary patency in TIPS placed with just a single stent-graft versus
those using additional stents was 90% vs 82%, 83% vs 71%,
81% vs 60% 6 months, 1 and 2 years respectively (p = 0.03).
In TIPS created with multiple stents, primary patency of those
with BMS versus PTFE-covered extensions was 84% vs 78%,
73% vs 69%, and 69% vs 46% at 6 months, 1 and 2 years
respectively (p = 0.28). Regression analysis demonstrated the
length by which a TIPS was extended and the final distance of
the HV end to the HCJ were not predictors of patency failure
(p>0.1 and p = 0.06 respectively). Conclusion If the HV end
of PTFE-covered TIPS is within 2 cm of the HCJ, the primary
patency is not determined by the actual distance from the HCJ
nor is it improved by extending the TIPS to the HCJ. If extended,
PTFE-covered extensions offer no patency benefit over BMS.
The best patency rates occur with single PTFE-covered TIPS.
Disclosures:
The following people have nothing to disclose: Charles N. Weber, Gregory J.
Nadolski, Michael C. Soulen
Disclosures:
The following people have nothing to disclose: Ashok K. Choudhury, Ankur Jin-
dal, Chandan K. Kedarisetty, Tanmay S. Vyas, Ajeet S. Bhadoria, Shiv K. Sarin
265
WITHDRAWN
334A AASLD ABSTRACTS
267
Does transjugular intrahepatic portosystemic shunt
(TIPS) with covered stents modify the natural course of
decompensed cirrhosis?
Xavier Adhoute1, Paul Castellani1,
Guillaume Penaranda2,
Olivier
Monnet3, Herve Perrier1, Bernard L. Pol4, Cyril Muller3, Arthur
Laquiere1, Valerie Oules1, Patrick Beaurain3, Christian Boustiere1,
Olivier Bayle3, Marc Bourlière1; 1Hepatology, hôpital saint-joseph,
Marseille, France; 2Biostatistics, ALPHABIO Laboratory, Marseille,
France; 3Radiology, hôpital saint-joseph, Marseille, France; 4Hepa-
tobiliairy Surgery, hôpital saint-joseph, Marseille, France
Purpose : To analyze the impact of TIPS with covered stents on
survival of patients with “severe” portal hypertension compared
to a control group treated medically. To assess complications
associated with implantation of the TIPS. Material and methods
: 344 consecutive patients were hospitalized for decompen-
sated cirrhosis (Child-Pugh B 60% / C 40%) from 01/2008
to 12/2012. Covered stent was implanted in 98 patients
for refractory ascites or recurrent gastrointestinal bleeding.
Assessment of median survival (MS) with and without TIPS, MS
according to Child-Pugh score and after matching 1:1 (n=130)
for age, Child-Pugh score, MELD score, presence of hepatocel-
lular carcinoma HCC, to a control group having a first decom-
pensation. Results :TIPS implantation was successful in 100%
of rates. The mean portosystemic pressure gradient decreased
from 18.5±4.5 mmHg to 5.8±2.6 mmHg. MS of patients with
TIPS (n=98) was 29.4 months [22-38.6] vs. 12.9 months
[10.2-18.3] without TIPS (n=246), p=0.0015 ; MS of child-
pugh B patients with TIPS (n=69) was 38.6 months [29.4-48.7]
vs. 19.1 months [14.1-35.3] without TIPS (n=137), p=0.0183;
MS of child-pugh C patients with TIPS (n=29) was 17.4 months
[10.1-25.3] vs. 8 months [6.2-11.2] without TIPS (n=109),
p=0.22. TIPS was a prognostic variable associated with sur-
vival in univariate analysis (p=0.015). HCC, alcoholic hepatitis
were more frequent in patients without TIPS (respectively 31%
vs. 8%, p <.0001, 17% vs. 10%, p=0.05). After matching 1:1
for age (61 ±10), Child-Pugh score (B 66%, C 34%), MELD
score (17.0±4.2) and presence of HCC (9%), esophageal var-
ices grade 2 or 3 (p=0.003), refractory ascites (p=0.01), an
increase in the portosystemic gradient (p=0.008) were signifi-
cantly more frequent in the TIPS group. Median survival was
26 months in the TIPS group (n=65) vs. 27 months without TIPS
(n=65), p=1.00. Median follow up was 12 months. Rate of
infection did not differ between the 2 groups. Main complica-
tions of TIPS (recurrent encephalopathy 34%, stent dysfunction
24.5%, strangulated umbilical hernia 9%, congestive heart
failure 7.5%) did not affect patient survival. Conclusion : in this
series, TIPS with covered stents appears to improve the natural
history of Child-Pugh B cirrhosis with recurrent decompensa-
tion. Conversely, decreasing portosystemic pressure gradient
does not alter the progression of Child-Pugh C cirrhosis with
prolonged decompensation. Earlier implementation of a tips
should be discussed for some child-pugh B patients with recur-
rent ascites or gastrointestinal bleeding.
Disclosures:
Xavier Adhoute - Speaking and Teaching: bayer
Marc Bourlière - Advisory Committees or Review Panels: Schering-Plough,
Bohringer inghelmein, Schering-Plough, Bohringer inghelmein; Board Member-
ship: Bristol-Myers Squibb, Gilead, Idenix; Consulting: Roche, Novartis, Tibotec,
Abott, glaxo smith kline, Merck, Bristol-Myers Squibb, Novartis, Tibotec, Abott,
glaxo smith kline; Speaking and Teaching: Gilead, Roche, Merck, Bristol-Myers
Squibb
The following people have nothing to disclose: Paul Castellani, Guillaume
Penaranda, Olivier Monnet, Herve Perrier, Bernard L. Pol, Cyril Muller, Arthur
Laquiere, Valerie Oules, Patrick Beaurain, Christian Boustiere, Olivier Bayle
HEPATOLOGY, October, 2014
268
Factors associated with medication adherence in
patients living with cirrhosis
Suzanne Polis1,5, Ling Zhang1, Amany Zekry1,3, Ritin Fernandez2,4;
1Gastroenterology & Hepatology, St George Hospital, Kogarah,
NSW, Australia; 2Centre for Research in Nursing and Health, St
George Hospital, Kogarah, NSW, Australia; 3University of New
South Wales, St George Clinical School of Medicine, Kogarah,
NSW, Australia; 4School of Nursing and Midwifery, University of
Wollongong, Wollongong, NSW, Australia; 5VHEPP, The Kirby
Institute, Randwick, NSW, Australia
Medication adherence is a complex and dynamic interplay of
disease specific factors, medication related factors and indi-
vidual factors such as medication and disease knowledge,
beliefs and self efficacy. Improving patient’s medication adher-
ence is challenging yet a vital component in the treatment and
management of liver cirrhosis. Our study aimed to determine
adherence patterns and identify which factors contribute to
non-adherence in people living with liver cirrhosis. Methods
Participants diagnosed with cirrhosis attending a tertiary based
liver clinic were invited to complete a self reported survey. The
questionnaire included items relating to demographic infor-
mation, adherence to medications and knowledge of liver dis-
ease and treatment. Data were entered collated, checked and
analysed using SPSS version 21. Results Data were obtained
from 29 patients (24, 83%) males), median age 57 years (SD
9.2). Eleven (45%) of the patients who were prescribed medi-
cations measured low medication adherence using a medica-
tion-taking scale. The most commonly reported reasons for this
non-adherence included running out of medications, forgetting,
being away from home and sleeping through the dose. Mean
scores for medication self efficacy, beliefs about medication
and social supports were high at 2.58 (SD.0.6), 2.53 (SD
0.6) and 2.2 (SD 0.07) respectively. Overall patients reported
good knowledge of liver cirrhosis, individualised care plan and
medication regime with approximately 60% of the participants
correctly answering nine or more of the thirteen assessment
questions. Overall knowledge of prescribed medications was
high, however 10 (35%) said that they would adjust medi-
cation if their symptoms improved without telling their doctor
and 13 (45%) believed that herbal medications would help
their liver. Participants 16 (55%) had incorrect knowledge of
hepatocellular carcinoma (HCC) surveillance programs and
nutritional requirements with 22 (76%) reported that the liver
cleansing diet would improve liver health and 11 (38%) had
limited knowledge about dietary supplements. Conclusion To
our knowledge this is the first study to investigate adherent
behaviour in patients diagnosed with cirrhosis. Our study
reported low medication adherence in 45% of participants
who were prescribed medication. Running out of medications
and forgetting were the most common reason for non-adher-
ence. Gaps of patient knowledge related to cirrhosis, nutri-
tion and HCC surveillance were identified. Further research to
improve patient knowledge and develop strategies to improve
adherence are needed.
Disclosures:
The following people have nothing to disclose: Suzanne Polis, Ling Zhang,
Amany Zekry, Ritin Fernandez
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
269
Children with HCV: The impact of disease and treatment
on patients, caregivers and families
Rachel A. Annunziato1,2, Samantha G. Lee3, Elizabeth Galici1,
Alexander Newcorn1, Ronen Arnon2; 1Psychology, Fordham Uni-
versity, Bronx, NY; 2Pediatrics, Icahn School of Medicine at Mount
Sinai, New York, NY; 3Hospital Medicine, Connecticut Children’s
Medical Ceter, Hartford, CT
Hepatitis C virus (HCV) treatment with Pegylated Interferon
(subcutaneous weekly injections by a caregiver) and Ribavi-
rin orally is the current treatment for HCV infected-pediatric
patients. Treatment is delivered for either 24 weeks (HCV gen-
otypes 2 or 3) or 48 weeks (HCV genotypes 1 or 4). Previous
research on children with HCV has examined a wide range
of patient psychosocial outcomes but little is known about the
impact of HCV and this prolonged treatment on caregivers
and families. HCV treatment may be especially taxing on fam-
ilies due to mode of transmission and accompanying feelings
of guilt, concerns about stigma, the nature of treatment (e.g.,
weekly injections delivered by family members), possible side
effects, and fears about unsuccessful remission. The present
findings are from a case series aiming to broaden our under-
standing of the baseline characteristics of families starting treat-
ment as well as the impact of HCV treatment. A brief patient,
caregiver, and family assessment packet was given before and
immediately after treatment, but before the final outcome of
treatment was known. During the study period, 10 families at
our site began treatment for HCV. Patients were a mean age
of 11.62 (SD=3.74) and 6 were female. Each family was
given a battery assessing patient quality of life, (the Pediatric
Quality of Life Inventory; PedsQL), parental distress related to
their child’s illness (Impact of Events Scale; IES), and overall
family functioning (Family Assessment Device; FAD). At base-
line, as shown in Table 1, patients displayed poorer quality
of life than population norms, caregiver distress was elevated
(above an established cut-off of 19) and family functioning was
also in the “stressed” range. After treatment, all parameters
worsened. This difference was significant for family functioning
only, t=3.13, p=.05, as FAD scores rose above a cut-off for
clinical concern. In conclusion, in this case series of patients
in treatment for HCV, significant psychosocial stress was noted
for individuals and families and this was exacerbated over the
course of treatment. In addition to screening for patient depres-
sion, a known possible side effect, families may benefit from
additional support as well given the implications of HCV and
grueling nature of its treatment.
Table 1. Psychosocial assessment mean scores pre and post treat-
ment
Disclosures:
The following people have nothing to disclose: Rachel A. Annunziato, Samantha
G. Lee, Elizabeth Galici, Alexander Newcorn, Ronen Arnon
335A
270
A single-center report of hepatitis A and hepatitis B vac-
cination performance in patients with chronic hepatitis C
(CHC): A quality improvement project
Bobbi Jo Quigley1,2, Matthew Kowgier2, Colina Yim2; 1Toronto
Community Hep C Program, South Riverdale Community Health
Centre, Toronto, ON, Canada; 2Toronto Centre for Liver Disease,
University Health Network, Toronto, ON, Canada
Background: Co-infection of CHC with hep-A or B is associated
with increased risk of advanced liver disease and death. Prac-
tice guidelines and health authorities recommend CHC patients
be tested for hep-A and B and vaccinated preventively. How-
ever, the US NHANES and VA databases shows only 32-42%
of patients with chronic liver disease are vaccinated for hep-B.
This study aims to determine the extent of meeting these rec-
ommendations in a tertiary care liver center and to identify
measures for improvement, if results are suboptimal. Methods:
A retrospective chart review study. Hep-C antibody (anti-HCV)
positive patients were identified from clinic electronic documen-
tation records. Collected data included patient age, gender,
biopsy report, ultrasound and non-invasive markers of fibro-
sis, hep-A and B serology (HBsAg, anti-HBc, anti-HBs, anti-
HAV). For missing data in electronic records, paper charts
were reviewed manually to retrieve information. Clinic vacci-
nation records were also reviewed to confirm results. Results:
Preliminary results show of the 2,907 patients identified with
positive anti-HCV, 1,172 had incomplete viral hepatitis serol-
ogies in electronic records, resulting in a subsequent manual
search for results in patient paper charts. Results to date show
out of 2,907 patients, 2,485 (85.5%) were tested for hep-B,
1,427 (49.1%) tested for hep-A. Occurrences of Hep-B and C
co-infection were identified in 29 patients. Of those tested for
hep-A, 926 of 1,427 patients (71.7%) were immune. For hep-
B, 445 (25.7%) had prior exposure to hep-B and had immunity
(HBsAg negative, anti-HBc positive, anti-HBs positive) whereas
247 (14.2 %) had previous hep-B exposure but did not develop
immunity (HBsAg negative, anti-HBc positive, anti-HBs nega-
tive) and 342 (19.71%) received vaccination (HBsAg –ve, anti-
HBc –ve, anti-HBs +ve). Clinic immunization records showed
that 96 patients received their hep-A vaccine and 136 patients
received hep-B vaccine from clinic. Post vaccination tests were
performed in 89/96 patients for hep-A and 124/136 patients
for hep-B. Of patients tested for post-vaccination, 52 (58.4 %)
became Hep-A immune and 81(65.3%) hep-B immune. Conclu-
sion: Preliminary results show documented immunity for hep-A
and B in CHC patients is inadequate. We aim to recommend
measures to improve access to Hep-A and B vaccinations, such
as: measures to improve adherence to practice guidelines,
mandatory documentation of hep-A and B status and immuni-
zation record, a new model of nursing care e.g. use of medical
directives for vaccination, and a stringent follow up plan in
clinic.
Disclosures:
Colina Yim - Advisory Committees or Review Panels: Merck Canada, Gilead,
Janssen
The following people have nothing to disclose: Bobbi Jo Quigley, Matthew Kow-
gier
336A AASLD ABSTRACTS
271
Two Types of Fatigue in Subjects with Chronic Liver Dis-
ease Can Be Distinguished Through Correlations with
Physical Activity and Mental Symptoms
Ali A. Weinstein1,2, Heibatollah Baghi3, Carey Escheik1, Lynn
Gerber1,2, Zobair Younossi1,4; 1Betty and Guy Beatty Center
for Integrated Research, Inova Health System, Falls Church, VA;
2Center for the Study of Chronic Illness and Disability, College of
Health and Human Services, George Mason University, Fairfax,
VA; 3Department of Global and Community Health, College of
Health and Human Services, George Mason University, Fairfax,
VA; 4Center for Liver Diseases, Department of Medicine, Inova
Fairfax Medical Campus, Falls Church, VA
Background: Fatigue is a common symptom whose origin is
poorly understood and treatment is not well documented. One
potential reason is that fatigue is an umbrella term for a vari-
ety of different types of symptom clusters. The purpose of this
investigation was to determine if it was possible to separate
fatigue self-reports into two distinct types of fatigue symptom
clusters, physical and mental fatigue. Methods: Confirmatory
factor analysis (FA) from data collected in a prospective, nat-
ural history study of patients visiting a liver disease clinic with
diagnosis of NAFLD or Hepatitis C (HCV) was conducted using
several fatigue metrics frequently used in Chronic Liver Dis-
ease (CLD). Specifically, a principal component analysis with
varimax rotation was utilized. Investigators selected items to
try to differentiate physical (peripheral) from mental (central)
fatigue. These were then compared with an independent mea-
sure of activity (Human Activity Profile, HAP) and measures of
mood and affect (SF-36). Results: CLD patients were included
(N=106, 52% male; age: 51±10; 74% Caucasian, 12% Afri-
can-American, 4% Hispanic and 10% other). Two discrete fac-
tors were extracted which account for 66% of the variance in
the data. These two factors were one clustering around fatigue
related to physical activity and the other related to the affective
descriptors of fatigue. The correlation between these factors
was r=-0.329, supporting the independence of the factors. In
addition, Cronbach’s alpha (reliability) for the two factors was
0.88 and 0.92, respectively. These high reliability coefficients
demonstrate that the items of the questionnaires are homoge-
nous within each factor. The fatigue related to physical activity
factor (Peripheral Fatigue) was related to a validated mea-
sure of average level of physical activity (r=0.524, p<0.01),
while the affective factor (Central Fatigue) was less related
to the physical activity (r=-0.313, p<0.01). Central fatigue
was related to the mental component of the SF-36 (SFMCS)
(r=-0.467; p<0.01), whereas the peripheral fatigue was not
related to the mental component of SF-36 (r= -0.004; p=0.97).
Conclusions: In this prospective study of subjects with CLD,
two factors pertaining to fatigue were identified. These are
non-overlapping, suggesting that peripheral fatigue and central
fatigue are separate constructs, and each correlates uniquely
with specific measures of physical activity and mental health.
Disclosures:
The following people have nothing to disclose: Ali A. Weinstein, Heibatollah
Baghi, Carey Escheik, Lynn Gerber, Zobair Younossi
HEPATOLOGY, October, 2014
272
Characteristics of Nutritional Intake in End-Stage Liver
Disease Secondary to Viral Hepatitis, NASH, and Alco-
holic Liver Disease
Anna Marie Hefner1,2, Cynthia D. Connelly2, Kathy S. James2,
Catherine Hill1, Preeti Reshamwala1, Tarek Hassanein1; 1San
Diego University, San Diego, CA; 2Southern California Liver Cen-
ters, Coronado, CA
Introduction: The liver plays a fundamental role in our body
and influences the nutritional status. When a liver injury occurs,
malnutrition may be exacerbated. Malnutrition has been
reported as high as 90% depending on the patient population
studied and the disease severity. Due to the multiple causes
of cirrhosis, there are a variety of dietary habits from protein
energy malnutrition to over nourishment. Studies have focused
on hospitalized patients. Aims: The purpose of this study was to
describe the nutritional patterns of patients with end stage liver
disease secondary to viral hepatitis, non-alcoholic steatohepati-
tis and alcoholic liver disease in an outpatient setting. Subjects:
36 patients were identified with a diagnosis of ESLD (17 men,
mean age 56.4 ±9.4 and 19 women, mean age 56.8±12.2
years) undergoing follow up between June 2012 and March
2013. The etiology of cirrhosis was Hepatitis C (n=15), non-al-
coholic hepatitis (n=11), and alcoholic liver disease (n=10).
The subjects had an average of 2.7 co-morbidities ranging
from 0-4. The most frequently seen co-morbidities were diabe-
tes mellitus and hypertension. Ten percent of the subjects were
taking 1-3 medications and 90% were taking 4 or more medi-
cations. Twenty-four hour diet recalls were done at each clinic.
Results: The results showed the subjects with NASH cirrhosis
consumed more daily fruits, average 1.33 servings, than either
the HCV subjects or subjects with alcoholic cirrhosis, 0.77
and 0.5 servings respectively. Vegetables and protein, albeit
low, was consistent across groups ranging from 1.3 to 1.75
servings and 1.7 to 2.2 servings respectively. Differences were
shown in diary consumption with the HCV subjects consuming
at least one dairy product a day and the subjects with alco-
holic cirrhosis consuming less than a quarter of a dairy product
daily. A one way anova between groups analysis of variance
did not show statistical significance. Conclusion: In conclusions
subjects with ESLD of different etiologies were found to:1) not
taking adequate nutrients, 2) consume fewer fruits, vegetables,
protein, and dairy, 3) had an increase in empty calories, 4)
breakfast commonly skipped and 5) once cirrhotic, etiology
made no difference in nutritional habits.
Disclosures:
Tarek Hassanein - Advisory Committees or Review Panels: AbbVie Pharmaceuti-
cals, Bristol Myers Squibb; Grant/Research Support: Janssen R&D, Bristol-Myers
Squibb, Salix Pharmaceuticals, Sundise Traditional Chinese Pharmaceuticals,
Boehringer-Ingelheim, Vertex Pharmaceuticals, Ikaria Pharmaceuticals, Idenix
Pharmaceuticals, Eiasi Pharmaceuticals, Gilead Sciences, Inc., AbbVie Pharma-
ceuticals; Speaking and Teaching: Bristol Myers Squibb, Gilead Sciences, Inc.,
Baxter, Salix
The following people have nothing to disclose: Anna Marie Hefner, Cynthia D.
Connelly, Kathy S. James, Catherine Hill, Preeti Reshamwala
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
273
Absence of the intestinal microbiota exacerbates hepa-
tobiliary disease in a murine model of primary scleros-
ing cholangitis
James H. Tabibian1,2, Steven P. O’Hara1,2, Christy E. Trussoni1,2,
Pamela S. Tietz1,2, Patrick L. Splinter1,2, Taofic Mounajjed3, Lee R.
Hagey4, Nicholas F. LaRusso1,2; 1Division of Gastroenterology and
Hepatology, Mayo Clinic, Rochester, MN; 2Center for Cell Signal-
ing in Gastroenterology, Mayo Clinic, Rochester, MN; 3Division
of Anatomic Pathology, Mayo Clinic, Rochester, MN; 4Division of
Gastroenterology, University of California, San Diego, La Jolla, CA
Introduction: Primary sclerosing cholangitis (PSC) is a chronic,
idiopathic, fibro-inflammatory cholangiopathy usually associ-
ated with inflammatory bowel disease and with no effective
pharmacotherapy. The role of the intestinal microbiota in the
etiopathogenesis of PSC may be fundamentally important yet
remains obscure. Thus, using the mdr2-/- mouse model of PSC,
we tested the hypothesis that germ-free (GF) mdr2-/- mice
develop a distinct PSC phenotype compared to conventional-
ly-housed (CV) mdr2-/- mice. Methods: Mdr2-/- mice (n=12)
were re-derived as GF by embryo transfer, maintained in iso-
lators, and sacrificed at 60 days in parallel with age- and sex-
matched CV mdr2-/- mice. Serum biochemistries were assessed
by clinical chemistry and gallbladder bile acids by high-pres-
sure liquid chromatography. H&E- and Trichrome-stained liver
sections were examined by a hepatopathologist in a blinded
manner and validated morphometrically, biochemically, and
by cytokeratin 7 immunofluorescence microscopy (IFM). Chol-
angiocyte senescence was assessed by p16I in situ hybridiza-
tion in liver sections and by β-galactosidase (SA-β-gal) staining
in a culture-based model of insult-induced senescence. Continu-
ous variables were analyzed with Wilcoxon rank-sum test, and
categorical variables were analyzed with Fisher’s exact test.
Results: Serum biochemistries, including alkaline phosphatase,
aspartate aminotransferase, and bilirubin, were significantly
higher in GF mdr2-/- than in CV mdr2-/- mice (p<0.01). Pri-
mary bile acid profiles were similar, while secondary bile acids
were absent in GF mdr2-/- mice consistent with the absence of
intestinal microbiota. Hepatic fibrosis, ductular reaction, and
ductopenia were significantly more severe in GF mdr2-/- mice
(p<0.01) and confirmed by morphometry on picosirius red-
stained sections, hepatic hydroxyproline assay, and IFM on
cytokeratin 7-immunostained liver sections, respectively. Chol-
angiocyte senescence, previously shown by us to be charac-
teristic of PSC, was significantly increased in GF mdr2-/- mice
and abrogated in vitro by ursodeoxycholic but not deoxycholic
acid. Conclusions: GF mdr2-/- mice exhibit exacerbated bio-
chemical and histologic features of PSC and increased chol-
angiocyte senescence, a characteristic and potential mediator
of progressive biliary disease. Ursodeoxycholic acid, a com-
mensal microbial metabolite and anti-cholestatic compound,
abrogates cholangiocyte senescence in vitro. These findings
demonstrate the importance of the commensal microbiota and
its metabolites in protecting against biliary injury and support
further studies of their role as potential biomarkers and thera-
peutic targets in PSC.
Disclosures:
The following people have nothing to disclose: James H. Tabibian, Steven P.
O’Hara, Christy E. Trussoni, Pamela S. Tietz, Patrick L. Splinter, Taofic Mou-
najjed, Lee R. Hagey, Nicholas F. LaRusso
337A
274
Lipopolysaccharide (LPS)-induced cholangiocyte N-Ras
activation requires epidermal growth factor receptor
(EGFR) activation
Christy E. Trussoni, Patrick L. Splinter, James H. Tabibian, Steven
P. O’Hara; Mayo Clinic, Rochester, MN
Introduction: Cholangiocytes (biliary epithelial cells) actively
participate in microbe-induced, proinflammatory responses in
the liver and contribute to biliary inflammatory and infectious
cholangiopathies. The molecular mechanisms regulating these
processes remain largely unknown. We previously demon-
strated that cholangiocyte TLR-dependent N-Ras activation
contributes to the proinflammatory/ proliferative response to
pathogen recognition. Using a cell culture model of cholangio-
cyte response to pathogen recognition, we test the hypothesis
that LPS-induced activation of N-Ras requires transactivation of
the EGFR. Methods: H69 cells, an SV40-transformed human
cholangiocyte cell line, or normal human cholangiocytes
(NHC), low passage human biliary epithelial cells isolated from
normal liver, were treated with LPS in the presence or absence
of EGFR, ADAM metallopeptidase domain 17 (TACE), or SRC
inhibitors. Ras activation assays were performed using a GST-
Ras Binding Domain activation assay. Co-immunoprecipitations
and acceptor photobleaching Förster Resonance Energy Trans-
fer (FRET) were performed to assess the LPS-induced proximity
of TLR/MyD88 and EGFR/Grb2 receptor complexes. Quanti-
tative RT-PCR and proliferation assays were performed in cells
cultured in the presence or absence of the inhibitors or an
siRNA to Grb2. Immunofluorescence for phospho-EGFR was
performed on patient samples from primary sclerosing chol-
angitis, primary biliary cirrhosis, hepatitis C virus-infected and
normal control livers. Results: LPS-treatment induced the rapid
interaction between the TLR/MyD88 and EGFR/Grb2 signal-
ing apparatus and biphasic N-Ras activation with an imme-
diate (<5 minutes) and a delayed (~30 minutes) phase. The
early N-Ras activation phase was insensitive to both Src and
TACE inhibitors, while the delayed phase required EGFR, Src,
and TACE and correlated with EGFR phosphorylation. Both
TACE inhibition and Grb2 depletion prevented LPS-induced
IL-6 and IL8 expression (p<0.05) and proliferation (p<0.01).
Moreover, cholangiocytes from PSC livers exhibit increased
EGFR phosphorylation compared to disease and normal con-
trols (p<0.01). Conclusions: Our results suggest that EGFR is
essential for LPS-induced TLR4/MyD88-mediated N-Ras activa-
tion and induction of a robust proinflammatory response. These
findings have implications not only for revealing the signaling
potential of TLRs, but also implicate the EGFR as an integral
component of cholangiocyte TLR-induced proinflammatory and
reparative processes. Moreover, these findings demonstrate the
potential importance of this signaling pathway in hepatobiliary
disease.
Disclosures:
The following people have nothing to disclose: Christy E. Trussoni, Patrick L.
Splinter, James H. Tabibian, Steven P. O’Hara
275
Ezrin, a membrane cytoskeletal cross-linker is essential
for the regulation of biliary flow in mice
Ryo Hatano, Kaori Akiyama, Shinji Asano; Department of Molec-
ular Physiology, College of Pharmaceutical Sciences, Ritsumeikan
University, Kusatsu, Japan
The secretin dependent biliary secretion of ions and water by
transporters and/or channels is essential for the regulation of
biliary flow. The cystic fibrosis transmembrane conductance
338A AASLD ABSTRACTS
regulator (CFTR) plays a key role in the chloride secretion into
the bile. In the cystic fibrosis (CF) patients, totally 5 to 10%
of patients develop the progressive biliary fibrosis resembling
primary sclerosing cholangitis. The loss of CFTR in mice also
leads to the liver failure. ERM (ezrin-radixin-moesin) proteins
are identified as cross-linkers between plasma membrane
proteins and actin cytoskeleton. Ezrin interacts with Na+/
H+ exchanger regulatory factor-1 (NHERF1) via its N-terminal
binding domain and with actin cytoskeleton via its C-terminal
actin-binding domain. CFTR is associated with NHERF1 via its
c-terminal PDZ binding motif. In the liver, ezrin, but not radixin
or moesin, is exclusively expressed in the cholangiocytes and
colocalizes with CFTR and NHERF1 at apical membrane of
cholangiocyte. In the present study, we have found that ezrin
knockdown (Vil2kd/kd) mice develop severe hepatic failure
characterized by extensive bile duct proliferation, periductular
fibrosis, and intrahepatic bile acid accumulation. In these mice,
apical membrane localizations of CFTR and NHERF1 were
disturbed in the bile ducts. Stable expression of a dominant
negative form of ezrin in immortalized mouse cholangiocytes
also led to the reduction of the surface expression of CFTR. Fur-
thermore, the surface expressions of other transport proteins,
which are required for the apical ion and water transport in
bile duct including Anion exchanger 2 (AE-2) and aquaporin
1 (AQP1), were also disturbed in cholangiocytes. Reduced
surface expression of these transport proteins was accompa-
nied by reduced CFTR-mediated Cl- efflux activity. These data
suggest that dysfunction of ezrin mimics important aspects of
the pathological mechanisms responsible for cholangiopathies
via the regulation of apical membrane transport in bile ducts.
Disclosures:
The following people have nothing to disclose: Ryo Hatano, Kaori Akiyama,
Shinji Asano
276
Regulation of cholangiocyte IL-6 release by extracellular
adenosine
Elise G. Lavoie, Jessica R. Goree, Michel Fausther, Jonathan A.
Dranoff; Internal Medicine / Division of Gastroenterology and
Hepatology, University of Arkansas for Medical Sciences, Little
Rock, AR
Background. Cholangiocytes release a variety of inflammatory
mediators in response to injury. Cholangiocyte release of IL-6
is of particular importance, since it is necessary for liver regen-
eration. However, the mechanisms regulating IL-6 in cholan-
giocytes are largely unknown. Since adenosine is increasingly
recognized as a potent mediator of liver injury, we tested the
hypothesis that extracellular adenosine induces upregulation
of IL-6 in cholangiocytes in a physiologically relevant fash-
ion. Specific Aims. The goals of this project were to: identify
adenosine receptors and determine the mechanisms by which
extracellular adenosine upregulates IL-6 in cholangiocytes
and to determine whether mice lacking these pathways have
impaired response to liver regeneration. Methods. Cell culture
experiments were performed in H69 cells. Determination of
adenosine receptors was assessed by RT-PCR, and immunohis-
tochemistry. Assessment of IL-6 expression was determined by
qRT-PCR and ELISA. The role of the A2b receptor as a regulator
of IL-6 release in H69 cells was tested by inhibition with the
A2b-specific antagonist MRS-1754 and A2b-specific siRNA.
The functional role of A2b in liver regeneration was tested by
partial hepatectomy performed in A2b -/- and wt mice. Results.
At the mRNA level, A2b was the primary adenosine receptor
expressed by H69 cells, and A2b was localized at the plasma
membrane level. Since the A2b receptor is uniquely coupled
HEPATOLOGY, October, 2014
to Gs and Gq proteins, we tested the effects of adenosine
on cAMP and Ca2+ generation. We found that adenosine
upregulated cAMP and generated Ca2+i signals. Adenosine
upregulated IL-6 mRNA and IL-6 protein released by H69 cells,
and this was blocked by MRS-1754 and A2b-specific siRNA.
Interestingly, IL-6 upregulation was blocked by inhibition of
Ca2+i but not cAMP. In response to partial hepatectomy, A2b
knockout mice exhibited blunted and delayed regeneration
without change in survival. Conclusions. This study provides
evidence of a novel pathway in which extracellular adenosine
induces intracellular cAMP and Ca2+ signals, of which the
latter stimulates IL-6 upreguation. Adenosine-sensitive upregula-
tion of IL-6 is important but not necessary in the injury response
to partial hepatectomy.
Disclosures:
The following people have nothing to disclose: Elise G. Lavoie, Jessica R. Goree,
Michel Fausther, Jonathan A. Dranoff
277
Role of the miR-125b- regulated HDC/histamine/VEGF
axis during the progression of biliary proliferation in
the PSC/MDR2-/- mouse model
Yuyan Han3, Laura Hargrove2, Lindsey Kennedy1, Allyson B.
Graf1, Sharon DeMorrow3,2, Fanyin Meng1,2, Quy P. Nguyen1,
Victoria Huynh3, Heather L. Francis1,2; 1Central Texas Veteran’s
Healthcare System, Temple, TX; 2BaylorScott and White Hospital,
Temple, TX; 3Texas A&M HSC COM, Temple, TX
Background: Primary sclerosing cholangitis (PSC) is a chronic
liver disease that is characterized by cholestasis and inflamma-
tion of cholangiocytes, resulting in bile duct strictures, which
affects the entire biliary epithelium. MDR2-/- mice are used
as a model of human PSC; however, the full characterization
of the biliary epithelium in this model is undefined. During
cholestatic injury induced by bile duct ligation (BDL), there is
an upregulation of histamine (HA) secretion, histidine decar-
boxylase (HDC) expression and vascular endothelial growth
factor (VEGF) secretion and expression in cholangiocytes. We
have shown that miR-125b expression is downregulated in
BDL mice and BDL-induced liver injury is regulated by the miR-
125b/HDC/HA/VEGF axis. Our study aims to (i) characterize
biliary proliferation/damage in MDR2-/- mice at various ages;
and (ii) determine if the miR-125b/HDC/HA/VEGF axis medi-
ates biliary proliferation/damage in MDR2-/- mice. Methods:
MDR2-/- and matching wild type (WT) were sacrificed from
1 to 36 weeks of age. We collected serum, cholangiocytes
and liver blocks. By immunohistochemistry (IHC), we measured
intrahepatic bile duct mass (IBDM) using CK-19 and prolifera-
tion by PCNA in liver sections. In total liver we evaluated the
expression of PCNA, HDC, VEGF-A, BAX, caspase 3 and miR-
125b by real-time PCR. To determine if miR-125b has a direct
effect on cholangiocytes, we silenced miR-125b expression
in vitro using a miR-125b inhibitor and measured prolifera-
tion by MTT assay, histamine secretion by EIA and VEGF-A
expression by real-time PCR. Results: We found by both CK-19
and PCNA IHC, a progressive pattern of increased IBDM and
cholangiocyte proliferation that peaked at 6-8 weeks followed
by a steady decline from 10-36 weeks of age with proliferation
returning to levels of WT mice at 36 weeks. The gene expres-
sion pattern of CK-19, PCNA, HDC and VEGF-A was similar
to proliferation data, whereas the pattern of apoptosis demon-
strated an opposite trend. Similar to the BDL model, miR-125b
expression was decreased at peak proliferative weeks. In vitro,
we found that inhibition of miR-125b expression increased pro-
liferation, histamine secretion and VEGF-A expression. Conclu-
sion: Our results demonstrate that there is a progressive pattern
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
of proliferation followed by bile duct loss in MDR2-/- mice
beginning at 1 week of age through 36 weeks of age. Similar
to BDL-induced liver injury, the miR-125b/HDC/HA/VEGF axis
regulates biliary proliferation in this model of PSC. Targeting
this axis may be a potential therapeutic avenue for PSC. The
MDR2-/- mouse may be an effective model to study molecular
and pathological mechanisms of PSC.
Disclosures:
The following people have nothing to disclose: Yuyan Han, Laura Hargrove, Lind-
sey Kennedy, Allyson B. Graf, Sharon DeMorrow, Fanyin Meng, Quy P. Nguyen,
Victoria Huynh, Heather L. Francis
278
Characterization of cultured cholangiocytes isolated
from livers of patients with primary sclerosing cholan-
gitis
Christy Trussoni1,2, James H. Tabibian1,2, Steven P. O’Hara1,2, Pat-
rick L. Splinter1,2, Julie Heimbach3, Nicholas F. LaRusso1,2; 1Divi-
sion of Gastroenterology and Hepatology, Mayo Clinic, Rochester,
MN; 2Center for Cell Signaling in Gastroenterology, Mayo Clinic,
Rochester, MN; 3Division of Transplant Surgery, Mayo Clinic,
Rochester, MN
Introduction: Primary sclerosing cholangitis (PSC) is a chronic,
idiopathic, incurable cholangiopathy in which the pathogene-
sis remains obscure, in part because of the lack of appropri-
ate experimental models. Here, through cellular, molecular,
and next-generation sequencing (NGS) methods, we describe
the development of a PSC patient-derived cholangiocyte cell
line and characterization of the phenotypic and signaling
features. Methods: We isolated cholangiocytes from stage 4
PSC patient liver explants by dissection, differential filtration,
and immune-magnetic bead separation. We maintained chol-
angiocytes in culture and assessed for: i) cholangiocyte, cell
adhesion, and inflammatory markers; ii) proliferation rate; iii)
transepithelial electrical resistance (TEER); iv) cellular senes-
cence; and v) transcriptomic profiles by NGS. We used two
well-established normal human cholangiocyte cell lines (H69
and NHC) for comparison. Results: Isolated PSC cells expressed
cholangiocyte (e.g. cytokeratin 7 and 19) and epithelial cell
adhesion markers (EPCAM, ICAM) and were negative for
hepatocyte and myofibroblast markers (albumin, α-actin). Pro-
liferation rate was lower for PSC compared to normal chol-
angiocytes (4 vs. 2 days, respectively, p<0.01). Maximum
TEER was also lower in PSC compared to normal cholangio-
cytes (100 vs. 145 Ωcm2, p<0.05). IL-6 and IL-8 (protein and
mRNA) were both increased compared to NHCs and H69s (all
p<0.01). The proportion of cholangiocytes staining positive for
senescence-associated β-galactosidase was markedly higher
in PSC cholangiocytes compared to NHCs (48% vs. 5%,
p<0.01). Lastly, NGS confirmed cholangiocyte marker expres-
sion in isolated PSC cholangiocytes and extended our findings
that pro-inflammatory and senescence-associated markers are
increased in PSC compared to normal cholangiocytes. Conclu-
sions: We have demonstrated that high-purity cholangiocytes
can be isolated from human PSC liver and grown in primary
culture. Isolated PSC cholangiocytes exhibit a phenotype that
may reflect their in vivo contribution to disease and serve as a
vital tool for in vitro investigation of biliary pathobiology and
identification of new therapeutic targets in PSC.
Disclosures:
The following people have nothing to disclose: Christy Trussoni, James H. Tabib-
ian, Steven P. O’Hara, Patrick L. Splinter, Julie Heimbach, Nicholas F. LaRusso
339A
279
The Fraction of Bile Ducts Lost in Portal Areas Correlates
with Degree of Fibrosis and Alkaline Phosphatase Levels
in Patients with Primary Biliary Cirrhosis
Mazen Noureddin1,2, David E. Kleiner1, Xiongce Zhao1, Jason L.
Eccleston1, Daniel Woolridge1, Nabil Noureddin1, T. Jake Liang1,
Jay H. Hoofnagle1, Theo Heller1; 1Liver Diseases Branch, NIH,
behtesda, MD; 2USC, Los Angeles, CA
Background: In primary biliary cirrhosis (PBC), predictive mod-
els have been developed to assess disease severity, survival,
and treatment response. Classical histological systems have
been used but do not always correlate with the disease severity
or outcome. Pathological findings that may correlate with the
disease severity were investigated. Patients and Methods: This
was a cross sectional analysis of clinical, laboratory and his-
tological data from 95 patients with liver biopsy proven PBC
who were seen at the Clinical Center of the National Institutes
of Health between 1979 and 2011. Inflammation and fibro-
sis were evaluated using the Ishak scoring system. Semi-quan-
titative scoring (0-3) was used to evaluate ductular reaction
and aberrant hepatocyte staining with keratin 7 (K7). The bile
duct loss fraction (BDLF) was calculated by [1- (number of por-
tal areas with ducts/total number of portal areas identified)].
Results: 90% of patients were women and 83% were white.
At entry and before any treatment, 61 patients had mild Ishak
fibrosis scores (0-2), 28 moderate (3-4) and 6 advanced scores
(5-6). Comparing patients with mild, moderate and advanced
fibrosis there were statistical differences in: platelet count (254
± 91, 187 ± 96, 66; P=0.04), INR (1.0, ± 0.1, 1.1 ± 0.1, 1.3
± 0.1; P= 0.02), and alkaline phosphatase (435 ± 344, 697
± 597, 755 ± 227; P=0.02) while there were no differences
in aminotransferase, bilirubin, or immunoglobulin levels. Histo-
logically, the total inflammation scores were higher in the mod-
erate fibrosis (9.3 ± 2.8) compared to advanced (7.0 ± 2.8)
and mild groups (7.5 ± 2.5) (P=0.02). The BDLF increased with
higher fibrosis scores (0.4 ± 0.3 for mild, 0.5 ± 0.3 for mod-
erate and 0.9± 0.1 for advanced cases; P=0.0001) while the
degree of K7 staining in the rest of the biopsy was not different.
Moreover, BDLF correlated robustly with alkaline phosphatase
(r=0.48; P<0.0001), a surrogate maker of disease progression
and treatment response. BDLF did not correlate with presence
of symptoms of itching or fatigue. Conclusion: BDLF reflects the
percentage of bile duct loss in portal tracts in PBC. It correlates
with alkaline phosphatase and degree of fibrosis. This finding
may allow for development of a more rigorous and clinically
predictive histological scoring system for PBC.
Disclosures:
The following people have nothing to disclose: Mazen Noureddin, David E.
Kleiner, Xiongce Zhao, Jason L. Eccleston, Daniel Woolridge, Nabil Noureddin,
T. Jake Liang, Jay H. Hoofnagle, Theo Heller
280
Altered Functional Connections in the Brain of Patients
With Primary Biliary Cirrhosis are Associated with
Fatigue
Victoria Mosher1,2, Mark G. Swain3, Robert P. Myers3, Glenda
M. MacQueen5,6, Bradley G. Goodyear2,4; 1Medical Science,
University of Calgary, Calgary, AB, Canada; 2Seaman Family MR
Research Centre, Calgary, AB, Canada; 3Liver Unit, Calgary Divi-
sion of Gastroenterology and Hepatology, Calgary, AB, Canada;
4Radiology, University of Calgary, Calgary, AB, Canada; 5Psychi-
atry, University of Calgary, Calgary, AB, Canada; 6Mathison Cen-
tre for Mental Health Research & Education, Calgary, AB, Canada
Introduction: Fatigue affects up to 85% of patients with Primary
Biliary Cirrhosis (PBC) and is a major contributor to decreased
340A AASLD ABSTRACTS
quality of life. However, fatigue in PBC is not related to mea-
sures of disease severity. Despite its impact on patients, the
cause of fatigue in PBC remains poorly understood. Previous
functional magnetic resonance imaging (fMRI) studies have
demonstrated an association between putamen (part of the
basal ganglia) activity and fatigue in a number of non-he-
patic disorders. Therefore, we used resting-state fMRI (ie. in
the absence of a task) to determine if functional connections
with the putamen are altered in PBC patients in association
with fatigue scores. Methods: Ten PBC patients (none with
advanced liver fibrosis) and ten sex- and age-matched healthy
controls underwent a resting-state fMRI scan. Brain maps of
functional connection strength with the putamen were gener-
ated using time series analysis. These maps were compared
between groups, using each patient’s Fatigue Severity Scale
(FSS) score as a covariate. Results: Compared to healthy con-
trols, PBC patients exhibited reduced functional connection
strength with the right thalamus (receives sensory input from
the body), the left globus pallidus (sends inhibitory input to
the motor system), and areas of the brain involved in emo-
tional processing (including the right anterior cingulate cor-
tex and bilateral caudate). In addition, PBC patients exhibited
reduced functional connection strength with bilateral premotor
cortices, involved in refining motor movements and providing
input to the thalamus. Greater FSS scores were associated with
decreased functional connection strength with the right primary
somatosensory cortex (receives input from the thalamus) and
left hippocampus (involved in memory)(Figure 1). Conclusions:
Our results suggest that PBC patients exhibit reduced functional
brain connectivity with areas of the basal ganglia, which have
been implicated in fatigue. These data also suggest that PBC
impacts the motor network of the brain, which could contribute
to clinical manifestations of fatigue. Moreover, patients that
report higher levels of fatigue exhibit a further reduction of
functional connection strength between the putamen and the
right superior frontal gyrus, suggesting that symptom severity
can manifest as measurable changes in the functional organi-
zation of the brain.
Disclosures:
Mark G. Swain - Advisory Committees or Review Panels: Roche, Gilead, Idenix,
Boehringer-Ingelheim, Janssen; Grant/Research Support: Roche, Gilead, Bris-
tol-Myers-Squibb, Boehringer-Ingelheim, Janssen
Robert P. Myers - Advisory Committees or Review Panels: Roche, Merck, Ver-
tex, Norgine Ltd., GE Healthcare ; Grant/Research Support: Echosens, Roche,
Merck; Speaking and Teaching: KNS Canada, Roche, Merck, Vertex
Glenda M. MacQueen - Advisory Committees or Review Panels: Pfizer, Lund-
beck, Sunovion; Speaking and Teaching: Lilly
The following people have nothing to disclose: Victoria Mosher, Bradley G.
Goodyear
HEPATOLOGY, October, 2014
281
Sub-stratification of hepatocellular carcinoma risk in
men with primary biliary cirrhosis: results of an interna-
tional multicenter study
Palak J. Trivedi1, Willem J. Lammers2, Henk R. van Buuren2,
Annarosa Floreani3, Albert Pares4, Angela C. Cheung5, Cyriel
Y. Ponsioen6, Christophe Corpechot7, Marlyn J. Mayo8, Pietro
Invernizzi9, Pier Maria Battezzati10, Frederik Nevens11, Andrew
Mason12, Kris V. Kowdley13, Ka-Kit Li1, Tony Bruns1, Mohamad
Imam14, Teru Kumagi15, Nora Cazzagon3, Irene Franceschet3,
Llorenc Caballeria4, Kirsten Boonstra6, Raoul Poupon7, Ana Lleo9,
Keith D. Lindor16, Harry L. Janssen6, Bettina E. Hansen2, Gideon
Hirschfield1; 1Centre for Liver Research and NIHR Institute of Bio-
medical Research, University of Birmingham, Birmingham, United
Kingdom; 2Dept of Gastroenterology and Hepatology, Erasmus
University Medical Centre, Rotterdam, Netherlands; 3Department
of Surgery, Oncology and Gastroenterology, University of Padua,
Padua, Italy; 4Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS,, Uni-
versity of Barcelona, Barcelona, Spain; 5Liver Clinic, Toronto West-
ern & General Hospital, University Health Network, Toronto, ON,
Canada; 6Dept of Gastroenterology and HepatologY, Academic
Medical Center, Amsterdam, Netherlands; 7Centre de Référence
des Maladies Inflammatoires des VoiesBiliaires, Hôpital Saint-An-
toine, APHP, Paris, France; 8Digestive and Liver diseases, UT
Southwestern Medical Center, Dallas, TX; 9Liver Unit and Center
for Autoimmune Liver Diseases, Humanitas Clinical and Research
Center, Rozzano (MI), Italy; 10Department of Health Sciences,
Università degli Studi di Milano, Milan, Italy; 11Dept of Hepatol-
ogy, University Hospitals Leuven, KULeuven, Belgium; 12Divison of
Gastroenterology and Hepatology, University of Alberta, Edmon-
ton, AB, Canada; 13Liver Center of Excellence, Digestive Disease
Institute, Virginia Mason Medical Center, Seattle, WA; 14Dept
Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN;
15Department of Gastroenterology and Metabology, Ehime Univer-
sity graduate School of Medicine, Ehime, Japan; 16Arizona State
University, Phoenix, AZ
Background: Hepatocellular carcinoma (HCC) is an infrequent
yet critical event in primary biliary cirrhosis (PBC) and devel-
opment is heavily influenced by patient gender. However, it
remains unclear whether HCC risk can be further stratified in
men, a population deemed inherently high-risk. Methods: Indi-
vidual patient-data was collected from over 15 North American
and European liver centres, spanning >40-years observation
period. Risk-factor analysis was performed using Cox propor-
tional hazard regression models and Kaplan-Meier estimates
(SPSSv21). Results: Across a cohort of 4565 patients with con-
firmed PBC (median follow-up 7.1 years), 123 cases of HCC
were identified. Men were more likely to develop HCC than
women (incidence rate: 6.7 vs. 2.6 cases per 1,000 patient
years; HR: 2.91, 1.9-4.8 p<0.0001), and this difference
retained significance when restricting the analysis to males
and females with advanced disease at PBC diagnosis (HR 2.9,
95% CI 1.60-5.32, p<0.001). However, significant differences
between genders were no longer apparent when the incidence
was compared in patients with early-stage PBC (p=0.49). The
proportion of PBC patients receiving ursodeoxycholic acid
(UDCA) was similar between men and women (84% versus
85%, respectively; p=0.75); however, on stratifying for bio-
chemical response (Paris-I) the highest HCC risk was observed
in non-responding male patients, and significantly greater than
male-responders and female non-responders (overall log-rank
p<0.001; Figure 1). Conclusion: Male gender is a significant
risk factor for development of HCC in PBC although effective
risk stratification can be furthered by assessment of disease
stage and application of biochemical response criteria.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Figure 1: HCC incidence stratified according to gender and bio-
chemical disease stage
Disclosures:
Palak J. Trivedi - Grant/Research Support: Wellcome Trust
Albert Pares - Consulting: Lumena Pharmaceuticals
Cyriel Y. Ponsioen - Consulting: AbbVIE; Grant/Research Support: AbbVIE, Sch-
ering Plough, Dr. Falk Pharma, Tramedico Netherlands
Marlyn J. Mayo - Grant/Research Support: Intercept, Salix, NGM, Lumena,
Gilead
Frederik Nevens - Consulting: CAF, Intercept, Gore, BMS, Abbvie, Novartis,
MSD, Eumedica, Janssen; Grant/Research Support: Ipsen, Roche, MSD, Astellas
Kris V. Kowdley - Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research
Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria,
Janssen, Merck, Mochida, Vertex
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sci-
ences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support:
Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck,
Medtronic, Novartis, Roche, Santaris
The following people have nothing to disclose: Willem J. Lammers, Henk R. van
Buuren, Annarosa Floreani, Angela C. Cheung, Christophe Corpechot, Pietro Inv-
ernizzi, Pier Maria Battezzati, Andrew Mason, Ka-Kit Li, Tony Bruns, Mohamad
Imam, Teru Kumagi, Nora Cazzagon, Irene Franceschet, Llorenc Caballeria,
Kirsten Boonstra, Raoul Poupon, Ana Lleo, Keith D. Lindor, Bettina E. Hansen,
Gideon Hirschfield
282
A Mouse Model of Fibrous Cholangiopathy
Sumera Rizvi, Anuradha Krishnan, Maria Eugenia Guicciardi, Ste-
ven F. Bronk, Gregory J. Gores; Division of Gastroenterology and
Hepatology, Mayo Clinic, Rochester, MN
Background and Aims: Primary sclerosing cholangitis (PSC)
is an enigmatic, progressive cholestatic liver disease charac-
terized by a fibrous cholangiopathy of large and small bile
ducts. Treatment options for PSC are limited and lack robust
efficacy. Both bile acid toxicity and death receptor signaling
have been implicated in the pathogenesis of PSC (Fickert et
al., Am J Pathol. 2006; Takeda et al., Proc Natl Acad Sci U S
A. 2008). Because death receptor signaling is modulated by
cellular inhibitor of apoptosis (cIAP) proteins, we explored the
role of cIAP-1 and -2 in the pathogenesis of PSC. Methods:
Human PSC (N=20, stage IV) and nonalcoholic steatohepatitis
liver sections (NASH) (N=20) were examined by immunohis-
tochemistry (IHC). Mice liver sections were examined by IHC,
Sirius red staining, and TUNEL assay. Mouse cholangiograms
were obtained by injecting a radio opaque liquid silicone poly-
mer containing lead chromate into the biliary system followed
by microCT with 3-D reconstruction. Results: Expression of
cIAP-1 and -2 proteins in interlobular bile ducts was markedly
reduced in human PSC liver sections compared to NASH. To
ascertain if cIAP-1 and -2 elimination was sufficient to induce
PSC changes, C57Bl/6 mice fed a 0.2% diet of the hydro-
phobic bile acid deoxycholate (DCA) were treated with and
without AT-406 (oral gavage, 100 mg/kg/d for 14 days),
341A
a SMAC mimetic which induces rapid cellular elimination of
cIAP proteins. Mice receiving both AT-406 plus DCA displayed
a non-obliterative, fibrous cholangiopathy of the interlobular
bile ducts as assessed by Sirius red staining, which was not
observed with DCA alone (2.5-fold increase, p<0.01). Signif-
icant apoptosis within the bile ducts, as evidenced by a 4-fold
increase in TUNEL positive cells, also occurred with AT-406
plus DCA compared to DCA alone (p<0.001). Cholangiogra-
phy of the AT-406 plus DCA treated mice demonstrated irreg-
ularity of segmental bile ducts and pruning of the biliary tree.
However, liver function tests revealed no elevation of alkaline
phosphatase or bilirubin. Finally, AT-406 treatment of a human
cholangiocyte cell line in vitro resulted in extensive elimination
of cIAP-1 and -2 with caspase-dependent cell death consistent
with activation of a death receptor signaling pathway. In con-
clusion, we have developed a murine model of non-oblitera-
tive, fibrous cholangiopathy with cholangiographic alterations
of segmental and peripheral bile ducts. These data suggest
new cytoprotective therapeutic strategies for PSC (i.e., caspase
inhibitors).
Disclosures:
Gregory J. Gores - Advisory Committees or Review Panels: Delcath, Genentech,
IntegraGen, Generon
The following people have nothing to disclose: Sumera Rizvi, Anuradha Krish-
nan, Maria Eugenia Guicciardi, Steven F. Bronk
283
Increased BMI is associated rapid progression of fibrosis
in Primary Sclerosing Cholangitis (PSC)
Aliya Gulamhusein1,2, Danielle Reid2, Bertus Eksteen2; 1Depart-
ment of Medicine, University of Toronto, Toronto, ON, Canada;
2Snyder Institute for Chronic Diseases, University of Calgary, Cal-
gary, AB, Canada
Background: Obesity has become a global epidemic and
has led to large increases in non-alcoholic fatty liver disease
(NAFLD). In parallel to the general population, we have also
detected an increase incidence in the mean body mass index
(BMI) in individuals with Primary Sclerosing Cholangitis (PSC).
Increased BMI in Primary Biliary Cirrhosis (PBC) is associated
with more advanced fibrosis but the effect of BMI in PSC is
unknown. Aim: To examine the effect of BMI on fibrosis stage
and progression in PSC. Methods: 291 PSC patients were
recruited from the Calgary PSC cohort and stratified according
to initial BMI at presentation. BMI <25 as normal, 25-30 as
overweight and >30 kg/m2 as obese. Fibrosis stage were
measured at least once every 12 months by transient elastog-
raphy using Fibroscan® and classified as F0 to F4 fibrosis.
We examined the fibrosis stage at presentation and the time
in months of progression to the next fibrosis stage. Data from
1368 patient years of follow up were assessed. Patients with
existing cirrhosis at their first presentation or less than 1 year of
follow up data were excluded. Results: 247 cases were eligible
for the study. 176 individuals had a normal body weight (BMI
<25), 57 were overweight (BMI 25-30) and 14 obese (BMI
>30). Mean times of progression to the next fibrosis stage were
51 months, 47 months and 13 months for normal body weight,
overweight and obese PSC patients respectively. In addition,
obese PSC patients were associated with a more advanced
fibrosis stage at presentation compared to normal or over-
weight cases. Conclusion: Significant proportions of patients
with PSC can be classified as overweight or obese. Obesity
(BMI 30 kg/m2) in PSC is associated with significantly more
advanced fibrosis at presentation and more rapid fibrosis pro-
gression as measured by non-invasive transient elastography.
Disclosures:
342A AASLD ABSTRACTS
The following people have nothing to disclose: Aliya Gulamhusein, Danielle Reid,
Bertus Eksteen
284
Activation of mDCs and CD8+ T cells is associated with
PSC-like cholangiopathy induced by small bowel bac-
terial overgrowth in a mouse model of autoimmune
biliary disease
Qingqing Wang1, Vijay Saxena1, Bin Wang1, Lili Miles2, Marnie
A. Ryan3, Jorge A. Bezerra3, William M. Ridgway4, Jaimie D.
Nathan1; 1Division of Pediatric General & Thoracic Surgery, Cin-
cinnati Children’s Hospital Medical Center, Cincinnati, OH; 2Divi-
sion of Pathology, Cincinnati Children’s Hospital Medical Center,
Cincinnati, OH; 3Division of Gastroenterology, Hepatology, and
Nutrition, Cincinnati Children’s Hospital Medical Center, Cincin-
nati, OH; 4Division of Immunology, Allergy and Rheumatology,
University of Cincinnati College of Medicine, Cincinnati, OH
BACKGROUND: The pathogenesis of primary sclerosing chol-
angitis (PSC) is largely unknown due to lack of an ideal animal
model. The association of PSC with inflammatory bowel dis-
ease suggests a critical role of gut-derived factors in its patho-
genesis. Our aim was to investigate the role of small bowel
bacterial overgrowth (SBBO) in the development of PSC-like
cholangiopathy. METHODS: We surgically created a jejunal
self-filling blind loop (SFBL) to induce SBBO in a genetically
susceptible mouse strain (NOD.B6Abd3), developed by intro-
gression of a 1-Mb non-MHC insulin-dependent diabetes locus
from B6 onto NOD background. Control mice underwent lapa-
rotomy (sham). Bacterial 16s rRNA gene sequencing was used
to analyze bacterial populations of jejunal lumen content. H/E
and Trichrome staining were used to assess hepatic inflamma-
tion and fibrosis. Flow cytometry was utilized to assess liver
immune cell profiles. Chemokine expression was assessed by
ELISA (serum) and by RT-PCR (liver tissue). RESULTS: Creation
of SFBL led to dramatic increase in bacterial counts in jejunal
lumen content, compared to sham mice. Gram-positive bacte-
rial families Lactobacillales and Clostridiales and Gram-nega-
tive bacterial family Porphyromonadaceae were significantly
less abundant in SFBL mice. However, Gram-negative bacterial
families Enterobacteriaceae and Bacteroidaceae and phylum
Verrucomicrobia were significantly more abundant in SFBL.
Trichrome staining of liver sections revealed characteristic PSC-
like lesions in 40% of SFBL mice, consisting of intrahepatic
periductal fibrosis, compared to 0% of sham mice. CD11c+CD-
11b+PDCA1- myeloid dendritic cells (mDCs) were significantly
increased in SFBL livers with PSC-like lesions (SFBL-PDF) com-
pared to SFBL livers without PSC-like lesions (SFBL-NON-PDF).
Although the expression of co-stimulatory markers CD80 and
CD86 in hepatic mDCs did not show significant difference
between SFBL-PDF and SFBL-NON-PDF mice, MHC-I expres-
sion was significantly increased and MHC-II expression was
significantly decreased in hepatic mDCs in SFBL-PDF mice.
Compared to SFBL-NON-PDF and sham mice, SFBL-PDF mice
had significantly increased CD8+CD44+ T cells and CCL3
and CCL4 mRNA levels in the liver, and significantly increased
CCL3 and CCL4 in serum. CONCLUSIONS: Our results sug-
gest that creation of SFBL induced quantitative and qualitative
changes in gut microbiota, contributing to the development
of PSC-like lesions in NOD.B6Abd3 mice. The development
of PSC-like lesions in NOD.B6Abd3 may be triggered by the
activation and expansion of liver mDCs, which in turn recruit
activated CD8+ T cells via T cell chemoattractant chemokines
CCL3 and CCL4.
Disclosures:
HEPATOLOGY, October, 2014
Jorge A. Bezerra - Grant/Research Support: Molecular Genetics Laboratory,
CHMC
The following people have nothing to disclose: Qingqing Wang, Vijay Saxena,
Bin Wang, Lili Miles, Marnie A. Ryan, William M. Ridgway, Jaimie D. Nathan
285
Changes of the hepatic transcriptome in human extra-
hepatic cholestasis
Frank G. Schaap1, Marlon J. Jetten2, Marcel H. Herwijnen2,
Maarten L. Coonen2, Jos C. Kleinjans2, Peter L. Jansen1, Steven
Olde Damink1; 1Department of Surgery, Maastricht University,
Maastricht, Netherlands; 2Department of Toxicogenomics, Maas-
tricht University, Maastricht, Netherlands
Background Bile salt (BS) toxicity plays an important role in
cholestatic liver injury. Adaptive mechanisms are operational to
reduce hepatic toxicity and promote urinary elimination of BS in
cholestasis. Following up on the observation that ectopic FGF19
expression in the human cholestatic liver comprises an adap-
tive strategy to reduce BS synthesis (Hepatology 49:1228), we
now explore the human hepatic transcriptome to gain further
insight into molecular networks affected by cholestasis. Meth-
ods Total RNA was isolated from liver biopsies of patients with
pancreatic tail cancer or benign liver tumors without cholestasis
(controls,n=9), patients with cholestasis due to periampullary
malignancies (cholestatic,n=9), and initially jaundiced patients
with periampullary malignancies receiving pre-operative bili-
ary drainage (drained,n=10). mRNA and miRNA expression
profiles were determined using Agilent arrays. Results Median
total BS and bilirubin level was 194 and 186 mmol/L, resp., in
cholestatic patients, with notable elevation of cholestatic injury
markers (GGT 1055U/L, AP 540U/L) and transaminases
(AST 232U/L, ALT 388U/L). In patients receiving pre-oper-
ative biliary drainage total BS, bilirubin and transaminases
were within the normal range. Despite resolution of cholestasis,
GGT (281U/L) and AP (190U/L) remained elevated in this
group. Hepatic mRNA/miRNA profiles were generated with
17581 mRNAs and 504 miRNAs meeting array QC criteria.
The transcriptome of control and drained groups was largely
similar with only a single differentially expressed (DE) mRNA
apparent (criteria: fold change >1.5 and adjusted P value
<0.05). Cholestasis resulted in pronounced changes of the
transcriptional landscape when compared with control (1353
DE mRNAs, 47 DE miRNAs) and drained (111 DE mRNAs, 2
DE miRNAs) groups. Overrepresentation analysis indicated a
multitude of pathways affected by cholestatic conditions includ-
ing ECM organization, regulation of actin cytoskeleton and
biotransformation. Alterations pertaining to BS homeostasis
included downregulation of BS synthesis (CYP7A1), repres-
sion of BS uptake (SLCO1B1/3) and induction of basolateral
efflux transporters (SLC51A/B) in cholestatic liver. Conclusions
Extrahepatic cholestasis elicits large scale alterations in hepatic
mRNA and miRNA expression. A notable difference in the
number of DE mRNAs/miRNAs was apparent when compar-
ing cholestatic with control and drained groups, with the latter
two having similar serum biochemistry and identical mRNA/
miRNA profiles. Follow-up studies are required to assess the
interaction between miRNA and mRNA networks and the role
of the identified pathways in cholestatic liver injury.
Disclosures:
The following people have nothing to disclose: Frank G. Schaap, Marlon J. Jet-
ten, Marcel H. Herwijnen, Maarten L. Coonen, Jos C. Kleinjans, Peter L. Jansen,
Steven Olde Damink
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
286
High serum levels and liver expression of sclerostin in
patients with primary biliary cirrhosis. Association with
markers of bone remodeling and severity of cholangitis
Silvia Ruiz-Gaspa2,3, Laia Gifre3, Nuria Guañabens3, Rosa
Miquel4, Pilar Peris3, Ana Monegal3, Albert Pares1,2; 1Liver Unit,
Hospital Clinic, Barcelona, Spain; 2Hospital CLinic, CIBERehd,
IDIBAPS, University of Barcelona, Barcelona, Spain; 3Metabolic
Bone Diseases Unit, Hospital Clinic, CIBERehd, IDIBAPS, University
of Barcelona, Barcelona, Spain; 4Department of Pathology, Hospi-
tal Clinic, University of Barcelona, Barcelona, Spain
Background and aims: Sclerostin, an inhibitor of the Wnt path-
way is involved in the regulation of osteoblastogenesis and
its role in the development of bone disease in primary biliary
cirrhosis (PBC), a disease characterized by low bone forma-
tion, is unknown. Therefore, we have assessed the circulating
levels and the liver gene and protein expression of sclerostin in
this cholestatic disease. Methods: Serum sclerostin levels were
measured in 83 women with PBC (mean age: 60 ± 12 years)
and 101 control women of the same age. Lumbar and femoral
bone mineral density (BMD) as well as parameters of min-
eral metabolism and bone remodeling (Ca/P, PTH, 25OHD,
PINP, bone ALP, sCTX, NTX and osteocalcin) were measured.
Moreover, sclerostin gene expression in the liver was assessed
in samples of liver tissue taken by biopsy in 11 PBC patients
and 5 healthy controls by real time PCR, and presence and
distribution of sclerostin was evaluated in liver slices from 11
patients by immunohistochemistry. The presence and severity
of histologic lesions were assessed semiquantitatively in the
same liver samples. Results: Seventy-seven percent of patients
had low BMD (22% osteoporosis and 55% osteopenia). PBC
patients had higher sclerostin levels than controls (76.7±38.6
vs. 32.5±14.7 pmol/L, p<0.001). Serum sclerostin correlated
inversely with markers of bone formation PINP (p=0.05) and
osteocalcin (p=0.03), and bone resorption, NTX (p=0.01)
and sCTX (p=0.03). Sclerostin mRNA in the liver was overex-
pressed as compared with control samples (2.7±0.3 fold vs
healthy liver). Sclerostin was detected by immunohistochemistry
in 7 of the 11 liver samples but not in controls, and mainly
located in the bile ducts. Sclerostin was directly associated
with the severity of cholangitis (p=0.02) and indirectly with
the degree of lobular inflammation (p=0.03), but not with the
degree of fibrosis neither with the Ludwig’s histologic stage.
Sclerostin mRNA expression was higher in samples positive by
immunohistochemistry (2.9 ±0.4vs 2.5 ± 0.3, p: n.s.), and par-
ticularly in those with lobular granuloma (3.6±0.6 vs 2.4±0.2,
p=0.02). Conclusion: The increased expression of sclerostin
in the liver and the association with histologic cholangitis may
explain the high serum levels of this protein in patients with pri-
mary biliary cirrhosis, thus suggesting that sclerostin influences
the decreased bone formation in this cholestatic disease.
Disclosures:
Albert Pares - Consulting: Lumena Pharmaceuticals
The following people have nothing to disclose: Silvia Ruiz-Gaspa, Laia Gifre,
Nuria Guañabens, Rosa Miquel, Pilar Peris, Ana Monegal
343A
287
Contribution of polymorphic LINE-1 retrotransposon
insertion in SLCO1B3 gene to susceptibility to drug-in-
duced cholestasis
Tatehiro Kagawa, Kazuya Anzai, Kota Tsuruya, Yoshitaka Arase,
Shunji Hirose, Koichi Shiraishi, Tetsuya Mine; Gastroenterology,
Tokai University, Isehara, Japan
[Background and Aim] Drug-induced cholestasis is a rare,
but sometimes, fatal disease. Underlying mechanisms remain
unknown. Organic anion transporting polypeptides OATP1B1
(gene: SLCO1B1) and OATP1B3 (gene: SLCO1B3) were iden-
tified as responsible for Rotor syndrome. We have recently
demonstrated that six Japanese patients with Rotor syndrome
were homozygous for the insertion of LINE-1 (L1) retrotrans-
poson in intron 5 of SLCO1B3 and for c.1738C>T (p.R580X)
nonsense mutation in SLCO1B1. Intronic L1 insertion in
SLCO1B3 causes skipping of exon 5 or exons 5-7 in SLCO1B3
mRNA, yields immature stop codon, and results in the gener-
ation of truncated OATP1B3 protein. OATP1B1 and 1B3 are
involved in hepatic uptake of bilirubin glucuronides, bile acids,
and steroidal and thyroid hormones, as well as various drugs
such as statins and anticancer drugs. Therefore, their genetic
abnormalities may cause acquired cholestasis. In this study we
analyzed L1 insertion in SLCO1B3 and c.1738C>T mutation in
SLCO1B1 in Japanese patients with drug-induced cholestasis.
[Patients and Methods] A total of 44 Japanese patients with
drug-induced cholestasis were enrolled after written informed
consent was obtained. Inclusion criteria were (1) alkaline phos-
phatase (AP) greater than 2 times the upper limit of normal
(ULN), (2) R ≤ 2, when R was defined as alanine aminotrans-
ferase (ALT)/ULN divided by AP/ULN, and (3) absence of
other hepatobiliary diseases. A single-tube, three-primer PCR
assay was established to detect L1 insertion in SLCO1B3. The
c.1738C>T mutation in SLCO1B1 was genotyped by direct
sequencing. Allele frequency was compared with Japanese
controls (n=554). [Results] Median (min-max) age of the cases
was 65 (21-80) years and males were dominant (64%). The
main causative drugs were antiplatelet agents (20%), followed
by cardiovascular agents (15%), anticoagulants (10%), and
antidiabetic agents (10%). In SLCO1B3 polymorphism, inser-
tion (ins)/ins, ins/wild, and wild/wild genotype was present
in 2.3%, 20.5%, and 77.3% of the cases, respectively, while
in 0.2%, 10.5%, and 89.4% of the controls, respectively. The
allele frequency of L1 insertion was 12.5% of the cases, which
was significantly greater than the controls (5.4%, P=0.012,
odds ratio 2.5 [95% CI: 1.3-4.9]). The c.1738C>T mutation
in SLCO1B1 was not observed in both cases and controls.
[Conclusions] The genotype of L1 retrotransposon insertion in
SLCO1B3 was observed more frequently in Japanese patients
with drug-induced cholestasis than controls. As L1 insertion
potentially impairs the function of OATP1B3, the individuals
with this polymorphism might be predisposed to acquired
cholestasis.
Disclosures:
The following people have nothing to disclose: Tatehiro Kagawa, Kazuya Anzai,
Kota Tsuruya, Yoshitaka Arase, Shunji Hirose, Koichi Shiraishi, Tetsuya Mine
344A AASLD ABSTRACTS
288
The role of repeated brush cytology in detecting dyspla-
sia or cholangiocarcinoma in primary sclerosing cholan-
gitis before liver transplantation
Ammar Majeed1, Annika Bergquist1, Gunnar Söderdahl2, Maria
Castedal3, Karouk Said1; 1Department of Gastroenterology and
Hepatology, Karolinska University Hospital, Karolinska Institutet,
Stockholm, Sweden; 2Department of Transplantation Surgery,
Karolinska University Hospital, Huddinge,, Stockholm, Sweden;
3Transplant institute,, Sahlgrenska University Hospital, Gothen-
burg, Sweden
Aim: The performance of single and repeated brush cytol-
ogy in detecting dysplasia or cholangiocarcinoma (CCA) in
patients with primary sclerosing cholangitis (PSC) prior to liver
transplantation, and patients’ survival during follow-up was
compared to the histopathology of the explanted liver. Meth-
ods: All consecutive PSC patients undergoing liver transplan-
tation in Sweden between 1999 and 2013 were evaluated
(n=255). Patients were categorized using histopathology of the
explanted liver to determine the presence of CCA or dysplasia.
Sensitivity, specificity, and other measures of test performance
were calculated for single and repeated brush cytology, with or
without fluorescence in situ hybridization (FISH). Survival after
liver transplantation was analyzed using Kaplan-Meier esti-
mate. Results: Brush cytology was done before liver transplan-
tation in 117 of the 225 patients, of whom 65 patients were
brushed more than once. The sensitivity and specificity of brush
cytology for diagnosing dysplasia or CCA increased from 50%
and 81% respectively in patients with one sampling, to 100%
and 83% respectively in patients where repeated examinations
were performed (table 1). When considering only the sub-
group where FISH was also done in addition to brush cytology
(n=64), the presence of aneuploidy increased the sensitivity of
brush cytology in this subgroup from 83% to 95%, while the
finding of only diploid cells increased specificity from 90%
to 95%. Survival after liver transplantation was significantly
lower in the group with pre-transplantation undiagnosed CCA
in the explanted liver p<0.001). Conclusion: In PSC patients,
the utilization of repeated brush cytology or the combination
with FISH results in increased sensitivity and specificity for the
detection of dysplasia or CCA. Improving pre-transplantation
test performance is important as the presence of undiagnosed
CCA results in significantly worse survival when discovered in
the explanted native live
Test performance for the detection of cholangiocarcinoma or
dysplasia
ROC: receiver operating characteristics, LR: likelihood ratio, OR:
odds ratio, PPV: positive predictive value, NPV: negative predic-
tive value.
Disclosures:
The following people have nothing to disclose: Ammar Majeed, Annika Bergq-
uist, Gunnar Söderdahl, Maria Castedal, Karouk Said
HEPATOLOGY, October, 2014
289
Contribution of Next Generation Sequencing to the
genotyping of patients with hereditary cholestasis and
cholelithiasis
Véronique D. Barbu1, Isabelle Jéru2, Christophe Corpechot3,
Eric Fernandez2, Laure Muller2, Fabienne Dufernez2, Olivier
Chazouillères3, Yannick Marie4, Zhenyu Xu5, Chantal Housset3;
1LCBGM, Pôle de Biologie Médicale et Pathologie, UPMC Univ
Paris VI & INSERM UMRS_938 & APHP, HUEP, St Antoine, Paris,
France; 2LCBGM, Pôle de Biologie Médicale et Pathologie,, APHP,
HUEP, St Antoine, Paris, France; 3CMR MIVB, UPMC Univ Paris VI
& INSERM UMRS_938 & APHP, HUEP, St Antoine, Paris, France;
4ICM, Institut du Cerveau et de la Moëlle épinière, Hôpital de
la Salpêtrière, Paris, France; 5Bioinformatics, Sophiagenetics SA,
Lausanne, Switzerland
Background: Next generation sequencing (NGS) allows the
high-throughput sequencing of multiple genes in several sub-
jects, concomitantly. This new technology should lower the
cost and time of molecular analyses in hereditary cholestasis
and cholelithiasis, which comprise autosomal dominant and
recessive disorders, and the disease-causing genes of which
contain numerous exons. NGS might also help to identify new
genes in these disorders. Aims of the study : 1) Determine the
feasibility and input of a NGS strategy for the screening of the
genes implicated in the recessive disorders progressive familial
intrahepatic cholestasis (i.e. ABCB4, ABCB11 and ATP8B1)
and Dubin Johnson’s syndrome (i.e. ABCC2); 2) Screen 5
candidate genes encoding transporters (ABCG5, ABCG8,
SLC4A2) or bile acid receptors (NR1H4, GPBAR1). Materi-
als and Methods: Fifty-five consecutive unrelated patients (2/3
females), referred to our national reference laboratory for intra-
hepatic cholestasis or cholelithiasis genotyping, were investi-
gated. Genomic DNA was extracted from peripheral blood. A
DNA capture strategy was developed, allowing the concomi-
tant screening of 24 patients. Each DNA was converted to a
sequencing library by fragmentation, end repair, and ligation
to oligonucleotide adapters. Specific gene probes for the 154
coding exons of the 10 genes of interest were designed with
the Nimblegen software. Individual library fragments were dou-
ble captured and clonally amplified by solid surface bridge
amplification (MiSeq sequencer). The dropGenTM application
was used to analyze the raw data of sequencing. Results: NGS
was extremely time-efficient and accurate. Each analysis of 24
patients was completed within a week. Sanger sequencing con-
firmed all identified variants. The mean coverage was ≥96.5%
with a depth of 400X. In 37 patients, variants were detected
in ABCB4 (n=14), ABCB11 (n=9), ABCC2 (n=14) and/or
ATP8B1 (n=5) genes. In 5 patients, 2 of these genes were
mutated (e.g. ATP8B1/ABCB4). In 10 patients, the variant(s)
of one of these genes were associated with variant (s) in one
of the candidate genes, namely GPBAR1 (n=4), ABCG5 (n=5)
or ABCG8 (n=1). The homozygous ABCB11 p.Val444Ala
genotype, known to be associated with hormonal cholesta-
sis, was detected in 20 patients. Conclusions: NGS provides
multiple advantages over the classical methods for genotyping
subjects with hereditary cholestasis or cholelithiasis. The results
obtained in a small study population highlight the frequent com-
bination of variations in genes previously known to be involved
in these disorders, between themselves, and, with other genes,
mainly GPBAR1 and ABCG5.
Disclosures:
Olivier Chazouillères - Consulting: APTALIS, MAYOLY-SPINDLER
The following people have nothing to disclose: Véronique D. Barbu, Isabelle
Jéru, Christophe Corpechot, Eric Fernandez, Laure Muller, Fabienne Dufernez,
Yannick Marie, Zhenyu Xu, Chantal Housset
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
290
Fenofibrate is Effective adjunctive Therapy in the Treat-
ment of Primary Biliary Cirrhosis: A Meta-Analysis
Alla Grigorian1, Houssam E. Mardini2, Christophe Corpechot3,
Raoul Poupon3, Cynthia Levy1; 1Hepatology, University of Miami,
Miami, FL; 2Gastroenterology and Hepatology, University of Ken-
tucky College of Medicine, Lexington, KY; 3Service d’Hépatolo-
gie, Hôpital Saint-Antoine, Assistance-Publique Hôpitaux de Paris,
Paris, France
Background and Aim: Fenofibrate is a novel therapy for Pri-
mary Biliary Cirrhosis (PBC). We sought to perform a system-
atic review and a meta-analysis of studies that assessed the
efficacy of fenofibrate in the treatment of PBC patients. Meth-
ods: electronic database search was performed for relevant
studies. Database searched included PubMed, Scopus, and
ScienceDirect. In addition, search of abstracts presented in the
main scientific meetings in the field and articles in press was
performed. Random effect model was used to pool the effect
size across studies for changes in means of alkaline phospha-
tase, GGT, bilirubin and IgM levels before and after treatment
and the overall rate of having complete response to fenofibrate
therapy. Publication bias, heterogeneity testing and sensitivity
analysis were also performed. Results: Six studies with 102
patients (90% female) met the inclusion criteria. All studies
were case crossover where patients who had no or incomplete
response to UDCA had fenofibrate added at a dose of 100-
200 mg daily. Treatment duration ranged from 8-100 weeks.
Treatment with fenofibrate was associated with a significant
decrease in the pooled mean alkaline phosphatase (-114 IU/L,
95% CI:-152 to -76, p<0.0001); a significant decrease in
GGT level (-92 IU/L, 95%CI:-149 to -43; p=0.0004); signif-
icant decrease in total bilirubin (-0.11mg/dl;95%CI:-0.18 to
-0.08; p=0.0008), and a significant decrease in IgM level
(-88mg/dl; 95%CI:-119 to -58; p<0.0001);. The pooled com-
plete response rate was 69% (95% CI: 53-82%; p=0.024).
The odds ratio of achieving complete response while on fenofi-
brate was 2.43 (95% CI: 1.44-4.1, p=0.0009). Conclusions:
Fenofibrate therapy at doses of 100-200 mg daily appears to
be an effective adjunctive therapy in PBC patients who had no
or incomplete response to UDCA. There is a critical need for
larger scale randomized trial to confirm its efficacy and define
its position in the treatment paradigm of PBC.
Disclosures:
Cynthia Levy - Consulting: Lumena, Gilead, Evidera
The following people have nothing to disclose: Alla Grigorian, Houssam E. Mar-
dini, Christophe Corpechot, Raoul Poupon
291
Fenofibrates do not improve transplant-free survival
despite biochemical response in patients with primary
biliary cirrhosis
Angela C. Cheung1, Javier M. Meza-Cardona2, Matthew Kow-
gier1, E. Jenny Heathcote1, Harry L. Janssen1,3, Jordan J. Feld1;
1Toronto Western Hospital Liver Center, University of Toronto,
Toronto, ON, Canada; 2Universidad Nacional Autonoma De
Mexico, Mexico City, Mexico; 3Erasmus MC, University Medical
Center, Rotterdam, Netherlands
Background: Primary biliary cirrhosis (PBC) is a chronic,
cholestatic liver disease that can lead to cirrhosis & liver fail-
ure. Ursodeoxycholic acid (UDCA) improves transplant-free sur-
vival, but up to 40% may not achieve adequate biochemical
response. Fibrates may decrease alkaline phosphatase (ALP),
but no study has examined their impact on transplant-free sur-
vival. Aim: To demonstrate whether fibrates 1) Lead to bio-
345A
chemical response in UDCA nonresponders (drop in >40%
in ALP), 2) Impact bilirubin, which has been correlated with
disease prognosis, 3) Impact rates of transplant-free survival &
decompensated cirrhosis. Methods: 438 patients were catego-
rized as non-responders if they had a <40% drop in ALP after
one year of UDCA. A time-dependent propensity score was
derived to determine the probability of patients receiving feno-
fibrates. Primary outcome measure: transplant-free survival,
reaching minimal listing criteria or decompensated cirrhosis.
Secondary outcome: biochemical response and change in bil-
irubin. Results: Of 387 eligible patients, 133/387 (34.4%)
were nonresponders: 49/133 (36.8%) were on a fenofibrate
and UDCA (FF) and 84/133 (63.2%) on UDCA alone (UDCA).
The propensity score was derived from baseline age, time from
diagnosis, cirrhosis, bilirubin and ALT. Time on lipidil was
336±402 days. Those with decompensated cirrhosis had a
lower mean bilirubin over time in the FF group compared to
the UDCA group. In the FF group, 25/33 (75.8%) of patients
had >40% drop in ALP after >100 days of treatment. Similar
number of patients decompensated (19.0% UDCA; 18.4% FF,
p=1.00), died/underwent transplant (14.3% both FF & UDCA
groups, p=1.00) (Figure 1). 8/49 (16.3%) stopped fenofibrate
due to adverse events (most common: hepatitis & abdominal
pain). Conclusion: Fenofibrates lead to biochemical response,
but do not have a clear impact on transplant-free survival or
decompensated cirrhosis in PBC.
Disclosures:
E. Jenny Heathcote - Consulting: Axcan Pharma, Gilead Sciences, Hoffman-La-
Roche, Merck, Tibotec (Johnson & Johnson), Axcan Pharma, Gilead Sciences,
Hoffman-LaRoche, Merck, Tibotec (Johnson & Johnson), Axcan Pharma, Gilead
Sciences, Hoffman-LaRoche, Merck, Tibotec (Johnson & Johnson), Axcan Pharma,
Gilead Sciences, Hoffman-LaRoche, Merck, Tibotec (Johnson & Johnson); Grant/
Research Support: Axcan Pharma, Boehringer Ingelheim, Bristol-Myers Squib,
Gilead Sciences, GlaxoSmithKline, Hoffman-LaRoche, Intercept Pharma, Merck,
Tibotec (Johnson & Johnson), Vertex, Axcan Pharma, Boehringer Ingelheim, Bris-
tol-Myers Squib, Gilead Sciences, GlaxoSmithKline, Hoffman-LaRoche, Intercept
Pharma, Merck, Tibotec (Johnson & Johnson), Vertex, Axcan Pharma, Boeh-
ringer Ingelheim, Bristol-Myers Squib, Gilead Sciences, GlaxoSmithKline, Hoff-
man-LaRoche, Intercept Pharma, Merck, Tibotec (Johnson & Johnson), Vertex,
Axcan Pharma, Boehringer Ingelheim, Bristol-Myers Squib, Gilead Sciences,
GlaxoSmithKline, Hoffman-LaRoche, Intercept Pharma, Merck, Tibotec (Johnson
& Johnson), Vertex; Speaking and Teaching: Axcan Pharma, Gilead Sciences,
Hoffman-LaRoche, Merck, Tibotec (Johnson & Johnson), Axcan Pharma, Gilead
Sciences, Hoffman-LaRoche, Merck, Tibotec (Johnson & Johnson), Axcan Pharma,
Gilead Sciences, Hoffman-LaRoche, Merck, Tibotec (Johnson & Johnson), Axcan
Pharma, Gilead Sciences, Hoffman-LaRoche, Merck, Tibotec (Johnson & Johnson)
346A AASLD ABSTRACTS
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sci-
ences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support:
Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck,
Medtronic, Novartis, Roche, Santaris
Jordan J. Feld - Advisory Committees or Review Panels: Idenix, Merck, Janssen,
Gilead, AbbVie, Merck, Theravance, Bristol Meiers Squibb; Grant/Research
Support: AbbVie, Boehringer Ingelheim, Janssen, Gilead, Merck
The following people have nothing to disclose: Angela C. Cheung, Javier M.
Meza-Cardona, Matthew Kowgier
292
Assessment of Environmental Exposures among 1000
North American Primary Sclerosing Cholangitis Patients
with and without Inflammatory Bowel Disease
John E. Eaton1, Brian D. Juran1, Elizabeth J. Atkinson2, Erik M.
Schlicht1, Xiao Xie2, Mariza de Andrade2, Craig Lammert3, Velimir
A. Luketic4, Joseph A. Odin5, Ayman A. Koteish6, Kris V. Kowdley7,
Kapil B. Chopra8, Gideon M. Hirschfield9, Naga P. Chalasani3,
Konstantinos Lazaridis1; 1Division of Gastroenterology & Hepatol-
ogy, Mayo Clinic, Rochester, MN; 2Division of Biomedical Statis-
tics and Informatics, Mayo Clinic, Rochester, MN; 3Department of
Medicine, Indiana University School of Medicine, Indianapolis,
IN; 4Gastroenterology and Hepatology, Virginia Commonwealth
University, Richmond, VA; 5Department of Medicine, The Mount
Sinai School of Medicine, New York, NY; 6Department of Medi-
cine, Johns Hopkins University School of Medicine, Baltimore, MD;
7Digestive Disease Institute, Virginia Mason Medical Center, Seat-
tle, WA; 8Division of Gastroenterology, Hepatology and Nutrition,
University of Pittsburgh, Pittsburgh, PA; 9Centre for Liver Research
and NIHR Biomedical Research Unit, University of Birmingham,
Birmingham, United Kingdom
Background & Aims: It has been postulated that primary scle-
rosing cholangitis (PSC) develops through immune mediated
mechanisms triggered by complex gene-environment interac-
tions in susceptible individuals. However, the relationships
between PSC and the environment are largely unknown. While
tobacco use has been reported to have a negative associa-
tion with PSC, other exposures particularly dietary habits and
methods of food preparation have not been well explored.
Our aims were to validate or refute associations reported in
previous studies and to identify novel environmental exposures
among PSC patients. Methods: We performed a case-control
analysis utilizing self-administered questionnaires. Cases were
recruited from 8 academic medical centers across North Amer-
ica and controls were recruited from the Mayo Clinic during
annual visits for preventive health care. Responses between
cases (n=1000) and controls (n=663) were compared using
multivariable logistic regression adjusted for age and gender.
The model was further stratified based on inflammatory bowel
disease (IBD) status (with IBD n=741; without IBD n=259).
Results: A history of smoking was inversely associated with PSC
only when IBD was present (OR, 0.5; 95% CI 0.4-0.7) but not
among PSC patients without IBD (OR, 0.9; 95% CI 0.7-1.2).
Moreover, women with PSC (irrespective of the presence of
IBD) were less likely to have received hormone replacement
therapy (HRT) (OR, 0.5; 95% CI 0.4-0.7) and were more likely
to have recurrent urinary tract infections (UTI’s) (OR, 1.6; 95%
CI 1.2-2.3) when compared to controls. Furthermore, PSC
patients regardless of gender or IBD status were less likely to
eat fish (OR, 0.4; 95% CI 0.3-0.6), vegetables (OR, 0.9; 95%
CI 0.8-0.9) and grilled/barbecued meat (OR, 0.8; 95% CI
0.7-0.9). In contrast, PSC patients with and without IBD were
more likely to consume steak/burgers that were more well-done
(OR, 1.3; 95% CI 1.2-1.5). Conclusions: To date, this is the
largest study (which represents approximately 3% of the esti-
mated PSC patient population in the United States) that exam-
HEPATOLOGY, October, 2014
ines environmental exposures and PSC. IBD (rather than PSC)
was associated with smoking. Women with PSC were more
likely to have recurrent UTI’s and less likely to receive HRT.
Furthermore, dietary intake and methods of food preparation
differs in PSC patients when compared to controls. Estrogen,
recurrent UTI’s and dietary habits may be relevant to the patho-
genesis of PSC and warrant further study. These findings have
the potential to lay the foundations for future studies to examine
the complex interactions between genes and environmental
exposures in PSC.
Disclosures:
Velimir A. Luketic - Grant/Research Support: Intercept, Merck, Idenix, Vertex,
Gilead, BMS, Novartis, abbvie, Genfit, Takeda
Joseph A. Odin - Advisory Committees or Review Panels: Bristol Meyers Squibb,
AbbVie
Kris V. Kowdley - Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research
Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria,
Janssen, Merck, Mochida, Vertex
Gideon M. Hirschfield - Advisory Committees or Review Panels: Centocor/J&J,
Medigene, Intercept, Falk Pharma ; Consulting: Lumena, Intercept
Naga P. Chalasani - Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-
rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin
The following people have nothing to disclose: John E. Eaton, Brian D. Juran,
Elizabeth J. Atkinson, Erik M. Schlicht, Xiao Xie, Mariza de Andrade, Craig
Lammert, Ayman A. Koteish, Kapil B. Chopra, Konstantinos Lazaridis
293
Efficacy Trial of All-trans Retinoic Acid (ATRA) in com-
bination with Ursodeoxycholic Acid (UDCA) in Primary
Sclerosing Cholangitis (PSC)
David N. Assis1, Osama Abdelghany2, Shi-Ying Cai1, Andrea A.
Gossard3, John E. Eaton3, Jill C. Keach3, Yanhong Deng4, Ste-
phenson W. Nkinin5, Kenneth D R. Setchell5, Maria Ciarleglio4,
Keith D. Lindor6, James L. Boyer1; 1Medicine - Section of Digestive
Diseases, Yale University School of Medicine, New Haven, CT;
2Pharmacy, Yale-New Haven Hospital, New Haven, CT; 3Gastro-
enterology and Hepatology, Mayo Clinic, Rochester, MN; 4Public
Health, Yale University, New Haven, CT; 5Pediatrics, Cincinnati
Children’s Hospital Medical Center, Cincinnati, OH; 6Arizona
State University, Tempe, AZ
Background: Effective medical therapies for PSC are needed.
Moderate dose UDCA improves serum biochemistry but does
not change the disease course. ATRA can activate FXR (farne-
soid X receptor) and RXR (retinoid X receptor) and repress
CYP7A1 and bile acid synthesis in human hepatocytes. In ani-
mal models of biliary injury ATRA improved hepatic inflam-
mation and fibrosis when combined with UDCA (He et al.
Hepatology 2011; Cai et al. J. Pharm. Exp. Ther. 2014). Aim:
To determine if ATRA + UDCA improve serum parameters of
cholestasis in PSC patients with alkaline phosphatase (AP)
>1.5xULN despite moderate-dose UDCA for ≥6 months. Meth-
ods: Patients were enrolled at Yale and Mayo Liver Clinics.
ATRA capsules were compounded and dosed at 45 mg/m2/
day divided b.i.d.. Combination therapy was given for 12
weeks followed by a 12-week washout. Baseline labs were
compared to the end-of-treatment and to washout. Results:
Twenty-one subjects were screened and 19 enrolled. Mean
age was 45±11 years, 74% Caucasian and 74% male; 63%
had large duct vs. 37% with small-duct PSC, 79% had IBD and
median Mayo PSC Risk Score was -0.03±0.7. Mean UDCA
dose was 18±6 mg/kg/day. Fifteen subjects completed 12
weeks of therapy. Mean AP significantly declined (356±209
vs. 318±225 U/L, p=0.046); 20% achieved ≥30% reduc-
tion. Interestingly, mean alanine aminotransferase (ALT) also
declined (94±55 vs. 56±32 U/L, p=0.007) along with serum
bile acid levels (41±52 vs. 28±45 umol/L, p=0.04). Mean
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
LDL (131±60 vs. 155±51 mg/dL, p=0.055) and triglyceride
(86±31 vs. 145±45 mg/dL, p=0.003) levels increased while
HDL decreased (61±21 vs. 41±11 mg/dL, p=0.01). Mean
serum levels of bile acid intermediate 7a-hydroxy-4-cholesten-
3-one (C4) significantly decreased (17±19 vs. 9±11 ng/mL,
p=0.04) indicating that ATRA inhibited bile acid synthesis.
There was no difference in bilirubin or peripheral regulatory T
cell frequency. At washout, clinical parameters and C4 levels
returned to baseline (p=NS). Four subjects failed to complete
12 weeks of therapy (headache N=2, tinnitus N=1, obstruc-
tive jaundice from a known stricture N=1). The most common
adverse effects were headache (63%) and tinnitus (26%).
Gradual ATRA introduction over 7 days decreased headache
severity and improved tolerability. Summary: Twelve-week
combination therapy with ATRA + moderate dose UDCA sig-
nificantly decreased serum AP, ALT, and bile acids levels.
Side effects were frequent at the full ATRA dose. Conclusion:
ATRA is a potent inhibitor of bile acid synthesis in humans.
Further evaluation of combination therapy with a lower dos-
ing of ATRA, UDCA and other new agents is recommended.
(NCT01456468)
Disclosures:
Kenneth D R. Setchell - Stock Shareholder: Asklepion Pharmaceuticals, LLC
The following people have nothing to disclose: David N. Assis, Osama Abdel-
ghany, Shi-Ying Cai, Andrea A. Gossard, John E. Eaton, Jill C. Keach, Yanhong
Deng, Stephenson W. Nkinin, Maria Ciarleglio, Keith D. Lindor, James L. Boyer
294
Galectin-3 Plays a Role in Primary Biliary Cirrhosis by
Mediating Inflammasome Signaling
Jijing Tian1, Tzu-I Chao1, Yu Sasaki1, Fu-Tong Liu1,2, M. Eric Ger-
shwin1, Natalie Torok1, Joy Jiang1; 1Internal Medicine, UCDMC,
Sacramento, CA; 2Dermatology, National Taiwan University, Tai-
pei, Taiwan
Galectin-3 a lectin family member is a known mediator of stel-
late cell activation and liver fibrosis, and active Kupffer cells
(KC) are described as a major source of galectin 3 in the liver.
Macrophages play a significant role in the pathogenesis of
primary biliary cirrhosis (PBC) however, the early inflammatory
events are not well described. We hypothesize that the bile
acid-induced galectin-3 mediates inflammasome signaling in
macrophages contributing to the progression of PBC. Methods:
Liver tissues from PBC patients and healthy controls; and from
the dnTGFβRII transgenic mice a model of PBC/autoimmune
cholangitis and wt controls were collected for Western blot
and real-time qPCR to analyze the expression of galectin-3,
NLRP3, ASC and IL-1β. The cleavage of caspase-1 and IL-1β
in PBC patients was also examined by Western blot. For in
vitro studies, primary mouse KC were isolated from wt and the
galectin-3-/- mice and treated with deoxycholic acid (DCA)
with/without recombinant galectin-3. The cells were collected
for qPCR to analyze the activation of inflammasome-related
transcripts and for immunoprecipitation (IP) to detect the asso-
ciation of galectin-3 and NLRP3. Results: The mRNA levels
of galectin-3, NLRP3, ASC and IL-1β significantly increased
in the livers of the PBC patients (p<0.05, p<0.05, p<0.05
and p< 0.05 respectively) and in the dnTGFβRII mice (p<0.01,
p<0.05, p<0.001 and p<0.05) compared to the healthy con-
trols. The protein levels of galectin-3, NLRP3 and the activation
of caspase-1 and IL-1β were also elevated in the PBC patients.
In wt KC, DCA significantly induced the expression of NLRP3
(p<0.05), IL-1β (p<0.01), INFγ (p<0.01), IL-10 (p<0.05) and
IL-17A (p<0.05). However, the induction of these genes was
attenuated in the galectin-3-/- KC (p<0.01, p<0.001, p<0.01,
p<0.05 and p<0.01). Recombinant galectin-3 partially
347A
reversed the expression of the above genes in the knockout KC.
Co-IP assay showed that galectin-3 associated with the NLRP3
in KC. Conclusion: Galectin-3 expression and inflammasome
activation are induced in PBC patients and in dnTGFβRII mice.
DCA induces inflammasome activation in KC resulting in the
release of proinflammatory mediators, in a galectin 3-depen-
dent manner. Galectin-3 hence could be a potential therapeutic
target in PBC.
Disclosures:
Natalie Torok - Consulting: Genentech/Roche
The following people have nothing to disclose: Jijing Tian, Tzu-I Chao, Yu Sasaki,
Fu-Tong Liu, M. Eric Gershwin, Joy Jiang
295
An International Phase 3 Study of the FXR Agonist
Obeticholic Acid in PBC Patients: Effects on Markers
of Cholestasis Associated with Clinical Outcomes and
Hepatocellular Damage
Frederik Nevens1, Pietro Andreone2, Giuseppe Mazzella2, Sim-
one I. Strasser3, Christopher L. Bowlus4, Pietro Invernizzi5, Joost
Drenth6, Paul J. Pockros7, Jaroslaw Regula8, Michael Trauner9,
Annarosa Floreani10, Simon Hohenester11, Velimir A. Luketic12,
Mitchell L. Shiffman13, Karel J. van Erpecum14, Victor Vargas15,
Catherine Vincent16, Bettina E. Hansen17, Roya Hooshmand-Rad18,
Shawn Sheeron18, David Shapiro18; 1UZ Leuven, Leuven, Belgium;
2Universitaria di Bologna, Bologna, Italy; 3Royal Prince Alfred Hos-
pital, Sydney, NSW, Australia; 4University of California-Davis,
Sacramento, CA; 5Humanitas Clinical and Research Center, Roz-
zano, Italy; 6UMC St. Radboud, Nijmegen, Netherlands; 7Scripps
Clinic, La Jolla, CA; 8Cancer Centre, Warsaw, Poland; 9Medi-
cal University of Vienna, Vienna, Austria; 10Università di Padova,
Padova, Italy; 11LMU University of Munich, Munich, Germany;
12McGuire DVAMC, Richmond, VA; 13Liver Institute of Virginia,
Newport News, VA; 14UMC Utrecht, Utrecht, Netherlands; 15Hos-
pital Vall d’Hebron, Barcelona, Spain; 16Centre Hospitalier Univer-
sitaire de l’Université de Montréal-St. Luc, Montréal, QC, Canada;
17Erasmus MC, University Medical Center Rotterdam, Rotterdam,
Netherlands; 18Intercept Pharmaceuticals, Inc., San Diego, CA
Obeticholic acid (OCA, 6-ethyl chenodeoxycholic acid) is
a highly potent, selective FXR agonist. In Ph2 PBC studies,
10-50mg OCA (±UDCA) produced significant biochemical
improvement in cholestasis and inflammatory markers. The
Global PBC Study Group (GPBCSG) confirms patients with
alkaline phosphatase (ALP) >1.67x ULN or bilirubin >ULN have
a greatly increased risk of liver transplant or death [HR (95%
CI): 2.83 (2.4-3.4); p =1x10-34]. This was an international,
double-blind, placebo-controlled (PBO) trial. PBC patients
±UDCA (if taking UDCA, on a stable dose) with ALP≥1.67x
ULN or bilirubin <2x ULN were randomized to PBO, OCA 5
or 10mg for 12mo. Patients randomized to 5mg were titrated
to 10mg after 6mo, if necessary; pre-study UDCA continued.
The primary endpoint was attaining the GPBCSG ALP/Bilirubin
goal and ALP reduction ≥15%. Markers of inflammation (CRP)
and apoptosis (CK18) were also evaluated at 6 and 12mo. All
groups were well-matched. Mean age: 55.8yrs, female: 91%,
Caucasian: 94%. The median UDCA dose was 15.4 mg/kg;
7% were UDCA-intolerant. Overall, 91% of patients completed
the study. The primary endpoint was achieved: OCA was supe-
rior to PBO, a highly statistically significantly greater proportion
of OCA treated patients achieved the ALP/Bili response goal
(see table). After 6mo, ALP significantly improved (p<0.0001)
with OCA dose: PBO, -6.8% (±3.5), 5mg, -27.4% (±3.4),
10mg, -36.5% (±3.5). Pruritus, generally mild to moderate,
was the most common and dose related adverse event (AE).
The incidence of AEs other than pruritus was no worse with
348A AASLD ABSTRACTS
OCA (PBO, 90%, 5/10mg OCA, 89%, 10mg OCA, 86%).
An 82-yr old patient with pre-existing congestive heart failure
taking OCA died due to worsening of the condition. Overall,
serious adverse events (SAEs) occurred in 22 (10%) of patients
and, although there were more SAEs in the OCA groups, none
were considered drug-related and there were no apparent pat-
terns. Modest mean reductions in HDL (16%,5/10mg OCA,
26%,10mg OCA) were observed with OCA. OCA produced
highly statistically, clinically meaningful improvements in bio-
chemical criteria that are strongly correlated with clinical ben-
efit. Pruritus was the principal AE, but had a lower incidence
in the titration group compared to 10 mg. Starting patients on
5mg OCA and titration to 10mg based on the clinical response
appears to be an appropriate dosing strategy.
Disclosures:
Frederik Nevens - Consulting: CAF, Intercept, Gore, BMS, Abbvie, Novartis,
MSD, Eumedica, Janssen; Grant/Research Support: Ipsen, Roche, MSD, Astellas
Pietro Andreone - Advisory Committees or Review Panels: Roche, Janssen-Cilag,
Gilead, MSD/Schering-Plough, Abbvie, Boehringer Ingelheim; Grant/Research
Support: Roche, Gilead; Speaking and Teaching: Roche, MSD/Schering-Plough,
Gilead
Simone I. Strasser - Advisory Committees or Review Panels: Janssen, AbbVie,
Roche Products Australia, MSD, Bristol-Myers Squibb, Gilead, Norgine, Bayer
Healthcare; Speaking and Teaching: Bayer Healthcare, Bristol-Myers Squibb,
MSD, Roche Products Australia, Gilead, Janssen
Christopher L. Bowlus - Advisory Committees or Review Panels: Gilead Sciences,
Inc; Consulting: Takeda; Grant/Research Support: Gilead Sciences, Inc, Inter-
cept Pharmaceuticals, Bristol Meyers Squibb, Lumena; Speaking and Teaching:
Gilead Sciences, Inc
Paul J. Pockros - Advisory Committees or Review Panels: Janssen, Merck, Genen-
tech, BMS, Gilead, Boehinger Ingelheim, AbbVioe; Consulting: Genentech,
Lumena, Regulus, Beckman Coulter, RMS; Grant/Research Support: Novartis,
Intercept, Janssen, Genentech, BMS, Gilead, Vertex, Boehinger Ingelheim,
Lumena, Beckman Coulter, AbbVie, RMS, Novartis, Merck; Speaking and Teach-
ing: Genentech, BMS, Gilead
Michael Trauner - Advisory Committees or Review Panels: MSD, Janssen, Gilead,
Abbvie; Consulting: Phenex; Grant/Research Support: Intercept, Falk Pharma,
Albireo; Patent Held/Filed: Med Uni Graz (norUDCA); Speaking and Teaching:
Falk Foundation, Roche, Gilead
Simon Hohenester - Speaking and Teaching: Dr. Falk Pharma
Mitchell L. Shiffman - Advisory Committees or Review Panels: Merck, Gilead,
Boehringer-Ingelheim, Bristol-Myers-Squibb, Abbvie, Janssen; Consulting: Roche/
Genentech, Gen-Probe; Grant/Research Support: Merck, Gilead, Boehring-
er-Ingelheim, Bristol-Myers-Squibb, GSK, Abbvie, Beckman-Coulter, Achillion,
Lumena, Intercept, Novarit, Gen-Probe; Speaking and Teaching: Roche/Genen-
tech, Merck, Gilead, GSK, Janssen, Bayer
Karel J. van Erpecum - Advisory Committees or Review Panels: Bristol Meyers
Squibb, Abbvie
Roya Hooshmand-Rad - Employment: Intercept pharmaceuticals Inc.
Shawn Sheeron - Employment: Intercept Pharmaceuticals
David Shapiro - Employment: Inttercept Pharmaceuticals
The following people have nothing to disclose: Giuseppe Mazzella, Pietro Inv-
ernizzi, Joost Drenth, Jaroslaw Regula, Annarosa Floreani, Velimir A. Luketic,
Victor Vargas, Catherine Vincent, Bettina E. Hansen
HEPATOLOGY, October, 2014
296
Noninvasive testing are poor surrogate markers for
fibrosis staging and liver-related outcomes in patients
with primary biliary cirrhosis who do not respond to
ursodeoxycholic acid
Angela C. Cheung1, Javier M. Meza-Cardona2, Matthew Kow-
gier1, Harry L. Janssen1,3, Jordan J. Feld1; 1Toronto Western Hos-
pital Liver Center, University of Toronto, Toronto, ON, Canada;
2Universidad Nacional Autonoma De Mexico, Mexico City, Mex-
ico; 3Erasmus MC, University Medical Center, Rotterdam, Nether-
lands
Background: Primary biliary cirrhosis (PBC) is a chronic, choles-
tatic liver disease that can lead to cirrhosis and liver failure.
Few studies have examined the utility of noninvasive tests (NITs)
of fibrosis in PBC. Aim: To determine the accuracy of nonin-
vasive tests (FIB-4, AST/ALT, APRI, ultrasound) in predicting
advanced fibrosis as compared with liver biopsy. Methods:
387 charts were assessed and nonresponders (patients with
<40% decline in alkaline phosphatase (ALP) after 1 year of
treatment with ursodeoxycholic acid) with liver biopsy, FIB-4,
AST/ALT and APRI were included. The annual mean value for
noninvasive markers of fibrosis were calculated using values
taken within a year of their liver biopsy. Using ordinal regres-
sion and ROC curves, we determined the predictive accuracy
of NITs as compared to liver biopsy (primary outcome). Sec-
ondary outcome measure: Correlation with end of follow-up
outcomes. Results: 72 patients met inclusion criteria. Patients
were dichotomized into histologically defined early (stage 0-2;
EF) and late fibrosis (stage 3-4; LF), with 51 and 21 patients
in each respective group. Median age at diagnosis was 47.0
and 43.1 years (EF and LF groups respectively). Patients were
followed for a median 11.7±6.3 (EF) and 11.9±7.2 years (LF).
Approximately 19% of patients decompensated, died or under-
went transplant/met minimal listing criteria in both groups.
AST/ALT was not a significant predictor of advanced fibrosis
on biopsy (p=0.154), in contrast to APRI (p=0.019) and FIB-4
(0.026). The AUROCs for AST/ALT, APRI, FIB-4 were 0.599,
0.602 and 0.636 respectively. Ultrasound performed poorly,
with an AUROC of 0.654 even in the presence of portal hyper-
tension. No test, including liver biopsy, was predictive of sur-
vival despite up to 24 years of follow-up. Conclusion: Survival
in patients with PBC, even in cirrhotic patients who do not
respond to UDCA, is in excess of 10-15 years, which empha-
sizes the challenge in using clinical endpoints as outcome mea-
sures in clinical trials. Non-invasive testing does not accurately
predict the presence of fibrosis in patients with PBC. Ultrasound
performs poorly and should not be used to diagnose cirrhosis
in this population.
Disclosures:
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sci-
ences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support:
Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck,
Medtronic, Novartis, Roche, Santaris
Jordan J. Feld - Advisory Committees or Review Panels: Idenix, Merck, Janssen,
Gilead, AbbVie, Merck, Theravance, Bristol Meiers Squibb; Grant/Research
Support: AbbVie, Boehringer Ingelheim, Janssen, Gilead, Merck
The following people have nothing to disclose: Angela C. Cheung, Javier M.
Meza-Cardona, Matthew Kowgier
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
297
Applicability and Prognostic Value of Histologic Scoring
Systems in Primary Sclerosing Cholangitis
Elisabeth M. de Vries1, Joanne Verheij2, Stefan G. Hubscher4,
Mariska M. Leeflang3, Kirsten Boonstra1, Ulrich Beuers1, Cyriel
Y. Ponsioen1; 1Gastroenterology and Hepatology, Academic
Medical Center, Amsterdam, Netherlands; 2Pathology, Academic
Medical Center, Amsterdam, Netherlands; 3Clinical Epidemiol-
ogy, Biostatistics and Bioinformatics, Academic Medical Center,
Amsterdam, Netherlands; 4Cellular Pathology, School of Cancer
Sciences, University of Birmingham, Birmingham, United Kingdom
Introduction Primary sclerosing cholangitis (PSC) is a chronic
cholestatic liver disease, affecting intra-and extrahepatic bile
ducts. Common hepatic histologic changes include inflam-
mation, accumulation of copper binding protein (CBP), duc-
topenia and concentric periductal fibrosis. At present there
is no PSC-specific histologic scoring system to evaluate both
disease activity and progression. The aim of this study was
to assess if three scoring systems designed primarily to assess
disease severity in chronic hepatitis (Ishak 1995) or PBC (Lud-
wig 1978, Nakanuma 2010) could also be used for grad-
ing and/or staging PSC. Methods For this cohort study, PSC
patients from a Dutch population-based cohort, who under-
went diagnostic liver biopsy were included. Two expert liver
pathologists evaluated biopsy slides in tandem. Grading was
scored using the Nakanuma system (cholangitis activity, hep-
atitis activity) and the Ishak system. Staging was scored using
the Nakanuma system (fibrosis, bile duct loss, CBP deposition)
the Ishak system and the Ludwig system. Association of grading
and staging with transplant-free survival, as well as time to liver
transplantation (Ltx) alone was estimated using Kaplan Meier
survival curve and log-rank test. Results Sixty-four patients
were included, with a median follow up of 112 months (IQR
71-179). Mean age at diagnosis was 38 years (±14), 63%
were male. Forty-four patients (69%) had large duct PSC and
43 (67%) had concomitant inflammatory bowel disease (IBD).
A total of 9 patients reached an endpoint (7 Ltx, 2 death from
CCA) in a median time of 103 months (IQR 34-160). During
grading and staging of biopsies, consensus was reached in
100% of cases. Histologic grading according to Ishak was
highly significantly associated with time to Ltx (p=0.007). His-
tologic staging of fibrosis and CBP deposition (dichotomized),
according to Nakanuma was significantly associated with
transplant-free survival ( p=0.006 and p=0.01 respectively).
Ishak and Ludwig staging scores also showed a statistically
significant association with transplant-free survival ( p<0.001
and p<0.001 respectively). Conclusion The Nakanuma, Ishak
and Ludwig scoring systems are applicable to PSC liver biop-
sies. A significant association was shown between Ishak grade
and time to Ltx. Staging of PSC using all three systems is highly
associated with transplant-free survival. Our observations sug-
gest that these staging systems may be useful in the evaluation
of disease severity and as response parameters to therapeutic
interventions in PSC patients.
Disclosures:
Ulrich Beuers - Consulting: Intercept, Novartis; Grant/Research Support: Zam-
bon; Speaking and Teaching: Falk Foundation, Gilead, Roche, Scheringh, Zam-
bon
Cyriel Y. Ponsioen - Consulting: AbbVIE; Grant/Research Support: AbbVIE, Sch-
ering Plough, Dr. Falk Pharma, Tramedico Netherlands
The following people have nothing to disclose: Elisabeth M. de Vries, Joanne
Verheij, Stefan G. Hubscher, Mariska M. Leeflang, Kirsten Boonstra
349A
298
Relation of gallbladder enlargement with bile acid
homeostasis and colorectal malignancy in primary scle-
rosing cholangitis
Mourad Aissou1, Lionel Arrivé2, Dominique Rainteau3, Sara
Lemoinne1, Astrid Donald D. Kemgang Fankem1,4, Delphine
Firrincieli1, Nicolas Chignard1, Christophe Corpechot1,4, Oliv-
ier Chazouillères1,4, Chantal Housset1,4; 1UMR_S 938, UPMC
& Inserm, Paris Cedex 12, France; 2Radiology, AP-HP, Hôpital
Saint-Antoine, Paris Cedex 12, France; 3ERL U1157, Sorbonne
Universités, UPMC Univ Paris 06 & Inserm, Paris Cedex 12,
France; 4Hepatology, AP-HP, Hôpital Saint-Antoine, Paris Cedex
12, France
Background and aim: Gallbladder enlargement is frequent in
primary sclerosing cholangitis (PSC). In mice, bile acid homeo-
stasis can be modified by a gallbladder shunt. The aim of
this study was to assess the potential cause and influence of
gallbladder enlargement on bile acid homeostasis and disease
course in PSC. Patients and methods: The study population
comprised 77 PSC patients who underwent a three-dimen-
sional magnetic resonance cholangiography (3D-MRC) and a
mass spectrometry analysis of serum bile acids within less than
a month. Patients were followed for 9±5 years. Gallbladder
volume was calculated by the analysis of 3D-MRC images and
the median value (69 mL) was taken as a cutoff to separate
patients into two groups. Results: Gallbladder was enlarged in
35 patients (89 [86-106] mL) and within normal range in 42
(41 [35-47] mL). Patients with enlarged gallbladders did not
significantly differ from others regarding gender (65% vs. 66%
males), median age (43 vs. 42 years), time from diagnosis (5
vs. 5.5 years), body mass index (21.6 vs. 23.7), associated
inflammatory bowel disease (71% vs. 50%), UDCA treatment
(89% vs. 90%), other MRI features including cystic abnormali-
ties (8.5% vs. 12%), clinical or histological parameters of liver
disease (Mayo risk score of -0.18 [-0.45-0.27] vs. -0.005
[-0.63-0.56]). Notably, malignancy was less frequent in the
group with enlarged gallbladder, occurring in 2 (5.7%) vs.
11 (26.2%) patients with normal gallbladder size (P=0.029).
Colorectal cancer in particular was 6.7-fold less frequent,
occurring in 1 (2.8%) vs. 8 (19%) patients (P=0.037, OR=6.7
[0.9- 354])). In patients with enlarged gallbladder, the serum
concentrations of secondary bile acids were lower than in other
patients (1.6 [1.3-1.9] vs. 2.5 [2-3.1] μmol/L, P=0.0004).
This was true for deoxycholic acid (0.7 [0.5-1] vs. 2.2 [1-6-3]
μmol/L, P=0.0001), a secondary bile acid known to promote
colon carcinogenesis. Patients in this group also had higher
concentrations of primary bile acids (10.5 [6.6-16.7] vs. 4.3
[3.5-5.3] μmol/L, P=0.0001) and of UDCA (44.0 [29.4-52]
vs. 27.2 [14.6-31.1] μmol/L, P=0.001). Furthermore, they
had higher serum concentrations of the gallbladder-relaxing
hormone FGF19 (211.6 [168.6-234.6] vs. 88.6 [72.7-121.6]
pg/mL, P=0.0001), which concentration was correlated with
gallbladder volume (R2=0.46, P=0.001) Conclusion: Gallblad-
der is enlarged in approximately half of PSC patients, which
can be caused by increased FGF19 levels, and which is asso-
ciated with a lack of secondary bile acids, enhanced UDCA
enrichment and a lower prevalence of colorectal cancer, con-
sistent with protective properties of gallbladder enlargement
in PSC.
Disclosures:
Olivier Chazouillères - Consulting: APTALIS, MAYOLY-SPINDLER
The following people have nothing to disclose: Mourad Aissou, Lionel Arrivé,
Dominique Rainteau, Sara Lemoinne, Astrid Donald D. Kemgang Fankem, Del-
phine Firrincieli, Nicolas Chignard, Christophe Corpechot, Chantal Housset
350A AASLD ABSTRACTS
299
Do patients with “early” PBC benefit from UDCA treat-
ment? -results from the nationwide cohort study in
Japan-
Atsushi Tanaka1, Junko Hirohara2, Yasuni Nakanuma3, Hirohito
Tsubouchi4, Hajime Takikawa1; 1Department of Medicine, Teikyo
University School of Medicine, Tokyo, Japan; 2The Third Depart-
ment of Internal Medicine, Kansai Medical University, Osaka,
Japan; 3Department of Human Pathology, Kanazawa University
Graduate School of Medicine, Kanazawa, Japan; 4HGF Tissue
Repair and Regenerative Medicine, Kagoshima University Grad-
uate School of Medical and Dental Sciences, Kagoshima, Japan
[Background and Aims] Although it is well established that
treatment with ursodeoxycholic acid (UDCA) improves long-
term outcome in patients with primary biliary cirrhosis (PBC),
it is still uncertain whether “early” PBC, with normal or low
ALP levels and at early histological stages, would benefit from
UDCA treatment. In Japan nationwide surveys for PBC have
been performed every three year since 1980, and so far clini-
cal data of 7,376 cases have been accumulated. In the current
study we examined the long-term outcome of asymptomatic
PBC patients with normal or low ALP and at early histological
stages in whom UDCA treatment was not initiated. [Subjects
and Methods] Patients in the database who met the following
criteria were enrolled in this retrospective study. At diagnosis,
1) serum AMA were positive, 2) no symptoms were noted, and
3) serum ALP levels were within or less than 1.5 times upper
normal limit. Furthermore, the criteria also included 4) histolog-
ical findings were compatible with PBC and Scheuer stages
I or II, 5) no treatment was initiated at diagnosis or within at
least 6 months thereafter, and 6) the outcome was clearly docu-
mented. [Results] Among 7,376 patients with PBC, 86 patients
(M/F=6/80, age at diagnosis 56.1+/-10.5 yo) met these cri-
teria and were included in this study. The followed-up period
of these patients was 6.6+/-5.7 years. Seventy patients (81%)
remained untreated during all observational periods. On the
other hand, UDCA treatment was commenced in 16 patients
(19%) due to elevation of serum ALP, and the interval between
presentation and treatment was 25.9 months in average. Five
patients died (6%) and two liver-related deaths were observed,
and 5- and 10-year liver transplantation-free survival rates were
98%/88%, comparable with those with UDCA monotherapy
in the whole cohort. The development of liver-related symptoms
was observed in 6 patients (7%) and 5- and 10-year liver-re-
lated symptoms free rate were 95%/92%, which were signifi-
cantly better than those with UDCA monotherapy (p<0.001,
log-rank test). [Conclusion] The current study suggested that
treatment of PBC patients with UDCA may be awaited until ALP
elevation if they had 1) no symptom, 2) normal or <1.5 xULN
ALP levels, and 3) Scheuer stages I-II.
Disclosures:
Hirohito Tsubouchi - Grant/Research Support: MSD, Chugai Pharmaceutical, Kan
Research Institute, Daiichi-Sankyo, Eisai, Tanabe Mitsubishi
Hajime Takikawa - Consulting: Mitsubishi Pharma, Mitsubishi Pharma, Mitsubishi
Pharma, Mitsubishi Pharma; Grant/Research Support: Schering-Plough, Chugai,
Schering-Plough, Chugai, Schering-Plough, Chugai, Schering-Plough, Chugai
The following people have nothing to disclose: Atsushi Tanaka, Junko Hirohara,
Yasuni Nakanuma
HEPATOLOGY, October, 2014
300
A possible involvement of endoplasmic reticulum stress
in the process of biliary epithelial autophagy and senes-
cence in primary biliary cirrhosis
Motoko Sasaki1, Masami Miyakoshi1, Yasunori Sato1, Yasuni
Nakanuma1,2; 1Human Pathology, Kanazawa University Gradu-
ate School of Medicine, Kanazawa, Japan; 2Pathology, Shizuoka
Cancer Center, Nagaizumi, Japan
Background/Aims: Accumulating data suggest that dereg-
ulated autophagy followed by cellular senescence in biliary
epithelial cells (BECs) may be closely related to the abnormal
expression of mitochondrial antigens and following autoim-
mune pathogenesis in primary biliary cirrhosis (PBC). Given
endocytoplasmic reticulum (ER) stress affect a process of auto-
phagy, we hypothesized that ER stress may be involved in the
deregulated autophagy and cellular senescence in biliary epi-
thelial lesions in PBC. Methods: We examined the expression
of ER stress markers (GRP78, CHOP, XBP-1, spliced form and
protein disulfide isomerases; PDI) at mRNA and protein lev-
els in cultured BECs treated with glycochenodeoxycholic acid
(GCDC, 200 μM), palmitic acid (PA, 200-400μM; control,
oleic acid) and ER stress inducer, tunicamycin (TM, 0.5μg/
ml). The effect of pretreatment with tauroursodeoxycholic acid
(TUDCA, 1mM) on the induction of ER stress was also exam-
ined. The degree of autophagy and cellular senescence in cul-
tured BECs treated with GCDC, PA, TM was assessed using
the immunoblot of microtubule-associated proteins-light chain
3β (LC3), Immunocytochemistry for p62/suquestosome-1 (p62)
and a detection of senescence-associated β-galactosidase (SA-β-
gal) activity. We also examined immunohistochemically the
expression of ER stress markers: PDI and GRP78 and its associ-
ation with autophagy-related markers LC3, p62 and senescent
markers p16INK4a and p21WAF1/Cip1 in livers taken from
the patients with PBC (n=43) and 49 control diseased and nor-
mal livers such as primary sclerosing cholangitis (PSC). Results:
The expression of ER stress markers was significantly increased
in cultured BECs treated with GCDC, PA and TM (p<0.05).
Pretreatment with TUDCA significantly suppressed ER stress in
BECs treated with GCDC, PA and TM (p<0.05). Autophagy,
deregulated autophagy with p62 accumulation and cellular
senescence were induced in cultured BECs treated with GCDC,
PA and TM. Pretreatment with TUDCA further increased the
degree of autophagy in BECs treated with GCDC, PA and TM.
Pretreatment with TUDCA suppressed the stress-induced cellular
senescence in cultured BECs (p<0.05). An intense granular
and vesicular expression of ER stress markers, PDI and GRP78,
was seen in damaged small bile ducts (SBDs) in PBC. The
expression of PDI and GRP78 was significantly more extensive
in SBDs in PBC, compared with control livers (p<0.05). The
expression of ER stress markers was correlated with the expres-
sion of LC3 and p16INK4a and p21WAF1/Cip1 in PBC. In
conclusion, ER stress may play a role in the pathogenesis of
deregulated autophagy and cellular senescence in biliary epi-
thelial lesions in PBC.
Disclosures:
The following people have nothing to disclose: Motoko Sasaki, Masami Miya-
koshi, Yasunori Sato, Yasuni Nakanuma
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
301
Younger patients presenting with Primary Biliary Cirrho-
sis are more likely to have cognitive impairment
Laura Griffiths1, David Jones1, Jessica K. Dyson2, George F. Mells3,
Richard N. Sandford3; 1Institute of Cellular Medicine, Newcastle
University, Newcastle upon Tyne, United Kingdom; 2Liver Unit,
Freeman Hospital, Newcastle upon Tyne, United Kingdom; 3Aca-
demic Department of Medical Genetics, University of Cambridge,
Cambridge, United Kingdom
Introduction: Data from the UK-PBC cohort have shown that
patients presenting with Primary Biliary Cirrhosis (PBC) at a
younger age have a greater symptom burden, particularly
fatigue and autonomic dysfunction. Previous studies have
demonstrated that cognitive dysfunction is prevalent in PBC.
Aim: To evaluate the prevalence of cognitive impairment in the
UK-PBC patient cohort and identify relevant associations. Meth-
ods: The UK-PBC dataset was analysed. This observational
study used the cognitive domain of the PBC-40, the Orthostatic
Grading Scale (OGS) and the Epworth Sleepiness Scale (ESS).
Results: Data on 2187 patients were analysed. 27% of PBC
patients had clinically significant cognitive impairment. Patients
without evidence of advanced liver disease (normal bilirubin
and albumin) had a higher prevalence of clinically significant
cognitive impairment (37%) than the group as a whole. Para-
doxically, given the positive correlation between age and cog-
nitive dysfunction in the normal ageing population, cognitive
dysfunction was significantly associated with both a younger
age at diagnosis (r=-0.14, p<0.0001) and a younger age
at entry into the study (r=0.11 p<0.0001). This is compared
with a positive correlation of r=0.103 seen in an age and sex-
matched community control population. Patients under 50 years
old at presentation had significantly more cognitive dysfunction
than those >60 (35% v 19%, CS=37.9, p<0.0001). Cognitive
dysfunction was not associated with duration of disease or
response to ursodeoxycholic acid. Autonomic symptoms were
strongly associated with cognitive symptoms in both <50 and
>60 patients (<50: mean OGS 5.5 ± 3.7 with cog symptoms
v 2.3 ± 2.6, p<0.0001). ESS scores were significantly higher
in the <50 patients with significant cognitive symptoms than
>60 (p=0.001). Cognitive impairment was associated with
significantly increased social dysfunction in younger patients
compared to older (62% v 42%, CS=10.5, p=0.001). This is
important as we know social dysfunction is closely linked to
perceived quality of life in PBC. Conclusions: Cognitive dys-
function is frequent in PBC and, contrary to expectation, is sig-
nificantly commoner in patients presenting at a younger age.
This argues against cognitive dysfunction in PBC simply being
a manifestation of advancing age or hepatic encephalopathy.
The cognitive impairment seen in younger patients may in part
be due to additional sleep disturbance in this age group, with
autonomic dysfunction contributing in both age groups. Cog-
nitive dysfunction is under-recognised and unappreciated and
warrants further research.
Disclosures:
David Jones - Consulting: Intercept
Richard N. Sandford - Advisory Committees or Review Panels: Otsuka; Grant/
Research Support: Intercept
The following people have nothing to disclose: Laura Griffiths, Jessica K. Dyson,
George F. Mells
351A
302
Ongoing Activation of Autoantigen-Specific B cells in
Primary Biliary Cirrhosis
Jun Zhang1, Weici Zhang1, Patrick S. Leung1, Christopher L.
Bowlus2, Sandeep S. Dhaliwal2, Ross L. Coppel3, Aftab A. Ansari4,
Guo-Xiang Yang1, Jinjun Wang1, Thomas P. Kenny1, Xiao-Song
He1, M. Eric Gershwin1; 1Internal Medicine, University of Califor-
nia, Davis, CA; 2Division of Gastroenterology and Hepatology,
University of California at Davis, Sacramento, CA; 3Department
of Microbiology, Monash University, Melbourne, VIC, Australia;
4Department of Pathology, Emory University School of Medicine,
Atlanta, GA
Background. Antimitochondrial antibodies have served as a
fingerprint to identify mechanisms that lead to loss of tolerance
in primary biliary cirrhosis (PBC). AMAs recognize not only the
E2 component of pyruvate dehydrogenase (PDC-E2), but also
chemical xenobiotics with structural similarity to the inner lipoyl
domain of PDC-E2. It is unclear whether such autoantibodies
result from de novo activated autoantigen-specific B cells, or
from B cells primed when self tolerance was compromised. We
examined B cell and plasmablasts phenotype, frequency, iso-
type and pattern of autoantibody reactivity in PBC and controls
by comparing binding activities to PDC-E2 and to two repre-
sentative etiologically associated xenobiotics, 2-octynoic acid
(2OA) and 6, 8-bis (acetylthio) octanoic acid (SAc). Methods.
Firstly, using a total of 58 subjects, including 27 with PBC, 13
with PSC and 18 healthy controls, we monitored the frequen-
cies of B cell subsets and focused on the frequency of PDC-E2
specific responses of plasmablasts by ELISPOT. Additionally,
we analyzed the plasmablast-derived antibodies compared
to plasma antibodies to quantitate reactivity against PDC-E2,
2OA and SAc. Finally, we characterized the phenotype of
PDC-E2-specific plasmablasts. Results. Importantly, the frequen-
cies of total B cells, naïve B cells, class-unswitched memory B
cells, and class-switched memory B cells are similar between
PBC and controls. Strikingly, however, 10% of the total IgG
and IgA plasmablast and 23% of the IgM plasmablast popu-
lation were uniquely reactive with PDC-E2 in PBC (p< 0.01).
Plasmablast reactivity to the control antigen, tetanus toxoid,
was similar in all groups, indicating that PDC-E2-specific anti-
body secreting cells represent newly activated plasmablasts,
rather than re-activation of the pool of PDC-E2-specific memory
B cells. Plasma antibodies from PBC, but not controls, reacted
to PDC-E2, 2-OA and SAc. In contrast, the plasmablast-derived
polyclonal antibodies from PBC reacted with PDC-E2, but did
have detectable reactivity against 2OA and SAc. Interestingly,
PDC-E2-specific plasmablasts expressed the homing receptors,
CXCR7 and CCR10, suggesting a mechanism for the migra-
tion of PDC-E2-specific plasmablasts to the epithelial ligands,
CXCL12 and CCL28. Conclusions. The dramatic elevated fre-
quency of circulating plasmablasts specific for PDC-E2, but not
reactive to xenobiotics, is consistent with an ongoing intense
activation of autoantigen-specific B cells by cognate antigen.
Finally, this chronic and intense response suggests that immu-
notherapeutic approaches in PBC must focus on the original
forbidden sin, the loss of tolerance to PDC-E2.
Disclosures:
Christopher L. Bowlus - Advisory Committees or Review Panels: Gilead Sciences,
Inc; Consulting: Takeda; Grant/Research Support: Gilead Sciences, Inc, Inter-
cept Pharmaceuticals, Bristol Meyers Squibb, Lumena; Speaking and Teaching:
Gilead Sciences, Inc
The following people have nothing to disclose: Jun Zhang, Weici Zhang, Patrick
S. Leung, Sandeep S. Dhaliwal, Ross L. Coppel, Aftab A. Ansari, Guo-Xiang
Yang, Jinjun Wang, Thomas P. Kenny, Xiao-Song He, M. Eric Gershwin
352A AASLD ABSTRACTS
303
Risk stratification in primary biliary cirrhosis using the
UK-PBC Research Cohort
Marco Carbone1,2, Stephen Sharp8, Michael A. Heneghan3,
James Neuberger4, Gideon M. Hirschfield4, Andrew K. Bur-
roughs5, Andrew Bathgate6, Mervyn H. Davies7, Carolyn Adgey1,
Paul Trembling1, Kate D. Williamson1, Laura Griffiths1, Teegan R.
Lim1, Nick Wareham8, David E. Jones9, Graeme J. Alexander2,
Richard N. Sandford1, Heather J. Cordell10, George F. Mells1,2;
1Academic Department of Medical Genetics, University of Cam-
bridge, Cambridge, United Kingdom; 2Division of Gastroenter-
ology and Hepatology, Cambridge University Hospital National
Health Service (NHS) Foundation Trust, Cambridge, United King-
dom; 3Institute of Liver Studies, Kings College Hospital NHS Trust,
London, United Kingdom; 4Liver Unit, Queen Elizabeth Hospital,
Birmingham, United Kingdom; 5Sheila Sherlock Liver Centre, Royal
Free Hospital, London, United Kingdom; 6Liver Unit, Royal Infir-
mary of Edinburgh, Edinburgh, United Kingdom; 7Liver Unit, St
James Hospital, Leeds, United Kingdom; 8MRC Epidemiology Unit,
University of Cambridge, Cambridge, United Kingdom; 9Institute
of Cellular Medicine, Newcastle University, Newcastle, United
Kingdom; 10Institute of Genetic Medicine, Newcastle University,
Newcastle, United Kingdom
BACKGROUND:UDCA response predicts outcome in primary
biliary cirrhosis (PBC).However, existing predictive models
dichotomise UDCA response and fail to recognise a continuum
of risk.Also,risk stratification based on UDCA response does
not take the stage of the liver disease into account. We anal-
ysed data from the UK-PBC Cohort to determine whether vari-
ables reflecting disease stage might improve current prognostic
models;and to compare models treating UDCA response as a
continuous versus categorical variable.METHODS:We under-
took time-to-event analysis using the Cox proportional hazard
regression model.The entry point was the date of presentation
and the endpoint was the date of ‘failure’ (liver transplant for,or
death from, PBC-related liver failure).The Akaike information
criterion (AIC) was used as model-selection criterion;the model
with the lower AIC was considered the model that better fits
the data.RESULTS:Data were available for 2274 PBC patients
treated with UDCA for at least one year.On multivariate analy-
sis,the liver biochemistry after one year of UDCA most-strongly
predicted failure,i.e. bilirubin(P=1.31x10-19),transaminas-
es(P=1.92x10-12)and alkaline phosphatase(P=0.003).How-
ever,variables reflecting disease stage had effects independent
of UDCA response,i.e. baseline bilirubin(P=0.0002),creati-
nine(P=0.0102),albumin(P=0.0001), platelet count(P=0.0006)
and splenomegaly(P=0.0005)(Table 1).Modelling UDCA
response with continuous variables(AIC=1228)fitted the sur-
vival data better than modelling UDCA response as a dichoto-
mous variable, e.g. Paris I(AIC = 2614),Paris II(AIC = 2626)
and Toronto criteria(AIC=2685). CONCLUSION:Treatment
of PBC should undoubtedly be guided by the biochemical
response. However,risk assessment might be improved by tak-
ing the stage of the liver disease into account and by recognis-
ing that the biochemical response is a continuum.Further work
will be to develop continuous risk models so that treatment may
be directed towards achieving maximal reduction in risk.
HEPATOLOGY, October, 2014
Cox proportional hazard regression model of variable at presen-
tation and liver biochemistry at 12 months after UDCA therapy
(N=2274)
Note:variables are expressed as ratio x ULN or LLN.
*ALT or AST level are used interchangeably
Disclosures:
James Neuberger - Speaking and Teaching: novartis, astellas
Gideon M. Hirschfield - Advisory Committees or Review Panels: Centocor/J&J,
Medigene, Intercept, Falk Pharma ; Consulting: Lumena, Intercept
David E. Jones - Consulting: Intercept
Richard N. Sandford - Advisory Committees or Review Panels: Otsuka; Grant/
Research Support: Intercept
The following people have nothing to disclose: Marco Carbone, Stephen Sharp,
Michael A. Heneghan, Andrew K. Burroughs, Andrew Bathgate, Mervyn H.
Davies, Carolyn Adgey, Paul Trembling, Kate D. Williamson, Laura Griffiths, Tee-
gan R. Lim, Nick Wareham, Graeme J. Alexander, Heather J. Cordell, George
F. Mells
304
NGM282 is a Potent Modulator of Bile Acid Synthesis in
Humans via Suppression of CYP7A1 Activity
Stephen Rossi1, Michael Elliott1, Kenneth D. Setchell2, Stephenson
W. Nkinin2, Jian Luo1, Lei Ling1, Krishna P. Allamneni1, Hui Tian1,
Alex M. DePaoli1; 1NGM Biopharmaceuticals, Inc., South San
Francisco, CA; 2Cincinnati Children’s Hospital Medical Center,
Cincinnati, OH
Background and Aims: NGM282 is an engineered recom-
binant protein variant of the ileal hormone human fibroblast
growth factor 19 (FGF19) which down-regulates the classical
pathway of bile acid (BA) synthesis by specifically suppressing
hepatic CYP7A1. NGM282 decreases serum concentrations of
7a-hydroxy-4-cholesten-3-one (C4), a surrogate biomarker for
CYP7A1-mediated BA synthesis, in both mice and monkeys.
The direct activity of NGM282 on BA synthesis in humans was
evaluated by measuring serum C4 concentrations in a Phase
1 clinical study. Methods: NGM282 was dosed daily in the
morning (AM) over 6 consecutive days at 0.1, 0.3, 1 and 3 mg
vs placebo. Serum C4 and total BAs were measured pre-meal
(fasted) and 4.5 hours post-meal (fed) at Screening (Day -1)
and on Day 7. NGM282 levels were collected for pharmaco-
kinetic (PK) calculations and correlation to pharmacodynamic
markers. Quantification of C4 was performed using liquid chro-
matography electrospray ionization tandem mass spectrometry
with stable-isotope dilution analysis. Results: NGM282 signifi-
cantly decreased serum C4 levels in a dose-dependent manner
from Day -1 to Day 6 in both fasted and fed states at the 0.3,
1 and 3 mg dose (Figure 1) and consistent with the magnitude
of change observed in animal models. Median % change from
Day -1 ranged from a 28-95% decrease fasted and a 64-95
% fed vs a 16-51% increase with placebo. Dose-dependent
decreases in C4 were consistent with the observed dose pro-
portional PK of NGM282. Maximal biologic activity was seen
in all subjects dosed with 3 mg where as “no effect” dose was
at 0.1 mg. Conclusions: Administration of NGM282 resulted
in a rapid and potent suppression of C4 in healthy human
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
subjects, reflective of decreased BA synthesis via the classical
pathway. These data support the potential therapeutic activity
of NGM282 in BA-related cholestatic disorders. Exploratory
studies are currently underway in patients with primary biliary
cirrhosis.
Figure 1. Median Serum C4 Concentrations
Disclosures:
Stephen Rossi - Employment: NGM Biopharmaceuticals, Inc; Stock Shareholder:
NGM Biopharmaceuticals, Gilead Sciences
Michael Elliott - Employment: NGM; Stock Shareholder: NGM
Jian Luo - Employment: NGM Biopharmaceuticals
Lei Ling - Employment: NGM Biopharmaceuticals, Inc.; Stock Shareholder: NGM
Biopharmaceuticals, Inc.
Hui Tian - Employment: NGM Biopharma
Alex M. DePaoli - Employment: NGM Biopharmaceuticals
The following people have nothing to disclose: Kenneth D. Setchell, Stephenson
W. Nkinin, Krishna P. Allamneni
305
Obeticholic Acid in PBC Patients: The Utility of Titration
Based on Therapeutic Response and Tolerability
Christopher L. Bowlus1, Paul J. Pockros2, Joost Drenth3, Ann-
arosa Floreani4, Catherine Vincent5, Velimir A. Luketic6, Karel
J. van Erpecum7, Victor Vargas8, Mitchell L. Shiffman9, Frederik
Nevens10, Richard Pencek11, Roya Hooshmand-Rad11, David Sha-
piro11; 1University of California-Davis, Sacramento, CA; 2Scripps
Clinic, La Jolla, CA; 3UMC St. Radboud, Nijmegen, Netherlands;
4Università di Padova, Padova, Italy; 5Centre Hospitalier Universi-
taire de l’Université de Montréal-St. Luc, Montreal, QC, Canada;
6McGuire DVAMC, Richmond, VA; 7UMC Utrecht, Utrecht, Neth-
erlands; 8Hospital Vall d’Hebron, Barcelona, Spain; 9Liver Institute
of Virginia, Newport News, VA; 10UZ Leuven, Leuven, Belgium;
11Intercept Pharmaceuticals, Inc., San Diego, CA
The Phase 3 POISE trial evaluated the efficacy and safety of
obeticholic acid (OCA), a derivative of chenodeoxycholic acid
and potent farnesoid-X receptor agonist, in patients with PBC.
The primary endpoint was defined as alkaline phosphatase
<1.67xULN and a ≥15% ALP reduction and a bilirubin ≤ULN
which was achieved by a significantly higher proportion of
patients treated with OCA compared to placebo (p<0.0001).
The aim of this analysis was to evaluate if titration of OCA
would improve tolerability while remaining efficacious. This
was an international, double-blind, placebo-controlled (PBO)
trial. PBC patients ±UDCA (if taking UDCA, on a stable dose)
with ALP≥1.67x ULN or bilirubin <2x ULN were randomized to
PBO, OCA 5 or 10mg for 12mo. Patients randomized to 5mg
were titrated to 10mg after 6mo if 5 mg was well tolerated and
the primary endpoint had not been met. This analysis focuses
on the efficacy and tolerability of OCA in those subjects ran-
353A
domized to 5 mg OCA who subsequently were or were not
titrated to 10 mg. All groups were well-matched. Mean age:
55.8yrs, female: 91%, Caucasian: 94%, 7% were not tak-
ing UDCA. Overall, 91% of patients completed the study. The
titration arm showed comparable efficacy to the 10 mg group
with a lower overall incidence of pruritus (table). Of the 69 5
mg OCA subjects who completed 6 mo, 33 titrated to 10 mg
resulting in 13 additional responders by 12 mo. 4 subjects
who were eligible to titrate did not due to pruritus. One subject
discontinued due to pruritus after up-titration to 10 mg. OCA
given to PBC patients with an inadequate response to or unable
to tolerate UDCA produced highly statistically, clinically mean-
ingful improvements in liver biochemistries which have been
shown to be strongly correlated with clinical benefit. Titration of
OCA based on therapeutic response and tolerability mitigated
pruritus while maintaining efficacy.
Disclosures:
Christopher L. Bowlus - Advisory Committees or Review Panels: Gilead Sciences,
Inc; Consulting: Takeda; Grant/Research Support: Gilead Sciences, Inc, Inter-
cept Pharmaceuticals, Bristol Meyers Squibb, Lumena; Speaking and Teaching:
Gilead Sciences, Inc
Paul J. Pockros - Advisory Committees or Review Panels: Janssen, Merck, Genen-
tech, BMS, Gilead, Boehinger Ingelheim, AbbVioe; Consulting: Genentech,
Lumena, Regulus, Beckman Coulter, RMS; Grant/Research Support: Novartis,
Intercept, Janssen, Genentech, BMS, Gilead, Vertex, Boehinger Ingelheim,
Lumena, Beckman Coulter, AbbVie, RMS, Novartis, Merck; Speaking and Teach-
ing: Genentech, BMS, Gilead
Karel J. van Erpecum - Advisory Committees or Review Panels: Bristol Meyers
Squibb, Abbvie
Mitchell L. Shiffman - Advisory Committees or Review Panels: Merck, Gilead,
Boehringer-Ingelheim, Bristol-Myers-Squibb, Abbvie, Janssen; Consulting: Roche/
Genentech, Gen-Probe; Grant/Research Support: Merck, Gilead, Boehring-
er-Ingelheim, Bristol-Myers-Squibb, GSK, Abbvie, Beckman-Coulter, Achillion,
Lumena, Intercept, Novarit, Gen-Probe; Speaking and Teaching: Roche/Genen-
tech, Merck, Gilead, GSK, Janssen, Bayer
Frederik Nevens - Consulting: CAF, Intercept, Gore, BMS, Abbvie, Novartis,
MSD, Eumedica, Janssen; Grant/Research Support: Ipsen, Roche, MSD, Astellas
Richard Pencek - Employment: Intercept Pharmaceuticals; Stock Shareholder:
Intercept Pharmaceuticals
Roya Hooshmand-Rad - Employment: Intercept pharmaceuticals Inc.
David Shapiro - Employment: Inttercept Pharmaceuticals
The following people have nothing to disclose: Joost Drenth, Annarosa Floreani,
Catherine Vincent, Velimir A. Luketic, Victor Vargas
354A AASLD ABSTRACTS
306
Clinical Course And Outcome Of Patients With Scleros-
ing Cholangitis In Critically Ill Patients (Sc-Cip): High
Mortality Without Liver Transplantation
Harald Hofer1,
Gernot Zollner2,
Peter Fickert2,
Ivo Graziadei3,
Michael Trauner1; 1Department of Gastroenterology and Hepatol-
ogy, Medical University of Vienna, Vienna, Austria; 2Department
of Internal Medicine, Medical University of Graz, Graz, Austria;
3Department of Internal Medicine, Hospital Hall, Hall, Austria
Background: Sclerosing cholangitis in critically ill patients
(SC-CIP) is a progressive biliary disease developing in a sub-
group of patients during intensive care treatment. It is charac-
terized by biliary casts/obliteration, formation of strictures and
destruction of intrahepatic bile ducts consecutively leading to
liver cirrhosis and liver failure. Aim of the study was to char-
acterize clinical course, outcome and prognostic features of
patients with SC-CIP. Patients and Methods: 49 patients (34
male, age: 46.0+14.2, (mean+SD, years)) with SC-CIP, diag-
nosed by endoscopic retrograde cholangiography (ERC) were
retrospectively analyzed. No patient had evidence of preex-
isting hepato-biliary disease or inflammatory bowel disease.
Histological evaluation of liver biopsies, ICU and endoscopic
treatment as well as outcome were evaluated. Results: Respira-
tory failure (N=11), severe polytrauma (N=9), sepsis (N=7),
lung transplantation (N=5), surgery (N=5), cardiopulmonary
rescuscitation (N=4) and burn injuries (N=3), were the most
common reasons for hospitalization. Mean duration of hospi-
talization at the ICU was 73.9+44 days. All patients required
prolonged mechanical ventilation (mean duration: 45+28
days), with the need of extracorporal membrane oxygenation
(ECMO) in 11 patients. Laboratory findings at the time of ERCP
were: bilirubin: 14.9[0.4-18]; (mg/dl, median[range]), GGT:
29[1.3-60.8] (xULN, median[range]), AP: 10.8[1.1-28.0],
(xULN, median[range]). Sphincterotomy, extraction of casts/
sludge and dilations of dominant strictures were performed
during ERCP. During follow up 26 patients died and 4 patients
were transplanted. Number of organ failure and organ replace-
ment therapy were independent risk factors for mortality. Con-
clusion: Critical reduction of hepatic oxygen delivery may lead
to initial bile duct injury in ICU patients. Vasopressor treatment
and sedoanalgesia, hepatic ischemia, as well as translocation
of endotoxins and bacteria from the gut may further perpetuate
progressing SC-CIP, which carries a high mortality as a high
proportion of these patients rapidly develop liver cirrhosis and
liver failure.
Disclosures:
Harald Hofer - Speaking and Teaching: Janssen, Roche, MSD, Gilead, Abbvie
Peter Fickert - Consulting: Falk Foundation, Falk Foundation, Falk Foundation,
Falk Foundation; Speaking and Teaching: Roche Austria, Gilead Austria, MSD
Austria, MERCK Austria, Roche Austria, Gilead Austria, MSD Austria, MERCK
Austria, Roche Austria, Gilead Austria, MSD Austria, MERCK Austria, Roche
Austria, Gilead Austria, MSD Austria, MERCK Austria
Michael Trauner - Advisory Committees or Review Panels: MSD, Janssen, Gilead,
Abbvie; Consulting: Phenex; Grant/Research Support: Intercept, Falk Pharma,
Albireo; Patent Held/Filed: Med Uni Graz (norUDCA); Speaking and Teaching:
Falk Foundation, Roche, Gilead
The following people have nothing to disclose: Gernot Zollner, Ivo Graziadei
HEPATOLOGY, October, 2014
307
Successful Immunotherapy of Autoimmune Cholangitis
by Adoptive Transfer of Foxp3+ Regulatory T Cells
Hajime Tanaka1,2, Weici Zhang1, Guo-Xiang Yang1, Koichi
Tsuneyama3, Patrick S. Leung1, Ross L. Coppel4, Aftab A. Ansari5,
Zhe-Xiong Lian6, William M. Ridgway7, M. Eric Gershwin1; 1Inter-
nal Medicine, University of California, Davis, CA; 2Department
of Gastroenterology and Metabolism, Nagoya City University
Graduate School of Medical Sciences, Nagoya, Japan; 3Depart-
ment of Diagnostic Pathology, Graduate School of Medicine
and Pharmaceutical Science for Research, University of Toyama,
Toyama, Japan; 4Department of Microbiology, Monash University,
Melbourne, VIC, Australia; 5Department of Pathology, Emory Uni-
versity School of Medicine, Atlanta, GA; 6Institute of Immunology
and School of Life Sciences, University of Science and Technology
of China, Hefei, China; 7Division of Immunology, Allergy and
Rheumatology, University of Cincinnati College of Medicine, Cin-
cinnati, OH
Background: dnTGFβRII mice develop high titer AMAs and his-
tologic features characteristic of autoimmune cholangitis, with
striking similarities to human PBC. There is increasing interest in
the potential use of regulatory T cells (Tregs) as immunotherapy
to treat diseases characterized by loss of tolerance. We have
taken advantage of the dnTGFβRII model and, in particular, an
ability to induce autoimmune cholangitis in Rag1-/- recipients
by adoptive transfer of dysregulated CD8+ T cells from dnT-
GFβRII mice. Such adoptively transferred Rag1-/- recipients
develop severe portal inflammation with both histologic and
cytokine evidence of intense inflammation. Methods: Rag1-
/- mice, at four weeks of age, received either CD8+ T cells
from dnTGFβRII mice with co-transfer of either Foxp3+ Tregs
derived from wild-type and otherwise healthy C57BL/6 mice,
or dnTGFβRII mice. Recipient mice were monitored for histol-
ogy including portal inflammation and intra-lobular biliary
cell damage, phenotypic changes in recipient lymphoid pop-
ulations and local and systemic cytokine production. Results:
Adoptive transfer of CD8+ T cells into Rag-/- recipients led to
the characteristic autoimmune cholangitis at approximately 8
weeks following transfer. Importantly, co-transfer of CD8+ T
cells from dnTGFβRII mice with Foxp3+ Treg cells from dnTG-
FβRII mice did not alter this adoptive transfer of immunopathol-
ogy. However, and of striking importance, co-transfer of CD8+
T cells from dnTGFβRII mice with wild-type Foxp3+ T cells from
C57BL/6 mice, significantly reduced the immunopathology,
including portal inflammation, bile duct damage, and dramatic
down-regulation of the secondary inflammatory response. In
addition, to focus on the mechanisms of action of the ability of
C57BL/6 Tregs to reduce autoimmune cholangitis, we noted
significant differential expression of GARP, CD73, CD101,
and CD103 and a functionally significant increase in IL-10 in
Tregs from C57BL/6 compared to dnTGFβRII mice. Conclu-
sion: These data highlight the therapeutic potential of Treg cells
in reducing the excessive autoreactive T cell responses in this
murine model of primary biliary cirrhosis and reflects a novel
venue for treatment of patients who have undergone a breach
of tolerance.
Disclosures:
The following people have nothing to disclose: Hajime Tanaka, Weici Zhang,
Guo-Xiang Yang, Koichi Tsuneyama, Patrick S. Leung, Ross L. Coppel, Aftab A.
Ansari, Zhe-Xiong Lian, William M. Ridgway, M. Eric Gershwin
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
308
Protein Profiles of Apoptotic Bodies from Biliary Epithe-
lial Cells
Ana Lleo2, Weici Zhang1, W. Hayes McDonald3, Patrick S.
Leung1, Ross L. Coppel4, Aftab A. Ansari5, David H. Adams6,
Simon C. Afford6, Pietro Invernizzi2, M. Eric Gershwin1; 1Inter-
nal Medicine, University of California, Davis, CA; 2Liver Unit and
Center for Autoimmune Liver Diseases, Humanitas Clinical and
Research Center, Rozzano, Italy; 3Vanderbilt University School of
Medicine, Nashville, TN; 4Department of Medical Microbiology,
Monash University, Melbourne, VIC, Australia; 5Department of
Pathology, Emory University School of Medicine, Atlanta, GA;
6Institute of Biomedical Research, Birmingham, United Kingdom
Background. There is increasing data suggesting a role for
the apoptotic blebs of biliary epithelial cells (BECs) as a caus-
ative mechanism that leads to selective biliary destruction and
an intense pro-inflammatory micro-environment. Methods. We
have isolated and analyzed apoptotic bodies from normal
human BECs, renal tubular epithelial cells (HRPTEpiC), bron-
chial epithelial cells (BrEPC) and BECs from primary biliary
cirrhosis (PBC) and controls by comparative shotgun pro-
teomics using columns coupled to a LTQ ion trap mass spec-
trometer nanospray source; samples were isolated and run
independently. Tandem mass spectra were evaluated using the
Uniprot database and pathway analysis using The Pathway
Interaction NCI Database (http://pid.nci.nih.gov) as well as
the STRING (Search Tool for Retrieval of Interacting Genes)
software (http://string-db.org/). Results. A total of 40,843 dis-
tinct peptides and 6,160 protein groups were identified within
apoptotic bodies from HiBEC, BrEPC, and HRPTEpiC. Similar
numbers were identified in BECs from PBC and controls. Inter-
estingly, 11 proteins were found to be specific for apoptotic
bodies of HiBEC. Eight proteins were unique to apoptotic bod-
ies from BrEPC and HRPTEpiC, and absent from HiBEC. Fur-
ther, comparison of the global proteome of apoptotic bodies to
that of intact cells from HiBEC, HRPTEpiC, and BrEPC identified
a total of 3,152 protein groups within HiBECs, HRPTEpiCs,
and BrEPCs. Of the 11 proteins uniquely found in the apoptotic
bodies of HiBEC cells, 4 of the 11 (ANXA6, LRP1, PAPS2,
and SERPH) were found to be present in all three intact cell
lines. One protein, HSPB6, was found only in intact HiBEC, but
not intact HRPTEpiC or BrEPC. However, the other 6 proteins
uniquely found in blebs of HiBEC (A6NN80, B4DN38, GPC6,
Q6ZR44, RAB11A AND VGFR3), were not found in intact
cells. Finally, of the 3,152 protein groups, only 3 proteins
found in intact HiBEC cells, but not in HiBEC apoptotic bodies
(ANXA3, PYGB, and ITPR3). Six proteins were found to be
specifically located in apoptotic bodies from PBC compared
to apoptotic bodies from controls and only 2 proteins were
unique to apoptotic bodies from controls that are absent in
those from PBC. Analysis of the cellular pathways in HiBEC
and found in apoptotic bodies identified essential inflammation
pathways, including the Notch signaling pathway, IL8 and
CXCR2-mediated signaling, integrin signaling, and proteins
that regulate cell growth and division. Conclusion: The sig-
nature proteins identified by this unique technology implicate
specific pathways that may shed light on potential therapeutic
intervention.
Disclosures:
The following people have nothing to disclose: Ana Lleo, Weici Zhang, W.
Hayes McDonald, Patrick S. Leung, Ross L. Coppel, Aftab A. Ansari, David H.
Adams, Simon C. Afford, Pietro Invernizzi, M. Eric Gershwin
355A
309
Efficacy of Obeticholic Acid In Primary Biliary Cirrhosis
as Assessed by Response Criteria Associated With Clini-
cal Outcome: A Poise Analysis
Velimir A. Luketic1, Pietro Invernizzi2, Michael Trauner3, Jaroslaw
Regula4, Giuseppe Mazzella5, Simone I. Strasser6, Annarosa
Floreani7, Simon Hohenester8, Karel J. van Erpecum9, Paul J.
Pockros10, Bettina E. Hansen11, Henk R. van Buuren11, Frederik
Nevens12, Richard Pencek13, Roya Hooshmand-Rad13, David Sha-
piro13; 1McGuire DVAMC,, Richmond, VA; 2Liver Unit and Center
for Autoimmune Diseases, Humanitas Clinical and Research Cen-
ter, Rozzano, Italy; 3Medical University of Vienna, Austria, Austria;
4Cancer Centre, Warsaw, Poland; 5Universitaria di Bologna, Bolo-
gna, Italy; 6Royal Prince Alfred Hospital, Sydney, NSW, Austra-
lia; 7Azienda Ospedaliera – Università di Padova, Padova, Italy;
8LMU University of Munich, Munich, Germany; 9UMC Utrecht,
Utrecht, Netherlands; 10Scripps Clinic, L Jolla, CA; 11Erasmus MC,
University Medical Center, Rotterdam, Netherlands; 12UZ Leuven,
Leuven, Belgium; 13Intercept Pharmaceuticals, Inc, San Diego, CA
Aim: Obeticholic acid (OCA, 6-ethyl chenodeoxycholic acid)
is a highly potent, selective FXR agonist. Efficacy and safety of
OCA was evaluated in an international double-blind placebo
(PBO) controlled trial (POISE). The Global PBC Study Group
(GPBCSG) confirms patients with alkaline phosphatase (ALP)
>1.67x ULN or bilirubin >ULN have a greatly increased risk
of liver transplant or death [HR (95% CI): 2.83 (2.4-3.4); p
=1x10-34]. Additional prognostic criteria are associated with
clinical outcomes in PBC patients. This analysis evaluated the
efficacy of OCA per these criteria. Methods: POISE was con-
ducted in PBC patients ±UDCA (if taking UDCA, on a stable,
continuing dose) with ALP≥1.67xULN or bilirubin <2xULN;
subjects were randomized to PBO, OCA 5 or 10 mg for 12
mo. Patients randomized to 5 mg were titrated to 10mg after
6mo, based on response and tolerability. The primary end-
point was attaining the GPBCSG ALP/Bilirubin goal and ALP
reduction ≥15%. Disease severity criteria of Paris I, Paris II, and
Rotterdam were also assessed. Results: All groups were well-
matched. Mean age: 55.8yrs, female: 91%, Caucasian: 94%.
The median UDCA dose was 15.4 mg/kg; 7% were UDCA-in-
tolerant. Overall, 91% of patients completed the study. The
primary endpoint was achieved: significantly greater propor-
tion of OCA treated patients achieved the primary endpoint.
Results based on additional criteria are presented in the table.
Pruritus, generally mild to moderate, was the most common and
dose related AE; few OCA patients withdrew due to pruritus
(<6%). The incidence of AEs other than pruritus was no worse
with OCA (PBO, 90%, 5/10 mg OCA, 89%, 10 mg OCA,
86%). Overall, serious adverse events (SAEs) occurred in 22
(10%) of the patients and, although there were more SAEs in
the OCA treatment groups, none were considered drug-related
and there were no apparent patterns in the SAEs. Conclusions:
OCA given to PBC patients with an inadequate response to or
unable to tolerate UDCA produced highly statistically, clinically
meaningful improvements according to several disease severity
criteria, which have been shown to be strongly correlated with
clinical benefit. No significant changes were seen according
to the Rotterdam criteria, likely due to the high percentage of
normal patients.
356A AASLD ABSTRACTS
Disclosures:
Michael Trauner - Advisory Committees or Review Panels: MSD, Janssen, Gilead,
Abbvie; Consulting: Phenex; Grant/Research Support: Intercept, Falk Pharma,
Albireo; Patent Held/Filed: Med Uni Graz (norUDCA); Speaking and Teaching:
Falk Foundation, Roche, Gilead
Simone I. Strasser - Advisory Committees or Review Panels: Janssen, AbbVie,
Roche Products Australia, MSD, Bristol-Myers Squibb, Gilead, Norgine, Bayer
Healthcare; Speaking and Teaching: Bayer Healthcare, Bristol-Myers Squibb,
MSD, Roche Products Australia, Gilead, Janssen
Simon Hohenester - Speaking and Teaching: Dr. Falk Pharma
Karel J. van Erpecum - Advisory Committees or Review Panels: Bristol Meyers
Squibb, Abbvie
Paul J. Pockros - Advisory Committees or Review Panels: Janssen, Merck, Genen-
tech, BMS, Gilead, Boehinger Ingelheim, AbbVioe; Consulting: Genentech,
Lumena, Regulus, Beckman Coulter, RMS; Grant/Research Support: Novartis,
Intercept, Janssen, Genentech, BMS, Gilead, Vertex, Boehinger Ingelheim,
Lumena, Beckman Coulter, AbbVie, RMS, Novartis, Merck; Speaking and Teach-
ing: Genentech, BMS, Gilead
Frederik Nevens - Consulting: CAF, Intercept, Gore, BMS, Abbvie, Novartis,
MSD, Eumedica, Janssen; Grant/Research Support: Ipsen, Roche, MSD, Astellas
Richard Pencek - Employment: Intercept Pharmaceuticals; Stock Shareholder:
Intercept Pharmaceuticals
Roya Hooshmand-Rad - Employment: Intercept pharmaceuticals Inc.
David Shapiro - Employment: Inttercept Pharmaceuticals
The following people have nothing to disclose: Velimir A. Luketic, Pietro Inv-
ernizzi, Jaroslaw Regula, Giuseppe Mazzella, Annarosa Floreani, Bettina E.
Hansen, Henk R. van Buuren
HEPATOLOGY, October, 2014
310
FXR Agonist Obeticholic Acid: Pruritus, A Common Side
Effect Ameliorated by Dose Titration
Ulrich Beuers1, David E. Jones2, Marlyn J. Mayo3, Pietro Andre-
one4, Giuseppe Mazzella 5, Simon Hohenester 6, Annarosa
Floreani7, Simone I. Strasser8, Christopher L. Bowlus9, Pietro Inv-
ernizzi10, Joost Drenth11, Paul J. Pockros12, Jaroslaw Regula13,
Velimir A. Luketic14, Karel J. van Erpecum15, Victor Vargas16,
Catherine Vincent17, Roya Hooshmand-Rad18, Shawn Sheeron18,
David Shapiro18; 1Department of Gastroenterology and Hepatol-
ogy, AMC, Amsterdam, Netherlands; 2Institute of Cellular Medi-
cine, Newcastle University Medical School, Newcastle Upon Tyne,
United Kingdom; 3UT Southwestern Medical Center, Dallas, TX;
4Dipartimento di Scienze Mediche e Chirurgiche, University of
Bologna, Bologna, Italy; 5Clinical Medicine, University of Bologna,
Bologna, Italy; 6Department of Medicine II, niversity of Munich,
Munich, Germany; 7University of Padova, Padova, Italy; 8Royal
Prince Alfred Hospital, Sydney, NSW, Australia; 9UC Davis, Sac-
ramento, CA; 10Liver Unit and Center for Autoimmune Diseases,
Humanitas Clinical and Research Center, Rozzano, Italy; 11Gas-
troenterology & Hepatology, UMC St. Radboud, Nijmegen, Neth-
erlands; 12Div. of Gastro/Hepatology, Scripps Clinic, La Jolla,
CA; 13Cancer Centre, Warsaw, Poland; 14Hepatology Section,
Virginia Commonwealth University School of Medicine, Richmond,
VA; 15Gastroenterology, UMC Utrecht, Utrecht, Netherlands;
16Hospital Vall d’Hebron, Barcelona, Netherlands; 17Unité de
recherche clinique, CHUM Hôpital St-Luc, Montréal, QC, Canada;
18Intercept Pharmaceuticals, San Diego, CA
Obeticholic acid (OCA), a potent, selective FXR agonist in
development for PBC produced significant improvement in
cholestasis markers in Phase2 PBC trials at OCA 10 – 50 mg
(±UDCA). Pruritus, a hallmark PBC symptom of unknown etiol-
ogy, was the most frequently occurring dose-related AE result-
ing in early discontinuation in up to 24% at 50 mg. In a Phase3
PBC trial (POISE), lower doses also resulted in clinically and
highly statistically significant liver biochemistry improvement
(p<0.0001 vs. Placebo). POISE treatment emergent (TE) pruri-
tus is characterized here. In a 1 yr, international, double-blind,
placebo-controlled trial, 217 PBC patients (ALP≥1.67x ULN/
TBili > ULN) were randomized to Placebo (PBO), OCA 5 mg
or 10 mg. Patients randomized to 5 mg were titrated to 10
mg after 6 mo (TITR) based on biochemistry/tolerability; pre-
trial UDCA continued. Baseline pruritus was recorded using
a severity scale (Mild/Moderate/Severe). TE Pruritus was
recorded using AE data and a visual analogue scale (VAS).
Protocol-allowed pruritus interventions included drug interrup-
tion, dose interval change and medications. Pruritus, mostly
mild to moderate, was the most common dose-related AE (PBO,
38%, TITR, 56%, 10mg, 68%). Only 1 (1%) of patients in the
TITR group discontinued due to pruritus (after starting 10mg),
vs 10% in the 10 mg group. Incidence and severity of TE pru-
ritus improved during 2nd half of the trial (Table). Overall,
<6% withdrew due to pruritus. Although on-Study VAS scores
initially were higher in OCA patients vs PBO (p= 0.0005 at w2
and 0.0314 at 6 mo in 10 mg OCA), the difference was not
statistically significant in the TITR arm and negligible for both
arms at 12 mo vs PBO. Starting treatment at 5mg and increas-
ing to 10mg, if appropriate, ameliorates OCA related pruritus
while maintaining efficacy.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
>6-12 mo: PBO N=70, TITR N=69, 10 mg N= 64
Disclosures:
Ulrich Beuers - Consulting: Intercept, Novartis; Grant/Research Support: Zam-
bon; Speaking and Teaching: Falk Foundation, Gilead, Roche, Scheringh, Zam-
bon
David E. Jones - Consulting: Intercept
Marlyn J. Mayo - Grant/Research Support: Intercept, Salix, NGM, Lumena,
Gilead
Pietro Andreone - Advisory Committees or Review Panels: Roche, Janssen-Cilag,
Gilead, MSD/Schering-Plough, Abbvie, Boehringer Ingelheim; Grant/Research
Support: Roche, Gilead; Speaking and Teaching: Roche, MSD/Schering-Plough,
Gilead
Simon Hohenester - Speaking and Teaching: Dr. Falk Pharma
Simone I. Strasser - Advisory Committees or Review Panels: Janssen, AbbVie,
Roche Products Australia, MSD, Bristol-Myers Squibb, Gilead, Norgine, Bayer
Healthcare; Speaking and Teaching: Bayer Healthcare, Bristol-Myers Squibb,
MSD, Roche Products Australia, Gilead, Janssen
Christopher L. Bowlus - Advisory Committees or Review Panels: Gilead Sciences,
Inc; Consulting: Takeda; Grant/Research Support: Gilead Sciences, Inc, Inter-
cept Pharmaceuticals, Bristol Meyers Squibb, Lumena; Speaking and Teaching:
Gilead Sciences, Inc
Paul J. Pockros - Advisory Committees or Review Panels: Janssen, Merck, Genen-
tech, BMS, Gilead, Boehinger Ingelheim, AbbVioe; Consulting: Genentech,
Lumena, Regulus, Beckman Coulter, RMS; Grant/Research Support: Novartis,
Intercept, Janssen, Genentech, BMS, Gilead, Vertex, Boehinger Ingelheim,
Lumena, Beckman Coulter, AbbVie, RMS, Novartis, Merck; Speaking and Teach-
ing: Genentech, BMS, Gilead
Karel J. van Erpecum - Advisory Committees or Review Panels: Bristol Meyers
Squibb, Abbvie
Roya Hooshmand-Rad - Employment: Intercept pharmaceuticals Inc.
Shawn Sheeron - Employment: Intercept Pharmaceuticals
David Shapiro - Employment: Inttercept Pharmaceuticals
The following people have nothing to disclose: Giuseppe Mazzella, Annarosa
Floreani, Pietro Invernizzi, Joost Drenth, Jaroslaw Regula, Velimir A. Luketic,
Victor Vargas, Catherine Vincent
311
Incidence of and Risk Factors for Primary Biliary Cirrho-
sis-associated Hepatocellular Carcinoma: Large-Scale
Data from China
Xue-Xiu Zhang1,2, Li-Feng Wang2, Zheng Zhang2, Fu-Sheng
Wang1,2; 1The Institute of Translational Hepatology, Beijing 302
Hospital, Peking University Health Science Center;, Beijing, China;
2Research Center for Biological Therapy, Beijing 302 Hospital,
Beijing, China, Beijing, China
Background and Aims:Until now, prevalence of hepatocellular
carcinoma (HCC) in primary biliary cirrhosis (PBC) is estab-
lished in UK, USA and Japan, and suggested that many fac-
tors were associated with the development of hepatocellular
carcinoma (HCC) in patients with primary biliary cirrhosis
(PBC). However, limited data is available regarding the clin-
ical characteristics of PBC-associated HCC patients in China.
This study was designed to investigate the clinical features of
PBC-associated HCC patients in China, and further analyze
its relative risk factors. Methods: Clinical data of 1255 PBC
patients including 52 HCC patients in our hospital from Jan-
uary 2002 to December 2013 were collected and analyzed.
357A
Moreover, a case-control study, including 20 PBC-associated
HCC patients and 77 PBC patients without HCC, was con-
ducted to analyze the risk factors for HCC development in
PBC patients. Results: In our study, the total HCC incidence
in Chinese PBC patients was 4.13% (52/1255), and further
study showed that there was higher HCC incidence in male
patients than that in female patients (9.52% vs 3.31%, P <
0.05). Higher proportion of blood transfusion, alcohol intake
and smoking occurred in male PBC-associated HCC patients,
and they suffered from greater degree of liver injury as indi-
cated by higher levels of ALT, AST, ALP, and GGT (P < 0.05
for each). From the subsequent case-control study, we found
that BMI, family history of malignancies and history of alco-
hol intake were associated with the development of HCC in
PBC patients (P < 0.05 for each). In multivariable analysis,
BMI (OR, 1.294; 95% CI, 1.054-1.589), and history of alco-
hol intake (OR, 9.204; 95% CI, 1.019-83.129) were signifi-
cantly associated with increased odds of HCC. Conclusions:
HCC is not rare in Chinese PBC patients. Moreover, the HCC
incidence is higher and liver injury is more serious in male
patients than that in female patients. BMI and history of alcohol
intake are risk factors for HCC development in PBC patients.
Therefore, PBC patients may benefit from abstinence of alco-
hol intake and control of body weight. Xue-Xiu Zhang, Li-Feng
Wang, contributed equally to this study. *Correspondence to:
Prof Fu-Sheng Wang, Research Center for Biological Therapy,
fswang302@163.com, Beijing 302 Hospital, No. 100, the 4th
Western Ring Middle Road, Beijing 100039, China.
Disclosures:
The following people have nothing to disclose: Xue-Xiu Zhang, Li-Feng Wang,
Zheng Zhang, Fu-Sheng Wang
312
Possible impairment of mucosal-associated invariant T
cells in the liver of patients with primary biliary cirrhosis
Toru Setsu, Satoshi Yamagiwa, Kentaro Tominaga, Naruhiro
Kimura, Hiroki Honda, Hiroteru Kamimura, Masaaki Takamura,
Minoru Nomoto; Niigata University Graduate School of Medical
and Dental Sciences, Niigata, Japan
BACKGROUND/AIM: Human mucosal-associated invariant T
(MAIT) cells constitute a unique subset of innate-like T lympho-
cytes characterized by a semi-invariant T cell receptor (TCR)
repertoire (made of an invariant Vα7.2-Jα33 TCRα chain) capa-
ble of recognizing bacterial products. Although MAIT cells are
abundant in the human gut and liver, the involvement of MAIT
cells in the pathogenesis of liver diseases remains unclear. In
consideration of the possible association between bacterial
infections and primary biliary cirrhosis (PBC), we focused on
the role of MAIT cells in PBC. METHODS: Heparinized periph-
eral blood and liver biopsy specimens were collected from
13 patients with PBC and 11 patients with chronic viral hep-
atitis (CVH). Surgically removed liver tissues distant from the
tumor in 10 patients with metastatic liver tumors were used as
control livers (Control). Mononuclear cells were separated by
Ficoll-gradient, and then various surface markers were inves-
tigated by flow cytometry. mRNA expression was quantified
by real-time PCR. Cytokine production was investigated using
peripheral blood MAIT cells after stimulation with anti-CD3/
CD28-coupled beads in the presence or absence of IL-7. We
also investigated the distribution of Vα7.2+ CD161+ cells in the
liver by immunohistochemical staining. RESULTS: In the Con-
trols, CD3+ TCR-γδ- CD161high Vα7.2+ MAIT cells comprised
6.8% (median) (range 1.1-17.9) of the total T cells in the liver
but only 1.6% (0.1-6.7) of the total T cells in the blood. Intra-
hepatic MAIT cells constituted a significantly lower proportion
358A AASLD ABSTRACTS
in PBC patients (1.9%, 0.7-8.8) than in CVH patients (8.9%,
0.2-20.7) and Controls. We found a significant decrease in
the proportion of activated CD69+ MAIT cells in the liver of
patients with PBC compared to patients with CVH and Controls.
After the normalization of alkaline phosphatase by treatment
with ursodeoxycholic acid, MAIT cells increased in the blood.
Although MAIT cells express high levels of the IL-7 receptor (IL-
7R), MAIT cells in the liver of patients with PBC expressed less
IL-7R (66.8%, 60.0-70.5) than in the liver of patients with CVH
(76.3%, 44.4-93.7) and Controls (89.1%, 38.5-94.8). We
also confirmed that the functions of MAIT cells were dynami-
cally regulated by the presence of IL-7.
Disclosures:
The following people have nothing to disclose: Toru Setsu, Satoshi Yamagiwa,
Kentaro Tominaga, Naruhiro Kimura, Hiroki Honda, Hiroteru Kamimura,
Masaaki Takamura, Minoru Nomoto
313
Circulating bile acids and sterol levels in patients with
cholestatic pruritus. Effects of albumin dialysis using
MARS
Albert Pares1, Miriam Perez-Cormenzana2, Alvaro Diaz-Gonza-
lez1, Rebeca Mayo2, Azucena Castro2, Antoni Mas1; 1Liver Unit,
Hospital Clinic, Barcelona, Spain; 2OWL Metabolomics, Bilbao,
Spain
Background and aims: Serum metabolomic profile and
changes before and after treatment with albumin dialysis
using the molecular adsorbents recirculating system (MARS)
were assessed in patients with cholestatic pruritus to identify
metabolites potentially associated with the pathogenesis of
itch Patients and Methods: Serum samples were obtained from
85 patients with primary biliary cirrhosis, 21 with pruritus (9
with resistant pruritus before MARS) and 64 without pruritus.
Moreover, serum samples before and after MARS and albumin
dialyzate were taken in the 9 patients with resistant pruritus.
Metabolite extraction was accomplished by fractionating the
samples into pools of species with similar physicochemical
properties, and three different platforms were used to perform
optimal profiling of: a) fatty acyls, bile acids, steroids and
lysoglycerophospholipids; b) amino acids; and c) glycerolip-
ids, sterol lipids, sphingolipids, and glycerophospholipids. The
analyses were performed by UPLC-ESI-TOF-MS and multivariate
and univariate analyses. Results: More than 470 metabolites
were identified. Bile acids were significantly higher in patients
with pruritus (p<0.001), particularly in those with resistant pru-
ritus. Cortisol (p=0.02) and androsterone sulfate were in lower
levels, while pregnenolone sulfate and an isomer of dehydroe-
piandrosterone sulfate (DHEAS) were higher in patients with
pruritus. Most metabolites decreased in sera after MARS and
the differences were particularly significant for sterols, N-acyl
ethanolamines, 1-ether,2–acylglycero-phosphoetanolamine
and free sphingoid bases. MARS treatment resulted in a signifi-
cant reduction of primary bile acids (p = 0.03) and secondary
bile acids, pregnenolone sulfate (p=0.007), DHEAS (p=0.02),
an androsterone sulfate isomer (p=0.003), some glycero-
phospholipids and kynurenine (p=0.02). Four of these serum
metabolites, including bile acids were identified in the albumin
dialysate. Conclusion: Cholestatic pruritus is associated with
increased bile acids and changes in the lipid profile. MARS
therapy for pruritus results in a decrease of circulating metab-
olites especially phospholipids, primary bile acids and sterols.
This metabolomic analysis identifies a panel of biomarkers that
could participate into the pathogenesis of cholestatic pruritus.
Disclosures:
Albert Pares - Consulting: Lumena Pharmaceuticals
HEPATOLOGY, October, 2014
The following people have nothing to disclose: Miriam Perez-Cormenzana,
Alvaro Diaz-Gonzalez, Rebeca Mayo, Azucena Castro, Antoni Mas
314
The neogenesis of high endothelial venules and the for-
mation of tertiary lymphoid organs in primary biliary
cirrhosis
Hayato Baba, Koichi Tsuneyama; University of Toyama, Toyama,
Japan
Purose: Recently, it has been reported that the migration of
inflammatory cells via high endothelial venules (HEVs) is
related to the pathogenesis in various chronic inflammatory
diseases. Moreover, it is known that inflammatory areas with
HEVs sometimes show the characteristics of secondary lym-
phoid tissue, and these structures are called “tertiary lymphoid
organs (TLOs)”. In the present study, to examine whether the
neogenesis of HEVs and the formation of TLOs are occurred in
primary biliary cirrhosis (PBC), we performed the histopatho-
logical study. Methods: We examined the liver specimens of
21 PBC cases, 13 chronic viral hepatitis-C (CVH) cases, and 5
normal cases. We performed immunohistochemistry for MECA-
79, which is well-established marker of HEVs, CD3, CD20,
CD21, CD83, and CCR-7. Results: In PBC livers, HEVs labeled
by MECA-79 were observed more frequently in portal areas
with lymphoid aggregation in PBC than in CVH (78% versus
27%; p < 0.01 Fisher’s exact test). On the other hand, HEVs
were never observed in normal livers. In addition, CCR-7+ lym-
phocytes, which migrate to peripheral tissues via HEVs, were
observed more frequently in inflammatory cites in PBC livers
compared to CVH livers. Moreover, in PBC livers, HEVs were
observed in 77% of portal areas with bile duct obstruction,
whereas they were observed in 28% of portal areas without
bile duct obstruction (p < 0.01 Fisher’s exact test). Next, we
examined whether TLO’s features are recognized in 13 PBC
cases, in which HEVs were remarkably observed. As a result,
all these cases contained at least one inflammatory area with
following features specific to lymphoid tissues; (1) follicular
dendritic cells (FDCs) labeled by CD 21 were observed (2) B
cells labeled by CD20 surrounded FDCs and formed germinal
center (3) Distinct but adjacent T cell, labeled by CD3, and B
cell components were recognized (4) Dendritic cells labeled
by CD83 were observed in the margin of T cell area. Conclu-
sions: We revealed the neogenesis of HEVs and the formation
of TLOs in PBC livers. These phenomena can be related to the
pathogenesis of PBC.
Disclosures:
The following people have nothing to disclose: Hayato Baba, Koichi Tsuneyama
315
Geoepidemiology of primary biliary cirrhosis in Central
Greece
Nikolaos Gatselis1, Kalliopi Zachou1, Asterios I. Saitis1, Elias Spy-
rou1, George K. Koukoulis2, George N. Dalekos1; 1Department of
Medicine and Research Laboratory of Internal Medicine, Medical
School, University of Thessaly, Larissa, Greece; 2Department of
Pathology, Medical School, University of Thessaly, Larissa, Greece
Background and aims: Genetic and environmental factors have
been implicated in primary biliary cirrhosis (PBC) pathogene-
sis. Our aim was to describe the epidemiological character-
istics and the spatial distribution of PBC in Central Greece.
Methods: The study was performed in Thessaly, one out of the
thirteen regions of Greece, which covers most of the part of
Central Greece. During the last 13 years, 281 PBC patients
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
(253 females, 90%) residents of Thessaly region were appro-
priately diagnosed. Results: The mean±SD age of the patients
during the initial presentation was 57±13 years. Antimitochon-
drial antibodies were detected in 93.2% of the patients, while
48.8% were asymptomatic. Among known risk factors, a his-
tory of urinary tract infection was reported in 6.4%, hormonal
estrogen replacement in 1.4%, previous/active smoking in
24.9%, presence of other autoimmune disease in 21.7%, and
family history of autoimmune disease in 7.5% (familial PBC in
4.3%). The median annual incidence was 23 new cases per
year. The date of first manifestation of the disease could be
identified in 99 patients, with a marked peak during the spring
(P=0.01). The overall prevalence of PBC in Thessaly was 373
per 1 million inhabitants, which was not equally distributed. Six
districts showed a prevalence >800 per 1 million inhabitants.
Conclusion: There is an increased prevalence of PBC in Central
Greece with remarkable geographic clustering. These data
along with seasonal variability may suggest environmental risk
factors in PBC pathogenesis.
Disclosures:
The following people have nothing to disclose: Nikolaos Gatselis, Kalliopi
Zachou, Asterios I. Saitis, Elias Spyrou, George K. Koukoulis, George N. Dalekos
316
Hepatic sarcoidosis: To treat or not to treat?
Nicole M. Welch1, Andrew Aronsohn2, K. Gautham Reddy2,
Nancy Reau2, Donald M. Jensen2, Helen S. Te2; 1Department of
Medicine, University of Chicago Medical Center, Chicago, IL;
2Center for Liver Disease, Department of Medicine, University of
Chicago Medical Center, Chicago, IL
Background: Despite recent advances in immunotherapy, data
on the benefits of treatment of hepatic sarcoidosis are limited.
Aim: To compare the course and outcomes of patients treated
for hepatic sarcoidosis with those of untreated patients. Meth-
ods: Patients with hepatic sarcoidosis, diagnosed clinically,
radiographically or histologically (ICD code 135) in the Liver
Clinic of the University of Chicago from July 2000 to June
2012, were identified. Demographic, clinical, laboratory, his-
tologic and treatment data were obtained and analyzed with
the Stata software. Results: 70 patients were included in the
study, with a mean follow-up of 57±51 months. 28(40%) were
males, with a mean age of 49±10 yrs. 80% were African
Americans. 32% were asymptomatic, while 40% had gas-
trointestinal symptoms. The prominent liver test abnormality
was an elevated alkaline phosphatase (AP) level (375±383
IU/L). Angiotensin-converting enzyme (ACE) levels were ele-
vated only in 49% of tested patients (n=53). Of 55 patients
who had a liver biopsy, 30(55%) had no fibrosis, 14(25%)
had stage 1-2, and 9(16%) had stage 3-4. 13 patients (11
treated) had paired liver biopsies over a 59±38 mos interval;
6(46%, 1 untreated) showed no change, 6(46%, 1 untreated)
showed improved fibrosis, while 2(15%) showed worse
fibrosis at follow-up. 52(74%) patients were treated for sar-
359A
coidosis, 31(60%) with corticosteroids, 19(37%) with ursode-
oxycholic acid, 18(35%) with other immunotherapy agents.
Demographic and baseline laboratory data and the follow-up
periods were similar between the treated (Tx) and the untreated
(No Tx) groups, except for a higher albumin in the No Tx group
(4.2±0.4 vs 3.9±0.5 g/dL, p=0.02) and a lower AP in the No
Tx group (224±207 vs 428±416 IU/L, p=0.05). Comparison
of baseline and follow-up laboratory data for each group are
shown in the table. 6% of patients in each group either died or
required OLT. Conclusions: Liver chemistry tests may improve in
hepatic sarcoidosis with or without therapy, although untreated
patients had lower AP at baseline in this study. Transplant-free
survival is similar in treated and untreated patients.
Disclosures:
K. Gautham Reddy - Advisory Committees or Review Panels: AASLD Transplant
Hepatology Pilot Steering Committee, ACG Training Committee, Program Direc-
tor’s Caucus Steering Committee; Grant/Research Support: Intercept, Ocera,
Merck, Lumena
Nancy Reau - Advisory Committees or Review Panels: Kadmon, Jannsen, Vertex,
Idenix, AbbVie, Jannsen; Grant/Research Support: Vertex, Gilead, Genentech,
AbbVie, BMS, Jannsen, BI
Donald M. Jensen - Grant/Research Support: Abbvie, Boehringer, BMS, Genen-
tech/Roche, Janssen
Helen S. Te - Advisory Committees or Review Panels: Gilead Sciences, Jansenn
Pharmaceuticals; Grant/Research Support: Abbvie, BMS
The following people have nothing to disclose: Nicole M. Welch, Andrew Aron-
sohn
317
Age at Presentation and Gender are Predictors of
Increased Mortality Over Long-Term Follow-Up in Pri-
mary Biliary Cirrhosis (PBC)
Jessica K. Dyson1, Laura Griffiths2, Samantha J. Ducker2, David
E. Jones1,2; 1Liver Unit, Freeman Hospital, Newcastle upon Tyne,
United Kingdom; 2Institute of Cellular Medicine, Newcastle Univer-
sity, Newcastle upon Tyne, United Kingdom
Background: Recent findings from the prospective UK-PBC
patient cohort have shown that non-response to ursodeoxycho-
lic acid (UDCA) therapy is associated with increased risk of
death or need for transplant in PBC. Younger age at presenta-
tion and male gender were associated with increased risk of
UDCA non-response. Although the implication is that age at
presentation and gender are therefore risk factors for death
and transplantation in PBC, the link as yet, has only been an
indirect one. Here we set out to utilise the historic Newcastle
cohort to directly explore the impact of age at presentation and
gender on outcomes in PBC. Aims: To utilise a large and com-
prehensive, geographically defined, long-term follow-up cohort
of PBC patients and matched community controls to explore the
impact of age at presentation and gender on actual outcome
in PBC. Methods: Kaplan-Meier survival analysis in the com-
prehensive North-East England PBC patient cohort of 588 PBC
patients (529 female) incident between 1979 and 2003, prior
to the widespread use of UDCA in Newcastle. Cohort partic-
360A AASLD ABSTRACTS
ipants were followed up to death or transplant, or the end of
2010 (whichever was latest). Full outcome data were available
for all participants. Results: The 588 patients in the cohort were
followed up for a total of 5900 patient years. 218/529 (41%)
of the female patients had died or been transplanted compared
with 30/59 (51%) males. Survival to death or transplant was
significantly reduced in the PBC patients compared to controls
(p<0.0001, Hazard Ratio (HR) 2.8 (95% CI 1.7-2.9)), with
impairment seen in both female and male patients compared to
controls (p<0.0001, HR 2.8 (95% CI 1.7-3.0) & p<0.05, HR
3.0 (95% CI 1.1-5.0) respectively). Survival to death or trans-
plant was significantly better in female than male PBC patients
(p=0.01, HR 0.6 (95% CI 0.3-0.9)). Age at presentation had a
significant and stepwise impact on survival. Amongst the PBC
patients presenting under the age of 60 as a whole, survival
was substantially reduced compared with controls matched for
age at point of diagnosis (p<0.0001, HR 13.1 (95% CI 1.7-
26.6)). Conclusions: Younger age at presentation and male
gender are important factors in determining risk of death or
need for transplant in PBC and should be included for models
of stratified disease management.
Disclosures:
David E. Jones - Consulting: Intercept
The following people have nothing to disclose: Jessica K. Dyson, Laura Griffiths,
Samantha J. Ducker
318
The FXR Agonist Obeticholic Acid (OCA) Improves Liver
Biochemistry Parameters Correlated With Clinical Bene-
fit Across a Range of Patient Characteristics
Pietro Andreone1, Giuseppe Mazzella1, Simone I. Strasser2, Chris-
topher L. Bowlus3, Pietro Invernizzi4, Joost Drenth5, Paul J. Pockros6,
Jaroslaw Regula7, Michael Trauner8, Annarosa Floreani9, Simon
Hohenester10, Velimir A. Luketic11, Mitchell L. Shiffman12, Karel
J. van Erpecum13, Victor Vargas14, Catherine Vincent15, Bettina
E. Hansen16, Frederik Nevens17, Richard Pencek18, Roya Hoosh-
mand-Rad18, Shawn Sheeron18, David Shapiro18; 1Universitaria
di Bologna, Bologna, Italy; 2Royal Prince Alfred Hospital, Sydney,
NSW, Australia; 3UC Davis, Sacramento, CA; 4Humanitas Clin-
ical and Research Center, Rozzano, Italy; 5UMC St. Radboud,
Nijmegen, Netherlands; 6Scripps Clinic, La Jolla, CA; 7Cancer
Centre, Warsaw, Poland; 8Medical University of Vienna, Vienna,
Austria; 9Università di Padova, Padova, Italy; 10LMU University of
Munich, Munich, Germany; 11McGuire DVAMC, Richmond, VA;
12Liver Institute of Virginia, Newport News, VA; 13UMC Utrecht,
Utrecht, Netherlands; 14Hospital Vall d’Hebron, Barcelona, Spain;
15Centre Hospitalier Universitaire de l’Université de Montréal-St.
Luc, Montreal, QC, Canada; 1618Erasmus MC, University Medical
Center, Rotterdam, Netherlands; 17UZ Leuven, Leuven, Belgium;
18Intercept Pharmaceuticals, Inc, San Diego, CA
Background and aims: The Phase 3 POISE trial evaluated the
efficacy and safety of obeticholic acid (OCA), a derivative of
chenodeoxycholic acid and potent farnesoid-X receptor ago-
nist, in patients with PBC. The primary endpoint was achieved
by a significantly higher proportion of patients in both OCA
dose groups compared to placebo. We analyzed the response
to OCA across a broad range of patient characteristics that
can affect prognosis. Methods: This international, double-blind,
placebo-controlled trial, randomized PBC patients with alkaline
phosphatase (ALP)>1.67xULN and/or bilirubin < 2xULN to
placebo, OCA 5mg or 10mg for 1y. Patients randomized to
5mg were titrated to 10mg after 6mo, based on liver biochem-
istry and tolerability; pre-study UDCA continued. The primary
endpoint was attaining an ALP<1.67xULN, a ≥15% reduction
in ALP and a bilirubin ≤ULN. This analysis assessed the effect
HEPATOLOGY, October, 2014
of age at diagnosis, PBC duration and baseline ALP on efficacy
endpoints. Results: Of 216 randomized patients (mean age:
55.8yrs, 91% female, 94% Caucasian and 93% on UDCA),
91% completed the study. All groups were well-matched.
Regardless of age at diagnosis, PBC duration, or baseline ALP
levels, a significantly higher proportion of patients receiving
OCA achieved the primary endpoint compared to placebo
(table). OCA was well tolerated overall, with mild to moder-
ate pruritus being the most common and dose-related adverse
event. Conclusions: OCA given to PBC patients with an inade-
quate response to or unable to tolerate UDCA produced highly
statistically significant, clinically meaningful improvements in
liver biochemistry which have been shown to correlate strongly
with clinical benefit. The effect of OCA was consistent regard-
less of age at diagnosis, duration of PBC and baseline ALP
subgroups.
Disclosures:
Pietro Andreone - Advisory Committees or Review Panels: Roche, Janssen-Cilag,
Gilead, MSD/Schering-Plough, Abbvie, Boehringer Ingelheim; Grant/Research
Support: Roche, Gilead; Speaking and Teaching: Roche, MSD/Schering-Plough,
Gilead
Simone I. Strasser - Advisory Committees or Review Panels: Janssen, AbbVie,
Roche Products Australia, MSD, Bristol-Myers Squibb, Gilead, Norgine, Bayer
Healthcare; Speaking and Teaching: Bayer Healthcare, Bristol-Myers Squibb,
MSD, Roche Products Australia, Gilead, Janssen
Christopher L. Bowlus - Advisory Committees or Review Panels: Gilead Sciences,
Inc; Consulting: Takeda; Grant/Research Support: Gilead Sciences, Inc, Inter-
cept Pharmaceuticals, Bristol Meyers Squibb, Lumena; Speaking and Teaching:
Gilead Sciences, Inc
Paul J. Pockros - Advisory Committees or Review Panels: Janssen, Merck, Genen-
tech, BMS, Gilead, Boehinger Ingelheim, AbbVioe; Consulting: Genentech,
Lumena, Regulus, Beckman Coulter, RMS; Grant/Research Support: Novartis,
Intercept, Janssen, Genentech, BMS, Gilead, Vertex, Boehinger Ingelheim,
Lumena, Beckman Coulter, AbbVie, RMS, Novartis, Merck; Speaking and Teach-
ing: Genentech, BMS, Gilead
Michael Trauner - Advisory Committees or Review Panels: MSD, Janssen, Gilead,
Abbvie; Consulting: Phenex; Grant/Research Support: Intercept, Falk Pharma,
Albireo; Patent Held/Filed: Med Uni Graz (norUDCA); Speaking and Teaching:
Falk Foundation, Roche, Gilead
Simon Hohenester - Speaking and Teaching: Dr. Falk Pharma
Mitchell L. Shiffman - Advisory Committees or Review Panels: Merck, Gilead,
Boehringer-Ingelheim, Bristol-Myers-Squibb, Abbvie, Janssen; Consulting: Roche/
Genentech, Gen-Probe; Grant/Research Support: Merck, Gilead, Boehring-
er-Ingelheim, Bristol-Myers-Squibb, GSK, Abbvie, Beckman-Coulter, Achillion,
Lumena, Intercept, Novarit, Gen-Probe; Speaking and Teaching: Roche/Genen-
tech, Merck, Gilead, GSK, Janssen, Bayer
Karel J. van Erpecum - Advisory Committees or Review Panels: Bristol Meyers
Squibb, Abbvie
Frederik Nevens - Consulting: CAF, Intercept, Gore, BMS, Abbvie, Novartis,
MSD, Eumedica, Janssen; Grant/Research Support: Ipsen, Roche, MSD, Astellas
Richard Pencek - Employment: Intercept Pharmaceuticals; Stock Shareholder:
Intercept Pharmaceuticals
Roya Hooshmand-Rad - Employment: Intercept pharmaceuticals Inc.
Shawn Sheeron - Employment: Intercept Pharmaceuticals
David Shapiro - Employment: Inttercept Pharmaceuticals
The following people have nothing to disclose: Giuseppe Mazzella, Pietro Inv-
ernizzi, Joost Drenth, Jaroslaw Regula, Annarosa Floreani, Velimir A. Luketic,
Victor Vargas, Catherine Vincent, Bettina E. Hansen
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
319
FXR Agonist Obeticholic Acid: Sustained Improvement in
Markers of Cholestasis and Long-Term Safety in Patients
with Primary Biliary Cirrhosis through 4 Years
Kris V. Kowdley1,
Richard Pencek2,
Tonya Marmon2,
David Shap-
iro2, Roya Hooshmand-Rad2; 1Benaroya Research Institute, Seattle,
WA; 2Intercept Pharmaceuticals, Inc., San Diego, CA
Obeticholic acid (OCA, 6-ethyl chenodeoxycholic acid) is a
highly potent FXR agonist being developed for the treatment
of primary biliary cirrhosis. Efficacy and safety of OCA,
given as monotherapy, was evaluated in a 12-week, Phase 2,
double-blind placebo controlled trial and showed significant
improvement in alkaline phosphatase (ALP), bilirubin and other
indices of cholestasis, inflammation and hepatic function. This
was followed by an open-label long-term extension period in
which patients either continued OCA or switched from pla-
cebo to OCA. This analysis evaluated the safety and efficacy
of OCA through 3.5 and 4 years of treatment. During the
ongoing open label extension period, subjects initiated OCA
at 10mg once daily and titrated to 50mg based on response
and tolerability. Ursodeoxycholic acid (UDCA) was added
in 11 subjects. Subjects (N=28): mean age 58yrs; female:
78%; Caucasian: 96%. Baseline: ALP: 442±275U/L; bilirubin:
4.6±3.2mmol/L; GGT: 460±318U/L; ALT: 91±61U/L; AST:
72±39 U/L. Median exposure was 3.8 (2.6-4.2yrs). Nine
subjects terminated early overall; 6 due to AEs, 4 of which
were pruritus. The majority of patients received OCA doses ≤
25mg. Improvement in serum liver biochemical tests through 4
years of treatment was observed. Pruritus, the most common
AE, improved with long-term treatment; The incidence of new
onset pruritus declined after the 1st year and severity tended to
decrease with continued treatment. PBC is a chronic cholestatic
liver disease with persistent significant unmet need. Long-term
OCA treatment in this study maintained a durable improvement
in ALP and other hepatic biochemistry analytes with no new
safety findings and improved tolerability.
Data are mean(SE). *p≤0.05 change from baseline
Disclosures:
Kris V. Kowdley - Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research
Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria,
Janssen, Merck, Mochida, Vertex
Richard Pencek - Employment: Intercept Pharmaceuticals; Stock Shareholder:
Intercept Pharmaceuticals
Tonya Marmon - Employment: Intercept Pharmaceuticals, Inc; Stock Shareholder:
Intercept Pharmaceuticals, Inc
David Shapiro - Employment: Inttercept Pharmaceuticals
Roya Hooshmand-Rad - Employment: Intercept pharmaceuticals Inc.
361A
320
Secondary Sclerosing Cholangitis Following Major Burn
Injury
Ella Veitsman1,7, Yael Haviv-Yadid2,7, Oranit Cohen-Ezra1,7, Orit
Pappo3,7, Yael Inbar4,7, Josef Haik5,7, Galia Rahav6,7, Ziv Ben
Ari1,7; 1center for liver diseases, sheba medical center, Ramat
Gan, Israel; 2Intensive Care Unit, sheba medical center, Ramat
Gan, Israel; 3Department of pathology, sheba medical center,
Ramat Gan, Israel; 4Department of Radiology, sheba medical
center, Ramat Gan, Israel; 5Department of Plastic Surgery, sheba
medical center, Ramat Gan, Israel; 6Infectious Disease Unit, sheba
medical center, Ramat Gan, Israel; 7Sackler School of Medicine,
Tel Aviv University, Tel Aviv, Israel
Secondary sclerosing cholangitis in critically ill patients (SSC-
CIP) is a relatively new previously unrecognized entity which
may lead to severe biliary disease with rapid progression to
cirrhosis. It is possibly mediated by ischemic damage of the
biliary tree, followed by bacterial colonization and progressive
destruction of biliary ducts. SSC-CIP is described very rarely
in patients following major burn. We present for the first time
a case series of patients with rapidly progressive SSC–CIP
requiring aggressive intensive care treatment following major
burn injury. The radiologic, endoscopic, medical and surgi-
cal treatments as well as the clinical course and outcome of
these patients were retrospectively analyzed and reviewed.
SSC-CIP was diagnosed in 6 consecutive patients hospitalized
due to major burn injuries at the Intensive Care Unit (ICU) of
the Sheba Medical Center, during the period from January
2008 to August 2013. SSC–CIP was diagnosed when ERCP
or MRCP demonstrated the typical appearance of irregular
intrahepatic bile ducts with multiple strictures and dilatations
and/or, when a liver biopsy demonstrated severe cholestasis
and degenerative biliary epithelium. Patency of portal vein and
hepatic artery was confirmed by abdominal ultrasonography
with a Doppler study. All patients were males; none of them
had recorded evidence of pre-existing liver disease. Ages var-
ied from 18 to 56 years old. All patients suffered from severe
(grade 2-3) burn injuries with Total Burn Surface Area ranging
from 35% to 95%. Mean length of ICU hospitalization was
115 (38-192) days. All patients required mechanical ventila-
tion (with a mean peep pressure of 10cmH2O) and the admin-
istration of catecholamines for hemodynamic stabilization. All
patients demonstrated severe cholestasis with a median alka-
line phosphatase level of 2113 IU/l (range, 1194-3032IU/l)
and median total bilirubin level of 28.3 mg/dl (range, 16.0-
40.7mg/dl). The diagnosis of SSC-CIP was confirmed by ERCP
in one patient, MRCP in 4 patients and in 2 patients by a liver
biopsy. Five patients were treated with Ursodeoxycholic acid
in dose of 15mg/kg. Two patients developed multiple hepatic
abscesses that were drained and grew hospital acquired multi-
ple resistant bacteria. Two patients underwent orthotopic liver
transplantation. Three patients (50%) died. In conclusion, SSC-
CIP following major burn injury is a rapidly progressive disease
with a poor outcome. Awareness of this grave complication
is needed for prompt diagnosis and considerations of a liver
transplantation. The pathogenic mechanisms leading to this
condition warrant further elucidation.
Disclosures:
The following people have nothing to disclose: Ella Veitsman, Yael Haviv-Yadid,
Oranit Cohen-Ezra, Orit Pappo, Yael Inbar, Josef Haik, Galia Rahav, Ziv Ben Ari
362A AASLD ABSTRACTS
321
Discrepant Expression of miR-139-5p Between Serum
and Liver in Patients with Primary Biliary Cirrhosis, and
its Possible Cellular Origin
Tomohiro Katsumi1,
Masashi Ninomiya2,
Kyoko Tomita1,
Chikako
Sato1, Kazuo Okumoto1, Yuko Nishise1, Hisayoshi Watanabe1,
Takafumi Saito1, Yoshiyuki Ueno1; 1Gastroenterology, Yamagata
University, Yamagata, Japan; 2Biochemistry and Molecular Biol-
ogy, Mayo Clinic, Rochester, MN
[Background] PBC is considered to be an autoimmune disease,
although its pathogenesis remains unclear. MicroRNAs (miR-
NAs) are known to be involved in the pathogenesis of a variety
of diseases. In a previous study, we found that patients with
PBC had serum miRNA profiles distinct from those with other
liver diseases. Moreover, we found that these miRNA profiles
showed differences in serum among three subtypes of PBC: 1)
gradual progressive type (G type), 2) portal hypertension type
(PH type), and 3) hepatic failure type (HF type). Accordingly,
we evaluated the expression of these miRNAs in both serum
and liver tissue, and sought the possible cellular origin of the
miRNAs. [Methods] Patients with each of the three PBC sub-
types, and healthy subjects as a control, were enrolled (n=5,
respectively). Total RNA was extracted from individual serum
and a library was prepared. Circulating miRNAs were detected
using an Illumina Genome Analyzer IIx. After mapping to the
database (miRBase), these miRNAs sufficiently validated were
further evaluated. Differences in the levels of miRNA were also
examined by the laser capture microdissection (LCM) using
paraffin-embedded liver tissues. Areas containing hepatocytes
and infiltrating lymphocytes were selectively dissected, and
the cell-derived miRNAs were quantified using a digital PCR
apparatus (QuantStudioTM 3D). The expressions of specific
miRNAs were then further confirmed using in situ hybridization.
[Results] Among a total of 1514 miRNAs obtained, 97 miR-
NAs were found to differ significantly among the four groups
(p<0.05). Heat map demonstrated that the miRNA profiles
of both the HF and PH types were clustered differently from
those of the G type and controls. Especially, miR-139-5p was
significantly under-expressed in both the PH and HF type. qRT-
PCR using serum samples also confirmed these data from deep
sequencing. Digital PCR using tissue samples demonstrated
that the levels of lymphocyte-derived miR-139-5p were higher
than those from hepatocytes. In situ hybridization also revealed
a higher incidence of miR-139-5p positivity in lymphocytes
exhibiting CNSDC. [Conclusion] Comprehensive analysis has
demonstrated characteristic miRNA expression profiles among
the subtypes of PBC, miR-139-5p being characteristically
down-regulated in serum from progressive subtypes. Results
obtained from liver samples suggested that infiltrating lympho-
cytes were the source of miR-139-5p, although the levels of
expression did not reflect those in serum samples. Our present
findings suggest the involvement of a specific miRNA, miR-
139-5p, in the pathogenesis of PBC, and especially in progres-
sive clinical subtypes.
Disclosures:
Yoshiyuki Ueno - Advisory Committees or Review Panels: Jansen, Gilead Science;
Speaking and Teaching: BMS
The following people have nothing to disclose: Tomohiro Katsumi, Masashi
Ninomiya, Kyoko Tomita, Chikako Sato, Kazuo Okumoto, Yuko Nishise, Hisay-
oshi Watanabe, Takafumi Saito
HEPATOLOGY, October, 2014
322
Patient Experience and Characteristics of Cholestatic
Pruritus in the UK-PBC Research Cohort
Vinod S. Hegade1, George F. Mells2, Ulrich Beuers3, Andreas E.
Kremer4, Pietro Invernizzi5, Tom H. Karlsen6, Gideon Hirschfield7,
Richard N. Sandford2, Stuart Kendrick1, David E. Jones1; 1Institute
of Cellular Medicine, Newcastle University, Newcastle, United
Kingdom; 2Academic Department of Medical Genetics, Univer-
sity of Cambridge, Cambridge, United Kingdom; 3Department
of Gastroenterology and Hepatology, Tytgat Institute for Liver
and Intestinal Research, Academic Medical Center, Amsterdam,
Netherlands; 4Department of Medicine, Friedrich-Alexander Uni-
versity of Erlangen-Nuremberg, Erlangen, Germany; 5Liver Unit
and Center for Autoimmune Liver Diseases, Humanitas Clinical
and Research Center, Milan, Italy; 6Norwegian PSC Research
Center, Oslo University Hospital, Oslo, Norway; 7Centre for Liver
Research, Institute of Biomedical Research, University of Birming-
ham,, Birmingham, United Kingdom
Introduction: Pruritus is a common problem in cholestatic
liver diseases such as Primary Biliary Cirrhosis (PBC). Pruri-
tus has negative impact on patient quality of life. There are
limited studies on characteristics, patient reported experience
of cholestatic itch and its treatment. Aim: To utilize the data
from the UK-PBC Research Cohort: 1) to report the prevalence
and severity of pruritus in patients with primary biliary cirrho-
sis (PBC), 2) to describe patient reported information on their
experience of itch and anti-pruritic therapy they had received.
Methodology: This was an observational cross-sectional study
of PBC patients recruited into the UK-PBC Research Cohort in
which pruritus has been characterized as follows: 1) Frequency
of itch (never, rarely, occasionally, frequently, all the time); 2)
Experience of itch since diagnosis based on the PBC-40 itch
domain; 3) Intensity of worst itch since diagnosis and in the
last 7 days, measured using a visual analogue scale (VAS)
and a 0-10 grading scale (GS); 4) Treatment for itch since
diagnosis of PBC. We defined persistent itch as pruritus occur-
ring ‘frequently’ or ‘all the time’, and severe itch as persistent
itch combined with PBC-40 itch score ≥10.Results: Data were
available for 2705 PBC patients without a liver transplant.
1889 patients (69.8%) had experienced itch at some point
in their illness. Of these, 880 (46.5%) had persistent itch and
428 (22.6%) had severe itch. Table 1 summarizes main results.
Correlation between VAS and GS of itch intensity was sta-
tistically significant (Spearman’s correlation coefficient 0.95,
p<0.01). Patients with severe itch had received the following
treatments: colestyramine (217, 51%), rifampicin (70, 16.3%)
and naltrexone (33,7.7%). Notably,193 (45%) patients with
severe pruritus reported no anti-pruritic treatment at all. Conclu-
sions: Our results highlight the prevalence of pruritus in PBC. In
the UK-PBC cohort, nearly a third of patients had experienced
itch, of whom approximately one-half had persistent itch and
one-quarter had severe itch. However, it would seem that treat-
ment of itch was unsatisfactory as many patients with severe
pruritus did not receive any anti-pruritic therapy. Our results
also suggest need for improvement in the awareness among
clinicians for better management of cholestatic pruritus in PBC.
Table 1.Patient Experience and Treatment of Cholestatic Pruritus
in the UK-PBC Cohort (n=2705)
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Disclosures:
Ulrich Beuers - Consulting: Intercept, Novartis; Grant/Research Support: Zam-
bon; Speaking and Teaching: Falk Foundation, Gilead, Roche, Scheringh, Zam-
bon
Richard N. Sandford - Advisory Committees or Review Panels: Otsuka; Grant/
Research Support: Intercept
Stuart Kendrick - Advisory Committees or Review Panels: GlaxoSmithKline
Research and Development Limited; Employment: GlaxoSmithKline Research and
Development Limited; Grant/Research Support: GlaxoSmithKline Research and
Development Limited
David E. Jones - Consulting: Intercept
The following people have nothing to disclose: Vinod S. Hegade, George F.
Mells, Andreas E. Kremer, Pietro Invernizzi, Tom H. Karlsen, Gideon Hirschfield
323
HLA-DR3 transgenic NOD mice, a novel model for auto-
antigen induced autoimmune hepatitis
Yipeng Wang1,2, Muhammed Yuksel1,3, Junhua Guo1,4, Ningwen
Tai1, Xiaoyan Xiao1,5, Pascal Lapierre6, David Chella7, Huiping
Yan2, Isabelle Colle3, Giorgina Mieli Vergani8, Diego Vergani8,
Yun Ma8, Li Wen1; 1Endocrinology, Yale university, New haven,
CT; 2Clinical Research Centre for Autoimmune Liver Disease,
Beijing You-an Hospital, Beijing, China; 3hepatology, Ghent uni-
versity hospital, Ghent, Belgium; 4Rheumatology, Beijing 301 Hos-
pital, Beijing, China; 5Nepherology, Qilu Hospital, Shangdong
University, China; 6Division of Gastroenterology, Hepatology and
Nutrition, Sainte-Justine University Hospital, Montreal, QC, Can-
ada; 7Immunology, Mayo Clinic, Rochester, MN; 8King’s College
School of Medicine, Institute of Liver Study, London, United King-
dom
Autoimmune hepatitis (AIH) in humans is a severe inflammatory
liver disease, characterized by interface hepatitis on histol-
ogy and by the presence of circulating autoantibodies and
hyper-gammaglobulinemia. There are two types of AIH, type-1
(AIH-1) and type-2 (AIH-2) characterized by distinct autoim-
mune serology. Patients with AIH-1 are positive for anti-smooth
muscle and/or anti-nuclear (SMA/ANA) autoantibodies
whereas patients with AIH-2 have anti-liver kidney microsomal
type 1 (anti-LKM-1) and/or anti-liver cytosol type 1 (anti-LC1)
autoantibodies. Cytochrome P4502D6 (CYP2D6) is the anti-
genic target of anti-LKM-1 and formiminotransferase cyclode-
aminase (FTCD) the antigenic target of anti-LC1. AIH, both type
1 and type 2, is also linked to the Human Leukocyte Antigen
(HLA) alleles -DR3, -DR4 and -DR7. Early animal models of AIH
did not faithfully represent the human disease. We developed a
novel mouse model of AIH using the HLA-DR3 transgenic mouse
on the non-obese diabetic (NOD) background (DR3-NOD).
Immunization of DR3-NOD mice with a DNA plasmid, coding
for human CYP2D6/FTCD fusion protein, leads to a sustained
elevation of alanine aminotransferase (ALT), development of
ANA, and chronic immune cell infiltration and parenchymal
fibrosis on liver histology. Immunized mice show an enhanced
Th1 response and paucity of regulatory T cells (Treg) in the liver
and a CYP2D6/FTCD specific T cell response in vitro. This new
animal model will help in elucidating further the pathogenesis
of AIH and in evaluating the efficacy and safety of immunoreg-
ulatory therapeutic interventions in vivo.
Disclosures:
Isabelle Colle - Advisory Committees or Review Panels: MSD, Janssen, MSD, Gil-
ead; Grant/Research Support: Bayer; Patent Held/Filed: Trombogenics; Speak-
ing and Teaching: BMS, Janssen
The following people have nothing to disclose: Yipeng Wang, Muhammed Yuk-
sel, Junhua Guo, Ningwen Tai, Xiaoyan Xiao, Pascal Lapierre, David Chella,
Huiping Yan, Giorgina Mieli Vergani, Diego Vergani, Yun Ma, Li Wen
363A
324
Long term follow-up and 10-year outcomes of sec-
ond-line therapy in Autoimmune Hepatitis
Daniel Klintman1,2, Naina Shah1, Javier Bustamante1,3, Michael
A. Heneghan1; 1King’s College Hospital NHS Foundation Trust,
Institute of Liver Studies, Denmark Hill, London, United Kingdom;
2Department of Gastroenterology and Hepatology, Skane Univer-
sity Hospital, Malmo, Sweden; 3Hospital Universitario Cruces,
Department of Gastroenterology and Hepatology, Baracaldo,
Spain
Background: Autoimmune Hepatitis (AIH) is a heterogenous dis-
ease with variable onset and progress. Over 85% of patients
respond well to steroids and/or thiopurines (AZA). However, in
some cases this treatment is not tolerated or sufficient. Alterna-
tive treatment options with tacrolimus (tac) and mycophenylate
mofetil (MMF) have been described in small series with short
follow-up. In this study, we describe long-term follow-up of a
cohort of patients with difficult-to-treat AIH with respect to com-
plications, transplantation and survival. Patients and methods:
In a single-centre, retrospective study of 23 patients diagnosed
with AIH 1988-2009 and treated with tac and/or MMF, we
analysed treatments and potential risk-factors for complications
and outcomes, reasons for alternative treatments, rates of liver
transplantation and survival. For AIH diagnosis, we used IAIHG
criteria. For statistical analyses, Chi-2 and Kruskall-Wallis tests
were used. Results: 12/23 patients were female. Median age
at diagnosis was 30 years (13-65). Median follow-up time was
10 years (1-24). Initial treatment for all patients was steroids ±
AZA. The patients were given tac (n=11) or MMF (n=12) after
a median of 3 months (0-9 years), mainly due to intolerance
(n=12) or response failure (n=11). This resulted in complete
response in 9 patients (39%) and partial response or response
with relapse in 11 patients (48%). There was no difference
in response between the tac and MMF group (p>0,05). 8
patients, mainly non-responders, received another alterna-
tive treatment or a combination of tac and MMF. 4 of these
responded well. 6/23 (26%) of the patients were eventually
transplanted, at a median of 7,5 years (4-19) after diagnosis.
3/6 had suboptimal adherence to medication vs. 1/17 in the
non-transplant group (p<0,01). 2/6 had multiple side effects
limiting treatment options. 3 patients died during the follow-up,
1 of complications to AIH. Acute presentation, age at diagno-
sis or antibody titres were not significant predictors of outcome
in this study (p>0,05). By the end of the follow-up, 14/15
patients not transplanted were in remission, 7/15 were taking
MMF and/or tac and 8/15 were back on steroids ± AZA.
Conclusions: This 10-year follow-up study of 23 AIH-patients
suggests that: - MMF and tacrolimus are generally effective and
well tolerated in AIH-patients. - There is no major difference in
outcomes between MMF and tacrolimus treatments. - Subopti-
mal adherence to medication constitutes a significant risk factor
for transplantation. - Although more complicated to treat, the
overall outcome of this group is good, with low mortality and
high probability of eventual remission.
Disclosures:
Javier Bustamante - Advisory Committees or Review Panels: Bayer, Bayer; Grant/
Research Support: Bayer
The following people have nothing to disclose: Daniel Klintman, Naina Shah,
Michael A. Heneghan
364A AASLD ABSTRACTS
325
Circulating macrophage activation markers, CD163 and
CD206, are associated with disease severity and treat-
ment response in patients with autoimmune hepatitis
Henning Gronbaek1, Martin Kreutzfeldt1, Niels Jessen2, Sidsel
Rødgaard-Hansen3, Konstantin Kazankov1, Thomas D. Sandahl1,
Hendrik V. Vilstrup1, Holger J. Møller3; 1Medical Department V,
Aarhus University Hospital, Aarhus, Denmark; 2Department of
Endocrinology (MEA), Aarhus University Hospital, Aarhus, Den-
mark; 3Department of Clinical Biochemistry, Aarhus University Hos-
pital, Aarhus, Denmark
Introduction: Autoimmune hepatitis (AIH) is characterized by
chronic inflammation and fibrosis. Soluble (s)CD163, a specific
marker for activated macrophages, is a marker for disease
activity, fibrosis, portal hypertension and prognosis in acute
and chronic liver diseases. We hypothesized elevated sCD163
and sCD206 levels in AIH patients with acute disease activity
and higher levels in non-responders than non-responders. Meth-
ods: We included 113 AIH patients (female/male 85/28,
median age 50 (range: 17-79)), 93 with autoimmune hepatitis
and 20 with overlap syndromes of AIH-PSC (n=7) and AIH-PBC
(N=13). We measured sCD163 and sCD206 by ELISA and
associated levels with parameters of disease activity and cirrho-
sis. Results: Soluble CD163 was significantly elevated in AIH
patients with acute disease activity compared to AIH respond-
ers (6.96(3.3-15.4) vs. 1.62(0.80-3.24) mg/L). sC163 levels
correlated significantly with ALT (rho=0.47, P<0.001), IgG
(rho=0.48, P<0.001), bilirubin (rho=0.30, P<0.001), alkaline
phosphatase (rho=0.38, P<0.001), coagulation factors(II,VII,X)
(rho=-0.30, P<0.01) and thrombocytes (rho=-0.24, P=0.014).
There was no difference in sCD163 levels between the different
groups of patients with or without cirrhosis at time of diagnosis.
sCD206 showed a similar but less significant pattern. Con-
clusion: sCD163 and sCD206 levels were markedly elevated
in patients with acute activity in AIH and were normalized in
patients on anti-inflammatory treatment, even in patients with
cirrhosis. Our data support significant macrophage activa-
tion in AIH and sCD163 may serve as a marker for treatment
response of AIH patients.
Disclosures:
Henning Gronbaek - Grant/Research Support: Novartis, Ipsen
Holger J. Møller - Grant/Research Support: Danish Council for Strategic
Research; Independent Contractor: IQ-Products, NL; Patent Held/Filed: Aarhus
University; Stock Shareholder: Affinicon Aps
The following people have nothing to disclose: Martin Kreutzfeldt, Niels Jessen,
Sidsel Rødgaard-Hansen, Konstantin Kazankov, Thomas D. Sandahl, Hendrik
V. Vilstrup
326
Can a dietary supplement induce autoimmune hepatitis?
Marina Roytman1,2, Peter Poerzgen1, Christine L. Lee2, Leslie
Huddleston1, Peter K. Bryant-Greenwood3, Timothy Kuo1, Linda
L. Wong4, Naoky Tsai1,2; 1Liver Center, Queen’s Medical Center,
Honolulu, HI; 2Department of Medicine, John A. Burns School of
Medicine, Honolulu, HI; 3Department of Pathology, Queen’s Med-
ical Center, Honolulu, HI; 4Department of Surgery, John A. Burns
School of Medicine, Honolulu, HI
Purpose: The etiology of autoimmune hepatitis (AIH) is largely
unknown, but xenobiotics, rare viruses and drugs like minocy-
cline and nitrofurantoin have been implicated. With this report
we want to bring attention to dietary supplements as a possi-
ble trigger for AIH. OxyElite Pro New Formulation (USPlabs,
Dallas, Texas), a popular weight-loss herbal dietary supple-
ment was linked to severe hepatotoxicity in 56 patients across
the US. Our center has encountered 35 of these cases and
HEPATOLOGY, October, 2014
seen most of them recover after discontinuation of OxyElite
Pro. We now report a subgroup of patients that went on to
developed AIH. Methods: Clinical data on demographics, drug
use, laboratory studies, biopsies and outcomes were collected.
We assessed causality and severity of liver injury according
to Roussel Uclaf Causality Assessment Method/ Council for
International Organizations of Medical Sciences (RUCAM/
CIOMS) scale and Drug-Induced Liver Injury Network (DILIN)
method respectively. We assessed likelihood of AIH diagnosis
using the Revised Original Scoring System of the International
Autoimmune Hepatitis Group. Results: 35 patients with acute
liver injury were identified at our medical center between May
2013 and January 2014. Two patients were transplanted, two
died, 25 recovered. Six patients continued to have progressive
worsening of liver function despite discontinuation of OxyElite
Pro. Four out of six patients were hospitalized at initial pre-
sentation, all had liver biopsies. Histology was consistent with
AIH and distinctly different from other patients with OxyElite
Pro DILI. All six patients were treated with corticosteroids and
entered remission thus strengthening the diagnosis of AIH. Use
of the Revised Original Scoring System revealed 2 cases as
definite and 3 cases as probable. Conclusions: We report six
cases of AIH in the setting of DILI due to OxyElite Pro in a
five month period (August 2013-January 2014) observed in
a single center. We postulate that DILI due to OxyElite Pro
has induced de novo AIH or unmasked preexisting, quiescent
disease.
* Revised Original Scoring System.
SMA: anti-smooth muscle antibody
ANA: anti-nuclear antibody
6-MP: 6-mercaptopurine
Disclosures:
Marina Roytman - Advisory Committees or Review Panels: Gilead; Speaking and
Teaching: Gilead
Linda L. Wong - Speaking and Teaching: Bayer, Bayer
Naoky Tsai - Advisory Committees or Review Panels: Gilead, Vertex; Consulting:
BMS, Gilead, Merck; Grant/Research Support: BMS, Gilead, Genentech, Ver-
tex, Novartis, GSK, Bayer, Abbvie, Janssen, beckman; Speaking and Teaching:
BMS, Gilead, Genentech, Vertex, Merck, Salix, Bayer, Janssen
The following people have nothing to disclose: Peter Poerzgen, Christine L. Lee,
Leslie Huddleston, Peter K. Bryant-Greenwood, Timothy Kuo
327
Analysis of Liver Stiffness Measured by Transient Elas-
tography in Autoimmune Hepatitis
Ja Kyung Kim, Hae Won Kim, Jung Il Lee, Kwan Sik Lee; Dept. of
Internal Medicine, Gangnam Severance Hospital, Yonsei Univer-
sity College of Medicine, Seoul, Republic of Korea
Backgrounds and aims: Previous studies evaluated the use-
fulness of non-invasive assessment of liver fibrosis in patients
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
with autoimmune hepatitis (AIH) only as a part of chronic liver
disease category. The aims of this study were to evaluate per-
formance of transient elastography (TE) in AIH patients and to
predict cut-off values of significant fibrosis, defined as stages
III and IV fibrosis by METAVIR score. Patients and methods:
Sixty patients, diagnosed as AIH at Gangnam Severance Hos-
pital between Jan 2008 and Feb 2014, were included in this
study. Diagnosis was made based on the diagnostic criteria by
‘Revised Original Scoring System of the International Autoim-
mune Hepatitis Group (1999)’. TE was performed to measure
liver stiffness (LS) between 1 and 3 month after the diagnosis
was made when acute flare of hepatitis was relieved. For-
ty-seven patients had liver biopsy performed for staging of
liver fibrosis. Results: Patients were female predominant (M:F
= 6:41) and 15 patients (31.9%) had significant fibrosis. On
univariate analysis, the variables associated with significant
fibrosis detected by liver biopsy are ALP (P = 0.016), GGT (P
= 0.008), INR (P = 0.021), LS (P = 0.003) and duration for
AST normalization after initiation of treatment (P = 0.002).
On multivariate analysis, LS (OR = 1.216, 1.012-1.462, 95%
CI), and duration for AST normalization (OR = 1.025, 1.002-
1.048, 95% CI) were independent variables associated with
significant fibrosis. The cut-off of LS ≥ 9.1 kPa had 94.4% sen-
sitivity and 100% specificity for predicting significant fibrosis.
The cut-off of LS ≥ 10.4 kPa had 100% sensitivity and 100%
specificity for liver cirrhosis. LS predicted significant fibrosis
(P = 0.0002) and liver cirrhosis (P = 0.001) better than APRI
in AIH by AUROC. Conclusions: Transient elastography was
proved to be a simple, reliable and useful method for assessing
significant liver fibrosis in autoimmune hepatitis.
Disclosures:
The following people have nothing to disclose: Ja Kyung Kim, Hae Won Kim,
Jung Il Lee, Kwan Sik Lee
328
The IL-7/CD127 axis negatively modulates the function
of regulatory T-cells in autoimmune hepatitis
Rodrigo Liberal, Charlotte R. Grant, Yun Ma, Michael A.
Heneghan, Giorgina Mieli-Vergani, Diego Vergani, Maria Serena
Longhi; Institute of Liver Studies, King s College London, London,
United Kingdom
Background and aims: Autoimmune hepatitis (AIH) is associ-
ated with numerical and functional CD4+CD25+ regulatory
T-cell (Treg) defects. Bona-fide Tregs are negative for CD127
– the α chain of the IL7 receptor – normally expressed on acti-
vated effector T-cells. IL7 is known to impact Treg function and
survival. The aim of the current study was to evaluate the extent
of Treg activation in AIH and to explore the role of the IL7/
CD127 axis in modulating Treg function. Methods: 44 ANA/
SMA+ AIH patients and 20 healthy subjects (HS) were studied.
T-cell phenotype, transcription factor and cytokine profile was
determined by flow cytometry. Immunomagnetically-isolated
CD4 T-cells were cultured with TGFβ and IL2 to favour Treg
skewing; their phenotype and cytokine profile was assessed
by flow cytometry 4 days later. CD127+ and CD127– cell
ability to suppress was tested in a proliferation assay following
co-culture with CD4+ target cells. Purified CD4+, CD127+ and
CD127- cells were incubated in the absence or presence of IL7
or IL2 for 20 minutes and then assessed for phospho-STAT5
expression. Their proliferation in response to IL7 was assessed
after 48 hours. Results: The frequency of CD127+ cells within
undivided CD4+CD25+ Tregs was higher in patients than in
HS. CD127+ cells from both groups displayed lower frequen-
cies of FOXP3+ and CTLA4+ cells and higher proportions of
Tbet+, RORC+, IFNγ+ and IL17+ lymphocytes than CD127– cells.
365A
When the CD127– subset was analyzed, lower frequencies of
IL10+ cells were noted in patients compared to HS. Exposure
to Treg skewing conditions resulted in: 1) reduction of CD127
expression in AIH and 2) increase in the frequency of IL10+
cells within CD127– cells in HS. In both groups addition of
CD127-, but not of CD127+ cells, resulted in marked suppres-
sion of target cell proliferation, which was partially abrogated
in the presence of anti-IL-10 monoclonal antibody. Exposure to
IL7 did not change the expression of phospho-STAT5 in puri-
fied CD4+, CD127+ or CD127- cells, but it led to a significant
increase in CD4+ and CD127+ cell proliferation, more evident
in AIH. Exposure to IL2 increased phospho-STAT5 expression
within CD127-, but not within the CD127+ subset both in AIH
and HS. Conclusion: CD127+ cells are more frequent within
Tregs from AIH patients and display a pro-inflammatory pheno-
type. At variance with their CD127- counterpart, CD127+ cells
exert poor suppression. In contrast to IL2, IL7 does not induce
the expression of phospho-STAT5 and promotes the prolifera-
tion of CD4 effectors. Taken together, these data show that the
IL7/CD127 axis negatively modulates the function of Tregs in
patients with AIH.
Disclosures:
Michael A. Heneghan - Speaking and Teaching: Falk
The following people have nothing to disclose: Rodrigo Liberal, Charlotte R.
Grant, Yun Ma, Giorgina Mieli-Vergani, Diego Vergani, Maria Serena Longhi
329
Down-regulation of hepcidin production in patients with
autoimmune liver diseases
Nikolaos Gatselis1, Aggeliki Lyberopoulou2,5, Kalliopi Zachou1,
Georgia Chachami2,5, Petros Eliades3, Stella Gabeta1, Efrosyni
Paraskeva4, Avgi Mamalaki3, George K. Koukoulis6, George
Simos2,5, George N. Dalekos1; 1Department of Medicine and
Research Laboratory of Internal Medicine, Medical School, Uni-
versity of Thessaly, Larissa, Greece; 2Laboratory of Biochemistry,
Medical School, University of Thessaly, Larissa, Greece; 3Labo-
ratory of Molecular Biology and Immunobiotechnology, Hellenic
Pasteur Institute, Athens, Greece; 4Laboratory of Physiology, Med-
ical School, University of Thessaly, Larissa, Greece; 5Institute of
Biomedical Research & Technology (BIOMED), Larissa, Greece;
6Department of Pathology, Medical School, University of Thessaly,
Larissa, Greece
Background and aims: Hepcidin is synthesized in the liver and
plays a pivotal role in iron metabolism by controlling both
intestinal iron absorption and iron release from macrophages.
Chronic inflammation and iron overload up-regulate hepcidin
synthesis in order to reduce plasma iron concentration, while
anemia and hypoxia down-regulate the production of hep-
cidin in order to increase iron availability. We investigated
herein the possible role of hepcidin in diverse chronic liver
diseases. Methods: Serum hepcidin levels and liver hepcidin
mRNA were quantified in 126 patients (52 males) with dif-
ferent chronic liver diseases: chronic HCV infection (n=21),
chronic HBV infection (n=23), chronic cholestatic liver diseases
(primary biliary cirrhosis and primary sclerosing cholangitis,
PBC/PSC) (n=34), autoimmune hepatitis (AIH) (n=16) and
non-alcoholic fatty liver disease (n=32). Hepcidin mRNA levels
were determined by extraction of total RNA from liver biopsy
specimens and real-time quantitative RT-PCR. Hepcidin was
quantified in patients’ sera drawn at the biopsy day by ELISA.
Results: Both hepatic mRNA and serum hepcidin levels were
significantly lower in female patients (p=0.035 and p=0.021,
respectively). Univariate analysis showed a positive correlation
between hepcidin serum levels and hemoglobulin (p<0.01) as
well as albumin (p=0.03), while they were negatively associ-
366A AASLD ABSTRACTS
ated with age (p=0.011) and alkaline phosphatase (p=0.04).
Hepcidin mRNA levels were positively correlated with ferri-
tin (p=0.006) and negatively with γ-glutamyl-transpeptidase
(p=0.028). Finally, comparing the disease groups, hepcidin
was significantly decreased in the sera of AIH and PBC/PSC
patients, even after normalization for the corresponding serum
ferritin levels at the same time-points, by calculation of hep-
cidin/ferittin ratio (p<0.001). However, no differences were
noticed in hepcidin mRNA between groups. Linear regression
analysis model adjusted for confounding factors including fer-
ritin, demonstrated that AIH and PBC/PSC were independently
associated with decreased hepcidin levels in serum (p=0.02).
Conclusions: Simultaneous determination of hepcidin mRNA
in liver biopsies and hepcidin serum concentration in patients
with chronic liver diseases showed that hepcidin production is
negatively down-regulated in patients with AIH and PBC/PSC
probably due to post-transcriptional events. This may contribute
to liver iron accumulation and the progression of liver fibrosis.
Disclosures:
The following people have nothing to disclose: Nikolaos Gatselis, Aggeliki
Lyberopoulou, Kalliopi Zachou, Georgia Chachami, Petros Eliades, Stella
Gabeta, Efrosyni Paraskeva, Avgi Mamalaki, George K. Koukoulis, George
Simos, George N. Dalekos
330
Prevalence, Natural History And Outcome Of Overlap
Syndrome Versus Autoimmune Hepatitis In The Indian
Continent
Lovkesh Anand1, Cyriac A. Philips1, Varsha Bhat1, Chhagan
Bihari2, Ajeet S. Bhadoria3, Shiv K. Sarin1; 1HEPATOLOGY,
INSTITUTE OF LIVER AND BILIARY SCIENCES, New delhi, India;
2Pathology, Institute of liver and biliary sciences, New Delhi, India;
3Epidemiology, INSTITUTE OF LIVER AND BILIARY SCIENCES,
New delhi, India
BACKGROUND AND AIMS: The prevalence and spectrum
of autoimmune hepatitis (AIH) and overlap syndrome (OS) is
known to vary in different geographic regions of the world.
Both these diseases are strictly defined by the presence of
at least two of the three recognized biochemical, serologi-
cal, and histological criteria. We aimed at defining the two
patient populations and their demographic, clinical, serolog-
ical and eventual outcome in the Indian continent. PATIENTS
AND METHODS: Patients admitted to our hospital in past 4
years were reviewed retrospectively. The diagnosis was con-
firmed using simplified AIH score and Paris criteria for AIH
and OS respectively. RESULTS: Of the 7686 patients anal-
ysed, 254(3.3%) patients were found to fulfill criteria for AIH
and OS. Out of this, 174 (68.5%) were AIH and 80 (31.5%)
were OS. Majority of the patients were females accounting
for 71.3% (n=124) of AIH and 72.8% (n= 58) of OS. Patients
with OS were older (46y vs. 42 y) and had higher bilirubin
levels (median 3.4 g/dl, IQR 1.8-11.8) as compared to AIH
(2.2g/dl; 1.2-5.9). Standard autoimmune markers were com-
parable, though, atypical autoimmune marker such as p-ANCA
was seen more in OS group (10.1%, n= 8). Osteopenia, as
measured by DEXA, was more severe in OS patients (21.7%,
n=13), p=0.01. Liver stiffness (FibroscanR) was higher in
patients with OS (median 28.4; IQR 17.3 - 43; p<0.001).
Patients of OS predominantly presented with cirrhosis 72.5%
(n= 58) as compared to AIH 64.9% (n=113); p = 0.08. At first
presentation, 56.3% of OS patients had decompensation in
contrast with 37.9% of AIH patients; p-0.03. Overall, patients
with OS carried poorer prognosis, as 8.8% died as compared
to 5.2% of AIH; p=0.18. The presence of ASMA in the titre of
1:40 or 1:20 was associated with higher incidence of decom-
pensation among patient in both the groups (p=0.04). The
HEPATOLOGY, October, 2014
presence of ANA in the titre of 1:40 or 1:80 was negatively
associated with decompensation in patients of AIH, but not
in case of OS (p = 0.05). CONCLUSIONS: AIH and OS are
not uncommon as chronic liver disease in the Indian continent.
Patients with OS are older and present more often as cirrhosis
with decompensation with a poor prognosis. Decompensation
is more likely in patients who harbour ASMA (p= 0.04). We
propose that high suspicion in diagnosis and lower threshold
in performing liver biopsy in seemingly non-classical AIH would
yield early diagnosis and could improve survival benefit in this
group.
Disclosures:
The following people have nothing to disclose: Lovkesh Anand, Cyriac A. Philips,
Varsha Bhat, Chhagan Bihari, Ajeet S. Bhadoria, Shiv K. Sarin
331
Prednisolone Changes mRNA and lincRNA Expression
Profiles to Suppress Autoimmunity in CD4+ T Cells of
Autoimmune Hepatitis Type 1
Ryo Nakagawa1,2, Ryosuke Muroyama2, Sayaka Ito2, Keiko
Takano1, Wenwen Li2, Kaku Goto2, Masanori Nakano1, Chi-
sato Saeki1, Yasuo Matsubara2, Naoya Kato1, Mikio Zeniya1;
1Department of Gastroenterology and Hepatology, The Jikei Uni-
versity School of Medicine, Tokyo, Japan; 2Division of Advanced
Genome Medicine, The Institute of Medical Science, The University
of Tokyo, Tokyo, Japan
Background/Aim: Autoimmune hepatitis (AIH) type 1, often
occurs in middle age females, is a progressive autoimmune
liver disease of unknown pathogenesis. Under the prednisolone
(PSL) treatment, the progression of disease is mild in almost
patients. However, some patients resist the PSL treatment, and
some patients who achieved the remission by the PSL treatment
recurrent easily without the PSL treatment. Thus, we analyzed
the dynamics of gene expression by PSL treatment including
messengerRNA (mRNA), long intergenic non-codingRNA (lin-
cRNA), and microRNA (miRNA) in CD4+ T cells to reveal the
mechanisms of PSL treatment for AIH. Methods: Clinically and
pathologically diagnosed 2 naïve AIHs, 7 AIHs in remission,
and 7 healthy controls, who agreed to provide samples with
written informed consent, were enrolled in this study. This study
was approved by the institutional review board. Total RNA was
extracted from CD4+ T cells purified from peripheral blood. The
comprehensive analysis of the genes were undergone using
microarray with statistics (ANOVA). The data were classified
by hierarchical clustering and were analyzed for the function
bioinformatically using Gene ontology (GO) analysis and path-
way analysis. Results: Microarray study showed that 2,957
mRNAs (p<0.05, fold change>1.5), 574 lincRNAs (p<0.05,
fold change>1.5), and 17 miRNAs (p<0.05, fold change>1.2)
were differentially expressed among 3 groups. By the hier-
archical clustering, each group was clearly distinguished by
mRNA and lincRNA expression, and their expression profiles
were classified into 4 clusters. Interestingly the patterns of lin-
cRNA cluster were in inverse correlation with those of mRNA
cluster. Moreover, bioinformatics revealed that 4 clusters of
mRNA expression profile had the independent function each
other by GO and pathway analyses. Conclusions: The gene
expression profile of AIH in remission was not only different
from naïve AIH, but also from healthy control, suggesting that
the PSL testament for AIH dose not lead CD4+ T cells to normal
condition but changes the expression profile to suppress the
autoimmunity. These findings may contribute to the develop-
ment of better treatment strategies against AIH.
Disclosures:
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
The following people have nothing to disclose: Ryo Nakagawa, Ryosuke Mur-
oyama, Sayaka Ito, Keiko Takano, Wenwen Li, Kaku Goto, Masanori Nakano,
Chisato Saeki, Yasuo Matsubara, Naoya Kato, Mikio Zeniya
332
Fast corticosteroid tapering and early fibrosis stages:
important risk factors for type 1 autoimmune hepatitis
relapse in Japan
Atsushi Takahashi1, Kazumichi Abe1, Hiromasa Ohira1, Yasuhiro
Miyake2, Masanori Abe3, Kazuhide Yamamoto2, Yoshiyuki
Suzuki4, Morikazu Onji3, Hirohito Tsubouchi5; 1Gastroenterol-
ogy and Rheumatology, Fukushima Medical University School of
Medicine, Fukushima, Japan; 2Gastroenterology and Hepatology,
Okayama University Graduate School of Medicine, Dentistry, and
Pharmaceutical Sciences, Okayama, Japan; 3Gastroenterology
and Metabology, Ehime University Graduate School of Medicine,
Matsuyama, Japan; 4Hepatology, Toranomon Hospital, Tokyo,
Japan; 5Kagoshima City Hospital, Kagoshima, Japan
Background: Autoimmune hepatitis (AIH) sometimes relapses
after immunosuppressive therapies are discontinued or some-
times even when they are still being administered. Furthermore,
relapse often occurs in the absence of AIH risk factors. Aim:
This study aimed to identify the frequency of relapse and to
analyze the risk factors associated with relapse in type 1 AIH
patients. Methods: Clinical characteristics and therapeutic pro-
cesses were assessed from 146 type 1 AIH patients. Relapse
was defined as serum ALT levels ≥60 IU/L after corticosteroid
treatment and serum ALT normalization (≤30 IU/L). The cortico-
steroid reduction rate (mg/week) was calculated by using the
following formula: reduction dose (initial corticosteroid dose
(mg) - corticosteroid dose (mg) at ALT normalization) / dura-
tion of corticosteroid treatment from initiation until ALT normal-
ization (week). Results: Relapse was identified in 44 (30.1%)
type 1 AIH patients after alanine aminotransferase (ALT) level
normalization. ALT levels significantly increased when cortico-
steroid treatment was initiated, and histological examination
identified that fibrosis stages were not progressed in relapsed
patients compared with that in sustained remission patients.
There was no intergroup difference in the proportions of dis-
continued immunosuppressive therapies (13.6% vs. 7.8%, p
= 0.277). Moreover, there were no intergroup differences in
the proportions of concomitant medications such as ursodeoxy-
cholic acid or azathioprine at the time of ALT level normaliza-
tion However, both reduction dose and rate of corticosteroid
taper until ALT normalization increased in relapsed patients
compared with sustained remission patients. Particularly, in
129 patients who did not receive pulse therapy, the reduction
rate of corticosteroid taper and early fibrosis stages were sig-
nificantly increased in relapsed patients compared with those
in sustained remission patients. Multivariate analysis revealed
that reduction rate of corticosteroids and fibrosis stages were
significantly associated with relapse. The both reduction dose
and rate were positively correlated with initial corticosteroid
dose, ALT, and total bilirubin, respectively. Conclusion: Early
fibrosis stages at corticosteroid initiation and a corticosteroid
taper rate until ALT normalization were important AIH relapse
risk factors.
Disclosures:
Kazuhide Yamamoto - Advisory Committees or Review Panels: Shionogi Phar-
maceutical Co; Grant/Research Support: Tanabe Mitsubishi Co, MSD, Chugai
Pharmaceutical Co, Esai Co
Hirohito Tsubouchi - Grant/Research Support: MSD, Chugai Pharmaceutical, Kan
Research Institute, Daiichi-Sankyo, Eisai, Tanabe Mitsubishi
The following people have nothing to disclose: Atsushi Takahashi, Kazumichi
Abe, Hiromasa Ohira, Yasuhiro Miyake, Masanori Abe, Yoshiyuki Suzuki, Mori-
kazu Onji
367A
333
Serum sterol levels indicate distorted cholesterol homeo-
stasis in cirrhotic patients with primary biliary cirrhosis
Marcin Krawczyk1, Ewa Wunsch2, Dieter Luetjohann3, Frank Lam-
mert1, Piotr Milkiewicz2,4; 1Department of Medicine II, Saarland
University Hospital, Homburg/Saar, Germany; 2Liver Research
Laboratories, Pomeranian Medical University, Szczecin, Poland;
3Institute for Clinical Chemistry and Clinical Pharmacology, Univer-
sity Clinics of Bonn, Bonn, Germany; 4Liver and Internal Medicine
Unit, Department of General, Transplant and Liver Surgery, Medi-
cal University of Warsaw, Warsaw, Poland
Background: New cholesterol derives from de novo synthesis
and intestinal absorption. Serum cholesterol precursor (e.g.,
lathosterol, desmosterol) and plant sterol concentrations (e.g.,
sitosterol, campesterol) represent valid surrogate marker for
cholesterol biosynthesis and intestinal absorption, respectively.
Since chronic liver diseases affects cholesterol homeostasis, we
systematically investigated sterol serum levels in patients with
primary biliary cirrhosis (PBC) with and without liver cirrhosis.
Patients and methods: Overall, we recruited 111 non-trans-
planted PBC patients (age 22 - 83 years, 101 females). In this
cohort, a total of 30 individuals (27%) presented with liver
cirrhosis at diagnosis. Serum concentrations of plant sterols,
cholesterol and its precursors were measured by gas chroma-
tography/mass spectrometry (GC/MS). Patients with results
suggesting familial hypercholesterolemia or hyperphytosterol-
emia were excluded from subsequent analyses. Serum markers
were compared between cirrhotic and non-cirrhotic patients
with non-parametric tests. Results: PBC patients with liver cir-
rhosis demonstrate significantly higher sitosterol and campes-
terol concentrations than non-cirrhotic individuals (P = 0.0002
and P = 0.0067, respectively). Serum levels of lathosterol and
desmosterol are lower in these patients (P = 0.0001 and P
= 0.013, respectively), who display a trend to lower serum
cholesterol concentrations (P = 0.064). In cirrhotic patients,
we identified increased sitosterol:cholesterol and campester-
ol:cholesterol but decreased lathosterol:cholesterol ratios (all
P < 0.0001). Overall, the ratios of phytosterols to cholesterol
precursors are significantly (all P > 0.0001) higher in patients
with liver cirrhosis as compared to non-cirrhotic individuals.
Discussion: PBC patients with liver cirrhosis are characterized
by decreased cholesterol synthesis and increased sterol absorp-
tion as compared to non-cirrhotic individuals. Determination of
serum sterols may improve clinical stratification of patients with
PBC. Further studies are required to investigate the associa-
tion between liver metabolism in PBC and systemic cholesterol
homeostasis.
Disclosures:
The following people have nothing to disclose: Marcin Krawczyk, Ewa Wunsch,
Dieter Luetjohann, Frank Lammert, Piotr Milkiewicz
334
Metabolic syndrome induces a more rapid progression
of fibrosis evaluated with transient elastography in
early primary biliary cirrhosis
Nora Cazzagon1, Laura Costa1, Irene Franceschet1, Alessandra
Buja2, Liliana Chemello3, Luisa Cavalletto3, Francesco P. Russo1,
Annarosa Floreani1; 1Dept. of Surgery, Oncology and Gastroen-
terology, University of Padova, Padova, Italy; 2Laboratory of Public
Health and Population Studies, Dept. of Molecular Medicine, Uni-
versity of Padova, Padova, Italy; 3Dept. of Medicine, University of
Padova, Padova, Italy
Background: Metabolic syndrome (MS) is a comorbidity,
possibly associated to PBC in up to 30% of patients, which
368A AASLD ABSTRACTS
increases the risk of death for cardiovascular events. How-
ever, its role in determining a liver disease progression has
not been established so far. Transient elastography (TE) is a
useful tool for assessing liver fibrosis in PBC, but its perfor-
mance in longitudinal studies is still scanty. Aim: To assess
liver fibrosis progression in patients with PBC (associated
or not to MS) using TE after a 2-year interval from the initial
diagnosis (histologically confirmed in all patients). Patients
and method: A total of 80 consecutive patients with PBC (19
of whom having MS) underwent a prospective TE analysis at
baseline and after 2-year interval. The median follow-up was
25 months, (range 21-27 months). All patients were treated
with UDCA (15 mg/Kg/day). MS was defined MS according
to the American Heart Association criteria. Wilcoxon Matched-
Pairs Signed-Ranks Test was applied to verify the difference in
the median progression of liver stiffness (LS). Mann Whitney
test and Spearman coefficient of correlation (rho) were used
as appropriate. Results: A significant overall progression of
the mean LS was observed in patients with PBC (8.9±5.5 kPa
vs 10.2±7.6 kPa, p=0.0071). No significant difference was
observed in fibrosis progression in patients with histological
stage I at baseline (Δ 1.4±2.2 kPa, p=0.07), but a significant
increase was observed in patients with moderate or advanced
fibrosis (stage II-III-IV) (Δ 1.3 ± 4.8 kPa, p=0.04). No signifi-
cant difference was observed in the progression of LS between
patients with or without MS (Δ 1.6±5.8 kPa vs Δ 1.2± 4.1 kPa,
p= ns). Subgrouping patients for the presence/absence of MS
and the histological stage at diagnosis, a significant difference
in progression of LS was observed in patients with MS+stage
II vs those without MS+stage II (p= 0.02). TE was positively
correlated with Mayo score at baseline and after two years
of follow-up (rho 0=0.33, p<0.05 and rho1=0.33, p<0.05).
Conclusions: Patients with PBC (with histological stage II-III-IV)
demonstrated a significant progression in LS after a 2-year
follow-up. MS added a significant risk in fibrosis progression in
patients with histological stage II.
Disclosures:
The following people have nothing to disclose: Nora Cazzagon, Laura Costa,
Irene Franceschet, Alessandra Buja, Liliana Chemello, Luisa Cavalletto, Fran-
cesco P. Russo, Annarosa Floreani
335
Fibrates improve liver tests in primary sclerosing chol-
angitis with incomplete biochemical response to ursode-
oxycholic acid: update of a pilote study
Sara Lemoinne1,2, Christophe Corpechot1,2, Astrid Donald D.
Kemgang Fankem1,2, Farid Gaouar1, Raoul Poupon1,2, Olivier
Chazouillères1,2; 1Service d’Hépatologie, Centre de Référence des
Maladies Inflammatoires des Voies Biliaires, Hôpital Saint-Antoine,
Assistance-Publique Hôpitaux de Paris, Paris, France; 2INSERM,
UMRS_938, F-75012 Paris, France UPMC Univ Paris 06, F-75012
Paris, France, Paris, France
Background: In patients with primary sclerosing cholangitis
(PSC), ursodeoxycholic acid (UDCA) has no proven benefit
on survival but improves serum liver tests and surrogate mark-
ers of prognosis. In the absence of other medical treatment
with proven efficacy, UDCA is widely used in European PSC
patients. However newer therapies are obviously needed.
Fibrates are PPAR agonists that exert anti-inflammatory prop-
erties in several experimental models of autoimmunity and
small series have suggested their beneficial effect on liver bio-
chemistries in primary biliary cirrhosis. In 2010, we reported
improvement of liver tests under fenofibrate for 6 to 12 months
in some PSC patients with an incomplete biochemical response
to UDCA. Aim: To confirm the safety and efficacy of fibrates in
HEPATOLOGY, October, 2014
a PSC population with extended number of patients and dura-
tion of therapy.Methods: This retrospective single-center study
included patients with PSC treated with fibrates (fenofibrate
200mg/d or bezafibrate 400 mg/d) for at least 6 months in
addition to UDCA, after an incomplete biochemical response
(ALP ≥ 1.5 ULN) to UDCA (15-20mg/kg/d for at least 1 year).
Patients with associated liver diseases, especially auto-immune
hepatitis, were not included. ANOVA and Wilcoxon tests were
performed to compare serum liver biochemistries at baseline,
3, 6, 9, 12, 18, 24, 36 and 48 months. Results: Fifteen patients
were included : 10 males, median age 51 years, 9 with inflam-
matory bowel disease, median liver stiffness = 12.7 kPa (cor-
responding to fibrosis ≥ F3). Median duration of treatment
with fibrates was 17.5 months (6.7-60.8). Under treatment
with fibrates, ALP, GGT and ALT decreased significantly (p=
0.0001, 0.02 and 0.02 respectively). Biochemical improve-
ment occurred early and 55% patients had ALP ≤1.5 ULN at 3
months.Total bilirubin and albumin remained unchanged. Two
patients with dominant biliary stenosis developed cholelithi-
asis. No serious adverse event related to fibrates occurred.
Conclusion:This study confirms that addition of fibrates induces
a significant biochemical improvement in PSC patients with
incomplete response to UDCA. Further studies are warranted
to investigate the potential clinical benefit of fibrates in this
context.
Course of liver tests during treatment with fibrates
Disclosures:
Olivier Chazouillères - Consulting: APTALIS, MAYOLY-SPINDLER
The following people have nothing to disclose: Sara Lemoinne, Christophe Cor-
pechot, Astrid Donald D. Kemgang Fankem, Farid Gaouar, Raoul Poupon
336
Related Factors for Treatment-Dependent Autoimmune
Hepatitis
Berna Gürsel1, Fulya Gunsar1, Funda Yilmaz2, Zeki Karasu1,
Galip ERsoz1, Ulus S. Akarca1; 1Gastroenterology, Ege University
Medical School, Izmir, Turkey; 2Pathology, Ege University Medical
School, Izmir, Turkey
More than 80% of patients with autoimmune hepatitis are good
responders to conventional treatment with azathioprine and
prednisone. A small proportion of patients flares during pred-
nisone tapering (treatment-dependent patients) according to
AASLD guideline. We aimed to define response-related param-
eters in patients with autoimmune hepatitis (AH). Methods: The
patients with AH who were followed up for at least 6 months
were included into the study. Treatment-dependency was
defined as ALT elevation during prednisolon tapering. Those
remained in remission with maintenance dose of prednisolon
and/or azathioprine were defined as good responder(GR).
Demographic data of the patients, baseline blood test values
and biopsy findings, treatment options, laboratory tests at 6
months of treatment, length of the time of ALT normalization,
and prognostic changes in the disease were investigated as
associated with treatment-dependency and good response. The
number of exacerbations during prednisolon tapering were
investigated as well. Results Twenty five of 81 patients with
AH were treatment dependent (TD). Mean age was 52+18
(M/F:1/24) and 55+13 (M/F:8/48) in TD and GR patients,
respectively. Six of 25 TD patients had more than 3 times exac-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
erbations during prednisone tapering. The patients with >3
exacerbations were younger than those with <3 exacerbations
(56,6+16 vs 37+15, p:0,02). ALT normalized within 6 months
in 16 (69,6%) TD patients and in 46 (88,5%) GR patients
(p<0,046). Maintenance dose of prednisolon was higher in
TD patients (8,05±4,8 vs 4,98±2,2 mg/day; p. 0,016) as
expected. Duration of prednisone treatment was longer in
TD patients (44±29 vs 27±22 months; p:0,013). Side effects
(29% vs 8,3%) and dose reductions (43% vs 20%) of azathio-
prine were more common in TD patients (p<0,05). ALT, AST,
GGT, globulin levels were higher in TD patients comparing
to GR patients at 6th month of therapy (p<0,05). Anti smooth
muscle antibody (ASMA) positivity was more common in TD
patients with higher number of exacerbations (%80 vs %27,8;
p:0,056). Liver disease progression was observed in 9 TD
(36%) patients and in 8 (14%) GR patients during a median of
27 (6-168) months of follow up (p:0.027). Conclusions. Treat-
ment dependent patients use higher dose of prednisolon with
longer duration. Their biochemical remission is achieved later
comparing to GR patients’. Azathioprine side effects or intol-
erance are important issues for treatment dependency. As TD
patients have more progressive liver disease, other immmuno-
supresive drugs such as mycophenolate mofetil or cyclosporine
should be tried.
Disclosures:
Ulus S. Akarca - Advisory Committees or Review Panels: GILEAD, BMS, MSD
The following people have nothing to disclose: Berna Gürsel, Fulya Gunsar,
Funda Yilmaz, Zeki Karasu, Galip ERsoz
337
Successful ex-vivo normothermic oxygenated machine
perfusion of human donor livers
Janske Reiling1,2, David S. Lockwood1,3, Andrew H. Simpson4,
Catherine M. Campbell5, Kim Bridle1,6, Nishreen Santrampur-
wala1,6, Laurence J. Britton1,6, Darrell H. Crawford1,6, Cornelis H.
Dejong2,7, Jonathan Fawcett1,3; 1School of Medicine, The Univer-
sity of Queensland, Brisbane, QLD, Australia; 2NUTRIM - School
for Nutrition, Toxicology and Metabolism, Maastricht University,
Maastricht, Netherlands; 3Queensland Liver Transplant Service,
Princess Alexandra Hospital, Brisbane, QLD, Australia; 4Visiting
Medical Officer Perfusion, Department of Cardiac Anaesthetics,
Princess Alexandra Hospital, Brisbane, QLD, Australia; 5Envoi
Specialist Pathologists, Brisbane, QLD, Australia; 6Gallipoli Medi-
cal Research Foundation, Greenslopes Private Hospital, Brisbane,
QLD, Australia; 7Department of Surgery, Maastricht University
Medical Centre, Maastricht, Netherlands
Introduction: Currently empirical criteria are used to determine
usability of donor livers however they have a low predictive
value and alternative methods to determine viability are desir-
able. This ongoing study aimed to assess the feasibility of using
a normothermic liver perfusion protocol in human donor livers,
rejected as unsuitable for transplantation, as a tool to assess
whether they would in fact be viable for clinical use. Meth-
ods: Organ retrieval and cold perfusion were performed in a
standardized fashion using University of Wisconsin solution.
In addition, blood from the donor was collected as perfusion
solution. The perfusion circuit consisted of a single centrifugal
pump which circulates perfusate out of the inferior vena cava
through an oxygenator / heat exchanger and then split into a
pressure-controlled hepatic artery supply and gravity fed portal
venous supply via a reservoir. Throughout the perfusion period
of up to six hours there was continuous monitoring of haemo-
dynamic parameters and blood, bile, liver and bile duct tissue
samples were collected. Results: At the time of submission, one
liver donated after cardiac death (DCD) and one donated after
369A
brain death (DBD) have been studied. Both livers were meta-
bolically active throughout the perfusion period reflected by
lactate clearance (peak lactate 9 and 8.16 mmol/L; 0.95 and
2.56 mmol/L at the end of perfusion), urea production (4.4
and 4 mmol/L at start of perfusion; 11 and 7.9 mmol/L at end
of perfusion) and bile production. Liver histology obtained at
the end of the perfusion period showed no evidence of hepa-
tocellular injury. However, there was extensive biliary injury
in the DCD liver as reflected by epithelial cell loss and mural
necrosis of both the left and right hepatic duct. Conclusion:
This study shows that normothermic oxygenated machine per-
fusion is feasible from a technical perspective in donor liver
currently deemed unsuitable for transplant. This continuing
study is comparing the results of both DCD and DBD donor
livers. The extensive degree of biliary damage in the DCD liver
may underline the need to consider biliary tract integrity when
assessing graft viability.
Disclosures:
Darrell H. Crawford - Advisory Committees or Review Panels: Roche Products
Pty Ltd, Bristol Myers Squibb, Gilead Sciences, Novartis, MSD, Abbvie, Jansen;
Consulting: Roche Products Pty Ltd; Grant/Research Support: Roche Products
Pty Ltd; Speaking and Teaching: Roche Products Pty Ltd, Bristol Myers Squibb,
Gilead Sciences, MSD
The following people have nothing to disclose: Janske Reiling, David S. Lock-
wood, Andrew H. Simpson, Catherine M. Campbell, Kim Bridle, Nishreen Sant-
rampurwala, Laurence J. Britton, Cornelis H. Dejong, Jonathan Fawcett
338
Serum zinc levels are associated with decompensated
liver function and reduced survival in patients awaiting
liver transplantation
Kilian Friedrich, Christian Rupp, Andreas Wannhoff, Wolfgang
Stremmel, Daniel Gotthardt; Internal Medicine IV, University Hos-
pital of Heidelberg, Heidelberg, Germany
Background and Aims: Zinc is an important trace element with
catalytic and defensive functions. We assessed the impact of
zinc deficiency in patients with end-stage liver disease (ESLD)
awaiting liver transplantation. Methods: Serum zinc levels were
measured at the time of evaluation for liver transplantation in
ESLD patients (n = 265). Patients were dichotomized in two
groups: low and normal zinc serum levels. Results: Medium
serum zinc levels were 8.59 mmol/l ± 3.1. Kaplan Meier
analysis showed impaired time to hydropic decompensation,
hepatic encephalopathy, spontaneous bacterial peritonitis and
hepatorenal syndrome (all p=.000, respectively) for patients
with reduced serum zinc levels. Serum zinc levels remained an
independent risk factor for development of hepatic encephalop-
athy (OR = .82 ; 95% CI: .73-.92; p = .001) and hepatorenal
syndrome (OR = .79 ; 95% CI: .68-.91; p = .001) when sub-
jected to multivariate analysis. Furthermore, actuarial survival
free of liver transplantation was reduced for patients with low
serum zinc levels (low zinc: 22.2 months; 95% CI: 17.4–27.0
vs. normal zinc: 30.1 months; 95% CI: 25.5–35.0; p = .003).
Patients with primary sclerosing cholangitis (PSC) are particu-
larly affected by reduced zinc levels (low zinc: 12.5 months ±
2.4; 95% CI: 7.7–17.2 vs. normal zinc: 39.1 months ± 4.7;
95% CI: 29.8–48.5) resulting in impaired survival (p =.001)
while this was not the case for patients with viral liver disease
(p =.294), alcoholic liver diseaes (p =.545) or patients clas-
sified with other hepatic disorder (p =.087). In PSC patients,
serum zinc levels remained an independent predictor of sur-
vival when subjected to multivariate analysis (OR = .80; 95%
CI: .64-.98; p = .038). Conclusions: We were able to identify
serum zinc levels as a predictor of reduced survival in ESLD
patients, particularly in PSC patients. Whether zinc supplemen-
370A AASLD ABSTRACTS
tation might be beneficial for patients on liver transplantation
list needs to be further addressed.
Disclosures:
The following people have nothing to disclose: Kilian Friedrich, Christian Rupp,
Andreas Wannhoff, Wolfgang Stremmel, Daniel Gotthardt
339
The impact of Model for End Stage Liver Disease Sodium
(MELD-Na) prioritization for liver transplantation on
wait list and post-transplant survival
Sheeva Johnson2, Barry Schlansky1, Willscott E. Naugler1; 1Med-
icine/Gastroenterology, Oregon Health & Sciences University,
Portland, OR; 2Public Health & Preventive Medicine, School of
Medicine, Oregon Health & Sciences University, Portland, OR
Background: Patients are prioritized for liver transplantation (LT)
by their anticipated 90-day wait list mortality using the MELD
score, but the MELD underestimates wait list mortality when
hyponatremia is present. A revised MELD that incorporates
the added mortality due to hyponatremia, the MELD-Na, was
shown to reduce wait list mortality in hyponatremic patients in
a modeling study. In UNOS Region 6, regional agreement has
resulted in prioritization of cirrhotic patients with hyponatremia
for LT using a MELD-Na exception since 2008. Aims: (1) Deter-
mine if patients granted a MELD-Na exception in Region 6 have
similar waitlist mortality compared to patients with similar MELD
scores without hyponatremia. (2) Determine if patients granted
a MELD-Na exception in Region 6 have similar post-transplant
survival compared to patients with similar MELD scores without
hyponatremia. Methods: In the UNOS registry, we selected all
patients listed for LT in Region 6 from Jan 2008 to Mar 2014
who received a MELD-Na prioritization exception based on
regional agreement. We compared their wait list mortality to a
MELD-matched group listed for LT without hyponatremia using
multiple Cox regression. We then compared post-LT mortality
of MELD-Na prioritized patients who received LT with a MELD-
matched group without hyponatremia who received LT using
multiple Cox regression. Results: Because of the regional agree-
ment, the number of patients in UNOS Region 6 receiving a
MELD-Na exception has grown steadily since 2008, reach-
ing levels of up to 20% of all MELD exceptions, significantly
exceeding numbers from other regions (most < 1%). Patients
receiving the MELD-Na exception had low waitlist mortality,
comparable to MELD-matched patients without hyponatremia.
[Post-transplant survival analysis in process, to be reported at
the Liver Meeting]. Conclusions: MELD-Na prioritization using
a regional agreement equalized waitlist mortality, as predicted
by a prior modeling study.
Disclosures:
The following people have nothing to disclose: Sheeva Johnson, Barry Schlansky,
Willscott E. Naugler
340
Impact of Donation after cardiac death (DCD) allografts
on incidence and severity of recurrent hepatitis C (HCV)
and graft survival post liver transplantation (LT) for HCV
Shiva Kumar, Rachel Pedersen; Liver Transplant Program, Aurora
St. Luke’s Medical Center, Milwaukee, WI
Objective To determine the impact of DCD allografts on inci-
dence and severity of recurrent HCV, response to therapy and
graft survival following LT for HCV Methods We conducted
a retrospective review of all LT performed at a single center
from July 2007 - Feb 2014. HCV recipients of DCD allografts
(Group 1) were compared to non-DCD HCV recipients (Group
HEPATOLOGY, October, 2014
2) during the same study period. Only HCV RNA positive
recipients of solitary LT were included. The following variables
were analyzed: donor age, warm and cold ischemic time,
recipient age, MELD score, presence of HCC. Variables were
compared using chi-square test for categorical variables and
student’s t-test for continuous variables. HCV recurrence was
defined as biochemical graft dysfunction with detectable HCV
RNA by PCR, confirmed histologically. Severe recurrence was
defined as presence of > stage 2 fibrosis within a year of LT or
development of cirrhosis secondary to recurrent HCV. Antiviral
therapy consisted of a 48 week course of Pegasys, Ribavirin
(and Telaprevir after July 2011). SVR was defined as negative
HCV RNA 24 weeks post treatment. Primary outcome measures
were incidence and severity of HCV recurrence and response
to therapy. Secondary outcome measure was graft survival.
Results 196 LT were performed during the study period, of
which, 159 were primary single organ LT, 33 combined LKT
and 4 liver re-LT. Median MELD was 24. 58/196 (30%) under-
went LT for HCV. Among HCV patients, 21 (36%) received a
DCD allograft and 37 (64%) did not. Groups 1 and 2 were
similar, except for lower MELD at LT and longer cold ischemic
time in Group 1 . 88% of HCV patients were genotype 1 (81%
DCD, 92% non-DCD). 1 and 3 year graft survival were 89%
& 89% in Group 1 and 85% & 72% respectively in Group 2
(p=0.34). HCV recurrence at 1 and 3 years occurred in 53%
and 76% in Group 1 and 33% and 67% respectively in Group
2 (p=0.10). Severe HCV recurrence was noted at 1 and 3
years in 29% and 53% of patients in Group 1 and only 11%
and 22% respectively in Group 2 (p=0.05). 8 (38%) patients in
Group 1 and 11 (30%) in Group 2 received antiviral therapy.
SVR was achieved in in 1 (12%) and 9 (82%) in Groups 1 &
2 respectively (p=0.01) Conclusions Although the incidence
of recurrent HCV was similar among DCD and non-DCD HCV
recipients, recurrence was more severe with poorer response
to antiviral therapy among DCD recipients. Recurrent HCV
did not impact graft survival at 1 and 3 years of follow up in
DCD recipients. However, given the unfavorable characteristics
of recurrent HCV in DCD recipients, longer term follow up is
needed to determine the impact of recurrent HCV on graft and
patient survival in DCD LT recipients.
Disclosures:
The following people have nothing to disclose: Shiva Kumar, Rachel Pedersen
341
Improving the Quality of MELD Upgrade Petitions for
Hepatocellular Carcinoma Beyond the Milan Criteria in
UNOS Region 8
Joel P. Wedd1, Jane Gralla1, Betsy Gans2, Sue Dunn3, Harvey
Solomon4, Michael D. Voigt5, Scott W. Biggins1; 1University of
Colorado Denver, Aurora, CO; 2United Network for Organ Shar-
ing, Richmond, VA; 3Donor Alliance, Denver, CO; 4Saint Louis
University, St. Louis, MO; 5University of Iowa, Iowa City, IA
The current liver graft allocation system in the United States
allows automatic exception MELD points for patients with hepa-
tocellular carcinoma (HCC) within the Milan Criteria (MC).
Granting such priority for patients with HCC beyond the MC
and downstaged patients is controversial and requires petition-
ing of a United Network of Organ Sharing (UNOS) Regional
Review Board. The quality of those petitions may be lacking,
which could impact appropriate priority decisions for this grow-
ing group of patients. Aim: To evaluate the informational qual-
ity of petitions for downstaged HCC and HCC beyond the MC
and to analyze the impact of an intervention to improve that
quality. Methods: A novel Quality Assessment Tool (QAT) was
created to evaluate the quality of petitions in UNOS Region
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
8. The QAT was piloted on 30 petitions. An intervention,
a Standardized Template (ST) was created using feedback
from regional stakeholders and includes all information felt
necessary for appropriate priority decisions. Thirty sequential
petitions after adoption of the ST were evaluated for quality,
approval rate, and measurements of vote favorability. Student’s
T-test and Wilcoxon rank sum tests were used for the analysis.
Results: Pilot data using the QAT showed a mean quality of
73%. The ST was implemented in 3/2013. In the 30 peti-
tions analyzed after implementation of the ST, 13 used the ST
(43%) whereas 17 (57%) did not. The approval rate was high,
100% (95% CI 100-100%) and 88 (95% CI 71-105%) for
petitions using and not using the ST, respectively (p=0.164).
Mean score from the QAT was 96% (95% CI 93-99%) and
75% (95% CI 70-80%) for those using and not using the ST,
respectively (p=<0.001). The mean percentage of yes votes
from reviewers was 78% (95% CI 70-85%) and 66% (95% CI
58-75%) for petitions using and not using the ST, respectively
(p=0.047). The median differential between yes and no votes
was 4.0 (IQR 3-4) and 2.0 (IQR 2-4) for petitions using and not
using the ST, respectively (p=0.035). Conclusions: The quality
of MELD upgrade petitions for HCC beyond the MC is poor
and is improved with the use of the ST. Improved enforcement
of the petition may improve compliance and the quality of the
petitions. Further study of the influence of HCC petitions on
dropout rate and recurrent HCC after transplant are needed
when data are available. Consideration for use of similar tem-
plates in other regions and for other conditions for which peti-
tions are common but not currently standardized is warranted.
Disclosures:
The following people have nothing to disclose: Joel P. Wedd, Jane Gralla, Betsy
Gans, Sue Dunn, Harvey Solomon, Michael D. Voigt, Scott W. Biggins
342
Utilization of Simultaneous Liver-Kidney Transplants
Continues to Vary Dramatically by UNOS Region
Paul J. Gaglio1,2, Wendy Rabbenou2, Sander S. Florman1,
Tomoaki Kato1, Milan Kinkhabwala1, Glyn Morgan1, Mark S. Orl-
off1, Lewis Teperman1, Samantha DeLair1; 1New York Center for
Liver Transplantation, Troy, NY; 2Medicine, Albert Einstein College
of Medicine, Bronx, NY
Introduction: Over the last several years, the number of
deceased donor simultaneous Liver-Kidney transplants (SLK)
has increased. However, guidelines for SLK, including when
these combined organ transplants are appropriate based on
serum creatinine, underlying liver and renal disease, etiology
of renal dysfunction and time on dialysis are contentious. Inap-
propriate SLK removes an organ from the donor pool which
would more appropriately be utilized for a patient awaiting
kidney transplantation, and failure to provide SLK to a patient
who requires prolonged dialysis and kidney transplantation
following isolated LT is similarly inappropriate. We hypoth-
esize that the use of SLK varies by region, and is unrelated
to mean MELD at the time of transplantation. Our group has
previously presented data related to SLK transplants performed
between 2002-2010. This data set is herein augmented with
additional results from 2011 and 2012. Methods: Utilizing
data provided by UNOS, we performed a retrospective review
of all SLK performed from 2002-2012, analyzed the percent-
age of SLK performed in each region based on total number of
liver transplants (LT) performed, the ratio of % SLK performed
to mean MELD at the time of transplantation, and assessed
rate of change in number of SLK by year by region. Results:
During this time period, 3,865 SLK and 56, 693 isolated LT
were performed. Nationally, the ratio of SLK to LT was 6.7%.
371A
This ratio was dramatically different when comparing regions,
with the highest ratio in regions 7, 1, and 5 (13, 10, and 9%
respectively) and lowest in regions 6, 9, and 11 (3.4, 4.1,
and 4.3%). The mean increase per year in number of SLK per-
formed was 22, but also varied dramatically by region, with
an increase of 52, 50 and 35 transplants in regions 3, 7, and
5 respectively, and -3, 1, and 2 in regions 1, 6, 8. When ana-
lyzing the ratio of % of SLK versus total LT to mean MELD score
at the time of transplantation in each region, significant differ-
ences were also found, with the highest ratios in regions 7 and
1 (.394, .324) and lowest in regions 9, 6 and 11(.126, .128,
.162). Conclusions: 1) Utilization of SLK varies significantly
when comparing UNOS regions 2) The increased utilization of
SLK does not appear to correlate to increased wait list MELD
score at the time of transplantation in regions performing the
highest % of SLK. In fact, lowest utilization of SLK is occurring in
regions with some of the highest wait list MELD scores. 3) These
findings suggest that a uniform policy related to utilization of
SLK should be adopted
Disclosures:
Paul J. Gaglio - Advisory Committees or Review Panels: Merck, Vertex, Salix, BI,
BMS, Janssen; Grant/Research Support: Merck, Gilead, Vertex, Otsuka, Genen-
tech, BI; Speaking and Teaching: Merck, Gilead, Vertex, Salix, Otsuka, Janssen
Tomoaki Kato - Grant/Research Support: Novartis
The following people have nothing to disclose: Wendy Rabbenou, Sander S.
Florman, Milan Kinkhabwala, Glyn Morgan, Mark S. Orloff, Lewis Teperman,
Samantha DeLair
343
Palliative Care Utilization in ESLD Patients Denied Trans-
plant Candidacy
Sean G. Kelly, Parul D. Agarwal; Gastroenterology, University of
Wisconsin, Madison, WI
Background: End Stage Liver Disease (ESLD) is the 7th lead-
ing cause of patient mortality in the U.S. with 26,000 deaths
annually. Hepatocellular carcinoma (HCC) accounts for an
additional 18,000 deaths yearly, often occurring in the back-
ground of cirrhosis. Liver transplantation (LT) is curative, how-
ever only a minority of patients with ESLD and/or HCC are in
receipt of this treatment. Aim: To evaluate utilization of pallia-
tive care services to patients with ESLD, not deemed eligible
for LT, at a tertiary care center. Methods: A database was
created following review of LT selection meetings at our center
from 2007-2012. Suitable patients, who completed LT evalu-
ation but were deemed unsuitable for listing were identified
and included in the analysis. Patients were excluded if their
evaluation was incomplete, the patient was deceased, or did
not have follow-up care at our institution following denial of
listing. The medical chart of each patient was reviewed and rel-
evant information retrieved. Results: There were a total of 116
patients in our cohort. The average interval between denial
of LT listing and involvement of palliative care was 149 days.
Mean survival was 137 days after denial of listing, which
excludes 19 patients (15.5%) with unknown date of death. 38
patients (32.8%) were hospitalized following denial, excluding
admissions for palliative treatments. Comfort measures were
initiated in all patients prior to death, though this occurred on
date of death for 20 patients (17.2%). Following transplant
denial, the mean number of hospital stays was 0.73 among the
entire cohort and 2.66 among those with one or more stays.
The mean inpatient length of stay was 4 days among entire
cohort and 15 days among patients with one or more stays.
Nine patients (8%) required ICU care with an average LOS of
7.3 days. 69 patients (59.4%) received hospice care with an
average LOS of 22 days. 29 patients (25%) had HCC and of
those, 9 (31%) had palliative treatments. Advance directives
372A AASLD ABSTRACTS HEPATOLOGY, October, 2014

were on file for 88 patients (75.9%). Conclusions: Palliative The following people have nothing to disclose: Allison J. Kwong, Jennifer C. Lai,
Jennifer L. Dodge, John P. Roberts
care was instituted shortly after removal from waitlist or denial
of transplant candidacy in the majority of patients. One third
of patients were hospitalized after denial and inpatient status
was predictive of additional hospitalizations after denial. Fur- 345
ther studies are needed to study how best to optimize care for Predicting Recurrent Hepatocellular Carcinoma and Sur-
patients with ESLD and avoid costly interventions that fail to vival after Liver Transplantation: The importance of time
improve outcomes or quality of life. to transplant
Disclosures: Marypat Pauly1,3, Bradley Winston1,7, Jean-Luc Szpakowski1,3,
The following people have nothing to disclose: Sean G. Kelly, Parul D. Agarwal Lisa M. Nyberg1,4, David H. Smith5, Jin Sun2, Alice Ducey2, Celia
D. Clarke2, Barbara Piasecki1,6, Ruth Brentari2; 1Gastroenterol-
ogy, Kaiser Permanente, Sacramento, CA; 2National Transplant
344 Services, Kaiser Permanente, Oakland, CA; 3Northern California,
Waiting for liver transplant (LT): Outcomes for LT candi- Kaiser Permanente, Oakland, CA; 4Southern California, Kaiser
dates listed with low MELD without exception points Permanente, San Diego, CA; 5Northwest, Kaiser Permanente, Port-
land, OR; 6Colorado, Kaiser Permanete, Denver, CO; 7MidAtlan-
Allison J. Kwong1, Jennifer C. Lai2, Jennifer L. Dodge3, John P.
tic States, Kaiser Permanente, Rockville, MD
Roberts3; 1Medicine, University of California, San Francisco, San
Francisco, CA; 2Gastroenterology/Hepatology, University of Cal- Liver Transplant (LT) offers patients with Hepatocellular Car-
ifornia, San Francisco, San Francisco, CA; 3Surgery, University of cinoma (HCC) the best opportunity for cure. Waiting 6
California, San Francisco, San Francisco, CA months has been proposed to allow time for “tumor biology”
to express itself. To date, analysis has largely examined time
Background: The Model for End-Stage Liver Disease (MELD)
between listing and transplant. Our analysis took advantage
score, which estimates short-term mortality, determines priority
of an integrated system in order to look at time from diagno-
for liver transplantation (LT). However, longer-term outcomes on
sis to transplant (TDT) and evaluate factors associated with
the waitlist for patients who are initially listed with low MELD
HCC recurrence and overall survival. Methodology: This is a
scores are not well characterized. Methods: All adults listed
retrospective analysis of patients transplanted for HCC from
for primary LT at a single, high-volume LT center from 2005-12
January, 2002 -December, 2009. Patients from 5 states were
with an initial laboratory MELD between 10-21 were evalu-
transplanted at 8 different LT programs and followed from
ated. Excluded were those listed with MELD exception points,
diagnosis for at least 4 years post-transplant or until death or
who underwent living donor LT (LDLT) or transplant at another
re-transplant. Age, gender, Alpha fetoprotein at transplant, lab
center, or who were removed from the waitlist for non-medical
data, number and size of lesions, number of local regional
reasons. Patients were followed through 3/30/2014. Out-
therapy (LRT), and explant data was analyzed. We compared
comes and causes of death were identified by UNOS and
groups using Fisher’s exact test for categorical variables and
confirmed through an electronic medical record review. Multi-
Wilcoxon rank-sum test for continuous variables. Risk factors
variable logistic regression evaluated predictors of death com-
for recurrence were analyzed using Cox proportional hazard
pared to deceased donor liver transplantation (DDLT). Results:
models. Kaplan-Meier analysis was used to estimate overall sur-
654 patients were listed from 2005-12 with initial laboratory
vival and time to recurrence for 4 different groups of patients.
MELD 10-21 and without exception points: median age was
Results: 1,416 patients underwent LT from Jan 2002- Dec
55 years [interquartile range (IQR) 50-60], 65% were male,
2009; 367 had HCC. Of 292 in the final cohort; 77% were
median MELD score at listing was 15 (IQR 13-17). By the end
male, 78% within Milan, median last AFP prior to transplant
of follow-up, 24% had undergone DDLT at a median wait-time
was 11.8 ng/ml (IQR: 5.12-57.9). 10.6% had recurrent HCC
of 11 months (IQR 5-20). 34% died at a median wait-time
of whom 55% were males and 83% were within Milan. On
of 15 months (IQR 7-29). Among the 106 patients for whom
univariate analyses, gender, TDT, last pre-transplant AFP, and
cause of death could be identified, 82% died of causes that
number of tumors on explant were predictors of HCC recur-
could be specifically related to end-stage liver disease or the
rence. In a multivariate Cox regression model, last pre-trans-
development of hepatocellular carcinoma. Those who died ver-
plant AFP >400, female gender, and increased number of
sus those who underwent DDLT differed by age (mean 56 vs.
tumors on explant were statistically significantly associated with
54 years, p=0.03) but were similar in terms of gender, race,
higher HCC recurrence. TDT missed significance (p=0.12.)
and etiology of liver disease. Median MELD at DDLT vs. death
Kaplan-Meier analysis showed survival of 63.4% and 32.8%
was 28 (IQR 19-36) vs. 21 (IQR 15-30) [p<0.01]. In univari-
at 18 and 48 months respectively for those with recurrence
able logistic regression, predictors of death vs. DDLT were age
compared to 91.7% and 87.8% for those without recurrence.
(OR 1.03 per year, p=0.03), liver disease due to alcohol use
Recurrence was highest (40.9%) among patients with AFP >
(OR 2.7, p=0.04), bilirubin at the time of listing (OR 0.87
400, independent of TDT; and lowest (7.3%) among those
per mg/dL, p=0.001), and initial weight (OR 0.98 per kg,
with AFP of less than 400 and TDT > 6 months. Conclusion:
p=0.002). In multivariable logistic regression, only age and
Patients with AFP>400 had the highest HCC recurrence rate
initial weight were predictive of death vs. DDLT. Conclusion: LT
independent of TDT. In patients with AFP <400 those trans-
candidates listed with a laboratory MELD 10-21 who ultimately
planted >6m after diagnosis had the lowest recurrence and the
die on the wait-list experience longer wait-times than patients
highest survival. This may strengthen the argument to ablate
who survive to DDLT. However, patients with low MELD scores
and wait. Although TDT failed to reach statistical significance it
at the time of listing remain at significant risk for death due to
is one factor that can be controlled and may become important
liver-related causes and may benefit from more timely access to
in considering optimal time to transplant.
transplantation, such as LDLT or acceptance of high-risk donor
Disclosures:
livers. Predictors of death compared to transplantation may
Lisa M. Nyberg - Grant/Research Support: Merck, Vertex, Gilead, Abbvie, Bris-
allow for early identification of patients who are at risk for tol Myers Squibb
waitlist mortality.
The following people have nothing to disclose: Marypat Pauly, Bradley Winston,
Disclosures: Jean-Luc Szpakowski, David H. Smith, Jin Sun, Alice Ducey, Celia D. Clarke,
Barbara Piasecki, Ruth Brentari
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
346
Value Of Preoperative Evaluation Of Cadavaric Liver
Donors With Transient Elastography In Marginal Liver
Donors
Remy Schwarzer, Simona Bota, Rafael Paternostro, Jagdeep
Singh, Tamara Braunschmid, Ferdinand Mühlbacher, Clemens
Kietaibl, Thomas Reiberger, Mattias Mandorfer, Michael Trauner,
Markus Peck-Radosavljevic, Gabriela Berlakovich, Arnulf Ferlitsch;
Gastroenterology and Hepatology, Medical University of Vienna,
Vienna, Austria
Aim The preoperative decision whether a graft is suitable for
orthotopic liver transplantation (OLT),finally judged during
organ harvesting, can be difficult.We aimed to analyze the
value of transient elastography(TE) in the selection of eligible
liver grafts of marginal donors. Methods All potential cadav-
eric liver donors who were reported at the Medical University
Vienna between 2012 and 2014 were evaluated by TE for
liver stiffness(LS). LS was assessed in all donors after brain
death at the intensive care unit. All measurements included had
at least 10 valid tracings. Poorly reliable measurements accord-
ing the definition of Boursier et al. 2013 (Hepatology) give at
least Journal and year were excluded from our study. Marginal
donors were classified according the definition of Eurotrans-
plant: age (>65 years), BMI (>30), Time of ventilation (>7
days), Serum sodium (>165mmol/L), Serum ASAT (>105U/L),
Serum ALAT (>90U/L) and Serum Bilirubin (>3mg/L). Results
44 potential donors (including 29 marginal donors, 66.0%)
were screened. 33 grafts were finally selected for OLT includ-
ing 12 non-marginal (12/15; 80%) and 21 marginal (21/29,
72.4%) grafts. In marginal donors median LS were 7.6 kPA(IQR
6.2-10.9)(range2.9-20) in livers selected for transplantation
and 10.9 kPA(IQR 7.5-12.1)(range 5.6-20) in excluded livers
(p<0.05). LS showed good correlation with macroscopic find-
ing such as edge, surface and consistence (Table 1). In grafts
with normal edge LS were 7.3kPa (range3.9-20) in grafts suit-
able for oLT (20/22 donors) and 13.8 kPA (range7.9-19.6) in
grafts refused for oLT (2/22 donors).In grafts with abnormal
edge LS were 6.7kPa (range2.9-8.2) in grafts suitable for oLT
(4/12 donors) and 10.9 kPA (range5.6-19.8) in grafts refused
for oLT (8/12 donors). Results for surface and consistence are
displayed in table 1. Table 1 (please see Images) Conclusions
LS can be helpful to identify potential deceased marginal liver
donors. FurthermoreTE might be a valuable tool to identify suit-
able grafts among donor livers with abnormal macroscopic
findings.
Disclosures:
Simona Bota - Speaking and Teaching: Janssen Pharmaceutica, Boehringer Ingel-
heim, Bristol-Myers Squibb
Thomas Reiberger - Grant/Research Support: Roche, Gilead, MSD, Phenex;
Speaking and Teaching: Roche, Gilead, MSD
Mattias Mandorfer - Consulting: Janssen ; Grant/Research Support: Roche, MSD;
Speaking and Teaching: Boehringer Ingelheim, Roche, Bristol-Myers Squibb,
Janssen
Michael Trauner - Advisory Committees or Review Panels: MSD, Janssen, Gilead,
Abbvie; Consulting: Phenex; Grant/Research Support: Intercept, Falk Pharma,
Albireo; Patent Held/Filed: Med Uni Graz (norUDCA); Speaking and Teaching:
Falk Foundation, Roche, Gilead
373A
Markus Peck-Radosavljevic - Advisory Committees or Review Panels: Bayer, Gil-
ead, Janssen, BMS, AbbVie; Consulting: Bayer, Boehringer-Ingelheim, Jennerex,
Eli Lilly, AbbVie; Grant/Research Support: Bayer, Roche, Gilead, MSD; Speak-
ing and Teaching: Bayer, Roche, Gilead, MSD, Eli Lilly
The following people have nothing to disclose: Remy Schwarzer, Rafael Pater-
nostro, Jagdeep Singh, Tamara Braunschmid, Ferdinand Mühlbacher, Clemens
Kietaibl, Gabriela Berlakovich, Arnulf Ferlitsch
347
Significance of Initial Poor Function after Liver Trans-
plantation
Gilles Uijtterhaegen1, Thamara Perera2, Jan R. Colpaert1, Hans
Van Vlierberghe3, Roberto Troisi1, Xavier Rogiers1, Darius Mirza2;
1Hepatobiliary Surgery, Ghent University Hospital, Ghent, Bel-
gium; 2Liver Unit, Queen Elizabeth Hospital Birmingham, Birming-
ham, United Kingdom; 3Hepatology, Ghent University Hospital,
Ghent, Belgium
Introduction: Initial poor function (IPF) is a term used to describe
temporary malfunction of the transplanted liver. Over 15 differ-
ent definitions of IPF can be found in the literature and there is
only a few cases in which its impact on survival is described. In
this paper we try to evaluate the impact of different definitions
of IPF on long term survival. Materials and methods: Two-hun-
dred-fifty-seven transplantations performed between July 2007
and October 2009 at Queen Elizabeth Hospital Birmingham
were analysed. A four year survival analysis was performed
for five definitions of IPF after transplantation. Transplantations
performed with DBD (219) or DCD (38) livers were analysed
separately. LDLT, transplantation in children, and retransplan-
tation were excluded. Results: Primary non function occurred
in four cases (1,5%). The rate of IPF differed from 13,0% to
41,5% depending on the definition used. In patients trans-
planted with DBD livers, only one definition showed a signifi-
cant difference (p=0.021) in patient survival. The results show
that the difference in survival occurs in the first 6 months after
survival. In a six months survival analysis three of the five defi-
nitions show a significant difference in survival, but the most
significant definition is the definition of Strasberg (p=0.004),
based on transaminase-level, INR and bilirubin. Conclusion:
This study shows that IPF is an important risk factor for death
after transplantation. Of the five analysed definitions there is
only one definition showing a strong influence on survival. The
IPF definition of Strasberg is the definition of choice to select a
large patient group at risk for death.
Disclosures:
The following people have nothing to disclose: Gilles Uijtterhaegen, Thamara
Perera, Jan R. Colpaert, Hans Van Vlierberghe, Roberto Troisi, Xavier Rogiers,
Darius Mirza
374A AASLD ABSTRACTS
348
WITHDRAWN
349
Clinician Assessments of Health Status Predict Need for
Liver Transplant (LT) Independent of MELD, Especially in
Women
Jennifer C. Lai, Kenneth E. Covinsky, Hilary Hayssen, Blanca C.
Lizaola, John P. Roberts, Norah Terrault, Sandy Feng; UCSF, San
Francisco, CA
Background: MELD predicts 90-day risk of death in cirrhotics
and is currently used to prioritize candidates for LT. Yet, one in
5 LT candidates dies on the wait-list. We aimed to determine
whether hepatologist assessments of health status could pre-
dict need for LT independent of MELD. Methods: From 2012-
13, primary hepatologists(MD) of all adult cirrhotics listed for
LT with lab MELD≥12 at an LT clinic were asked at the visit:
“How would you rate your patient’s overall health today, com-
pared to others with cirrhosis, on a 5-point scale (0=excel-
lent, 5=very poor)?” MDs were categorized by years(y) of
hepatology practice (≥5 vs <5y). Logistic regression assessed
the odds of the primary outcome death/delisting for being
too sick for LT. Area under receiver operating characteristic
(AUROC) curves assessed the ability of MELD and MD ratings
to predict death/delisting. Results: 345 LT candidates were
followed for a mean(SD) of 11(7) months: 35% female, mean
age 58(9)y, 22% hepatocellular carcinoma. Mean(SD) MELD
was 17(4), 34% ascites, 23% encephalopathy. Mean(SD) MD
rating was 2.4(1.3). The association between MD rating and
MELD was ρ=0.28 (p<0.01). 50(15%) died/were delisted.
Regardless of MELD, MD rating ≥3(“poor”) was associated
with a significantly increased risk of death/delisting (Figure).
MD AUROCs were similar by yrs in practice (≥5y: 0.68 vs
<5y: 0.61; p=0.62) and did not differ from MELD AUROC
(MD 0.68; 95%CI 0.59-0.77 vs MELD 0.60; 95%CI 0.51-
0.69; p=0.12). However, MDs were superior in predicting
death/delisting of female candidates (MD 0.76; 95%CI 0.63-
0.88 vs. MELD 0.56; 95%CI 0.43-0.70; p=0.02). Conclu-
sions: Clinicians, regardless of years in practice, can identify LT
candidates at high risk of death/delisting – particularly women
– independent of MELD. Objectifying this “eyeball test” may
inform interventions targeted at this vulnerable subgroup and
mitigate gender disparities in LT.
Disclosures:
Norah Terrault - Advisory Committees or Review Panels: Eisai, Biotest; Con-
sulting: BMS, Merck; Grant/Research Support: Eisai, Biotest, Vertex, Gilead,
AbbVie, Novartis, Merck
HEPATOLOGY, October, 2014
The following people have nothing to disclose: Jennifer C. Lai, Kenneth E. Covin-
sky, Hilary Hayssen, Blanca C. Lizaola, John P. Roberts, Sandy Feng
350
Transplant-needed alcoholic cirrhosis: which patients
can reach the transplant waiting list? A preliminary
case-control study
Benjamin Rolland1, Anne Clerget1, Alexandre Louvet2, Sébastien
Dharancy2, Philippe Mathurin2, Olivier COTTENCIN1; 1Addiction
Medicine, University Hospital of Lille, Lille cedex, France; 2Hepa-
tology, Univ Hospital of Lille, Lille, France
INTRODUCTION: Alcoholic liver disease (ALD) may require
orthotopic liver transplantation (OLT), in which case patients
should durably and resolutely maintain alcohol abstinence
before being placed on the transplant waiting list (TWL). In this
context, the individual features underlying whether a subject
will succeed in stopping alcohol and thus been placed on the
TWL are poorly studied. We hypothesized that the previous
psychiatric history and the severity of the alcohol use disorder
(AUD) of patients may contribute to determine the drinking
outcome after patients have been acquainted with the necessity
of OLT. METHODS: between January 1, 2013 to September
1, 2013, among all the cirrhotic patients aware of the need
for OLT for at least 6 months and who met consensual criteria
for OLT, we retrospectively defined two groups of subjects: A)
the ‘TWL’ patients who, at the assessment time: 1) had been
abstinent for at least 3 months and 2) had been placed on
the TWL; and B) the ‘non-TWL’ patients who: 1) still met the
DSM-5 criteria for AUD; 2) had not been placed on TWL. In
each patient were assessed: 1) the psychiatric history, using
the mini international neuropsychiatric interview 5.0 (MINI), 2)
the number of DSM-5 criteria for AUD over the year preceding
the last alcohol consumption. Direct between-group compari-
sons were performed. Informed written consent was obtained
from patients and the study protocol was approved by a local
ethics committee. RESULTS: in the ‘non-TWL’ group (n= 18),
by comparison with the TWL group (n=26), the mean age was
49.3 ± 10.1 vs. 53.1 ± 10.2 years (p=0.22), and the sex ratio
was 11% vs. 28% females (p=0.08). The presence of lifelong
psychiatric disorders was 55.6% vs. 6% (p<.001). Notably,
44.4% on-TWL subjects exhibited mood disorder. The number
of DSM-5 criteria for AUD was 7.27 ± 2.0 in non-TWL subjects
vs. 2.5 ± 3.3 (p<.001) in TWL subjects. Overall, the item “Giv-
ing up important social, occupational or recreational activities
because of alcohol use” was found in 83.3% patients of the
non-TWL group, vs. 23% of the TWL group (p<.0001). CON-
CLUSION: these preliminary findings suggest that patients with
psychiatric history, especially mood disorders, and with a high
number of DSM-5 criteria were more unlikely to reach TWL.
Protracted history of social or occupational consequences of
alcohol misuse was particularly associated with difficulty to
quit drinking. While systematic psychiatric and addiction eval-
uation is recommended before OLT, i.e., in patients already
placed on the TWL, patients who are unable to spontaneously
fulfill the abstinence prerequisites for TWL should also be con-
sistently evaluated.
Disclosures:
Benjamin Rolland - Consulting: Ethypharm; Grant/Research Support: Ethypharm;
Speaking and Teaching: Lundbeck, RB Pharma, AstraZeneca, Servier
Sébastien Dharancy - Board Membership: NOVARTIS; Speaking and Teaching:
ROCHE, ASTELLAS
Philippe Mathurin - Board Membership: Schering-Plough, Janssen-Cilag, BMS,
Gilead, Abvie; Consulting: Roche, Bayer, Boehringer
The following people have nothing to disclose: Anne Clerget, Alexandre Louvet,
Olivier COTTENCIN
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
351
The Impact of an Institutional Change in Prothrombin
Time Methodology on INR and MELD Scores in Liver
Transplant Evaluations
Dennis Kumral1, Nicolas M. Intagliata2, Neeral L. Shah2, Stephen
H. Caldwell2, Patrick G. Northup2, Curtis K. Argo2; 1Internal Med-
icine, University of Virginia, Charlottesville, VA; 2Gastroenterology
and Hepatology, University of Virginia, Charlottesville, VA
Background: Allocation of liver grafts based on the model for
end-stage liver disease (MELD) has been questioned because
the prothrombin time (PT) measurement in cirrhosis patients may
change with different commercially available thromboplastin
reagents due to variations in the international sensitivity index
(ISI). This can result in inter-laboratory variation in international
normalized ratio (INR) and subsequently MELD scores (Am J
Transplant 2007, 7:1624-28; Liver Int 2008, 28:1344-51).
On April 1, 2013, our hospital laboratory electively changed
the thromboplastin used in the PT/INR from PT-HS (ISI of 1.464)
to Recombiplastin (ISI of 0.870). Theoretically, this change
would yield lower INR and MELD scores in cirrhosis patients at
our institution and thus impact accessibility to organs. Methods:
27 patients listed for liver transplant between April 1, 2012-
March 31, 2013 (Cohort A) were compared to 36 patients
listed between April 1, 2013 and March 31, 2014 (Cohort
B). Two patients from Cohort A and 5 patients from Cohort B
were listed due to hepatocellular carcinoma (HCC)-exception.
Creatinine, total bilirubin, and INR were recorded from our
clinical laboratory near the time of listing and used to calcu-
late native MELD scores for both groups. Student’s t-tests were
performed to compare mean INR and MELD scores from the
two cohorts. Results: Patients in Cohort A had a mean INR of
1.41 and mean MELD of 13.9 compared to Cohort B with a
mean INR of 1.39 and mean MELD of 13.8. Student’s t-tests
showed no statistically significant difference in INR (p = 0.799)
or MELD (p = 0.955) between cohorts. Conclusion: Variations
in laboratory methodologies, such as a change in the thrombo-
plastin reagent used to determine PT/INR, could affect native
MELD scores; therefore, we expected overall INR and MELD
scores to decrease following the change to a thromboplastin
with a lower ISI. On the contrary, we found no evidence of
a major trend in these values before and after the change in
thromboplastin, supporting the relative robustness of the MELD.
However, a limitation of this study was that our patients had
INR values on the lower end of spectrum in both cohorts and
inter-laboratory variability of INR has been shown to be greater
with higher mean INRs (Am J Transplant 2007, 7:1624-280).
Disclosures:
Neeral L. Shah - Grant/Research Support: Boehringer Ingelheim
Stephen H. Caldwell - Advisory Committees or Review Panels: Vital Therapy;
Consulting: Wellstat diagnostics; Grant/Research Support: Genfit, Gilead Sci-
ences
Patrick G. Northup - Grant/Research Support: Hemosonics, Bristol Meyer Squibb
Curtis K. Argo - Consulting: Wellstat Diagnostics; Independent Contractor:
Genentech/Roche
The following people have nothing to disclose: Dennis Kumral, Nicolas M. Inta-
gliata
375A
352
iPod Video Games Training Improves Overall Cognitive
Performance in Patients with Covert Hepatic Encepha-
lopathy
Jasmohan S. Bajaj1, Leroy Thacker3, Douglas M. Heuman1, James
Hovermale1, Edith A. Gavis1, HoChong Gilles1, Melanie White1,
James Wade2; 1Gastroenterology, Hepatology and Nutrition, VCU
and McGuire VAMC, Richmond, VA; 2Psychiatry, VCU Medical
Center, Richmond, VA; 3Biostatistics, VCU Medical Center, Rich-
mond, VA
Despite its adverse impact on daily functioning, drug therapy
for covert HE(CHE) is not standard. Therefore, non-drug strat-
egies for improving cognition are needed. Aim:Evaluate if
cognitive rehabilitation with video games improves cognitive
performance in domains that are within &outside the training
focus. Methods: CHE cirrhotics were recruited for an 8 week
trial with 4 visits. During all visits, pts were given different
versions of standard CHE tests [inhibitory control ICT: lures/
targets outcomes & Number connection A/B NC-A/B, Digit
symbol DS & Block design tests BD) with an unrelated cognitive
measure (Hopkins Verbal learning HVLT: outcomes delayed/
total recall). Visit 1 & 2 were 2 wks apart without any inter-
vention to gauge learning. At visit 2 an iPod was given with 2
games: IQ Boost (working memory task levels 2-4 difficulty) &
Arcade Challenge (psychomotor accuracy; levels:0-100) that
are related to CHE domains. Pts were told to play the games for
≥30min/day for 4 wks; progress was recorded in the iPod. All
tests were repeated at visit 3 &iPod returned. Visit 4 occurred
2 wks later to gauge cognition without the iPod. Cognitive
analysis on tests related to video game domains (CHE tests)
& the unrelated domain (HVLT) were performed. Results: 20
CHE pts(12 men, 56 yrs, MELD 10) were recruited. There was
a significant improvement in NC-A/B, DS & BD between visits
1 & 2 showing a learning effect without further change during
the study (table). ICT lures/targets that correspond to the iPod
games, improved significantly only when the iPod games were
played and returned to baseline after the iPods were returned.
iPod games: Mean peak difficulty level reached on iPod games
was 3 for IQBoost and 78 for Arcarde Challenge with mean
45±18 min/day of use. HVLT: there was a significant improve-
ment in the test unrelated to CHE or iPod games on delayed
recall. 27% of pts’ performance became normal from impaired
at visit 4 after iPod (p<0.004). A non-significant trend towards
increased total recall after the iPod games was seen. Conclu-
sion: Cognitive rehabilitation using iPod video games improves
cognitive performance in related as well as unrelated domains
of verbal learning in cirrhotics with CHE.
Cognitive improvement in Domains Related&Unrelated to Games
#p<0.05 visit 1 vs 2, *p<0.05 before/after games, †p<0.05
after games stopped
High score on lures/NC-A/B=poor cognition
High score on rest=good cognition
Disclosures:
Jasmohan S. Bajaj - Advisory Committees or Review Panels: Salix, Merz, otsuka,
ocera, grifols, american college of gastroenterology; Grant/Research Support:
salix, otsuka, grifols
376A AASLD ABSTRACTS
Douglas M. Heuman - Consulting: Bayer, Grifols, Genzyme; Grant/Research
Support: Exilixis, Novartis, Bayer, Bristol Myers Squibb, Scynexis, Ocera, Mann-
kind, Salix, Globeimmune, Roche, SciClone, Wyeth, Otsuka, Ikaria, UCB, Cel-
gene, Centocor, Millenium, Osiris; Speaking and Teaching: Otsuka, Astellas
HoChong Gilles - Speaking and Teaching: Bayer/Onyx
The following people have nothing to disclose: Leroy Thacker, James Hovermale,
Edith A. Gavis, Melanie White, James Wade
353
The role of probiotics in the treatment of minimal
hepatic encephalopathy. A prospective, randomized,
placebo-controlled, double-blind study
Jiannis Vlachogiannakos1, Panayota Vasianopoulou2, Nikos Via-
zis2, Matilda Chroni3, Theodoros Voulgaris1, Spiros D. Ladas1,
Dimitrios G. Karamanolis2; 1Academic Department of Gastroen-
terology, University of Athens, Medical School, Laiko General
Hospital, Athens, Greece; 2Department of Gastroenterology,
Evangelismos General Hospital, Athens, Greece; 3Otolaryngology
Department, Evangelismos General Hospital, Athens, Greece
Background - Aim: Minimal hepatic encephalopathy (MHE)
is the mildest form in the spectrum of hepatic encephalopathy
(HE) and describes patients with cirrhosis who have no clinical
symptoms of brain dysfunction but perform worse on psycho-
metric tests compared with healthy subjects. It is considered an
important disorder that may seriously impair daily functioning
and quality of life in patients with cirrhosis. In this prospective
study, we investigated the potential role of a probiotic in the
treatment of MHE, in patients with cirrhosis. Methods: In a
period of 18 months, we screened 142 consecutive patients
without overt HE for MHE using both, psychometric (number
connection test, NCT) and neurophysiological (brainstem audi-
tory evoked potentials, BAEP) modalities. MHE was defined by
abnormality on at least one test modality. Seventy eight (55%)
patients diagnosed with MHE and 72 of them were equally ran-
domized into Lactobacillus plantarum 299v at a dose of 1010
units per sachet (Lp299v) or identical placebo, given twice a
day for a period of 12 weeks. All tests were repeated on the
12-week visit. Results: Seventy two patients (62 men, mean
(SD) age: 59 (10), 58% alcoholic cirrhosis, mean (SD) Child-
Pugh score: 6.4 (1.6), 46% Child-Pugh A, mean (SD) MELD
score: 11.9 (3.6)) were randomized to receive Lp299v (n=37)
or placebo (n=35). At baseline, there were no significant dif-
ferences between the groups in demographics, liver function
tests, serum fasting NH3 levels or performance of psychomet-
ric and neurophysiological tests. One patient in the placebo
group withdrew consent. Two patients in the Lp299v group
and one patient in the placebo group stopped study because
of side-effects. Six patients in the placebo group versus none in
the Lp299v group developed overt HE during the 12-week trial.
The adherence of patients who completed the study was excel-
lent (>80%). After 12 weeks, MHE was reversed in 21 patients
(57%) of the probiotic group but in only 3 patients (8.6%) who
received placebo and the difference was statistically significant
(p<0.001). Moreover, the performance of the NCT test signifi-
cantly improved in the treatment group (p=0.02) as well as the
performance of the BAEP (p=0.03). Serum fasting NH3 levels
significantly decreased in the treatment group (p=0.015) while
no changes were found in the placebo group. Conclusions:
We have shown that the administration of a probiotic (Lp299v)
achieved a significant rate of MHE reversal compared to pla-
cebo in patients with liver cirrhosis and it might be considered
as a valuable alternative for the treatment of MHE.
Disclosures:
Dimitrios G. Karamanolis - Grant/Research Support: Roche, Merck Sharp and
Dome
HEPATOLOGY, October, 2014
The following people have nothing to disclose: Jiannis Vlachogiannakos, Pan-
ayota Vasianopoulou, Nikos Viazis, Matilda Chroni, Theodoros Voulgaris, Spi-
ros D. Ladas
354
Differential expression of neurodegeneration related
genes in a new model of episodic hepatic encephalop-
athy
Teresa García-Lezana1,2, Jordi Romero-Giménez1, Laia Cha-
varria1,2, Marc Oria1,2, Joan Genescà1,2, Juan Cordoba1,2;
1Liver Unit, Institut de Recerca Hospital Vall Hebron. Universitat
Autònoma de Barcelona, Barcelona, Spain; 2Centro de Investi-
gación Biomédica en Red de Enfermedades Hepáticas y Digesti-
vas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
Introduction. Hepatic encephalopathy (HE) is a severe compli-
cation of cirrhosis classically considered as a reversible meta-
bolic disease. However, recent studies suggest that repeated
episodes of HE could cause permanent damage to brain tissue
and neuronal loss. The aims of our study are the development
of a new animal model of episodic HE, triggered by hyperam-
monaemia or/and peripheral inflammation, that would repro-
duce the neurological impairments found in patients and the
identification of neurodegeneration evidences by differential
gene expression analysis. Materials & methods. Portocaval
anastomosis (PCA) operated rats underwent a 6 months drug
treatment to simulate episodic HE. From fourth weeks after sur-
gery rats were regularly administered every two weeks: a sin-
gle dose of ammonium acetate (55mM/kg x min) to increase
blood ammonia or LPS (3mg/Kg) to trigger inflammation,
a combined dose of LPS + ammonium acetate or vehicle.
Sham-operated rats were treated with vehicle following the
same schedule. In order to measure neurological impairments,
throughout the treatment, 12 different reflexes were checked
in each animal at baseline and 3 hours after infusion and the
number of positive reflexes was recorded. At the end of the
treatment animals were sacrificed and brains removed for the
study of gene expression in cortex and cerebellum. Results.
Animals administered ammonium acetate showed a significant
loss of reflexes between baseline stage and 3h post-infusion
(pre-infusion = 12; post-infusion = 9; P=0,0025), at least 50%
of reflexes disappeared in 36% of those animals. Gene expres-
sion analysis revealed, in ammonium acetate treated rats, a
down regulation of genes related with neurodegeneration as
Adora2 in cortex and a remarkable up regulation of trastiretin
(TTR) in cerebellum, a gene associated with human amyloido-
sis, (Fold Change TTR = 17.4). LPS-treated animals exhibited
an overexpression of several inflammation related genes: C3,
CXCL13 and LCN2 (Fold Change: Cortex = 3.3; Cerebellum
= 3.4). In both cases gene expression was compared with
sham-operated controls and data validated by Real-Time PCR.
Conclusion. This new model of HE reproduces neurological
disturbances after simulated episodes of HE with ammonia as
a precipitant factor. The changes observed by gene expression
analysis in cerebellum suggest that, motor impairments could
be caused by the damaging effects of ammonia overdose in
neurons of central nervous system.
Disclosures:
The following people have nothing to disclose: Teresa García-Lezana, Jordi
Romero-Giménez, Laia Chavarria, Marc Oria, Joan Genescà, Juan Cordoba
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
355
Ammonia acts as a damage associated molecular pat-
tern (DAMP) producing multi organ injury and inflam-
mation through a Toll-Like-Receptor-4 (TLR4) dependent
pathway
Yalda Sharifi1, Gavin Wright1,2, Francesco De Chiara1, Nathan
Davies1, Laia Chavarria3, Marc Oria1,3, Francesco Scaravilli4,
Rajiv Jalan1; 1Hepatology, Institute of liver and Digestive Health,
London, United Kingdom; 2Hepatology, Basildon & Thurrock Uni-
versity Hospital, Essex, United Kingdom; 3Malalties Hepatiques,
Val Hebron Institut de Recerca (VHIR), Barcelona, United Kingdom;
4Institute of Neurology, UCL, London, United Kingdom
Background: Ammonia is thought to be central in the pathogen-
esis of hepatic encephalopathy (HE) but recent studies suggest
that ammonia may have pleiotropic effects and be involved
in the pathogenesis of portal hypertension, immune dysfunc-
tion and cachexia of liver failure. The mechanisms of these
deleterious effects of ammonia remain uncertain. In previous
studies, a close synergy between ammonia and inflammation
has been demonstrated but the mechanism of this synergy is
uncertain. TLR4 is a ubiquitous receptor for several ligands and
signalling through this is associated with activation of NFkB
and cytokine production. The aims of this study were to test the
hypothesis that ammonia acts as a DAMP, which may induce
multi-organ dysfunction acting through the TLR4 mediated
pathway. We also aimed to determine whether TLR4 in the
brain was important in modulating brain ammonia metabolism
and swelling. Materials and Methods: 4 groups of mice were
studied: Wild-type control (WT, n=10), WT-hyperammonemia
(WT-NH3, n=10), TLR4-/- control (TLR4-KOC, n=6), TLR4-/-+
hyperammonemia (TLR4-/—NH3, n=13). Hyperammonemia
was induced with addition of 0.2 M ammonium chloride to
drinking water, 3-days after which they were sacrificed and
plasma and brain collected for biochemical and histological
analysis.1HNMR of the isolated cortex was performed to study
the brain metabolism of ammonia. Results: Induction of hyper-
ammonemia to pathophysiological concentrations (340.9 ± 32
WT-NH3, 247.6± 18.7 TLR4-/—NH3 ) resulted in significant
liver (albumin 30.3± 0.9 WT-NH3 vs 26.27± 0.9 TLR4-/—
NH3, urea 8.3± 0.1 WT-NH3 vs 7.2± 0.4 TLR4-/—NH3 ) and
renal (creatinine) injury (11.84±0.7 WT-NH3 vs 7.19± 0.3
TLR4-/—NH3) in WT mice, which was significantly abrogated
in the TLR4-KO mice (p<0.006, p<0.001, p<0.0001 respec-
tively). Hyperammonemia resulted in a significant increase in
brain water in WT animals, which was significantly reduced in
the TLR4-KO cohort (p 0.05).1H NMR spectroscopy of the corti-
cal brain revealed that lactate and glutamine were significantly
lower in hyperammonemic WT vs groups TLR4-/- (p<0.05,
p<0.004 respectively). Conclusion: The results of this study
strongly support the concept that ammonia act as a DAMP
producing multiple organ injury and inflammation through a
TLR4 dependant pathway. For the first time, the data from this
study show that TLR4 modulates brain ammonia metabolism
and accumulation of lactate and glutamine leading to brain
swelling explaining the synergy between ammonia and inflam-
mation in the pathogenesis of HE. We conclude that TLR4 inhi-
bition may reduce ammonia induced brain swelling and is
therefore an important target of therapy.
Disclosures:
Nathan Davies - Patent Held/Filed: UCL
Rajiv Jalan - Consulting: Ocera Therapeutics, Conatus; Grant/Research Support:
Grifols, Gambro
The following people have nothing to disclose: Yalda Sharifi, Gavin Wright,
Francesco De Chiara, Laia Chavarria, Marc Oria, Francesco Scaravilli
377A
356
Portal hypertension due to outflow block in non-cirrhotic
patients with nonalcoholic fatty liver disease
Yohei Koizumi1, Masashi Hirooka1, Hironori Ochi1, Fujimasa
Tada1, Teruki Miyake1, Yoshio Tokumoto1, Atsushi Hiraoka2,
Masanori Abe1, Bunzo Matsuura1, Yoichi Hiasa1; 1Department
of Gastroenterology and Metabology, Ehime University Gradu-
ate School of Medicine, Toon, Japan; 2Gastroenterology Center,
Ehime Prefectural Central Hospital, Matsuyama, Japan
Background and aims: The aim of this study was to prospec-
tively evaluate whether the characteristics of hepatic blood flow
change in patients with nonalcoholic fatty liver disease (NAFLD)
occurred at a milder stage of fibrosis compared with patients
with chronic hepatitis due to hepatitis C virus (CH-C). Methods:
A total of 995 subjects were enrolled. Hepatic blood flow was
measured by Doppler ultrasonography, and the arterio-portal
ratio (A/P ratio) was calculated. Elasticity of the spleen was
measured, and the SEP score (splenic elasticity ×1.63-2.88)
was calculated. In a pilot study, hepatic blood flow was mea-
sured in 142 patients with NAFLD and 121 patients with CH-C
diagnosed histologically. In a validation set, hepatic blood
flow was measured in 753 subjects with NAFLD based on ultra-
sonographic findings to confirm accuracy and reproducibility.
The institutional review board approved this study, and patients
provided written informed consent prior to entry into the study.
Results: In the NAFLD group, median A/P ratios in F0, F1, F2,
F3, and F4 patients were 1.8, 2.0, 2.5, 3.2, and 3.7, respec-
tively. The A/P ratio was significantly higher in stage 2 than in
stage 0 patients with NAFLD (P<0.01). In the CH-C group, the
A/P ratio was significantly increased in stage 3 than in stages
0, 1, and 2. Increased splenic elasticity was also observed
at earlier stages of fibrosis in patients with NAFLD than in
those with CH-C. Median A/P ratios in F0, F1, F2, F3, and F4
patients were 1.3, 1.7, 1.9, 2.5, and 3.6, respectively, in the
CH-C group. As for the A/P ratio, the SEP score increased with
increased severity of hepatic fibrosis. Median SEP scores in
F0, F1, F2, F3, and F4 patients were 2.9, 3.8, 4.3, 5.4, and
10.7, respectively, in the NAFLD group, and 3.6, 4.4, 4.5,
7.7, and 11.7, respectively, in the CH-C group. Associations
between thrombocytopenia and change in hepatic blood flow
and SEP score were assessed. The A/P ratio was significantly
increased in patients with platelet count <200,000/μL in the
NAFLD group, while this ratio was increased in patients with
platelet count <160,000/μL in the CH-C group. This hepatic
hemodynamic change was also observed in the larger valida-
tion group. In NAFLD patients with mild thrombocytopenia,
pericellular fibrosis was the only significant predictor of hepatic
hemodynamic change on multivariate analysis. Conclusions:
Alteration of hepatic blood flow occurred from an earlier
stage of hepatic fibrosis in NAFLD patients than in with CH-C
patients. This alteration was observed even in patients with
mild thrombocytopenia due to NAFLD and appeared related to
outflow block in the sinusoidal area.
Disclosures:
The following people have nothing to disclose: Yohei Koizumi, Masashi Hirooka,
Hironori Ochi, Fujimasa Tada, Teruki Miyake, Yoshio Tokumoto, Atsushi Hira-
oka, Masanori Abe, Bunzo Matsuura, Yoichi Hiasa
378A AASLD ABSTRACTS
357
Adrenal insufficiency is associated with the clinical out-
come in patients with decompensated cirrhosis
Evangelos Cholongitas1, Ioannis Goulis1, George Kokkonis1,
Parthenis Chalevas1, Spyros Gerou2, Evangelos Akriviadis1; 14th
Department of Internal Medicine, Medical School of Aristotle Uni-
versity, Thessaloniki, Greece; 2Analysis Medical SA, Thessaloniki,
Greece
Background: Although the pathogenesis and the clinical
impact of adrenal insufficiency (AI) in patients with decom-
pensated cirrhosis (DeCi) have not been fully elucidated, a
recent study showed that AI is associated with impairment of
circulatory function and higher probability of sepsis (Acevedo
J et al, Hepatology 2013) Aim: to evaluate the association
between AI and outcome [death or liver transplantation (LT)] in
patients with DeCi. Methods: all patients with DeCi but without
active complication admitted between 3/2011 and 3/2013
were included. In each patient, clinical and laboratory data,
including the serum levels of corticosteroid-binding globulin
(CBG), interleukin (IL)-1, IL-6 and tumor necrosis factor (TNFa)
were recorded. Salivary cortisol (SC) and serum total cortisol
(STC) were assessed before (T0) and 1 h (T60) following an
injection of corticotropin (250μg). Results: we evaluated 80
consecutive patients (54 men, age 56±12 years). At T0 and
T60, SC were 5.4±4ng/mL and 16±12ng/mL, respectively
and STC were 12±5μg/dL and 24±7μg/dL, respectively. Free
cortisol index (FCI: STC/CBG) at T0 and T60 were 9.3±7
and 19.8±19nmol/mg. Patients with AI [defined as (STC-
T60)–(STC-T0)<9μg/dL when STC-T0<35μg/dL] [group 1,
n=27 (34%)], compared to those without AI [group 2, n=53
(66%)], had significantly lower mean systolic blood pressure
(105±12 vs 115±13mmHg, p=0.05), serum sodium (132±7
vs 138±15mEq/L, p=0.03), HDL (30±14 vs 42±19mg/dL,
p=0.005), FCI-T60 (12±2 vs 22±18 nmol/mg, p=0.004) and
albumin (2.7±0.5 vs 3.2±0.5g/dL, p=0.013), and higher bil-
irubin (6.5±9 vs 3.4±5mg/dL, p=0.03) and plasma rennin
activity (18±12 vs 9±8ng/mL*h, p=0.04). Median levels of
IL-1 (37 vs 49pg/mL), IL-6 (68 vs 96pg/mL) and TNFa (10
vs 18pg/mL) were not different between groups (p>0.05 for
both comparisons). Group 1 patients, compared to group 2
patients, had more frequently a previous history of sponta-
neous bacterial peritonitis (SBP) [8/27 (30%) vs 3/53 (6%),
p=0.003], and they had worse liver transplantation-free sur-
vival [17/27 (63%) vs 20/53 (37%), p=0.03)] after a follow
up of 16 (6-24) months. Patients with a previous history of
SBP (n=11), compared to those without history of SBP (n=69),
had significantly lower levels of STC-T0 (9±4 vs 13±6μg/dL,
p=0.01) and STC-T60 (18±5μg/dL vs 26±7μg/dL, p=0.002).
Neither previous history of encephalopathy nor variceal bleed-
ing were significantly associated with the presence of AI. Con-
clusions: the presence of AI in patients with DeCi seems to have
obvious clinical implications since it is associated with circula-
tory dysfunction, increased risk for SBP and worse outcome.
Disclosures:
George Kokkonis - Independent Contractor: BRISTOL MEYERS SQUIB, MERCK
SHARP AND DOHME, ROCHE HELLAS
The following people have nothing to disclose: Evangelos Cholongitas, Ioannis
Goulis, Parthenis Chalevas, Spyros Gerou, Evangelos Akriviadis
HEPATOLOGY, October, 2014
358
Hepatic and Renal expression of the ammonia trans-
porter Rhesus protein (Rhcg) plays a critical role in mod-
ulating hyperammonemia and hepatic encephalopathy
in liver failure
Yalda Sharifi1, Gavin Wright1,2, Nathan Davies1, Abeba Habte-
sion1, Fausto Andreola1, Rajiv Jalan1; 1Hepatology, UCL institute
for Hepatology and Digestive Health, London, United Kingdom;
2Hepatology, Institute of liver and Digestive Health, London, United
Kingdom
Introduction: Ammonia is central in the pathogenesis of hepatic
encephalopathy (HE). Although ammonia gas (1-2%) can dif-
fuse readily across the plasma membrane, ammonium ions
(98%) need to be transported into cells for metabolism. Rhcg
is a recently described ammonia transporter, trans-membrane
protein that is expressed in the kidneys and involved in modu-
lating acid-base balance. Its expression in the liver disease and
brain is unknown. This study was designed to determine the
role of this protein in mediating hyperammonemia and hepatic
encephalopathy in liver failure. Materials and Methods: Three
studies were performed. Study 1:Gene and protein expression
of Rhcg was determined in the liver, kidney and the brains of
sham operated (Sham, n=6) and bile duct ligated (BDL, n=6)
rats.Study 2. Induced hyperammonemia study:Wild type (WT,
n=10), and Rhcg knock-out mice (Rhcg-KO, n=11) were treated
with NH3Cl or saline (0.2 M) for 3-days in the drinking water
after which they were sacrificed and their plasma ammonia
and brain water measured. Study 3.Induction of acute liver
failure (ALF): WT (n=7) and the Rhcg-KO (n=7) animals were
administered 500mg/Kg acetaminophen (APAP) or saline, IP.
Animals were sacrificed at coma stages and plasma ammo-
nia and brain water were measured. Results: Study 1. Plasma
ammonia and brain water was significantly higher in BDL ani-
mals compared with the Sham animals (p<0.01 each). This
was associated with significantly greater gene and protein
expression of Rhcg in the liver (7-fold) and kidneys (2-fold)
but not the brain. Study 2. Basal levels of ammonia in the
Rhcg-KO animals were significantly higher than the WT ani-
mals (p<0.04) and remained twice the value after induction
of hyperammonemia (p<0.01).Study 3. Arterial ammonia was
significantly higher in the ALFanimals compared with controls
(p<0.0002), which was higher in the Rhcg-KO animals com-
pared with WT group and this was associated with reduced
time to coma stages (p<0.05) and significantly greater brain
water (p<0.01) in the Rhcg-KO animals. Conclusion: The
results of this study show for the first time, a critical role for the
hepatic and renal expression of the ammonia transporter, the
Rhcg protein, as a mechanism that regulates ammonia levels
in health, during hyperammonemia and liver failure. Further
understanding the mechanisms of its regulation may provide
new approaches to treating hepatic encephalopathy.
Disclosures:
Nathan Davies - Patent Held/Filed: UCL
Rajiv Jalan - Consulting: Ocera Therapeutics, Conatus; Grant/Research Support:
Grifols, Gambro
The following people have nothing to disclose: Yalda Sharifi, Gavin Wright,
Abeba Habtesion, Fausto Andreola
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
359
Pentoxifylline therapy for hepatopulmonary syndrome:
Longer duration is superior to combination with rifaxi-
min, a RCT
Naveen Kumar1, Chandan K. Kedarisetty1, Sachin Kumar3, Ankur
Jindal1, Ajeet S. Bhadoria2, Shiv K. Sarin1; 1Hepatology, Institute
of liver and biliary sciences, New Delhi, India; 2Epidemiology,
Institute of liver and biliary sciences, New Delhi, India; 3Pulmonol-
ogy, Institute of liver and biliary sciences, New Delhi, India
BACKGROUND & AIMS: Hepatopulmonary syndrome (HPS)
occurs in upto 10% patients with cirrhosis. Endotoxemia related
TNF-alpha and nitric oxide-mediated vascular dilatation are the
likely pathogenetic mechanisms. Treatment of HPS is unsatis-
factory with variable results with 4-12 weeks of pentoxifylline
therapy and limited options for drug combinations. Role of
antibiotic therapy in HPS has not been properly evaluated.
PATIENTS AND METHODS: We conducted a randomized con-
trolled trial (NCT01676597) of pentoxifylline and rifaximin
combination (Gr A) for 12 weeks in patients who initially failed
to respond to 12 weeks of pentoxifylline monotherapy and
compared it with long-term pentoxifylline monotherapy (Gr B).
Patients with cirrhosis and HPS as evidenced by intrapulmo-
nary vascular dilation on saline contrast ECHO and baseline
PaO2< 90 mmHg were included in the study. Patients with con-
current significant cardiopulmonary illness, advanced enceph-
alopathy, antibiotic use, listed for transplant or malignancy
were excluded. The primary end-point was of improvement in
arterial oxygen saturation (PaO2) by at least 5 mm Hg from the
baseline. RESULTS: Forty two patients with HPS were enrolled.
Most of the enrolled patients were male (93%), mean age 49
yrs. with the aetiology of underlying cirrhosis being predom-
inantly ethanol or cryptogenic (43% and 45% respectively).
The baseline parameters were CTP-8.6±1.8, MELD-15.6±2.78
and PaO2-71.1± 8.5 mm Hg. There was also no correlation
between the grades of shunting seen on saline contrast echo-
cardiography and the clinical severity of HPS. The response
rate after 12 weeks of pentoxifylline was 27% in the 33 evalu-
able patients. The 24 non-responders were randomized to Gr.
A (n=12) and B (n=12). The response rate of the 19 evaluable
patients in the two arm (9 in Gr A and 10 in Gr B) was 67%
and 60% respectively after a total treatment duration of 24
weeks. An associated improvement in maximal oxygen uptake
(VO2 max) was seen in responders. CONCLUSIONS: Pent-
oxifylline remains the drug with maximum benefit in HPS. The
response seems to be related to the duration of treatment with
more than 60% response rate with 24 week treatment as com-
pared to 27% response at 12 weeks of treatment. There seems
to be no additional benefit of adding rifaximin to pentoxifylline
in response. Improvement in cardiopulmonary profile occurs in
HPS patients responding to drug.
Pre and post-treatment Pao2 in both the treatment groups
Disclosures:
The following people have nothing to disclose: Naveen Kumar, Chandan K.
Kedarisetty, Sachin Kumar, Ankur Jindal, Ajeet S. Bhadoria, Shiv K. Sarin
379A
360
Prevalence of Bone Disease in Cirrhosis
Mohamed A. Chinnaratha1, Rosemary J. McCormick2, Rachel
Wundke2, Richard J. Woodman1, Alan J. Wigg1,2; 1School of
Medicine, Flinders University, Bedford Park, SA, Australia; 2Gas-
troenterology and Hepatology, Flinders Medical Centre, Bedford
Park, SA, Australia
Bone disease (BD) is a major complication of cirrhosis. Previous
studies investigating the prevalence of BD in cirrhosis have
focussed on patients with a single aetiology or those awaiting
liver transplant. Our aim was to determine the prevalence of
BD (both osteopenia and osteoporosis) in an unselected cohort
of cirrhotic patients with mixed aetiology and severity; and to
determine risk factors for BD in cirrhosis. METHODS: A single
centre review of prospectively collected data for consecutive
patients newly diagnosed with cirrhosis between Sep 2009
and Dec 2012. All patients underwent Bone Mineral Density
(BMD) assessment using Dual Energy X-ray Absorptiometry
(DEXA) within 3 months of diagnosis. Relevant clinical and
biochemical data were collected on diagnosis and with fol-
low-up patient survey. Osteoporosis was defined as a T-score
<-2.5 SD. Binary logistic regression was used to determine risk
factors associated with BD (T-score <-1 SD or a Z-score <-2 SD).
RESULTS: Data was collected for a total of 406 subjects (67%
males) with a mean (±SD) age of 56.2 (±10.9) years. Alco-
hol (41.1%), hepatitis C (HCV) + alcohol (16.5%) and HCV
(16%) were the most common aetiologies. 84% of patients
were either Childs-Pugh class A or B with a mean MELD (±SD)
score of 12.4 (±5.7). The prevalence of BD was 56% of the
total cohort. Osteoporosis was present in 20.5% (66/320) of
patients with a T-score measurement. Moderate or severe vita-
min D deficiency (≤50 nmol/L) was present in 54% (212/389)
and fragility fractures in 3.3% (12/362) of patients. In multi-
variate analysis, only older age and lower BMI were significant
independent risk factors for BD (Table) with both displaying a
linear trend. Amongst females, high serum FSH level, irrespec-
tive of menopausal status, was associated with BD in univariate
analysis but was no longer associated with BD after adjustment
for age and BMI. CONCLUSION: This is the largest study of
bone disease in unselected cirrhotic subjects with mixed aeti-
ology and disease severity. We observed a high prevalence
of bone disease and vitamin D deficiency in this cohort which
would support routine screening on diagnosis. Increasing age
and lower BMI were independent risk factors for BD in both
genders.
Disclosures:
The following people have nothing to disclose: Mohamed A. Chinnaratha, Rose-
mary J. McCormick, Rachel Wundke, Richard J. Woodman, Alan J. Wigg
380A AASLD ABSTRACTS
361
Branched-chain amino acids improve intestinal malab-
sorption of dietary long-chain fatty acids and preserve
intestinal fatty acid transporters in liver cirrhosis
Yasunori Yamamoto, Hiroki Utsunomiya, Teruki Miyake, Keitaro
Kawasaki, Hiroaki Nunoi, Kenichirou Mori, Yoshio Ikeda, Yoichi
Hiasa; Department of Gastroenterology and Metabology, Ehime
University Graduate School of Medicine, Ehime, Japan, Toon,
Japan
Background & Aims: Malnutrition is associated with an
increased risk of mortality in patients with liver cirrhosis (LC).
Such patients often show a blunted chylomicronemic response
and a decrease in the intestinal absorption of dietary long-chain
fatty acid (LCFA). We previously found histological changes in
the intestinal villi of patients with portal hypertension due to LC.
Branched-chain amino acids (BCAA) have been demonstrated
to reduce gut atrophy. We aimed to clarify the mechanisms
of the blunted chylomicronemic response and the effects of
BCAA in patients with LC. Patients and Methods: This study
comprised 20 healthy subjects (Controls) and 43 patients with
LC (19 with portal hypertension (PH(+)LC), 24 without portal
hypertension (PH(-)LC)). We performed additional analyses of
patients with PH(+)LC, who were treated with BCAA. 13C-la-
beled palmitate (an LCFA) was administered directly to the
duodenum using gastrointestinal endoscopy. Breath 13CO2
levels were measured to quantify metabolized fatty acids. We
also evaluated the expression of LCFA transporters in intestinal
specimens from these groups. Results: Overall 13CO2 excre-
tion was significantly lower in the PH(+)LC group than in the
control and PH(-)LC groups (P<0.001). Serum concentrations
of apolipoprotein B-48 were lower in the PH(+)LC group than
in the control and PH(-)LC groups; indicating that the transport
of dietary LCFA via chylomicrons was decreased. Moreover,
jejunal levels of fatty acid transporter protein 4 (FATP4) and
microsomal triglyceride transfer protein (MTTP), which are
molecules associated with chylomicron formation, were sig-
nificantly decreased in PH(+)LC patients. In contrast, BCAA
treatment produced a significant increase in 13CO2 excretion
in PH(+)LC patients (P<0.01) compared to pre-treatment levels.
Similarly, BCAA treatment resulted in elevated serum concen-
trations of apolipoprotein B-48 in the PH(+)LC group compared
to the pre-treatment PH(+)LC group. Moreover, jejunal mRNA
levels of MTTP were increased in the PH(+)LC group after BCAA
treatment (P<0.001) Conclusion: Significant malabsorption of
dietary long chain fatty acids occurs in the jejunum of PH(+)
LC patients. This change is likely related to a decrease in the
chylomicronemic response attributable to decreases in FATP4
and MTTP. Our results also suggest that BCAA promotes the
intestinal absorption of LCFA and preserves intestinal fatty acid
transporters in patients with LC.
Disclosures:
The following people have nothing to disclose: Yasunori Yamamoto, Hiroki Utsu-
nomiya, Teruki Miyake, Keitaro Kawasaki, Hiroaki Nunoi, Kenichirou Mori,
Yoshio Ikeda, Yoichi Hiasa
HEPATOLOGY, October, 2014
362
Association between Malnutrition in Patients with Liver
Cirrhosis and the Presence of Hepatic Encephalopathy
Astrid Ruiz-Margáin1, Ricardo Macías-Rodríguez1, Andres Duar-
te-Rojo2, Angeles Espinosa-Cuevas3, Aldo Torre1; 1Gastroenterol-
ogy, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador
Zubiran”, Mexico City, Mexico; 2Division of Gastroenterology and
Hepatology, University of Arkansas for Medical Sciences, Little
Rock, AR; 3Nephrology and Mineral Metabolism, Instituto Nacio-
nal de Ciencias Médicas y Nutrición “Salvador Zubiran”, Mexico
City, Mexico
Background: Hepatic encephalopathy (HE) reflects a spectrum
of neuropsychiatric abnormalities seen in patients with liver
dysfunction; HE has multiple triggers and some studies suggest
that malnutrition is an important trigger of HE. Phase angle
(PhA) obtained from bioelectrical impedance has been success-
fully used as a nutritional marker in several diseases. Aim: To
evaluate the association between malnutrition assessed by PhA
and the presence of overt HE. Materials and methods: This was
a prospective cohort study. Clinical (presence of HE and com-
plications), nutritional (bioelectrical impedance derived PhA)
and biochemical evaluations were performed. Malnutrition was
defined as PhA ≤4.9°. Student T test or X2 method were used.
Kaplan-Meier curves and Cox regression were used to evaluate
the incidence of HE. Results: 220 patients (60% females) were
included. Most frequent etiology of cirrhosis was hepatitis C
infection (36%). When we divided the population according
to nutritional status (PhA ≤ or >4.9°) there were no significant
differences in demographic, clinical and biochemical variables
between groups, except for age, which was higher in malnour-
ished patients. Mean follow-up was 34 months (9/48 min/
max). Kaplan-Meier curves showed higher proportion of HE
in the malnourished group (39%) compared to the well-nour-
ished group (13%) (p=0.012) (Figure 1) In the Cox regression
controlling for MELD score and age, malnutrition remained
associated with HE [HR= 2.12 (1.07-4.21)]. Conclusion: Mal-
nourished patients with liver cirrhosis have higher risk of devel-
oping HE when compared to well-nourished patients. Although
the mechanism is unknown, sarcopenia leading to reduced
extra-hepatic metabolism of ammonia might be implicated.
Whether improving nutritional status can prevent or delay the
development of episodes of HE warrants further testing.
Disclosures:
Andres Duarte-Rojo - Advisory Committees or Review Panels: Gilead Sciences;
Grant/Research Support: Vital Therapies
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
The following people have nothing to disclose: Astrid Ruiz-Margáin, Ricardo
Macías-Rodríguez, Angeles Espinosa-Cuevas, Aldo Torre
363
Bumetanide normalizes brain edema in rats with bile
duct ligation: evidence for increased BBB permeability
via NKCC1
Jimmy Huynh, Cristina R. Bosoi, Christian Parent-Robitaille, Méla-
nie Tremblay, Christopher F. Rose; Hepato-Neuro Labo, CRCHUM,
Université de Montréal, Montréal, QC, Canada
Background: Brain edema is a serious complication associated
with hepatic encephalopathy (HE) due to chronic liver disease
(CLD). An increase in blood brain barrier (BBB) ion permeabil-
ity can occur across an intact BBB through alterations in trans-
port mechanisms. NH4+ has very similar ionic properties to K+
and can be transported through K+ channels and cotransport-
ers, implying that hyperammonemia could result in BBB hyper-
permeability. An increase in BBB permeability via transport
Na+-K+-2Cl- (NKCC1) has shown to promote brain edema
and astrocyte swelling under pathophysiological conditions
such as ischemia. Aim: To study the BBB integrity (vasogenic vs
cytotoxic) and the role of NKCC1 in the pathogenesis of brain
edema in cirrhotic rats. Methods: Two distinct animal models
of HE are used in the present study; 1) biliary cirrhosis model
(6 weeks bile duct ligation (BDL)). 2) portacaval shunt model
(4 weeks portacaval anastomosis (PCA)). Both models develop
hyperammonemia however brain edema is only observed in
BDL. BBB breakdown was assessed by measuring brain extrav-
asation of Evans blue and sodium fluorescein (injected i.v).
Expression of BBB tight junction proteins (occludin, claudin-5,
ZO-1 and ZO-2) were assessed by Western blot. Bumetanide
was administered (i.p) for 10 days in BDL and SHAM animals.
Brain water content was measured in the frontal cortex using
the specific gravimetric method. Levels of brain NKCC1 mRNA
were evaluated by RT-PCR in cerebral microvessels. Results:
Extravasation of Evans blue and sodium fluorescein was not
detected and no significant change in all tight junction protein
was observed in both BDL and PCA models. Brain water content
was reduced in bumetanide-treated BDL rats compared to con-
trol (77.66±0.15% vs 78.12±0.21%). In brain microvessels,
NKCC mRNA increased in BDL rats compared to BDL SHAM
(0.78±0.09 vs. 1.92±0.42) whereas no change was found in
PCA compared to PCA SHAM (1.72±0.52 vs. 1.53±0.23).
Conclusions: BDL rats did not demonstrate a change in BBB
integrity or expression of tight junction proteins concluding
brain edema in BDL is not of vasogenic origin. Furthermore,
since brain edema was only observed in BDL rats (vs PCA),
this implies additional factors aside ammonia, are involved in
the pathogenesis of brain edema. Moreover, an increase of
NKCC1 mRNA and an attenuation of brain edema following
bumetanide treatment were demonstrated in BDL rats suggest-
ing NKCC1 plays a role in the development of brain edema in
CLD. These results demonstrate the potential therapeutic use of
bumetanide for the treatment of HE.
Disclosures:
The following people have nothing to disclose: Jimmy Huynh, Cristina R. Bosoi,
Christian Parent-Robitaille, Mélanie Tremblay, Christopher F. Rose
381A
364
Incidence and outcome of newly diagnosed portal vein
thrombosis in patients with cirrhosis awaiting liver
transplantation
Cindy S. Law1, Manjil Chatterji4, Kristina Chacko5, Thomas D.
Schiano2,3, Charissa Y. Chang2,3; 1Icahn School of Medicine at
Mount Sinai, New York, NY; 2Division of Liver Diseases, Mount
Sinai Medical Center, New York, NY; 3Recanati/Miller Trans-
plantation Institute, Mount Sinai Medical Center, New York, NY;
4Division of Radiology, Mount Sinai Medical Center, New York,
NY; 5Division of Digestive and Liver Diseases, Montefiore Medical
Center, Bronx, NY
BACKGROUND: The incidence and natural history of acute
portal vein thrombosis (PVT) in cirrhotic patients is poorly under-
stood. We performed a case control study of cirrhotic patients
listed for liver transplantation (LT) at Mount Sinai Medical Cen-
ter to determine the: 1) incidence of new PVT in cirrhotics await-
ing LT, 2) natural history of PVT, and 3) risk factors for poor
clinical outcome in cirrhotics who develop PVT. METHODS: A
retrospective chart review of patients listed for LT between Jan
1, 2002 and Dec 31, 2011 was performed. Subjects with new
PVT (defined as PVT in a patient whose prior imaging showed
patent PV) were identified via review of radiology, operative,
and explant pathology reports. Diagnosis, partial vs complete
PVT, segmental (sPV) vs main (MPV) PVT and radiologic out-
come (resolution, progression) of cases were confirmed through
blinded review by a radiologist. Cirrhotic controls without PVT
were matched (2:1) for age and time on the waitlist. Imaging
and clinical outcomes (death on the waitlist, transplantation)
were assessed. RESULTS: 1,761 patients were listed for LT
between 2002-2011. 1,148 cases were excluded for reasons
including HCC (n=739), chronic PVT (n=26), PVT prior to list-
ing (n=77), and prior TIPS (n=59). We identified 20 cases
of new PVT on imaging and 8 cases of incidental PVT found
at the time of LT. Incidence of PVT was 4.6% over 10 years.
No patients received anticoagulation. Most of the imaging
cases involved MPV only (n=10) or MPV + sPV (n=7) and 3
involved sPV only (n=3). 14 had follow-up imaging, of which
there were 4 (28%) cases of progression, 7 (50%) cases of no
change, and 3 (21%) cases of improvement, recanalization or
cavernous transformation. There were 11 deaths on the waitlist
(55% mortality rate) among PVT cases. Median time between
PVT diagnosis and death was 133 days. Development of PVT
while on the waitlist was associated with an increased risk for
death (OR 3.44, p=0.03) compared to controls. A significantly
increased risk for death while waiting was observed in patients
with any involvement of the main PV (OR 6.73, p=0.002) or
complete PVT (OR 10.33, p=0.003), but not in those with only
sPVT (OR 2.36, p=0.49) or partial PVT (OR 3.37, p=0.08)
compared to controls. CONCLUSIONS: The development of
PVT in cirrhotic patients awaiting LT is associated with a high
mortality rate. Spontaneous improvement of PVT is uncommon.
Patients with cirrhosis who develop main PVT or complete PVT
warrant consideration for intervention trials using anticoagu-
lation. Prioritization on the waiting list with a variance may
mitigate the burden of high mortality without transplant seen in
this population.
Disclosures:
Thomas D. Schiano - Advisory Committees or Review Panels: vertex, salix, merck,
gilead, pfizer; Grant/Research Support: massbiologics, itherx
Charissa Y. Chang - Consulting: Gilead
The following people have nothing to disclose: Cindy S. Law, Manjil Chatterji,
Kristina Chacko
382A AASLD ABSTRACTS
365
The determination of prognosis and disease progression
in patients with established cirrhosis
Zita Galvin, Audrey Dillon, Jennifer Russell, Damien Lowry, Ste-
phen Stewart; Centre for Liver Diseases, Mater Misericordiae Uni-
versity Hospital, Dublin, Ireland
Background and purpose of study Cirrhosis is a common
chronic disease and is associated with significant morbidity
and mortality. It is a dynamic process that evolves from early
cirrhosis without portal hypertension to end-stage decom-
pensated disease. Appropriate classification of a patient on
the cirrhosis spectrum is important from the point of view of
prognosis and management. The purpose of the study was to
evaluate some of the non-invasive fibrosis-scoring tools and to
establish which, if any, might be useful in determining the risk
of clinical disease progression in patients with compensated
cirrhosis Methods Consecutive compensated cirrhotic patients
attending the outpatient department over a two year period
were recruited for the study. Each patient had a baseline visit
and follow-up visits at regular intervals. Blood testing, tran-
sient elastography and psychometric testing were performed
at each visit. The study endpoints were the development of
ascites, hepatic encephalopathy, bleeding varices or liver-re-
lated death. Results Of 124 patients, 11 patients decompen-
sated/had a liver-related death during the study (median follow
up 15.4 months). On univariate analysis liver stiffness mea-
surement (LSM), Psychometric hepatic encephalopathy score
(PHES), bilirubin, AST, creatinine, AST/ALT ratio, AST platelet
ratio index, Fib4, European liver fibrosis score, Model for end
stage liver disease and Child Pugh score were associated with
death/decompensation (p<0.05). Bilirubin and LSM remained
significant on multivariate analysis (p<0.05). Bilirubin and liver
stiffness values were used to construct ROC curves to detect
decompensation/liver related death. Cut-off thresholds were
chosen in order to obtain the maximum sum of sensitivity and
specificity. A LSM cut-off threshold 35.6kPa had a sensitivity
of 72.7% and a specificity of 82.4% for detecting clinical out-
comes. A bilirubin cut-off threshold 25.5mmol/L had a sensitiv-
ity of 80.0% and a specificity of 84.7% for detecting clinical
outcomes. Kaplan-Meier survival analysis curves were con-
structed using the dichotomised results. According to Kaplan-
Meier analysis, liver stiffness greater than 35.6 kPa (log-rank
19.42; p=0.000011) and bilirubin greater than 25.5mmol/L
(log-rank 24.79; p=0.000001) were associated with a higher
risk of decompensation and a lower survival. Conclusion We
found that in a compensated, cirrhotic population of mixed
aetiology, the risk of decompensation/death was significantly
associated with liver stiffness and bilirubin. With greater num-
bers it should be possible to develop a composite prognostic
score using LSM and serum markers.
Disclosures:
Stephen Stewart - Advisory Committees or Review Panels: MSD, Gilead, BMS,
Abbvie; Grant/Research Support: MSD; Speaking and Teaching: Roche
The following people have nothing to disclose: Zita Galvin, Audrey Dillon, Jenni-
fer Russell, Damien Lowry
366
Effect of lactulose administration on gut microbiota in
patients with liver cirrhosis
Rakesh Aggarwal, Amit Goel, Aditya N. Sarangi, Ankur Singh, S.
Avani; Department of Gastroenterology, Sanjay Gandhi Postgrad-
uate Institute of, Lucknow, India
Objective: Lactulose is used for treatment and prevention of
hepatic encephalopathy (HE) and minimal hepatic encephalop-
athy (MHE). Its beneficial effect is believed to be mediated, at
HEPATOLOGY, October, 2014
least in part, by changes in gut flora. Since data on changes in
gut flora with lactulose are limited, we compared gut microbial
composition before and after lactulose administration. Meth-
ods: Patients with liver cirrhosis (LC) without HE who had no
gastrointestinal symptoms and no current or recent (6 weeks)
intake of lactulose, drugs that may alter gut motility or flora
were recruited, irrespective of etiology, severity and MHE sta-
tus. For each subject, morning stool specimens were collected
at baseline and after at least 6 weeks of lactulose (30 ml once
or twice a day, based on stool frequency response). These
were sequentially processed for DNA extraction, amplifica-
tion of V3 region of bacterial 16S rRNA, Illumina HiScan SQ
paired-end multiplex sequencing of the DNA library, merger
of sequence reads in opposing directions followed by quality
control checks, and comparison of good-quality reads (Phred
score ≥30) to Greengenes database for assignment of opera-
tional taxonomic units (OTU), using an open-reference algo-
rithm. OTUs accounting for ≥0.005% of total sequences were
compared using paired-t test. Results: The study included 11
patients (male 6; age: median 51 y, range 30-64) with LC
(hepatitis C 4, hepatitis B 1, alcohol intake 1, autoimmune
1, cryptogenic 4; Child-Pugh class A: 2, B: 8, C: 1). The 22
specimens yielded a mean of 622,748 ± 266,087 high-qual-
ity reads (total: 13,700,461). These reads were assigned to
17,716 OTUs, including 503 that accounted for >0.005%
of all sequences. Top phyla in pre-lactulose specimens were:
Bacteroidetes (72.2±12.1%), Firmicutes (20.1±11.0%), Proteo-
bacteria (5.7±6.1%), Actinobacteria (0.6±1.1%) and Fusobac-
teria (0.6±0.2%); abundance of none of these changed after
lactulose for 48 (41-90) days (62.8±23.3%, 23.8±20.2%,
9.5±7.2%, 1.8±3.4%, 1.7±5.6%, respectively). No bacterial
class, order, family, genus or species showed a change in
abundance after lactulose. Principal coordinate analysis of
unweighted UniFrac OTU profile distances showed no separa-
tion between pre- and post-lactulose flora. Measures of alpha
diversity of gut flora (PD whole tree, observed species, Chao
1 and Shannon diversity index) were similar before and after
lactulose administration. Conclusion: In our study, lactulose
administration for 6 weeks in patients with LC did not lead to
any discernible change in gut flora. This suggests that changes
in gut flora may not be a major mechanism of action of lactu-
lose in HE.
Disclosures:
The following people have nothing to disclose: Rakesh Aggarwal, Amit Goel,
Aditya N. Sarangi, Ankur Singh, S. Avani
367
Relation of CT determined Sarcopenia to Anthropome-
try, Dietary Calorific and Protein Intake and Survival in
Patients with Chronic Liver Disease
Sarah E. Brown1, Ziva Mrevlje1, Frances Dorman2, Natasha
Vidas2, Pauline A. Kane4, Michael A. Heneghan3, Julia Wendon1,
William Bernal1; 1Liver Intensive Care Unit, Kings College Hos-
pital, London, United Kingdom; 2Dept. Nutrition and Dietetics,
Kings College Hospital, London, United Kingdom; 3Institute of Liver
Studies, Kings College Hospital, London, United Kingdom; 4Dept.
Radiology, Kings College Hospital, London, United Kingdom
Background: Loss of muscle mass in patients with cirrhotic liver
disease (CLD) is now recognised as being both common and
prognostically important, with severe loss (sarcopenia) associ-
ated with markedly impaired survival. The factors involved in
its development are poorly understood, but inadequate intake
of calories and/or protein to sustain muscle mass may contrib-
ute. In patients with CLD we examined the relation of dietary
calorific and protein intake and standard anthropometry to
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
muscle mass assessed using CT image analysis, and associ-
ations with survival. Patients and Methods: 286 patients with
CLD undergoing liver transplantation assessment were studied.
All underwent nutritional and anthropometric assessment by
trained dietetic staff with HGS determined using a calibrated
dynamometer in the dominant arm. Abdominal CT imaging
was analysed using Sliceomatic software and L3 muscle area
determined. L3 skeletal muscle index (L3SMI) was calculated
adjusting for stature and gender and the lowest quartile clas-
sified as having sarcopenia. Results: Median age was 56 yrs
(IQR 48-61) and MELD 14 (11-18), 92 (32%) were female.
109 (38%) had CLD with an alcoholic etiology. Median BMI
was 26.1 kg/m2 (22.9-29.7) and 70% had HGS less than
85% predicted. Median caloric intake was 1684 (1311-2100)
kCal/d, 22.8 (16.9-28) kCal/kg/g and protein 65 (50-82)
g/d, 0.87 (0.74-1.03) g/kg/d. L3SMI correlated closely with
HGS (r=0.335, p<0.001) and Mid-Arm Muscle Circumference
(r=0.492, p<0.001) but not with MELD (r=0.01, p=0.98). It
correlated with weakly with protein intake by body wt (r=-
0.158, p<0.02) but not with calories (r=0.02, p=0.77).
Patients with sarcopenia did not differ in age or MELD score
from those with higher L3SMI but had lower BMI (22.1 (19.9-
25.1) vs. 26.9 (23.9-30.7), p<0.001), daily calorie (1500
kCal/d (1202-1800) vs. 1765 (1367-2250), p<0.005) and
protein intake (60 g/d (48-70) vs. 69 (50-85), p<0.05), but
intake by body weight did not differ (22.1 kCal/kg/d (17-
26.7) vs 22.8 (16.9-28) p=0.8) (0.87 g/kg/d (0.74-1.03) vs.
0.82 (0.64-1.07), p=0.24). Non-transplanted survival was sig-
nificantly worse in those with sarcopenia (log-rank p<0.005),
remaining significant with multivariate adjustment. Conclusion:
In patients with CLD, L3SMI as determined by CT imaging is
independently associated with non-transplanted survival, cor-
relating closely with anthropometric measures of muscle mass
and function but not with MELD score. Only limited association
was seen with dietary intake of calories and protein: other fac-
tors may be important in the development of clinical significant
muscle loss.
Disclosures:
Michael A. Heneghan - Speaking and Teaching: Falk
Julia Wendon - Consulting: Pulsion, Excalenz
William Bernal - Consulting: Vital Therapies Inc
The following people have nothing to disclose: Sarah E. Brown, Ziva Mrevlje,
Frances Dorman, Natasha Vidas, Pauline A. Kane
368
Comparison of Psychometric Hepatic Encephalopathy
Score (PHES) and Inhibitory Control Test (ICT) in diagno-
sis of minimal hepatic encephalopathy
Jerzy Jaroszewicz, Justyna Zbrzezniak, Natalia Kilisinska,
Agnieszka Stawicka, Aleksandra Swiderska, Mateusz Panasiuk,
Tadeusz W. Lapinski, Robert Flisiak; Department of Infectious Dis-
eases and Hepatology, Medical University of Bialystok, Bialystok,
Poland
The diagnosis of MHE is difficult due to an absence of feasi-
ble and reliable test. Currently PHES is regarded as a gold
standard but due to lack of standardization in many countries
usefulness of this test is limited. The aim of this study is to com-
pare PHES with computer based method - ICT. Patients and
methods. Fifty patients (median age 57yo, 31 male) with liver
cirrhosis without overt hepatic encephalopathy and fifty six
healthy volunteers (median age 54yo, 28 male) were included.
Psychometric Hepatic Encephalopathy Score (PHES) and the
inhibitory control test (ICT) - a computerized test of attention
and response inhibition were performed. All studied subjects
had MMSE>23 points and excluded neurologic, psychiatric
383A
disorders as well as active alcohol and psychoactive drugs
abuse. Results. The cut-off of <-5 points PHES score, suggesting
diagnosis of MHE was met in 16 patients (32%). Subjects with
MHE were older (62 vs 54, P=0.01) and had higher Child-
Pugh score (8.2 vs 6.9, P<0.01) while gender and level of
education were comparable. Interestingly alcohol aetiology of
cirrhosis (75% vs 38%, P<0.05) and type 2 diabetes (43% vs
18%, P<0.05) were more prevalent in patients with MHE. Of
note serum ammonia was only slightly higher in patients with
MHE (153 vs 118 ug/mL, P=0.06) and as many as 12 (35%)
subjects without MHE had its levels increased. The best perfor-
mance among single PHES components were observed with
regard to number connection tests A (R=78, P<0.001) and B
(R=86, P<0.001). On the other hand line tracing test was inde-
pendent from age and education but had lesser performance
(R=0.61, P<0.001). Computer based test ICT showed a good
association with PHES-score (AUC=0.846) and yields simpler
validation due to its correlation with age only. ICT cut-off of
27.8 (%/mistakes) has 82% sensitivity and 75% specificity in
diagnosis of MHE. Conclusions. Minimal hepatic encephalop-
athy might affect as many as one third of liver cirrhosis patients
without over hepatic encephalopathy. Among important fac-
tors of MHE diabetes mellitus should be considered Computer
based ICT can be used as an additional simple, tool in assess-
ment of minimal hepatic encephalopathy.
Disclosures:
Jerzy Jaroszewicz - Speaking and Teaching: Roche, Gilead, Abbott, MSD, BMS
Robert Flisiak - Advisory Committees or Review Panels: Gilead, Merck, Roche,
Bristol Myers Squibb, Janssen, Novartis, Abbvie; Grant/Research Support:
Roche, Bristol Myers Squibb, Janssen, Novartis, Gilead, Vertex, Merck; Speak-
ing and Teaching: Janssen, Merck, Roche, Bristol Myers Squibb, Gilead, Abbvie
The following people have nothing to disclose: Justyna Zbrzezniak, Natalia Kili-
sinska, Agnieszka Stawicka, Aleksandra Swiderska, Mateusz Panasiuk, Tadeusz
W. Lapinski
369
Comorbid Conditions and Demographic Factors Associ-
ated With Poor Outcome in Cirrhotic Patients Undergo-
ing Orthopedic Surgery in a Large Health Maintenance
Organization
Eric M. Nyberg, Michael Batech, T Craig Cheetham, Anshuman
Singh; Kaiser Permanente Southern California, San Diego, CA
Background: Previous studies have shown an increased mor-
bidity and mortality in cirrhotic patients undergoing orthopedic
surgery. However, there are little data examining demographic
and clinical factors that may contribute to adverse outcomes.
The aim of this study was to examine demographic and clinical
factors, and adverse outcomes in cirrhotics who have under-
gone orthopedic surgery. Methods: Retrospective matched
cohort study using data from Kaiser Permanente Southern
California. Participants received a diagnosis of cirrhosis from
01/01/2003-12/31/2013 and initial case criteria was
age>18, ≥ 6 months continuous health plan membership, and
a procedure code for orthopedic surgery. Up to 5 controls
were optimally matched based on age, gender, and cirrho-
sis diagnosis date. Data abstraction and summary was subse-
quently performed for demographics, socioeconomics, clinical
events, and decompensation events data. Decompensation
events were defined as development of ascites, variceal bleed-
ing, or hepatic encephalopathy. Multivariable conditional
logistic regression estimated risk of decompensation from
surgery. Results: We matched 4,263 cirrhotic controls with
853 cirrhotics who underwent orthopedic surgery. Mean age
was 60.5 (11.44 SD) years, and 52.2% were female. In the
study period, 267 (31.3%) cases had any decompensation
event vs 1,562 (37.1%) of controls. During the entire study
384A AASLD ABSTRACTS
period, cases were less likely to have decompensation com-
pared to matched controls [OR=0.78 (95% CI: 0.67, 0.92)]
after additional adjustment for race/ethnicity and household
income. Within the 90 days after surgery, cases had more
decompensation events compared to matched controls (24.1%
vs 19.1%). Using multivariable conditional logistic regression,
median annual household income <$45,000 vs. 45,000-
80,000 [1.22(1.05, 1.42)] and Hispanic vs. non-Hispanic
white race/ethnicity were associated with higher relative risk of
decompensation [1.45 (1.25, 1.68)]. Fewer cases had hepatic
encephalopathy, jaundice, and portal hypertension compared
to matched controls although more cases than matched con-
trols experienced sepsis. Comorbid conditions such as diabe-
tes, COPD, and chronic kidney disease (CKD) were seen with
increased frequency in cases vs. matched controls. Conclusion:
Cirrhotic patients experienced more decompensation within the
90 days after surgery compared to matched cirrhotic controls.
Hispanic race/ethnicity and lower household income were
associated with a higher risk of decompensation. Comorbid
conditions were seen with increased frequency in cases vs.
controls warranting further investigation.
Disclosures:
T Craig Cheetham - Grant/Research Support: Gilead, BMS
The following people have nothing to disclose: Eric M. Nyberg, Michael Batech,
Anshuman Singh
370
The Challenging Diagnosis of Minimal Hepatic Encepha-
lopathy: Does Critical Flicker Frequency Correlate to the
Psychometric Hepatic Encephalopathy Score?
Audrey Dillon, Zita Galvin, Stephen Stewart; Centre for Liver Dis-
ease, Mater Misericordiae University Hospital, Dublin 7, Ireland
The early diagnosis and treatment of Minimal Hepatic Enceph-
alopathy (MHE) has been associated with improved quality of
life and driving ability. Despite this, the presence of MHE is not
yet routinely tested for in everyday clinical practice. The Psy-
chometric Hepatic Encephalopathy Score (PHES) is considered
by International Society of Hepatic Encephalopathy and Nitro-
gen Metabolism (ISHEN) to be the test of choice in diagnosis
of MHE. We aim to compare Critical Flicker Frequency (CFF)
to PHES in the diagnosis of MHE. We also aim to calculate
an optimal CFF threshold in our population. There is no inter-
nationally validated CFF threshold, but a recent meta-analysis
proposed a threshold of 38 or 39 Hz. Methods: A prospective
cohort study began enrolment in July 2012 and 132 patients
with compensated cirrhosis have been enrolled. Patients with
overt neuropsychiatric disturbance, or any clinical sign of
decompensation were excluded. CFF was determined using
the portable Lafayette model 12021. Following a practice run,
flicker frequency was determined as a mean of 10 attempts.
PHES was performed using pen-and-paper and results com-
pared to United Kingdom normative data. A score of 2 or more
standard deviations below the mean diagnosed MHE. Statisti-
cal analysis was performed using SPSS v22. Results: 115 same
day CFF-PHES pairs were recorded in 90 patients. All patients
with more than 1 test were tested at at least 6 month intervals.
All patients had Child Pugh Score <9. 23/115 (20%) patients
had MHE by PHES. The median CFF was 54.09 (13.53–67.72)
Hz. Using a threshold of 39Hz, 85/115 (73.4%) patients had
MHE; using a threshold of 38Hz, 78/115 (67.8%) had MHE.
There was no correlation between raw PHES and CFF results
(Spearman rho = 0.128, p=0.171). There was also no cor-
relation between those with and without MHE by PHES and
CFF with mean CFF in those with MHE 33.7 Hz, and those
without, 36.6 Hz [ANOVA, p=0.11]. The area under the ROC
HEPATOLOGY, October, 2014
curve for CFF to detect MHE as detected by PHES was 0.644
(p=0.033). Sensitivity and Specificity of CFF to detect MHE
at the threshold of 38Hz are 83% and 29%, and at threshold
of 39 Hz, 83% and 36%, respectively. An optimum threshold
of 34 Hz in our population was chosen from the point on the
ROC curve that maximised sensitivity and specificity (65%,
65%). Using this threshold, 48/115 (41.7%) of patients had
MHE. Conclusion: CFF does not correlate to the PHES score. It
is therefore not suitable as a replacement for PHES in the diag-
nosis of MHE. It may reflect other neuropsychological defects
and may have a role as an adjunct to PHES in clinical practice.
Disclosures:
Stephen Stewart - Advisory Committees or Review Panels: MSD, Gilead, BMS,
Abbvie; Grant/Research Support: MSD; Speaking and Teaching: Roche
The following people have nothing to disclose: Audrey Dillon, Zita Galvin
371
Sarcopenia and Myosteatosis Increase the Risk of
Hepatic Encephalopathy in Cirrhotic Patients
Aldo J. Montano-Loza1, Andres Duarte-Rojo2, Christopher F. Rose3;
1Division of Gastroenterology & Liver Unit, University of Alberta,
Edmonton, AB, Canada; 2Division of Gastroenterology and Hepa-
tology, University of Arkansas for Medical Sciences, Little Rock,
AR; 3Neuroscience Research Unit, Hopital Saint-Luc (CRCHUM),
Université de Montréal, Montreal, QC, Canada
Background: Sarcopenia is one of the most common compli-
cations of cirrhosis and it is associated with increased mor-
tality. Muscle depletion is generally characterized by both a
reduction in muscle size and increased proportion of inter- and
intra-muscular fat denominated “myosteatosis”. Skeletal muscle
may serve as an alternative site of ammonia detoxification in
patients with cirrhosis. Aims: In this study we aimed to investi-
gate if sarcopenia and myosteatosis are associated with overt
hepatic encephalopathy in patients with cirrhosis. Methods: A
total of 678 cirrhotic patients undergoing assessment for liver
transplantation were studied. Sarcopenia and myosteatosis
(characterized as low muscle attenuation) were analyzed using
computed tomography (CT) scans at the level of the 3rd lumbar
vertebral body. The area of paraspinal skeletal muscle (L3 SMI)
at this location, and the muscle attenuation index were calcu-
lated (Figure 1 & 2). Hepatic encephalopathy was assessed
clinically by applying the West-Heaven criteria (grade 0-IV).
Results: Of the 678 patients, 457 patients were males (67%).
Cirrhosis was caused by HCV in 256 patients (38%), alcohol
in 152 (22%), NASH/cryptogenic in 171 (25%), autoimmune
liver disease in 53 (8%), HBV in 41 (6%), other etiology in 5
patients (1%); and 292 patients had concomitant HCC (43%).
Sarcopenia was noted in 291 patients (43%), and 353 patients
had myosteatosis (52%). A total of 216 patients (32%) had his-
tory of hepatic encephalopathy (162 grade I-II, 54 grade III-IV).
The prevalence of hepatic encephalopathy was significantly
higher in patients with sarcopenia (40 vs. 26%, P<0.001), and
myosteatosis (39 vs. 24%). By multivariate regression analysis
(adjusted to age, gender, and MELD score), both sarcopenia
(OR 1.68, (95% CI 1.04-2.40, P=0.03), and myosteatosis
(OR 1.97, 95% CI 1.32-2.99, P=0.001) were significantly
associated with hepatic encephalopathy. Conclusions: Cir-
rhotic patients with sarcopenia and myosteatosis have a higher
risk of overt hepatic encephalopathy. Skeletal muscle seems to
play a protective role in the pathogenesis of hepatic encepha-
lopathy in cirrhosis, and therapeutic strategies to improve the
muscle mass and quality may improve hepatic encephalopathy
in cirrhosis.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Disclosures:
Andres Duarte-Rojo - Advisory Committees or Review Panels: Gilead Sciences;
Grant/Research Support: Vital Therapies
The following people have nothing to disclose: Aldo J. Montano-Loza, Christo-
pher F. Rose
372
Bacterial antigen translocation in patients with cirrhosis
and minimal hepatic encephalopathy is associated with
increased serum ammonia and nitric oxide levels
Pablo Bellot1,3, Rocío Gallego-Durán2,3, Alba Moratalla1,3, Javier
Ampuero2,3, Pedro Zapater1,3, Manuela Roger1, Blanca Figuer-
uela2,3, Belén Martínez1, José M. González-Navajas1,3, Jose
Such1,3, Manuel Romero-Gómez2,3, Ruben Frances1,3; 1Hospital
General Universitario Alicante, Alicante, Spain; 2Hospital Univer-
sitario Valme, Sevilla, Spain; 3CIBERehd - Instituto de Salud Carlos
III, Madrid, Spain
Background&Aims: Bacterial translocation is a frequent event
in patients with cirrhosis and ascitic fluid. Minimal hepatic
encephalopathy (MHE) is also frequent among patients with
cirrhosis. Several enteric bacteria are natural producers of
ammonia. We investigated whether an association between
bacterial products translocation and serum ammonia levels can
be established in decompensated cirrhotic patients with MHE.
Patients&Methods: Consecutively admitted cirrhotic patients
with ascites and MHE from Hospital General Universitario de
Alicante, Spain, and Hospital Valme de Sevilla, Spain, were
included. Clinical and alytical data were recorded. MHE was
diagnosed by using the psychometric hepatic encephalopa-
thy score (PHES). Serum bacterial DNA, endotoxin, ammonia
and nitric oxide levels were measured. Results: Forty patients
were included in the study (29 male, mean age 60±9.8 years).
Etiology was mainly alcohol (n=22, 55%) and HCV (n=11,
27.5%). Fifteen patients (37.5%) presented ascites. Mean
MELD score was 10.9±4.6 and mean INR was 1.30±0.24.
Bacterial DNA was identified in 12 patients (30%) and corre-
sponded to Gram-negative microorganisms in 10 cases. No
differences were observed in any clinical or analytical variable
when when patients were distributed by the presence of bacte-
rial DNA. Serum levels of ammonia (2.30±0.92 vs 5.59±1.60
nmol/uL), endotoxin (1.76±0.65 vs 4.40±0.77 UE/mL) and
nitric oxide (15.10±2.54 vs 26.50±2.60 nmol/mL) were sig-
nificantly higher in patients with blood bacterial DNA translo-
cation (p<0.01 in all cases). Mean amplified bacterial DNA
concentration was (28. 5±3.9 ng/uL). Serum ammonia levels
showed a positive correlation with endotoxin levels (r=0.74,
p<0.01) and with nitric oxide levels (r=0.72, p<0.01) in the
overall series of patients. Among patients with bacterial DNA,
serum ammonia levels showed a positive correlation with
amplified bacterial DNA concentration (r=0.78, p<0.01). The
median PHES score was significantly higher in patients with
bacterial DNA translocation (-6 [-12 - -4] vs -8 [-11 - -5], p=
0.03) Conclusions: Bacterial antigenic product translocation
into blood in cirrhotic patients with mimimal hepatic encepha-
lopathy is associated with significantly increased serum ammo-
nia and nitric oxide levels.
385A
Disclosures:
Jose Such - Consulting: Sequana Medical, Sequana Medical, Sequana Medical,
Sequana Medical; Stock Shareholder: Sequana Medical, Sequana Medical,
Sequana Medical, Sequana Medical
Manuel Romero-Gómez - Advisory Committees or Review Panels: Roche Farma,
SA, MSD, SA, Janssen, SA., Abbvie,SA; Grant/Research Support: Gilead Sci-
ences, S.A.
The following people have nothing to disclose: Pablo Bellot, Rocío Galle-
go-Durán, Alba Moratalla, Javier Ampuero, Pedro Zapater, Manuela Roger,
Blanca Figueruela, Belén Martínez, José M. González-Navajas, Ruben Frances
373
Diabetes causes hepatic encephalopathy through bacte-
rial translocation—analysis of data from three random-
ized controlled trials
Peter Jepsen1,2, Hendrik V. Vilstrup1, Hugh R. Watson3; 1Depart-
ment of Hepatology and Gastroenterology, Aarhus University Hos-
pital, Aarhus, Denmark; 2Department of Clinical Epidemiology,
Aarhus University Hospital, Aarhus, Denmark; 3Sanofi Aventis
R&D, Sanofi Aventis, Paris, France
Background: Diabetes mellitus is a risk factor for hepatic
encephalopathy (HE) in cirrhosis patients, but the mechanism is
unclear. We examined whether it may be related to bacterial
translocation (BT) from the gut. Methods: We used the data
from three randomized controlled trials of satavaptan treat-
ment of ascites in cirrhosis patients. During the one-year fol-
low-up the participants were examined regularly for HE. We
included those with no history of HE before randomization and
followed them to first HE episode or death. They were divided
in two groups: The group with ‘probable BT’ was defined by
having spontaneous bacterial peritonitis or using proton pump
inhibitors, propulsives or laxatives, because such use suggests
that the gastrointestinal transit is prolonged. The other group
consisted of all other patients. Patients could switch between
the two groups during follow-up. We used Cox regression
to estimate the effect of diabetes on HE development and on
mortality in the two groups, and we adjusted for gender and
age, Child-Pugh score, serum creatinine, and serum sodium.
Results: We included 862 cirrhosis patients, and 193 (22%)
had diabetes, nearly all (96%) of type 2. During follow-up, 578
patients had ‘probable BT’ at some point. Fifty patients died,
and 181 developed HE. Patients with ‘probable BT’ had higher
HE incidence than other patients (54.0 vs. 20.5 per 100 per-
son-years), indicating a strong association between BT and HE
risk (Fig. 1). Among patients without ‘probable BT’ diabetes
was unassociated with development of HE (adjusted hazard
ratio [aHR] = 0.98, 95% CI 0.49–1.95). By contrast, among
patients with ‘probable BT’ diabetes was a strong risk factor
for HE development (aHR = 1.63, 95% CI 1.10–2.42). This
excess risk of HE was more pronounced for diabetics on insulin
(aHR vs. no diabetes = 2.00, 95% CI 1.25–3.21) than for
those on oral antidiabetics (aHR vs. no diabetes = 1.58, 95%
CI 0.85–2.94), or diet alone (aHR vs. no diabetes = 0.88,
95% CI 0.35–2.20). Diabetes increased mortality irrespective
of ‘probable BT’. Conclusion: Diabetes was a risk factor for
HE among cirrhosis patients provided that they were likely to
have BT. This finding indicates that diabetes aggravates BT or
weakens the immune response to BT in cirrhosis patients. The
dose-response relationship between the severity of diabetes
and the HE risk reinforced this interpretation.
Disclosures:
Hugh R. Watson - Employment: Sanofi-aventis R&D; Stock Shareholder: Sano-
fi-aventis R&D
The following people have nothing to disclose: Peter Jepsen, Hendrik V. Vilstrup
386A AASLD ABSTRACTS
374
The combination of MELD-Score and Critical Flicker Fre-
quency could filter patients needing no further testing
for covert hepatic encephalopathy
Robin A. Greinert, Cristina Ripoll, Marcus Hollenbach, Alexander
Zipprich; Department of Internal Medicine I, Martin-Luther-Univer-
sity Halle-Wittenberg, Halle, Germany
AIM: Diagnosis of covert hepatic encephalopathy (CHE) is
done with a combination of tests, which is manpower and time
consuming. A stepwise application of diagnostic tests could
avoid unnecessary testing and economize resources. The aim
of the present study was to determine the performance of the
critical flicker frequency (CFF), alone or in combination with
laboratory findings, as an initial test to evaluate which patients
should undergo further testing for the diagnosis of CHE. METH-
ODS: All patients with cirrhosis that were admitted between
January 2011 and December 2012 who underwent PSE-Syn-
drom-Test (PSE) and CFF were included. These tests are in the
standard evaluation of patients with cirrhosis in our center. CHE
was defined by abnormal age-corrected PSE without signs of
overt hepatic encephalopathy (OHE). Patients with OHE were
excluded. Data are described with proportions or medians
(interquartile range: IQR). Parametric or non-parametric tests
were used as appropriate. Multivariate logistic regression anal-
ysis was performed to identify predictors of CHE. ROC curves
were used to identify cut-offs of these independent predictors.
RESULTS: 117 patients with cirrhosis were included [age 59
(IQR 48-67) years; 32 % female; 74 % alcohol-associated; CFF
40 Hz (IQR 37-42); MELD 14 (IQR 11-19)]. 69 patients had
CHE (59 %) with a higher MELD [16 (IQR 13-21); p=0.001]
and a lower CFF [38 Hz (IQR 36-41) p=0.001] compared to
patients without HE. CHE was also associated with a higher
Child-Pugh score (p=0.003) and a higher prevalence of ascites
(93 % vs. 69 %; p=0.001). On multivariate analyses CFF [OR
0.83 (CI 0.74-0.94)] and MELD [OR 1.13 (CI 1.04-1.22)]
were identified as independent predictors of CHE. A CFF cutoff
of 43 Hz has a sensitivity of 96.1 % and a specificity of 35.7
% with a negative and positive predictive value of 89 % and
67 %, respectively. A MELD-Score with a cutoff value of 24
has a sensitivity of 97.4 % and a specificity of 30.4 % with a
positive and negative predictive value of 65.8 % and 89.5 %.
Most patients with a MELD-Score < 24 and a CFF > 43 Hz did
not have CHE (14/18, 78%) and with a MELD-Score > 24 and
CFF < 43 Hz most patients had CHE (10/11, 91%). Therefore,
27.3 % of patients could avoid further testing with PSE with a
diagnostic accuracy of 81 %. CONCLUSION: The combina-
tion of MELD-Score and CFF may be used as a first diagnostic
step to filter the patients, in whom further CHE testing could be
avoided. With this approach, further resource-consuming tests
could be spared in over 25% of patients.
Disclosures:
The following people have nothing to disclose: Robin A. Greinert, Cristina Ripoll,
Marcus Hollenbach, Alexander Zipprich
375
High Prevalence of Nodular Regenerative Hyperplasia
in Patients with End-Stage Heart Failure and Outcomes
after Cardiac Transplantation
Ken D. Nguyen, Aung Kaung, Anish V. Patel, Michelle Kittleson,
Marc L. Friedman, Maha Guindi, Vinay Sundaram, Tram T. Tran;
Cedars-Sinai Medical Center, Los Angeles, CA
AIMS: Nodular regenerative hyperplasia (NRH) is a rare
hepatic disorder, with an estimated prevalence of 2.56% seen
in autopsies. At a large transplant center we have noted a
HEPATOLOGY, October, 2014
high prevalence of NRH in patients with end-stage heart failure
(New York Heart Association [NHYA] class III-IV, stage D). It
is unknown how NRH affects patient survival after OHT. The
aim of the study is to evaluate impact of NRH on post-OHT
survival. METHODS: We conducted retrospective chart review
of patients older than 18 years, with end-stage heart failure
undergoing evaluation for OHT. Patients with multi-organ or
re-transplantation were excluded. NRH was diagnosed based
on pre-transplant liver biopsy. Patients with NRH who subse-
quently underwent OHT were included in survival analysis.
Post-transplant survival was compared to patients without NRH
on biopsy or those without liver biopsy who had no history of
liver disease, abnormal liver enzymes (defined as >2x ULN), or
abnormal liver imaging prior to OHT. Statistical analysis was
conducted using Fisher’s exact test, Cox proportional hazards
regression, and log-rank test. RESULTS: NRH was found in 23 of
65 (35%) patients with end-stage heart failure on pre-transplant
liver biopsy. 12 of these patients underwent OHT and were
compared to 99 control subjects without NRH. In patients with
at least one year of followup, there was no difference in 1-year
post-transplant survival (p=0.557) between NRH patients (8 of
9 patients, 88.9%) versus non-NRH patients (91 of 99 patients,
91.9%). Using Cox proportional hazards regression, the pres-
ence of NRH was not associated with worse longterm survival
when controlling for significant liver fibrosis (Metavir fibrosis
score F2-F4) and age at transplantation; results are summarized
on Table 1. Log-rank testing showed similar post-transplant sur-
vival between patients with and without NRH. CONCLUSION:
Although an overall rare finding, NRH is found frequently in
patients with end-stage heart failure. NRH is not associated
with worse 1-year or longterm post-transplant survival. NRH
in the absence of significant fibrosis or cirrhosis should not be
considered a contraindication to OHT.
Table 1: Cox proportional hazards regression after cardiac trans-
plant.
Abbreviations: CI - confidence interval, HR - hazard ratio, NRH -
nodular regenerative hyperplasia
Disclosures:
Vinay Sundaram - Advisory Committees or Review Panels: Salix, Gilead, Jansen;
Speaking and Teaching: Salix
Tram T. Tran - Advisory Committees or Review Panels: Gilead, Bristol Myers
Squibb; Consulting: Gilead, AbbVie, Janssen; Grant/Research Support: Bristol
Myers Squibb; Speaking and Teaching: Bristol Myers Squibb, Gilead
The following people have nothing to disclose: Ken D. Nguyen, Aung Kaung,
Anish V. Patel, Michelle Kittleson, Marc L. Friedman, Maha Guindi
376
Algorithm for Correcting Vitamin D Deficiency in
Patients Awaiting or Being Evaluated for Liver Trans-
plantation
Shai Posner3, Emily Schonfeld1, Alexis Pappas1, Dana R. Berg2,
Kian Bichoupan2, Thomas D. Schiano1, Andrea D. Branch1, Jona-
than Barsa2; 1Medicine, Icahn School of Medicine at Mount Sinai,
New York, NY; 2Internal Medicine, Mount Sinai Hospital, New
York, NY; 3Icahn School of Medicine at Mount Sinai, New York,
NY
Aims: To identify factors influencing the dose-response curve
of supplemental vitamin D3 (Vit-D) and 25-hydroxyvitamin D
[25(OH)D] in patients awaiting or being evaluated for liver
transplantation (LT) and to develop evidence-based guidance
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
for correcting vitamin D deficiency. Methods: This open-label
trial of adults with cirrhosis awaiting or being evaluated for LT
(NCT01575717) analyzed a two-tiered dosing regimen of oral
Vit-D in 66 patients with baseline 25(OH)D ≤ 25 ng/mL: 4000
IU/d of Vit-D for 25(OH)D ≤ 15 ng/mL (severe deficiency) and
2000 IU/d of Vit-D for 25(OH)D > 15 and ≤ 25 ng/mL (moder-
ate deficiency). Serum 25(OH)D levels were measured at 3 and
6 months. Dose-response data were analyzed in 48 patients
who maintained ≥ 80% adherence. The relationship between
baseline factors and changes in 25(OH)D per 1000 IU/d of
Vit-D were analyzed by multivariable linear regression. Results:
The median age was 60 yr, 75% were male, 54% were HCV
positive, 42% had hepatocellular carcinoma, 17% were black,
and the median natural MELD score was 10.9. Seventy-one per-
cent achieved 25(OH)D levels in the target range of 25-60 ng/
mL. No patient developed hypercalcemia or vitamin D toxicity.
The absolute increase in 25(OH)D was approximately two-fold
greater in severely deficient patients receiving 4000 IU/d than
in moderately deficient patients receiving 2000 IU/d (Table).
Multivariable linear regression revealed that the incremental
increase in 25(OH)D was inversely related to natural MELD
(beta = -0.26; p = 0.03) and age (beta = -0.16; p = 0.008).
Based on these data the dose of Vit-D needed to raise 25(OH)
D over 25 ng/mL = [(25 - Baseline 25(OH)D) + (Natural MELD
x 0.79) + (Age x 0.41) - 30.47] / 0.0064. Using modeling
techniques, we developed a point system for calculating dose,
scoring one point each for baseline 25(OH)D ≤ 15 ng/mL, age
≥ 55 yr, and natural MELD > 15, with a dose of 2000 IU/d
for 0 points, 4000 IU/d for 1-2 points, and 6000 IU/day for
3 points. Had we applied this, we estimate that all 48 patients
would have achieved 25(OH)D levels in the target range. Con-
clusions: This study provides dose-response data on Vit-D sup-
plementation in patients with cirrhosis and provides guidance
for correction of vitamin D deficiency. Both greater age and
more advanced liver disease, as indicated by a higher natural
MELD score, blunt responsiveness and predict need for dose
adjustments (DA031095, DK090317, CA152514).
Response to Vitamin D3 Supplementation
Disclosures:
Kian Bichoupan - Consulting: Janssen Pharmaceuticals, Gilead Sciences
Thomas D. Schiano - Advisory Committees or Review Panels: vertex, salix, merck,
gilead, pfizer; Grant/Research Support: massbiologics, itherx
Andrea D. Branch - Grant/Research Support: Kadmon, Gilead, Janssen
The following people have nothing to disclose: Shai Posner, Emily Schonfeld,
Alexis Pappas, Dana R. Berg, Jonathan Barsa
387A
377
Hepatopulmonary syndrome screening in a large trans-
plant center: Prevalence and impact on survival
Manuel Mendizabal1, David S. Goldberg2, Federico Piñero1,
Diego T. Arufe1, Pablo A. Testa1, Juan M. Coronel1, Maria Pia
Raffa1, Sergio Baratta3, Luis G. Podesta1, Michael B. Fallon4,
Marcelo O. Silva1; 1Liver Unit, Hospital Universitario Austral, Pilar,
Argentina; 2Gastroenterology, University of Pennsylvania, Philadel-
phia, PA; 3Cardiology, Hospital Universitario Austral, Pilar, Argen-
tina; 4Gastroenterology, Hepatology and Nutrition, The University
of Texas Health Science Center at Houston, Houston, TX
Background: The natural history of intra-pulmonary vascular
dilations (IPVD) in portal hypertension is poorly characterized
and the relationship to the development of hypoxemia and
hepatopulmonary syndrome (HPS) is unclear. Aims: To evalu-
ate the impact of IPVDs and HPS on long-term survival among
patients evaluated for liver transplantation (LT) and to assess
the development of HPS in those with IPVD. Methods: Data
from a prospective cohort of 267 patients evaluated for LT with
standardized screening for HPS were analyzed. Arterial blood
gases (ABG) and contrast-enhanced echocardiogram (CEE)
were recorded. IPVDs were identified with the occurrence
of microbubbles in the left atrium >3 cycles following right
atrial opacification. HPS was defined as the presence of IVPD
and hypoxemia (Alveolar-arterial [A-a] gradient >15mmHg)
in the absence of concomitant cardiopulmonary disease.
Results: 133 patients with negative CEE were compared to 55
patients with IVPD and 60 patients with HPS. Baseline demo-
graphics and clinical characteristics are described on table
1. Only 6 patients developed severe HPS (PaO2<60mmHg)
and 5 were granted with Model for End-Stage Liver Disease
(MELD) exception points. After LT evaluation 75%, 88% and
70% of the patients with negative CEE, IVPD and HPS were
listed, respectively. LT rate and death on the waiting list was
44%/19% in the negative CEE group, 44%/14% in the IVPD
group and 48%/28% in the HPS group, respectively (P=0.2).
Overall adjusted survival from the time of LT evaluationusing
multi-state survival models that accounted for pre- and post-LT
time was not statistically different among the three groups. 19
IVPD patients were followed with ABG over a mean duration
of 21 months (range 9-43).Basal and follow up arterial oxygen
and A-a gradient were 100±8 and 94±10 mmHg (P=0.01),
and 5±4 and 13±12 (P=0.04); respectively, with 7 patients
subsequently meeting HPS criteria. Conclusions: In a cohort of
patients where severe HPS is uncommon, survival in patients
with HPS and IVPD is similar compared to those with negative
CEE. Patients with IVPD appear to have a significant risk of
developing oxygenation impairment over time and may prog-
ress to HPS.
Baseline demographics and clinical characteristics
Disclosures:
David S. Goldberg - Grant/Research Support: Bayer Healthcare
Michael B. Fallon - Grant/Research Support: Bayer/Onyx, Eaisi, Gilead, Grifolis
The following people have nothing to disclose: Manuel Mendizabal, Federico
Piñero, Diego T. Arufe, Pablo A. Testa, Juan M. Coronel, Maria Pia Raffa, Sergio
Baratta, Luis G. Podesta, Marcelo O. Silva
388A AASLD ABSTRACTS
378
Disturbed sleep is highly prevalent in patients with cir-
rhosis and is independently associated with poor qual-
ity of life
Mollie Jackson, Raghavender Gotur, Edra Nordstrom, Eric S.
Orman, Raj Vuppalanchi, Naga P. Chalasani, Marwan Ghabril;
Gastroenterology and Hepatology, Indiana University, Indianap-
olis, IN
Background: Patients with cirrhosis frequently report disturbed
sleep, but its prevalence, determinants and consequences are
not well understood. Aim: To prospectively assess the presence,
determinants and impact of disturbed sleep in patients with
cirrhosis. Methods: Cirrhotics attending outpatient liver clinics
between 12/2012 and 12/2013 were invited to participate.
Subjects completed 4 questionnaires to assess; (a) sleep quality
using the Pittsburgh Sleep Quality Index (PSQI), (b) daytime
sleepiness using the Epworth Sleepiness Scale (ESS), (c) quality
of life using the Chronic Liver Disease Questionnaire (CLDQ)
score, and (d) muscle cramps. Demographic, clinical including
the history of preexisting sleep disorders and use of sedat-
ing medicines and laboratory data were collected. Hepatic
encephalopathy was assessed clinically and by psychometric
testing. Poor sleep is defined as PSQI>5. Predictors of poor
sleep and of quality of life were determined by simple and mul-
tiple regression analysis. Results: 200 subjects were enrolled (7
were excluded for non-completion, alternating sleep/work shifts
and interferon therapy). Of the 193 study subjects (58% men,
mean age 58±9 years) 157 (81%) had poor sleep (PSQI>5),
104 (54%) had excessive daytime sleepiness (ESS>8), and 90
(46%) reported muscle cramps. Subjects with poor sleep had
higher Childs class, poor quality of life, more frequent day time
sleepiness (ESS>8), and prescription narcotic/sedating med-
ication use (table 1). The predictors of poor sleep on multiple
logistic regression were; serum albumin (OR 0.4, 95%CI 0.2-
0.8, p 0.01), narcotics (odds ratio 5, 95%CI 1.4-18, p 0.01)
and muscle cramps (OR 5.1, 95%CI 1.9-15, p 0.002), but not
hepatic encephalopathy. The predictors of decreased quality of
life (CLDQ) on multiple linear regression were; PSQI>5 (β -36,
95%CI -24 to -49, p<0.001), muscle cramps (β -19, 95%CI
-10 to -28, p<0. 001), hepatic encephalopathy (β -16, 95%CI
-7 to -25, p<0.001) and prescription opioid use (β -12, 95%CI
-3 to -22, p 0.015). Conclusion: Disturbed sleep is frequent in
ambulatory cirrhotic patients, and is independently associated
with poor quality of life. Further studies are needed to better
understand the pathogenesis of poor sleep and its manage-
ment strategies.
Table 1
Disclosures:
Naga P. Chalasani - Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-
rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin
Marwan Ghabril - Grant/Research Support: Salix
The following people have nothing to disclose: Mollie Jackson, Raghavender
Gotur, Edra Nordstrom, Eric S. Orman, Raj Vuppalanchi
HEPATOLOGY, October, 2014
379
Apraxia in Patients with Liver Cirrhosis. Influence of
Hepatic Encephalopathy
Montserrat O. Flavia1,4, Victor Vargas1,3, Carlos Jacas2,3, M. Ven-
tura1,4, Irene Conejo1,4, Rafael Esteban1,3, Joan Cordoba1,3; 1Liver
Unit, Hospital Vall d’Hebron. Universidad Autonoma Barcelona,
Barcelona, Spain; 2Geriatric Service, Hospital Vall d’Hebron, Bar-
celona, Spain; 3Ciberehd, Instituto de Salud Carlos III, Madrid,
Spain; 4Vall d’Hebron- Institut de Recerca, Barcelona, Spain
Background: Patients with hepatic encephalopathy display
mental and motor changes. Many cirrhotic patients show some
type of neuropsycological abnormalities. However, apraxia
disorders have not been well characterized in them. Aim: To
assess the presence of apraxia in compensated and decompen-
sated cirrhotic patients and the influence of previous hepatic
encephalopathy. Methods: We designed a neuropsychologi-
cal test battery to assess the praxis that included: a) a subset
of praxis of the 2nd edition of the Boston’s Aphasia battery
(graphomotor and non graphomotor sequences, reciprocal
coordination, non symbolic intransitive praxis) and, b) Barce-
lona Test (bucofacial praxis, gestural intransitive praxis and
transitive praxis to command and imitation). In addition to this
battery, we also used other neuropsychological test to screen
general executive functions (FAB), speed of information pro-
cessing (Symbol digit oral version, SDO), complex cognitive
motor control (Grooved Pegboard, GP), and minimal hepatic
encephalopathy (PHES). This battery was administered to: a)
101 cirrhotic patients; 28 compensated and 73 decompen-
sated (27 with previous hepatic encephalopathy) and b) 101
healthy subjects matched by sex, age and years of education
(71 male/30 female; median age: 63 years; median education
years: 10 years). At the evaluation, none of the patients had
signs of hepatic encephalopathy. Results: Compared to healthy
subjects, cirrhotic patients showed significant impairment in
most praxis and related test: graphomotor sequences (p<0.
03), non graphomotor sequences (p<0.001), coordination
(p<0.001), non symbolic intransitive praxis (p<0.005), gestural
intransitive praxis (p<0.05), transitive praxis with all the body
to command (p<0.002), FAB (P<0.001), GP (p<0.001) and
SDO (p<0.001). There were no significant differences between
compensated and decompensated cirrhotic patients. In decom-
pensated cirrhosis, patients with previous encephalopathy had
significant impairment in most of the neuropsychological tests
(p<0.005) than those without previous encephalopathy. Sever-
ity of apraxia was correlated with age, PHES score and less
extended with severity of liver cirrhosis (MELD and Child-Pugh
scores). Conclusions: Apraxia disorders are present in patients
with hepatic cirrhosis. Cirrhotic patients had more apraxia dis-
orders than healthy subjects, especially among patients with
history of hepatic encephalopathy, who showed a higher fron-
tal-subcortical dysfunction. Minimal hepatic encephalopathy
may play a role in the severity of apraxia signs.
Disclosures:
Rafael Esteban - Speaking and Teaching: MSD, BMS, Novartis, Gilead, Glaxo,
MSD, BMS, Novartis, Gilead, Glaxo, Janssen
The following people have nothing to disclose: Montserrat O. Flavia, Victor Var-
gas, Carlos Jacas, M. Ventura, Irene Conejo, Joan Cordoba
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
380
Trends of Serial MELD Scores has an Incremental Prog-
nostic Value in Predicting In-Hospital Mortality of ICU
Cirrhotic Patients
Thoetchai Peeraphatdit1, Charat Thongprayoon3, Niyada Nak-
suk2, Roongruedee Chaiteerakij4,5, Lewis R. Roberts4; 1Department
of Internal Medicine, University of Minnesota, Minneapolis, MN;
2Cardiovascular Division, Mayo Clinic College of Medicine, Roch-
ester, MN; 3Department of Anesthesiology, Mayo Clinic College
of Medicine, Rochester, MN; 4Division of Gastroenterology and
Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic
Cancer Center, Rochester, MN; 5Department of Medicine, Faculty
of Medicine, Chulalongkorn University and King Chulalongkorn
Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
Background: Model for End Stage Liver Disease (MELD) score is
commonly tested daily to assess the severity of cirrhotic patients
in the intensive care unit (ICU). Whether serial MELD scores
are beneficial has not been well studied. Aim: To determine
the prognostic performance of serial evaluation and trends
of MELD scores in predicting in-hospital mortality in cirrhotic
patients admitted to the ICU Method: This is a retrospective
study conducted in a tertiary referral center. A total of 1,814
consecutive cirrhotic patients admitted to the ICU between
2003 and 2013 were included. Clinical information and daily
MELD scores during the first 7 days after the index ICU admis-
sion or until hospital discharge were abstracted. The perfor-
mance of daily MELD and trends of MELD scores in predicting
in-hospital mortality was assessed using area under receiver
operating characteristic (AUC) by logistic regression and land-
mark analysis. Result: The mean age was 60 years and 60%
were male. The initial MELD score was 20±9 (mean ± standard
deviation). Approximately 60% were admitted to the ICU due
to illnesses related to cirrhosis; 50% required mechanical ven-
tilation and hemodynamic supports. The in-hospital mortality
was 10% (n=181). The initial MELD score was an indepen-
dent predictor of in-hospital mortality (Odds ratio 1.04; 95%
confidence interval 1.01-1.07; p=0.002). The MELD scores
obtained during the first 3 days demonstrated an increasing
trend in the prognostic value as evident by an improvement
in AUC in predicting in-hospital mortality from 0.69 to 0.79
(Table). When the changes in MELD scores from prior values
were incorporated into the model, a significant increase in
AUC was observed, compared to the daily MELD scores alone
(p≤0.05). However, beyond day 3, neither daily MELD scores
nor changes in MELD scores added any incremental value in
mortality prognosis (Table). Conclusion: Trends of MELD scores
during the first 3 days of ICU admission improved the perfor-
mance of serial MELD scores in predicting in-hospital mortality
of cirrhotic patients admitted to the ICU.
AUC of daily MELD scores AUC of combined daily MELD scores
and changes from the prior scores
389A
Disclosures:
Lewis R. Roberts - Grant/Research Support: Bristol Myers Squibb, ARIAD Pharma-
ceuticals, BTG, Wako Diagnostics, Inova Diagnostics, Gilead Sciences
The following people have nothing to disclose: Thoetchai Peeraphatdit, Charat
Thongprayoon, Niyada Naksuk, Roongruedee Chaiteerakij
381
Metformin reduces hyperammonemia in portacaval
shunted rats inhibiting intestinal glutaminase activity
Antonio Gil-Gómez, Isidora Ranchal, Ana Isabel Gomez-Sotelo,
Marta García-Valdecasas, Angela Rojas, Jose A. Del Campo,
Manuel Romero-Gómez; Valme University Hospital, Seville, Spain
Background&aims: Metformin has been found able to pro-
tect cirrhotic patients against hepatic encephalopathy (HE)
(Ampuero et al. 2012). K-type glutaminase activity is increased
in HE and it has been proposed as the main source of ammo-
nia in liver disease. The aim of this work was to analyze the
effect of metformin on glutaminase (GLS1) gene expression
and K-type glutaminase enzyme activity in a rat model of HE.
Methods: RT-PCR and glutaminase activity assays were per-
formed in different tissues from 16 male Wistar rats that under-
went portacaval shunt (PCS). Eight animals were treated with
30 mg/kg/day of metformin for two weeks. RT-PCRs were
made using SensiFAST™ SYBR Lo-ROX One-Step Kit (Bioline,
EEUU) in presence of Gapdh and Gls1 primers (QIAGEN, Ger-
many) in an Eco™ Real Time PCR System (illumina®, EEUU).
Glutaminase activity was assayed following the colorimetric
protocol described by Heini. Plasma ammonia was measured
following the glutamate-dehidrogenase enzymatic assay in a
COBAS Integra® 700 (ROCHE, Switzerland). Results: Gls1
gene expression levels were not modulated in small intestine
by metformin (1.05±0.11 fold change in PCS rats receiving
metformin). In intestinal tissue, metformin treatment was associ-
ated with a significant inhibition of glutaminase activity levels
(0.277±0.11 mU/mg vs 0.142±0.07 mU/mg); p<0.05. In non-
treated PCS rats, plasma ammonia level reached 238.8±166.1
mg/dL. Treatment with metformin significantly decreased
plasma ammonia levels to 110.0±49.1 mg/dL;p<0.01. Con-
clusions: Metformin use decreases hyperammonemia in PCS
rats inhibiting intestinal glutaminase activity in small intestine
but did not modify intestinal Gls1 gene expression suggesting
a postranslational effect.
Disclosures:
Manuel Romero-Gómez - Advisory Committees or Review Panels: Roche Farma,
SA, MSD, SA, Janssen, SA., Abbvie,SA; Grant/Research Support: Gilead Sci-
ences, S.A.
The following people have nothing to disclose: Antonio Gil-Gómez, Isidora Ran-
chal, Ana Isabel Gomez-Sotelo, Marta García-Valdecasas, Angela Rojas, Jose
A. Del Campo
382
Cost-effectiveness of rifaximin treatment in patients with
hepatic encephalopathy
Duygu Bozkaya1, Andrew C. Barrett2, Kristen Migliaccio-Walle1;
1Xcenda, Palm Harbor, FL; 2Salix Pharmaceuticals, Raleigh, NC
Background: It is increasingly appreciated that patients with
hepatic encephalopathy (HE) require long-term prophylactic
therapy after experiencing an episode of overt HE. Rifaximin
550 mg is a minimally absorbed antimicrobial agent approved
for the reduction in risk of overt HE recurrence in the US.
Recent studies have demonstrated the effectiveness of rifaxi-
min in reducing episodes of HE, HE-related hospitalizations,
and HE-related mortality compared to lactulose alone. This
study aimed to assess whether these clinical benefits could be
390A AASLD ABSTRACTS
achieved at a reasonable cost in the US. Methods: A cost-ef-
fectiveness model from the third-party payer perspective in the
US was created to predict outcomes and costs of patients with
HE after initiation of maintenance therapy with lactulose with
or without rifaximin 550 mg twice daily to avoid recurrent HE
episodes. Costs included drug costs, hospitalizations, and liver
transplant; health outcomes were: hospitalizations (all-cause,
HE-related, non-HE-related), life-years (LYs), quality-adjusted
life-years (QALYs). Indirect costs were not included. Analyses
to estimate the incremental costs per hospitalization avoided
were run over a 6-month time frame, consistent with the dura-
tion of a randomized, placebo-controlled, multicenter trial.
Costs per LY gained and per QALY gained were estimated
over a lifetime horizon. Results: Changes in life expectancy
with rifaximin ranged from approximately neutral compared to
lactulose alone over 6 months (0.5 vs 0.4 years, respectively)
to double over a lifetime (5.7 vs 2.8 years). Similar results were
observed for QALYs. Extended life expectancy with rifaximin
translated into a 2-fold increase in patients being able to obtain
a liver transplant in their lifetime. Hospitalization rates were
lower over 6 months (0.27 vs 0.51 per patient) and marginally
higher over a lifetime (2.06 vs 1.98 per patient) with rifaxi-
min owing to added life expectancy. These outcomes were
estimated at an additional cost of $59,777 per patient in a
lifetime resulting in costs per LY and QALY gained of $20,287
and $26,672, respectively. Conclusion: The clinical benefits of
rifaximin (e.g., improved maintenance of remission, avoidance
of hospitalizations, reversal of HE and reduction in mortality)
combined with an acceptable economic profile demonstrate
the potential advantages of a rifaximin maintenance regimen
for patients with recurrent HE depending on willingness to pay
thresholds of the payer and time period considered.
Disclosures:
Duygu Bozkaya - Consulting: Xcenda
Andrew C. Barrett - Employment: Salix Pharmaceuticals, Inc.; Stock Shareholder:
Salix Pharmaceuticals, Inc.
Kristen Migliaccio-Walle - Stock Shareholder: Merck and Company
383
Fragmented QRS is an independent predictor of mortal-
ity in patients with decompensated cirrhosis
Mehmet Demir; 1Gastroenterology, Mustafa Kemal Üniversity,
Hatay, Turkey; 2Gatsroenterology, Mustafa Kemal University,
Hatay, Turkey
Background and aims: It has been reported that the fragmented
QRS (fQRS) is related to left ventricular systolic dysfunction
and diastolic dysfunction. Left ventricular systolic dysfunction
and diastolic dysfunction have been considered as a compo-
nent of cirrhotic cardiomyopathy. The aim of this study was
to determine the relationship between the presence of fQRS
and mortality in patients with decompensated cirrhosis. Meth-
ods: This study is a retrospective single-center study. Clinical
and laboratory parameters of all cirrhotic patients at he Med-
ical University of Mustafa Kemal between 2010-2014 were
recorded. Patients with underwent liver transplantation, pul-
monary hypertension, TIPS and hepatoma were excluded. The
study included 148 patients with cirrhosis (age: 58±9 years;
61% male; Child A/B/C: 8/40/99; etiologies: viral: 59%,
alcohol: 21%, cryptogenic: 17%, others: 3%). fQRS pattern
was described as presence of RSR’ manifested as existence of
additional R wave and notching in either R or S waves in ECG
recordings. The predictive factors of death were determined
through univariate and multivariate analyses with the Cox
regression model. Results: During a mean follow-up of 21 ± 6
months, 35.1% (52/148) patients had deaths. The prevalence
HEPATOLOGY, October, 2014
of fQRS was 31.8% (47/148) in patients with decompen-
sated cirrhosis. All-cause mortality (57.4% [27/47] vs 24.7%
[25/101]) were higher in patients with the fQRS compared
with the non-fQRS patients. Univariate analysis showed that >
60 years old (p=0.02), presence of fQRS (p=0.012), < 125
mEq/L serum levels of sodium (p<0.001), > 2 mg/dl creatinine
(p=0.02), >4 mg/dl for total bilirubin (p=0.04), > 10 Child-
Pugh score (p=0.011) and > 20 MELD score (p=0.019) were
risk factors for mortality in patients with decompensated cirrho-
sis. According to the multivariate analysis presence of fQRS,
serum levels of sodium, Child-Pugh score and MELD score were
an independent predictive factor of mortality (respectively,
p<0.001, p=0.008, p=0.005, p< 0.001). Conclusions: In this
study, fQRS was found an independent predictor of mortality
in patients with decompensated cirrhosis. These data suggest
that the presence of fQRS may be a novel noninvasive and
cheap marker for predicting mortality in patients with decom-
pensated cirrhosis. Further studies will be needed to confirm
these findings.
Disclosures:
The following people have nothing to disclose: Mehmet Demir
384
Pancreatic congestion in liver cirrhosis correlates with
impaired insulin secretion
Taira Kuroda1, Masashi Hirooka1, Mitsuhito Koizumi1, Hironori
Ochi1, Yoshiko Hisano2, Kenji Bando3, Bunzo Matsuura1, Teru
Kumagi1, Yoichi Hiasa1; 1Gastroenterology and Metabology,
Ehime University Graduate School of Medicine, To-on, Japan;
2Pathology, Ehime University Hospital, Toon, Japan; 3Diagnostic
Pathology, Saiseikai Imabari Hospital, Imabari, Japan
Purpose: Although impaired glucose tolerance is common in
cirrhosis, this condition’s pathogenesis remains undefined. This
study aimed to clarify pathogenesis related to the pancreas in
cirrhotic patients, and to evaluate associations between insulin
secretion and pancreatic congestion due to portal hyperten-
sion. Materials and Methods: This study protocol was approved
by the institutional review board, and informed consent was
obtained. Pancreatic perfusion parameter (i.e., drainage blood
flow) were analyzed by dynamic contrast-enhanced ultrasound
(CE-US) in 41 patients (20 cirrhotic, 21 non-cirrhotic; age,
67.9 ± 13.3; female, 19), and prospectively compared to
delta C-peptide immunoreactivity (ΔCPR). The primary outcome
measure was a correlation of the time-intensity curve derived
from the CE-US results (time from peak to 1/2 peak of the
wash-out phase) and ΔCPR. In a separate study, a retrospective
chart review was conducted, and vessels and islets of the pan-
creas were analyzed in 43 patients (20 cirrhotic, 23 controls;
age, 71.5 ± 11.6; female, 15). The primary outcome measure
was the correlation between the diameter of the pancreatic
venous walls and the percentage of the insulin-positive area
per islet. Results: In the CE-US study, the clinical characteristics
indicative of portal hypertension (e.g., ascites and varices) had
significantly higher incidences in the cirrhotic group than in the
control group. Analyses of perfusion parameters revealed that
drainage times were significantly greater in the cirrhotic group
(P < 0.0001). ΔCPR was significantly lower in the cirrhotic
group (P = 0.0050). Drainage time was significantly correlated
with ΔCPR (R = 0.42, P = 0.0069). In the histopathological
study, the islets were enlarged (P < 0.0001), but the percent-
age of insulin-positive area per islet was significantly decreased
in the cirrhotic patients, as compared with the control group
(P < 0.0001). Additionally, the percentage of insulin-positive
area per islet was significantly correlated with the diameter of
the pancreatic venous walls (R = 0.63, P < 0.0001). Conclu-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
sion: The presence of pancreatic congestion was evident both
clinically and pathologically in LC patients. Further, pancreatic
congestion correlated with decreased insulin secretion of the
pancreas. Thus, in LC patients, portal hypertension might be
among the factors that induce hepatogenous diabetes. If so, the
treatment of portal hypertension in cirrhotic patients, including
B-RTO, splenectomy, or β-blockers, may have the potential to
improve hepatogenous diabetes.
Disclosures:
The following people have nothing to disclose: Taira Kuroda, Masashi Hirooka,
Mitsuhito Koizumi, Hironori Ochi, Yoshiko Hisano, Kenji Bando, Bunzo Mat-
suura, Teru Kumagi, Yoichi Hiasa
385
Correlations of portal hypertensive gastropathy with
clinical/hemodynamic complications and survival in
patients with liver cirrhosis
Hyo Sun Kim, Ki Tae Suk, Eun Jin Kim, Sang Hyun Park, Chang
Seok Bang, Dong Joon Kim; Hallym university college of medicine,
Chuncheon, Republic of Korea
Background: Portal hypertensive gastropathy (PHG) is a com-
mon gastric mucosal lesion in liver cirrhosis (LC). It is unclear
whether PHG correlates more with portal hypertension or with
liver dysfunction. We evaluated correlation of PHG with clin-
ical/hemodynamic parameters in patients with LC. Methods:
Between January 2006 and May 2013, a total of 574 patients
with LC who underwent hepatic venous pressure gradient
(HVPG) and endoscopy were prospectively enrolled. PHG was
graded into none, mild, and severe (Baveno III consensus work-
shop). HVPG, Child–Pugh (CP) score, model for end-stage liver
disease (MELD) score, complications of LC, mortality, and clini-
cal staging (CS) of liver cirrhosis were compared according to
the grade of PHG. CS was defined as 1 (no varix), 2 (varix),
3 (ascites), and 4 (bleeding). Results: Etiologies of LC were
chronic hepatitis B (40.7%), alcoholic liver disease (38.1%),
chronic hepatitis C (9.6%), and others (11.5%). HVPG was
related with PHG grade (p<0.001). Mean CP score and MELD
score were increased according to PHG grade (p<0.001).
Complications of LC was correlated with the PHG grade
(p<0.05). The overall mortality rate according to PHG grade
(none, mild, severe) was 1%, 6% and 15%, respectively. The
mean survival time according to PHG grade was 89±0.9,
84.2±1.8, and 70.9±2.6 months, respectively (p<0.001). The
1, 5, and 7-year survival rate in patients of PHG grade was
100%, 99%, and 99% (none); 99%, 94%, and 94% (mild);
94%, 85%, and 85% (severe), respectively (p<0.001). In the
Cox regression, PHG grade, HVPG, CP score, and clinical
staging were risk factors for mortality (p<0.05). Conclusions:
PHG grade can be alternative diagnostic findings to estimate
prognosis of cirrhotic patients. PHG grade can give us useful
information about survival rates of patients who did not evalu-
ate HVPG.
391A
Disclosures:
The following people have nothing to disclose: Hyo Sun Kim, Ki Tae Suk, Eun Jin
Kim, Sang Hyun Park, Chang Seok Bang, Dong Joon Kim
386
Portal vein thrombosis is not associated with increased
mortality in cirrhotic patients
Kristin Berry1, Justin Taylor2, Iris W. Liou1, George N. Ioannou1,2;
1Veterans Affairs Puget Sound Health Care System, Seattle, WA;
2University of Washington, Seattle, WA
Background and Aims Portal vein thrombosis (PVT) is com-
mon in patients with cirrhosis and may have adverse clinical
consequences. We aimed to determine whether PVT is asso-
ciated with survival in patients with cirrhosis. Methods Using
the United Network for Organ Sharing registries from 2002
to 2013, we followed a cohort of transplant-naïve adults with
cirrhosis without hepatocellular carcinoma (n=66,506) from
the time of transplant listing until the time of transplantation or
death before transplantation. We used Cox proportional haz-
ards analysis and competing risks analysis to compare patients
who had PVT at the time of listing (n=2207) to those who
did not (n=64,299) with regards to the risk of transplantation
or death before transplantation, after adjusting for important
baseline characteristics. Patients were not followed after trans-
plantation, since post-transplant survival was irrelevant for our
study’s aims. Results During a mean follow-up of 1.78 years,
17,757 patients (27%) died before undergoing transplanta-
tion, 29,179 (44%) underwent transplantation, and 19,570
(29%) were still alive without having undergone transplanta-
tion. Compared to patients who did not have PVT, those with
PVT had lower mortality (adjusted hazard ratio [AHR] 0.88
95% CI 0.81-0.96), similar risk of transplantation (AHR 0.95,
95% CI 0.89-1.02), and lower risk of the combined outcome of
death or transplantation (AHR 0.92, 95% CI 0.88-0.97). Sim-
ilar results were found by competing risks analyses. Important,
independent predictors of mortality included age, MELD score,
serum albumin level, ascites, encephalopathy, diabetes, HCV
infection and low (BMI < 24.4 Kg/m2) Conclusions Among
patients on liver transplant waiting lists, those with PVT have
lower mortality than those without PVT.
392A AASLD ABSTRACTS
Outcomes of patients listed for liver transplantation according to
presence or absence of portal vein thrombosis (PVT) at the time of
listing
*Hazard ratio and adjusted hazard ratio are derived from Cox
proportional hazard regression; Sub-hazard ratio and adjusted
sub-hazard ratio are derived from competing risks analysis, with
transplantation and death as the competing risks.
‡Adjusted for MELD score, underlying liver disease, age, gender,
race/ethnicity, diabetes, body mass index, serum albumin, asci-
tes, dialysis, encephalopathy, and ABO blood group.
Disclosures:
The following people have nothing to disclose: Kristin Berry, Justin Taylor, Iris W.
Liou, George N. Ioannou
387
Pre-Transplant Hepatic Encephalopathy is Associated
with Significantly Lower Survival Following Liver Trans-
plantation
Robert J. Wong1,2, Robert G. Gish1,3, Ramsey Cheung1,2, Aijaz
Ahmed1; 1Gastroenterology and Hepatology, Stanford University
School of Medicine, Stanford, CA; 2Gastroenterology and Hepa-
tology, Palo Alto Veterans Affairs Medical Center, Palo Alto, CA;
3Hepatitis B Foundation, Doylestown, PA
Background: The development of hepatic encephalopathy (HE)
in patients with cirrhosis is a manifestation of hepatic decom-
pensation and portends poor prognosis. The MELD score does
not incorporate HE and may underestimate severity of hepatic
decompensation among patients with HE. In addition, it is
not clear if the severity of pre-transplant HE is associated with
lower survival following liver transplantation (LT). Aim: To eval-
uate the effect of pre-transplant HE on survival following LT.
Methods: All adult liver transplant recipients in the U.S. from
2003 to 2013 were evaluated using the United Network for
Organ Sharing registry. HE at the time of LT was categorized
as no HE vs. grade 1-2 HE vs. grade 3-4 HE. Multivariate
logistic regression was first utilized to determine predictors of
having HE at time of LT. Next, the effect of pre-transplant HE
on post-transplant survival was evaluated using Kaplan Meier
methods and multivariate Cox proportional hazards models.
Results: Among 63,177 patients that underwent LT, 35.3%
(n=22,295) had no evidence of pre-transplant HE, 53.2%
(n=33,595) had grade 1-2 HE, and 11.5% (n=7,287) had
grade 3-4 HE. When stratified by severity of HE, there was a
higher prevalence of hepatitis C virus (HCV) and hepatocellular
carcinoma (HCC) among patients with no HE. On multivariate
logistic regression, HCV (OR, 1.19; 95% CI, 1.13 – 1.25;
p<0.001), obesity (OR, 1.12; 95% CI 1.07 – 1.18; p<0.001),
and ascites (OR, 12.01; 95% CI, 11.30 – 12.75; p<0.001)
were all associated with increased risk of having HE at the time
of LT, whereas patients with HCC had lower risk of HE (OR,
0.53; 95% CI, 0.50 – 0.57; p<0.001). Compared to patients
with no HE, patients with grade 3-4 HE had significantly lower
post-LT survival (HR, 1.28; 95% CI, 1.18 – 1.38, p<0.001)
(Figure). HCV, HCC, and diabetes (DM) were all associated
with lower post-LT survival (Table). Conclusion: Among adult
liver transplant recipients in the U.S., the presence of grade 3-4
HE at the time of LT is associated with significantly lower post-LT
survival compared to patients with no clinical evidence of HE.
HEPATOLOGY, October, 2014
Predictors of Long-Term Post-Transplant Mortality
Disclosures:
Robert G. Gish - Advisory Committees or Review Panels: Merck, Genentech,
Roche, BMS, Gilead, Arrowhead; Stock Shareholder: Hepahope, Kinex, Arrow-
head
Ramsey Cheung - Grant/Research Support: Gilead Sciences
Aijaz Ahmed - Consulting: Bristol-Myers Squibb, Gilead Sciences Inc., Roche,
AbbVie, Salix Pharmaceuticals, Janssen pharmaceuticals, Vertex Pharmaceuti-
cals, Three Rivers Pharmaceuticals; Grant/Research Support: Gilead Sciences
Inc.
The following people have nothing to disclose: Robert J. Wong
388
Increased risk of Portal Vein Thrombosis in Non-Alco-
holic Steatohepatitis (NASH) and Cryptogenic Cirrhosis:
Evidence for a Thrombophilic State
Jonathan G. Stine1, Neeral L. Shah1, Curtis K. Argo1, Shawn Pel-
letier2, Stephen H. Caldwell1, Patrick G. Northup1; 1Gastroenter-
ology & Hepatology, University of Virginia, Charlottesville, VA;
2Transplant Surgery, University of Virginia, Charlottesville, VA
Portal vein thrombosis (PVT) is a common complication of cir-
rhosis that is sometimes implicated in hepatic decompensation,
inferior post-liver transplantation (LT) outcomes and decreased
overall survival. There is no consistent epidemiologic data
to suggest an increased risk of arterial or venous thrombotic
complications in NASH versus other forms of liver disease,
however, research suggests an increased risk of thrombosis.
The objective of this study was to examine the independent
association between NASH, cryptogenic cirrhosis and PVT in
patients awaiting LT. A total of 50,468 patients underwent
LT from January 2003 to December 2012. Of these, 3,503
patients (6.94%) had PVT. Baseline characteristics amongst
patients with NASH were similar when compared to those with
cryptogenic cirrhosis. Of patients with PVT, 17% had NASH or
cryptogenic cirrhosis. When comparing patients with NASH/
cryptogenic cirrhosis to a composite of all other causes of cir-
rhosis, an increased prevalence of PVT was again found with
10.27% having PVT at the time of LT compared to 6.51%
without (p<0.0001). The strongest risk factor independently
associated with a diagnosis of PVT in multivariate analysis
was cryptogenic/NASH cirrhosis (OR 1.451,95% CI 1.298-
1.622, p<0.001). Other multivariate factors predisposing to
PVT included hepatocellular carcinoma (OR 1.232; 95% CI
1.109-1.368, p<0.001), age (OR 1.009; 95% CI 1.006-
1.013, p<0.0001) and ascites severity (OR 1.239; 95% CI
1.168-1.314, p<0.001); Factors including cholestatic liver
disease and chronic hepatitis C were associated with a lower
incidence of PVT. Conclusions: NASH/cryptogenic cirrhosis
appears to predispose to portal vein thrombosis independent
of other risk factors for PVT. These epidemiologic findings pro-
vide support that NASH is a pro-thrombotic state should lead to
more research in treatment and prevention in this population.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Disclosures:
Neeral L. Shah - Grant/Research Support: Boehringer Ingelheim
Curtis K. Argo - Consulting: Wellstat Diagnostics; Independent Contractor:
Genentech/Roche
Stephen H. Caldwell - Advisory Committees or Review Panels: Vital Therapy;
Consulting: Wellstat diagnostics; Grant/Research Support: Genfit, Gilead Sci-
ences
The following people have nothing to disclose: Jonathan G. Stine, Shawn Pel-
letier, Patrick G. Northup
389
Hypercalcemia: A complication and predictor of mortal-
ity among patients with severe liver dysfunction
Suman Nayak 1, Rajendra P. Mathur 1, Sivaramakrishnan
Ramanarayanan1, Gyan Prakash1, Shiv K. Sarin2, Manoj Kumar2,
Chitranshu Vashishtha2, Rakhi Maiwall2, Ajeet S. Bhadoria2;
1nephrology, institute of liver and biliary science, New Delhi, India;
2hepatology, Institute of liver and biliary science, New Delhi, India
Introduction: Hypercalcemia has been hypothesized as a
complication of advanced chronic liver disease. The possi-
ble mechanism for hypercalcemia is increased bone resorp-
tion and decreased renal clearance. Over-prescription of
calcium in cirrhotics contributes to this. There is paucity of
data regarding hypercalcemia and its clinical relevance in
patients of advanced liver disease. Patient and Methods: A
prospective study was undertaken to study the prevalence,
predictors and clinical relevance of hypercalcemia among
hospitalized patients of advanced liver disease. 170 cirrhot-
ics were enrolled and divided into: hypercalcemic (Group 1)
(corrected calcium > 10.3 mg/dl) and normocalcemic (Group
2) (8.5-10.3 mg/dl). Results: Of 170, 98 (57.65%) patients
(77 males and 21 females) were classified in Gr.1 and 72
(42.35%) (59 males and 13 females) were in Gr 2, with mean
age being 57.01±11.5 yr and 51.64±13.3 yr respectively.
Mean calcium level in Gr1 was 11.87±1.656 mg/dl and in
group2 was 9.57±0.421 mg/dl. Liver functions were more
deranged in Gr1 than Gr2 (total bilirubin: 13.78 mg/dl vs
9.31 mg/dl, p value<0.001; AST: 143 IU/dl vs. 88 IU/dl,
p = .004). MELD score was significantly higher in Gr1 than
Gr2 (24.3±10.0 vs 21.5±6.6, p value = .001). Acute Kidney
injury (AKI) (71.4% Vs 48.6%) and hepatocellular carcinoma
(22.4% Vs. 8.3%) were significantly higher among hypercal-
cemia group as compared to normocalcemic group (p value
<0.05). Of the 170 patients, 142 (83.53%) recovered and
got discharged while 28 (16.47%) patients died. In the former
cohort, 54.2% patients had higher calcium level while in the
later 75% patients were hypercalcemic (p<0.05). On multi-
variate logistic regression analysis, presence of AKI (OR-2.8,
95%CI 1.2-6.7) was found as an independent predictor of
hypercalcemia among patients with severe liver dysfunction
(p value=0.014). Conclusions: Hypercalcemia is a frequent
393A
complication in patients of advanced cirrhosis with AKI and is
predictor of adverse outcome. A high index of suspicion and
early detection may reduce mortality in cirrhotics. Injudicious
and unsupervised use of oral calcium should be avoided.
Disclosures:
The following people have nothing to disclose: Suman Nayak, Rajendra P.
Mathur, Sivaramakrishnan Ramanarayanan, Gyan Prakash, Shiv K. Sarin,
Manoj Kumar, Chitranshu Vashishtha, Rakhi Maiwall, Ajeet S. Bhadoria
390
Platelet-derived microparticles in decompensated cir-
rhosis: relation to blood platelet level and indices of
coagulation
Nicolas M. Intagliata1, Stephen H. Caldwell1, Christine K. Rudy2,
Tae Hee Lee3, Patrick G. Northup1, Patcharin Pramoonjago4,
Josephine Lannigan5, Uta Erdbrugger2; 1Gastroenterology and
Hepatology, University of Virginia, Charlottesville, VA; 2Nephrol-
ogy, University of Virginia, Charlottesville, VA; 3Medicine, Kon-
yang University College of Medicine, Daejeon, Republic of Korea;
4Pathology, University of Virginia, Charlottesville, VA; 5Microbiol-
ogy, University of Virginia, Charlottesville, VA
Introduction: Cell-derived microparticles (MP) are small mem-
brane vesicles (0.1 to 1 μm) generated from cell activation
or apoptosis. MP, including platelet-derived MP (PMP), have
recently been implicated in pathologic mechanisms in cirrhosis
patients. We assessed PMP in decompensated cirrhosis patients
compared to healthy controls and sought relationships between
PMP and indices of coagulation using imaging flow cytometry
as a novel MP detection method with increased sensitivity.
Methods: Plasma was obtained from 12 adult hospitalized
patients with decompensated cirrhosis without renal failure and
compared to 6 healthy controls. Enumeration and phenotyping
of MP were determined from plasma using an imaging flow
cytometry (ImageStreamX) and the following surface markers:
Annexin 5 (AV) and platelets (CD41). Levels of MP were com-
pared between groups and with parameters of coagulation to
determine any potential relationships with levels of PMP and
coagulopathy. Rotational thromboelastometry (ROTEM) was
performed on fresh samples. A central coagulation laboratory
performed all other laboratory testing. Results: AV-positive MP
were significantly different between groups (Table 1). PMP con-
stituted a large proportion of the total MP in both groups, but
were significantly lower in the cirrhosis group as were blood
platelet levels when compared to controls. The ratio of PMP
to blood platelet levels was not different between groups, but
there was a significant correlation between overall PMP levels
and blood platelet levels (r=0.74, p=0.0005) in the overall
cohort. In the cirrhosis group, blood platelet levels correlated
significantly with ROTEM parameters of clot formation time
(-0.59, p=0.04) and maximal clot firmness (0.75, p=0.005). In
contrast, there were no significant correlations between levels
of PMP and other indices of coagulation, including fibrinogen,
INR and ROTEM parameters. Conclusions: Levels of PMP were
lower in decompensated cirrhosis and positively correlated
with blood platelet levels. This may result from decreased for-
mation of MP from reduced substrate. While blood platelet
level correlated with measures of coagulation, there were no
significant correlations between several different measures of
coagulation and PMP. Further studies are warranted to explore
other MP phenotypes and function, which may relate to mech-
anisms underlying the coagulopathy of cirrhosis.
394A AASLD ABSTRACTS
Table 1.
*units MP/μL; ^units k/μL; means with 95% CI in parenthesis
Disclosures:
Stephen H. Caldwell - Advisory Committees or Review Panels: Vital Therapy;
Consulting: Wellstat diagnostics; Grant/Research Support: Genfit, Gilead Sci-
ences
Patrick G. Northup - Grant/Research Support: Hemosonics, Bristol Meyer Squibb
The following people have nothing to disclose: Nicolas M. Intagliata, Christine K.
Rudy, Tae Hee Lee, Patcharin Pramoonjago, Josephine Lannigan, Uta Erdbrugger
391
Splenomegaly : splenic volume measurement by ultra-
sound, validity and reliability, clinical implications in
liver cirrhosis
Sang Gyune Kim1, Young Seok Kim1, Hee Jae Jung1, Sae Hwan
Lee3, Soung Won Jeong2, Jae Young Jang2, Young Don Kim4,
Gab Jin Cheon4, Hong Soo Kim3, Boo Sung Kim1; 1Gastroenterol-
ogy and hepatology, Soonchunhyang university Bucheon hospital,
Bucheon si, Republic of Korea; 2Soonchunhyang University Seoul
Hospital, Seoul, Republic of Korea; 3Soonchunhyang University
Chonan Hospital, Chonan, Republic of Korea; 4Gangneung Asan
Hospital, Gangneung, Republic of Korea
Background: For the diagnosis of liver cirrhosis, splenomeg-
aly has been widely used. However, there is few studies for
establishing the definition of splenomegaly. In this study, we
aimed to measure the splenic volume (SV) using ultrasonog-
raphy (USG) and compared with computed tomography (CT)
image as a reference standard and try to find out its relation-
ship with portal hypertension and best cut-off value for discrim-
inating cirrhosis from non-cirrhosis. Methods: 1,256 patients
who checked SV with USG from August 2007 to March 2014,
were included. We evaluated the reliability of SV measurement
which was performed by two sonographers simultaneously
from randomly selected 82 patients (164 cases) and assessed
the validity by the source image of CT from 105 patients. Liver
biopsy was done in 217 patients within 6 month from SV mea-
surement. We also evaluated the relationship of liver fibrosis
and hepatic venous pressure gradient (HVPG) and SV. We did
a sensitivity analysis with SV adjusted by body surface area
(BSA). Results: The concordance correlation coefficient (CCC)
between two sonographers was 0.9886 (95% confidence inter-
val [CI], 0.9816-0.9930) and CCC between the measurment
by USG and CT was 0.9721 (95% CI, 0.9556-0.9826). SV
was increased in male, young ages and significantly larger in
viral liver cirrhosis than in alcoholic liver cirrhosis. SV showed
a positive correlation with Child-Pugh score, MELD score and
was increased greatly in patient having esophageal varices,
gastric varices and ascites compared to those who have not.
There was a significant difference of SV between fibroscan
score (≤12 versus(vs.) >12 kPa) in viral liver cirrhosism, but
not in alcoholic liver cirrhosis. The AUROC of SV for the pre-
diction of F4 was 0.812 (95% CI, 0.749-0.865, p<0.001)
and the optimal cut-off value of SV was 300.3 cm3. SV/BSA
also showed a good prediction for F4 (AUC, 0.802; 95% CI,
0.736-0.857; p<0.001).However, there was no significance
of SV for predicting HVPG (≥12mmHg) (AUC, 0.578; 95% CI,
0.499-0.654; p=0.106). Conclusions: Splenic volume mea-
sured by USG is precise and accurate and highly associated
with the incidence of liver cirrhosis complications. Splenic vol-
HEPATOLOGY, October, 2014
ume about 300 cm3 was an optimal cut-off value to discrimi-
nate between cirrhosis and non-cirrhosis.
Disclosures:
The following people have nothing to disclose: Sang Gyune Kim, Young Seok
Kim, Hee Jae Jung, Sae Hwan Lee, Soung Won Jeong, Jae Young Jang, Young
Don Kim, Gab Jin Cheon, Hong Soo Kim, Boo Sung Kim
392
Hepatic encephalopathy may be associated with enzy-
matic impairment of ammonia metabolism: Is there a
case for studying urea cycle function in cirrhosis?
Raghavender Gotur1, Bryan E. Hainline2, Qin Sun3, Eric S.
Orman1, Naga P. Chalasani1, Marwan Ghabril1; 1Gastroenterol-
ogy, Indiana University, Indianapolis, IN; 2Medical and Molecular
Genetics, Indiana University, Indianapolis, IN; 3Molecular and
Human Genetics, Baylor College of Medicine, Houston, TX
Background: Cirrhotic patients with comparable level of liver
dysfunction do not uniformly manifest hepatic encephalopathy
(HE) or its severity. We hypothesized that defects in ammonia
metabolism resulting from liver dysfunction might explain this
variability. Aim: To quantitatively and qualitatively study amino
acid (AA) profiles in hospitalized cirrhotic patients with and
without HE at admission. Methods: 84 adults with cirrhosis
who were admitted to our center for various indications were
enrolled into this prospective study. Transplant or TIPS recip-
ients, portal vein thrombosis were excluded. Overt HE was
defined based on West Haven grade ≥2. Blood and urine
were collected within 24 hours of admission. Plasma was
assayed for AA and urine for AA, orotic acid and organic
acids at a reference clinical lab blinded to clinical data. In
addition to quantitative results, a qualitative assessment for the
AA profile for possible enzymatic defects in AA metabolism
was made. Variables were reported as percentages, or median
[interquartile range, (IQR)]. Results: Of 84 subjects, 25 had HE
(25) and non-HE groups were compared (table 1). Plasma AA
levels were similar, except for lower branched chain to aro-
matic AA (BCAAA) ratio in the HE group. Qualitative analysis
of plasma AA was deemed abnormal in 21 patients, and most
frequently suggested interpretation of the abnormal AA pattern
was of a possible urea cycle disorder (UCD) which was present
in 8 of 21 samples. A possible UCD pattern of plasma AA was
associated with numerically higher venous ammonia levels (86
[51-153] vs. 51 [31-74] mmol/L, p 0.16, but similar BCAAA
ratio (1.1 [0.8-1.2] vs. 1.1 [0.8-1.6], p=0.8). Urine orotic acid
levels were 0.9 [0.4-1.6] in HE and 1.1 [0.3-2.2] mmole/mole
of creatinine in non-HE subjects (p=0.8), with levels above the
normal range in 29% vs. 12% respectively (p=0.2). Qualitative
interpretation of urine orotic acid suggested possible UCD in
35% of HE vs. 10% of non-HE subjects (p=0.02). Organic
acids were suggestive of non-specific hepatic dysfunction in
61% of HE vs. 31% in non-HE subjects (p=0.02), but levels of
urine AA were similar. Conclusion: These data suggest that
impaired urea cycle function may account for overt HE in a pro-
portion of patients with decompensated cirrhosis. Further work
is needed to better understand the role of urea cycle dysfunc-
tion in the pathogenesis of overt HE in patients with cirrhosis.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Table 1
Disclosures:
Naga P. Chalasani - Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-
rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin
Marwan Ghabril - Grant/Research Support: Salix
The following people have nothing to disclose: Raghavender Gotur, Bryan E.
Hainline, Qin Sun, Eric S. Orman
393
Nutritional assessment in cirrhotic outpatients and its
impact on quality of life
Claudia I. Blanco1, Ma Guadalupe Martinez Galindo1, Alejandro
Ramon R. Angeles Labra1, Jose Armando Carmona Castañeda1,
Griselda Martínez Ramírez1, Adriana López Luría1, María D. Avila
Langarica1, María A. Barragán Valarezo1, Elizabeth Perez Cruz2,
Dolores Enciso González3, Felipe Zamarripa Dorsey1; 1Gastroen-
terology, Hospital Juárez de México, Federal District of Mexico,
Mexico; 2Nutrition Support, Hospital Juárez de México, Federal
District of México, Mexico; 3Sports Medicine, Hospital Juárez de
México, Federal District of México, Mexico
Background: Protein-calorie malnutrition is a common finding
in cirrhotic patients, described in up to 80%, regardless of
disease stage. Malnutrition is associated with increased risk of
complications and mortality, and it is considered a prognos-
tic factor in chronic liver disease. The SF-36 questionnaire is
an instrument that assesses the quality of life related to health
and consists of 36 questions that explore physical functioning,
social functioning, physical role, emotional role, mental health,
vitality, pain, and perception of overall health. Objective: To
assess protein-calorie malnutrition and its impact in quality of
life in cirrhotic outpatients. Methods: Prospective evaluation
of 78 cirrhotic outpatients. For nutritional state assessment
hand-gripped strength and phase angle from bioelectrical
impedance analysis were used. Malnutrition was considered
if dynamometry varied ± 2 SD of the corresponding normal
ranges, and if the phase angle was <5.44 °. Quality of life
was assessed with the SF-36 questionnaire. Results: The mean
age of the population was 56.28 ± 10.96 and 55.7 % were
female. Thirty-seven percent of the study population were Child
A, 38 % Child B, and 24 % Child C. According to hand-grip
strength 37.9% in Child A class, 43.3% in Child B, and 63.2
% in Child C were malnourished. Malnutrition was detected by
phase angle in 69 % Child A class, 86.7 % in Child B, and
42.1 % in Child C. When comparing the group of patients
with and without malnutrition detected by hand-grip strength,
statistically significant differences were found in the physical
component of the SF-36 questionnaire (p =0.001); and in pain,
vitality, social function and mental health (p <0.05). Malnour-
ished patients detected by bioimpedance showed no signifi-
cant changes in the questionnaire. The physical and mental
components of quality of life tended to be lower with increasing
disease severity according to Child-Pugh class without reaching
statistical significance. Conclusions: Malnutrition assessed by
395A
hand-grip strength but not by phase angle tended to be more
frequent with higher Child-Pugh class. Based on these findings,
we believe that hand-grip strength is a better tool for the detec-
tion of malnutrition in cirrhotic patients. Protein-energy malnu-
trition occurs in all stages of liver disease and it is related to
emergence of complications, and nutritional support should be
recommended in this population. Malnutrition had a negative
impact on quality of life of cirrhotic patients, and the physical
health component is the most affected. This questionnaire can
be a useful tool to assess response to therapeutic interventions
that may impact in overall survival.
Disclosures:
The following people have nothing to disclose: Claudia I. Blanco, Ma Guadalupe
Martinez Galindo, Alejandro Ramon R. Angeles Labra, Jose Armando Carmona
Castañeda, Griselda Martínez Ramírez, Adriana López Luría, María D. Avila
Langarica, María A. Barragán Valarezo, Elizabeth Perez Cruz, Dolores Enciso
González, Felipe Zamarripa Dorsey
394
Splenic artery embolization is associated with increased
morbidity and mortality in patients with cirrhosis or
liver transplantation
Indira Donepudi, Narayan Dharel, Angelo H. Paredes, Richard K.
Sterling, R. Todd Stravitz, Brian J. Strife, Mohammad S. Siddiqui,
Scott Matherly, Puneet Puri, Velimir A. Luketic, Carolyn Driscoll,
Arun J. Sanyal; Hepatology, Virginia Commonwealth University,
Richmond, VA
BACKGROUND: Splenic arterial embolization (SAE) is used
for a variety of indications prior to and after liver transplan-
tation. Although it is assumed SAE is less morbid than a sple-
nectomy, there is a paucity of data on clinical outcomes after
SAE. AIMS: The current study aimed to define the safety and
efficacy of SAE in cirrhotic subjects and liver transplant recipi-
ents. METHODS: This was a retrospective analysis of patients
undergoing SAE at the authors institution between 2010-2013.
The indications, complications and efficacy of SAE was eval-
uated. RESULTS: A total of 55 SAE (cirrhosis n=18, post-liver
transplant n=37) were performed during the study period.
The indications for SAE were as follows: Cirrhosis: hyper-
splenism 12, gastric varices with bleeding 1, splenic artery
aneurysm 1, splenic vein thrombosis with gastric varices 3,
splenic injury with bleeding 1); post-transplant: (splenic artery
steal syndrome 7, persistent hypersplenism 22, massive sple-
nomegaly 7, splenic artery aneurysm 1). Thrombocytopenia
was the principal manifestation of hypersplenism that led to
the procedure. Efficacy: SAE was successfully performed in
all cases and imaging confirmed partial splenic infarction in
52/55 of the cases. Bleeding was controlled in the subjects
with bleeding gastric varices. The platelet counts improved sig-
nificantly over time in those who had the procedure performed
after liver transplant but the platelet counts did not improve
significantly from baseline to 1, 3 or 6 months after SAE in
those with cirrhosis (means: 80000±78000 vs 84000±34000
vs 102000±63275 vs 116444±71098 cells/mm3). Safety:
10/18 cirrhotic subjects and 31/37 post-transplant subjects
developed significant abdominal pain requiring escalation
in pain control. 7/18 subjects with cirrhosis and 18/37
post-transplant subjects developed fever requiring further work
up after the SAE. 3/18 cirrhotic subjects developed sponta-
neous bacterial peritonitis and/or splenic abscess; one sub-
ject died from sepsis and acute on chronic liver failure. 5/18
cirrhotic subjects also had clinical decompensation within
30 days of the procedure although the MELD scores did not
change significantly from baseline to one month. Two cirrhotic
subjects developed splenic and portal vein thrombosis within
30 days of the procedure. One transplant recipient developed
396A AASLD ABSTRACTS HEPATOLOGY, October, 2014

multi-organ failure and died following SAE. CONCLUSIONS: lyzed data from 6 clinical studies of glycerol phenylbutyrate
SAE has a substantial morbidity and occasional mortality in (GPB), which lowers NH3 via an alternative pathway to urea,
both those with cirrhosis and following liver transplantation. to identify similarities in the two populations. Methods: The
There is a high risk of further decompensation of cirrhosis fol- relationship between NH3 and the risk and frequency of HAC
lowing SAE. The decision to perform SAE must consider these or HEE was analyzed in 100 UCD patients, ages 2 months to
serious risks to the patient. > 70 years, who participated in 2-4 week and/or 12-mo trials
Disclosures: and 178 adult cirrhotics with recurrent HE who participated in
Richard K. Sterling - Advisory Committees or Review Panels: Merck, Vertex, Salix, a 16-week randomized, double blind placebo-controlled study.
Bayer, BMS, Abbott, Gilead; Grant/Research Support: Merck, Roche/Genen- Results: In UCD pts with baseline NH3 ≥ the upper limit of nor-
tech, Pfizer, Gilead, Boehringer Ingelheim, Bayer, BMS, Abbott
mal (ULN), the rate of HAC was 5.3x that in those with NH3
Puneet Puri - Advisory Committees or Review Panels: Health Diagnostic Labora-
tory Inc.; Consulting: NPS Pharmaceuticals Inc.
<0.5x ULN (p=0.006). Similarly, in HE patients with baseline
NH3 >1.5 x ULN, the rate of HEE was 3.5x that in those
Velimir A. Luketic - Grant/Research Support: Intercept, Merck, Idenix, Vertex,
Gilead, BMS, Novartis, abbvie, Genfit, Takeda with NH3 <1.5 ULN (p<0.001). The risk of HAC/HEE was
Arun J. Sanyal - Advisory Committees or Review Panels: Bristol Myers, Gilead, increased in UCD/HE patients with baseline NH3 exceeding
Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Nimbus, Genentech, Echo- these levels (p<0.001). HE patients randomized to receive GPB
sens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept, had a reduced relative risk (RR) of HEE (RR=0.54; p=0.01),
Ikaria, Takeda, GalMed, Novartis, Gilead; Independent Contractor: UpToDate,
Elsevier which was similar for patients with baseline NH3 >1.5x ULN
The following people have nothing to disclose: Indira Donepudi, Narayan
(RR=0.56; p=0.08) or ≤1.5x ULN (RR=0.52; p=0.08). More-
Dharel, Angelo H. Paredes, R. Todd Stravitz, Brian J. Strife, Mohammad S. over, the relationships between NH3 and HEE/HAC rate were
Siddiqui, Scott Matherly, Carolyn Driscoll similar in HE/UCD patients (Figure). Conclusion: While dele-
terious NH3 thresholds may differ between UCDs and HE, the
data suggest that even modest chronic HA increases the risk
395 of episodic neurologic dysfunction. Thus, lowering NH3 in HE
Clinical significance of minimal hepatic encephalopathy patients may decrease their risk of HEE.
Zita Galvin, Audrey Dillon, Damien Lowry, Jennifer Russell, Ste-
phen Stewart; Centre for Liver Diseases, Mater Misericordiae Uni-
versity Hospital, Dublin, Ireland
Introduction and purpose of study Minimal hepatic encephalopathy (mHE) is the
primary cause of cognitive deficits in patients with cirrhosis. It has been reported
that these patients are more likely to develop overt hepatic encephalopathy
and are less likely to survive for the same length of time as their unimpaired
counterparts. The purpose of this study was to investigate if mHE is associated
with poorer outcomes in a cohort of compensated cirrhotic patients and also to
determine which psychometric test correlates best with patient outcome. Methods
Consecutive compensated cirrhotic patients attending the outpatient department
over a two year period were recruited for the study. Psychometric testing, includ-
ing the psychometric hepatic encephalopathy score (PHES), the repeatable bat-
tery for assessment of neuropsychological status (RBANS) and the critical flicker
fusion (CFF) test, were performed at each visit. For PHES and RBANS, mHE was
diagnosed in clinically unimpaired patients who scored Disclosures:
Stephen Stewart - Advisory Committees or Review Panels: MSD, Gilead, BMS,
Abbvie; Grant/Research Support: MSD; Speaking and Teaching: Roche
The following people have nothing to disclose: Zita Galvin, Audrey Dillon,
Damien Lowry, Jennifer Russell

396
Hyperammonemia (HA) as a Predictor of Episodic Neu-
rocognitive Dysfunction: Lessons From Clinical Studies of
Patients with Urea Cycle Disorders (UCDs) and Hepatic
Encephalopathy (HE)
Bruce F. Scharschmidt2, Richard Rowell2, Marzena Jurek2, Dion
F. Coakley2, Masoud Mokhtarani2, Uta Lichter-Konecki3, Susan
A. Berry8, George Diaz7, Brendan Lee1, William Rhead9, Don
C. Rockey5, Marwan Ghabril6, Parvez S. Mantry4, Robert S.
Brown3, John M. Vierling1; 1Baylor College of Medicine, Hous-
ton, TX; 2Hyperion Therapeutics, Brisbane, CA; 3Medical Center,
Disclosures:
Columbia University, New York, NY; 4Liver Institute, Methodist
Bruce F. Scharschmidt - Advisory Committees or Review Panels: JM Vierling, RS
Dallas Medical Center, Dallas, TX; 5Medical Univ. of South Caro-
Brown, Jr, P Mantry, DC Rockey, M Ghabril, G Diaz, B Lee, SA Berry, W Rhead,
lina, Charleston, SC; 6Indiana University, Indianapolis, IN; 7Icahn U Lichter-Konecki; Employment: M Mokhtarani, R Rowell, M Jurek, D Coakley,
School of Medicine, Mt Sinai, New York, NY; 8Univ. of Minne- BF Scharschmidt
sota, Minneapolis, MN; 9The Medical College of Wisconsin, Mil- Dion F. Coakley - Employment: Hyperion Therapeutics
waukee, WI Masoud Mokhtarani - Employment: Hyperion; Stock Shareholder: Hyperion
Background: Nitrogen retention in UCDs and HE is charac- Uta Lichter-Konecki - Grant/Research Support: Hyperion
terized by episodic HA crises (HAC) and HE episodes (HEE), Susan A. Berry - Grant/Research Support: Hyperion
respectively. While HA is accepted as a cause of HAC in Don C. Rockey - Grant/Research Support: Gilead, Actelion
UCDs, for which treatment focuses on ammonia (NH3) control, Marwan Ghabril - Grant/Research Support: Salix
the role of NH3 in HE is less well defined. We therefore ana-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Parvez S. Mantry - Consulting: Salix, Gilead, Janssen, Abbvie; Grant/Research
Support: Salix, Merck, Gilead, Boehringer-Ingelheim, Mass Biologics, Vital Ther-
apies, Santaris, Vertex, Bristol-Myers Squibb, Abbive, Bayer-Onyx; Speaking
and Teaching: Gilead, Janssen, Salix, Bayer-Onyx
Robert S. Brown - Advisory Committees or Review Panels: Vital Therapies; Con-
sulting: Genentech, Gilead, Merck, Abbvie, Janssen; Grant/Research Support:
Gilead, Merck, Vertex, AbbVie, Salix, Janssen, Vital Therapies
John M. Vierling - Advisory Committees or Review Panels: Abbvie, Bristol-Mey-
ers-Squibb, Gilead, Hyperion, Intercept, Janssen, Novartis, Merck, Sundise,
HepQuant, Salix; Grant/Research Support: Abbvie, Bristol-Meyers-Squibb,
Eisai, Gilead, Hyperion, Intercept, Janssen, Novartis, Merck, Sundise, Ocera,
Mochida; Speaking and Teaching: GALA, Chronic Liver Disease Foundation,
ViralEd
The following people have nothing to disclose: Richard Rowell, Marzena Jurek,
George Diaz, Brendan Lee, William Rhead
397
Hepatic Encephalopathy, A Preventable Readmission:
Implementation of Quality Indicators at a Tertiary Care
Center
Abdul Haseeb1, Juan F. Gallegos-Orozco2; 1Internal Medicine,
University of Utah, Salt lake City, UT; 2Gastroenterology, Hepatol-
ogy and Nutrition, University of Utah, Salt Lake City, UT
Purpose: Cirrhosis leads to 150,000 hospitalizations and costs
nearly 4 billion dollars each year. Despite the strides in achiev-
ing Quality Indicators (QI) in colorectal cancer screening, the
field of Gastroenterology lags behind in implementation of QI
in cirrhosis and hepatic encephalopathy (HE). The purpose of
this study is to assess effectiveness of inpatient care and imple-
mentation of QI in patients admitted with HE at our institution.
Methods: A retrospective chart review of inpatient admissions
with HE within a 2-year period was completed. We identified
all adult patients greater than 18 years of age admitted to
the University of Utah hospital from January 1, 2011 through
December 31, 2012 with a confirmed diagnosis of HE. Charts
were manually reviewed for demographics, medications at
both admission and discharge, grade of HE, known precipi-
tating factors for HE, clinical outcomes at discharge, and hos-
pital readmission rates. Implementation of proposed QI, which
include documentation of reversible factors, grading of enceph-
alopathy, and the use of lactulose or rifaximin at discharge
were studied. Descriptive statistics were computed. Results: In
this ongoing study, we analyzed data on 50 patients with a
total of 95 admissions. There were 31 males and 19 females
with a mean age of 59 years. The mean MELD score for this
cohort was 21. The precipitant factors for HE recognized at
admission included: 47%with opioid overuse, 46% with acute
kidney injury, 13% with gastrointestinal bleed, 12% with ben-
zodiazepine overuse, and 5% with spontaneous bacterial peri-
tonitis. During the course of admission, none of the patients
studied had documentation of the grade of encephalopathy
and only 16% had documented nutritional status. At discharge,
82% of the patients were continued on lactulose, whereas only
65% received rifaximin. After the first admission, 15 patients
had a readmission within 30 days and 19 patients had a read-
mission within 90 days. During the study period, 11 deaths
were observed in our cohort. Conclusion: Studies have shown
that QI for hepatic encephalopathy are usually met less than
50% of the time in large tertiary centers. Our study continues
to show similar lack of implementation of proposed QI. Learn-
ing from other chronic disease processes, such as congestive
heart failure, physician education and implementing system
initiatives play a major role in improving the quality of care in
cirrhosis. Multiple concurrent interventions like HE-specific dis-
charge order-sets, early identification of precipitating factors,
and effective inpatient documentation are needed to improve
quality measures and prevent readmissions with cirrhosis and
HE.
397A
Disclosures:
The following people have nothing to disclose: Abdul Haseeb, Juan F. Gal-
legos-Orozco
398
Sarcopenia in patients with liver cirrhosis – a gender
specific complication?
Thomas Zimmerer1, Thomas Hoertig1, Christoph Antoni1, Matthias
Ebert1, Johanna C. Nissen2; 1Department of Medicine II, University
Medical Centre Mannheim, Medical Faculty Mannheim, University
of Heidelberg, Mannheim, Germany; 2Institute of Clinical Radiol-
ogy and Nuclear Medicine, University Medical Center Mannheim,
Medical Faculty Heidelberg University, Mannheim, Germany
Background: Recent studies have shown that sarcopenia is a
frequent complication and independent risk factor for mortality
in patients with liver cirrhosis. However, most data derives from
patients on the waiting list for liver transplantation. Furthermore,
the association between sarcopenia and other cirrhosis related
complications like i.e. hepatic encepalopathy or hepatorenal
syndrome is unclear. The aim of the study was to determine the
prevalence of sarcopenia and other cirrhosis related complica-
tions in a cohort of cirrhotic patients treated in a tertiary center
outpatient clinic. Material and methods: All cirrhotic patients
treated in our outpatient clinic in the years 2009-2012 where
checked for abdominal cross sectional imaging (MRI and CT).
183 patients received at least one MRI or CT scan. On these
images, L3 vertebral level was identified and the cross sec-
tional area of the surrounding muscles was measured using
OsiriX DICOM viewer v.5.0.2. To normalize to stature the skel-
etal muscle index (SMI) was calculated by dividing the skeletal
muscle area by height squared. The diagnosis sarcopenia was
made if the SMI was ≤ 52,4 cm2/m2 in males and ≤ 38,5
cm2/m2 in females. The records of the patients were retrospec-
tively searched for height, etiology of cirrhosis, laboratory data
and complications of cirrhosis within 18 months from the time
point of abdominal imaging. Statistics included Chi2-Test, t-test
and Spearmans`s correlation coefficient. Results: 124 patients
were male, 59 were female. As there were significant differ-
ences in SMI evaluated by CT or MRI, and SMI cut offs are
determined in a CT study, patients with MRI were excluded.
Of the remaining 106 patients (71 male, 35 female) 61 of the
106 patients (58%) were sarcopenic. Sarcopenia was more
prevalent in males (66%) than in females (40%) (p=0,0103).
The prevalence increased with the Child-Pugh classes in men
(p=0,0002) but not in women. In men sarcopenia (p=0,3450)
and SMI (p=0,9460) did not differ between patients with or
without malignancies. Prevalence of sarcopenia increased with
the Child-Pugh classes in men with and without malignancies
(p=0,0269 and p=0,0036, respectively). In men, but not in
women, there was a significant correlation between SMI and
the number of cirrhosis related complications (p=0,0243)
and the number of hospital admissions (p=0,0081) within 18
months after the abdominal imaging (mean number of hos-
pital admissions: 1,43, of complications: 2,90). Conclusion:
Although limited by retrospective design and sample size our
study supports previous reports of a gender specific difference
in prevalence and impact of sarcopenia in cirrhotic patients.
Disclosures:
Christoph Antoni - Speaking and Teaching: Roche, MSD, BMS, Janssen, Gilead,
Falk Foundation
The following people have nothing to disclose: Thomas Zimmerer, Thomas Hoer-
tig, Matthias Ebert, Johanna C. Nissen
398A AASLD ABSTRACTS
399
VIATORR endoprosthesis do not self-expand to their
nominal diameters in cirrhotic livers: new evidence
toward the risk reduction of post-TIPS hepatic encepha-
lopathy
Filippo Schepis1, Francesco Vizzutti2, Guido Marzocchi3, Pietro
Quaretti9, Antonio G. Rampoldi4, Roberto Agazzi5, Rita Golfi-
eri6, Angelo Luca7, Fabrizio Fanelli8, Cristian Caporali3, Stefano
Colopi3, Luigi Rega2, Umberto Arena2, Ilaria Fiorina9, Lorenzo
Moramarco9, Aldo Airoldi4, Roberto Nani5, Matteo Renzulli6,
Cristina Mosconi6, Raffaele Bruno9, Stefano Fagiuoli5, Alessandro
Cannavale8, Tommaso Di Maira1, Stefano Gitto1, Erica Villa1;
1Department of Gastroenterology, University of Modena and Reg-
gio Emilia, Modena, Italy; 2Department of Medicine, University
of Firenze, Firenze, Italy; 3Department of Radiology, University
of Modena and Reggio Emilia, Modena, Italy; 4Department of
Radiology, Niguarda Hospital, Milano, Italy; 5Department of
Radiology, HPG23, Bergamo, Italy; 6Department of Radiology,
Sant’Orsola Hospital, Bologna, Italy; 7Department of Radiology,
ISMETT, Palermo, Italy; 8Department of Radiology, La Sapienza
University, Roma, Italy; 9Department of Radiology, San Matteo
Hospital, Pavia, Italy
Nitinol-based ePTFE-covered endoprosthesis (VIATORR©) rep-
resent the standard option for TIPS creation in cirrhotic patients.
No data exist on the VIATORR© ability to either self-expand to
nominal diameter or to maintain smaller calibers when under
ballooned to avoid unwarranted portosystemic pressure gradi-
ent (PSPG) drop. It is believed that post-TIPS PSPG should be
<12mmHg to avoid bleeding/ascites recurrence but ≥10mmHg
to avoid hepatic encephalopathy (HE) development. Our main
objective was to measure VIATORR© diameter in cirrhotic liv-
ers; secondary objectives were to determine the relationship
between endoprosthesis diameter and both post-TIPS levels of
PSPG and HE occurrence. Computed tomography scans of
198 cirrhotic patients from 8 Italian Centres were centralized
and retrospectively analyzed. All patients received 10mm nom-
inal diameter VIATORR©. Maximum diameter of 4 orthogo-
nal sections of VIATORR© was obtained after 3D multiplanar
reconstruction. Moreover, hepatic hemodynamic and follow-up
data of 95 subjects from two Centres were collected to deter-
mine the relationship between both VIATORR© ballooning and
CT-derived diameters and post-TIPS PSPG levels and post-TIPS
HE. Ballooning subgroups were as follow: 6mm=27, 7mm=19,
8mm=91, 9mm=24, and 10mm=37 subjects, respectively. Cor-
responding CT-derived average diameters were 7.5±0.5mm,
7.8±0.6mm, 8.1±0.5mm, 8.5±0.4mm, and 8.3±0.4mm
(p=0.0001 by ANOVA). After grouping according to balloon-
ing (≤6mm vs >6mm) and CT-derived (≤7mm vs >7mm) diam-
eters, proportions of patients (n=95) reaching a PSPG target
either <12mmHg or <10mmHg were 52.0% vs, 62.9% (p=ns)
and 24.0% vs 51.4% (p=0.018); 47.1% vs 75.0% (p<0.006)
and 27.5% vs 63.6% (p<0.0004), respectively. Correspond-
ing yearly cumulative risk of HE development was 20% vs,
48.6% (p=0.023) and 31.4% vs, 52.3% (p=0.048), respec-
tively. No significant differences in variceal bleeding or ascites
recurrence were observed. VIATORR© endoprosthesis do not
self expand to their nominal diameters in cirrhotic livers. A high
proportion of patients reaches a clinically acceptable PSPG
target after ballooning at 6mm (CT-derived maximum diameter
≤7mm). This strategy of TIPS positioning significantly decreases
the risk of post-TIPS HE development in cirrhotic patients.
Disclosures:
Filippo Schepis - Grant/Research Support: GORE, COOK; Speaking and Teach-
ing: GORE, COOK
Erica Villa - Advisory Committees or Review Panels: Abbvie, GSK; Grant/
Research Support: MSD, Roche
HEPATOLOGY, October, 2014
The following people have nothing to disclose: Francesco Vizzutti, Guido Mar-
zocchi, Pietro Quaretti, Antonio G. Rampoldi, Roberto Agazzi, Rita Golfieri,
Angelo Luca, Fabrizio Fanelli, Cristian Caporali, Stefano Colopi, Luigi Rega,
Umberto Arena, Ilaria Fiorina, Lorenzo Moramarco, Aldo Airoldi, Roberto Nani,
Matteo Renzulli, Cristina Mosconi, Raffaele Bruno, Stefano Fagiuoli, Alessandro
Cannavale, Tommaso Di Maira, Stefano Gitto
400
Portal vein thrombosis significantly increases mortality
in advanced cirrhosis with improved prognosis being
associated with portal vein recanalization
Carlos Noronha Ferreira1, Teresa Rodrigues2, Patrícia Sousa1, Fer-
nando Ramalho1, Paula Alexandrino1, José F. Velosa1; 1Serviço de
Gastrenterologia e Hepatologia, Hospital de Santa Maria, Lisboa,
Portugal; 2Laboratório de Biomatemática, Faculdade de Medicina
de Lisboa, Lisboa, Portugal
Clinical significance of portal vein thrombosis(PVT) in cirrho-
sis not associated with hepatocellular carcinoma(HCC) is
unclear. Aims 1.Analyse clinical features and factors asso-
ciated with mortality in cirrhotics with PVT. 2.Study effect
of anticoagulation(ACO) on portal vein recanalization(PVR)
and influence on outcome. Methods: The study included 65
consecutive cirrhotics with PVT without HCC. We analysed
effect of severity of cirrhosis, clinical features and PVT on
mortality at end of follow-up(FU). Mortality in study sample,
patients given ACO and those with PVR was compared to
controls-175 patients without PVT with similar severity of cir-
rhosis (Child-Pugh(CP),MELD scores). Statistical analysis-SPSS
21. Results: 63%(41)males, age:58.7±12y. Cirrhosis etiol-
ogy: Alcohol-62%(40); viral-11%(7); alcohol+viral-12%(8);
others-15%(10). Cirrhosis severity:CP-8(2-15),MELD-13(6-35).
CP class:A-19%(12),B-49(32),C-32%(21). Type of PVT: Acute-
88%(57),chronic-12%(8). Extent of PVT: Trunk-80%(52);left
branch-35%(23);right branch-57%(37);trunk+branch-
es-31%(20);superior mesenteric vein-28(18);splenic vein-
19%(12). Symptoms at PVT diagnosis:82%(53). Main
features:Variceal bleed-45%(29),abd pain-30%(19),fe-
ver-16%(10). ACO after PVT diagnosis given in 19 patients
(varfarin-15,LMWH-4). In 50 patients with FU imaging, PVR
noted in 50%(25)(Partial–13,total–12). Spontaneous PVR
noted in 22%(7/32) patients. Median follow-up:10(0-376)
m. Mortality: End of FU:25/65(39%); 1 year:37%(18/49),
3 years63%(22/35) Cirrhotics with PVT who died had higher
CP(p=0.004) and MELD(p=0.016 scores. Cirrhosis etiology,
type and extent of PVT and clinical features did not influence
mortality. CP class C cirrhotics with PVT had higher mortal-
ity at end of FU compared to class A+B (OR 6,95%CI1.9–
18.7,p=0.002). Overall, cirrhotics with PVT had similar
mortality compared to controls. ACO improved PVR rates
compared to no ACO(95%(18/19)vs22%(7/32), p<0.001)
(OR 0.019,95%CI0.002–0.161,p<0.001), but did not reduce
mortality compared to no ACO/controls. Patients with PVR
had lower mortality (OR 0.14,95%CI0.04–0.49,p=0.002).
Benefit of PVR on mortality reduction was observed only in
CP class C patients(p=0.028). Conclusions: PVT is associated
with higher mortality in CP class C cirrhosis. Spontaneous and
ACO induced PVR signficantly reduced mortality in patients
with cirrhosis and PVT.
Table 1. KM survival analysis - Factors influencing mortality at
end of follow-up in cirrhotics with PVT compared to controls
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Disclosures:
Carlos Noronha Ferreira - Advisory Committees or Review Panels: ABBVIE; Con-
sulting: Bristol Myers Squibb
José F. Velosa - Advisory Committees or Review Panels: Bristol Meyers Squibb,
Gilead Sciencs; Consulting: Roche Pharmaceutics
The following people have nothing to disclose: Teresa Rodrigues, Patrícia Sousa,
Fernando Ramalho, Paula Alexandrino
401
The Performance of Objective Nutrition Assessment
Tools and the Evaluation of Nutritional Intake in the Pre-
Liver Transplant Populatio
Kaleb J. Marr1, Abdel Aziz M. Shaheen1,3, Louisa Lam4, Lau-
ren Schock4, Melanie Stapleton1,3, Kelly W. Burak1,2, Maitreyi
Raman3; 1Internal Medicine, University of Calgary, Airdrie, AB,
Canada; 2Liver Unit, University of Calgary, Calgary, AB, Canada;
3Gastroenterology, University of Calgary, Calgary, AB, Canada;
4University of Calgary, Calgary, AB, Canada
Background and Aim: Malnutrition is common in cirrhosis and
is a leading cause of morbidity and mortality. Subjective Global
Assessment (SGA), the gold standard for assessing nutrition,
may not be a reliable assessment tool, due to limitations related
to weight, which may be artificially increased in the presence
of ascites, underestimating malnutrition. The aim of this pilot
study is to describe the performance of objective measures
of nutrition including dry body mass index (BMI), handgrip
strength (HGS), and mid arm circumference (MAC) in correla-
tion to SGA among cirrhotic patients on the liver transplant list.
Methods: Our prospective pilot study was conducted at Uni-
versity of Calgary high-risk malnutrition clinic (October 2012-
May 2014). All pre-liver transplant patients are assessed in this
clinic. We assessed nutritional status via: SGA (B or C); Dry-
BMI; HGS as measured in the dominant hand with a calibrated
dynamometer; and MAC. We also assessed recommended
and achieved calorie and protein intake. Non-parametric anal-
ysis was used to compare study groups. Spearman correlation
coefficient was used to assess correlation between different
tools. Results: We recruited 27 patients. the majority was male
(n=17, 63%) with a median age of 58 years (IQR: 50-61).
Fifteen patients were SGA B (55%), and 12 patients were SGA
C (45%). SGA C compared to SGA B patients were older (61
years vs 51 years, P=0.03). Calorie intake was higher among
SGA B than C (1881.3 vs 1529.9 kcal/day, P=0.08). Also,
protein intake was higher in SGA B than C (75 vs 60.8 g/day,
P=0.19). MAC was not significantly different between SGA B
than C in both females (25 vs 20cm, P=0.07) and males (27.5
vs 22cm, P=0.13). HGS was lower among SGA C compared
to B in both females (25 vs 40 PSI, P=0.02) and males (52
vs 77 PSI P=<0.01). There was a correlation between MAC
and HGS measurements (r=0.507, P=0.11). Conclusions: In
our pilot study, HGS and MAC demonstrated the potential to
be objective measures for the assessment of malnutrition in
cirrhotic patients. However, the impact of age on SGA status
needs further assessment. Indeed, cirrhotic patients with SGA
class B and C have lower calorie and protein intake than rec-
ommended. Poor intake, especially among SGA C patients, is
of significant clinical concern. Objective measures of nutrition
assessment in cirrhotics will reduce the dependence on subjec-
tive measures and allow accurate risk assessment. This may
in turn lead to a change in clinical practice toward ensuring
nutritional optimization in this high-risk population.
Disclosures:
Melanie Stapleton - Speaking and Teaching: Ferring
399A
Kelly W. Burak - Advisory Committees or Review Panels: Gilead, Gilead, Gilead,
Gilead, Janseen; Grant/Research Support: Bayer, Bristol Myers Squibb, Genen-
tech, Bayer, Bristol Myers Squibb, Genentech, Bayer, Bristol Myers Squibb,
Genentech, Bayer, Bristol Myers Squibb, Genentech, Boehrihnger Ingelheim;
Speaking and Teaching: Gilead, Astellas, Merck, Roche, Gilead, Astellas,
Merck, Roche, Gilead, Astellas, Merck, Roche, Gilead, Astellas, Merck, Roche
The following people have nothing to disclose: Kaleb J. Marr, Abdel Aziz M.
Shaheen, Louisa Lam, Lauren Schock, Maitreyi Raman
402
A multicenter survey of the efficacy and safety of
danaparoid sodium treatment for portal vein thrombosis
Takaaki Ohtake1, Kunihiko Tsuji2, Teruaki Kawanishi3, Tak-
uro Machida4, Hideyasu Takagi5, Shinichi Mezawa6, Yasuyuki
Yazaki7, Yasuhisa Shinomura5, Yutaka Kohgo1; 1Division of Gas-
troenterology and Hematology/Oncology, Department of Medi-
cine, Asahikawa Medical University, Asahikawa, Japan; 2Center
for Gastroenterology, Teine-Keijinkai hospital, Sapporo, Japan;
3Hokkaido Health Coop Sapporo Ryokuai Hospital, Sapporo,
Japan; 4Hokkaido Gastroenterology Hospital, Sapporo, Japan;
5Department of Gastroenterology, Rheumatology and Clinical
Immunology, Sapporo Medical University, Sapporo, Japan; 6Sap-
poro Kyoritsu Clinic, Sapporo, Japan; 7Kobayashi Hospital, Kit-
ami, Japan
[Background and aim] As a complication of cirrhosis, por-
tal vein thrombosis (PVT) is a critical condition that worsens
hepatic reserve function. The standard treatment is anticoagula-
tion therapy with unfractionated heparin, low-molecular-weight
heparin, or warfarin. Danaparoid sodium (DS) is a heparinoid
anticoagulant. Here we retrospectively report the efficacy and
safety of DS in the treatment of PVT. [Methods] This is a ret-
rospective epidemiological study analyzing integrated clini-
cal data of patients treated with DS for PVT. Six facilities in
Hokkaido, Japan participated in this study. Patients with first-
time treatment from register data were included. Patient per-
sonal information was protected by the anonymizing method.
[Results] Eighty-five patients [51 males, 34 females; median
age, 66 years (35–85)] were analyzed. Thrombosis sites
were the following: portal trunk only, 28 cases; portal trunk
with intrahepatic branches, 17; mainly intrahepatic branches,
36; and principal tributaries only (superior mesenteric vein or
splenic vein), 4. The complications observed were liver cir-
rhosis in 65% cases. The etiology was HBV-associated in 17
cases, HCV-associated in 21, alcoholic liver disease in 17,
both viral and alcohol in 4, autoimmune in 7, NASH-related
in 4, and others in 15. Complication rate of hepatocellular
carcinoma was 39%; furthermore, 47% patients were treated
for esophageal varices. Child–Pugh class of patients was A
in 41 and B + C in 44 cases. The duration of DS therapy
was median 14 days (4–150). Total dose of DS was median
37,500 units (5,000–255,000). Therapeutic efficacy was
complete resolution of thrombosis, 39%; residual thrombosis
<50%, 33%; residual thrombosis ≥50%, 6%; unchanged,
19%; and unknown, 3%. Univariate analysis revealed higher
serum ammonia levels as a predictive factor of therapeutic
efficacy of DS in clinical background and blood test before
treatment. In addition, higher dosage of DS tended to have
therapeutic efficacy. Two of 85 patients had adverse events:
one had bleeding from esophageal ulcer after endoscopic vari-
ceal ligation and the other had thrombocytopenia. In the mean
observation period of 747 days, 54 patients survived and 31
died. The efficacy of DS therapy and no complication of HCC
contributed to the cumulative survival by Kaplan–Meier curve
(p = 0.036 and 0.007, respectively). [Conclusions] In all, 72%
patients with PVT treated with DS had complete resolution of
thrombosis or <50% residual thrombosis. No serious adverse
events were observed. Efficacy of DS therapy contributed to
400A AASLD ABSTRACTS
the cumulative survival. These results support the efficacy and
safety of DS in the treatment of PVT.
Disclosures:
Hideyasu Takagi - Grant/Research Support: MSD K.K.
Yasuhisa Shinomura - Grant/Research Support: MSD K.K.
Yutaka Kohgo - Grant/Research Support: Novartis, Chugai-Roche, Asahikasei
Mecical, Mitsubishi Tanabe Pharm, Sapporo Beer Co
The following people have nothing to disclose: Takaaki Ohtake, Kunihiko Tsuji,
Teruaki Kawanishi, Takuro Machida, Shinichi Mezawa, Yasuyuki Yazaki
403
Change in epidemiology of chronic liver disease, 2004-
2013
Sumeet K. Asrani1, Maria A. Kouznetsova2, Andrew Masica2,
Brett Stauffer2, Michael Hagan1, Patrick Kamath3, James F. Trot-
ter1, Fasiha Kanwal4; 1Baylor University Medical Center, Baylor
Scott and White, Dallas, TX; 2Center for Clinical Effectiveness,
Baylor Scott and White, Dallas, TX; 3Mayo Clinic, Rochester, MN;
4Baylor College of Medicine, Houston, TX
Introduction: Chronic liver disease (CLD) related morbidity and
mortality has remained unchanged over the last 3 decades.
We hypothesized that a change in etiology and an aging CLD
population may be contributing to the persistent burden. Meth-
ods: We examined changes in the frequency and reasons of
CLD-related admissions and readmissions (2004-2013) across
the largest healthcare system in Dallas-Fort Worth (8 hospitals,
catchment area of 7 million, >130,000 annual admissions).
To decrease ascertainment bias, we also included manifesta-
tions of end stage liver disease (e.g. hepatorenal syndrome)
or other admissions that may be considered to be liver-re-
lated in patients with underlying CLD (e.g. sepsis). Finally, we
compared CLD related admissions to congestive heart failure
(CHF) admissions to examine CLD trends among the elderly.
Results: Between 2004-2013 there were 26,816 total CLD
related admissions. The median age increased from 53 to 57
years. Age specific admission rates (per 100,000) increased
2.5-fold for 55-64 (2,312 to 5,580) and 2-fold for persons
65-74 (1,291 to 2,501) and 75+ (596 to 1,143) with a cor-
responding increase in Medicare utilization (110% increase).
Admission rates (per 100,000 CLD admissions) related to
alcohol decreased (15,179 to 8,137) and those related to
viral hepatitis increased (8,075 vs. 11,949). The top 3 causes
for CLD admissions were pneumonia, sepsis and cellulitis,
accounting for 39.3% of all admissions. In 2013, rates per
100,000 CLD admissions were highest for infection (38,523)
followed by encephalopathy (9,894), anasarca/volume over-
load or depletion (2,027) and ascites (1,162). Reasons for
admission also changed over time: number of admissions (per
100,000 CLD admissions) for infections increased by 55%
and hepatic encephalopathy (HE) increased by 18%. Read-
mission rates were 20.5% (30d), 28.9% (90d) and 38.2% (1
year) after first hospitalization. The most common reason for
readmission (30d) was HE, alcoholic cirrhosis, and sepsis. We
further examined older CLD patients (>65 years). Median cost/
encounter was higher: $9,069 (CLD) vs. $7,995 (CHF). Inpa-
tient mortality/hospice was higher: 22.9% (CLD) vs. 11.6%
(CHF); alternatively fewer CLD patients received ancillary
support (home health/rehab) at discharge: 22.1% (CLD) vs.
30.2% (CHF). Reasons for admission and readmissions were
similar in the elderly population as compared to the rest of the
CLD population. Conclusion: There has been a change in the
epidemiology of CLD related admissions over time with a shift
towards infection and HE. Morbidity among elderly cirrhotics
may be increasing and has implications on national resource
allocation.
HEPATOLOGY, October, 2014
Disclosures:
The following people have nothing to disclose: Sumeet K. Asrani, Maria A. Kou-
znetsova, Andrew Masica, Brett Stauffer, Michael Hagan, Patrick Kamath, James
F. Trotter, Fasiha Kanwal
404
Blood Group Non-O is a Risk Factor for Portal Vein
Thrombosis
Elisabeth P. Plompen1, Sarwa Darwish Murad1, Massimo Primi-
gnani2, Elwyn Elias3, Jonel Trebicka4, Luc Lasser5, Bettina E. Han-
sen1,6, Juan Carlos Garcia-Pagan7, Dominique Valla8, Frank W.
Leebeek9, Harry L. Janssen1,10; 1Gastroenterology and Hepatol-
ogy, Erasmus MC University Medical Center, Rotterdam, Neth-
erlands; 2Gastroenterology Unit, IRCCS Maggiore Hospital,
Mangiagalli and Regina Elena Foundation, Milan, Italy; 3Liver
Unit, Queen Elizabeth University Hospital, Birmingham, United
Kingdom; 4Internal Medicine I, University Hospital of Bonn, Bonn,
Germany; 5Hepatogastroenterology, Centre Hospitalier Universi-
taire Brugmann, Brussels, Belgium; 6Public Health, Erasmus MC
University Medical Center, Rotterdam, Netherlands; 7Hepatic
Hemodynamic Laboratory, Liver Unit, Hospital Clinic, IDIBAPS
and Ciberehd, Barcelona, Spain; 8Service d’Hépatologie, Hopital
Beaujon, AP-HP, Inserm U773 and Université Denis Diderot-Paris
7, Clichy, France; 9Hematology, Erasmus MC University Medical
Center, Rotterdam, Netherlands; 10Liver Centre, Toronto Western
and General Hospitals, University Health Network, Toronto, ON,
Canada
Background and aims: Several risk factors for the development
of splanchnic vein thrombosis (SVT) have already been identi-
fied, but part of the etiology of SVT remains unknown. The aim
of this study was to elucidate the role of novel candidate single
nucleotide polymorphisms (SNPs), recently shown to increase
the risk of venous thromboembolism, as risk factors of SVT.
Methods: In this case-control study, patients with portal vein
thrombosis (PVT), Budd-Chiari syndrome (BCS) and controls
were recruited from the European Network for Vascular Dis-
ease of the Liver (EN-Vie) study cohort. Genotyping of 5 candi-
date SNPs – in the VWF (rs1063857), STXBP5 (rs1039084),
CYP4V2 (rs13146272), GP6 (rs1613662) and SERPINC1
(rs2227589) genes – and ABO blood group was performed
using a Taqman assay. Results: DNA samples were available
in 80 patients with PVT, 79 patients with BCS and 81 con-
trols. Of these, genotyping was successful in 77, 77 and 81
respectively. All SNPs were in Hardy-Weinberg equilibrium
(call rates >97%). Median age of our patients was 43.7 (IQR
31.0-54.4) years and 65 (42.2%) were male. An underly-
ing inherited thrombophilic factor was previously diagnosed
in 17 patients with PVT (22.1%) and 16 patients with BCS
(20.8%). A myeloproliferative neoplasm (MPN) was detected
in 26.3% of patients with PVT and 37.7% of those with BCS.
Blood group non-O was present in 81.6% of patients with PVT
as compared to 57.1% of patients with BCS and 58.8% of
controls (p=0.002). Presence of blood group non-O was asso-
ciated with an increased risk of PVT (OR 3.1, 95%CI 1.5-6.5,
p=0.002 for AA/GA versus GG at rs687289). No association
between blood group non-O and risk of BCS was observed (OR
0.9, 95%CI 0.5-1.8, p=0.8). Blood group non-O remained
independently associated with PVT after adjustment for age
and sex (OR 3.3, 95%CI 1.5-7.3, p=0.003). Presence of a
known underlying inherited thrombophilic factor did not alter
the association between blood group non-O and PVT com-
pared to patients with BCS (p for interaction term=0.13). The
association between blood group type non-O and PVT was
also not altered by the presence of a MPN (p for interaction
term=0.88). None of the 5 other novel candidate SNPs asso-
ciated with venous thromboembolism was associated with an
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
increased risk of PVT or BCS (p-values>0.05). Conclusions: In
this study, blood group non-O was discovered as an indepen-
dent risk factor for the development of PVT. Interestingly, this
factor was not associated with BCS. Blood group non-O is
therefore the first discriminant etiological factor described and
may be a lead to the unresolved issue of site-specificity of these
conditions.
Disclosures:
Juan Carlos Garcia-Pagan - Grant/Research Support: GORE
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sci-
ences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support:
Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck,
Medtronic, Novartis, Roche, Santaris
The following people have nothing to disclose: Elisabeth P. Plompen, Sarwa
Darwish Murad, Massimo Primignani, Elwyn Elias, Jonel Trebicka, Luc Lasser,
Bettina E. Hansen, Dominique Valla, Frank W. Leebeek
405
Role of the microRNA-FoxA2 axis in biliary-committed
progenitor cells during cholestatic liver injury
Kelly McDaniel2, Fanyin Meng1, Heather L. Francis1, Yuyan Han3,
Julie Venter3, Nan Wu3, Morgan Quezada2, Ying Wan2, Shan-
non S. Glaser1, Gianfranco Alpini1; 1Research, Medicine and
S&W Digestive Diseases Research Center, Central Texas Veterans
Health Care System, Texas A&M University and Scott & White
Digestive Diseases Research Center, Temple, TX; 2Scott & White
Digestive Diseases Research Center, Scott & White, Temple, TX;
3Medicine, Texas A&M University, Temple, TX
BACKGROUND & AIMS: The rodent biliary epithelium is a
complex network of interconnected ducts of different diameter,
small and large ducts. Biliary-committed progenitor cells (small
cholangiocytes, SMCCs) present in small ducts are more resis-
tant to hepatobiliary injury than large cholangiocytes (LGCCs)
lining large ducts. microRNAs and the definitive endoderm
marker, FoxA2, are key factors that regulate cell differentia-
tion and tissue regeneration. Our aim is to characterize the
functional role of the microRNA-FoxA2 axis in biliary progen-
itor cells during cholestatic liver injury. METHODS: miRNA
and mRNA expression in SMCCs and LGCCs was assessed
by microArray and PCR array analysis respectively. Bile duct
ligation (BDL) and MDR2 knockout mice (MDR2-/-) were used
as animal models of cholestatic liver injury. We also per-
formed studies to determine whether suitable biliary support
would permit hepatic repair and regrowth of the damaged
liver with healthy transplanted cholangiocytes in NOD/SCID
mice with BDL injury. RESULTS: We identified specific microR-
NAs including let-7b and miR-200b, which are differentially
reduced in SMCCs when compared to LGCCs by microRNA
microArray analysis. Also, FoxA2 was notably enhanced in
SMCCs when compared with LGCCs. Silencing of let-7b and
miR-200b, along with activation of FoxA2 expression were
observed in murine small bile ducts in BDL treated and MDR2-
/- mice liver, suggesting that they are important mediators for
biliary remodeling. FoxA2 has been demonstrated to be the
direct target of let-7b and miR-200b in biliary epithelial cells
by luciferase reporter assay. Because biliary progenitors/small
cholangiocytes can be transplanted in large numbers in the
peritoneal cavity, we examined the benefits of serum chemistry
from transplanted cells. Serum ALT and AST levels in NOD/
SCID mice engrafted with SMCCs (3x107, i.p.) showed sig-
nificant changes compared with vehicle treated mice (n =5),
along with the previously shown significantly improved Sirius
red staining. Reduced let-7b and miR-200b levels, along with
the enhanced expression of the definitive endoderm differen-
tiation marker FoxA2 was observed in BDL mice liver after
SMCC cell therapy. Also, activation of α-SMA and collagen-α1
401A
were observed in BDL treated and MDR2-/- mice liver, and
recovered after SMCC engraft. CONCLUSION: The therapeu-
tic effect of biliary-committed progenitor cells during cholestatic
liver injury is mediated by the let-7b/miR-200b-FoxA2 axis, the
known critical regulators of biliary development and injury. The
findings provide new insight into the therapeutic potentials of
small cholangiocytes during cholestatic liver injury and fibrosis.
Disclosures:
The following people have nothing to disclose: Kelly McDaniel, Fanyin Meng,
Heather L. Francis, Yuyan Han, Julie Venter, Nan Wu, Morgan Quezada, Ying
Wan, Shannon S. Glaser, Gianfranco Alpini
406
Modulation of β-catenin in experimental cholestasis: A
therapeutic opportunity
Kari Nejak-Bowen, Satdarshan (Paul) S. Monga; University of Pitts-
burgh, Pittsburgh, PA
Cholestatic liver diseases such as primary sclerosing cholangitis
(PSC) and primary biliary cirrhosis (PBC) result from impairment
of bile flow and are characterized by inflammation, ductular
reaction, and fibrosis. We have recently demonstrated that liv-
er-specific β-catenin knockout mice (Alb-cre β-catenin KO; KO1)
exhibit a dramatic decrease in liver injury, fibrosis, and atyp-
ical ductular proliferation (ADP) after bile duct ligation (BDL),
a model of cholestasis. Furthermore, we observed decreased
total hepatic bile acids (BA) in KO1 after BDL, concomitant
with enhanced farnesoid X receptor (FXR) activation. This led
to the discovery of a novel role for β-catenin in regulating BA
synthesis and transport through association with FXR. We
hypothesized that this interaction is independent of upstream
Wnt signaling. Furthermore, exogenous suppression of β-cat-
enin/FXR during cholestasis through administration of locked
nucleic acid (LNA) against β-catenin may alleviate injury and
disease progression. We performed BDL on Alb-cre LRP5/6
double KO mice (KO2), which lack canonical Wnt signaling
but harbor normal β-catenin/FXR complex, and compared to
wild-type (WT) and KO1. These mice showed an intermediate
phenotype, suggesting that ADP, which is inhibited in KO2, is
contributing to cholestasis. Next, we subjected WT mice to BDL
and concomitantly suppressed β-catenin expression with LNA.
These mice had fewer bile infarcts and decreased liver BA due
to loss of β-catenin/FXR complex. These findings support a dual
role of β-catenin in the pathogenesis of cholestatic liver disease
through exacerbation of ADP and dysregulation of BA metabo-
lism due to its interaction with FXR. Thus, β-catenin suppression
may provide novel therapeutic opportunities for alleviating the
progression of diseases like PSC and PBC.
Disclosures:
The following people have nothing to disclose: Kari Nejak-Bowen, Satdarshan
(Paul) S. Monga
407
Post-translational regulation of Polycystin 2 (PC2) pro-
tein expression by ubiquitination and autophagy as a
novel mechanism of cholangiocyte repair and reaction
to biliary damage
Carlo Spirli1, Carola M. Morell2, Ambra Villani1, Luca Fabris3,1,
Romina Fiorotto1, Mario Strazzabosco1,2; 1Section of Digestive
Diseases-Liver Center, Yale University, New Haven, CT; 2Depart-
ment of Surgery and Translational Medicine, University of Mila-
no-Bicocca, Milan, Italy; 3Department of Molecular Medicine,
University of Padova, Padova, Italy
A genetic defect of PC2 in cholangiocytes causes inappro-
priate production of cAMP, PKA-dependent activation of the
402A AASLD ABSTRACTS
ERK1/2 pathway, HIF1α-mediated VEGF production and stim-
ulation of cyst growth and disease progression in in polycystic
liver diseases (PLD). Based on these findings, we hypothesized
that modulation of PC2 may represent a fundamental mech-
anism to stimulate VEGF secretion during repair from biliary
damage. Results: we found that PC2 protein expression was
significantly reduced in livers from mice undergoing cholan-
giocyte damage (Mdr2-/—KO, bile duct ligation, treatment
with dehydrocollidine–DDC). However, PC-2-gene expression
was not reduced, suggesting that the decrease in PC2 protein
content was due to increased PC2 degradation. To understand
if factors involved in biliary damage, decreased PC2 protein
expression, mouse cholangiocytes were treated with IL-1β (20
U/ml), IFNγ (100 U/ml), TNFα (500 U/ml)), nitric oxide (NO)
donors (DETAnonoate, 250 mM) and ER stressors (thapsigargin,
2 mM). As shown in vivo, expression of PC2 protein was sig-
nificantly reduced, while its gene expression was unchanged.
Noteworthy, similar to genetic PC2 defects, downregulation
of PC-2 expression was associated to increased HIF1α tran-
scription activity and secretion of VEGF. In addition, we found
an increased expression of Herp, an ubiquitin-like protein that
promotes PC2 degradation by increasing the retrotranslocation
from the ER to the proteasome complex. Pre-treatment with the
proteasome inhibitor MG-132 restored the expression of PC2
in cells treated with cytokines but not in cells treated with NO
donors or with ER stressors. In these conditions, PC2 degra-
dation was inhibited by LY294002, an inhibitor of PI3K that
blocks the autophagosome formation and by blockade of lyso-
somes with cloroquine, suggesting that inhibition of autoph-
agy was able to restore the expression of PC2. In conclusion,
PC2 protein expression is modulated post-translationally by
pro-inflammatory cytokines, ER-stressors and NO-donors and is
specifically reduced in mice with biliary damage. PC2 degra-
dation is differentially mediated by proteasome during inflam-
mation and by autophagy during ER-stress. Downregulation
of PC2 protein expression in cholangiocytes increases HIF1α
transcriptional activity and VEGF secretion, thereby playing
a pivotal role in the regulation of cholangiocyte response to
biliary damage. Given the availability of proteasome inhibitors
and autophagy regulators for clinical use, these findings have
a strong translational relevance.
Disclosures:
The following people have nothing to disclose: Carlo Spirli, Carola M. Morell,
Ambra Villani, Luca Fabris, Romina Fiorotto, Mario Strazzabosco
408
ENDTP1/CD39 deficiency aggravates liver injury and
fibrosis in sclerosing cholangitis model in Mdr2-/- mice
Zhen-Wei Peng, Naoki Ikenaga, Susan B. Liu, Simon C. Robson,
Yury Popov; Division of Gastroenterology and Hepatology, Beth
Israel Deaconess Medical Center, Harvard Medical School, Bos-
ton, MA
BACKGROUND: Primary sclerosing cholangitis (PSC) is char-
acterized by inflammation and biliary-type fibrosis that ulti-
mately progresses to cirrhosis. ENDTP1/CD39 is a rate-limiting
ecto-enzyme responsible for extracellular ATP hydrolysis and
adenosine generation. We investigated the role of purinergic
signaling in regulating biliary fibrosis by studying the effects
of genetic CD39 ablation in Mdr2-/- model of PSC. METH-
ODS: Mdr2-/- mice spontaneously develop hepatic lesions
closely resembling primary sclerosing cholangitis. We gener-
ated Mdr2-/-;CD39-/- double-mutant mouse on congenic C57
background by crossing CD39-/- mouse to Mdr2-/-. Severity
of cholangitis and progression of liver fibrosis was evaluated
in Mdr2-/-;CD39+/+ and Mdr2-/-;CD39-/- by histology, bio-
HEPATOLOGY, October, 2014
chemical determination of collagen, and fibrosis-related gene
expression by RT-PCR. Inflammatory infiltrate was character-
ized by immunostaining and RT-PCR. Administration of sta-
ble ATP analogue (αβ-ATP, 1mg/mouse daily for 6 days) into
Mdr2-/- mice was performed in parallel experiments. RESULTS:
Genotyping of F2 progeny (n=140) revealed that 57% of dou-
ble-mutants expected by Mendelian genetics died in utero. Phe-
notyping at age of 8 weeks (when fibrotic lesions are already
well advanced) revealed mice lacking both Mdr2 and Cd39
genes develop significantly more liver injury, inflammation and
fibrosis compared to Mdr2-/-;Cd39+/+ littermates. Increased
collagen deposition was detected around injured bile ducts
(onion skinning), with a 30% increase in total hepatic collagen
levels as quantified via hydroxyproline. Exaggerated fibrotic
responses were associated with two-fold increases in serum
ALT levels and pro-fibrogenic gene expression. Aggravation
of liver disease in the absence of CD39 was associated with
a selective increase in CD8+ T cells, as evidenced by in situ
immunostaining and CD8 mRNA, while CD3 and CD4 did not
change. Liver phenotype associated with CD39 deficiency was
recapitulated with administration of stable ATP agonist αβ-ATP
for 6 days into CD39-sufficient Mdr2-/- mice. ATP agonism
resulted in a two-fold increase in serum ALT, COL1A1 and
TGFβ2 mRNA levels, CD8+ cell counts; pronounced ductu-
lar proliferation; and a trend towards higher hepatic collagen
levels. CONCLUSIONS: Purinergic signaling plays an indis-
pensable role in controlling severity of sclerosing cholangitis in
Mdr2-/- mice. CD39 deficiency aggravates liver injury, inflam-
mation and fibrosis in the Mdr2-/- model and is associated
with hepatic CD8+ T-cell influx. Scavenging extracellular ATP
appears to determine the protective role of CD39 in biliary
injury and fibrosis.
Disclosures:
Simon C. Robson - Grant/Research Support: Pfizer, NIH; Independent Contrac-
tor: eBioscience, Biolegend, EMD Millipore, Mersana; Speaking and Teaching:
ACP, Elsevier, ATC; Stock Shareholder: Nanopharma, Puretech
Yury Popov - Consulting: Gilead Sciences, Inc; Grant/Research Support: Gilead
Sciences, Inc, Takeda
The following people have nothing to disclose: Zhen-Wei Peng, Naoki Ikenaga,
Susan B. Liu
409
High Systemic Autotaxin Induces Itch in Mice
Ruth Bolier1, Dagmar Tolenaars1, Andreas E. Kremer3, Joanne Ver-
heij2, Ulrich Beuers1, Piter J. Bosma1, Ronald Oude Elferink1; 1Tyt-
gat Institute for Liver and Intestinal Research, Academic Medical
Center, Amsterdam, Netherlands; 2Pathology, Academic Medical
Center, Amsterdam, Netherlands; 3Internal Medicine, Friedrich-Al-
exander University of Erlangen-Nuremberg, Erlangen, Germany
Introduction: In patients with cholestatic diseases serum auto-
taxin (ATX) activity is increased and correlates with pruritus
(itch) intensity.(1) We hypothesized that circulating ATX causes
itch by local production of lysophosphatidate (LPA), known to
activate itch neurons.(1-4) Aim: To establish a mouse model
with elevated serum ATX to study the role of ATX in cholestatic
itch. Methods: Mouse models used: 1. Bile duct ligation vs.
sham operation in wt mice (n=5); 2. Atp8b1 mutant mice on
0.1% cholate (CA) diet vs. control diet (intrahepatic cholestasis,
n=14); 3. Pregnancy in Atp8b1 mutant mice vs. wt on CA diet
(intrahepatic cholestasis during pregnancy, n=7); 4. Wt and
Atp8b1 mutant mice on CA diet after i.v. injection of AAV8-Atx
or AAV8-mutant Atx (n=7). Scratch activity was measured for
12 h during 4 consecutive nights per condition, and corrected
for the decline in total locomotor activity during disease or
pregnancy. Immunohistochemistry for ATX and chromogranin A
(CgA) was performed on a range of human and murine tissues.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Results: Neither bile duct ligation nor induction of cholestasis in
Atp8b1 mutant mice by CA feeding caused scratch behaviour.
BDL caused no increase in serum ATX whereas CA feeding
in Atp8b1 mice caused only a 2-fold increase in serum ATX
activity (p<0.001). This was not increased by concomitant
pregnancy. Only after further induction of serum ATX by trans-
duction with AAV8-Atx (3.3- and 4.4-fold in wt and cholestatic
mice, respectively, p<0.0001), increased scratch activity was
observed (1.7-fold, p<0.001). ATX immunostaining of liver
tissue from these mice demonstrated high expression levels
in the majority of hepatocytes. Injection of virus harbouring
mutant inactive ATX gene had no effect on serum ATX activity
nor on scratch behaviour. Human but not murine CgA posi-
tive enteroendocrine cells (EECs) express high levels of ATX.
Conclusions: Induction of serum ATX during cholestasis and/
or pregnancy is much lower in mice than in man (2-fold vs. up
to 30-fold, respectively). As a consequence cholestatic and
pregnant mice do not itch. However, when serum ATX is fur-
ther induced by AAV-Atx transduction, to levels comparable to
that of cholestatic patients with itch, mice do show increased
scratch activity. Intestinal EECs provide a potential source of
serum ATX in humans that lacks in mice, addressing a possi-
ble explanation for the much lower serum ATX levels in mice
during cholestasis and pregnancy. References: 1. Kremer et al.
Gastroenterology 2010; 139:1008-1018. 2. Hashimoto et al.
Pharmacology 2004; 72:51-56. 3. Nieto-Posadas et al. Nat
Chem Biol 2011; 20:78-85. 4. Mishra and Hoon. Science
2013; 340:968-971.
Disclosures:
Ulrich Beuers - Consulting: Intercept, Novartis; Grant/Research Support: Zam-
bon; Speaking and Teaching: Falk Foundation, Gilead, Roche, Scheringh, Zam-
bon
The following people have nothing to disclose: Ruth Bolier, Dagmar Tolenaars,
Andreas E. Kremer, Joanne Verheij, Piter J. Bosma, Ronald Oude Elferink
410
Knockdown of the melatonin receptor, MT2, enhances
biliary hyperplasia and liver fibrosis in cholestatic bile
duct ligated (BDL) mice: novel evidence for a hepatopro-
tective role of MT2
Nan Wu3, Yuyan Han3, Debolina Ray3, Julie Venter3, Kelly
McDaniel2, Allyson Martinez3, Shanika Avila3, Eugenio Gaudio5,
Paolo Onori5, Antonio Franchitto6, Fanyin Meng1, Micheleine
Guerrier3, Holly A. Standeford4, Gianfranco Alpini1, Shannon
S. Glaser1; 1Research, Medicine and S&W Digestive Diseases
Research Center, Central Texas Veterans Health Care System and
S&W and Texas A&M University, Temple, TX; 2Research, Scott &
White, Temple, TX; 3Medicine, Texas A&M University, Temple, TX;
4Research, Central Texas Veterans Health Care System, Temple,
TX; 5Anatomical, Histological, Forensic Medicine and Orthopedics
Sciences, University Sapienza, Rome, Italy; 6Research, Eleonora
Lorillard Spencer Cenci Foundation, Rome, Italy
Cholangiocytes (that are normally dormant) proliferate during
the course of cholestatic liver diseases, a pathology that is
characterized by enhanced intrahepatic bile duct mass (IBDM),
liver damage and fibrosis. Melatonin exerts its effects by inter-
action with MT1 and MT2 receptors, and is synthesized from
tryptophan in the pineal gland as well as peripheral tissues/
organs such as retina and GI tract including the biliary tree.
Melatonin inhibits hyperplastic and neoplastic biliary growth
by interacting with MT1 receptors. Since the role of MT2 in
liver function is unknown, we evaluated the role of this recep-
tor in liver pathology. Methods: The studies were performed
in normal and 1 wk BDL wild type (WT) and MT2 knock out
(KO) mice. We evaluated the expression of MT2 in liver sec-
tions by immunohistochemistry (IHC), qPCR and immunoblots
403A
in cholangiocytes. Proliferation was evaluated by measurement
of IBDM by IHC for CK-19 in liver sections and qPCR and
immunoblots for PCNA in cholangiocytes. Apoptosis of cholan-
giocytes was evaluated by immunoblots and qPCR for Bax in
cholangiocytes. Liver injury was evaluated by H&E staining in
liver sections and serum levels of transaminases and bilirubin.
Fibrosis was evaluated by Sirius red staining in liver sections
and qPCR for fibronectin, collagen 1 alpha 1, alpha-SMA and
TGF-beta 1 in cholangiocytes. Results: In liver sections, normal
cholangiocytes as well as hepatocytes display low immunore-
activity for MT2, which markedly increased in cholangiocytes
after BDL. By qPCR and immunoblots, the biliary expression
of MT2 increased after BDL. In MT2 KO BDL mice, along with
depletion of MT2, there was enhanced IBDM in liver sections,
increased PCNA expression and decreased Bax expression
in cholangiocytes. In MT2 KO BDL mice, there was increased
lobular damage, serum levels of transaminanes and bilirubin,
and liver fibrosis evidenced by enhanced Sirius red staining in
liver sections and expression of fibronectin, collagen 1 alpha
1, alpha-SMA and TGF-beta 1 in cholangiocytes compared
to BDL WT mice. Conclusion: Activation of MT2 may be an
important approach for ameliorating biliary hyperplasia and
liver fibrosis in cholestatic liver diseases.
Disclosures:
The following people have nothing to disclose: Nan Wu, Yuyan Han, Debolina
Ray, Julie Venter, Kelly McDaniel, Allyson Martinez, Shanika Avila, Eugenio
Gaudio, Paolo Onori, Antonio Franchitto, Fanyin Meng, Micheleine Guerrier,
Holly A. Standeford, Gianfranco Alpini, Shannon S. Glaser
411
Attenuated liver fibrosis modulated by miR-141 in
secretin knockout mice during cholestatic liver injury
induced by bile duct ligation (BDL)
Yuyan Han3, Allyson Martinez3, Ying Wan2, Kelly McDaniel2,
Julie Venter3, Heather L. Francis1, Holly A. Standeford4, Shanika
Avila3, Debolina Ray3, Haibo Bai2, Nan Wu3, Yoshiyuki Ueno5,
Shannon S. Glaser1, Gianfranco Alpini1, Fanyin Meng1; 1Research
and Medicine, Central Texas Veterans Health Care System, Scott
& White Digestive Disease Research Center, Scott & White, Texas
A&M University, Temple, TX; 2Research, Scott & White Digestive
Disease Research Center, Scott & White, Temple, TX; 3Medicine,
Texas A&M University, Temple, TX; 4Research, Central Texas
Veterans Health Care System, Temple, TX; 5Gastroenterology,
Yamagata University, Yamagata, Japan
Background: microRNAs (miRNAs) are small non-coding RNAs
that regulate the course of cholestatic liver injury. miR-141, a
member of miR-200 family that is regulated by TGF-beta, can
reverse the fibrogenic activity of the liver. Activation of biliary
proliferation plays a role in the initiation/progression of liver
fibrosis. We have previously shown that: (i) secretin (SCT, only
secreted by cholangiocytes in the liver) stimulates cholangiocyte
proliferation by downregulation of miRNA 125b and let7a;
and (ii) knockout of SCT reduces biliary hyperplasia during
cholestasis. Thus, we hypothesize that SCT regulates liver fibro-
sis during cholestatic injury by changes in the expression of spe-
cific microRNAs. Methods: We first evaluated (by microRNA
PCR array) miRNA profile in total tissue and cholangiocytes
from normal WT mice, BDL and SCT knockout (KO) + BDL
mice. We measured collagen deposition in liver tissue by Sirius
red staining. The expression of the fibrotic markers, fibronectin,
α-SMA and MMP-2 was evaluated in total liver tissue by q-PCR.
sh-SCT transfected murine cholangiocytes (MCCs) were used
for the in vitro studies along with empty vector controls. Expres-
sion of miR-141 was quantitated by taqman q-PCR, whereas
expression of fibrosis-related markers (fibronectin and cyclin
D1, that initiates the transition from the late G1 to the S phase
404A AASLD ABSTRACTS
of cell cycle) and mesenchymal markers (vimentin and S100A4)
were measured by q-PCR and immunoblots. Results: MicroRNA
PCR array showed that several microRNAs (including miR-141,
miR-200c and miR-34a) were dysregulated in BDL WT liver
tissue. Specifically, miR-141 was markedly reduced in BDL and
returned to normal values in SCT KO BDL mice. The expression
of fibronectin, α-SMA and MMP-2 decreased in SCT KO BDL
compared to BDL WT mice, along with significant decreased
Sirius red staining and intrahepatic bile duct mass. Silencing
of SCT in MCCs (by shRNA) increased miR-141 expression
by ~3-fold, along with significant decreased expression of
CK-19 (biliary marker), and PCNA (a marker of proliferation)
compared to vector-transfected control. Inhibition of miR-141
in MCCs significantly increased the expression of fibronectin
and cyclin D1. Enhanced expression of vimentin and S100A4
was also observed in miR-141 silenced MCCs compared to
controls. Conclusion: We demonstrated that SCT modulates
miR-141 expression and gene expression as a pro-fibrotic/pro-
liferative mechanism in biliary disorders. Targeting of the SCT-
miR-141 axis may provide an important therapeutic strategy in
the recovery of liver fibrosis during cholestatic injury.
Disclosures:
Yoshiyuki Ueno - Advisory Committees or Review Panels: Jansen, Gilead Science;
Speaking and Teaching: BMS
The following people have nothing to disclose: Yuyan Han, Allyson Martinez,
Ying Wan, Kelly McDaniel, Julie Venter, Heather L. Francis, Holly A. Stande-
ford, Shanika Avila, Debolina Ray, Haibo Bai, Nan Wu, Shannon S. Glaser,
Gianfranco Alpini, Fanyin Meng
412
Activation of Sirtuin1 pathway reverses liver injury in a
cholic acid fed mouse model of cholestasis
Supriya Kulkarni, Carol J. Soroka, James L. Boyer; Internal Medi-
cine, Digestive Diseases, Yale University School of medicine, New
Haven, CT
BACKGROUND: FXR and PPARα pathways are crucial regu-
lators of bile flow and bile acid homeostasis. Sirtuin1 (Sirt1,
mammalian homolog of S. Cerevisiae enzyme Sir2) an NAD+
dependant deacetylase functions as master regulator of met-
abolic processes. Recent studies show that Sirt1 deacetylates
murine Fxr and activates Bsep, Shp. Sirt1 activates Pgc1α
that activates Pparα, an important transcriptional regulator
of Mdr2. Activators of Fxr and Pparα obeticholic acid and
fibrates, are being actively pursued as alternative therapeutic
interventions in cholestatic liver injury. Sirt1 being upstream
regulator of both pathways, our aim was to identify whether
cholestatic liver injury alters expression of Sirt1 and if Sirt1
could be targeted to alleviate cholestatic liver injury. METH-
ODS: Sirt1 protein expression was determined in mouse livers
7 days after bile duct ligation (BDL) and mice fed 1% cholic
acid (CA). C57Bl/6 mice (n=11-13, male, 8-9 weeks old)
were fed standard rodent chow or chow supplemented with
1% CA for 5 days. Both groups (n=5-6) were administered
either vehicle or Sirt1 activator, SRT1720 (50mg/kg/day) for
duration of the diet. At the end of study, plasma was analyzed
for ALT, bile acids and ALP levels and liver tissue was assessed
for hepatic bile acids, gene and protein expression of bile
acid transporters and Cyp7a1. RESULTS: Sirt1 protein expres-
sion was significantly (75%) reduced in livers from 7-day BDL
mice compared to sham controls. After 5 days, CA fed mice
demonstrated elevated plasma ALT (3.5 fold), plasma bile acid
(5 fold) and hepatic bile acid levels (10 fold) compared to
chow fed controls. Importantly, Sirt1 mRNA and protein were
also reduced by about 50% in CA fed mouse livers. In con-
trast, administration of SRT1720 to CA diet fed mice reduced
plasma ALT and bile acid levels by 40 and 50%, respectively.
HEPATOLOGY, October, 2014
SRT1720 administration also significantly decreased Cyp7a1
mRNA expression in both standard chow and CA fed mouse
livers and increased Shp and Sirt1 mRNA expression in CA
fed mouse livers. SRT1720 administration also significantly
reduced Ostα and increased Mrp2 expression in CA fed mouse
livers. CONCLUSION: Sirt1 protein and acetylation levels are
decreased in two different models of cholestasis (BDL and 1%
CA diet). Sirt1 activator SRT1720 decreased liver injury and
plasma bile acids in CA fed mice. These beneficial changes
were associated with down regulation of bile acid synthetic
pathways (Cyp7a1), presumably by increased deacetylation of
Fxr and induction of Shp as well as changes in Ostα and Mrp2
expression. This study demonstrates that Sirt1 activators are
potential therapeutic targets for cholestatic liver injury.
Disclosures:
The following people have nothing to disclose: Supriya Kulkarni, Carol J. Soroka,
James L. Boyer
413
Inhibition of mast cell histamine secretion by cromolyn
sodium treatment decreases BDL-induced liver inflam-
mation and fibrosis
Laura Hargrove2, Fanyin Meng1,2, Lindsey Kennedy1, Allyson B.
Graf1, Quy P. Nguyen1, Yuyan Han3, Victoria Huynh3, Heather L.
Francis1,2; 1BaylorScott and White Hospital, Temple, TX; 2Central
Texas Veteran’s Healthcare System, Temple, TX; 3Texas A&M HSC
COM, Temple, TX
Background: Features of chronic cholestasis include inflamma-
tion and progressive fibrosis, which is associated with biliary
hyperplasia and hepatic stellate cell (HSC) activation. Mast
cells release histamine (HA) that induces hepatic inflammation.
After bile duct ligation (BDL), there is enhanced (i) cholangio-
cyte proliferation and inflammation (ii) HA secretion and (iii)
mast cell infiltration. We have shown that (i) mast cells increase
biliary proliferation and (ii) the mast cell stabilizer, cromolyn
sodium (which inhibits mast cell HA release) decreases biliary
proliferation. We aimed to evaluate the effects of cromolyn on
BDL-induced liver fibrosis and inflammation. Methods: Nor-
mal and BDL rats were treated with saline or cromolyn sodium
(24 mg/kg/BW) by osmotic minipump for 2 wk. Serum, liver
blocks and cholangiocytes were obtained. Isolated hepatic
mast cells were obtained by magnetic bead separation. In liver
sections, CK-19 (intrahepatic bile duct mass, IBDM), PCNA
and Masson’s trichrome were measured. HSC activation was
evaluated by immunofluorescence for synaptophysin. By qPCR
we measured α-SMA, collagen I, fibronectin, MMPs, TGFβ,
IL-6 and IL-10. Circulating levels of TNFα, TGF-β, HA and IL-6
were evaluated by ELISA assay. In vitro, cholangiocytes and
HSCs were stimulated with mast cell supernatants from nor-
mal and BDL rats treated with saline or cromolyn before mea-
suring: proliferation by MTS, expression of α-SMA, collagen
I, fibronectin, MMPs, TGFβ, IL-6 and IL-10 and secretion of
HA, TNFα, TGFβ and IL-6 by EIA. Results: After 2 wk of BDL,
IBDM, biliary proliferation, HSC activation and fibrosis was
significantly enhanced, but all of these parameters were signifi-
cantly decreased after cromolyn treatment. α-SMA, collagen I,
fibronectin, MMPs, IL-6 and IL-10 were significantly reduced
in cromolyn-treated BDL rats compared to BDL controls. Serum
levels of HA, TGFβ, TNFα and IL-6 were all increased after
BDL, but decreased after cromolyn treatment. In vitro, stim-
ulation with supernatants from isolated mast cells from BDL
rats increased biliary and HSC proliferation and expression of
α-SMA, collagen I, fibronectin, MMPs, IL-6 and IL-10. Secretion
of HA, TNFα and IL-6 were increased after treatment with BDL
supernatant. When cholangiocytes or HSCs were treated with
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
isolated mast cell supernatants from cromolyn-treated rats there
was a marked decrease in all of these parameters. Conclusion:
Our studies reveal that mast cell derived histamine is potent
contributor to biliary proliferation, HSC activation and liver
inflammation and fibrosis. Modulation of mast cells may be an
option for the treatment of chronic cholestatic liver injury.
Disclosures:
The following people have nothing to disclose: Laura Hargrove, Fanyin Meng,
Lindsey Kennedy, Allyson B. Graf, Quy P. Nguyen, Yuyan Han, Victoria Huynh,
Heather L. Francis
414
Disruption of the normal circadian cycle by prolonged
exposure to darkness attenuates biliary hyperplasia
and liver fibrosis in MDR2 KO mice by modulation of
core clock gene expression
Allyson Martinez2, Debolina Ray2, Yuyan Han2, Fanyin Meng1,
Julie Venter2, Heather L. Francis1, Sharon DeMorrow2,4, Shanika
Avila2, Micheleine Guerrier2, Kelly McDaniel4, Lindsey Kennedy4,
Haibo Bai4, Holly A. Standeford3, Gianfranco Alpini1, Shannon
S. Glaser2; 1Research, Medicine and S&W Digestive Diseases
Research Center, Central Texas Veterans Health Care System,
Texas A&M University and S&W, Temple, TX; 2Medicine, Texas
A&M University, Temple, TX; 3Research, Central Texas Veterans
Health Care System, Temple, TX; 4Scott & White Digestive Dis-
eases Research Center, Scott & White, Temple, TX
Circadian rhythms play important roles in various biological
events including liver growth. We have previously shown that:
(i) melatonin inhibits biliary hyperplasia in cholestatic bile
duct-ligated (BDL) rats; and (ii) exposure to dark (that increases
melatonin release from the pineal gland) reduces intrahepatic
bile duct mass (IBDM) in BDL rats. Primary sclerosing cholan-
gitis (PSC) is a chronic inflammatory biliary disease character-
ized by periductal fibrosis and stricture formation, which can
ultimately lead to liver cancer. The information regarding the
pathogenesis as well as effective treatments for PSC is lack-
ing. We hypothesized that exposure of MDR2 KO mice (that
mimick some of the features of human PSC) to complete dark
ameliorates biliary growth and liver fibrosis. Methods: MDR2
KO and matching wild type (FVB) mice (10-12 wk of age) were
exposed to 12:12 hr light/dark cycles or complete dark for
1 wk before evaluating: (i) melatonin serum levels by EIA; (ii)
intrahepatic bile duct mass (IBDM) by CK-19 staining in liver
sections and biliary proliferation by q-PCR for PCNA in total
liver and purified cholangiocytes; (iii) liver damage by H&E
staining and serum levels of transaminases, alkaline phospha-
tase and bilirubin; (iv) liver fibrosis by Sirius red staining in liver
sections and q-PCR for α-SMA and fibronectin in total liver and
cholangiocytes; and (v) the mRNA expression of the core clock
genes Per1 and 2, Cry1 and 2, BMAL1 and CLOCK (media-
tors of cell mitosis) in total liver and cholangiocytes. Results:
Prolonged exposure to dark increased melatonin serum levels
in both WT and MDR2 KO mice compared to mice exposed to
12:12 hr light/dark cycles. There was enhanced: (i) IBDM and
biliary proliferation; and (ii) liver damage (by H&E staining
and serum chemistry) and enhanced fibrosis (evidenced by
increased Sirius red staining and expression of α-SMA and
fibronectin) in MDR2 KO mice compared to WT mice. The
increase in liver damage and fibrosis and biliary proliferation
was significantly reduced in MDR2 KO mice exposed to com-
plete dark compared to MDR2 KO mice exposed to 12:12 hr
light/dark cycles. When MDR2 KO mice were housed in com-
plete dark there was: (i) enhanced expression of BMAL1and
Per1; and (ii) decreased CLOCK and Cry1 expression com-
pared to MDR2 KO mice exposed to 12:12 hr light/dark
405A
cycles. Conclusion: Our results indicate that exposure to dark
inhibits biliary proliferation and liver fibrosis in MDR2 KO mice
by modulation of circadian rhythms. Dark therapy might be a
potential non-invasive approach for the management of some
cholangiopathies.
Disclosures:
The following people have nothing to disclose: Allyson Martinez, Debolina Ray,
Yuyan Han, Fanyin Meng, Julie Venter, Heather L. Francis, Sharon DeMorrow,
Shanika Avila, Micheleine Guerrier, Kelly McDaniel, Lindsey Kennedy, Haibo
Bai, Holly A. Standeford, Gianfranco Alpini, Shannon S. Glaser
415
Absence of BSEP/ABCB11 protects from cholestatic liver
injury in mice
Claudia D. Fuchs1, Gustav Paumgartner1, Annika Wahlström2,
Peter Chiba3, Tatjana Stojakovic4, Thierry Claudel1, Hanns-Ulrich
Marschall2, Michael Trauner1; 1Internal Medicine III, Medical Uni-
versity of Vienna, Wien, Austria; 2Sahlgrenska Academy, Institute
of Medicine, Department of Molecular and Clinical Medicine, Uni-
versity of Gothenburg, Gothenburg, Sweden; 3Institute of Medical
Chemistry, University of Vienna, Vienna, Austria; 4Clinical Institute
of Medical and Chemical Laboratory Diagnostics, Medical Univer-
sity of Graz, Graz, Austria
Background:Cholestasis is characterized as intrahepatic accu-
mulation of potentially cytotoxic bile acids which subsequently
leads to liver injury reflected by disruption of hepatocellular
integrity, inflammation, fibrosis, cirrhosis and increased risk for
development of cancer. Bile salt export pump (BSEP/ABCB11)
is the main canalicular bile acid (BA) transporter and therefore
the rate limiting step for hepatobiliary BA secretion. In this
study we aim to investigate the role of BSEP/ABCB11 in devel-
opment of cholestatic liver injury Methods: Wildtype (WT) and
ABCB11 knockout (KO) mice were subjected to common bile
duct ligation (CBDL) to induce cholestasis. Liver RNA profile
analysis was performed by RT-PCR. BA transporter expression
was also assessed at protein levels by western blots. Serum
biochemistry, hepatic TG, BA content/composition as well as
liver histology were assessed. Results: In contrast to WT mice,
mice lacking ABCB11 did not show liver injury after 7 days
of CBDL reflected by unchanged serum levels of liver trans-
aminases (ALT, AST), alkaline phosphatase, total cholesterol
and BA, whereas WT mice subjected to CBDL showed pro-
nounced cholestatic liver injury. Notably, ABCB11 KO mice
where protected from BDL-induced inflammation (reflected by
unchanged mRNA levels of F4/80 and MCP1) and fibrosis
(reflected by liver histology and unchanged mRNA levels of
Col1a1 and Col1a2 as well as aSMA protein levels) while
WT animals displayed significant up-regulation of both inflam-
matory and fibrotic markers. Interestingly, poly-hydroxylated
BAs (PHBA) in liver were 4fold increased in ABCB11 KO mice
after CBDL when compared to cholestatic WT mice (p<0,01).
In line, mRNA expression of Cyp2b10, the downstream target
of CAR – a nuclear receptor regulating BA detoxification and
basolateral excretion pathways, and known to be activated
via PHBA – was increased in ABCB11 KO mice after CBDL.
Protein levels of BA transporters such as NTCP, OATP (sinusoi-
dal uptake) and MRP2 (canalicular export) were reduced in
WT and increased in ABCB11 KO mice under cholestatic con-
ditions. Conclusion: Changes in BA metabolism which favor
detoxification of potentially toxic BAs protect ABCB11 KO mice
from development of cholestatic liver injury. Therefore, PHBAs
may open a new therapeutic avenue against cholestatic injury
and progress to more advanced stages of liver disease.
Disclosures:
406A AASLD ABSTRACTS
Michael Trauner - Advisory Committees or Review Panels: MSD, Janssen, Gilead,
Abbvie; Consulting: Phenex; Grant/Research Support: Intercept, Falk Pharma,
Albireo; Patent Held/Filed: Med Uni Graz (norUDCA); Speaking and Teaching:
Falk Foundation, Roche, Gilead
The following people have nothing to disclose: Claudia D. Fuchs, Gustav
Paumgartner, Annika Wahlström, Peter Chiba, Tatjana Stojakovic, Thierry Clau-
del, Hanns-Ulrich Marschall
416
Endoplasmic reticulum stress suppresses hepatic Abcb11
expression but does not induce overt cholestasis in mice
Anne S. Henkel, Brian E. LeCuyer, Shantel Olivares, Richard
Green; Gastroenterology and Hepatology, Northwestern Univer-
sity, Chicago, IL
Endoplasmic reticulum (ER) stress has been implicated in the
pathogenesis of numerous hepatic and metabolic diseases.
We now aim to determine the impact of ER stress on cholestasis
in mice. Methods: ER stress was pharmacologically induced
in C57BL/6J mice using tunicamycin at a cumulative dose
of 1mg/kg I.P over 5 days. Indicators of cholestasis and the
expression of bile acid-responsive genes were determined.
Results: Induction of ER stress in mice caused profound suppres-
sion of expression of the hepatic canalicular bile salt export
pump, abcb11 (0.12 ± 0.04 vs 1.08 ± 0.38 in vehicle-treated
mice, p<0.001). Despite suppression of abcb11, hepatic ER
stress did not induce overt cholestasis histologically and did not
increase plasma or hepatic bile acid concentration. ER stress
suppressed expression of the sodium/taurocholate cotrans-
porter (ntcp), which controls sinusoidal uptake of bile acids
into hepatocytes, and increased expression of the multidrug
resistance-associated protein 3 (mrp3, abcc3), a basolateral
bile acid efflux pump. Furthermore, induction of ER stress sup-
pressed expression of the bile acid synthetic enzymes, choles-
terol 7α-hydroxylase and sterol 27-hydroxylase, and activated
hepatic fibroblast growth factor 15 (fgf15). Conclusions:
Induction of ER stress in mice suppresses expression of hepatic
abcb11, the rate-limiting canalicular bile acid transporter,
yet does not induce overt cholestasis. The protection against
cholestasis in response to ER stress may be attributable to sup-
pression of bile acid synthetic enzymes, suppression of ntcp,
and enhanced expression of abcc3.
Disclosures:
The following people have nothing to disclose: Anne S. Henkel, Brian E. LeCuyer,
Shantel Olivares, Richard Green
417
Central expression of the hypothalamic neuropeptide
galanin is upregulated in rodent models of primary scle-
rosing cholangitis
Matthew McMillin1,2, Gabriel A. Frampton1,3, Cheryl Galindo1,2,
Heather L. Francis2,3, Sharon DeMorrow1,2; 1Texas A&M Health
Science Center, College of Medicine, Temple, TX; 2Central Texas
Veterans Healthcare System, Temple, TX; 3Baylor Scott & White
Health, Temple, TX
Primary sclerosing cholangitis (PSC) is a chronic cholestatic
liver disease associated with inflammation of the bile ducts and
an imbalance between cholangiocyte proliferation and loss.
Useful rodent models that mimic aspects of PSC include MDR2-
/- mice and bile duct ligation (BDL). We have shown that some
hypothalamic-derived hormones are altered after BDL as a
result of aberrant bile acid signaling in the hypothalamus and
that these neuropeptides are able to influence cholangiocyte
proliferation. Galanin is a hypothalamic-derived neuropeptide
capable of regulating the growth hormone releasing hormone
(GHRH)/growth hormone (GH) axis. The aims of this study
HEPATOLOGY, October, 2014
were to: i) assess hypothalamic expression of galanin in rodent
models of PSC, ii) determine the effects of bile acid signaling
on hypothalamic expression of galanin and iii) evaluate the
effects of central activation of galanin signaling on cholangio-
cyte proliferation. Methods: Tissue was collected from MDR2-/-
and wildtype (WT) mice and BDL rats. In parallel, the bile acids
cholic acid (CA), deoxycholic acid (DCA) and taurocholic acid
(TCA; 10 pmol icv) and a galanin analogue (M617; 100
pmol/day icv) were administered centrally to rats. In vitro,
hypothalamic neurons were treated with the above-mentioned
bile acids and the FXR agonist fexaramine (10 and 100 nM)
for 4 hr. The expression of galanin and GHRH in the hypothal-
amus and cell lines and GH in the pituitary was assessed by
qPCR and immnunofluorescence. Intrahepatic bile duct mass
(IBDM) was assessed by qPCR and immunohistochemistry for
cytokeratin 19 (CK-19). Results: In MDR2-/- mice, galanin and
GHRH expression in the hypothalamus and GH in the pituitary
were upregulated, and IBDM increased at 2 weeks, which
increased by 2 months and returned to WT levels by 6 months.
In BDL rats, galanin was upregulated 1 to 7 days after surgery,
paralleled by an increase in GHRH and GH expression and
IBDM. Treatment of hypothalamic neurons with bile acids and
fexaramine increased galanin mRNA expression in vitro and in
vivo, with DCA having the greatest effect. Central administra-
tion of M617 increased the expression of GHRH and GH in the
hypothalamus and pituitary, respectively, as well as increased
CK-19 mRNA expression and IBDM. Conclusions: Our data
provide evidence that the hypothalamic expression of galanin
and subsequent activation of the GHRH/GH axis is upregu-
lated via a mechanism involving bile acid signaling in models
of PSC. This galanin/GHRH/GH axis may contribute to chol-
angiocyte proliferation during cholestatic liver injury and may
be an effective therapeutic target for the maintenance of biliary
mass during cholestatic liver diseases.
Disclosures:
The following people have nothing to disclose: Matthew McMillin, Gabriel A.
Frampton, Cheryl Galindo, Heather L. Francis, Sharon DeMorrow
418
Ezetimibe prevents diosgenin-induced cholestatic liver
injury in mice
Yuji Tanaka, Toshinori Kamisako; Dept. of Clnical Laboratory Med-
icine, Kinki University Faculty of Medicine, Osakasayama, Japan
Diosgenin, a plant sterol in the yam, reduces plasma choles-
terol by increasing fecal cholesterol excretion. NPC1L1 plays a
role in the intestinal uptake and absorption of cholesterol and
plant sterols, and ezetimibe, a hypocholesterolemic drug, is
an NPC1L1 inhibitor. We have shown that diosgenin feeding
enhanced ethinyl estradiol-induced cholestasis in rats. The pur-
pose of this study was to examine whether diosgenin induces
cholestasis in mice and to determine whether ezetimibe ame-
liorates liver injury. Eight-week old male C57Bl/6 mice were
fed the following diets for 2 weeks: 1) AIN-93M diet (control),
2) 0.005% ezetimibe (E), 3) 2% diosgenin (D), and 4) 2%
diosgenin and 0.005% ezetimibe (DE). After 2 weeks, blood
samples were obtained and livers were removed as well as
ileum. Compared to control mice, D-feeding increased serum
levels of total bilirubin, alanine aminotransferase, alkaline
phosphatase (ALP), and bile acid and decreased serum total
cholesterol, HDL cholesterol, and LDL cholesterol. Serum bile
acids were not decreased but serum ALP was reduced in the
DE group compared to the D group. Hepatic cholesterol lev-
els were not changed in any group. Hepatic bile acid con-
centrations tended to be increased in the D group compared
to the control group and tended to be decreased in the DE
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
group compared to the D group. In liver, D-feeding tended
to reduce Abcg5 and Abcg8 mRNA and increased mRNA
expression of the xenobiotic receptors CAR and PXR target
genes, including Cyp2B10, Cyp3a11, Mrp2, Mrp3, Mrp4,
and Oatp1a4, compared to control mice. These data sug-
gest that PXR and CAR might play central roles in xenobiotic
sensing and detoxification after D-feeding. Compared to the
D group, DE-feeding restored hepatic Abcg8 mRNA expres-
sion and enhanced hepatic mRNA expression of HMGCoAR,
HMGCoAS, Cyp27a1, and the nuclear receptors PXR and FXR
target genes, such as Cyp3a11, Oatp1a4, PXR, BAAT, BACS,
and Bsep. These data suggest that ezetimibe might promote
cholesterol and bile acid synthesis after DE-feeding, resulting
in activation of the bile acid sensors FXR and PXR. In ileum,
D-feeding induced mRNA expression of Cyp3a11 and ezeti-
mibe reduced mRNA expression of LXRα, Abcg8, Mrp2, Mrp3,
MTTP, and Ostα, compared to control mice. In conclusion,
diosgenin induces cholestasis in mice as indicated by higher
serum total bilirubin, ALP, and bile acid levels. Ezetimibe pro-
tects against diosgenin-induced cholestatic liver injury, possibly
involving activation of bile acid receptors.
Disclosures:
The following people have nothing to disclose: Yuji Tanaka, Toshinori Kamisako
419
Necroptosis in human primary biliary cirrhosis and in
murine models of bile acid toxicity
Marta B. Afonso1, Marta Caridade1, Pedro M. Rodrigues1, Helena
Cortez-Pinto2,3, Rui E. Castro1, Cecília M. Rodrigues1; 1Research
Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy,
University of Lisbon, Lisboa, Portugal; 2Gastrenterology, Hospi-
tal Santa Maria, Lisbon, Portugal; 3Instituto Medicina Molecular
(IMM), Faculty of Medicine, University of Lisbon, Lisbon, Portugal
Cholestasis is a common pathological condition characterized
by retention of bile acids in liver and serum, with concomitant
hepatocellular necrosis and apoptosis. Regulated necrosis or
necroptosis was recently described as a cell death pathway
that shares upstream signaling elements of apoptosis and mor-
phological characteristics of necrosis. Thus, we aimed to eval-
uate the role of necroptosis in human primary biliary cirrhosis
(PBC), a cholestatic chronic liver disease, in animal models of
bile acid toxicity and in hepatocytes exposed to bile acids.
Receptor interacting protein 3 (RIP3), a central mediator of
necroptosis, was evaluated in liver specimens of patients with
PBC (n = 5) and healthy controls (n = 5) by immunohistochem-
istry. Bile duct ligation (BDL) was performed in male C57BL/6
mice to induce cholestasis and secondary fibrosis. To further
explore the role of toxic bile acids in necroptosis activation,
deoxycholic acid (DCA; 250 mg/Kg/day, oral gavage, 5
days) was administered to male Wistar rats. HepG2 cells
and primary rat hepatocytes were incubated with glycoche-
nodeoxycholic acid (GCDCA; 200 mM) or DCA (400 mM),
in the presence or absence of pan-caspase inhibitor, zVAD-
fmk (50 mM), and/or necroptosis inhibitor, necrostatin-1 (100
mM), or ursodeoxycholic acid (UDCA; 100 mM). PBC patients
showed a significant increase in liver RIP3 expression, when
compared with controls. In addition, BDL resulted in bile duct
hyperplasia, multifocal necrosis and fibrosis. Similarly, DCA
induced hepatocellular necrosis and inflammatory cell infiltra-
tion in rat liver. Concomitantly, liver proinflammatory cytokines
and circulating levels of transaminases and necrosis markers,
namely high mobility group box 1 (HMGB1) and cyclophilin
A, were increased in both animal models. Moreover, RIP3
was strongly sequestrated in the insoluble protein fraction of
liver lysates, which correlated with liver injury, confirming the
407A
role of necroptosis in pathogenesis. Finally, DCA and GCDCA
induced apoptosis in both HepG2 cells and rat hepatocytes. In
HepG2 cells, bile acid-induced cell death was completely abol-
ished by zVAD-fmk. Conversely, DCA and GCDCA induced
caspase-3-independent cell death, which was inhibited by
necrostatin-1, representing necroptosis of rat hepatocytes.
UDCA was also effective at modulating necroptosis. In conclu-
sion, necroptosis is activated in PBC and in liver injury induced
by toxic bile acids both in vitro and in vivo. As such, necropto-
sis may play a role in the pathogenesis of cholestatic liver dis-
ease and should be regarded as a potential therapeutic target.
Disclosures:
Helena Cortez-Pinto - Advisory Committees or Review Panels: Norgine, Lund-
beck; Speaking and Teaching: Janssen, Gilead Janssen
The following people have nothing to disclose: Marta B. Afonso, Marta Cari-
dade, Pedro M. Rodrigues, Rui E. Castro, Cecília M. Rodrigues
420
Paracrine Signaling From Transplanted Hepatocytes But
not From Liver Sinusoidal Endothelial Cells (LSEC) Res-
cues Mice From Acetaminophen (APAP)-Induced Acute
Liver Failure (ALF)
Preeti Viswanathan1, Yogeshwar Sharma2, Sriram Bandi2, Sanjeev
Gupta2; 1Pediatric Gastroenterology and Hepatology, Childrens
Hospital at Montefiore, Bronx, NY; 2Medicine and Pathology,
Albert Einstein College of Medicine, Yeshiva University, Marion
Bessin Liver Research Centre, Bronx, NY
Background: The pleiotropic roles of paracrine signaling
between endothelial and other liver cell types, including
hepatocytes, has been of major interest for ontogeny and
homeostatic mechanisms. More recently, LSEC were found
to contribute in liver regeneration or repair after toxic injury.
We hypothesized that the therapeutic potential of paracrine
signals contributed by hepatocytes versus LSEC could be dis-
cerned in suitable models, such as APAP-induced ALF, where
transplantation of mature hepatocytes or stem/progenitor cells
with matrix scaffolds in peritoneal cavity was sufficient with-
out needing liver reseeding for rescue. Methods and Results:
ALF was induced in C57BL/6 mice by 500mg/kg APAP i.v.
with around 70% mortality. Abnormal liver tests and histology
confirmed serious hepatic injury. Comet assays and γH2AX
staining in APAP-treated mice compared to healthy controls
confirmed onset of widespread oxidative DNA damage with
double-strand breaks. Absence of Ki67+ cells confirmed failure
of liver regeneration. Next, healthy mouse hepatocytes and
LSEC were isolated by collagenase perfusion and Percoll gra-
dients and transplanted into mice along with Cytodex3 micro-
carriers i.p. after APAP-induced ALF as follows: Group I, 2.5
or 5x106 hepatocytes alone; Group II, 1x106 LSEC alone;
Group III, 2.5x106 hepatocytes and 1x106 LSEC; Group
IV, microcarriers alone. The 5x105 hepatocytes and 1x106
LSEC represented around 10% of the mass of these cell types
in healthy mouse liver, respectively. The mortality declined to
35% in Group I after 5x106 hepatocytes, p<0.001, but not in
other groups, including recipients of 2.5x106 hepatocytes or
LSEC with or without 2.5x106 hepatocytes. Assays of hepatic
DNA damage with Comets or γH2AX staining reproduced this
difference. To determine the nature of paracrine factors, we
used high-density cytokine arrays, which showed GCSF, VEGF,
etc., in conditioned medium (CM) of healthy, but not APAP-
treated, hepatocytes. The benefit of these factors in APAP toxic-
ity was verified when cell viability and DNA damage improved
in cultured hepatocytes by CM only from healthy hepatocytes.
The activity of paracrine factors involved Jak-Stat3 signaling
since ruxolitinib, a specific blocker of this pathway, abolished
408A AASLD ABSTRACTS
this cytoprotection. We probed cytokine receptor-mediated sig-
naling and found hepatic Stat3 expression in Group 1 after
hepatocyte transplantation and not in other groups. Conclu-
sions: Hepatocyte-derived paracrine factors rescued mice from
APAP-induced ALF via Stat3 signaling without reseeding of the
native liver. Transplantation of LSEC will not likely be helpful
since these cells did not rescue mice from APAP-induced ALF.
Disclosures:
The following people have nothing to disclose: Preeti Viswanathan, Yogeshwar
Sharma, Sriram Bandi, Sanjeev Gupta
421
Pleiotrophin Regulates the Ductular Reaction by Con-
trolling the Migration of Cells in Liver Progenitor Niches
Gregory A. Michelotti1, Anikia Tucker1, Mariana V. Machado1,
Marzena Swiderska-Syn1, Steve S. Choi1, Leandi Kruger1, Kather-
ine S. Garman1, Cynthia A. Moylan1, Cynthia D. Guy2, Heather
Himburg3, John P. Chute3, Anna Mae Diehl1; 1Division of Gas-
troenterology, Duke University Medical Center, Durham, NC;
2Pathology, Duke University, Durham, NC; 3Medicine, UCLA, Los
Angeles, CA
Background. The ductular reaction (DR) is the periportal
accumulation of small ductules, myofibroblasts, and stroma
during liver injury. It involves mobilization of multi-potent liver
progenitor cells (LPCs) from canals of Herring, as well as the
migration and myofibroblastic trans-differentiation of hepatic
stellate cells (HSC) in the space of Disse. The mechanisms that
control the DR are unclear. Our Aim was to determine if the
DR is regulated by pleiotrophin (PTN) and its receptor, protein
tyrosine phosphatase receptor zeta (PTPRZ)-1. PTN regulates
“stemness”. HSC-derived myofibroblasts (MF) produce PTN,
as do perivascular cells in other stem cell niches. PTN-PTPRZ1
interaction inactivates PTPRZ1. The resultant accumulation of
tyrosine-phosphorylated proteins alters many signaling path-
ways. PTN and PTPRZ1 are known to control the egress of
stem cells from bone marrow. Methods: Livers were harvested
from PTN-GFP (PTN reporter) mice, PTN-PTN-knockout (KO)
mice, PTPRZ1-KO mice, and wild type (WT) controls (n=6-9
mice/group) 2 weeks after bile duct ligation (BDL). Effects on
expression of PTN and PTPRZ1, and the DR were evaluated by
qRT PCR, quantitative immunohistochemistry (IHC), and hepatic
hydroxyproline assay. LPCs and HSC from WT, PTN-KO, and
PTPRZ1-KO mice were also treated directly with PTN to char-
acterize tyrosine-phosphorylated proteins and assess effects
on gene expression, migration, and growth. Results: Although
freshly-isolated HSC and LPC lines expressed PTN and PTPRZ1
mRNAs, neither PTN nor PTPRZ1 protein was demonstrated
in healthy liver. BDL induced strong expression of PTN mRNA
and protein in MF-HSC and dramatically increased PTPRZ1
expression in MF-HSC and ductular-appearing LPCs. In WT
mice, BDL triggered a DR characterized by periportal accu-
mulation of collagen, Krt19(+) ductular cells, and aSMA(+)
MF derived from desmin (+) HSC. All aspects of this DR were
significantly increased in PTN-KO mice and significantly sup-
pressed in PTPRZ1-KO mice. PTN had no effect on the viability
or growth of cultured LPCs or MF-HSC but directly inhibited
migration of both cell types. The anti-migratory actions of PTN
required PTPRZ1 because PTN inhibited migration in HSC
that expressed PTPRZ1, but not PTPRZ1-KO HSC. PTN treat-
ment of PTPRZ1(+) liver cells caused accumulation of several
phosphoproteins, including an obligatory component of adher-
ens junctions and a protein that regulates podosome function
and integrins. Conclusions: The “stemness” factor, pleiotrophin,
and its receptor, PTPRZ1, regulate the ductular reaction to liver
HEPATOLOGY, October, 2014
injury by controlling the migration of resident cells in putative
adult liver progenitor niches.
Disclosures:
John P. Chute - Board Membership: C2Regenerate
Anna Mae Diehl - Consulting: Roche; Grant/Research Support: Gilead, Genfit
The following people have nothing to disclose: Gregory A. Michelotti, Anikia
Tucker, Mariana V. Machado, Marzena Swiderska-Syn, Steve S. Choi, Leandi
Kruger, Katherine S. Garman, Cynthia A. Moylan, Cynthia D. Guy, Heather
Himburg
422
Vivo Morpholino local inhibition of hepatic gonadotro-
pin-releasing hormone (GnRH) expression reduces liver
fibrosis in cholestatic rats through increased miR-125a
expression
Debolina Ray2, Yuyan Han2, Fanyin Meng1, Julie Venter2, Heather
L. Francis1, Sharon DeMorrow2,5, Yoshiyuki Ueno3, Matthew
McMillin2, Paolo Onori4, Haibo Bai5, Allyson Martinez2, Eugenio
Gaudio4, Shannon S. Glaser1, Gianfranco Alpini1; 1Research,
Medicine and S&W Digestive Diseases Research Center, Central
Texas Veterans Health Care System and Texas A&M University and
S&W Digestive Diseases Research Center, Temple, TX; 2Medicine,
Texas A&M University, Temple, TX; 3Gastroenterology, Yamagata
University, Yamagata, Japan; 4Anatomical, Histological, Forensic
Medicine and Orthopedics Sciences, University Sapienza, Rome,
Italy; 5S&W Digestive Diseases Research Center, Scott & White,
Temple, TX
MicroRNAs (miRNAs) are small non-coding RNAs that regulate
the course of cholestatic liver diseases. miR-125 is a highly
conserved family of miRNAs that regulate cellular prolifera-
tion during cholestatic liver injury. These miRNAs also regulate
the expression of VEGF that potentiates fibrosis during liver
injury. miR-125 targets several growth factors (e.g., VEGF)
and matrix metalloproteases (MMPs), a dysregulation of which
leads to aberrant proliferation, metastasis and cell invasion. Bil-
iary hyperplasia in bile duct ligated (BDL) rats is accompanied
by enhanced angiogenesis and fibrosis. We have previously
shown that GnRH (expressed and secreted by cholangiocytes
and hepatic stellate cells, HSCs) stimulates biliary proliferation
by autocrine/paracrine mechanisms. Thus, we hypothesize
that GnRH regulates liver angiogenesis/fibrosis during choles-
tatic injury by modulation of miR-125 family. Methods: We
evaluated (by microRNA PCR array) miRNA profiles in total
liver or cholangiocytes from normal and BDL rats treated with
mismatched or GnRH Vivo Morpholino sequences (1.0 mg/kg
BW/day to reduce the hepatic GnRH expression) administered
by an implanted portal vein catheter. One wk later, intrahe-
patic bile duct mass (IBDM) and collagen deposition was mea-
sured in liver by CK-19 and Sirius red staining respectively.
The expression of the fibrotic markers, fibronectin, α-SMA and
MMP-2 were evaluated in total liver and cholangiocytes by
qPCR. Mouse cholangiocytes (MCCs) stably transfected with
shRNA against GnRH were used for in vitro studies along with
empty vector controls. Expression of miR-125a was quantitated
by taqman qPCR. We also measured by qPCR the expression
of VEGF-A, and fibronectin, collagen 1 alpha 1 and MMP-2.
Results: MicroRNA PCR array shows that a group of microR-
NAs (including miR-125a/b) were upregulated in BDL rats
treated with GnRH Vivo Morpholino compared to mismatch
controls. Specifically, miR-125a significantly increased in BDL
rats treated with GnRH Vivo Morpholino compared to BDL rats
treated with mismatch Morpholino. The expression of fibronec-
tin, α-SMA and MMP-2 was decreased in BDL rats treated with
GnRH Vivo Morpholino compared to controls, along with sig-
nificantly decreased Sirius red staining and IBDM. Silencing of
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
GnRH in MCCs increased miR-125a expression and decreased
expression of fibrotic genes compared to controls. Conclusion:
Our findings demonstrate that local inhibition of hepatic GnRH
decreases biliary proliferation and liver fibrosis via regulation
of miR-125a. Targeting of the GnRH/miR-125/VEGF axis may
provide an important therapeutic strategy in the recovery of
liver fibrosis during cholestatic injury.
Disclosures:
Yoshiyuki Ueno - Advisory Committees or Review Panels: Jansen
The following people have nothing to disclose: Debolina Ray, Yuyan Han, Fanyin
Meng, Julie Venter, Heather L. Francis, Sharon DeMorrow, Matthew McMillin,
Paolo Onori, Haibo Bai, Allyson Martinez, Eugenio Gaudio, Shannon S. Glaser,
Gianfranco Alpini
423
Alternatively activated M2 macrophages promotes
hepatocyte differentiation in hepatic progenitor cell
mediated liver regeneration in acute on chronic liver
failure patients
Dhananjay Kumar1, Sheetalnath Rooge1, Smriti Shubham1, Adil
Bhat1, Charvi Syal1, Archana Rastogi4, Chhagan Bihari4, Vini-
yendra Pamecha3, Anupam Kumar1, Shiv K. Sarin2; 1Research,
Institute of Liver and Biliary Sciences, New Delhi, India; 2Hepa-
tology, Institute of Liver and Biliary Sciences, New Delhi, India;
3Hepato-Pancreato-Biliary (HPB) Surgery, Institute of Liver and Bil-
iary Sciences, New Delhi, India; 4Pathology, Institute of Liver and
Biliary Sciences, New Delhi, India
Background Macrophages play a myriad of role in both liver
degeneration & regeneration. This classical dual nature of mac-
rophage in both tissue damage & repair is imparted by its phe-
notypic plasticity. Though the promising role of macrophages
have recently been shown in the resolution of liver damage &
hepatic regeneration how exactly the changing microenviron-
ment of different setting of liver disease affect the polarization
of macrophage to different subtype & how different subtype
of macrophage affect hepatic regeneration is ill defined. Aim
To understand the effect of hepatic microenvironment on the
functional plasticity of hepatic macrophage & their role in liver
regeneration. Patients & Methods Macrophage plasticity were
analyzed by studying the expression of M1 & M2 macrophage
marker genes using RT-PCR in biopsy/explant liver from patients
with acute-on-chronic liver failure (ACLF, n=5), acute liver fail-
ure (ALF, n=11), decompensated liver disease (CLD, n=15).
Immunohistochemical staining were done for Ki67 (hepato-
cyte replication) & CK19 (HPC & intermediate hepatocytes)
for characterization of nature of hepatic regeneration & CD68
(liver tissue macrophages) CD163 (M2 macrophages) for anal-
ysis of macrophages in liver tissue samples from patients with
ACLF (n=15), ALF (n=21), CLD, (n=22). Expression CD68 &
CD163 macrophages were correlated with hepatocyte repli-
cation, HPC activation & maturation. Results RT-PCR analysis
documented significant increase in M2 gene markers CD163,
CD206 & TGM2 (p=.001, .001 & .002) & decrease in M1
markers iNOS & CD80 (p=.001, .001) in ACLF comparison
to CLD. Similarly there was significant increase in M2 gene
markers CD163, CD206 & TGM2 (p=.002, .002 & .002) &
decrease in M1 markers iNOS CD80 (p=.002, p=.002) in
ACLF comparison to ALF. Immunohistochemical analysis shows
increase in Ki67+ hepatocytes in ALF as compared to ACLF &
CLD (p=.0001, .0001). Further, the number of CK19+ HPC
& its maturational lineages was increased in ACLF than ALF
& CLD (p=.0001, .0002). Using spearman rho correlation
shows that CD163 positivity & M2/M1 macrophage ratio is
significantly associated with extant of HPC differentiation to
hepatocyte (p=.0001, .0004). Further Pu1 (yolk sac origi-
nated Kupffer Cells) & Myb (bone marrow originated monocyte
409A
derived macrophage) expression suggest significant increase
in Pu1 expression relative to CD68 in ACLF in comparison to
ALF & CLD (p=0.002, 0.001) suggesting majority of M2 mac-
rophage in ACLF are kupffer cells. Conclusions Alternatively
activated M2 macrophages are major population in ACLF liver
which promotes differentiation of HPC to hepatocyte. These M2
macrophages are of kupffer cell origin.
Disclosures:
The following people have nothing to disclose: Dhananjay Kumar, Sheetalnath
Rooge, Smriti Shubham, Adil Bhat, Charvi Syal, Archana Rastogi, Chhagan
Bihari, Viniyendra Pamecha, Anupam Kumar, Shiv K. Sarin
424
The pro-inflammatory and pro-fibrogenic actions of the
HIV-envelope protein gp120 are mediated by inflam-
masome activation and miR-29b
Andrea Cappon1, Raffaele Bruno2, Sandra Gessani3, Andrea
Masotti4, Fabio Marra1; 1University of Florence, Florence, Italy;
2IRCCS San Matteo, Pavia, Italy; 3Istituto Superiore di Sanità,
Rome, Italy; 4Ospedale Pediatrico Bambino Gesù, Rome, Italy
Background/aim: Patients with HCV/HIV co-infection show
faster progression of liver fibrosis, in part associated with
miRNA dysregulation and more severe inflammation. The HIV
protein gp120 modulates directional migration and expres-
sion of pro-fibrogenic cytokines in hepatic stellate cells (HSC),
through engagement of the chemokine receptor CCR5. The
NALP3 inflammasome is a critical pathway in the generation
of pro-inflammatory signals during liver injury. Aim of this study
was to evaluate the role miRNAs and inflammasome activa-
tion in mediating the effect HSC. Methods: HSC were isolated
from normal human liver tissue. Inflammasome complex gene
expression was measured by qRT-PCR. Levels of mature IL-1β
were assayed by ELISA. miRNA expression was evaluated via
RT-PCR. miR-29b mimic was transfected using Amaxa. Blood
mononuclear cells (MNc) were isolated from healthy volunteers.
Results: HSCs exposed to M-tropic gp120 (CN54) showed a
time-dependent up-regulation of Pycard, NALP3, Caspase-1
and IL-1β. ELISA showed increased levels of mature IL-1β in the
supernatants of gp120-stimulated cell. Pre-incubation of HSC
with neutralizing anti-CCR5 antibody reduced gp120-mediated
IL-1β production, showing that this receptor is required for acti-
vation of the inflammasome complex by gp120. Similar results
were obtained in MNc, where a CCR5 receptor antagonist
blocked inflammasome activation and IL-1β production. gp120
was found to modulate the expression of different miRNAs,
and in particular to down-regulate mir29b in HSC. Transfec-
tion of a miR-29b mimic in HSC blocked the ability of gp120
to induce procollagen-1 expression, a-SMA and TGF-b, while
didn’t affect IL-1b induction. Conclusions: These data indicate
that at least two pathways mediate the effects of gp120 on
monuclear cells and activated HSC. Inflammasome activation
through engagement of CCR5 contributes to proinflamatory
actions, whereas down-regulation of miR-29b regulates expres-
sion of procollagen-1, alpha-SMA and TGF-beta.
Disclosures:
Andrea Cappon - Grant/Research Support: ViiV
Fabio Marra - Advisory Committees or Review Panels: Abbott; Consulting: Bayer
Healthcare; Grant/Research Support: ViiV
The following people have nothing to disclose: Raffaele Bruno, Sandra Gessani,
Andrea Masotti
410A AASLD ABSTRACTS
425
Activation of Toll-Like-Receptors (TLR) on isolated
Kupffer cells (KC) and sinusoidal endothelial cells (SEC)
of the liver: Opposing effects on the production of the
vasoconstrictor Thromboxane B2
Julia Schewe, Lisa Selzner, Ingrid Liss, Burkhard Göke, Alexander
L. Gerbes, Christian J. Steib; Department of Medicine II, University
of Munich, Campus Grosshadern, Munich, Germany
Introduction: We have already shown an important role of
TLR-dependent formed Thromboxane (TX) for portal hyperten-
sion in cirrhosis in previous work (including Steib CJ et al.,
Hepatology 2010). Aim of the present study was to determine,
which liver cells play a relevant role for TX-production and
which TLR are involved in this process. Methods: KC and SEC
were isolated from mouse livers (male C57/Bl6) and stimu-
lated over 24h with various TLR-agonists (Pam3CSK4 [TLR 1/2]
0,1g/ml; HKLM [TLR 2] 10e8 cells/ml; Poly (I:C) [TLR 3] 10ng/
ml; LPS-EK [TLR 4] 10ng/ml; ST-FLA [TLR 5] 10ng/ml; FSL-1 [TLR
6/2] 1ng/ml; ssRNA40 [TLR 7] 0,25mg/ml; ODN1826 [TLR
9] 5mM; n=6 each). Thromboxane B2 (TXB2) efflux before and
after stimulation into the cell media was measured by ELISA
(mean±SD, *p<0.05). Results: TXB2-efflux (before stimulation
vs. after stimulation in pg/ml) is shown in table 1. Conclusion:
The activation of TLR 2, 4, 5, 2/6, and 9 on isolated KC of
healthy livers lead to a significant production of vasoconstric-
tive effective TXB2, whereas the activation of SEC through TLR
1/2, 3, 4, 6, 7 and 9 led to a decrease of TXB2 production.
Our findings provide an important basis to identify relevant
early stage microbial products for the formation of TXB2 in the
future and to develop targeted strategies to prevent complica-
tions of portal hypertension.
table 1: TXB2-efflux (before stimulation vs. after stimulation in pg/
ml)
*p<0.05
Disclosures:
The following people have nothing to disclose: Julia Schewe, Lisa Selzner, Ingrid
Liss, Burkhard Göke, Alexander L. Gerbes, Christian J. Steib
426
Cannabinoid Receptor 1 is Involved in Hepatic Inflam-
mation and Fibrosis in Mice by Regulating Bone Mar-
row-Derived Monocyte/Macrophage
Ping Mai, Le Yang, Lin Wang, Lei Tian, Shuangshuang Jia,
Yuanyuan Zhang, Xin Liu, Lin Yang, Liying Li; Cell Biology, Capital
Medical University, Beijing, China
Background & Aims: Endocannabinoid system (ECS) plays a
pivotal role in hepatic diseases. Cannabinoid receptor 2 (CB2)
has shown anti-inflammatory and anti-fibrogenic properties by
regulating immune cells. However, the relationship between
CB1 and inflammatory cells in liver injury is still undefined.
Methods: ICR mice were lethally irradiated and received bone
marrow (BM) transplantation from enhanced green fluorescent
protein transgenic mice. Four weeks later, mice of BM-rebuild
HEPATOLOGY, October, 2014
were subjected to carbon tetrachloride (CCl4)-induced liver
injury. Boyden chamber was used for cell migration assay.
Immunofluorescent staining and FACS were used to identify
BM-derived monocyte/macrophage (BMM). Latex beads were
used to perform phagocytosis of BMM. Expressions of inflam-
matory cytokines, CB1 and CB2 etc were determined by West-
ern blot, RT-qPCR and Cytometric Bead Array. Active RhoA and
Rac1 were measured by pull-down assay. Results: Endocanna-
binoid-related enzymes and receptors, which correlated with
inflammation/fibrosis parameters, showed significant changes
in mouse CCl4-injured liver. BMM significantly expressed CB1
and CB2. In vitro, the treatment of mAEA (CB1 agonist) caused
a concentration-dependent increase in BMM migration, but
JWH133 (CB2 agonist) had no influence. Pharmacological
inhibition or genetic knockdown of CB1 markedly attenuated
mAEA-mediated migration, but AM630 (CB2 antagonist) or
CB2 knockdown hardly influence mAEA-mediated migration.
Pull-down analysis showed that mAEA promoted active GTP-
bound RhoA protein levels of BMM but that Rac1-GTP changed
slightly. This added GTP-bound RhoA conformation by mAEA
was inhibited by AM281 or pertussis toxin (PTX, G(α)i/o
protein inhibitor). Moreover, mAEA-mediated migration was
impaired by PTX and Y27632 (the inhibitor of Rho-associated
protein kinase ROCK, downstream molecule of Rho) pretreat-
ment, suggesting mAEA-mediated migration depending on
G(α)i/o/RhoA/ROCK signal axis. In vivo, blockade of CB1
inhibited the recruitment of BMM, whereas no effects on the
migration of BM-originated T cells, dendritic cells and neutro-
phils. Furthermore, activation of CB1 enhanced the phagocytic
activity and cytokines expression of BMM, such as TNF-α, IL-6,
and MCP-1. In vivo, the blockade of CB1 markedly down-reg-
ulated the mRNA and protein levels of TNF-α, IL-6, IL-10, IL-12,
IFN-γ and MCP-1 in injured liver. Notably, inhibition of CB1
also ameliorated hepatic inflammation and fibrosis. Conclu-
sion: CB1 is involved in migration, phagocytosis and inflam-
matory cytokines production of BMM. The blockade of CB1
significantly attenuates hepatic inflammation and fibrosis.
Disclosures:
The following people have nothing to disclose: Ping Mai, Le Yang, Lin Wang, Lei
Tian, Shuangshuang Jia, Yuanyuan Zhang, Xin Liu, Lin Yang, Liying Li
427
Hepatic progenitor cells contribute to the progression of
liver fibrosis induced by 2-AAF/CCl4 in rats through the
non-canonical wnt pathway
Jiamei Chen1,2, Yongping Mu1, Yuyou Duan2, Ping Liu1; 1Insti-
tute of Liver Diseases,Shuguang Hospital,, Shanghai University of
Traditional Chinese Medicine, shanghai, China; 2Department of
Internal Medicine, Institute for Regenerative Cures, University of
California Davis Medical Center, SACRAMENTO, CA
It appears that hepatic progenitor cells may be transformed into
myofibroblasts and contribute a profibrotic effect in sustaining
the progression towards cirrhosis. In this study, we developed a
rodent cirrhosis model induced by subcutaneous injection with
50% of CCl4 for 8 weeks. In order to inhibit mature hepato-
cytes regeneration and increase hepatic progenitor cell expan-
sion and differentiation, the treated rats were fed with 2-AAF
during the period of cirrhosis progression. The results showed
that the expressions of hepatic oval cell markers (OV6 and
CK19) were increased significantly during fibrosis progres-
sion. In the CCl4/ 2-AAF treated rats, OV6 positive cells and
CK19 positive cells extended across the liver lobule, formed
bridges between portal tracts and divided the parenchyma into
smaller pseudo-lobules, as determined by immunohistochemi-
try. Double staining showed that OV6 was largely colocated
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
with α-SMA positive cells, and the number of cells positive for
both OV6 and α-SMA was obviously increased after adminis-
tration of 2-AAF. The expressions of Wnt4, Wnt5b, frizzled2,
frizzled3 and frizzled6 were markedly increased after admin-
istration of 2-AAF (p<0.01). Immunohistochemistry showed
that β-catenin protein was mostly localized to the nucleus of
cells before administration of 2-AAF; however, β-catenin was
found predominantly within the cytoplasm after administration
of 2-AAF. In addition, the expression level of β catenin was
not changed by the administration of 2-AAF, suggesting that
the activation of Wnt pathways was not mediated through the
classical β-catenin pathway. Moreover, after administration of
2-AAF, gene expression of frizzled1 and frizzled4 was mark-
edly decreased (p<0.01); however frizzled5 expression was
not significantly changed, indicating that non-canonical Wnt
signaling rather than Wnt/β-catenin signaling was primarily
activated. We also determined that the expression of TGF-β1
was markedly increased in vivo after administration of 2-AAF.
Expression of α-SMA and F-actin, as well as collagen types I
and IV were significantly increased after the WB-F344 cell line,
was treated with TGB-β1 for 24 hours. Additional investigation
revealed that both Wnt5b and frizzled2 expression were sig-
nificantly increased in WB-F344 cells after treatment with TGF-
β1 (p < 0.01), and β-catenin expression was not up-regulated
during the treatment. Thus, these in vitro results confirmed our
finding in vivo. In conclusion, our results indicate that hepatic
progenitor cells appear to transdifferentiate into myofibro-
blasts and exhibit a profibrotic effect in the fibrogenic process
through activating the non-canonical Wnt signaling pathway.
Disclosures:
The following people have nothing to disclose: Jiamei Chen, Yongping Mu,
Yuyou Duan, Ping Liu
428
Downregulation of pro-fibrotic and pro-inflammatory
genes in liver sinusoidal endothelial cells following acti-
vation of the bile acid receptors FXR and TGR5
Rachel McMahan1, Cara Porsche1, Michael Edwards2, Luciano
Adorini4, Moshe Levi3, Hugo R. Rosen1; 1Gastroenterology, Uni-
versity of Colorado, Aurora, CO; 2Division of Pulmonary Sciences
& Critical Care, University of Colorado, Aurora, CO; 3Renal Dis-
eases & Hypertension, University of Colorado, Aurora, CO; 4Inter-
cept Pharmaceuticals, Perugia, Italy
Background: Activation of the FXR and TGR5 bile acid receptor
pathways with the dual agonist INT-767 has been shown to
improve non-alcoholic fatty liver disease (NAFLD) in a murine
diet-induced obesity model. While the mechanisms of the liver
improvement remain to be fully elucidated direct effects of these
pathways on hepatocyte and macrophage function have been
demonstrated. In addition to these cells liver sinusoidal endo-
thelial cells (LSEC) have been shown to be important in the
progression of steatohepatitis. Here we evaluate the effects of
activation of the bile acid receptor pathways in liver sinusoi-
dal endothelial cells using microarray analysis. Methods: A
murine LSEC line was treated with a dual FXR/TGR5 agonist
(INT767, 30uM) and/or free fatty acids (palmitic acid and
oleic acid, 0.66mM) for 24 hours. RNA was isolated and gene
expression analysis was performed using the GeneChip Mouse
Gene 2.0 ST Array. Analysis of deferentially expressed genes,
canonical signaling pathways and upstream regulators was
analyzed using the Ingenuity Pathway Analysis (IPA) software.
Differential regulation was defined as 1.5-fold difference from
untreated LSEC (p<0.05, ANOVA). Results: Gene expression
analysis revealed that 29 genes were uniquely downregu-
lated following treatment with INT-767. A number of these
411A
downregulated genes have been shown to be important in
fibrosis and inflammation. IL-33, a member of the IL-1 super-
family, was significantly decreased following treatment with
the agonist (p=0.009). In addition, the expression targets for
pro-fibrotic (TGFbeta; p=0.001) and pro-inflammatory (IL-12,
p=0.04) master regulators were over-represented in our genes
responding to treatment. These pathways were predicted by
IPA to be inhibited by treatment with INT-767. Conclusion: We
demonstrate that activation of the bile acid receptor pathways
in murine LSECs results in a down regulation of pro-fibrotic and
pro-inflammatory genes. Understanding the effects of FXR and
TGR5 activation in LSEC could be important for both NAFLD
and other liver diseases.
Disclosures:
Luciano Adorini - Consulting: Intercept Pharmaceuticals
Moshe Levi - Grant/Research Support: Intercept, Genzyme-Sanofi
The following people have nothing to disclose: Rachel McMahan, Cara Porsche,
Michael Edwards, Hugo R. Rosen
429
Repair-related Activation of Hedgehog Signaling in
Stromal Cells Promotes Intrahepatic Hypothyroidism
Brittany Bohinc2, Gregory A. Michelotti1, Guanhua Xie1, Her-
bert Pang3, Ayako Suzuki1, Cynthia D. Guy4, Dawn L. Piercy1,
Leandi Kruger1, Marzena Swiderska-Syn1, Mariana V. Machado1,
Thiago A. Pereira1, Ann Marie Zavacki5, Manal F. Abdelmalek1,
Anna Mae Diehl1; 1Division of Gastroenterology, Duke Univer-
sity Medical Center, Durham, NC; 2Division of Endocrinology,
Duke University Medical Center, Durham, NC; 3Biostatistics and
BIoinformatics, Duke University, Durham, NC; 4Pathology, Duke
University, Durham, NC; 5Endocrinology, Brigham and Women’s
Hospital, Durham, NC
Objectives: Thyroid hormone (TH) is important for liver repair
because it regulates hepatic differentiation. Both serum TH lev-
els and hepatic deiodinases control intrahepatic TH activity.
TH substrate (thyroxine, T4) is converted into active hormone
(triidothyronine, T3) by deiodinase 1 (D1), but into inactive
hormone (reverse T3, rT3) by deiodinase 3 (D3). D3 transcrip-
tion is controlled by Hedgehog-regulated factors. Hedgehog
signaling increases during liver injury. Liver injury also changes
the relative expressions of D1 and D3. However, the cell types
and signaling mechanisms involved are unclear. We evaluated
the hypothesis that changes in hepatic deiodinases result from
repair-related activation of the Hedgehog pathway in stromal
cells. Methods: We localized deiodinase expression to specific
liver cell types and assessed deiodinase changes during injury
by performing bile duct ligation (BDL) in rats. To determine if
targeted manipulation of Hedgehog signaling in stromal cells
impacted hepatic TH homeostasis, we compared deiodinase
expression, TH content, and expression of TH-target genes in
BDL αSMA-CreERT2 × SMO/flox mice after treatment with vehi-
cle (control) or tamoxifen (to delete SMO and abrogate Hedge-
hog signaling in myofibroblasts). Humans with chronic liver
disease were also studied. Results: In healthy liver, hepatocytes
strongly expressed D1 and stromal cells weakly expressed D3.
During injury, hepatocyte expression of D1 decreased, while
stromal expression of D3 increased, particularly in myofibro-
blasts. Repair-related changes in deiodinases were accom-
panied by reduced intrahepatic TH content and TH-regulated
gene expression. Disrupting Hedgehog signaling in myofibro-
blasts reduced D3 and increased D1 expression, increased
intrahepatic T4 concentration, and normalized TH-specific
gene expression. Patients with advanced fibrosis had less D1
and more D3 than patients with mild fibrosis. Their serum rT3
levels were also increased. Moreover, lower serum fT3/rT3
412A AASLD ABSTRACTS
and fT4/rT3 distinguished advanced- from mild- fibrosis, even
in individuals with similar serum levels of TSH and fT4. Conclu-
sion: Hedgehog-dependent changes in liver stromal cells drive
repair-related changes in hepatic deiodinase expression that
promote intrahepatic hypothyroidism, thereby limiting exposure
to T3, an important factor for hepatic differentiation. Changes
in deiodinase expression correlate with reduced serum fT3/rT3
and fT4/rT3 ratios. Thus, increased serum rT3 may serve as a
novel biomarker of liver disease severity in humans.
Disclosures:
Manal F. Abdelmalek - Consulting: Islet Sciences; Grant/Research Support:
Mochida Pharmaceuticals, Gilead Sciences, NIH/NIDDK, Synageva, Genfit
Pharmaceuticals
Anna Mae Diehl - Consulting: Roche; Grant/Research Support: Gilead, Genfit
The following people have nothing to disclose: Brittany Bohinc, Gregory A.
Michelotti, Guanhua Xie, Herbert Pang, Ayako Suzuki, Cynthia D. Guy, Dawn L.
Piercy, Leandi Kruger, Marzena Swiderska-Syn, Mariana V. Machado, Thiago
A. Pereira, Ann Marie Zavacki
430
MicroRNA profiling of circulating exosomes during
experimental liver fibrosis
Li Chen1, Ruju Chen1, David Brigstock1,2; 1Clinical & Translational
Research, Nationwide Childrens Hospital, Columbus, OH; 2Sur-
gery, The Ohio State University, Columbus, OH
Background: Exosomes arise by inward budding of the limiting
membranes of multivesicular bodies which, upon fusion with the
plasma membrane, result in their secretion and deposition into
body fluids (e.g. blood, urine). Exosomes contain a complex
mixture of microRNAs (miRs), mRNAs and proteins that reflect
the transcriptional and translational status of the producer cell.
Since this molecular payload is a “fingerprint” of the dynamic
status of their producer cells, exosomes represent a potentially
valuable resource for assessing liver disease or pathology. Our
goal was to profile the microRNA content of serum exosomes
in experimental liver fibrosis. Methods: PureExo Exosome Iso-
lation Kits were used to isolate serum exosomes. MiR profiling
was performed on exosomal RNA from 1ml of pooled serum (5
mice; 200μl/mouse) using a mouse miRnome miR PCR Array.
miR profiling was performed for the 940 best characterized
miRs in the mouse miRnome on exosomes isolated from the cir-
culation of mice after 1 or 5 weeks of treatment with CCl4, as
compared to oil-treated controls, with liver injury/fibrosis con-
firmed histologically. Differentially expressed miRs were con-
firmed and/or further evaluated by qRT-PCR of exosomal RNA
independently obtained at 1-, 4- or 5-weeks of CCl4 adminis-
tration (n=5). Results: Isolated exosomes from mice serum were
bi-membrane vesicles, 50-200nm in diameter, and positive for
the exosome markers, CD9 and flotillin-1. Microarray analy-
sis revealed significant alterations in the expression of many
hundreds of miRs after either 1- or 5-wks of CCl4 treatment
as compared to their respective oil controls. We then focused
on selected miRs previously reported to be altered in fibrotic
liver, and confirmed the data by RT-PCR. The exosomal levels
of these miRs after 5 weeks of CCl4 (including up-regulation of
miR-7a, -21, -22, -24, -34a, -155, or -195, and down-regula-
tion of miR-27a, -192, -214, or -377) reflected their previously
documented changes at the tissue level in fibrotic liver. In addi-
tion, several exosomal miRs that have not yet to be reported in
the literature as being altered during liver fibrosis emerged as
potentially novel fibrosis markers (e.g. up-regulation of miR-26b
or -122; down-regulation of miR-9 or -196b). As compared to
their levels at 5 weeks, many of these miRs exhibited individu-
ally distinct patterns of expression during the course of fibrosis
progression. Conclusions: Dynamic changes occur in the miR
content of circulating exosomes during experimental hepatic
HEPATOLOGY, October, 2014
fibrosis supporting the concept that fibrosis progression and
severity is amenable to minimally-invasive assessment through
determination of signature exosomal miRs.
Disclosures:
The following people have nothing to disclose: Li Chen, Ruju Chen, David Brig-
stock
431
Soluble CD146, a novel endothelial marker, is related to
the severity of liver disease
Efrossini Nomikou2, Alexandra Alexopoulou1, Larisa E. Vasilieva1,
Danai Agiasotelli1, Spyros P. Dourakis1; 12nd Dept of Medi-
cine, Medical School University of Athens, Athens, Greece; 2First
Regional Transfusion and Haemophilia Centre, Hippokration Gen-
eral Hospital, Athens, Greece
BACKGROUND: Angiogenesis and inflammation have been
involved in the progression of fibrosis in patients with chronic
liver disease (CLD). Soluble CD146 (sCD146), a biomarker
which was recently characterized as a novel component of the
endothelial junction is implicated in endothelial proliferation.
AIM: To evaluate the performance of sCD146 in assessing
liver fibrosis and cirrhosis and determine if its levels are related
to the severity of liver disease in patients with cirrhosis. METH-
ODS: sCD146 levels were determined by a commercially
available immunoenzymatic technique in sixty-two consecutive
patients with cirrhosis, forty-three patients with CLD without
cirrhosis and twenty-seven healthy controls. Diagnosis of cir-
rhosis was based on liver histological findings and/or imag-
ing, endoscopic, clinical findings. The absence of cirrhosis in
patients with CLD was based on measurements of liver stiffness
by transient elastography and/or liver biopsy. Healthy controls
were recruited from the donors attending the Blood Transfusion
Centre. RESULTS: The median sCD146 values were signifi-
cantly higher in patients with cirrhosis [639 ng/ml (interquartile
range 421-887)] compared to non-cirrhotic CLD patients [317
ng/ml (267-414), (P < 0.001)] or to healthy controls [310 ng/
ml (233-345), P < 0.001]. Moreover, patients with compen-
sated cirrhosis had higher levels [400 ng/ml (325-533)] than
non-cirrhotic CLD patients (P = 0.016) but lower than patients
with decompensated cirrhosis [848 ng/ml (608-1001), P <
0.001]. In receiver operating characteristic (ROC) curve analy-
sis, the cut-off of 412 ng/ml showed a sensitivity of 78% and a
specificity of 75% for differentiating cirrhosis from CLD without
cirrhosis, offering good diagnostic accuracy (AUROC: 0.838).
A cut-off of 534 ng/ml offered a sensitivity of 83% and a
specificity of 78% for differentiating compensated from decom-
pensated cirrhosis (AUROC: 0.866). Furthermore, in patients
with cirrhosis, ALT, AST, total bilirubin and international nor-
malized ratio (INR) correlated positively with sCD146 levels [r
= 0.324, (P = 0.012), r = 0.549, (P < 0.001), r = 0.542, (P
< 0.001), r = 0.648, (P < 0.001), respectively). Most impor-
tantly, MELD score correlated significantly with sCD146 [r =
0.567, (P < 0.001)]. CONCLUSIONS: sCD146 is emerging
as a novel, easy to perform, sensitive, non-invasive plasma
biomarker, which can reliably detect advanced fibrosis and
predict decompensation of cirrhosis. It is well correlated with
severity of liver disease in cirrhotic patients.
Disclosures:
The following people have nothing to disclose: Efrossini Nomikou, Alexandra
Alexopoulou, Larisa E. Vasilieva, Danai Agiasotelli, Spyros P. Dourakis
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
432
Species differences in the antifibrotic effect of imatinib
Inge M. Westra1,2, Dorenda Oosterhuis1, Rick Mutsaers1, Geny
M. Groothuis2, Peter Olinga1; 1Pharmaceutical Technology and
Biopharmacy, Department of Pharmacy, Groningen, Netherlands;
2Pharmacokinetics, Toxicology and Targeting, Department of Phar-
macy, Groningen, Netherlands
Liver fibrosis is the progressive accumulation of connective tis-
sue that will ultimately result in structural and functional liver
deterioration. No effective drugs against liver fibrosis are avail-
able yet. A promising antifibrotic compound was imatinib, a
tyrosine kinase inhibitor, which has antifibrotic effects in vitro
and in vivo in rats. However, until now no patient trials with
imatinib have been reported that were successful and showed
antifibrotic efficacy in patients. The aim of this study is to
investigate the effect of imatinib on the early and end stage of
liver fibrosis using precision-cut liver slices (PCLS) from rat and
human liver tissue. For the early onset of fibrosis, PCLS from
both rat liver and healthy human liver tissue from patients after
partial hepatectomy or from redundant parts of liver tissue from
multi-organ donors were incubated up to 48 hours. For estab-
lished fibrosis, PCLS from rats after 3 weeks of bile-duct ligation
and from human liver tissue from explanted human cirrhotic
livers were incubated up to respectively 48 and 24 hours. The
viability was assessed by the ATP content of the PCLS. The
gene expression of the fibrosis markers, Heat Shock Protein
47 (HSP47) and Pro-collagen1A1 (PCOL1A1), and the pro-
tein expression of collagen 1 were determined. The antifibrotic
effect of imatinib was determined at the maximal non-toxic con-
centrations. Healthy human and rat PCLS and fibrotic rat PCLS
remained viable during incubation for 48 hours and showed
increased gene expression of the fibrosis markers HSP47 and
PCOL1A1. Fibrotic human liver slices remained viable for 24
hours and the gene expression of the fibrosis markers was
stable up to 24 hours. As shown before, Imatinib inhibited in
healthy and fibrotic rat PCLS the gene expression of Hsp47
(more than 50%) and Pcol1A1 (more than 80%), the protein
expression of collagen I was inhibited by more than 40 %. In
both healthy and fibrotic human PCLS imatinib did not have
an effect on the gene expression of fibrosis markers. In healthy
human PCLS imatinib did not influence the protein expression
of collagen I. In conclusion, clear species differences in the
antifibrotic effect of imatinib were apparent. These results may
explain why imatinib has not reached the market as effective
antifibrotic drug. PCLS from human (fibrotic) liver tissue are a
promising tool to study the efficacy of antifibrotic compounds in
the early and end stage of liver fibrosis and are useful to reveal
species differences in antifibrotic efficacy.
Disclosures:
The following people have nothing to disclose: Inge M. Westra, Dorenda Ooster-
huis, Rick Mutsaers, Geny M. Groothuis, Peter Olinga
433
Precise liver fibrosis staging by automated morphome-
try of liver biopsies: E-Metavir
Paul Cales1, Julien Chaigneau2, Jerome Boursier1, Gilles Hunault1,
Sophie Michalak2, Frederic Oberti1, Isabelle Fouchard-Hubert1,
Sandrine Bertrais1, Marie Christine Rousselet2; 1Hepatology
Department, Centre Hospitalier Universitaire d’ Angers, Angers
Cedex 9, France; 2Pathology, CHU, Angers, France
Introduction. Determining the severity of liver fibrosis is import-
ant for care management in chronic liver diseases. Classical
fibrosis stagings on biopsies are hampered by poor observer
reproducibility. Our main aim was to develop a precise fibrosis
413A
classification based on automated morphometric diagnosis to
avoid variability and increase diagnostic accuracy and pre-
cision compared to available fibrosis staging. Methods. 834
patients with chronic hepatitis C were included: 549 in the
derivation population and 285 in the validation population.
The pathological reference was Metavir fibrosis staging by con-
sensus between 2 experts. Automated morphometric analysis
included the area of porto-septal fibrosis (Modern Pathology
2014) and 43 other descriptors providing scores for clinically
significant fibrosis (CSF score by 5 descriptors) and cirrhosis
(FM4 score by 6 descriptors). Different fibrosis classifications
were derived from these scores according to published statisti-
cal merging. In the multicentric validation population, different
Metavir stagings were available: initial local pathologists, 2
central experts and their consensus. Results. Accuracy (cor-
rectly classified patients) in the derivation population was: CSF
classification (7 classes from CSF score): 94.2%; and FM4
classification (8 classes from FM4 score): 95.3%. The CSF/
FM4 classification was derived by combining the two previ-
ous classifications. We obtained 6 classes roughly reflecting
the 5 Metavir stages with cirrhosis distinguished as early or
definitive. CSF/FM4 classification combined the advantages
of the individual classifications with an accuracy of 96.2%.
The classification reproducibility was very high with intra-class
correlation coefficient =0.988. Fibrosis classifications were
validated by high correlations with independent liver fibrosis
descriptors (area of porto-septal fibrosis and noninvasive blood
tests or liver stiffness by Fibroscan) and significant differences
between the adjacent classes of these descriptors. In the valida-
tion population, CSF/FM4 classification accuracy was 98.2%,
which was superior to the initial Metavir staging: initial pathol-
ogists: 71.7% (p<0.001 vs 96.2% by CSF/FM4 classification),
first central expert: 81.3% (p<0.001), second central expert:
81.7% (p<0.001), and consensus opinion of central experts:
91.5% (p=0.001). Conclusion. A precise 6-stage fibrosis clas-
sification – E-Metavir – with excellent accuracy, reproducibility
and precision can be obtained by automated morphometry of
liver biopsies. E-Metavir can be used as a complement to clas-
sic histopathological diagnosis as required in clinical practice.
Disclosures:
Paul Cales - Consulting: BioLiveScale
Frederic Oberti - Speaking and Teaching: LFB, gore
Isabelle Fouchard-Hubert - Speaking and Teaching: JANSSEN
The following people have nothing to disclose: Julien Chaigneau, Jerome
Boursier, Gilles Hunault, Sophie Michalak, Sandrine Bertrais, Marie Christine
Rousselet
414A AASLD ABSTRACTS
434
Genome Wide Association Study (GWAS) identifies a
SNP near the MRC2 (mannose receptor C, type 2) gene
associated with increased liver collagen content in Cau-
casian HBV patients
Nezam H. Afdhal1, Thomas J. Urban2, Zachary D. Goodman3,
Keyur Patel4, Dongliang Ge5, Xin Guo5, Zhaoshi Jiang5, Xi Zhao5,
Matthew Paulson5, Anuj Gaggar5, Jeffrey Bornstein5, Mani Sub-
ramanian5, John G. McHutchison5, Sarah E. Kleinstein2, Nanye
Long2, David B. Goldstein2, Rohit Loomba6, Alexander J. Thomp-
son7; 1Harvard Medical School, Boston, MA; 2Center for Human
Genome Variation, Duke University, Durham, NC; 3Inova Health
System, Falls Church, VA; 4Division of Gastroenterology, Duke
Medical School, Durham, NC; 5Gilead Sciences, Inc., Foster City,
CA; 6Division of Gastroenterology, University of California San
Diego, San Diego, CA; 7St. Vincent’s Hospital, Melbourne, VIC,
Australia
Introduction: The dynamic relationship between collagen depo-
sition and collagen turnover is a central feature leading to
progressive liver fibrosis in patients with chronic liver disease
(CLD). We explored the host genetic associations with mor-
phometric quantitative collagen (MQC) content in patients with
chronic hepatitis B (CHB) infection. Methods: 84 Caucasian
CHB HBsAg+ patients in Phase 3 TDF studies that consented
for genomic analysis were included in the analysis. Unstained
liver biopsy slides prior to initiation of treatment were stained
with picosirius red and digital image analysis was used to
calculate the MQC content, expressed as percent collagen
area (PCA). Genotyping of 4.5 million SNPs was performed
using the Illumina Infinium HumanOmni5Exome BeadChip. The
association of PCA with each SNP was assessed by linear
regression, including age, gender, HBV genotype, and pop-
ulation structure as covariates. A Bonferroni-corrected P value
criterion of P<10-8 was used as the threshold for declaring
statistical significance. Results: 75% of patients had HBeAg
negative CHB; 80% had genotype D infection. Mean PCA
was 4.9% and 25% of patients had cirrhosis. Genome wide
association tests identified a significant association with SNP
rs80125374 (p=6.5 x 10-10) on chr 17, 11 kb upstream of
the gene encoding MRC2. The severity of liver fibrosis by Ishak
staging was not significantly associated with the SNP, though a
greater percentage of patients with the TT genotype had cirrho-
sis (27.3%, 18.8%, 0.0% in TT, CT, CC, respectively). Conclu-
sions: Using a GWAS design, a significant genetic association
was observed between a SNP near the MRC2 gene (involved
in the lysosomal degradation of collagen ligands) and quantita-
tive collagen levels in the liver in Caucasian patients with CHB.
It is unclear whether the SNP is associated with undetected
variants in the MRC2 gene, or is involved in regulation of
MRC2. The functional association of this SNP with liver fibrosis
and its biological role in other liver diseases requires further
investigation and validation.
HEPATOLOGY, October, 2014
Distribution of CC (2.4%), CT (19.0%), and TT (78.6%) geno-
types and relationship with PCA
Disclosures:
Nezam H. Afdhal - Consulting: Merck, Vertex, Idenix, GlaxoSmithKline, Spring-
bank, Gilead, Pharmasett, Abbott; Grant/Research Support: Merck, Vertex, Ide-
nix, GlaxoSmithKline, Springbank, Gilead, Pharmasett, Abbott
Thomas J. Urban - Patent Held/Filed: Schering Plough
Zachary D. Goodman - Consulting: Gilead Sciences, Abbvie; Grant/Research
Support: Gilead Sciences, Fibrogen, Galectin Therapeutics, Merck, Vertex, Syn-
ageva, Conatus
Keyur Patel - Advisory Committees or Review Panels: Merck; Consulting: Gilead
Sciences, Santaris, Akros, Nitto Denko; Grant/Research Support: Bristol Myers
Squibb
Dongliang Ge - Employment: Gilead Sciences, Inc
Zhaoshi Jiang - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead
Scieces, Inc.
Xi Zhao - Employment: Gilead Sciences
Matthew Paulson - Employment: Gilead Sciences
Anuj Gaggar - Employment: Gilead Sciences
Jeffrey Bornstein - Employment: Gilead Sciences
Mani Subramanian - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
David B. Goldstein - Advisory Committees or Review Panels: Astra Zeneca, NIH,
Biogen, Gordon Research Conference; Board Membership: Knome; Consulting:
glaxo smithkline, Severe Adverse Events Consortium, Roche, Gilead Sciences,
Inc, Scienta Advisors; Employment: Duke University; Grant/Research Support:
UCB, NIH, Biogen, Henry M Jackson Foundation, SAIC, Inc, Bill & Melinda
Gates Foundation, Eisai, Inc; Patent Held/Filed: patent IL28B findings, patent
ITPA findings, Merck & Company; Speaking and Teaching: Current Biology
magazine, Illumina, Regeneron, Dermatology Society; Stock Shareholder: Pfizer
Rohit Loomba - Consulting: Gilead Inc, Corgenix Inc, Janssen and Janssen Inc;
Grant/Research Support: Daiichi Sankyo Inc, AGA, Merck Inc
Alexander J. Thompson - Advisory Committees or Review Panels: Merck, Inc,
Roche, Janssen (Johnson & Johnson), BMS, GSK Australia, Novartis, GILEAD Sci-
ences, Inc; Consulting: GILEAD Sciences, Inc; Grant/Research Support: Merck,
Inc, Roche, GILEAD Sciences, Inc; Speaking and Teaching: Merck, Inc, Roche,
BMS, Janssen (Johnson & Johnson)
The following people have nothing to disclose: Xin Guo, Sarah E. Kleinstein,
Nanye Long
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
435
Factors influencing liver stiffness in chronic liver disease
Chikage Nakano1,2, Hiroko Iijima1,2, Tomoko Aoki1, Kenji
Hashimoto 1,2, Masahiro Yoshida 2, Akio Ishii 1, Tomoyuki
Takashima 1, Nobuhiro Aizawa 1, Naoto Ikeda 1, Hironori
Tanaka1,2, Hirayuki Enomoto1, Masaki Saito1, Seiichi Hirota3,
Shuhei Nishiguchi1; 1Division of Hepatobiliary and Pancreatic dis-
ease, Department of Internal of Medicine, Hyogo College of Med-
icine, Nishinomiya, Japan; 2Ultrasound Imaging Center, Hyogo
College of Medicine, Nishinomiya, Japan; 3Deparment of Surgical
pathology, Hyogo College of Medicine, Nishinomiya, Japan
Purpose: Shear waves have been recognized to be useful in
assessing liver fibrosis in a non-invasive manner. Reports have
shown its diagnostic performance in evaluating the degree of
severity in liver cirrhosis. We aimed to identify factors, such as
fibrosis, that associate with liver stiffness, and also to evaluate
the cancer risk. Methods: In 8783 patients with chronic liver
disease who underwent Virtual Touch Quantification (VTQ)
measurements from October 2008 to July 2013, 1061 patients
were subsequently underwent liver biopsy within 4 months. (1)
188 out of 1061 cases were F4, and were studied to determine
the correlations with Child-Pugh score (CP). (2) 905 patients
who had had no personal cancer history on their first visits to
our hospital were followed up; during the follow-up period, 45
cases developed cancer (“Middle” group) and 860 cases did
not develop cancer (“cancer-free” group). These two groups
were compared using multivariate analysis. Results: (1) In 188
cases, 132 cases were CP grade A (5 points), 36 cases were
grade A (6 points), 13 were grade B, 7 were grade C. VTQ
measurements were 2.07, 2.30, 2.58, 2.81 m/s, respectively,
and they showed that the liver got stiffer with the decrease of
the hepatic functional reserve. (2) Logistic regression analysis
indicated a high risk of developing cancers in the elder (Odds
ratio [OR] 1.93/10y.o.), male (OR 2.77), with the stiffer liver
(OR 2.38/1m/s), with low platelet count (OR 0.926), with
high fasting blood glucose (FBG) (OR 1.195/10mg/dl) cases
(p<0.001). The area under the receiver operating character-
istic curve (AUROC) for VTQ was 0.799 and was the highest
among all the parameters. The cut-off value using the nearest
neighbour technique was 1.47m/s (sensitivity 78%, specificity
75%, positive predictive value 13.7%). The cut-off value for
FBG was 94.5mg/dl, and cancer rates in groups of values
under the cut-off values in these two parameters were 0.53%
(2/375), while that in groups of values above the cut-off values
in these parameters was 25% (28/112), and there was an
increase in cancer risk (OR 46.9). Conclusion: Our results sug-
gest that non-invasive fibrosis assessment is useful in evaluating
the progress of liver cirrhosis and esophageal varices, also
predicting cancer risk. Combination of FBG and VTQ could
especially be useful in differentiating high cancer risk cases.
Disclosures:
The following people have nothing to disclose: Chikage Nakano, Hiroko
Iijima, Tomoko Aoki, Kenji Hashimoto, Masahiro Yoshida, Akio Ishii, Tomoyuki
Takashima, Nobuhiro Aizawa, Naoto Ikeda, Hironori Tanaka, Hirayuki Enom-
oto, Masaki Saito, Seiichi Hirota, Shuhei Nishiguchi
415A
436
Cartilage oligomeric matrix protein (COMP) serum lev-
els: a new non-invasive biomarker of liver fibrosis in
patients with chronic viral hepatitis
Stella Gabeta1, Kalliopi Zachou1, Zakera Shums2, Nikolaos Gat-
selis1, George K. Koukoulis3, Gary L. Norman2, George N. Dale-
kos1; 1Department of Medicine and Research Laboratory of Internal
Medicine, Medical School, University of Thessaly, Larissa, Greece;
2INOVA Diagnostics, Inc., San Diego, CA; 3Department of Pathol-
ogy, Medical School, University of Thessaly, Larissa, Greece
Background/aim: Cartilage oligomeric matrix protein (COMP)
is a regulator of the fibrillar collagen assembly, produced
by fibroblasts. High COMP serum levels have been found in
patients with rheumatoid arthritis and scleroderma. COMP is
also highly expressed within hepatocellular carcinoma tissues.
The aim of the study was to assess whether serum COMP lev-
els can be used as a non-invasive fibrosis marker in patients
with chronic viral hepatitis (CVH). Methods: Sera from 116
CVH patients, 66 with HBV [24 female; median age 53 (22-
76)] and 50 with HCV [21 female; median age 48,5 (25-69)]
were tested by COMP ELISA (AnaMar Medical). All patients
underwent transient elastography (TE) (all had 10 successful
acquisitions and an IQR/liver stiffness measurement <0.30).
APRI score was also calculated in all patients, while in 61
patients liver biopsy was performed. The patients were divided
into two groups according to Metavir score: F1/F2-group and
F3/F4-group. Results: 55/116 (47%) CVH patients were clas-
sified in F3/F4-group according to liver stiffness and 24/61
(39%) according to histology. COMP levels were significantly
increased in F3/F4-group either when liver stiffness (p<0.001)
or histology (p=0.009) was taken into account. COMP levels
correlated with TE measurements (r=0,5, p<0,001) and APRI
score (r=0.23, p=0.016). The level of 10 U/L predicted F3/
F4 stage with sensitivity 70% and specificity 82%. Conclusions:
COMP serum levels correlated with fibrosis stage assessed by
TE, APRI score and liver histology in CVH patients. High COMP
levels corresponded to advanced stage, suggesting COMP as
a sensitive potential non-invasive biomarker of liver fibrosis.
Disclosures:
Zakera Shums - Employment: INOVA DIAGNOSTICS
Gary L. Norman - Employment: INOVA Diagnostics
The following people have nothing to disclose: Stella Gabeta, Kalliopi Zachou,
Nikolaos Gatselis, George K. Koukoulis, George N. Dalekos
437
New canine liver cirrhotic model to develop a less inva-
sive regeneration therapy using cultured autologous
bone marrow-derived cells
Takashi Matsuda, Taro Takami, Tsuyoshi Ishikawa, Naoki Yama-
moto, Shuji Terai, Isao Sakaida; Department of Gastroenterology
and Hepatology, Yamaguchi University Graduate School of Medi-
cine, Ube, Yamaguchi, Japan
Background/Aims: We developed “Autologous bone marrow
cell infusion (ABMi) therapy”. This ABMi therapy is a safe and
efficient liver regeneration therapy for liver cirrhotic patients
using non-cultured autologous whole bone marrow (BM) cells,
which requires BM aspiration under general anesthesia. We
are developing a new liver regeneration therapy using cul-
tured autologous BM-derived mesenchymal stem cells (BMSCs)
from small amounts of BM fluid aspirated under local anes-
thesia. Before human clinical trials, the safety and efficacy of
cultured autologous BMSC infusion in medium-to-large animals
must be confirmed; thus, we developed a canine liver cirrhotic
model. Methods: A small amount of BM fluid was aspirated
416A AASLD ABSTRACTS
from canine humerus to assess BMSC characteristics. Repeated
oral administration of carbon tetrachloride (CCl4) ) (0.1 mL/
kg body weight, 5 times/week) was performed over 20 weeks
to induce liver cirrhosis. Cultured autologous BMSCs were
infused through a peripheral vein. Examination of blood was
performed before and at 4 weeks after infusion. We devel-
oped another canine liver cirrhotic model using an implanted
catheter to shorten the induction time and reduce individual
differences compared to oral dosing. CCl4 was repeatedly
injected for 10 weeks (high-dose period: 0.75 mL/kg body
weight, twice a week for 6 weeks; low-dose period: 0.25 mL/
kg body weight, twice a week for 4 weeks) to induce liver
cirrhosis. Cultured autologous BMSCs (4 × 10 5/kg) were
infused through a peripheral vein. Low-dose CCl4 was contin-
ued after the infusion, and blood examinations, ultrasonogra-
phy-guided liver biopsies, and indocyanine green (ICG) tests
were carried out before and at 4 weeks after infusion. Results:
Cultured canine BMSCs adhered to plastic and were CD44+,
CD90+, and CD45−. They differentiated into adipocytes and
osteocytes, consistent with known characteristics of BMSCs.
In cirrhotic canines given oral CCl4, serum prothrombin time
at 4 weeks after BMSC infusion was significantly improved
in the BMSC group (n = 4; 9.6 ± 1.2 sec) compared to the
controls (n = 3; 13.3 ± 1.6 sec; p < 0.05). In catheterized
cirrhotic canines, the Sirius red-stained liver fibrotic area was
also reduced (BMSCs: before, 11.0%, after, 7.8%; controls:
20.9% and 25%, respectively), consistent with the prolonged
half-life of ICG in controls (BMSCs: before, 12.6 min; after,
13.1 min, controls: 15.5 min and 20.8 min, respectively). Con-
clusions: We developed useful canine liver cirrhotic models
with repeated CCl4 administration, and confirmed that cultured
autologous BMSC infusion improved liver cirrhosis and pro-
moted liver regeneration without adverse effects.
Disclosures:
Shuji Terai - Speaking and Teaching: Otsuka Pharma.
The following people have nothing to disclose: Takashi Matsuda, Taro Takami,
Tsuyoshi Ishikawa, Naoki Yamamoto, Isao Sakaida
438
Spleen prevents the development of liver fibrosis by
Kupffer cell deactivation through lipocalin-2 production
in mice
Tomonori Aoyama1, Akira Uchiyama1, Kazuyoshi Kon1, Hironao
Okubo2, Shunhei Yamashina1, Kenichi Ikejima1, Shigehiro
Kokubu2, Akihisa Miyazaki2, Sumio Watanabe1; 1Gastroenter-
ology, Juntendo University, Tokyo, Japan; 2Gastroenterology, Jun-
tendo University Nerima Hospital, Tokyo, Japan
The spleen is linked to the liver by portal vein (PV). The spleen
regulates immune functions and produces cytokines which
may effect on the liver through PV, but the relation between
the spleen and the development of liver fibrosis is unclear.
Lipocalin-2 (Lcn2) is known as an extracellular transport pro-
tein with anti-microbial effects among other functions. To clar-
ify the role of the spleen, we performed splenectomy (SPX)
before carbon tetrachloride (CCl4) treatment. Methods: Male
C57BL/6 mice (WT) underwent SPX or sham operation (Sham).
One week later, mice were treated with CCl4 or vehicle twice
weekly for 6 weeks. Spleen samples were obtained from CCl4
or vehicle treated Sham mice. Splenic pro-inflammatory (TNF-α,
IL-6, and CCL2) and anti-inflammatory (IL-10 and Arginase-1)
cytokines and Lcn2 mRNA levels were measured by qPCR.
Splenic Gr1 and Lcn2 expressions were detected by immuno-
fluorescence. Liver fibrosis was evaluated by Sirius red staining
and α-SMA immunohistochemistry. Hepatic inflammatory and
fibrotic gene mRNA levels were detected by qPCR. Lcn2 levels
HEPATOLOGY, October, 2014
in PV were measured by ELISA. To clarify the effect of Lcn2 on
Kupffer cells (KCs), KCs were isolated from WT by collagenase
perfusion and treated by LPS with/without recombinant Lcn2
(rLcn2). Inflammatory properties of KCs were measured by
qPCR. Results: CCl4 treatment induced splenic red pulp dilation
due to congestion and increased nucleated cells. Splenic pro-
or anti-inflammatory cytokine mRNA levels were unchanged
by CCl4; however, splenic Lcn2 mRNA levels had a 35-fold
increase in CCl4 compared to vehicle treatment. Lcn2 was
mostly expressed on Gr1-positive cells, which were observed
in splenic red pulp and markedly increased in CCl4-treated
spleens. Interestingly, sirius red positive area was significantly
increased in CCl4-treated SPX mice compared to CCl4-treated
Sham mice (6.6 ± 0.4% vs 3.5 ± 0.2%, p<0.05). Hepatic
TNF-α, CCL2, collagen α(I)1, and TIMP-1 mRNA levels, and
α-SMA expression were remarkably increased in CCl4-treated
SPX mice. Lcn2 levels in PV after CCl4 treatment were signifi-
cantly decreased in SPX mice compared to Sham mice (327.5
± 35.0 ng/mL vs 465.9 ± 30.6 ng/mL, p<0.05). CCL2 and
TNF-α mRNA levels were significantly decreased after rLcn2
treatment on LPS-stimulated KCs. Conclusion: Spleen deficiency
enhanced CCl4-induced liver fibrosis. The mechanism of exag-
gerated liver fibrosis most likely involves decreased Lcn2 levels
in PV that led to excessive KC activation in this model. The
spleen may have a protective role in the development of liver
fibrosis by Lcn2 produced from Gr1-positive cells, and it could
be a new therapeutic target against liver fibrosis.
Disclosures:
The following people have nothing to disclose: Tomonori Aoyama, Akira Uchi-
yama, Kazuyoshi Kon, Hironao Okubo, Shunhei Yamashina, Kenichi Ikejima,
Shigehiro Kokubu, Akihisa Miyazaki, Sumio Watanabe
439
Serum Lysyl Oxidase Like 2 (sLOXL2) Levels Correlate
with Ishak Fibrosis Score and Decrease with Treatment
with Tenofovir Disoproxil Fumarate (TDF) in Patients
with Chronic Hepatitis B (CHB)
W. Ray Kim1, Rohit Loomba2, Preeti Lal3, Raul E. Aguilar Schall3,
Ann D. Johnson3, Jeffrey D. Bornstein3, Mani Subramanian3,
John G. McHutchison3, Stephen A. Harrison4, Arun J. Sanyal5;
1Stanford, Palo Alto, CA; 2University of California San Diego,
San Diego, CA; 3Gilead Sciences, Foster City, CA; 4Brooke Army
Medical Center, Fort Sam Houston, TX; 5Virginia Commonwealth
University School of Medicine, Richmond, VA
Introduction: Lysyl Oxidase Like 2 (LOXL2) is an extracellular
copper-dependent amine oxidase that catalyzes the forma-
tion of crosslinks in collagen. We assessed the relationship of
sLOXL2 levels with liver fibrosis and cirrhosis in patients with
CHB treated with TDF. Methods: Subjects in the pivotal TDF
registration trials who had stored serum samples available for
analysis at baseline and weeks 12, 48 and 240 were included
in the analysis. Liver biopsies were performed pre-treatment,
at weeks 48 and 240. sLOXL2 was measured using a highly
sensitive assay developed using 2 specific monoclonal anti-
bodies on a Singulex® platform. Results: Of the 641 subjects
originally randomized, 304 had stored serum available and
were included in the analysis. Of these, 225 had liver biopsies
at baseline and week 240. Characteristics (77% male, 63%
white, 30% Asian and 13% obese) of the subjects included in
the study matched well with those not included in the analysis.
sLOXL2 correlated with Ishak fibrosis stage at all time points.
In cross sectional analyses at baseline, the median sLOXL2
level correlated with necroinflammation by Knodell score
(p<0.0001) and with fibrosis by Ishak stage (791 pg/mL for
Ishak stage 0-2, 1091 pg/mL for Ishak 3-4 and 1370 for pg/
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
mL for Ishak 5-6; p<0.0001). In longitudinal analysis, sLOXL2
declined with treatment, with the largest decline seen in the
first 12 weeks. For all fibrosis stage categories, patients experi-
encing fibrosis regression consistently had lower sLOXL2 levels
than those without regression (Figure1). Conclusions: sLOXL2
correlates with fibrosis stage in patients with HBV. sLOXL2
declines with HBV treatment, likely indicating a decrease in
fibrogenesis. Overall, the data suggest that sLOXL2 is a poten-
tial measure of ongoing fibrosing disease and may be useful
not only to assess liver fibrosis at a given time but also to detect
reversal of fibrosis and cirrhosis.
Disclosures:
W. Ray Kim - Consulting: Bristol Myers Squibb, Gilead Sciences
Rohit Loomba - Consulting: Gilead Inc, Corgenix Inc, Janssen and Janssen Inc;
Grant/Research Support: Daiichi Sankyo Inc, AGA, Merck Inc
Preeti Lal - Employment: Gilead Sciences
Raul E. Aguilar Schall - Employment: Gilead Sciences, Inc.
Ann D. Johnson - Employment: Gilead Sciences
Jeffrey D. Bornstein - Employment: Gilead Sciences
Mani Subramanian - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Stephen A. Harrison - Advisory Committees or Review Panels: Merck, Nimbus
Discovery; Grant/Research Support: Merck, Genentech; Speaking and Teach-
ing: Merck, Vertex
Arun J. Sanyal - Advisory Committees or Review Panels: Bristol Myers, Gilead,
Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Nimbus, Genentech, Echo-
sens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept,
Ikaria, Takeda, GalMed, Novartis, Gilead; Independent Contractor: UpToDate,
Elsevier
440
How long a prognosis by liver fibrosis tests is accurate?
Sandrine Bertrais1, Jerome Boursier1,2, Frédéric Oberti2, Isabelle
Fouchard-Hubert2, Valerie Moal3, Paul Cales1,2; 1Faculty of Med-
icine, HIFIH Research Unit, UPRES 3859, SFR 4208, University of
Angers, Angers, France; 2Department of Liver-Gastroenterology,
University Hospital, Angers, France; 3Department of Biochemistry
and Genetics, University Hospital, Angers, France
INTRODUCTION: Recent studies have suggested that non-inva-
sive liver fibrosis diagnostic tests can predict liver complications
and survival. We aimed to identify the time window in which
a single evaluation of liver fibrosis may accurately predict mor-
tality and to assess whether prognostic performance may be
improved by combining tests. METHODS: 3,337 patients with
chronic liver disease of various causes have been enrolled in a
prospective cohort between 2005 and 2009. All patients had
a non-invasive evaluation of liver fibrosis at baseline, either
417A
by a blood test (APRI, FIB-4, Hepascore, FibroMeterV2G) or a
liver stiffness measurement (LSM by Fibroscan), or both. They
were followed until death (data obtained from national registry)
or up to January 2011. Time-dependent ROC curves [AUC(t)]
were used to assess the discriminative ability of liver fibro-
sis tests according to delay of prediction, and Harrell’s C-in-
dex was used as summary measure of discrimination over the
whole follow-up period. Multivariate prognostic models were
built in a random set of patients, and validated in the other
half of patients. RESULTS: 3,064 patients had LSM and 2,891
patients had blood sampling at baseline; 1,559 patients had
available data for all liver fibrosis tests. In this subgroup, the
follow-up period ranged from 0.002 to 6.0 years (median=2.8
years); 16.8% of patients died, 7.4% of deaths were liver-re-
lated. The discriminative ability of tests for mortality was the
greatest in the few months after the baseline measure; then
it decreased to a performance level that remains relatively
stable over 5 years: all tests (except APRI) had AUC(t)>0.70
to predict all-cause death, AUC(t) from 0.80 to 0.90 for liv-
er-related mortality. FibroMeterV2G had the highest C-index
(0.790, 95%CI=0.765-0.815), as compared to LSM and all
other blood tests (p<0.008). The diagnostic test combining
LSM and FibroMeterV2G, called E-FibroMeterV2G, showed
higher C-index than LSM alone (p=0.002). The best-fit multi-
variate Cox models (according to Akaïke information criteria)
in the training set included age, sex, LSM, FibroMeterV2G. In
the validation set, C-index was 0.834 [0.803-0.862] for the
prognostic model of all-cause mortality and 0.868 [0.831-
0.902] for the prognostic model of liver-related mortality. A
good match (calibration) between observed and estimated sur-
vival rates using these models was observed. CONCLUSION:
A single (baseline) evaluation of liver fibrosis can accurately
predict death in the following 5 years, and combination of clin-
ical data, blood test and LSM significantly improves all-cause
death risk prediction.
Disclosures:
Frédéric Oberti - Speaking and Teaching: LFB
Isabelle Fouchard-Hubert - Speaking and Teaching: JANSSEN
Paul Cales - Consulting: BioLiveScale
The following people have nothing to disclose: Sandrine Bertrais, Jerome
Boursier, Valerie Moal
441
Exhaled Breath Analysis Reveals New Biomarkers to
Diagnose Advanced Fibrosis in Patients with Chronic
Liver Disease
Mohammed Eyad Yaseen Alsabbagh, Ahmad Tarek Chami, Singh
Gurshawn, Mina Shaker, Ibrahim A. Hanouneh, David Grove,
Rocio Lopez, Nizar N. Zein, Raed Dweik, Naim Alkhouri; Cleve-
land Clinic, cleveland, OH
Background: The aim of this study was to investigate the utility of
breath volatile organic compounds (VOCs) measured by mass
spectrometry to diagnose advanced fibrosis in patients with
chronic liver disease (CLD). Methods: Patients were recruited
for this pilot study from the hepatology clinic at a tertiary care
center. Fibrosis was determined by an experienced pathologist
(F0-4) and advanced fibrosis was defined as F3-4. Exhaled
breath was collected on the same day of the liver biopsy and
analyzed per protocol using selective ion flow tube (SIFT-MS) to
identify new markers of advanced fibrosis. Results:49 patients
were included in the study with a mean age of 50.4± 10.1
years and 57% were male. 38% had chronic hepatitis C, 35%
had NAFLD, and 27% had other CLD. SIFT-MS analysis of
exhaled breath revealed that patients with advanced fibrosis
had significantly lower values of six compounds compared to
418A AASLD ABSTRACTS
those without advanced fibrosis (namely isoprene, trimethyl-
amine, ethane, acrylonitrile, pentane, and 1-heptene), p value
< 0.05 for all. Isoprene was found to have the highest accu-
racy for prediction of advanced fibrosis on biopsy with an area
under the ROC curve of 0.765 (95% CI 0.622-0.908). In addi-
tion, ethane andtrimethylamine were also found to have AUCs
of >0.70. Conclusion: Exhaled breath analysis is a promising
noninvasive method to detect advanced fibrosis in patients with
CLD. Isoprene, ethane, and trimethylamine are potential bio-
markersfor advanced fibrosis that deserve further validation.
Disclosures:
Naim Alkhouri - Advisory Committees or Review Panels: Gilead Sciences
The following people have nothing to disclose: Mohammed Eyad Yaseen
Alsabbagh, Ahmad Tarek Chami, Singh Gurshawn, Mina Shaker, Ibrahim A.
Hanouneh, David Grove, Rocio Lopez, Nizar N. Zein, Raed Dweik
442
Oral Treatment with PBI-4050 Reduces Fibrosis in Car-
bon Tetrachloride (CCl4)-Induced Hepatic Fibrosis
Brigitte Grouix, Kathy Hince, François Sarra-Bournet, Alexandra
Felton, Mikaël Tremblay, Shaun Abbott, Jean-Simon Duceppe, Bou-
los Zacharie, Pierre Laurin, Lyne Gagnon; ProMetic BioSciences
Inc., Laval, QC, Canada
Background: Liver fibrosis is a major health problem world-
wide. Chronic damage to the liver in conjunction with
increased deposition and altered composition of extracellular
matrix (ECM) lead to liver fibrosis. The specific purpose of
this study was to investigate the effect of PBI-4050, an anti-in-
flammatory/fibrotic compound, on hepatic fibrosis induced by
administration of carbon tetrachloride (CCl4) to C57BL/6 mice.
Methods: C57BL/6 mice were given intraperitoneal injection
of 10% CCl4 in olive oil at a dosage of 2 ml/kg, twice a week
for 8 weeks. Mice were treated from day 1 to 58 with oral
administration of PBI-4050 (100 or 200 mg/kg) and sacrificed
on Day 59. The degree of fibrosis in mouse liver was evalu-
ated by mRNA expression of fibrotic, remodeling and oxida-
tive stress markers as well as measurement of hydroxyproline
content in liver and histopathology analysis. Results: Extensive
collagen accumulation was observed in the liver of CCl4-
treated animals compared to control (non-CCl4) mice. Oral
treatment with PBI-4050 significantly reduced in a dose depen-
dent manner collagen deposition as measured by hydroxy-
proline and histological examination of the liver (Masson’s
trichrome staining). CCl4-treated mice developed liver fibrosis
with increased hepatic collagen I, tissue inhibitor of metallo-
proteinases (TIMP)-1, matrix metalloproteinase (MMP)-2, and
inducible NO synthase (iNOS) mRNA expression, which were
significantly reduced after treatment with PBI-4050. Moreover,
peroxisome proliferator-activated receptor-γ (PPARγ), which is
implicated in the pathogenesis of liver fibrosis and is markedly
decreased in CCl4-treated animals, was restored by PBI-4050
to the non-CCl4 control (normal) level. Conclusions: Our results
show that PBI-4050 reduces liver fibrosis in the CCl4-induced
hepatic fibrosis mouse model and may be used as a potential
novel therapy for hepatic fibrosis.
Disclosures:
Brigitte Grouix - Employment: ProMetic BioSciences Inc.
Kathy Hince - Employment: ProMetic BioSciences Inc
François Sarra-Bournet - Employment: ProMetic BioSciences Inc.; Stock Share-
holder: ProMetic BioSciences Inc.
Alexandra Felton - Employment: ProMetic BioSciences Inc.
Shaun Abbott - Employment: ProMetic BioSciences Inc.
Jean-Simon Duceppe - Employment: ProMetic BioSciences Inc.
Boulos Zacharie - Management Position: ProMetic BioSciences Inc.; Stock Share-
holder: ProMetic Life Sciences Inc.
HEPATOLOGY, October, 2014
Pierre Laurin - Management Position: ProMetic BioSciences Inc.; Stock Share-
holder: ProMetic Life Sciences Inc.
Lyne Gagnon - Management Position: ProMetic BioSciences Inc.
The following people have nothing to disclose: Mikaël Tremblay
443
Wisteria floribunda agglutinin-positive Mac-2 binding
protein as a predictor of liver fibrosis in patients with
non-alcoholic fatty liver disease
Masanori Abe1, Teruki Miyake1, Atsushi Kuno2, Yasuharu Imai3,
Yoshiyuki Sawai3, Keisuke Hino4, Yuichi Hara4, Shuhei Hige5,
Michiie Sakamoto6, Masaaki Korenaga7, Yoichi Hiasa1, Masashi
Mizokami7, Hisashi Narimatsu2; 1Department of Gastroenterol-
ogy and Metabology, Ehime University Graduate School of Med-
icine, Ehime, Japan; 2Research Center for Medical Glycoscience,
National Institute of Advanced Industrial Science and Technol-
ogy, Tsukuba, Japan; 3Department of Gastroenterology, Ikeda
Municipal Hospital, Ikeda, Japan; 4Department of Hepatology
and Pancreatology, Kawasaki Medical School, Kurashiki, Japan;
5Department of Hepatology, Sapporo-Kosei General Hospital,
Sapporo, Japan; 6Department of Pathology, Keio University School
of Medicine, Tokyo, Japan; 7The Research Center for Hepatitis and
Immunology, National Center for Global Health and Medicine,
Ichikawa, Japan
Background/Aims: An accurate evaluation of liver fibrosis in
patients with non-alcoholic fatty liver disease (NAFLD) is import-
ant for identifying those who may be at risk of developing
complications. The aims of this study were 1) to measure the
serum Wisteria floribunda agglutinin-positive Mac-2 binding
protein (WFA+-M2BP), which is a novel marker developed
for liver fibrosis using the glycan sugar chain-based immuno-
assay; and 2) to compare the results with clinical assessments
of fibrosis using histological stage. Patients and Methods: The
serum WFA+-M2BP values were measured in 289 patients
with NAFLD who underwent liver biopsy, and they were
based on WFA-antibody immunoassay using a chemilumi-
nescence enzyme immunoassay machine (HISCL-2000i; Sys-
mex, Kobe, Japan). The histological findings were evaluated
by three blinded, experienced liver-specific pathologists and
were validated by discussion. Predictive variables associated
with each stage of liver fibrosis were assessed using multi-
variate analyses. The diagnostic performances of the markers
were expressed as diagnostic specificity, sensitivity, and area
under the receiving operator characteristic (AUROC) curve.
The AUROC curve values for predicting the stage of fibrosis of
serum WFA+-M2BP were compared with five other indicators
(i.e., platelets, hyaluronic acid, AST/ALT ratio, AST-to-platelet
ratio index, and FIB-4 index). Results: The serum WFA+-M2BP
value in patients with stage 0 (n = 35), stage 1 (n = 113),
stage 2 (n = 49), stage 3 (n = 41), and stage 4 (n = 51) fibro-
sis had cutoff indexes of 0.57, 0.70, 1.02, 1.57, and 2.96,
respectively. All pairs of groups differed significantly from each
other according to the Steel-Dwass test. Multivariate regression
analysis showed that the serum WFA+-M2BP values predicted
the stage of fibrosis (≥ stage 2). The AUROC curve, sensitivity,
and specificity of serum WFA+-M2BP were 0.876, 85.9%,
and 74.6% for severe fibrosis, respectively, (≥ stage 3) and
0.879, 74.6%, and 87.0%, for cirrhosis, respectively. When
compared with the other surrogate markers and scoring sys-
tems, serum WFA+-M2BP had the greatest AUROC curve for
diagnosing severe fibrosis and cirrhosis. Conclusions: The mea-
surement of serum WFA+-M2BP values based on glycan-based
immunoassay provides an accurate and reliable method for
assessing the stage of liver fibrosis in patients with NAFLD. This
method appears quite promising as a means for evaluating
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
the natural course of the disease, therapeutic effects, and the
suitability of liver biopsy.
Disclosures:
Michiie Sakamoto - Grant/Research Support: MSD, Canon
The following people have nothing to disclose: Masanori Abe, Teruki Miyake,
Atsushi Kuno, Yasuharu Imai, Yoshiyuki Sawai, Keisuke Hino, Yuichi Hara,
Shuhei Hige, Masaaki Korenaga, Yoichi Hiasa, Masashi Mizokami, Hisashi
Narimatsu
444
Less invasive liver regeneration therapy for liver cir-
rhosis using cultured autologous bone marrow-derived
mesenchymal stem cells with redox-regulatory capacity
Taro Takami1, Shuji Terai1, Luiz Fernando Quintanilha1, Bruno D.
Paredes1, Koichi Fujisawa2, Naoki Yamamoto3, Isao Sakaida1,2;
1Department of Gastroenterology and Hepatology, Yamaguchi
University Graduate School of Medicine, Yamaguchi University,
Ube, Japan; 2Center for Reparative Medicine, Yamaguchi Univer-
sity Graduate School of Medicine, Yamaguchi University, Ube,
Japan; 3Yamaguchi University Health Administration Center,
Yamaguchi University, Yamaguchi, Japan
Background and Objectives: In our animal studies, we showed
that bone marrow cells (BMCs) infused via a peripheral vein
efficiently repopulate the cirrhotic liver and produce collage-
nases, resulting in reduced liver fibrosis, elevated serum albu-
min levels, and a significant increase in survival. We also
confirmed that frequent BMC infusion contributed to suppres-
sion of tumor initiation in hepatocarcinogenic cirrhotic mice.
Based on these results, we started “Autologous bone marrow
cell infusion therapy” for liver cirrhotic patients as liver regener-
ation therapy using non-cultured autologous whole BMCs, and
subsequently reported its safety and efficacy. This type of ther-
apy involves bone marrow (BM) aspiration under general anes-
thesia; therefore, we are presently developing a less invasive
liver regeneration therapy using cultured autologous BM-de-
rived mesenchymal stem cells (BMSCs) from small amounts
of BM fluid aspirated under local anesthesia. Here, we eval-
uated the role of BMSCs in liver regeneration and the under-
lying mechanisms. Methods: To assess the effects of cultured
BMSCs on liver cirrhosis, we systemically infused BMSCs into
thioacetamide-induced NOD-SCID cirrhotic mice. Liver fibrosis
and antioxidant effects were assessed with Sirius red staining
and a kinetic study of inhibition of diammonium salt oxida-
tion. We also screened the profile of microRNAs in BMSC-in-
fused livers using a miRNA array. We used thioacetamide to
induce oxidative stress in vitro and confirmed the protective
effects of BMSCs or exosomes derived from BMSCs on oxidant
conditions. We then measured cellular reactive oxygen spe-
cies (ROS) and factors related to oxidative stress resolution in
hepatocytes co-cultured with BMSCs or their exosomes. Results:
BMSC-infused NOD-SCID mice showed reduced liver fibrosis
(p<0.05), higher serum antioxidant activity (p<0.001), lower
levels of hepatic malondialdehyde (p<0.05) and significantly
higher amounts of hepatic miR-200a-3p, which targets Keap1
mRNA (ratio 3.67 vs. controls). Hepatocytes co-cultured with
not only BMSCs, but also their exosomes, showed lower levels
of ROS (p<0.001). Hepatocytes in which the miR-200a-3p
target site was blocked showed significantly higher levels of
ROS, despite supplementation with exosomes of BMSCs in
vitro. Conclusions: These results suggest that the infusion of
cultured BMSCs secreting exosomes, including miR-200a-3p,
helped to improve liver fibrosis by stabilizing redox homeosta-
sis. This indicates that a less invasive liver regeneration therapy
for liver cirrhotic patients using cultured autologous BMSCs is
highly possible.
Disclosures:
419A
Shuji Terai - Speaking and Teaching: Otsuka Pharma.
The following people have nothing to disclose: Taro Takami, Luiz Fernando
Quintanilha, Bruno D. Paredes, Koichi Fujisawa, Naoki Yamamoto, Isao Sakaida
445
A novel glycobiomarker: Wisteria floribunda agglutinin
Macrophage Colony-Stimulating Factor Receptor for
predicting carcinogenesis and survival of liver cirrhosis
patients
Etsuko Iio1,3, Makoto Ocho2, Akira Togayachi2, Noboru Shinkai3,
Masanori Nojima4, Atsushi Kuno2, Yuzuru Ikehara2, Izumi Hase-
gawa5, Kei Fujiwara3, Shunsuke Nojiri3, Takashi Joh3, Masashi
Mizokami6, Hisashi Narimatsu2, Yasuhito Tanaka1; 1Virology&
Liver unit, Nagoya City University Graduate School of Medical
Sciences, Nagoya, Japan; 2Research Center for Medical Glyco-
science, National Institute of Advanced Industrial Science and
Technology, Tsukuba, Japan; 3Gastroenterology and Metabolism,
nagoya city university, Nagoya, Japan; 4Division of Advanced
Medicine Promotion, The Advanced Clinical Research Center, The
Institute of Medical Science, The University of Tokyo, Tokyo, Japan;
5Gastroenterology, Social Insurance Chukyo Hospital, Nagoya,
Japan; 6The Research Center of Japan, Hepatitis and Immunology,
Kohnodai Hospital, International MedicalCenter, Ichikawa, Japan
[Background/Aims] Recently, we identified a novel liver fibro-
sis glycobiomarker Wisteria floribunda agglutinin (WFA)-reac-
tive colony stimulating factor 1 receptor (WFA+-CSF1R) using a
glycoproteomics-based strategy. Elevated expression of CSF1R
has been reported in a variety of malignancies of epithelial
origin, including breast, prostate, and ovarian carcinomas. The
aim of the present study was to assess the utility of measuring
WFA+-CSF1R levels for hepatocarcinogenesis and outcome in
patients with liver cirrhosis (LC). [Methods] WFA+-CSF1R and
total CSF1R levels were measured by an antibody-lectin sand-
wich ELISA in serum samples from 207 consecutive hepatitis
C virus (HCV)-infected patients from 1998 to 2013 in order to
evaluate impact on carcinogenesis and survival of LC patients.
The median age was 64 (21-87) and male was 110 (53.1%).
Among 108 patients with LC, 77 patients without hepatocel-
lular carcinoma (HCC) at baseline were analyzed for sur-
vival and carcinogenesis rates during a median of 51 months
(range,0-195) follow up. [Results] Serum WFA+ - CSF1R levels
were significantly higher in LC than CH patients [216.9 (34.3-
574.8) ng/ml vs. 82.3 (5.0-241.0) ng/ml] (p<0.001). In LC
patients without HCC (n = 77), the median WFA+ - CSF1R
levels were 214.8 (34.4-479.3) ng/ml, and the WFA+/Total -
CSF1R ratio was 0.21 (0.06-0.64). The AUC of WFA+ - CSF1R
for predicting overall survival calculated by time-dependent
ROC analysis was 0.868, and the HR was 2.20 (95% CI,
1.48-3.27, p < 0.001). The AUC of WFA+-CSF1R for predict-
ing survival was superior to other markers such as age, platelet
count, AFP, and APRI, and was equivalent to Fib4. The sur-
vival rate of LC patients with high WFA+ - CSF1R levels (≥230
ng/ml) was significantly worse than in those with lower levels
(p<0.0001), and similar data were observed in those with high
albumin levels (>3.5 g/dl, n = 52). Furthermore, the AUC of
WFA+/Total-CSF1R ratio for predicting the cumulative carcino-
genesis rate was 0.898, with an HR of 1.36 (95% CI 1.00-
1.85, p=0.047). The AUC of WFA+/Total-CSF1R ratio was
superior to other fibrosis and tumor markers (i.e. Fib4, APRI,
albumin, AFP, AFP-L3 and DCP) for predicting the cumulative
carcinogenesis rate. In fact, the carcinogenesis rate was sig-
nificantly higher in LC patients having the high ratio of WFA+/
Total-CSF1R (≥0.35, p=0.0019). The 4-year cumulative car-
cinogenesis rate in the group with a high WFA+/Total - CSF1R
ratio was significantly higher (70% vs. 36%). [Conclusions]
420A AASLD ABSTRACTS
Assessing serum levels of WFA+-CSF1R has diagnostic utility
for predicting carcinogenesis and survival of LC patients.
Disclosures:
Yasuhito Tanaka - Grant/Research Support: Chugai Pharmaceutical CO., LTD.,
MSD, Mitsubishi Tanabe Pharma Corporation, Dainippon Sumitomo Pharma
Co., Ltd., DAIICHI SANKYO COMPANY, LIMITED, Bristol-Myers Squibb
The following people have nothing to disclose: Etsuko Iio, Makoto Ocho, Akira
Togayachi, Noboru Shinkai, Masanori Nojima, Atsushi Kuno, Yuzuru Ike-
hara, Izumi Hasegawa, Kei Fujiwara, Shunsuke Nojiri, Takashi Joh, Masashi
Mizokami, Hisashi Narimatsu
446
Cholecystectomy Is Associated with an Increased Rate
of Hepatic Fibrosis Development Compared to Patients
with Chronic Hepatitis C Infection who are Non-re-
sponders to Interferon/Ribavirin
Donald J. Martin1,2, Rick A. Weideman4, Terri Crook1,3, Geri
Brown1,2; 1Division of Digestive and Liver Diseases, UT South-
western, Dallas, TX; 2Division of Digestive and Liver Diseases, VA
North Texas Health Care System, Dallas, TX; 3Pathology, VA North
Texas Health Care System, Dallas, TX; 4Pharmacy, VA North Texas
Health Care System, Dallas, TX
Introduction: Studies suggest that cholecystectomy is a risk
factor for nonalcoholic fatty liver disease, but it is not known
whether cholecystectomy is a risk factor for the progression
of other chronic liver diseases such as hepatitis C virus (HCV)
infection. The aim of this study is to assess whether cholecystec-
tomy is associated with increased rates of fibrosis, increased
incidence of cirrhosis and cirrhosis-related complications in
patients with chronic HCV infection. Methods: Among a total of
5,236 HCV-positive patients at the VA North Texas Healthcare
System, we retrospectively reviewed records of 88 patients who
had undergone cholecystectomy between 1998 and 2013.
We compared outcomes of these patients to 129 age, race,
and gender matched HCV-positive patients without cholecys-
tectomy, who had failed prior HCV-directed therapy. Patients
with sustained viral response (SVR) were not included as this
would alter fibrosis progression rates in the control group.
Demographics, presence of metabolic syndrome, alcohol use,
laboratory data and clinical progression of liver disease were
compared between the two groups using Student T-test, with
statistical significance defined as p<0.05. Degree of fibrosis
was assessed using FIB-4 and APRI, which were calculated
at time of HCV diagnosis and five years later. Cirrhosis was
defined as evidence of nodularity by imaging. Results: The
average age for the total population was 54.5 years, 52%
were white, 94% male, and 78% overweight or obese (aver-
age BMI 29). No difference in tobacco use, or cholesterol
levels was noted between the two groups. There were differ-
ences in alcohol consumption (p-value 0.013) and metabolic
syndrome (p-value < 0.001) between the two cohorts. Five
years after cohort entry, the cholecystectomy cohort was found
to have increased rates of hepatic fibrosis, development of cir-
rhosis, ascites, hepatic encephalopathy, and death compared
to the non- cholecystectomy cohort (Table 1). Importantly, abso-
lute change in APRI (0.73) in the cholecystectomy cohort was
different than then non-cholecystectomy cohort (0.36) (p-value
0.03). Conclusions: Cholecystectomy in patients with chronic
HCV may be associated with increased rate of fibrosis, devel-
opment of cirrhosis, ascites, hepatic encephalopathy and death
compared to non-responder HCV patients.
HEPATOLOGY, October, 2014
Table 1
Disclosures:
The following people have nothing to disclose: Donald J. Martin, Rick A. Weide-
man, Terri Crook, Geri Brown
447
Pro-C3-levels in patients with HIV/HCV coinfection
reflect fibrosis stage and degree of portal hypertension
Christian Jansen1, Diana J. Leeming2, Mattias Mandorfer3, Inger
Byrjalsen2, Robert Schierwagen1, Philipp Schwabl3, Morten A.
Karsdal2, Evrim Anadol1, Christian P. Strassburg1, Jürgen K. Rock-
stroh1, Markus Peck-Radosavljevic3, Søren Møller4, Flemming
Bendtsen4, Aleksander Krag5, Thomas Reiberger3, Jonel Trebicka1;
1Internal Medicine I, University of Bonn, Bonn, Germany; 2Nordic
Bioscience, Kopenhagen, Denmark; 3Medical University of Vienna,
Vienna, Austria; 4University of Copenhagen, Kopenhagen, Den-
mark; 5University of Southern Denmark, Odense, Denmark
Background: Liver-related deaths represent the leading cause
of mortality among patients with HIV/HCV coinfection, and
are mainly related to complications of fibrosis and portal hyper-
tension (PHT). However, biomarkers for prediction of fibrosis
progression and the degree of PHT in patients with HIV/HCV
coinfection are currently not available. Thus, we assessed the
value of extracellular matrix (ECM) degraded fragments in
peripheral blood as biomarkers for fibrosis and PHT in HIV/
HCV coinfection. Methods: Fifty-eight patients (67% male, mean
age: 36.5 years) with HIV/HCV coinfection were included in
this study. Hepatic venous pressure gradient (HVPG) was mea-
sured in forty-three patients. The fibrosis stage was determined
using the FIB4-Score. ECM degraded products (C4M, MMP-
2/9 degraded type IV collagen; C5M, MMP-2/9 degraded
type V collagen; PRO-C3, neoepitope specific propeptide of
type III collagen formation) were measured in peripheral blood
by ELISA PRO-C3 Results: HVPG showed strong and significant
correlations with FIB4-Score (rs=0.628; p=7*10-7). PRO-C3
significantly correlated with HVPG (rs=0.354; p=0.02), ala-
nine aminotransferase (rs=0.30; p=0.038), as well as with
FIB4-Score (rs=0.3230; p=0.035). C4M and C5M levels were
higher in patients with PHT. Conclusion: PRO-C3-levels reflect-
ing true type III collagen formationcorrelated to hepatic injury,
liver fibrosis stage, and PHT in HIV/HCV-co-infected patients.
Furthermore, C4M and C5M were associated with increased
portal pressure in HIV/HCV coinfection. Circulating markers of
hepatic ECM remodeling might be helpful in the diagnosis and
monitoring of liver disease severity and PHT in patients with
HIV/HCV coinfection.
Disclosures:
Diana J. Leeming - Employment: Nordic Bioscience
Mattias Mandorfer - Consulting: Janssen; Grant/Research Support: MSD, Roche;
Speaking and Teaching: Janssen, Roche, Bristol-Myers Squibb, Boehringer Ingel-
heim
Inger Byrjalsen - Employment: Nordic Bioscience A/S
Morten A. Karsdal - Stock Shareholder: Nordic Bioscience
Christian P. Strassburg - Advisory Committees or Review Panels: Novartis, Roche;
Speaking and Teaching: Novartis, Merz, MSD, Falk Pharma, BMS, Abbvie
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Jürgen K. Rockstroh - Advisory Committees or Review Panels: Abbvie, BI, BMS,
Merck, Roche, Tibotec, Abbvie, Bionor, Tobira, ViiV, Gilead, Janssen; Consult-
ing: Novartis; Grant/Research Support: Merck; Speaking and Teaching: Abbott,
BI, BMS, Merck, Roche, Tibotec, Gilead, Janssen, ViiV
Markus Peck-Radosavljevic - Advisory Committees or Review Panels: Bayer, Gil-
ead, Janssen, BMS, AbbVie; Consulting: Bayer, Boehringer-Ingelheim, Jennerex,
Eli Lilly, AbbVie; Grant/Research Support: Bayer, Roche, Gilead, MSD; Speak-
ing and Teaching: Bayer, Roche, Gilead, MSD, Eli Lilly
Thomas Reiberger - Grant/Research Support: Roche, Gilead, MSD, Phenex;
Speaking and Teaching: Roche, Gilead, MSD
The following people have nothing to disclose: Christian Jansen, Robert Schi-
erwagen, Philipp Schwabl, Evrim Anadol, Søren Møller, Flemming Bendtsen,
Aleksander Krag, Jonel Trebicka
448
Longitudinal hepatic and PBMC gene expression profil-
ing of HIV and/or HCV-infected patients with advanced
liver disease treated with simtuzumab, an anti-LOXL2
antibody
Eric G. Meissner1, Mary McLaughlin1, Lindsay A. Matthews1, Bit-
too Kanwar2, Jeffrey D. Bornstein2, Joseph A. Kovacs1, Shyam
Kottilil1, Caryn G. Morse1; 1NIH/NIAID, Bethesda, MD; 2Gilead
Sciences, Foster City, CA
Lysyl oxidase-like 2 (LOXL2) is an extracellular matrix enzyme
that promotes cross-linking of type-1 collagen and whose levels
in serum correlate with extent of hepatic fibrosis. An ongo-
ing phase 2 clinical trial is evaluating the safety and efficacy
of simtuzumab (SIM), a humanized monoclonal antibody that
inhibits LOXL2 enzymatic activity, in HIV and/or HCV-infected
adults with advanced liver fibrosis (Ishak fibrosis score 3-6).
Study participants receive SIM 700 mg IV every 2 weeks for
24 weeks. To explore the effect of treatment on transcriptional
profiles, we performed gene expression analysis of paired pre-
and post-treatment liver biopsies and whole blood obtained
from 12 participants who have completed all infusions: 2 with
HIV and non-alcoholic steatohepatitis, 5 with HCV mono-infec-
tion, and 5 with HIV/HCV co-infection. On pre-treatment liver
biopsies, 6 of these 12 patients had an Ishak fibrosis score
of 5-6, 3 had a hepatic venous pressure gradient of ≥ 12,
and the group median ALT was 84. Total RNA was extracted
from liver tissue stored in RNAlater and whole blood stored in
PAXgene RNA tubes. Transcriptional profiling was performed
using the Affymetrix Human ST 2.0 Gene Array. Application
of low stringency cutoffs (fold change >1.25 and unadjusted
p-value of <0.05) identified 1,217 differentially expressed
genes in liver and 549 genes in blood; only 24 genes were
represented in both datasets. Ingenuity Pathway Analysis (IPA)
of hepatic gene expression identified TGF-β signaling as differ-
entially regulated with treatment, with predicted activation of
TGF-β3 and IL-10 pathways. The Disease and Biological Func-
tion analysis predicted reduced activity of fibrosis and insulin
resistance pathways. Modulation of these pathways was not
observed in the whole blood transcriptome analysis. Conclu-
sions: LOXL2 inhibition with SIM is associated with modulation
of transcriptional pathways implicated in hepatic fibrosis. Fur-
ther exploration of these pathways may contribute to a better
understanding of mechanisms of fibrosis and impact of treat-
ment with SIM. Larger clinical trials are required to evaluate the
utility of LOXL2 inhibition with SIM on reversal of fibrosis from
various etiologies.
Disclosures:
Bittoo Kanwar - Employment: Gilead Sciences
Jeffrey D. Bornstein - Employment: Gilead Sciences
The following people have nothing to disclose: Eric G. Meissner, Mary McLaugh-
lin, Lindsay A. Matthews, Joseph A. Kovacs, Shyam Kottilil, Caryn G. Morse
421A
449
Aspirin Use is Associated with Lower Liver Fibrosis Indi-
ces among Adults in the United States
Zhenghui G. Jiang1, Linda Feldbrügge1,3, Elliot B. Tapper1, Yury
Popov1, Tahereh Ghaziani1, Simon C. Robson1, Kenneth Muka-
mal2; 1Gastroenterology and Hepatology, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, MA; 2General
Medicine and Primary Care, Beth Israel Deaconess Medical Cen-
ter, Harvard Medical School, Boston, MA; 3Surgery, University
Hospital Leipzig, Leipzig, Germany
Background: The antiplatelet and anti-inflammatory properties
of aspirin have been widely exploited in the management of
cardiovascular diseases. Our preliminary studies in animal
models suggest that platelets potentially promote liver injury
and fibrosis. This raises the question of whether aspirin could
be used to reduce or prevent liver fibrosis. Methods: We con-
ducted a population-based cross-sectional study of 14,407 US
adults from the National Health and Nutrition Examination Sur-
vey III (NHANES III). We investigated the associations between
the use of aspirin, ibuprofen (an control NSAID without signif-
icant antiplatelet activities) and liver fibrosis measured by four
non-invasive indices: FIB4, NFS, APRI and Forns. Results: The
use of aspirin was associated with significantly lower scores of
liver fibrosis measured by all four indices, after adjustment for
confounders (Table 1). In comparison, no associations were
seen with ibuprofen use. We hypothesized that if there was a
causal link between aspirin use and decreased liver fibrosis,
the effect size would be larger among people with chronic liver
diseases. When compared to individuals without substantial
risk factors for chronic liver diseases, the inverse association
of aspirin use with fibrosis indices was 16 times (16.1 ± 10.8)
larger among those individuals with viral hepatitis B or C and
3 times (2.9 ± 0.4 and 2.8 ± 0.9) larger among heavy alcohol
users and individuals with hepatic steatosis on liver ultrasound.
Conclusions: The use of aspirin, but not ibuprofen, is associ-
ated with lower indices of liver fibrosis among US adults; espe-
cially among those with or at risk for chronic liver diseases. The
role of aspirin warrants further investigation for prevention and
treatment of liver fibrosis.
The association between aspirin / ibuprofen use and liver fibrosis
indices
Multivariate regression models are adjusted for age, gender, eth-
nicity, BMI, smoking, alcohol history, income poverty index, his-
tories of coronary artery disease, stroke, diabetes, hypertension,
arrhythmia and hepatic steatosis.
Disclosures:
Yury Popov - Consulting: Gilead Sciences, Inc; Grant/Research Support: Gilead
Sciences, Inc
Simon C. Robson - Grant/Research Support: Pfizer, NIH; Independent Contrac-
tor: eBioscience, Biolegend, EMD Millipore, Mersana; Speaking and Teaching:
ACP, Elsevier, ATC; Stock Shareholder: Nanopharma, Puretech
The following people have nothing to disclose: Zhenghui G. Jiang, Linda Feld-
brügge, Elliot B. Tapper, Tahereh Ghaziani, Kenneth Mukamal
422A AASLD ABSTRACTS
450
Fibrosis regression in hepatitis C patients with cirrho-
sis: Ishak fibrosis score and CPA pre treatment predict
regression post sustained virological response
Paolo Nieddu1,2, Ameet Dhar2, Robert D. Goldin3, Nimzing
Ladep2, Sarosh Khan2, Mark R. Thursz2, Ashley S. Brown2; 1Med-
icine, Gastroenterology Section, Università di Cagliari, Cagliari,
Italy; 2Medicine, Hepatology Section, Imperial College, London,
United Kingdom; 3Histopatology, Imperial College, London, United
Kingdom
Background and aims: Evidence in Hepatitis B patients with
cirrhosis suggests fibrosis can regress following virological
suppression. No study has investigated the factors associated
with fibrosis regression in HCV related cirrhosis following a
sustained virological response (SVR). We aimed to identify the
factors associated with regression of fibrosis in HCV cirrhotics
following SVR. Methods: HCV patients with histological proven
cirrhosis, who had undergone a SVR were enrolled (n=45).
Transient elastography was performed to estimate liver stiffness
measurements (LSM) at an average interval of 61.3 months (11-
130 months) after completion of treatment. A LSM cut off of <
7.9 kPa was used to indicate presumed fibrosis regression, and
< 4.9 kPa to indicate presumed fibrosis resolution. Each sub-
ject’s pre-treatment liver biopsy was analysed for Collagen Pro-
portionate Area (CPA) and for percentage alpha-smooth muscle
actin (%ASMA) expression. Results: 57.7%(26/45) of patients
demonstrated presumed fibrosis regression, 12.5%(6/45) pre-
sumed fibrosis resolution and 42.3%(19/45) no presumed
fìbrosis regression. Patients with presumed fibrosis regression
had a significantly lower mean CPA (9.6+/-1 .12vs 18.0+/-
1.23; p=0.0001) and mean %ASMA expression (10.86%+/-
1.44 vs 18.73+/-1.61; p=0.001) on pre-treatment biopsies
than patients with no presumed regression. Ishak fibrosis score
5 was significantly more likely to result in presumed fibrosis
regression (93.3%vs 39.3%; p= 0.008) compared to Ishak
score 6. Conclusions: In HCV cirrhotics with a SVR, pre-treat-
ment Ishak fibrosis stage, CPA and %ASMA expression predict
fibrosis regression using LSM. These parameters may be used
to stratify patients at risk of remaining cirrhotic post SVR, in
order to prioritise patients for therapy with the new interferon
free regimens.
Disclosures:
Mark R. Thursz - Advisory Committees or Review Panels: Gilead, BMS, Abbott
Laboratories
Ashley S. Brown - Advisory Committees or Review Panels: MSD, Roche, Bris-
tol-Myers-Squibb, Gilead, Janssen, Abbvie, Achillion; Speaking and Teaching:
MSD, Roche, Bristol-Myers Squibb, Gilead, Janssen, Abbvie
The following people have nothing to disclose: Paolo Nieddu, Ameet Dhar, Rob-
ert D. Goldin, Nimzing Ladep, Sarosh Khan
451
Assessment of regression of fibrosis using Fibroscan® in
patients with chronic hepatitis B receiving antiviral treat-
ment beyond 5 years
Young Eun Chon1, Myung Sung Min2, Kyu Sik Jung1, Kwang-Hyub
Han1, Seung Up Kim1, Do Young Kim1, Sang Hoon Ahn1, Jun
Yong Park1; 1Department of Internal Medicine, Yonsei university
college of medicine, Seoul, Republic of Korea; 2Department of
Biostatics, Jungwon University, Seoul, Republic of Korea
Background: The association between suppression of hepatitis
B virus replication on regression of liver fibrosis has been previ-
ously reported, however, performing liver biopsy to assess the
fibrotic burden is impractical. We aimed to evaluate the long-
term assessment of fibrosis regression by serial liver stiffness
(LS) measurement using Fibroscan® during antiviral treatment,
HEPATOLOGY, October, 2014
and to investigate the predictors for persistent fibrosis regres-
sion. Methods: Between March 2006 and April 2010, we
prospectively enrolled chronic hepatitis B (CHB) patients who
underwent LS measurement and liver biopsy before starting
nucleot(s)ide analogues and showed histologically moderate
to severe inflammation or significant fibrosis, with a high viral
loads [HBV DNA≥2,000 IU/mL]. After starting antiviral treat-
ment, annual LS measurement for 5 years or further during anti-
viral treatment was performed. Significant fibrosis regression
was defined as a ≥ 30% drop of LS value from the baseline,
and persistent fibrosis regression was defined as significant
fibrosis regression identified in three consecutive measurements
performed in Year 3, 4, and 5. Results: A total of 120 patients
received antiviral treatment and annual LS measurement for
5 years. At baseline, the median LS value was 12.1 dB/m,
and 89 (74.2%) patients showed F4 fibrosis (cirrhosis) on liver
biopsy. During 5 years of antiviral treatment, the median LS
value significantly decreased as years go by (10.3 dB/m at
Year 1; 9.0 dB/m at Year 2; 8.6 dB/m at Year 3; 7.3 dB/m at
Year 4; and 6.9 dB/m at Year 5; P<0.001). Significant fibrosis
regression was identified in 30.0%, 48.3%, 54.2%, 65.0%,
and 60.8% patients at Year 1,2,3,4, and 5, respectively,
and persistent fibrosis regression was present in 56 (46.7%)
patients. Multivariate analyses identified a higher baseline LS
value as a predictor for persistent fibrosis regression (P<0.001;
hazard ratio, 1.186; 95% confidence interval, 1.091–1.290).
Conclusion: In patients with CHB receiving long-term antiviral
treatment, the annual LS measurement revealed that fibrosis
regression slows down but continues during treatment. Baseline
fibrotic burden represented as LS value is a single independent
predictor for persistent fibrosis progression.
Disclosures:
The following people have nothing to disclose: Young Eun Chon, Myung Sung
Min, Kyu Sik Jung, Kwang-Hyub Han, Seung Up Kim, Do Young Kim, Sang Hoon
Ahn, Jun Yong Park
452
Development of Novel Lipidnanoparticle siRNA Delivery
System Targeting Collagen Chaperone Protein HSP47
for Clinical Treatment of Liver Fibrosis
Wenbin Ying1, Jun Zhang1, Yun Liu1, Li Wang1, Jihua Liu1, Jian
Liu1, Jingyuan Yu1, Jean-Pierre Clamme1, Jiping Yao1, Lishuang
Xu1, Donald A. Kaiser1, Yasunobu Tanaka2, Miyono Miyazaki2,
Keiko Kajiwara2, Kenjiro Minomi2, Yoshiro Niitsu3; 1Molecular
Therapeutic, Nitto Denko Technical Corporation, Oceanside, CA;
2Hokkaido Laboratory-MTD, Hokkaido University, Sapporo, Japan;
3Molecular Target Exploration, Sapporo Medical University School
of Medicine, Sapporo, Japan
HSP47 is a unique gene target in the collagen-mediated fold-
ing pathway leading to the formation of liver fibrosis. Strategy
of using siRNA targeting HSP47 for liver fibrosis treatment
was first reported by Sato et al. (2008). Since this prototype
formulation is not applicable for clinical use, proprietary lipid
nanoparticle formulation, ND-L02-s0201, were developed to
encapsulate modified HSP47 siRNA incorporating vitamin
A-derivative targeting components. Pre-clinical efficacy studies
showed dose-dependent HSP47 gene knockdown from both
in vitro transfection in activated primary rat HSC and single
dose intravenous administration in quick dimethylnitrosamine
(DMN) induced liver damage model. In vivo pharmacology
evaluation in chronic DMN induced rat liver fibrosis models
showed that 1x/week treatments for 5 weeks improved over-
all animal health condition as reflected by improved survival
and body weight. Specific evaluation of liver fibrosis parame-
ters including hepatic hydroxyproline levels, image-quantified
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS 423A

Sirius Red staining, semi-quantitative histopathology score of

liver fibrosis following H&E staining and Trichrome staining
all provided strong evidence of collagen deposition reduction
and liver fibrosis resolution. GLP-toxicological studies in non-hu-
man primate showed a >20-fold safety margin with no signif-
icant adverse effect. Phase I clinical trial has been completed
in 66 healthy individuals in U.S. for single-dose escalation
study evaluating the safety, tolerability, and pharmacokinetics
of ND-L02-s0201 injection. The escalation study successfully
reached the highest planned dose at 0.8 mg/kg (concentration
based on siRNA NDT-05-0038) with no steroid-based premed-
ication applied. All doses were well tolerated with no adverse
effect noted during clinical observation.
Disclosures:
Wenbin Ying - Management Position: Nitto Denko Technical Corporation
The following people have nothing to disclose: Jun Zhang, Yun Liu, Li Wang, Disclosures:
Jihua Liu, Jian Liu, Jingyuan Yu, Jean-Pierre Clamme, Jiping Yao, Lishuang Xu, Philip Wong - Advisory Committees or Review Panels: merck, roche, gilead;
Donald A. Kaiser, Yasunobu Tanaka, Miyono Miyazaki, Keiko Kajiwara, Kenjiro Grant/Research Support: merck, roche, gilead, vertex
Minomi, Yoshiro Niitsu
Marc Deschenes - Advisory Committees or Review Panels: Merk, gilead, vertex,
janssen, roche
Giada Sebastiani - Advisory Committees or Review Panels: Boheringer Ingelheim,
453 Roche, Novartis; Grant/Research Support: ViiV, Vertex; Speaking and Teaching:
Merck, Gilead, Echosens
Subclinical cirrhosis diagnosed by transient elastogra- The following people have nothing to disclose: Tianyan Chen, Remy E. Wong,
phy demonstrates increased risk of severe clinical out- Kathleen C. Rollet-Kurhajec, Rasha Alshaalan, Peter Ghali
comes and HCC
Tianyan Chen, Remy E. Wong, Kathleen C. Rollet-Kurhajec, Rasha
Alshaalan, Philip Wong, Marc Deschenes, Peter Ghali, Giada 454
Sebastiani; Medicine, McGill University Health Centre, Montreal, Irbesartan for severe fibrosis in chronic hepatitis C: a
QC, Canada double-blind randomized trial (ANRS HC19 Fibrosar)
Background/Aims: Diagnosis of liver cirrhosis at pre-clinical Paul Cales1, Yannick Bacq2, Jean-Pierre Vinel3, Corinne Bonny4,
stage is challenging due to lack of any finding. We evaluated Jean-Louis Payen5, Dominique Guyader6, Albert Tran7, Dominique
outcomes of subclinical cirrhosis (SC) diagnosed by transient G. Larrey8, Christine Silvain9, Marie Christine Rousselet1, Fred-
elastography (Fibroscan). Methods: Patients with chronic liver eric Oberti1, Mélanie Simony9, Fabrice Carrat10; 1Hepatology
disease (CLD) and a valid Fibroscan were divided into: 1) Department, Centre Hospitalier Universitaire d’ Angers, Angers
SC (Fibroscan ≥13kPa and no thrombocytopenia, nor signs Cedex 9, France; 2Hepatology Department, CHU, Tours, France;
of advanced liver disease on ultrasound or endoscopy); 2) 3Hepatology Department, CHU, Toulouse, France; 4Hepatology
non-cirrhotic CLD (Fibroscan <13kPa). Patients with Fibroscan Department, CHU, Clermont-Ferrand, France; 5Hepatology Depart-
≥13kPa and signs of advanced liver disease were excluded. ment, CHG, Montauban, France; 6Hepatology Department, CHU,
We used multivariate logistic regression analysis for factors Rennes, France; 7Hepatology Department, CHU, Nice, France;
associated with baseline SC. Incidence of severe outcomes 8Hepatology Department, CHU, Montpellier, France; 9Inserm-
(HCC, variceal bleeding, ascites) and any outcome (severe ANRS, Paris, France; 10INSERM Unit 444, Université Pierre et
outcomes, thrombocytopenia, ultrasonographic or endoscopic Marie Curie, Paris, France
signs) was computed. Multivariate Cox proportional hazard
Introduction. Fibrosis regression is a major target in chronic
models adjusted for age, sex, HIV coinfection, diabetes and SC
liver disease treatment. In chronic hepatitis C (CHC), fibrosis
were used. Results: 702 patients (median age 49 years, 60%
may not regress even after successful treatment. Angiotensin
male) were included in 2010-2013. 101 (14%) had SC, 601
II type 1 receptor antagonists (ARA2) have shown anti-fibrotic
(86%) had non-cirrhotic CLD. Histology was available for 25%
properties in numerous pre-clinical and clinical studies. A small
of SC patients and 65% of them had advanced fibrosis or cir-
randomized ARA2 trial showed a significant decrease in fibro-
rhosis. Factors associated with SC at baseline were older age
sis area (Kim Liver Int 2012). We thus evaluated ARA2 admin-
(OR=1.1; 95% CI 1.0-1.3), HIV co-infection (OR=3.5; 1.8-6.8)
istration in CHC. Methods. 166 patients with CHC and Metavir
and higher APRI (OR=2.6; 1.9-3.7). Over 726 person-years
F stages 2 or 3 were allocated to receive either irbesartan (I)
(PY) of follow-up, incidence rate of any outcome was higher in
150 mg/d or a placebo (P) per os for 2 years in 27 centers.
those with SC (10.4/100 PY; 95% CI 4.3-16.6) compared to
The study started in October 2006 and ended in April 2013.
those with non-cirrhotic CLD (2.9/100 PY; 1.6-4.2). Incidence
All patients had contraindications for or refused IFN-based reg-
rate of severe outcomes was 3.5/100 PY (0.1-6.9) in SC and
imens. The patients had clinical evaluation, liver biopsy, and
0 in non-cirrhotic CLD group. SC was associated (HR=3.2; 1.4-
non-invasive fibrosis tests (blood and stiffness) at inclusion and
7.2) with progression to outcomes. Figure 1 depicts survival
end of follow-up. Liver biopsies were centrally evaluated with
curve of progression to outcomes by SC status. Conclusions:
Metavir staging by expert consensus and detailed automated
SC has a distinct clinical course, including risk of HCC. Screen-
morphometric measures including 44 descriptors, among
ing of CLD patients by Fibroscan may help early identification
which was porto-septal fibrosis area (main judgment criteria),
of those with SC who need surveillance and specific therapy.
to obtain morphometric scores for significant fibrosis (SF) and
cirrhosis (F4). Follow-up visits were planned at 1, 3 and every
6 months. Results. Baseline characteristics were: 58% male,
age 56±9 yrs. Treatment groups were well balanced except
for Metavir F at central reading, P vs I respectively, F1: 4.9
vs 1.2%, F2: 75.6 vs 63.1%, F3: 17.1 vs 33.3%, F4: 2.4 vs
424A AASLD ABSTRACTS
2.4% (p=0.048); this was also suggested by morphometric F4
score: 0.13±0.30 vs 0.16±0.31, p=0.07. Paired liver biop-
sies were available in 79% of patients but analyzed in ITT.
Changes in morphometry were, P vs I respectively: porto-septal
fibrosis area: 0.43±2.19 vs 0.26±2.40%, p=0.73; morpho-
metric SF score: 0.02±0.28 vs 0.02±0.25, p=0.75; morpho-
metric F4 score: 0.08±0.36 vs 0.07±0.36, p=0.20. There was
an interaction (p=0.002) between treatment and fibrosis stage
in F4 score with opposite treatment effects between F1+F2
(0.12±0.29 vs 0.03±0.25, p=0.04) and F3+F4 (-0.07±0.55
vs 0.15±0.49, p=0.24). The rates of Metavir progression/
regression (≥1F/≤1F) were, P vs I respectively: 12.1 vs 16.9%
/ 16.7 vs 14.8%, p=0.84. Changes in liver stiffness were,
1.5±5.1 vs 0.8±3.8 kPa, p=0.68. No serious adverse events
were attributed to treatment. Mean arterial pressure changes
were: -3.5 ± 11.3 vs -9.3 ± 17.0 mmHg, p=0.06. Conclusion.
A 2-year regimen of Irbesartan 150 mg/d did not significantly
alter the course of liver fibrosis pathological patterns in CHC,
even as assessed by precise morphometry. However, anti-fi-
brotic effect might depend on baseline fibrosis level, as already
suggested.
Disclosures:
Paul Cales - Consulting: BioLiveScale
Yannick Bacq - Speaking and Teaching: roche, gilead sciences, bristol-Myers
Squibb
Jean-Pierre Vinel - Grant/Research Support: Roche, Gore, LFB
Dominique Guyader - Advisory Committees or Review Panels: ROCHE, GILEAD,
IRIS, ABBVIE; Board Membership: MERCK; Grant/Research Support: JANSSEN;
Speaking and Teaching: BMS
Albert Tran - Board Membership: BMS, Gilead
Dominique G. Larrey - Board Membership: ROCHE GENE, MSD, TIBOTEC/
JANSSEN, ABBOTT, BOEHRINGER, BMS, GILEAD; Consulting: BAYER, SANOFI,
PFIZER, SERVIER-BIG, AEGERION, MMV, BIAL-QUINTILES, TEVA, ORION, NEG-
MA-LERADS, ASTELLAS; Grant/Research Support: Roche, Boehringer, BMS, GIL-
EAD; Independent Contractor: ABBOTT
Frederic Oberti - Speaking and Teaching: LFB, gore
Fabrice Carrat - Consulting: BMS
The following people have nothing to disclose: Corinne Bonny, Jean-Louis Payen,
Christine Silvain, Marie Christine Rousselet, Mélanie Simony
455
Improvements in APRI and FIB-4 fibrosis scores correlate
with decreases in sCD14 in HIV-1 infected adults receiv-
ing cenicriviroc over 48 weeks
Melanie Thompson1, Will Chang2, Helen Jenkins2, Amy Flynt3,
Millie Gottwald2, Eric Lefebvre2; 1AIDS Research Consortium of
Atlanta, Atlanta, GA; 2Tobira Therapeutics, Inc., South San Fran-
cisco, CA; 3PharPoint Research, Inc., Durham, NC
Background: Cenicriviroc (CVC), a novel, oral, once-daily C-C
chemokine receptor type 2 and 5 (CCR2/CCR5) antagonist,
has demonstrated favorable safety and anti-HIV activity in clin-
ical trials. CVC demonstrated antifibrotic activity in two animal
models of liver disease. Post-hoc analyses were conducted on
APRI and FIB-4 scores in Study 202 (NCT01338883). Meth-
ods: 143 adults with CCR5 tropic HIV-1, body mass index
≤35kg/m2 and no apparent liver disease (ie, ALT/AST Grade
≤2, total bilirubin ≤upper limit of normal, no HBV, HCV, active
or chronic liver disease, or cirrhosis) were randomized 4:1 to
CVC or efavirenz (EFV). APRI and FIB-4 scores were calculated.
Change in score category from baseline to Weeks 24 and
48 was assessed in patients with non-missing data. Correla-
tions between changes from baseline in APRI and FIB-4 scores,
and monocyte chemotactic protein-1 (MCP-1; CCR2 ligand)
and sCD14 (inflammatory biomarker) levels were evaluated.
Results: At baseline, more patients on CVC than EFV had APRI
≥0.5 and FIB-4 ≥1.45; proportion of CVC patients above these
HEPATOLOGY, October, 2014
thresholds decreased at Weeks 24 and 48 (Table). Significant
correlations were observed at Week 24 between changes in
APRI score and MCP-1 levels (p=0.014), and between FIB-4
score and sCD14 levels (p=0.011), and at Week 48, between
changes in APRI (p=0.028) and FIB-4 scores (p=0.007) and
sCD14 levels. Conclusions: In this population with no apparent
liver disease, CVC treatment was associated with improve-
ments in APRI and FIB-4 scores, and correlations were observed
between changes in APRI and FIB-4 scores and sCD14 levels at
Week 48. Proven CCR2/CCR5 antagonism, antifibrotic effects
in animal models and extensive clinical safety data all support
clinical studies of CVC in liver fibrosis.
Disclosures:
Melanie Thompson - Advisory Committees or Review Panels: Janssen/Tibotec
Therapeutics (Data Safety Monitoring Board), Viiv Healthcare (Data Safety Mon-
itoring Board); Grant/Research Support: Bristol Myers Squibb, Inc. (via AIDS
Research Consortium of Atlanta), Gilead Sciences (via AIDS Research Consor-
tium of Atlanta), Geovax, Inc. (via AIDS Research Consortium of Atlanta), Kowa
Research Institute (via AIDS Research Consortium of Atlanta), Pfizer Inc. (via
AIDS Research Consortium of Atlanta), Janssen/Tibotec Therapeutics (via AIDS
Research Consortium of Atlanta), Merck & Co. (via AIDS Research Consortium
of Atlanta), Tobira Therapeutics (via AIDS Research Consortium of Atlanta), Viiv
Healthcare (via AIDS Research Consortium of Atlanta)
Will Chang - Employment: Tobira Therapeutics Inc.
Helen Jenkins - Employment: Tobira Therapeutics, Inc.
Millie Gottwald - Stock Shareholder: Gilead Sciences, Alexza Pharmaceuticals
Eric Lefebvre - Employment: Tobira Therapeutics Inc., San Francisco, CA, USA
The following people have nothing to disclose: Amy Flynt
456
A 6-Gene Score Associated With Advanced Stages of
Presymptomatic HBV Related Fibrosis
Mingyi Xu, Ying Qu, Qingqing Zhang, Lungen Lu; Shanghai First
People’s Hospital, Shanghai Jiao Tong University School of Medi-
cine, Shanghai, China
Background & aims: HBV related liver fibrosis (HRLF) has been
shown to involve complex interactions in genomics. Methods:
143 patients were divided into 3 groups including control,
Fibrosis and HCC. Affymetrix GeneChip was used. Genome
data analysis was obtained by GeneSpring GX software, Sig-
nificant Analysis of Microarray (SAM) and Prediction Analysis
of Microarray (PAM). Then qRT-PCR was used to verify predic-
tor genes. Results: The expression pattern of 678 significant
genes identified by SAM showed different feature in significant
HRLF (≥S2). A subset of 18 predictor genes, which were iden-
tified by PAM, was defined to have “Fibrotic Risk” signature of
HRLF. Six predictor genes were differentially expressed among
S4, S1-S3 and S0 group (Figure 1). AUROCs of 6 genes
were 0.85-0.88 in diagnosing significant HRLF (≥S2). Total 6
predictor genes including CD24, CXCL6, EHF, ITGBL1, LUM
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
and SOX9 were found to have AUROCs among 0.90-0.96
in discriminating cirrhosis. Univariate logistic regression anal-
ysis also identified their expression in liver tissue associated
with cirrhosis. Conclusions: These findings provide a molecular
portrait of genomes in HRLF. A set of 6 “Fibrotic Risk” genes
are promising predictors for diagnosis of advanced stages of
presymptomatic HBV related fibrosis.
Disclosures:
The following people have nothing to disclose: Mingyi Xu, Ying Qu, Qingqing
Zhang, Lungen Lu
457
Localizations and functional roles of MMP-1 in the early
and advanced stages of human non-alcoholic steato-
hepatitis
Hiroaki Yokomori1, Isao Okazaki2, Masaya Oda3, Wataru Ando4,
Yutaka Suzuki5, Tsutsui Nobuhiro5, Eigoro Yamanouchi6, Hajime
Kuroda7, Soichi Kojima8, Mitsuko Hara8, Yutaka Inagaki9; 1Inter-
nal Medicine, Kitasato University Medical Center, Saitama, Japan;
2Internal Medicine and Clinical Laboratory, International University
Hospital of Health and Welfare, Tochigi, Japan; 3Internal Medicine,
Sanno Medical Center and International University of Health and
Welfare, Tokyo, Japan; 4Department of Pharmaceutical Science,
Kitasato University, tokyo, Japan; 5Surgery, International University
of Health and Welfare, Tochigi, Japan; 6Radiology, International
University of Health and Welfare, Tochigi, Japan; 7Pathology,
International University of Health and Welfare, Tochigi, Japan;
8Riken Advanced Science Institute, Saitama, Japan; 9Department
of Regenerative Medicine, Tokai University School of Medicine
and Institute of Medical Sciences, Isehara, Japan
Backgrounds & aims: Although a certain population of patients
with non-alcoholic fatty liver disease develops non-alcoholic ste-
atohepatitis (NASH) and cirrhosis with/without hepatocellular
carcinoma, its underlying mechanisms are virtually unknown.
Portal veinous blood in NASH patients contains high levels of
sugar, lipids and amino acids, and hepatic sinusoidal endo-
thelial cells (HSECs) play as a gate-keeper to prevent hepato-
cyte injury. CapillaryECs have lots of caveolae on their surface
where caveolin(CAV)-1 works as a signal transduction center.
The present study aimed at elucidating the functional contribu-
tion of CAV-1 and the fibrosis-relating enzymes such as MMP-1
and TGF-β to the pathophysiology of NASH. Methods: Twen-
ty-six histologically proven NASH patients including three cases
with NASH-derived HCC, and normal liver specimens obtained
from 5 patients with metastatic liver cancer were enrolled. The
study was approved by the ethical committees, and the written
consent was obtained from the all patients. CAV-1, MMP-1,
latent form and active form of TGF-β were stained by immu-
425A
nohistochemistry (IHC) and immunoelectron microscopy (IEM).
To discriminate cells expressing CAV-1, MMP-1, and TGF-β,
dual staining with CD68, CD34, vimentin/α-SMA, and CK19
and OV-6 was used as a marker of Kupffer cells (KCs), capil-
lary endothelial cells, hepatic stellate cells (HSC), and hepatic
progenitor cells (HPCs), respectively. Results: In an early stage
of NASH, co-localization of CAV-1 and MMP-1 was demon-
strated by IEM predominantly in KC, HSE and HSC, suggesting
activation of those cells in the progression of NASH. Consistent
with these findings, IHC revealed that expression of type I pro-
collagen and the active form of TGF-β were observed around
the cells with ballooning injury. In contrast, IHC and IEM exam-
ination of liver specimens obtained from the advanced stage
of NASH patients revealed remarkable expression of CAV-1
and MMP-1 in proliferating HPCs that were stained positive for
CK19 or OV-6. Type I procollagen was observed at the edge
of proliferating capillary endothelial cells closed to the ductular
proliferation stained positive for OV-6 suggesting the formation
of fibrous tissue. The sprouriting capillary ECs with MMP-1 on
the caveolae along the luminal and abluminal portions of cell
membrane, suggest the functional role of MMP-1 in angiogene-
sis. Conclusions: In an early stage of NASH, MMP-1 expressed
in KC/HSEC/HSC participates in the progression of disease.
In contrast, it may contribute to the repair and regeneration
of injured sinusoidal structure through the caveolae signal net-
work in the advanced stage of NASH.
Disclosures:
The following people have nothing to disclose: Hiroaki Yokomori, Isao Okazaki,
Masaya Oda, Wataru Ando, Yutaka Suzuki, Tsutsui Nobuhiro, Eigoro Yamanou-
chi, Hajime Kuroda, Soichi Kojima, Mitsuko Hara, Yutaka Inagaki
458
Increased autophagy is associated with ductular reac-
tion in human cirrhotic livers
Tzu-Min Hung1,2, Po-Huang Lee1,3; 1Department of Surgery,
National Taiwan University Hospital, Taipei, Taiwan; 2Department
of Medical Research, E-DA Hospital, Kaohsiung, Taiwan; 3Depart-
ment of Surgery, E-DA Hospital, Kaohsiung, Taiwan
Autophagy is a lysosomal degradation mechanism that has
been implicated in chronic liver diseases. An association
between activated autophagy and hepatic fibrogenesis has
been demonstrated in mouse models. This study aimed to verify
whether altered autophagy plays a role in human cirrhotic
livers. Surgical specimens were obtained from donor livers
(normal controls), non-cirrhotic portions of livers from patients
with hepatocellular carcinoma and from cirrhotic livers. The
expression of autophagy-related LC3B was analyzed using
immunostaining, Western blotting and quantitative real-time
polymerase chain reaction (RT-PCR). Compared with non-cir-
rhotic livers, patients with cirrhotic livers had increased LC3B
mRNA and protein levels. Additionally, elevated autophagic
activity assessed via the colocalization of LC3B with lyso-
some-associated membrane protein-1 (LAMP-1) was observed
in the cirrhotic livers. Furthermore, using double immunostain-
ing, we found that autophagy was increased in the cytoker-
atin 19 (CK19)-labeled ductular reactions, and we identified
a significantly positive correlation between LC3B and CK19
expression levels. Conclusion: autophagy is upregulated in
human cirrhotic livers, correlating with the degree of ductular
reaction and fibrosis severity. Therefore, it is reasonable that
targeting autophagy may have therapeutic value for patients
with cirrhosis of the liver.
Disclosures:
The following people have nothing to disclose: Tzu-Min Hung, Po-Huang Lee
426A AASLD ABSTRACTS
459
The hitch with non-invasive tests of liver fibrosis: eval-
uated by binary AUROC but used with stage classifica-
tions
Paul Cales1, Jerome Boursier1, Isabelle Fouchard-Hubert1, Fred-
eric Oberti1, Victor de Ledinghen2, Vincent Leroy3; 1Hepatology
Department, Centre Hospitalier Universitaire d’ Angers, Angers
Cedex 9, France; 2Hepatology Department, CHU, Bordeaux,
France; 3Hepatology Department, CHU, Grenoble, France
Introduction. The performance of non-invasive tests of liver fibro-
sis is evaluated in publications and institutions by AUROC with
an obligatory binary target: significant fibrosis or cirrhosis.
However, this appears problematic since i) the fibrosis stage
is unknown before performing a non-invasive test, and thus the
test the best-adapted to the patient’s condition is unknown, and
ii) in clinical practice, clinicians use fibrosis stage classifications
reflecting pathological staging. However, these classifications
have never been comprehensively evaluated. Our aim was
thus to evaluate the diagnostic characteristics of classifications
used in clinical practice. Methods. 679 patients with chronic
hepatitis C were included in the study and had the following
examinations: liver biopsy (Metavir, morphometry), Fibrotest
(FT), FibroMeter (FM), CirrhoMeter (CM), Fibroscan (FS) and
Elasto-FM (EFM). For Fibroscan, we used a recent classification
(JCG 2014) that offers performance superior to that of diag-
nostic target cut-offs. Classifications were evaluated in terms
of accuracy and precision compared to Metavir reference:
correlation, concordance, mean difference in F stages between
tests and dispersion (number of F stages per class of the test
classification). Fibrosis classes were used with their median
numerical score (e.g. 1.5 for F1/2). Results. 1/ Accuracy: well
classified pts by classification: FT: 38.3%, FM: 84.1%, FS:
88.2%, CM: 83.2%, EFM: 91.7% (p<0.001). AUROC for sig-
nificant fibrosis (score/classification): FT: 0.782/0.766, FM:
0.821/0.802, FS: 0.802/0.782, CM: 0.799/0.774, EFM:
0.855/0.837. 2/ Precision: difference in F Metavir vs F clas-
sification: FT: 1.01±0.82, FM: 0.72±0.57, FS: 0.68±0.57,
CM: 0.75±0.59, EFM: 0.62±0.57 (p<0.001). Precision var-
ied according to age with a cut-off at 45 years. There was a
significant difference as a function of this cut-off between FT
and FS: FT upgraded F before 45 years: 0.15±1.20 but down-
graded it after: -0.47±1.27 (p<0.001); FS did the opposite:
-0.31±0.87 vs 0.02±0.88 (p<0.001). Correlations (Rs) of F
classifications with porto-septal fibrosis area were: Metavir:
0.687. FT: 0.409. FM: 0.489. CM: 0.464. FS: 0.536. EFM:
0.571. Conclusion. The binary performance of classifications
is slightly below but nonetheless close to that of scores, thus
they are robust. In contrast, the rate of well-classified patients
varied very significantly from 38 to 92% between tests. Classi-
fication precision was also significantly different between two
tests as a function of age. Combining a blood test with elasto-
metry cumulates the advantages of performance and precision.
Disclosures:
Paul Cales - Consulting: BioLiveScale
Isabelle Fouchard-Hubert - Speaking and Teaching: JANSSEN
Frederic Oberti - Speaking and Teaching: LFB, gore
Victor de Ledinghen - Advisory Committees or Review Panels: Merck, Janssen,
Gilead, BMS, Abbvie; Grant/Research Support: Gilead, Janssen; Speaking and
Teaching: AbbVie, BMS
Vincent Leroy - Board Membership: roche, merck, gilead, bms, roche, merck,
gilead, bms, roche, merck, gilead, bms, roche, merck, gilead, bms; Consulting:
jansen, jansen, jansen, jansen; Grant/Research Support: roche, gilead, bms,
roche, gilead, bms, roche, gilead, bms, roche, gilead, bms; Speaking and Teach-
ing: bms, merck, gilead, roche, bms, merck, gilead, roche, bms, merck, gilead,
roche, bms, merck, gilead, roche
The following people have nothing to disclose: Jerome Boursier
HEPATOLOGY, October, 2014
460
Hfe and hemojuvelin regulate hepcidin expression and
iron metabolism via the same pathway: Genetic evi-
dence from single and double knockout mice
Patricia Kent1, Nicole Wilkinson1, Marco Constante2, Konstan-
tinos Gkouvatsos1, John Wagner1, Manuela M. Santos2, Kostas
Pantopoulos1; 1Lady Davis Institute for Medical Research, McGill
University, Montreal, QC, Canada; 2Centre de Recherche, Centre
Hospitalier de l’Université de Montréal (CHUM), Montreal, QC,
Canada
Functional inactivation of HFE or hemojuvelin (HJV) is caus-
atively linked to adult or juvenile hereditary hemochromatosis,
respectively. Systemic iron overload results from inadequate
expression of hepcidin, the iron regulatory hormone. While
HJV regulates hepcidin by amplifying bone morphogenetic
protein (BMP) signaling, the role of HFE in the hepcidin path-
way remains enigmatic. We investigated the pathophysiolog-
ical implications of combined Hfe and Hjv ablation in mice.
Isogenic Hfe-/- and Hjv-/- mice were crossed to generate dou-
ble Hfe-/-Hjv-/- progeny. Wild type control and mutant mice
of all genotypes were analyzed for serum, hepatic and splenic
iron content, expression of liver hepcidin and BMP signaling,
in response to a normal or an iron-enriched diet. As expected,
Hfe-/- and Hjv-/- mice developed relatively mild or severe
iron overload, respectively, which correlated to the degree of
hepcidin inhibition. The double Hfe-/-Hjv-/- mice exhibited an
indistinguishable phenotype to single Hjv-/- counterparts with
regard to suppression of hepcidin, serum and hepatic iron
overload, splenic iron deficiency and BMP signaling, under
both dietary regimens. Conclusion. The hemochromatotic phe-
notype caused by disruption of Hjv is not further aggravated
by combined Hfe/Hjv deficiency. Our results provide genetic
evidence that Hfe and Hjv operate in the same pathway for the
regulation of hepcidin expression and iron metabolism.
Disclosures:
The following people have nothing to disclose: Patricia Kent, Nicole Wilkinson,
Marco Constante, Konstantinos Gkouvatsos, John Wagner, Manuela M. Santos,
Kostas Pantopoulos
461
Acute Intermittent Porphyria: High incidence of Patho-
genic HMB-Synthase (HMBS) Non-Synonymous SNPs
(nsSNPs) in Genomic Databases Suggests Other
Genetic/Environmental Factors Cause the Acute Attacks
Brenden Chen, Jörg Hakenberg, Ramakrishnan R. Srinivasan,
Dana O. Doheny, Inga Peter, Constanza Solis-Villa, Rong Chen,
David F. Bishop, Makiko Yasuda, Robert J. Desnick; Genetics and
Genomic Sciences, Mount Sinai School of Medicine, New York,
NY
Acute Intermittent Porphyria (AIP) is an autosomal dominant
hepatic porphyria due to the half-normal activity of the heme
biosynthetic enzyme, hydroxymethlbilane synthase (HMBS).
The disease is characterized by life threatening acute neuro-
visceral attacks, which are triggered by factors that induce the
up-regulation of hepatic 5’-aminolevulinic acid synthase. To
date, over 360 HMBS mutations that lead to acute attacks of
AIP have been reported in the Human Genome Mutation Data-
base (HGMD). The disease prevalence in Western Europe,
based on newly diagnosed patients with acute attacks (Elder
et al. J Inherit Metab Dis, 2013), ranges from 1 in 158,000
to 222,000. It is estimated that only 10% of AIP heterozygotes
have acute attacks. However, neither the frequency of patho-
genic HMBS mutations that markedly reduce enzyme activity
nor the actual disease penetrance is known. To estimate the
incidence of known and likely pathogenic HMBS mutations,
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
we searched the databases of the 1K Human Genome Project
and the NHLBI Exome Sequencing Project to identify nsSNPs in
various racial/ethnic populations. Thirteen nsSNPs were iden-
tified in Caucasians with allele frequencies from <0.001 to
0.28%, for a surprisingly high combined frequency of 0.73%
(1 in 137). Four (combined frequency of 0.44% or 1 in 230)
have been reported in HGMD as causing AIP acute attacks.
The remaining nine are novel, accounting for a combined
frequency of 0.28% (1 in 360). To determine their potential
pathogenicity, the novel mutations were analyzed by 18 in
silico programs. Of these, three nsSNPs were predicted as
deleterious (D65H, I71T, A122P), for a combined allele fre-
quency of 0.15% (1 in 670). Four nsSNPs (V237M, R246C,
I54L, S45L) were predicted to be tolerated, benign or likely
polymorphisms, while two nsSNPs (R246H and R355Q) had
equivocal predictions. All nsSNPs are being expressed in vitro
to determine which encode enzymes with markedly reduced
HMBS activity. In addition, efforts are directed to identify in
the dbGaP database possible disease phenotypes associated
with the pathogenic HMBS nsSNPs. Thus, the incidence of the
four known and three predicted pathogenic HMBS mutations in
Caucasians may be as high as 0.59% (1 in 170). The pene-
trance of this hepatic porphyria may be unusually low, even if
the frequency of pathogenic alleles is 1 in 103. As the preva-
lence of patients who have had acute attacks is ~ 1 in 20,000
in Sweden to ~1 in 200,000 in Western Europe, our results
suggest the importance of modifying genes and environmental
triggering factors causing the acute attacks.
Disclosures:
Makiko Yasuda - Patent Held/Filed: Alnylam Pharmaceuticals
Robert J. Desnick - Advisory Committees or Review Panels: Recordati Rare Dis-
eases; Consulting: Alnylam Pharmaceuticals; Grant/Research Support: Alnylam
Pharmaceuticals; Patent Held/Filed: Alnylam Pharmaceuticals; Stock Share-
holder: Alnylam Pharmaceuticals
The following people have nothing to disclose: Brenden Chen, Jörg Hakenberg,
Ramakrishnan R. Srinivasan, Dana O. Doheny, Inga Peter, Constanza Solis-Villa,
Rong Chen, David F. Bishop
462
Lorcaserin Improves the NASH Clinical Score in the
Majority of High-Risk Patients: a Retrospective Analysis
of Three Phase 3 Studies
Wajahat Z. Mehal1, Randi Fain2, Alan Glicklich3, Yuhan Li2, Wil-
liam Shanahan3, William Soliman2; 1Yale University, New Haven,
CT; 2Eisai, Inc., Woodcliff Lake, NJ; 3Arena Pharmaceuticals, Inc.,
San Diego, CA
Background: Moderate weight loss has been shown to result
in histologic improvement in non-alcoholic steatohepatitis
(NASH). Lorcaserin is a selective 5-HT2C agonist approved
for chronic weight management. Three large, double-blind,
randomized studies (BLOOM: N Engl J Med. 2010;363:245-
56; BLOSSOM: J Clin Endocrinol Metab. 2011;96:3067-77;
BLOOM-DM: Obesity. 2012;20:1426-36) have demonstrated
the effectiveness of lorcaserin in inducing weight loss in
patients with a body mass index of 27 to 45. We conducted
a retrospective analysis to determine the ability of 52 weeks
of lorcaserin 10 mg bid to improve NASH. The NASH clinical
score predicts the presence of histologic NASH and was used
as an indicator of NASH activity. Methods: Data were pooled
from 3 clinical trials of similar design comparing lorcaserin and
placebo in overweight or obese patients with or without type 2
diabetes (NCT00603902, NCT00395135, NCT00603291).
All patients received diet and exercise counseling. The modi-
fied intent-to-treat/last observation carried forward population
was analyzed for patients with both baseline and end of treat-
ment NASH clinical score data. Liver parameters (ALT, AST)
427A
and weight loss in the MITT/LOCF population were assessed
as % change from baseline. The NASH clinical score was ana-
lyzed by comparing proportions of patients shifting from high
or very high scores at baseline (NASH-pos) to low or interme-
diate scores (NASH-neg) at week 52. Results: Approximately
7% of control (182/2519) and lorcaserin-treated (190/2702)
patients had a high-risk NASH clinical score, and both groups
had an AST/ALT ratio of 0.9. Lorcaserin-treated patients
showed significant improvements vs placebo in ALT (% change
from baseline to week 52, -2.4 vs 3.0), AST (0.1 vs 2.6) as
well as significant weight loss (-5.8 vs -2.4), all P<0.001. In
an analysis of the time course of treatment effect, significant
weight loss with lorcaserin vs placebo was seen as early as
week 2, with peak effect at week 36; peak effect of lorcaserin
on liver enzyme levels was at week 24. Significantly more
patients treated with lorcaserin (120/190, 63.2%) vs pla-
cebo (89/182, 48.9%) switched from NASH-pos at baseline
to NASH-neg at week 52 (P=0.006). Conclusions: Lorcaserin
treatment for 52 weeks was associated with greater improve-
ment in serum LFT parameters than placebo, and improvement
in NASH clinical score in the majority of high-risk patients.
Lorcaserin may be a treatment option for overweight/obese
patients with non-alcoholic fatty liver disease/NASH.
Disclosures:
Wajahat Z. Mehal - Management Position: Gloabl BioReserach Partners
Randi Fain - Employment: Eisai Inc
Alan Glicklich - Employment: Arena Pharmaceuticals; Stock Shareholder: Arena
Pharmaceuticals
Yuhan Li - Employment: Eisai, Inc
William Shanahan - Employment: Arena Pharmaceuticals; Management Position:
Arena Pharmaceuticals; Stock Shareholder: Arena Pharmaceuticals
William Soliman - Employment: Eisai Inc
463
No increased risk of hepatocellular carcinoma in cirrho-
sis due to Wilson’s disease during long term follow up
Suzanne van Meer1, Robert A. de Man2, Aad P. van den Berg3,
Roderick Houwen4, Francisca Linn5,6, Peter D. Siersema1, Karel J.
van Erpecum1; 1Department of Gastroenterology and Hepatology,
University Medical Center Utrecht, Utrecht, Netherlands; 2Depart-
ment of Gastroenterology and Hepatology, Erasmus Medical Cen-
ter, Rotterdam, Netherlands; 3Department of Gastroenterology and
Hepatology, University Medical Center Groningen, Groningen,
Netherlands; 4Department of Pediatrics, University Medical Center
Utrecht, Utrecht, Netherlands; 5Department of Neurology, Univer-
sity Medical Center Utrecht, Utrecht, Netherlands; 6Rudolf Magnus
Institute of Neuroscience Utrecht, Utrecht, Netherlands
Background and aims: Although liver cirrhosis is a frequent
complication in Wilson’s disease (WD), data on risk of hepato-
cellular carcinoma (HCC) in these patients are scarce. We here
report HCC risk in a well-defined cohort with unequivocally
proven WD with long-term follow-up (FU) and correlate HCC
risk to efficacy of decoppering treatment and severity of liver
disease. Methods: All patients with a confirmed diagnosis of
WD (Leipzig score ≥ 4) in three Dutch university referral hos-
pitals were included in this retrospective cohort study. End of
FU was defined as date of diagnosis of HCC, liver transplanta-
tion, death or last available hospital visit. Results: In total, 130
patients with WD were followed during a median FU of 15
years (range 0.1-51.2). Total years of FU was 2336. Median
age at diagnosis was 16 years (range 0-43). Presentation was
asymptomatic, exclusively hepatic, neurologic, combined and
unknown in 4%, 55%, 9%, 30% and 2% of cases, respectively.
Median Leipzig score was 8 points (range 4-13). At base-
line, cirrhosis was present in 74 patients (57% of total: 64%
428A AASLD ABSTRACTS
compensated and 36% decompensated). At end of FU, liver
disease severity was improved, stable or deteriorated in 20%,
46% and 24% of all cases, respectively. Twenty-eight patients
received a liver transplant. Five patients died due to complica-
tions of their liver disease and two deaths were related to liver
transplantation. In patients who were treated for at least one
year (n=111), zinc, penicillamine or trientine (alone, sequen-
tially or combined) were prescribed in 92%, 69% and 14%
of patients, respectively. At the end of FU, efficacy of decop-
pering, based on values of serum non-ceruloplasmin-bound
copper concentration (aim: <10 mg/dL) and 24-hour-urinary
copper excretion (aim: <100 mg/24 hours), was excellent in
34% of patients, moderate in 42%, poor in 13% and unknown
in 11%. Two patients developed HCC. The first patient was a
39-year-old male and presented with decompensated cirrhosis
in combination with HCC. The second patient was a 63-year-
old female with unequivocal WD diagnosed 50 years earlier.
Despite excellent decoppering at the end of FU, she progressed
to decompensated cirrhosis in which an HCC developed. No
additional risk factors for liver disease were present in both
patients. Estimated annual HCC risk for all patients was 0.09%
(95% confidence interval: 0.01-0.28). Subgroup analysis in
cirrhotic patients revealed an annual HCC risk of 0.14% (95%
confidence interval: 0.02-0.45). Conclusion: Even in case of
cirrhosis, HCC risk is low in Wilson’s disease and appears not
related to efficiency of decoppering. Our data do not support
regular HCC surveillance in WD.
Disclosures:
Robert A. de Man - Advisory Committees or Review Panels: Norgine; Grant/
Research Support: Gilead, Biotest
Karel J. van Erpecum - Advisory Committees or Review Panels: Bristol Meyers
Squibb, Abbvie
The following people have nothing to disclose: Suzanne van Meer, Aad P. van
den Berg, Roderick Houwen, Francisca Linn, Peter D. Siersema
464
Patients with Wilson disease without detectable ATP7B
mutations
Albert Stättermayer1, Heinz M. Zoller2, Karl Heinz Weiss3, Ferenc
Szalay4, Radan Bruha5, Roderick Houwen6, Rudolf E. Stauber7,
Petra E. Steindl-Munda1, Harald Hofer1, Wolfgang Stremmel3,
Peter Ferenci1; 1Gastroenterology & Hepatology, Medical Univer-
sity of Vienna, Vienna, Austria; 2Medicine II, Medical University of
Innsbruck, Innsbruck, Austria; 3Gastroenterology and Hepatology,
University Hospital Heidelberg, Heidelberg, Germany; 4Medicine
I, Semmelweis University, Budapest, Hungary; 5Internal Medicine
IV, Charles University, Prague, Czech Republic; 6Pediatric Gastro-
enterology, Wilhelmina Children’s Hospital, Utrecht, Netherlands;
7Gastroenterology & Hepatology, Medical University of Graz,
Graz, Austria
Background/aim: Wilson disease (WD) is an inherited autoso-
mal-recessive disorder of hepatic copper excretion resulting in
copper accumulation in the liver. The responsible gene muta-
tion is located within the ATP7B gene encoding for a P-type
copper transporting ATPase. More than 500 mutations in the
ATP7B gene have been described so far. Nevertheless, in up to
seven percent of patients with WD, no mutation can be found.
Aim of our study was to identify diagnostic characteristics of
patients with WD without detectable mutations in ATP7B. Meth-
ods: Clinical data and DNA for genetic analysis were obtained
from WD patients as part of an international cooperation proj-
ect. The diagnosis of WD was established if the WD diagnostic
score recommended by the EASL Clinical Practice Guidelines
on WD was ≥ 4. Mutation analysis was carried out by direct
sequencing on an ABI Prism 310 Genetic Analyzer (Perkin
Elmer, Norwalk, USA). Next-generation sequencing is ongo-
HEPATOLOGY, October, 2014
ing and was performed in ten patients so far. Results: Out of
1294 WD patients collected since 1985 in 65 (5.0%) patients
no mutation in the ATP7B gene could be detected. Thirty-nine
(60.0%) of them were male. Thirty-one patients (47.7%) pre-
sented with neurologic symptoms and 29 (44.6%) with hepatic
symptoms (of whom one had fulminant hepatic failure). Five
(7.7%) patients were asymptomatic siblings of patients with
WD. Mean age at onset of WD was 19.5±10.9 years and
21.4±10.5 years at diagnosis. Kayser-Fleischer corneal rings
were present in 38 (58.5%) patients. Hepatic copper content
was available in 33 patients (784±586 mg/g dry weight; SD)
and coeruloplasmin was decreased in 50 (76.9%) patients
(mean: 8.9±7.6 mg/dL). Conclusions: Our data suggest that
yet unidentified mutations of genes other than ATP7B might
lead to a disease identical to WD. Further research is needed
to get more insights into the causes of copper overload in
patients without mutations in ATP7B.
Disclosures:
Rudolf E. Stauber - Advisory Committees or Review Panels: Gilead, Janssen-Cilag,
AbbVie, BMS; Grant/Research Support: MSD; Speaking and Teaching: Roche
Harald Hofer - Speaking and Teaching: Janssen, Roche, MSD, Gilead, Abbvie
Peter Ferenci - Advisory Committees or Review Panels: Roche, Idenix, MSD, Jans-
sen, AbbVie, BMS, Tibotec, Böhringer Ingelheim; Patent Held/Filed: Madaus
Rottapharm; Speaking and Teaching: Roche, Gilead, Roche, Gilead, Salix
The following people have nothing to disclose: Albert Stättermayer, Heinz M.
Zoller, Karl Heinz Weiss, Ferenc Szalay, Radan Bruha, Roderick Houwen, Petra
E. Steindl-Munda, Wolfgang Stremmel
465
Sex differences in liver SAM:SAH ratios and gene tran-
script levels after pre-and post-natal choline supple-
mentation and copper chelation treatment in an animal
model of Wilson disease
Valentina Medici1, Noreene Shibata1, Kusum K. Kharbanda2,
Charles H. Halsted1; 1Division of Gastroenterology and Hepa-
tology, UC Davis Medical Center, Sacramento, CA; 2Research
Service, Veterans Affairs Nebraska-Western Iowa Health Care
System, Omaha, NE
Background. Methionine metabolism, central to DNA methyl-
ation reactions, may provide epigenetic regulation of genes
involved in liver damage in Wilson disease (WD). We hypoth-
esized that peri-natal maternal treatment with choline could
modify the sex specific response to penicillamine in offspring
in the tx-j model of WD. Methods. Control (choline 8 mmol/
Kg) or choline supplemented (36 mmol/Kg) diets were fed to
wildtype and tx-j female mice starting at 2 weeks before mating
and continuing in offspring up to 24 weeks of age. A subgroup
of tx-j of both sexes received oral penicillamine with or without
choline supplemented diet from 12 to 24 weeks of age. Results.
Decreased S-adenosylmethionine (SAM) to S-adenosylhomo-
cysteine (SAH) ratio, an index of DNA methylation capacity,
was decreased in each sex of offspring tx-j mice, compatible
with the known down-regulation of SAH hydrolase levels in this
mouse model of WD (Table 1). The SAM:SAH ratio was higher
in untreated female versus male tx-j mice (p<0.05). Separate
choline or penicillamine treatments were associated with simi-
lar increases of SAM:SAH ratio in male tx-j vs wildtype levels.
Whereas the ratio was increased by each separate treatment
in tx-j males, it was reduced by each separate treatment in
tx-j females, but was unchanged in either sex by the combina-
tion of choline and penicillamine. Transcript levels of Dnmt3b,
a regulator of DNA methylation in tx-j mice, were increased
in untreated tx-j of either sex, and were down-regulated by
separate or combined penicillamine and choline treatment in
male tx-j, but were unchanged by any treatment in female tx-j
mice. Grp78 transcript levels were increased in tx-j mice of
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
both sexes, reduced to control levels by choline in tx-j males,
but only by combined penicillamine and choline treatment in
female tx-j mice. Conclusions. Our results indicate different sex
responses to copper chelation and methyl donors in the tx-j
model of WD that could explain different phenotype between
genders in WD.
Table 1.
Different letters indicate significant differences in each row
(p<0.05). m=males; f=females.
Disclosures:
The following people have nothing to disclose: Valentina Medici, Noreene Shi-
bata, Kusum K. Kharbanda, Charles H. Halsted
466
Using hIPSCs to model liver disease associated with
classic mutations of alpha-1 antitrypsin
Tamara Taketani1,2, Maria P. Ordonez1,2, Lawrence S. Goldstein1;
1UCSD, La Jolla, CA; 2Pediatric Gastroenterology, Rady Children’s
Hospital San Diego, San Diego, CA
A major obstacle to the development of new therapies is the
poor understanding of how genetic modifiers alter the onset
and outcome of various diseases. A classic example is AAT
deficiency, a metabolic liver disease in which the mutant gene
and its product are known, but where clinical progression and
outcome are extremely variable and thought to be influenced
by genetic modifiers. Despite being the leading genetic cause
of liver disease in children, mutations of AAT occur infrequently
when compared to sporadic liver diseases. The relatively low
incidence of AAT deficiency makes it impossible to obtain
insight into the genetic factors that may affect progression of
disease from genome-wide association studies (GWAS). The
study of hepatocytes derived from AAT mutant human induced
pluripotent stem cells (hIPSC) may overcome this limitation by
identifying cellular phenotypes that correlate with clinical sever-
ity of disease in existing AAT patients. For this purpose, we
have generated hIPSC lines from AAT patients (ZZ) with vari-
able degrees of liver disease, including those without evidence
of liver damage and those who have suffered a more aggres-
sive course leading to end stage liver disease. We are using
control and AAT hIPSC-derived hepatocyte like cells (HLCs) to
probe the hypothesis that the significant heterogeneity seen
in disease progression due to AAT ZZ mutations is related
to genetically determined variability of fundamental biologi-
cal hepatocyte processes involved in cellular disposal, stress
response, and cell survival pathways. Prior data obtained in
mouse and cell line models has shown that autophagy may act
as a primary route of intracellular degradation of mutant AAT
protein. Although traditionally regarded as a cellular adap-
tive process triggered by nutrient deprivation, autophagy in
hepatocytes may also provide an important hepatoprotective
mechanism. Our preliminary results show that HLCs derived
from AAT mutant patients with no evidence of liver disease
429A
(AAT NLD) have increased activation of autophagy at baseline
compared to AAT mutants with severe liver disease (AAT LD).
Our data supports a role for autophagy as a potential modifier
in the pathobiology of AAT related liver disease and opens
the way for mechanistic studies involving this and other basic
biological pathways that may modulate hepatic injury in AAT.
Our studies can impact the way we approach AAT deficiency:
1) by developing predictive diagnostics through discovery of
biomarkers that identify patients at risk for severe liver disease,
and 2) by promoting therapeutic candidate discovery through
validation of new or existing therapeutic targets in live human
hepatocytes.
Disclosures:
The following people have nothing to disclose: Tamara Taketani, Maria P.
Ordonez, Lawrence S. Goldstein
467
A propensity score-matched cohort study of the effect of
vitamin E in NAFLD patients
Gi Hyun Kim, Jin Wook Kim, Jung Wha Chung, Eun Sun Jang,
Sook-Hyang Jeong; Department of Internal Medicine, SNU Bun-
dang hospital, Seongnam, Republic of Korea
Background: Controlled clinical trials have shown that vitamin
E improves liver histology and biochemical profiles in patients
with nonalcoholic steatohepatitis. However, its effect in overall
NAFLD patients has not been fully elucidated. In this study, we
sought to determine the short-term effect of vitamin E, off-treat-
ment durability of response, and predicting factors for vitamin
E response in NAFLD patients. Methods: A cohort of 1953
NAFLD patients who visited our outpatient clinic between Jan.
2005 and Mar. 2013 was constructed by using the electronic
medical record system (BESTCARE). After excluding comor-
bid liver diseases, 257 patients who received vitamin E and
416 control patients were matched for propensity scores. The
matched covariates included age, sex, BMI, AST, ALT, pres-
ence of DM or dyslipidemia. An ALT response was defined
as a decrease to ≤40 U/L and by ≥30% of baseline. Logistic
regression analysis was performed in order to assess the effect
of vitamin E after adjusting potential confounders. Results: Pro-
pensity score matching selected 130 and 105 patients from
vitamin E group and control group, respectively. Mean vitamin
E treatment duration was 5.72 months. ALT response was sig-
nificantly higher in vitamin E group (63.1 vs. 23.8%, p < 0.01).
The off-treatment response was not durable, however, with no
significant differences in ALT response 6 months after cessation
of vitamin E. Vitamin E treatment was a significant predictor for
ALT response by multivariate logistic regression. Female sex
and old age were predictors for vitamin E response. Conclu-
sions: Short-term Vitamin E treatment significantly reduces ALT
level compared to propensity score-matched control in NAFLD
patients.
Disclosures:
The following people have nothing to disclose: Gi Hyun Kim, Jin Wook Kim, Jung
Wha Chung, Eun Sun Jang, Sook-Hyang Jeong
430A AASLD ABSTRACTS
468
Variability in erythrocyte and plasma porphyrin levels
in erythropoietic protoporphyria and X-linked protopor-
phyria
Eric Gou1, John D. Phillips2,
Manisha Balwani3,
Montgomery
Bissell4, Joseph R. Bloomer5, Herbert L. Bonkovsky6, Robert J.
Desnick3, Hetanshi Naik3, Karl E. Anderson1; 1Preventive Medi-
cine and Community Health, University of Texas Medical Branch,
Galveston, TX; 2Medicine, University of Utah, Salt Lake City, UT;
3Genetics and Genomic Sciences, Mt. Sinai School of Medicine,
New York, NY; 4Medicine, University of California San Francisco,
San Francisco, CA; 5Medicine, University of Alabama, Birming-
ham, AL; 6Medicine, Carolinus HealthCare System, Charlotte, NC
Purpose: Erythropoietic protoporphyria (EPP), the most common
porphyria in children and the third most common in adults,
results from mutations of ferrochelatase (FECH), which catalyzes
ferrous iron insertion into protoporphyrin IX to complete heme
synthesis. X-linked protoporphyria (XLP) is less common, has the
same clinical phenotype and is due to gain of function muta-
tions of erythroid δ-delta-aminolevulinic acid synthase (ALAS2).
Both result in accumulation of protoporphyrin and painful,
nonblistering cutaneous photosensitivity that profoundly affects
quality of life, and can be complicated by life-threatening hepa-
topathy. Information on variability in porphyrin levels and pho-
tosensitivity in the absence of hepatopathy is limited. Methods:
We studied 195 subjects (109 males, 87 females, 10 months
to 75 years of age) with typical nonblistering photosensitivity.
EPP or XLP was confirmed biochemically by the University of
Texas Medical Branch at Galveston Porphyria Laboratory, and
in most by identification of FECH or ALAS2 mutations at the Mt.
Sinai Porphyria Center. Those not yet DNA tested were classi-
fied as EPP (56 subjects) or XLP (1 subject) by the proportions of
erythrocyte metal-free and zinc protoporphyrin. Subjects with
protoporphyric hepatopathy, which further increases porphyrin
levels, were excluded. Levels were repeated over time to deter-
mine variability, and individuals with the same mutations were
compared. Results: Differences in total erythrocyte protoporphy-
rin between subjects exceeded variation within subjects over
time (p<0.0001), which was greater with longer follow up.
Erythrocyte porphyrin levels were higher and less variable over
time than plasma porphyrins, suggesting lack of equilibrium.
Porphyrin levels on average and the proportion of zinc pro-
toporphyrin were higher in the 15 subjects with XLP and ALAS2
mutations (12 families with 3 different mutations) than in the
178 subjects with EPP and FECH mutations (79 families with
22 different mutations, p<0.0004). Differences in erythrocyte
porphyrin levels among unrelated subjects with different FECH
or ALAS2 mutations were significantly greater than among
those who shared the same mutations. Conclusions: Defining
variability in erythrocyte and plasma porphyrins is important
for assessing photosensitivity and risk for hepatopathy in EPP
and XLP. In XLP, protoporphyrin is higher on average and zinc
protoporphyrin is consistently higher than in EPP. Individual
differences were smaller in patients with the same mutations,
suggesting genotype-phenotype correlation.
Disclosures:
Joseph R. Bloomer - Grant/Research Support: Clinuvel, Inc., American Porphyria
Foundation, NIH 5U54 DK083909
Herbert L. Bonkovsky - Advisory Committees or Review Panels: Clinuvel, Inc.,
Novartis Pharmaceuticals, Clinuvel, Inc., Novartis Pharmaceuticals, Clinuvel,
Inc., Novartis Pharmaceuticals, Clinuvel, Inc., Novartis Pharmaceuticals; Consult-
ing: Alnylam, Inc, Clinuvel, Inc., Novartis Pharmaceuticals, Lundbeck Pharmaceu-
ticals, Boehringer-Ingelheim, Clinuvel, Inc., Novartis Pharmaceuticals, Lundbeck
Pharmaceuticals, Boehringer-Ingelheim, Clinuvel, Inc., Novartis Pharmaceuticals,
Recordati Rare Chemicals, Clinuvel, Inc., Novartis Pharmaceuticals; Grant/
Research Support: Clinuvel, Inc, Vertex, Novartis Pharmaceuticals, Clinuvel, Inc,
Vertex, Novartis Pharmaceuticals, Clinuvel, Inc, Vertex, Novartis Pharmaceuti-
cals, Clinuvel, Inc, Vertex; Speaking and Teaching: Lundbeck Pharmaceuticals,
Lundbeck Pharmaceuticals
HEPATOLOGY, October, 2014
Robert J. Desnick - Advisory Committees or Review Panels: Recordati Rare Dis-
eases; Consulting: Alnylam Pharmaceuticals; Grant/Research Support: Alnylam
Pharmaceuticals; Patent Held/Filed: Alnylam Pharmaceuticals; Stock Share-
holder: Alnylam Pharmaceuticals
The following people have nothing to disclose: Eric Gou, John D. Phillips, Mani-
sha Balwani, Montgomery Bissell, Hetanshi Naik, Karl E. Anderson
469
Osteoporosis and bone fractures in alcoholic liver dis-
ease: A systematic review and meta-analysis
Chang Seok Bang, Hyo Sun Kim, Sang Hyun Park, Eun Jin Kim, Ki
Tae Suk, Dong Joon Kim; Department of Internal Medicine, Hallym
University College of Medicine, Chuncheon, Republic of Korea
Purpose: Excessive alcohol consumption is a well-established
risk factor for osteoporosis and bone fractures. However, light
to moderate amount of alcohol ingestion is known to be associ-
ated with higher bone mineral density (BMD) and low fracture
rate. The aim of this study was to evaluate current evidence
on osteoporosis and bone fractures in alcoholic liver disease
(ALD). Methods: Case-control or cohort studies were identi-
fied from databases (PubMed, EM-BASE, and the Cochrane
Library). Searching keywords used were ‘alcoholic liver dis-
eases’, ‘osteoporosis’, or ‘bone fractures’ using Boolean opera-
tors. The prevalence of any fractures or osteoporosis, and BMD
scores were extracted and analyzed using risk ratios (RRs) and
standardized mean difference (SMD). A random effect model
was applied. Results: In total, 16 studies were identified and
analyzed. Overall, ALD showed RR of 1.944 (95% CI: 1.354-
2.791) for the development of bone fractures. However, ALD
showed RR of 0.849 (0.523-1.380) for the development of
osteoporosis. BMD was not statistically different between ALD
and control group, although lower in patients with ALD (SMD
in femur BMD: -0.172, -0.453-0.110) (SMD in spine BMD:
-0.169, -0.476-0.138). Sensitivity analyses showed consistent
results. Publication bias was detected in the analysis of bone
fractures and osteoporosis. Conclusion: Current publications
indicate significant association between bone fractures and
ALD, independent of osteoporosis or BMD. Due to the qual-
itative and quantitative heterogeneity among studies, further
research using homogeneous populations and control of con-
founding risk factors for fractures are needed to elucidate the
mechanism of bone fractures in ALD.
Association between alcoholic liver disease and bone fractures.
The size of each square is proportional to the study’s weight. Dia-
mond is the summary estimate from the pooled studies with 95%
CI. CI: confidence interval. (Random effect model)
Disclosures:
The following people have nothing to disclose: Chang Seok Bang, Hyo Sun Kim,
Sang Hyun Park, Eun Jin Kim, Ki Tae Suk, Dong Joon Kim
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
470
Elevated alkaline phosphatase predicts response in
polycystic liver disease during somatostatin analogue
therapy: a multi-center pooled analysis on individual
patient data
Tom J. Gevers1, Frederik Nevens2, Vicente E. Torres3, Marie C.
Hogan3, Joost Drenth1; 1Gastroenterology and Hepatology, Rad-
boudUMC, Nijmegen, Netherlands; 2Hepatology, KU Leuven,
Leuven, Belgium; 3Nephrology and hypertension, Mayo clinic,
Rochester, MN
Somatostatin analogues (SA) reduce liver volumes (LVs)
in patients with polycystic liver disease (PLD). However,
these patients show a considerable variability in treatment
responses, making it difficult to predict response to SA ther-
apy. Our aim was to identify specific patient, disease or
treatment characteristics that predict response in PLD during
SA therapy. We pooled the individual patient data of 4 tri-
als (NCT00771888,NCT00426153, NCT01157858,
NCT01354405) of long-acting SAs (120 mg lanreotide or 40
mg octreotide) for 6 or 12 months in PLD that included liver
volume as the primary outcome. We performed uni- and mul-
tivariate linear regression analysis with 9 preselected patient,
disease and drug variables to identify independent predictors
of response, defined as percent change in LV. Secondary out-
come was percent change in kidney volume in the ADPKD sub-
group. All analyses were adjusted for baseline LV and center
effect (random). We included 153 PLD patients (86% female,
mean age 50 years, median LV 4974 ml, 69% ADPKD) from 3
international centers, all treated with octreotide (n=70) or lan-
reotide (n=83). Mean reduction in LV was 4.2% (range -31.7%
to +9.7%). Uni- and multivariate linear regression revealed that
elevated baseline alkaline phosphatase (ALP) was associated
with increased response during SA therapy (-2.7%, 95% CI
-5.1% to -0.2%, p = 0.037), independently of baseline LV.
Duration of therapy (6 vs 12 months), SA type and eGFR did
not affect response. Elevated ALP remained associated with LV
response (-3.2%, 95% CI -6.0 to -0.3%, p=0.029) in ADPKD
patients (n=100), but did not predict response in kidney vol-
umes (0.1%, 95% CI -3.1 to 3.3%, p = 0.97). Elevated ALP
is associated with response in polycystic liver disease during
SA therapy, and could possibly serve as a prognostic marker
in this disease.
Disclosures:
Frederik Nevens - Consulting: CAF, Intercept, Gore, BMS, Abbvie, Novartis,
MSD, Eumedica, Janssen; Grant/Research Support: Ipsen, Roche, MSD, Astellas
Vicente E. Torres - Grant/Research Support: Otsuka
Marie C. Hogan - Consulting: Hoffmann LaRoche; Employment: Mayo Clinic;
Grant/Research Support: Novartis, NIH, PKD Foundation
The following people have nothing to disclose: Tom J. Gevers, Joost Drenth
471
A Phase I Pharmacokinetic Profiling Study in Patients
Receiving Trientine Dihydrochloride for the Treatment of
Wilson Disease
Karl Heinz Weiss1, Ulrike Teufel2, Jan Pfeiffenberger1, Christian
Rupp1, Andreas Wannhoff1, Wolfgang Stremmel1, Daniel Got-
thardt1; 1Internal Medicine IV, University Hospital Heidelberg, Hei-
delberg, Germany; 2Pediatrics, University Hospital Heidelberg,
Heidelberg, Germany
Background and aim: Trientine dihydrochloride (trientine) is a
common treatment for Wilson disease, however data on phar-
macokinetics are limited to healthy subjects. Aim of the study
was to determine PK parameters assumed to be representative
of steady state in Wilson disease patients treated with trien-
431A
tine. ClinicalTrials.gov Identifier: NCT01874028 Patients and
methods: Twenty subjects (9 male, 4 children, mean age 39.3
y [12-61]) with confirmed diagnosis of Wilson disease were
exposed to trientine after oral dosing at the standard dose for
that subject. Blood samples were taken 0,5; 1; 1,5; 2; 3; 4; 6;
8 and 12 h after dosing. Concentration of trientine in plasma
samples were measured by LC-MS/MS after protein precipita-
tion extraction over the calibration range of 20-2000 ng/mL
Results: Trientine was absorbed rapidly, with tmax occurring
between 0.48 and 4.08 hours post dose. There was some
variability in exposure, with a 10-fold range in Cmax, and a
13.8-fold range in AUC0-t. This variability was slightly lower
when PK parameters were dose-normalised (6.7-fold range
in Cmax/D and an 11.6-fold range in AUC0-t/D). The termi-
nal half-life, where defined, was broadly consistent between
subjects (range of 2.33-6.99 hours). The AUC0-8 was able
to be calculated in 14 of the 20 subjects, however since the
dosing occurred at pharmacokinetic steady state the AUC0-t
is representative of exposure during the dosing interval. There
was no marked difference in PK parameters between adult
subjects (n=16) and children (n=4). The Cmax range was 508-
3100 ng/mL in adults and 309-1940 ng/mL in children – the
equivalent ranges for AUC0-t were 1240-17100 ng.h/mL and
1500 8060 ng.h/mL respectively. When PK parameters were
normalised for dose given, the Cmax/D and AUC0-t/D for chil-
dren were contained within the ranges for the adult subjects.
Conclusion: The pharmacokinetics of trientine in Wilson dis-
ease subjects was similar to that reported in healthy subjects.
Disclosures:
The following people have nothing to disclose: Karl Heinz Weiss, Ulrike Teufel,
Jan Pfeiffenberger, Christian Rupp, Andreas Wannhoff, Wolfgang Stremmel,
Daniel Gotthardt
472
Hemodynamic differences in the very early phase of
hepatocellular carcinoma (HCC) using contrast-en-
hanced ultrasonography (CEUS)
Akiko Saito1, Satoshi Katagiri1, Masakazu Yamamoto1, Keiko Shi-
ratori1, Masayuki Nakano2, Toshio Morizane2; 1Institute of Gas-
troenterology, Tokyo Women’s Medical University, Tokyo, Japan;
2Ofunachuo Hospital, Kanagawa, Japan
CEUS usefulness has been confirmed in several studies, though
hemodynamic details of HCC in the very early phase have not
yet been reported. A novel method, inflow-time mapping, facil-
itates recognizing arterial and portal flows separately. Thus,
we divided the very early phase into pure arterial and early
portal phases, and examined CEUS reliability for HCC diag-
nosis. METHODS: Starting in 2007, we performed CEUS in
408 patients with pathologically confirmed hepatocellular nod-
ules. We identified 146 nodules in 146 patients in whom the
432A AASLD ABSTRACTS
nodule, intrahepatic artery and portal vein could be seen in a
single section. There were 118 HCC (8 poorly, 73 moderately
and 37 well-differentiated) and 28 benign nodules. For nodule
hemodynamics, we focused especially on the pure arterial and
early portal phases up to 1 min after Sonazoid (0.01ml/kg)
injection with subsequent phase up to 30 minutes. Enhance-
ments of nodules as compared to non-tumor parenchyma
were divided into 3 types; hyper, iso and hypo. We calcu-
lated covariance-adjusted sensitivities for nodule enhancement
combinations of these three phases. We used Prosound F75
and Ascendus with inflow-time mapping, arterial capture or a
time-intensity curve. RESULTS: 1) Poorly differentiated (PD) HCC
showed three enhancement patterns, hypo-hyper-hypo, hypo-
iso-hypo and hyper-hyper-hypo, with respective likelihoods of a
nodule being PD of 65%, 13% and 8%. 2) All moderately dif-
ferentiated (MD) HCC were hyper in the pure arterial and hypo
in the subsequent phase. Hypo, iso and hyper enhancement
were all seen in the early portal phase. If a nodule showed
the hypo, iso or hyper, the respective likelihoods of being MD
were 96%, 83% and 79%. 3) Well-differentiated (WD) HCC
showed seven complex patterns but 68% were hypo in the
arterial phase. If all three phases were hypo, the nodule was
WD. All hypo-iso-iso nodules were WD. Similarly, the iso-iso-
hypo and iso-iso-iso patterns indicated a nearly 95% likelihood
of a nodule being WD. The hypo-iso-hypo pattern carried a
13% risk of PD, though the remaining 87% were WD. 4) Most
benign nodules were hyper in both pure arterial and early por-
tal phases. The subsequent phase could be hyper, iso or hypo.
Nodules with all three phases being hyper were consistently
benign. Of those with an iso subsequent phase, 95% were
benign. The hyper-hyper-hypo pattern was rare but 12% were
benign nodules. CONCLUSION: By dividing the very early
phase into pure arterial and early portal phases, CEUS can
provide information useful for determining the likely degree
of HCC differentiation and for distinguishing early stage HCC
from benign nodules.
Disclosures:
The following people have nothing to disclose: Akiko Saito, Satoshi Katagiri,
Masakazu Yamamoto, Keiko Shiratori, Masayuki Nakano, Toshio Morizane
473
Correlation of Enhancement Pattern of CEUS with Histo-
pathologic Feature in Small Nodular Lesions in Chronic
Liver Disease
Seung Kak Shin, Yun Soo Kim, Oh Sang Kwon, Duck Joo Choi,
Ju Hyun Kim; Internal medicine, Gachon University Gil Medical
Center, Incheon, Republic of Korea
Background/Aim: Distinguishing small nodular lesions in cir-
rhotic liver is sometimes difficult with conventional dynamic
imaging studies. Contrast-enhanced ultrasound (CEUS) is useful
for characterization of focal liver lesions by showing different
vascular patterns. This study aimed to evaluate the usefulness
of CEUS for the differentiation of dysplastic nodule (DN), early
HCC and progressed HCC in chronic liver disease. Methods:
Fifty-four patients with liver nodule less than 3cm in diameter
who underwent liver CEUS and ultrasound-guided liver biopsy
from August 2012 to May 2014 were retrospectively reviewed.
CEUS using SonoVue was conducted by the same experienced
physician. The CEUS findings were compared with histopathol-
ogy, clinical data and other dynamic contrast imaging such as
CT and MRI. Results: 1) The tumor nodules were categorized
into three groups: DN (n=8), early HCC (Edmonson grade
I) (n=16) and progressed HCC [(grade II (n=15) and grade
III (n=15)]. The mean tumor size (cm) in DN, early HCC and
progressed HCC was 1.61 ± 0.42, 1.59 ± 0.48 and 1.87 ±
HEPATOLOGY, October, 2014
0.59, respectively. The number of patients with liver cirrhosis
was 45 (83.3%). 2) The enhancement patterns (arterial-de-
layed phase) of CEUS in early HCC were 5(31.2%) hyper-
hypo, 5(31.2%) hyper-iso, 3(18.8%) reticular hyper-hypo and
3(18.8%) others (1 hypo-hypo, 1 hyper-hyper, 1 iso-hypoen-
hancement). The enhancement patterns of CEUS in progressed
HCC were 25(83.4%) hyper-hypo, 4(13.3%) hyper-iso and
1(3.3%) reticular hyper-hypoenhancement. There was signifi-
cant difference in enhancement pattern of CEUS between early
HCC and progressed HCC (p=0.001). 3) The enhancement
patterns in DN were 6 (75.0%) iso-iso and 2(25.0%) others
(1 hypo-hypo, 1 hypo-isoenhancement). There was signifi-
cant difference in enhancement pattern of CEUS between DN
and HCC (p<0.001). 4) In 30 cases of HCC which showed
typical (hyper-hypo) enhancement with CEUS, 5(16.7%) and
7(23.3%) of arterial hyperenhancement were not detected with
CT and MRI, respectively. On the other hand, in 9 cases of
HCC which showed atypical (hyper-iso) enhancement pattern
with CEUS, 7(77.8%) of delayed wash-out were detected with
MRI. Conclusions: CEUS could be considered useful modality
for differentiation between early HCC and progressed HCC or
DN and HCC in small liver nodule with diameter less than 3
cm in chronic liver disease. In HCC less than 3 cm in diameter,
CEUS was more sensitive than CT or MRI to detect arterial
enhancement. On the other hand, MRI was more sensitive than
CEUS to detect delayed wash-out.
Disclosures:
The following people have nothing to disclose: Seung Kak Shin, Yun Soo Kim,
Oh Sang Kwon, Duck Joo Choi, Ju Hyun Kim
474
Preoperative predictive value of 18F-fluorodeoxyglu-
cose positron emission tomography/computed tomog-
raphy for microvascular invasion of small hepatocellular
carcinoma
Tomoki Kobayashi, Hiroshi Aikata, Hiromi Kan, Takayuki Fuku-
hara, Noriaki Naeshiro, Tomokazu Kawaoka, Masataka Tsuge,
Akira Hiramatsu, Michio Imamura, Yoshiiku Kawakami, Hideyuki
Hyogo, Kazuaki Chayama; Department of Gastroenterology and
Metabolism, Hiroshima University Hospital, Hiroshima, Japan
Background&Aim: Microvascular invasion (MVI) is a poor prog-
nostic indicator of the recurrence of hepatocellular carcinoma
(HCC), even after curative liver resection. The detection of MVI
before treatment is important in the decision of the treatment
strategy between radiofrequency ablation and surgical resec-
tion in small HCCs equal to or less than 30mm. However, MVI
is difficult to detect with current imaging modalities. Therefore,
this study was designed retrospectively to evaluate the ability of
F-fluorodeoxyglucose positron emission tomography/computed
tomography (FDG-PET) to predict MVI of small HCCs. Methods:
The consecutive 36 patients who were preoperatively exam-
ined with FDG- PET and underwent curative hepatectomy for
small HCC (< 3cm in greatest dimension) were enrolled in this
retrospective cohort study. The assessment of the maximum stan-
dardized uptake value (SUV max) of tumor was performed by
independent radiologists who were not aware of the patient’s
clinical histories and were blind with regard to the pathological
findings. The cut-off value for SUV max of tumor was obtained
using receiver operating characteristic (ROC) curve. While,
pathological assessment of resected tumors was performed by
independent pathologists who were blind with regard to imag-
ing findings. Risk factors for MVI were analyzed by multivariate
analyses of clinicopathological variables including SUV max
of tumors. Results: (1) The median SUV max of tumor was 2.9
(2.3-8.4) and 4 (11.1%) patients were positive for SUV max of
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
tumor >5.0. The median tumor marker levels were 10.9 (0.9-
2330)ng/ml for AFP, 3.2 (0.5-77)% for AFP-L3, 34 (10-7676)
mAU/ml for PIVKA-II. 17 nodules (53%) were classified into
simple nodular type, 19 nodules (47%) into non-simple nodular
type from resected specimen. Well-differentiated tumors were
present in 7 (19%) patients, moderately differentiated tumor in
26 (72%) patients, and poorly differentiated tumor in 3 (8%)
patients. Intrahepatic micrometastasis was present in 2 (6%)
patients, and MVI was present in 6 patients (17%) on patho-
logic examination. (2) The SUV max >5.0 was suggested to
be the best cut-off value for predicting the presence of MVI by
ROC curve (area under the curve[AUC]= 0.678). The sensitiv-
ity, specificity, PPV, NPV and accuracy in predicting MVI were
50%, 97%, 75%, 91% and 89% for SUV max of tumor >5.0
respectively. (3) Multivariate analysis showed that SUV max of
tumor >5.0 was an independent and significant risk factor for
MVI (OR29, 95%CI2.3-374, p=0.010). Conclusions: FDG-PET
might be useful for predicting MVI of small HCCs.
Disclosures:
Kazuaki Chayama - Consulting: Abbvie; Grant/Research Support: Dainippon
Sumitomo, Chugai, Mitsubishi Tanabe, DAIICHI SANKYO, Toray, BMS, MSD;
Speaking and Teaching: Chugai, Mitsubishi Tanabe, DAIICHI SANKYO, KYO-
RIN, Nihon Medi-Physics, BMS, Dainippon Sumitomo, MSD, ASKA, Astellas,
AstraZeneca, Eisai, Olympus, GlaxoSmithKline, ZERIA, Bayer, Minophagen,
JANSSEN, JIMRO, TSUMURA, Otsuka, Taiho, Nippon Kayaku, Nippon Shin-
yaku, Takeda, AJINOMOTO, Meiji Seika, Toray
The following people have nothing to disclose: Tomoki Kobayashi, Hiroshi
Aikata, Hiromi Kan, Takayuki Fukuhara, Noriaki Naeshiro, Tomokazu Kawa-
oka, Masataka Tsuge, Akira Hiramatsu, Michio Imamura, Yoshiiku Kawakami,
Hideyuki Hyogo
475
Indication of super-delayed phase image acquisition
of Gd-EOB-DTPA enhanced MRI to improve poor con-
trast images on routine hepatobiliary phase images for
detection of liver lesion
Satoshi Kobayashi, Kazuto Kozaka, Azusa Kitao, Norihide
Yoneda, Hiroshi Ikeno, Osamu Matsui, Toshifumi Gabata; Radiol-
ogy, Kanazawa University School of Medicine, Kanazawa, Japan
Purpose Hepatobiliary phase (HBP) of Gd-EOB-DTPA (EOB)
enhanced MRI enable us to depict most of the hepatic neo-
plasms since normal hepatic hepatocytes uptake EOB and
abnormal lesions do not uptake EOB. However, some of the
cases do not show good parenchymal EOB uptake and difficult
to depict hepatic lesions as hypointense lesion on HBP images
about 20 minutes after EOB injection. The purpose of this study
is to elucidate the significance and indication of super-delayed
phase (SDP) images of Gd-EOB-DTPA enhanced MRI on liver
imaging. Materials and Methods 85 cases, who have exam-
ined EOB enhanced MRI for closer examination of hepatic
lesions, and taken SDP images approximately 90 minutes after
iv administration of EOB are subjected to this study. To evalu-
ate the degree of hepatic enhancement, at first the correlation
between two different index (quantitative liver-spleen contrast
ratio (QLSC) and hepatic vascular/parenchymal enhancement
ratio (HER)) on late phase (LP; obtained 3min. after iv admin-
istration of EOB), HBP and SDP were assessed. Then, Pearson
correlation coefficients were calculated between QLSC of LP
(QLSC-LP), HBP (QLSC-HBP) and SDP (QLSC-SDP). Since 1.5
is determined as sufficient liver enhancement cut-off value of
QLSC on previous studies, cut-off values of QLSC-LP to achieve
100% sensitivity of QLSC-HBP and QLSC-SDP of more than 1.5,
cut-off value of QLSC-HBP to achieve 100% sensitivity of QLSC-
SDP of more than 1.5 were determined. Finally, parenchymal
contrast increase was compared between each Child-Pugh (CP)
class groups with HER. Chi square test was used for statistics
and p<0.05 was considered statistical significant. Result Pear-
433A
son correlation coefficients of two different indexes, QLSC and
HER were 0.75 on LP (p<.0001), 0.88 on HBP (p<.0001),
0.80 on SDP (p<.0001) respectively. Average QLSC-LP, QLSP-
HBP and QLSC-SDP were 0.96±0.23, 1.37±0.44, 1.73±0.58,
respectively. Pearson correlation coefficient between QLSC-LP
and QLSP-HBP, QLSC-LP and QLSC-SDP, QLSP-HBP and QLSC-
SDP were 0.78, 0.61, 0.85, respectively (p<.001 in all com-
binations). Cut-off values of QLSC-LP and QLSC-HBP to achieve
100% sensitivity of QLSC-SDP of more than 1.5 were 1.21
and 1.38 respectively. HER of HBP and SDP in CP-A poor
HBP (n=27), CP-B poor HBP (n=47), CP-C poor HBP (n=2)
were 0.83±0.14 and 0.60±0.13, 0.90±0.16 and 0.65±0.16,
1.03±0.16 and 0.99±0.19, respectively (all combinations
except CP-C showed significance difference). Conclusion SDP
image acquisition in EOB enhanced MRI for evaluation of liver
lesions might be useful technique to acquire good hepatic
parenchymal contrast except in CP-C cases and poor QLSC
cases below than 1.38 on HBP.
Disclosures:
The following people have nothing to disclose: Satoshi Kobayashi, Kazuto
Kozaka, Azusa Kitao, Norihide Yoneda, Hiroshi Ikeno, Osamu Matsui, Toshifumi
Gabata
476
Single-center experience with stereotactic liver surgery:
A review over 5 years
Vanessa M. Banz1, Pascale Tinguely1, Mathias Worni1, Philip
Mueller2, Daniel Inderbitzin1, Delphine Ribes2,3, Matthias Peter-
hans3, Stefan Weber2, Daniel Candinas1; 1Department of Vis-
ceral Surgery and Medicine, Inselspital, University Hospital Berne,
Berne, Switzerland; 2ARTORG Center for Biomedical Engineering,
Berne, Switzerland; 3CAScination AG, Berne, Switzerland
Introduction Image-guided surgical planning can be imperative
in complex liver surgery, facilitating pre- and intra-operative
management. More recently, stereotactic image guidance of
surgical instruments (navigation) has advanced to a clinically
applicable level. This resulted in higher geometric accuracy
during tumor resection/ablation as well as better alignment of
the surgical site with available preoperative imaging compared
to conventional surgery. Here, we aimed to characterize techni-
cal improvements and suitable indications for image-guidance
in open liver surgery. Methods Retrospective, single-center
analysis of 69 prospectively treated patients during 3 phases,
characterized by their registration method (alignment between
site and preoperative image data): registration by surface
landmarks only (phase 1; from 03/09-12/11); single surface
and parenchymal landmarks (phase 2; 01/12-03/13), and
ultrasound (US)-based volume registration (phase 3; 04/13-
05/14). Primary endpoint was accuracy between virtual and
real hepatic lesion measured in millimeters. Secondary end-
point: characterization of indication spectrum. Results Phase
1: 24 patients underwent image-guided liver surgery (IGLS)
with colorectal liver metastases (CRLM; 15 patients), neuroen-
docrine liver metastases (NET; 1 patient), hepatocellular car-
cinoma (HCC; 5 patients), and others (3 patients). Phase 2:
n=19 patients; CRLM=9, NET=1, HCC=6, others=3. Phase 3:
n=26, CRLM=13, NET=7, HCC=2, others=4. Application of
IGLS during phase 1 was performed in highly select patients
according to a feasibility protocol where therapeutic qual-
ity was still unclear (accuracy: 8mm, navigated instrument:
CUSA). Improved technology in phase 2 (accuracy: 8mm in
selected volume of interest (VOI), navigated instruments: CUSA
and microwave ablation (MWA)) allowed broadening the
range of indications without compromising short-term surgi-
cal outcomes. In phase 3 (accuracy: 5 mm in VOI, navigated
434A AASLD ABSTRACTS
instrument: MWA), US-based registration resulted in higher
accuracy allowing use of IGLS also in vanishing and very small,
difficult to target central lesions. Conclusion Patients requiring
MWA +/- targeted resection for multiple, smaller (vanishing)
lesions (eg. bilobar or central CRLM/NET) might benefit most
from IGLS given increased geometric accuracy owing to utili-
zation of US based navigation and challenges for conventional
surgical treatment. Prospective and multicenter clinical trials
including clinically relevant long-term outcome measures such
as recurrence-free and overall survival are needed to better
define the role of IGLS.
Disclosures:
Matthias Peterhans - Employment: CAScination AG; Stock Shareholder: CASci-
nation AG
Stefan Weber - Stock Shareholder: CAScination AG
Daniel Candinas - Board Membership: Cascination AG; Stock Shareholder:
Cascination AG
The following people have nothing to disclose: Vanessa M. Banz, Pascale
Tinguely, Mathias Worni, Philip Mueller, Daniel Inderbitzin, Delphine Ribes
477
Complications related to percutaneous biopsies of the
liver, pancreas, lymph nodes and tumors in the retro-
peritoneal space performed under ultrasound control
Stoyan S. Handzhiev; Dept. Gastroenterology, Hepatology and
Liver Tansplantology,, Military Medical Academy, Sofia, Bulgaria,
Sofia, Bulgaria
Aim: To analyze the frequency, profile and the clinical imag-
ing characteristics of the complications following percutane-
ous biopsies of the liver, pancreas and retroperitoneal targets,
lymph nodes, tumors, and to present an algorithm for in-time
detection, monitoring, treatment and prevention of these com-
plications. Material: An analysis was made on 2200 US
controlled percutaneous biopsies that were followed by hem-
orrhages, pain and fever in some cases: (1150 liver biopsies,
850 pancreatic biopsies, 230 lymph nodes’ and retroperito-
neal tumors for a 10-year period). Methods: The method per-
formed was percutaneous ultrasound controlled large needle
biopsy (LNB) with 18G (1.2mm) and 16G (1.4mm) with Aloka
Prosound 2-5 and α.10 US equipment in real time with Dop-
pler assistance and Contrast-Enhanced Ultrasound (CEUS) in
some cases, with aspiration of and cutting (Tru-cut) in automatic
mode (Gun-like) and semiautomatic regime of shooting. Results:
In 15 (1.3%) cases with liver biopsies hemorrhagic complica-
tions followed the procedure as in 1 (0.08%) with a large met-
astatic liver the massive hemoperitoneum ended in death and
in 2 (0.17%) a hemorrhagic shock developed without fatal out-
come. In 14 (1.6%) cases with pancreatic biopsies hematoperi-
toneum developed without fatal outcome and without shock.
In 245 (29%) and in 135 (16%) from the series, pain and
fever respectively were to be found, but were not present 12
hours after the puncture. In the rest 230 retroperitoneal biop-
sies of lymph nodes and tumor formations we did not observe
any complications of clinical importance. The results’ analysis
shows a direct relationship between the number of the biopsy
shots (more than 2)and the type of target lesion (liver cirrhosis,
metastatic liver, primary liver cancer, lymphangiomahepatis)
and the following hemorrhagic complications as well as a lack
of relationship between the size of the needle (18 or 16 G),
the biopsy mode (aspiration; Tru-cut) and the mechanism of the
shooting device (automatic or semi-automatic).
Disclosures:
The following people have nothing to disclose: Stoyan S. Handzhiev
HEPATOLOGY, October, 2014
478
Increased Rate of Pre-transplant Magnetic Resonance
Imaging Under-staging of Hepatocellular Carcinoma in
Patients With Transjugular Intrahepatic Portosystemic
Shunts
She-Yan Wong1, Dina Halegoua-De Marzio1, Colette Shaw2,
Jesse M. Civan1; 1Gastroenterology and Hepatology, Thomas Jef-
ferson University Hospital, Philadelphia, PA; 2Radiology, Thomas
Jefferson University Hospital, Philadelphia, PA
Introduction: Patients undergoing liver transplantation with
hepatocellular carcinoma (HCC) within Milan Criteria have
better outcomes. Although radiographic under-staging has
been previously reported at 25-40%, it is unknown whether
patients with transjugular intrahepatic portosystemic shunts
(TIPS) are at increased risk for under-staging. Our aim was to
correlate staging on pre-operative magnetic resonance imag-
ing (MRI) with explant surgical pathology, in patients with
HCC and TIPS, undergoing liver transplantation. Methods: This
was a single center retrospective observational study of all
patients, with HCC and TIPS, undergoing liver transplantation
from 1/1/00 to 12/31/12, and with pre-transplant MRI per-
formed within 90 days of surgery. Correlation between MRI
and surgical pathology was assessed by manual review of
formal reports. Technical limitations of MRI quality, and any
history of loco-regional therapy, were noted. Results: Of 169
patients undergoing liver transplant with HCC at our center,
12 met inclusion criteria. Of these, 6 patients (50%) had TNM
under-staging on MRI as compared to liver explant pathology,
including 2 patients (16.7%) beyond Milan Criteria on explant
surgical pathology. Disagreement on staging was T0 vs. T1
in 1 case, T1 vs T2 in 3 cases, and T0 vs. T2 in 2 cases. No
patients were found to be over-staged. Of the patients with
under-staging, specific limitations in quality of pre-transplant
MRI were noted in 3 cases (50%). Details of staging and prior
loco-regional treatments are summarized in Table 1. Conclu-
sion: We observed under-staging in 50% of patients undergo-
ing liver transplant with HCC and TIPS, which is a rate higher
than previously reported for the larger population of patients
undergoing liver transplant for HCC. We speculate that a com-
bination of scatter artifact from the TIPS itself, as well as alter-
ations in blood flow to the tumor due to the TIPS, contributed to
this phenomenon. Therefore, heightened surveillance of HCC
in patients with TIPS may be indicated.
Table 1
Disclosures:
Jesse M. Civan - Advisory Committees or Review Panels: Salix Pharmaceuticals;
Consulting: Merck
The following people have nothing to disclose: She-Yan Wong, Dina Hale-
goua-De Marzio, Colette Shaw
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
479
Hepatic Angiomyolipoma Mimicking Hepatocellular
Carcinoma: Clinical, Magnetic Resonance Imaging and
Pathological Characteristics in 9 Cases
Chunping Wang1, Hongyan Li1, Hong Wang1, Xiaodong Guo2,
Changchun Liu3, Xudong Gao1, Jianhui Qu1, Ze Liu1, Xiu juan
Chang1, Yin Ying Lu1, Zhen Zeng1, Min Lou1, Ke-Qin Hu4, Yong-
ping Yang1; 1Center of Therapeutic Research for Hepatocellular
Carcinoma, 302nd Hospital, Beijing, Beijing, China; 2Center of
Pathology, 302 Hospital, Beijing, China; 3Center of Radiology,
302 Hospital, Beijing, China; 4Division of GI/Hepatology, Uni-
versity of Califrnia, Irvine, School of Medicine, Orange, CA, USA,
Irvine, CA
Background & Aims: Hepatic angiomyolipoma (HAML) is a
rare mesenchymal tumor of the liver with marked histologi-
cal diversity. The present study was to review the magnetic
resonance imaging (MRI) and clinical pathological features
of HAML resembling hepatocellular carcinoma (HCC). Meth-
ods: Nine patients who underwent surgical resection and had
pathological diagnosis of HAML were retrospectively analyzed.
Results: All nine patients had a solitary hepatic mass with a
median size of 4 cm (from 1.4cm to 15.3 cm). Seven cases
were identified as incidental liver tumors during health screen-
ing and two patients were diagnosed for hepatic mass when
visited hospitals with unspecific abdominal discomfort. Prior to
resection, six cases were diagnosed as HCC on MRI. As shown
in Figure 1, MRI with dual-echo sequences showed a large
amount of lipids in five cases. The enhancement pattern of MRI
was classified into two types, in 2 cases, lesions with small or
no vessels which demonstrated prolonged enhancement (one
mixed type and one myomatous type) and in 7 cases, lesions
with abundant central vessels which rapidly decreased (three
mixed types and four myomatous types) in the portal venous/
delayed phase. All patients underwent resection of hepatic
tumor and no recurrence was observed during follow-up of
median 10 months. By immunohistochemistry, the tumor cells
demonstrated positive immunostaining for human melanoma
black-45, smooth muscle actin, and CD34. Conclusions: All
our 9 patients with HAML presented with none, or non-specific
clinical manifestations. The definitive diagnosis of HAML relies
on pathology and immunohistochemistry, but not MRI. Key-
words: Liver; Angiomyolipoma
Fig. 1 MR imaging of mixed type(A and B) and myomatous pre-
dominant(C and D) HAML. a: double echo sequence; b: fat sup-
pression sequence; c: T1 sequence; d: T2 sequence; e: arterial
phase; f:portal venous phase; g:delayed phase;h:histopathology.
Type I(A,C): Enhanced scanning showed obvious enhancement
in arterial phase, which was strengthened in portal venous and
delayed phase . Type II(B,D): lesions showed obvious enhance-
ment in arterial phase, while disappeared in portal venous and
delayed phase.
Disclosures:
Ke-Qin Hu - Grant/Research Support: BMS, Gilead, Merck, Vertex, Genentech;
Speaking and Teaching: BMS, Gilead, Merck, Vertex, Genentech
435A
The following people have nothing to disclose: Chunping Wang, Hongyan Li,
Hong Wang, Xiaodong Guo, Changchun Liu, Xudong Gao, Jianhui Qu, Ze Liu,
Xiu juan Chang, Yin Ying Lu, Zhen Zeng, Min Lou, Yongping Yang
480
Metabolic tumor volume by Fluorine-18 fluorodeoxyglu-
cose positron emission tomography as useful predictor
for early recurrence after recurrence in intrahepatic
cholangiocarcinoma
Satoru Seo1, Etsuro Hatano1, Yuji Nakamoto2, Kenji Takemoto1,
Kojiro Taura1, Tadahiro Uemura1, Kentaro Yasuchika1, Akira
Mori1, Toshimi Kaido1, Hideaki Okajima1, Shinji Uemoto1; 1Sur-
gery, Kyoto University, Kyoto, Japan; 2Diagnostic Imaging and
Nuclear Medicine, Kyoto University, Kyoto, Japan
Background: Patients with intrahepatic cholangiocarcinoma
(ICC) have poor prognosis. Fluorine-18 fluorodeoxyglucose
positron emission tomography (FDG-PET) has been widely used
to diagnose various tumors. We previously reported that FDG-
PET was useful tool to predict lymph node metastasis, P-gp
expression and recurrence of ICC. Recently, metabolic tumor
volume (MTV) measured by FDG-PET has been introduced to
show overall tumor activity of glucose metabolism, while stan-
dardized uptake value (SUV) shows only one point of tumor
activity. Purpose: The current study was designed to evaluate
the usefulness of MTV for predicting post-operative early recur-
rence in ICC by FDG-PET. Methods: Eighteen patients with ICC
undergoing hepatectomy between May 2005 and February
2013 were enrolled in this study. SUV max and MTV were
measured, and all values are expressed as means ± SD. Differ-
ences between two groups were analyzed using Student’s t-test
as unpaired data. The survival rate was calculated using the
Kaplan-Maier method and risk factors for early recurrence of
ICC within 6 months were analyzed in univariate and multivar-
iate fashion with clinical and pathological factors. A P-value <
0.05 was considered statistically significant. Results: Five-year
survival rate was 47.8%. Eight patients (44.4%) had post-op-
erative early recurrence. MTV was significantly higher in early
recurrence group (291.8 ± 275.7) than that in no early recur-
rence group (14.1 ± 10.7, P=0.0055), while SUV was signifi-
cantly higher in early recurrence group (7.9 ± 1.5) than that
in no early recurrence group (5.5 ± 1.9, P=0.012). In univari-
ate analysis, early recurrence group had more tumor numbers
(P = 0.0112), MTV>30cm3 (P = 0.0189), and larger tumor
size (P = 0.0033) compared to no early recurrence group. In
multivariate analysis, MTV>30cm3 was an only independent
predictor of post-operative early recurrence (odds ratio: 4.8; p
= 0.0022). Conclusion: MTV by FDG-PET could be more useful
predictor for post-operative early recurrence of ICC than SUV.
Disclosures:
The following people have nothing to disclose: Satoru Seo, Etsuro Hatano, Yuji
Nakamoto, Kenji Takemoto, Kojiro Taura, Tadahiro Uemura, Kentaro Yasuchika,
Akira Mori, Toshimi Kaido, Hideaki Okajima, Shinji Uemoto
436A AASLD ABSTRACTS
481
A safety, feasibility and accuracy study of laparoscopic
computer-assisted navigated microwave ablation of
liver tumors
Pascale Tinguely1, Delphine Ribes3,4, Jacob Freedman2, Silja Karl-
gren2, Fusagila Matteo3, Matthias Peterhans4, Stefan Weber3,
Daniel Candinas1, Henrik Nilsson2; 1Department of Visceral
Surgery and Medicine, University Hospital of Berne, Berne, Swit-
zerland; 2Division of Surgery, Department of Clinical Sciences,
Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden;
3ARTORG Center for Biomedical Engineering, Berne, Switzerland;
4Cascination AG, Berne, Switzerland
Objective In cases where resection of malignant liver lesions
is not possible, local ablation can be an alternative to obtain
cure. In situations where a percutaneous approach for some
reason is precluded, laparoscopy in combination with nav-
igation technology based on preoperative imaging enables
a minimally invasive approach for ablative treatment. This
study aimed to evaluate the safety, feasibility and accuracy
of microwave ablation (MWA) of malignant liver lesions using
laparoscopic computer assisted liver surgery (LCALS). Methods
Patients presenting with primary liver tumors or liver metastases
treated by MWA assisted by LCALS (CASCination AG, Swit-
zerland) in two centers were included in the study. Based on
preoperative images where lesions were visible, 3D reconstruc-
tions of the liver were obtained. After minimal laparoscopic
mobilization of the liver, a 4-landmark registration method was
applied to match the liver to the model and enable navigation.
Placement of microwave needles was performed using the tar-
geting module of the navigation system. MWA was carried
out by application of microwave energy at 100-120 W with
ablation time adjusted to lesion size. Registration accuracy
was assessed by fiducial registration error (FRE). The number
of registration attempts and time needed for each registration
was measured as well as operating time and length of stay
(LOS). Clavien-Dindo scores were used to evaluate postop-
erative complications. Results During a 15-month period, a
total of 26 patients (12 HCC, 12 colorectal cancer metastases,
2 neuroendocrine metastases) were included with a median
of 3 lesions (min 1-max 25) treated in each patient. Median
lesion size was 1.16ml (0.1-34.2). A median of 3 (1-26)
attempts of registration was necessary to reach a median FRE
of 8.58 mm (2.54-13.95). Median time of registration was
1min (25s-4.20min). Median operating time was 69 minutes
(31-301) and median LOS was 2 (1-11) days. Conversion to
open surgery was necessary in one case. Nine patients had
mild complications (Clavien-Dindo grade I-II) and one had a
grade IIIa complication (liver abscess). There was no 30-day
mortality. Out of 146 lesions targeted, 15 lesions (22 %) were
incompletely ablated according to CT or MRI at one month
follow-up. Conclusions MWA using LCALS is technically feasi-
ble and safe with low complication rates and short associated
LOS. The targeting accuracy is acceptable and possible also
with a high number of lesions in selected cases. In contrast to
mere ultrasound-guided ablation, LCALS offers a wider range
of targeting trajectories making more lesions accessible for safe
ablation, and also allows treatment of vanishing lesions.
Disclosures:
Delphine Ribes - Employment: CAScination
Matthias Peterhans - Employment: CAScination AG; Stock Shareholder: CASci-
nation AG
Stefan Weber - Stock Shareholder: CAScination AG
Daniel Candinas - Board Membership: Cascination AG; Stock Shareholder:
Cascination AG
The following people have nothing to disclose: Pascale Tinguely, Jacob Freed-
man, Silja Karlgren, Fusagila Matteo, Henrik Nilsson
HEPATOLOGY, October, 2014
482
Diagnostic Accuracy and Reliability of Supersonic Shear
Imaging in Comparison with Transient Elastography
for Assessment of Liver Fibrosis in Patients with Chronic
Liver Disease
Masato Yoneda, Emmanuel Thomas, Seth N. Sclair, Eugene R.
Schiff; Schiff Center for Liver Diseases, University of Miami Miller
School of Medicine, Miami, FL
Background & Aims: Assessment of the severity of liver fibrosis
is critical for the evaluation and determination of prognosis in
patients with chronic liver disease (CLD). Transient elastography
(TE) received approval from the U.S. Food and Drug Adminis-
tration (FDA) in 2013 and it is predicted that clinicians in the
U.S will be using it increasingly. The aim of this study was to
compare elastography measurments of liver fibrosis using the
Supersonic Shear Imaging (SSI) and TE in CLD. Methods: This
was a prospective study of 195 patients (mean age 56.8; BMI
26.5) in which liver stiffness was assessed using TE (M probe
or XL probe used when the M probe is unreliable for obtaining
measurement in obese patients) and SSI during the same clinic
visit. Our study included patients with the following underlying
liver conditions: 121 chronic hepatitis C, 19 chronic hepatitis
B, 17 NAFLD, 7 PBC 8 PSC, 9 HCV/HIV and 14 with other
liver diseases. We acquired reliable measurements using the
median value obtained from 10 (TE) or 5 (SSI) valid liver stiff-
ness measurements (LSM), respectively with a success rate of >
60% with an IQR of < 30%. Results: By TE, reliable LSM were
obtained in 112 (57.4%) and 78 (40%) patients using the M
and XL probe, respectively in 190 out of 195 patients (total
reliability of TE was 97.4%). The mean BMI was 24.0 kg/m2
and 29.7kg/m2, respectively. On the other hand, reliable LSM
were obtained in 176 (90.3%) patients by SSI. When reliable
measurements were obtained, there was a very significant cor-
relation between LSM obtained by TE and SSI (r = 0.91, p
<0.0001). LSM obtained by TE and SSI were also significantly
correlated with noninvasive scoring systems such as FIB4, AST/
ALT ratio, and AST to platelet ratio. When compared with histo-
logical findings from 95 patients who underwent liver biopsy,
the AUROC by TE and SSI for detecting fibrosis stage F > 3
was 0.877 (sensitivity 69%, specificity 94%) and 0.898 (sensi-
tivity 92%, specificity 75%), respectively. Furthermore, AUROC
for detecting cirrhosis (F=4) by TE and SSI were 0.9453 (sen-
sitivity 90%, specificity 93%) and 0.9741 (sensitivity 100%,
specificity 87%), respectively. Conclusions: When only the M
probe was used, a significantly lower percentage of reliable
LSM were made using TE as compared to SSI. When the XL
probe is utilized, TE was more reliable than SSI in determining
liver stiffness in obese patients. Therefore, similar or higher
rates of reliable LSM were made with TE as compared to SSI
when both the M and XL probes were used. Furthermore, SSI
and TE were similarly accurate in diagnosing liver fibrosis in
patients with chronic liver disease.
Disclosures:
Eugene R. Schiff - Advisory Committees or Review Panels: Bristol Myers Squibb,
Gilead, Merck, Janssen, Salix Pharmaceutical, Pfizer; Grant/Research Support:
Bristol Myers Squibb, Abbott / AbbVee, Gilead, Merck, Conatus, Medmira,
Roche, Janssen, Orasure Technologies, Discovery Life Sciences, Siemens
The following people have nothing to disclose: Masato Yoneda, Emmanuel
Thomas, Seth N. Sclair
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
483
Recombinant Human Acid Sphingomyelinase Clears
Hepatic Sphingomyelin in Adults with Niemann-Pick
Disease Type B
Beth Thurberg1, Melissa Wasserstein2, Simon Jones3, Thomas D.
Schiano2, Gerald F. Cox1; 1Genzyme, a Sanofi company, Cam-
bridge, MA; 2Icahn School of Medicine at Mount Sinai, New York,
NY; 3Manchester Centre for Genomic Medicine St. Mary’s Hospi-
tal, CMFT, University of Manchester, Manchester, United Kingdom
Introduction: Acid sphingomyelinase deficiency (ASMD) is a
lysosomal storage disorder characterized by abnormal sphin-
gomyelin accumulation in multiple cell types, primarily within
the liver, spleen, and lungs, leading to significant clinical
disease. The clinical spectrum ranges from an infantile-onset
visceral and neurodegenerative disease with death in early
childhood (Niemann-Pick Disease type A; NPD A) to a vari-
able-onset visceral disease with no neurodegeneration and
prolonged survival (Niemann-Pick Disease type B; NPD B).
Liver manifestations include hepatomegaly, fibrosis, and cir-
rhosis. Recombinant human acid sphingomyelinase (rhASM)
is in early clinical development as an enzyme replacement
therapy for the non-neurological manifestations of ASMD. A
phase 1 single-ascending-dose study investigated the safety
and pharmacokinetics (PK) of single dose administration of
rhASM in adult patients. A phase 1b study was conducted to
evaluate the tolerability, safety, and PK of repeat-dose admin-
istrations of rhASM in adult patients. This study also assessed
the pharmacodynamic effects of rhASM in liver biopsies after
6 months of treatment. Methods: Five adult patients with NPD
B underwent within-patient dose escalation of intravenous
rhASM every 2 weeks starting at 0.1 mg/kg and reaching the
maximum targeted dose of 3 mg/kg. Liver biopsies obtained
at baseline and 6 months post-treatment were evaluated for
sphingomyelin accumulation by morphometric analysis at the
light microscopic level, and were further examined by electron
microscopy. Results: At baseline, sphingomyelin storage was
present in both Kupffer cells and hepatocytes, and ranged from
9.8% to 58.8% of the microscopic field. After 6 months of
treatment, all 4 patients with evaluable liver biopsies (one of
five post-treatment biopsies was insufficient for sphingomyelin
evaluation) showed significant reductions in sphingomyelin.
Sphingomyelin storage in post-treatment biopsies ranged from
1.2% to 9.5% of the microscopic field, corresponding to an
84% to 92% reduction from baseline. Conclusions: This is the
first study to demonstrate the histopathological clearance of
hepatic sphingomyelin in patients with ASMD by rhASM. The
reduction in liver sphingomyelin illustrates the pharmacody-
namic impact of rhASM on ASMD.
Disclosures:
Beth Thurberg - Employment: Genzyme, a Sanofi company
Simon Jones - Advisory Committees or Review Panels: Synageva BioPharma,
genzyme, shire, biomarin; Grant/Research Support: Synageva BioPharma, shire,
biomarin, genzyme, ultragenyx
Thomas D. Schiano - Advisory Committees or Review Panels: vertex, salix, merck,
gilead, pfizer; Grant/Research Support: massbiologics, itherx
Gerald F. Cox - Advisory Committees or Review Panels: Roche, Cognition Ther-
apeutics, Neurophage; Grant/Research Support: Probiodrug, GE Healthcare;
Management Position: Genzyme, a Sanofi company
The following people have nothing to disclose: Melissa Wasserstein
437A
484
Comparison of 2-dimensional and 3-dimensional
magnetic resonance elastography (MRE) for diagnosis
of advanced fibrosis in patients with biopsy-proven
NAFLD: A prospective study
Rohit Loomba1,2, Tanya Wolfson2, William Haufe4, Jonathan
Hooker4, Nikolaus M. Szeverenyi4, Brandon Ang3, Archana
Bhatt3, Cynthia A. Behling7, Mark A. Valasek5, Grace Y. Lin5,
Anthony C. Gamst2, David A. Brenner1, Meng Yin6, Richard
Ehman6, Claude B. Sirlin4; 1Division of Gastroenterology and
Epidemiology, University of California, San Diego, La Jolla, CA;
2Computational and Applied Statistics Laboratory (CASL), SDSC,
University of California, San Diego, La Jolla, CA; 3NAFLD Trans-
lational Research Unit, Division of Gastroenterology, University
of California, San Diego, La Jolla, CA; 4Liver Imaging Group,
Department of Radiology, University of California, San Diego, La
Jolla, CA; 5Department of Pathology, University of California, San
Diego, La Jolla, CA; 6Department of Radiology, Mayo Clinic, Roch-
ester, MN; 7Department of Pathology, SHARP Memorial Hospital,
San Diego, CA
Introduction: Magnetic resonance elastography (MRE) quan-
titatively depicts liver stiffness by imaging applied mechan-
ical waves in the liver. In general, this requires 3D imaging
of the wavefield. However, commercially-available MRE sys-
tems use special technology to create wave patterns that can
be adequately captured with single 2D images, simplifying
the implementation and allowing it to be used on almost any
MRI scanner. While 2D-MRE requires certain approximations,
studies have that it has high performance in the diagnosis of
hepatic fibrosis. However, a 3D-MRE approach remains attrac-
tive, promising even more accurate measurements. Advances
in MRI technology have made 3D-MRE feasible on certain
MRI systems. This is the first report of diagnostic accuracy of
3D-MRE compared with 2D-MRE in predicting advanced fibro-
sis. Aim: The aim of this study was to prospectively assess
the diagnostic accuracy of 3D-MRE and compare it to that of
2D-MRE for diagnosis of advanced fibrosis in patients with
biopsy-proven NAFLD. Methods: This cross-sectional analysis
of a prospective study included 102 consecutive patients (55%
women) with biopsy-proven NAFLD who underwent a stan-
dardized research visit: history, clinical exam, liver biopsy and
MRE. ROC analysis was performed to assess the accuracy of
MRE in diagnosing advanced fibrosis (stage 3 and 4). The
radiologist and pathologist were blinded to clinical and pathol-
ogy/imaging data, respectively. Biopsies were scored with
the NASH-CRN histologic system. Results: The mean (±sd) of
age and BMI was 50.4 (± 13.6) yrs and 32.2 (± 5) kg/m2,
respectively. The median time interval between biopsy and
3D-MRE was 39 days (range 22-46). The number of patients
with fibrosis stage 0, 1, 2, 3 and 4 were 41, 34, 12, 10 and
5. The area under the ROC curve (AUROC) for discriminat-
ing advanced fibrosis from stage 0-2 fibrosis for 3D-MRE was
0.981 (p-value<0.001) and for 2D-MRE was 0.920 (p-value
<0.001), respectively. The best threshold of 3D-MRE for sep-
arating advanced fibrosis from stage 0-2 fibrosis was ≥ 2.43
Kpa, and it had a sensitivity of 1 (95% CI, 0.75-1), specific-
ity 0.94 (95% CI, 0.86-0.98), PPV 0.72 (95% CI,0.47-0.90)
and NPV 1.0 (95% CI, 0.95-1). 5 (out of 79) patients with
stage 0-2 fibrosis were misclassified but all 15 patients with
advanced fibrosis were correctly classified. In head-to-head
comparison, 3D-MRE had higher AUROC than 2D-MRE for
diagnosis of advanced fibrosis (p-value<0.05). Conclusions:
This prospective study showed that while 2D-MRE has robust
characteristics for detection of advanced fibrosis in patients
with biopsy-proven NAFLD, a 3D-MRE approach provides even
higher diagnostic performance.
438A AASLD ABSTRACTS
Disclosures:
Rohit Loomba - Consulting: Gilead Inc, Corgenix Inc, Janssen and Janssen Inc;
Grant/Research Support: Daiichi Sankyo Inc, AGA, Merck Inc
Cynthia A. Behling - Grant/Research Support: NASH CRN
Meng Yin - Patent Held/Filed: Mayo Clinic, Mayo Clinic, Mayo Clinic, Mayo
Clinic
Richard Ehman - Board Membership: Resoundant Inc; Management Position:
Resoundant Inc; Patent Held/Filed: Mayo Clinic / GE, Mayo Clinic / GE; Stock
Shareholder: Resoundant Inc.
Claude B. Sirlin - Advisory Committees or Review Panels: Bayer; Grant/Research
Support: GE, Pfizer, Bayer; Speaking and Teaching: Bayer
The following people have nothing to disclose: Tanya Wolfson, William Haufe,
Jonathan Hooker, Nikolaus M. Szeverenyi, Brandon Ang, Archana Bhatt, Mark
A. Valasek, Grace Y. Lin, Anthony C. Gamst, David A. Brenner
485
The feasability of Transient Elastography using M and
XL probes for assesing liver stiffness – a practice audit
of 3235 examinations on a multi-etiology cohort
Ioan Sporea, Flavia Motiu, Alina Popescu, Roxana Sirli, Ruxandra
G. Mare, Oana Gradinaru Tascau, Alexandra Deleanu, Isabel
Dan; Department of Gastroenterology and Hepatology, “Victor
Babes” University of Medicine and Pharmacy, Timisoara, Roma-
nia, Timisoara, Romania
Introduction: Liver Stiffness Measurements (LSMs) using Tran-
sient Elastography (TE) is widely used in the management of
the patients with chronic liver disease. Aim: to examine the
feasibility and reliability of LSM by TE and to assess the benefit
of using both M and XL probes. Materials and methods: We
studied retrospectively a group of 3235 patients with chronic
liver disease (chronic hepatitis HCV, HBV, ethanolic, ASH,
NASH, Primary biliary cirrhosis, autoimmune hepatitis) referred
to our Department to assess liver fibrosis by TE. We used the
M Probe (standard probe – transducer frequency 3.5 MHz)
and XL Probe (transducer frequency 2.5 MHz) in overweight
and obese patients. In all patients the M probe was used first,
and if the results were unreliable we used the XL probe. Reli-
able measurements were defined as the median of 10 valid
measurements with a success rate ≥ 60% and an interquar-
tile range < 30%. Results of liver elasticity were expressed in
kiloPascals (kPa). Results: The studied group included 3235
patients with an average BMI of 28 kg/m2. Valid measure-
ments were obtained by M probe in 2015 patients (62.2%)
with an average BMI of 26.1 kg/m2. The average BMI of the
patients evaluated with XL probe was 31.3 kg/m2, higher than
in patients who could be evaluated by M probe. Of the 1220
patients with unreliable results with M probe, valid measure-
ments were obtained with XL probe in 1011 patients (80%).
Only in 209 cases we did not obtain valid measurements with
either probe, finally we obtained valid measurements in 93.5%
of cases. Conclusion: The feasibility of M probe was 62.2 %
in our Department. Reliable measurements using both M or
XL probe allowed the evaluation of liver stiffness in 93.5% of
cases. The use of XL probe, especially in patients with BMI>
29 kg/m2 increases the feasibility of non-invasive diagnosis of
liver fibrosis by TE.
Disclosures:
Ioan Sporea - Advisory Committees or Review Panels: Siemens
The following people have nothing to disclose: Flavia Motiu, Alina Popescu,
Roxana Sirli, Ruxandra G. Mare, Oana Gradinaru Tascau, Alexandra Deleanu,
Isabel Dan
HEPATOLOGY, October, 2014
486
Quantitative Assessment of Liver Fibrosis by Digital
Image Analysis: Relationship to Ishak Staging and Elas-
ticity by Shear-wave Elastography
Ender G. Yegin1, Korkut Yegin2, Faruk Erdem Kombak1, Emrah
Karatay1, Davut Tüney1, Cigdem Ataizi Celikel1, Osman C. Ozdo-
gan1; 1Marmara University Faculty of Medicine, Istanbul, Turkey;
2Electrical and Electronics Engineering, Yeditepe University, Istan-
bul, Turkey
Background: Assessment of liver fibrosis is critical in determin-
ing the value of non-invasive surrogate tests. Diagnostic accu-
racies of surrogates usually rely on histopathological stagings
as the comparator which describe architectural fibrosis patterns
without quantifying the amount. Our aim was to analyze the
relationship between fibrosis staged by Ishak and quantified
by digital image analysis (DIA), and to reveal the optimum
performance of shear-wave elastography (SWE) using quanti-
tative DIA measurements as comparative histological standard.
Patients and methods: The area proportion of fibrosis (PA%)
were measured by DIA from images of trichrome, collagen I and
III immunohistochemistry stained sections of 168 chronic hepati-
tis patients. SWE was performed in 105 patients. The accuracy
of SWE for predicting fibrosis levels defined by quantitative
PA thresholds (≥2.5%, ≥5%, ≥10%, ≥20%) as well as by Ishak
stages was assessed using area under ROC curves (AUROCs).
Results: DIA was highly reproducible (ICC=0.926–0.961) with
all three stains. A good correlation between PA and elasticity
was present for more advanced fibrotic disease (trichrome PA≥
10%, rs=0.732, p=0.000) rather than milder fibrotic disease
(trichrome PA <10%, rs=0.308, p=0.006). With the advance-
ment of fibrosis either by stages or PA thresholds, discriminative
accuracy of SWE gradually increased, but was less satisfactory
for milder fibrosis levels (AUROCs; F≥1-0.711, F≥2-0.692,
F≥3-0.740, F≥4-0.832, F≥(5-6)-0.966; trichrome PA ≥2.5%-
0.754, ≥5%-0.768, ≥10%-0.840, ≥20%-0.968). Conclusions:
DIA may serve as a reproducible quantitative reference stan-
dard for surrogate tests. SWE‘s performance and correlation
with fibrosis amount were better for advanced levels of fibrosis,
but less satisfactory for milder fibrosis levels.
Disclosures:
The following people have nothing to disclose: Ender G. Yegin, Korkut Yegin,
Faruk Erdem Kombak, Emrah Karatay, Davut Tüney, Cigdem Ataizi Celikel,
Osman C. Ozdogan
487
Accuracy of Real-Time Shear Wave Elastography for
Assessing Liver Fibrosis in Chronic Liver Disease: A Pilot
Study
Oranit Cohen-Ezra1,5, Yeroham Kleinbaum2,5, Orit Pappo3, Muriel
Webb4, Ella Veitsman1, Tania Bradichevsky1,5, Yael Inbar2,5,
Sima Katsherginsky2, Peretz Weiss1, Keren Tsaraf1, Ziv Ben-Ari1,5;
1Liver Disease Center, Sheba Medical Center, Ramat Gan, Israel;
2Department of Radiology, Sheba Medical Center, Ramat Gan,
Israel; 3Department of Histopathology, Sheba Medical Center,
Ramat Gan, Israel; 4Gastroenterology Institute, Sourasky Medical
Center, Tel Aviv, Israel; 5Sackler School of Medicine, Tel Aviv
University, Tel Aviv, Israel
Real-time shear wave elastography (SWE) is a novel, nonin-
vasive method to assess liver fibrosis stage by measuring liver
stiffness. SWE has the advantage over transient elastography
of imaging liver stiffness in real time while guided by a B-mode
image. Thus, the region of measurement can be guided with
both anatomical and tissue stiffness information.This single-cen-
ter study was conducted to assess the accuracy of SWE in
patients with chronic liver disease in comparison with liver
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
biopsy. Six hundred and eighty five consecutive patients
with chronic liver disease (age 49.3 ± 14.2 years, 52.3%
male, BMI 26.8 ± 5.8m2/kg) scheduled for SWE (using the
ultrasound system, Aixplorer SuperSonic Imagine, France) by
referring physicians were studied. The liver disease etiology
was HCV in 78.3%, NAFLD in 10.3% and other etiologies
in 11.4% (HBV, PBC, PSC). The hepatic fibrosis stage using
SWE were compared with the histological findings on liver
biopsy (as the reference standard) performed in 76 patients.
Fibrosis was staged according to the METAVIR scoring sys-
tem. Analyses of receiver operating characteristic (ROC) curve
were performed to calculate optimal area under the ROC
curve (AUROC) for F0- F1 versus F2-F4, F0-F2 versus F3- F4
and F0-F3 versus F4 for real-time SWE. Using real-time SWE,
liver stiffness values increased in parallel with degree of liver
fibrosis. When comparing F0-F1 versus F2- F4 (significant
fibrosis), F0-F2 versus F3- F4 (significant fibrosis) and F0-F3
versus F4 (cirrhosis) AUROCs were: 0.978 (95%CI: 0.0173,
0.9463) (P < 0.0001) and 0.986 (95% CI: 0.9646, 1.00) (P
< 0.0001) and 0.971 (95%CI: 0.9338, 1.00) (P < 0.0001)
respectively for SWE. The technical failure of the real-time SWE
was 2.64%. Conclusion: The performance of real-time SWE in
diagnosing cirrhosis was excellent. Real-time SWE is highly
accurate in assessing significant fibrosis (≥F2). SWE is effective
in the non-invasive assessment of liver fibrosis, and its inclusion
in an ultrasound device could facilitate its incorporation into
routine clinical practice.
Disclosures:
The following people have nothing to disclose: Oranit Cohen-Ezra, Yeroham
Kleinbaum, Orit Pappo, Muriel Webb, Ella Veitsman, Tania Bradichevsky, Yael
Inbar, Sima Katsherginsky, Peretz Weiss, Keren Tsaraf, Ziv Ben-Ari
488
The Usefulness of Non-invasive Liver Stiffness Measure-
ment by Fibroscan® for Risk Management of HCC in
Chronic Hepatitis C Patients Who Achieved Sustained
Virological Response (SVR)
Nobuhito Taniki1, Hirotoshi Ebinuma1, Nobuhiro Nakamoto1,
Akihiro Yamaguchi1, Takeru Amiya1, Yuko Wakayama1, Hiroko
Murata1, Po-sung Chu1, Shingo Usui1, Hidetsugu Saito2, Takanori
Kanai1; 1Keio University, School Of Medicine, Tokyo, Japan;
2Keio University, School of Pharmacy, Tokyo, Japan
Background and aims: The introduction of direct acting anti-
viral agents (DAAs) has dramatically increased the SVR rate
in chronic hepatitis C treatment. It is believed that when
patients achieve SVR, the degree of liver fibrosis improves, and
therefore, the incidence of hepatocellular carcinoma (HCC)
decreases. However, clinically, HCC does occur in some
patients who achieved SVR. Previously we reported the useful-
ness of non-invasive liver stiffness measurement by Fibroscan®
for HCC prediction in chronic hepatitis C patients. In this study,
we focus on liver oncogenesis in patients who achieved SVR
and evaluate the usefulness of non-invasive liver stiffness mea-
surement by Fibroscan®. Methods: From April 2003 to May
2014, 946 patients of chronic hepatitis C, who underwent
measurement of liver stiffness by Fibroscan® at our depart-
ment were included, and were analyzed retrospectively in this
study. These patients were grouped as SVR and non-SVR cases,
and factors contributing to liver oncogenesis were analyzed
in each group. These factors include gender, age, platelets
count, serum type 4 collagen-7S, liver stiffness (measured by
Fibroscan®), albumin, total bilirubin, prothrombin time, and
the degree of liver steatosis evaluated by controlled attenuation
parameter (CAP, measured by Fibroscan®) and liver to spleen
(L/S) ratio of computed tomography (CT) density. Result: Of the
439A
946 patients included in this study, one hundred and fourteen
patients (12.1%) achieved SVR. Twenty-one patients (18.4%)
from the SVR group developed HCC during follow-up, while
304 patients (36.5%) in non-SVR group. In analysis of the all
patients, age, platelets, type 4 collagen-7S, liver stiffness, albu-
min, prothrombin time, total bilirubin and CAP were significant
correlating factors to liver oncogenesis by univariate analysis.
On the other hand, in SVR patients, only age, liver stiffness and
albumin remain significant. Moreover, by multivariate analysis
using logistic regression analysis showed that only age and
liver stiffness remain as correlating factors to liver oncogenesis,
both in analyses of all cases and the SVR group. In SVR group,
HCC may be well predicted by age, with cut-off value set at
over 68 years (AUC=0.7854), and by liver stiffness, with cut-
off value set at over 10.8kPa (AUC=0.79509). Conclusion:
Non-invasive liver stiffness measurement by Fibroscan® is use-
ful for HCC prediction not only in patients of persistent HCV
infection, but also in patients who achieved SVR. Moreover,
age remains significant predictive factor in SVR cases, and
regular HCC screening is still necessary for those patients who
achieved SVR.
Disclosures:
The following people have nothing to disclose: Nobuhito Taniki, Hirotoshi
Ebinuma, Nobuhiro Nakamoto, Akihiro Yamaguchi, Takeru Amiya, Yuko
Wakayama, Hiroko Murata, Po-sung Chu, Shingo Usui, Hidetsugu Saito,
Takanori Kanai
489
Magnetic resonance elastography is useful as non-in-
vasive diagnostic method for predicting liver fibrosis in
nonalcoholic fatty liver disease
Kento Imajo1, Takaomi Kessoku1, Yasushi Honda1, Yuji Ogawa1,
Hironori Mawatari1, Masato Yoneda2,1, Satoru Saito1, Atsushi
Nakajima1; 1Division of Gastroenterology, Yokohama City Uni-
versity School of Medicine, Yokohama city, Japan; 2University of
Miami Miller School of Medicine, Miami, FL
Introduction: To investigate the clinical usefulness of magnetic
resonance elastography (MRE) in patients with a diagnosis of
liver fibrosis in nonalcoholic fatty liver disease (NAFLD) and
compare MRE results with transient elastography and serum
fibrosis marker test results. Methods: Our cohort consisted of
107 patients with liver biopsy-diagnosed NAFLD including 62
patients with steatohepatitis and 45 patients with nonalcoholic
fatty liver (NAFL). All patients with NAFLD underwent MRE,
transient elastography, and serum liver fibrosis marker testing
(hyaluronic acids, type IV collagen 7 S domain). Results: When
comparing MRE or transient elastography results with liver
biopsy results, the best cutoff for apparent fibrosis (stage 2-4)
was 3.5kPa (AUROC = 0.902, sensitivity = 0.862, specificity
= 0.910) or 7.4kPa (AUROC = 0.851, sensitivity = 0.822,
specificity = 0.819), respectively. Significant correlations
between liver stiffness measured with MRE and the following
parameters were observed: liver stiffness measured with tran-
sient elastography (r = 0.822, P < .0001), serum level of hyal-
uronic acid (r = 0.722, P = .0003), and serum level of type
IV collagen 7 S domain (r = 0.796, P = .0002). Conclusion:
There is a significant positive correlation between liver stiffness
measured with MRE and severity of liver fibrosis in patients with
NAFLD. The diagnosability of MRE for liver fibrosis in NAFLD
were not inferior to those of transient elastography.
440A AASLD ABSTRACTS
Disclosures:
The following people have nothing to disclose: Kento Imajo, Takaomi Kessoku,
Yasushi Honda, Yuji Ogawa, Hironori Mawatari, Masato Yoneda, Satoru Saito,
Atsushi Nakajima
490
Spleen stiffness correlates with spleen size but not liver
fibrosis in patients with alcoholic liver disease
Maja Thiele, Bjørn S. Madsen, Aleksander Krag; Department of
Gastroenterology and Hepatology, Odense University Hospital,
Odense C, Denmark
Background & Aims: Spleen stiffness (SS) has been correlated
to liver fibrosis in patients with chronic viral hepatitis, possibly
due to spleen fibrogenesis rather than congestion driven by
portal hypertension. We aimed at assessing whether SS also
increase in alcoholic fibrosis before decompensated cirrhosis is
present and whether SS is correlated to spleen size. Methods:
Patients with all degrees of alcoholic liver fibrosis (METAVIR
F0/1/2/3/4 = 11/15/12/3/30) and no concurrent liver dis-
ease were included in a prospective, single-center study. Liver
biopsy and SS using FibroScan (Echosens, France) were per-
formed on the same day in an ultrasound-guided manner. SS
measurements were considered a failure if less than 10 valid
measurements could be acquired. Results: 71 patients with
valid SS measurements were included (77% male, mean age
57 years). The majority of patients with cirrhosis were compen-
sated (Child A/B/C = 22/7/1). The median spleen diameter
was 11.5 cm (range 7.4-19 cm) and 28 patients (39%) had an
enlarged spleen above 12 cm. While there were no differences
in SS between fibrosis grades F0, F1, F2 and F3 (median 27
kPa, test for difference between groups P>0.2), SS increased
significantly in patients with cirrhosis (median 47 kPa, test for
difference between F0-3 and F4 P<0.001). Additionally, SS
increased significantly from Child A (median 44 kPa) to Child
B (median 72 kPa) in patients with cirrhosis (P=0.023). In spite
of the higher median, SS was only fair at diagnosing cirrhosis
(AUROC 0.75, 95% CI 0.64-0.89), possibly due to a high
variance (interquartile range for F4 = 38 kPa). SS was poorer
at diagnosing ≥F2 fibrosis (AUROC 0.71, 95% CI 0.58-0.83).
SS was higher in patients with an enlarged spleen compared
to patients with normal sized spleens (median 30 kPa versus
42 kPa, P=0.026). Additionally, increasing SS correlated with
larger spleen diameter independently of the presence of cirrho-
sis (correlation coefficient 3.38, 95% CI 1.64-5.12, P<0.001).
Conclusions: SS does not increase with increasing degree of
liver fibrosis in non-cirrhotic patients with alcoholic liver dis-
ease. The highest SS values are found in patient with Child B
HEPATOLOGY, October, 2014
cirrhosis and in patients with enlarged spleens, independently
of the presence of cirrhosis. Additionally, SS is not good at
predicting cirrhosis in a population of compensated cirrhotics.
This suggests that the increase in SS observed in patients with
alcoholic liver cirrhosis is largely driven by congestion due to
portal hypertension.
Disclosures:
The following people have nothing to disclose: Maja Thiele, Bjørn S. Madsen,
Aleksander Krag
491
Muscle fat infiltration using total psoas density in com-
puted tomography predicts mortality in cirrhosis
Christos K. Triantos1, Andreas Karatzas2, Maria Kalafateli1,
Paraskevi Tselekouni1, Georgios Tsiaoussis1, Nikolaos Koukias1,
Efstratios Koutroumpakis1, Konstatinos Thomopoulos1, Vasiliki
Nikolopoulou1, Christina Kalogeropoulou2, Chrisoula Labropou-
lou-Karatza C3; 1Department of Gastroenterology, University
Hospital of Patras, Patra, Greece; 2Department of Radiology, Uni-
versity Hospital of Patras, Patras, Greece; 3Department of Internal
Medicine, University Hospital of Patras, Patras, Greece
Background/Aim: Malnutrition is a well-known complication
in patients with liver cirrhosis and it has been proposed that
scoring systems should include evaluation of sarcopenia to
better assess mortality among patients with cirrhosis (Clin Gas-
troenterol Hepatol 2012 Feb;10(2):166-73) . We aimed to
evaluate muscle fat infiltration (assessed by muscle density
in CT Hounsfield Units (HU)) and its prognostic value in this
setting. Methods: Ninety eight consecutive patients with cir-
rhosis (71 males; median age, 63 (range 27-93) years) that
underwent a CT scan at the fourth to fifth lumbar (L4-L5) verte-
brae were studied. Univariate and multivariate Cox regression
analysis was used to determine predictors of survival. Results:
BMI: median 26 (range 17-45.2), MELD score: median 11
(6-29), Child-Pugh(CP)score: median 7 (5-13), CP stage: A=48
(39%), B=39 (38.8%), C=9 (9.2%), hepatocellular carcinoma
(HCC): 14 (14.3%), portal vein thrombosis (PVT): 6 (6.1%), fol-
low-up: median 45 (1-140) months. Median L4-L5 total psoas
area (TPA): 2022 (777-3806) mm2, L4-L5 average total psoas
density (ATPD): 42.52 (21.26-59.8) HU. ATPD was signifi-
cantly correlated with creatinine (r=-0.41, p<0.001), albu-
min (r=0.224, p=0.035), MELD score (r=-0.218, p=0.034),
TPA (r=0.415, p<0.001) and TPA/h2 (r=0.372, p=0.002).
Fifty-four patients (55.1%) died during follow-up. In the uni-
variate analysis, factors associated with survival were HCC
(hazard ratio (HR): 0.486, 95% CI: 0.256-0.925, p=0.028),
CP score (HR: 1.2, 95% CI: 1.057-1.365, p=0.005), albu-
min (HR: 0.578, 95% CI: 0.346-0.967, p=0.037), PVT (HR:
0.323, 95% CI: 0.125-0.836, p=0.02) and ATPD stratified
by gender (HR: 0.969, 95% CI: 0.944-0.994, p=0.015). In
the multivariate analysis, higher CP score (HR: 1.2, 95% CI:
1.021-1.41, p=0.027) and lower ATPD stratified by gender
(HR: 0.965, 95% CI: 0.936-0.995, p=0.023) were predictors
of mortality. Conclusion: Muscle fat infiltration is a negative
predictive factor for survival in liver cirrhosis. There is a need
for further investigation of the predictive value of indicators of
nutritional status in the every-day clinical practice in patients
with liver cirrhosis.
Disclosures:
The following people have nothing to disclose: Christos K. Triantos, Andreas
Karatzas, Maria Kalafateli, Paraskevi Tselekouni, Georgios Tsiaoussis, Nikolaos
Koukias, Efstratios Koutroumpakis, Konstatinos Thomopoulos, Vasiliki Nikolopou-
lou, Christina Kalogeropoulou, Chrisoula Labropoulou-Karatza C
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
492
Supersonic shear imaging predicts cirrhosis and
advanced fibrosis in chronic hepatitis C patients
Shih-Jer Hsu1, Yu L. Tan2, Ding-Shinn Chen3,4, Jia-Horng Kao3,4;
1Department of Internal Medicine, National Taiwan University Hos-
pital Yun-Lin Branch, Yunlin County, Taiwan; 2Graduate School of
Health Industry Management, National Yunlin University of Sci-
ence and Technology, Yunlin County, Taiwan; 3Graduate Insti-
tute of Clinical Medicine, National Taiwan University College of
Medicine, Taipei, Taiwan; 4Department of Internal Medicine and
Hepatitis Research Center, National Taiwan University Hospital,
Taipei, Taiwan
Background: Staging hepatic fibrosis is important in the man-
agement of chronic hepatitis C. The elastic modulus of liver
has been shown to correlate well with histologic fibrosis stage.
Supersonic shear imaging (SSI) is based on the acoustic radia-
tion force imaging technique to generate shear waves in liver
tissue and is able to quantify the elastic modulus of liver. Thus
SSI seems promising for the quantification of liver stiffness.
Methods: Chronic hepatitis C patients naïve to anti-viral ther-
apy were enrolled. Liver stiffness, expressed in kPa, was mea-
sured with SSI using a SuperSonic Imagine Aixplorer diagnostic
ultrasound scanner. Liver stiffness measurement with Fibroscan
system was simultaneously performed for comparison. Liver
histological examinations performed within 2 years were eval-
uated for the correlation of liver stiffness with METAVIR fibrosis
stage. Results: A total of 191 chronic hepatitis C patients (97
men and 94 women; mean age, 63.1 years) were enrolled.
Liver stiffness values measured by SSI and Fibroscan had a
good correlation (r = 0.8653, P<0.0001). Seventy patients
had received liver histological examination within 2 years.
The mean±SD of SSI liver stiffness for each fibrosis stage was
6.9±1.9 (F1), 10.3±2.4 (F2), 12.7±2.7 (F3), and 21.6±6.9
(F4), respectively. Using 13.6kPa as cut-off value, the sensi-
tivity, specificity, positive predictive value (PPV), and negative
predictive value (NPV) of SSI in discriminating advanced fibro-
sis (≥F3) was 81.6%, 95.7%, 93.9.%, and 75.0%, respec-
tively. With a cut-off value of 15.6kPa the sensitivity, specificity,
PPV, and NPV of SSI in predicting cirrhosis is 88.9%, 97.1%,
96.0%, and 91.7%, respectively. Conclusion: The liver stiff-
ness measurement in chronic hepatitis C patients is comparable
between SSI and Fibroscan systems. SSI appears to be a prom-
ising non-invasive method for liver fibrosis evaluation.
Boxplot of SSI (black box) and Fibroscan (white box) for each
fibrosis stage.
Disclosures:
Ding-Shinn Chen - Consulting: BMS, GSK, Gilead, Roche, Merck, BMS, GSK,
Gilead, Roche, Merck
441A
The following people have nothing to disclose: Shih-Jer Hsu, Yu L. Tan, Jia-Horng
Kao
493
The usefulness of spleen stiffness evaluated by Acoustic
Radiation Force Impulse (ARFI) elastography for assess-
ing liver fibrosis
Simona Bota, Ioan Sporea, Oana Gradinaru Tascau, Alina
Popescu, Roxana Sirli, Mirela Danila; Department of Gastroenter-
ology and Hepatology, “Victor Babes” University of Medicine and
Pharmacy, Timisoara, Romania, Timisoara, Romania
Background and aim: Recently, spleen stiffness (SS) assessed
by various elastographic methods was evaluated for predicting
liver fibrosis. Very good results were published for liver fibro-
sis assessment using SS by Acoustic Radiation Force Impulse
(ARFI) elastography (1). Our aim was to try to validate these
cut-offs in an independent cohort of patients with chronic hep-
atitis B and C, considering liver biopsy (LB) as the “gold-stan-
dard” method for liver fibrosis evaluation. Methods: Our study
included 71 patients evaluated in the same session by LB and
SS by ARFI elastography. The mean age of the patients was
46.3 ± 12.6 years, 39.4% having chronic hepatitis B and
60.6% chronic hepatitis C. We aimed for 10 valid SS mea-
surements for each patient and a median value expressed in
meters/second (m/s) was calculated. Similar with the study
of Chen et al (1), reliable SS measurements were considered
the median of 10 valid SS measurements with an interquar-
tile range interval (IQR) <30%. For SS, the following cut-offs
were analyzed (1): F≥2: 2.74 m/s, F≥3: 3.14 m/s and F=4:
3.32 m/s. Results: Reliable SS measurements were obtained in
only 64/71 patients (90.1%), which were included in the final
analysis. The distribution of liver fibrosis on LB in this cohort
of patients was: F0-0%, F1-17.2%, F2-51.6%, F3-23.4% and
F4-7.8%. According to the pre-specified cut-off values, the per-
formance of SS by ARFI elastography for predicting diferent
stages of liver fibrosis is presented in table. Conclusions: In our
patient cohort, SS by ARFI elastography had not the same very
good accuracy for predicting different stages of liver fibrosis as
in the paper of Chen et al (1). Because of the very good pos-
itive predictive value for predicting the presence of significant
fibrosis and very good negative predictive value for exclud-
ing the presence of liver cirrhosis, SS by ARFI elastography
might be use as a supplementary diagnostic tool in patients
with chronic viral hepatitis. References 1. Chen SH, Li YF, Lai
HC,et al. Noninvasive assessment of liver fibrosis via spleen
stiffness measurement using acoustic radiation force impulse
sonoelastography in patients with chronic hepatitis B or C. J
Viral Hepat. 2012;19:654-63.
Disclosures:
Simona Bota - Speaking and Teaching: Janssen Pharmaceutica, Boehringer Ingel-
heim, Bristol-Myers Squibb
Ioan Sporea - Advisory Committees or Review Panels: Siemens
The following people have nothing to disclose: Oana Gradinaru Tascau, Alina
Popescu, Roxana Sirli, Mirela Danila
442A AASLD ABSTRACTS
494
Comparison between 2D-real time Shear Wave Elas-
tography (2D-SWE) and simple serological scores for
liver fibrosis assessment for clinical routine, considering
Transient Elastography (TE) as reference method
Simona Bota, Rafael Paternostro, Alexandra Etschmaier, Remy
Schwarzer, Petra Salzl, Mattias Mandorfer, Tuul Purevsambuu,
Monika Ferlitsch, Christian Kienbacher, Thomas Reiberger,
Michael Trauner, Markus Peck-Radosavljevic, Arnulf Ferlitsch; Div.
of Gastroenterology & Hepatology, Dept. of Internal Medicine III,
Medical University of Vienna, Vienna, Austria
Background and aim: 2D-Shear Wave elastography (2D-SWE)
is a new method for non-invasive assessment of liver fibro-
sis. Our aim was to assess the performance of 2D-SWE and
simple serological scores for liver fibrosis assessment, consid-
ering TE as reference method. Methods: Our study included
127 consecutive patients with chronic liver disease undergoing
both by TE (FibroScan, Echosens, Paris, France) and 2D-SWE
(Aixplorer, SuperSonic Imagine S.A., Aix-en-Provence, France).
Biochemical parameters were recorded to calculate the nonin-
vasive fibrosis scores. TE reliability criteria defined as: median
of 10 valid LS measurements with a SR≥60% and IQR<30%.
2D-SWE results were recorded as median value of 3 valid
LS measurements. TE cut-offs to stage liver fibrosis were used
according to a recent meta-analysis (Tsochatzis-J Hepatol
2011): F1: 6kPa, F2: 7.2kPa, F3: 9.6kPa and F4: 14.5kPa.
Results: Reliable LS measurements by TE and 2D-SWE were
obtained in 74.8% and 98.4% of patients (p<0.0001),
respectively. The following noninvasive fibrosis scores were
correlated in univariate analysis with fibrosis estimated by TE:
2D-SWE (r=0.699; p<0.0001), Forns (r=0.534; p<0.0001),
King’s (r=0.512; p<0.0001), APRI (r=0.373, p=0.001) Fibro-
sis Index score (r=0.363; p=0.0008) and Lok score (r=0.316,
p=0.006), while FIB-4 (r=0.195; p=0.09) was not correlated.
In multivariate analysis only LS by SWE was significantly cor-
related with fibrosis estimated by means of TE (p<0.0001).
The best LS cut-off by 2D-SWE for predicting different stages
of liver fibrosis, considering TE as the “reference method”, are
presented in the table. Conclusions: 2D-SWE results in a higher
rate of successful liver stiffness measurements than TE and has
a very good value for predicting the presence of severe fibrosis
and liver cirrhosis.
Disclosures:
Simona Bota - Speaking and Teaching: Janssen Pharmaceutica, Boehringer Ingel-
heim, Bristol-Myers Squibb
Mattias Mandorfer - Consulting: Janssen ; Grant/Research Support: Roche, MSD;
Speaking and Teaching: Boehringer Ingelheim, Roche, Bristol-Myers Squibb,
Janssen
Thomas Reiberger - Grant/Research Support: Roche, Gilead, MSD, Phenex;
Speaking and Teaching: Roche, Gilead, MSD
Michael Trauner - Advisory Committees or Review Panels: MSD, Janssen, Gilead,
Abbvie; Consulting: Phenex; Grant/Research Support: Intercept, Falk Pharma,
Albireo; Patent Held/Filed: Med Uni Graz (norUDCA); Speaking and Teaching:
Falk Foundation, Roche, Gilead
Markus Peck-Radosavljevic - Advisory Committees or Review Panels: Bayer, Gil-
ead, Janssen, BMS, AbbVie; Consulting: Bayer, Boehringer-Ingelheim, Jennerex,
Eli Lilly, AbbVie; Grant/Research Support: Bayer, Roche, Gilead, MSD; Speak-
ing and Teaching: Bayer, Roche, Gilead, MSD, Eli Lilly
The following people have nothing to disclose: Rafael Paternostro, Alexandra
Etschmaier, Remy Schwarzer, Petra Salzl, Tuul Purevsambuu, Monika Ferlitsch,
Christian Kienbacher, Arnulf Ferlitsch
HEPATOLOGY, October, 2014
495
The two faces of non-invasive assessment of liver dis-
ease severity: correlation between liver stiffness and
hepatic vein arrival times
Francesco Ridolfi1, Teresa Abbattista2, Annamaria Schimizzi3,
Eugenio Brunelli1; 1Ospedale di Senigallia, Division of Gastro-
enterology, Senigallia, Italy; 2Ospedale di Senigallia, Division of
Radiology, Senigallia, Italy; 3Ospedale di Jesi, Division of Internal
Medicine, Jesi, Italy
Increasing deposition of fibrotic tissue and vascular derange-
ments in the hepatic vascular system are the major features in
the development of liver disease. Hepatic Vein Arrival Time
(HVAT), i.e. the time an ultrasound contrast agent reaches the
hepatic vein after intravenous injection, was found to be lower
in cirrhotic patients. Transient elastography measures the speed
of propagation of elastic waves through the liver, such that
fibrotic livers generate higher liver stiffness measurements. Aim
of this study was to correlate liver stiffness with data obtained
by Contrast-Enhanced UltraSound (CEUS) of the liver. Thirty
consecutive patients affected by virus related chronic liver dis-
eases were enrolled. After a standard B-Mode and Doppler
examination, a bolus injection of 2.5 ml of Sonovue® (Bracco
SpA, Milan, Italy) was injected intravenously followed by a
saline flush. Using an ultrasound machine built-in contrast soft-
ware, the intensity of a main hepatic vein was recorded from
20 seconds before (the basal enhancement trace) to 2 minutes
after SonoVue® injection and we evaluated: the Hepatic Vein
Arrival Time (HVAT), the Time To Peak (TTP) and the peak
of contrast enhancement. Liver stiffness measurements were
performed by FibroScan® (Echosens, Paris, France) by expe-
rienced operators. All patients were measured using the 3.5
MHz standard M probe. The final liver stiffness result was
expressed in kPa and was the median value of 10 measure-
ments. No side effects related both to SonoVue® injection and
to FibroScan® examination were observed. Spearmann’s coef-
ficient of rank correlation between HVAT and liver stiffness was
observed to be -0,399 (95% Confidence interval -0,664 to
-0,0453, p<0.05), thus confirming the hypothesis that fibrotic
livers showed lower HVATs and higher values of liver stiffness.
No significant correlation was observed among liver stiffness
and TTP or the peak of contrast enhancement. When endo-
scopic signs of portal hypertension (such as oesophageal var-
ices or hypertensive gastropathy) were assumed to be as the
gold standard of liver cirrhosis, Receiver Operating Curves
(ROC) analysis demonstrated liver stiffness to have the best
accuracy in diagnosing liver cirrhosis with respect to HVAT
(Area Under the ROC [AUROC]: 0.972 vs. 0.781). Combining
liver stiffness ≤ 12.5 kPa and HVAT ≥ 18 seconds we reached
100% specificity for the diagnosis of liver cirrhosis. Earlier
HVATs and higher values of liver stiffness can be observed
during the progression of liver diseases. Liver CEUS and liver
stiffness showed a good accuracy and combining these two
tools a non-invasive diagnosis of liver cirrhosis can be reliabil-
ity done.
Disclosures:
The following people have nothing to disclose: Francesco Ridolfi, Teresa Abbat-
tista, Annamaria Schimizzi, Eugenio Brunelli
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
496
Alkaline phosphatase, but not ongoing alcohol abuse,
influence liver stiffness measurements in alcoholic liver
disease
Maja Thiele1, Bjørn S. Madsen1, Christian Jansen2, Christian P.
Strassburg2, Jonel Trebicka2, Aleksander Krag1; 1Department of
Gastroenterology and Hepatology, Odense University Hospital,
Odense C, Denmark; 2Department of Internal Medicine, University
of Bonn, Bonn, Germany
Background & Aims: Supersonic shear-wave elastography
(SWE) has not been investigated in patients with alcoholic
liver disease, and there is sparse data regarding transient
elastography (TE). A particular concern is whether ongoing
alcohol abuse and inflammation affects liver stiffness measure-
ments. Methods: In two cohorts of patients with prior or cur-
rent alcohol abuse the influence of METAVIR fibrosis stage,
ongoing drinking, alanine transaminase (ALT), alkaline phos-
phatase, AB0 blood type, BMI, smoking, gender and age
on SWE and TE measurements and failure rates were eval-
uated by regression analysis. SWE were considered a fail-
ure if less than three measurements could be obtained with
a Q-box of at least 15mm and a standard deviation below
30% of the mean. Results: 252 patients were included (61%
male, mean age 55 years). The majority of patients had a
liver biopsy performed on the same day as the elastographies
(n=141, METAVIR F0/1/2/3/4 = 31/34/19/9/48). Of the
included patients, 72 were still drinking alcohol, of whom 36
were classified as abusers (>24g of alcohol per day for men
and >16g/d for women). The median ALT and alkaline phos-
phatase were 34 U/L (interquartile range 24) and 98 U/L
(interquartile range 63). There was no evidence of collinearity.
In univariate regression analysis, degree of fibrosis, alcohol
abstinence and level of alkaline phosphatase correlated with
higher liver stiffness values measured by SWE. Degree of fibro-
sis and alkaline phosphatase correlated with higher TE mea-
surements. Neither alcohol overuse nor ALT were predictors
of liver stiffness. In multivariate analysis, degree of fibrosis
and level of alkaline phosphatase correlated with higher liver
stiffness for both SWE (fibrosis grade, coefficient 4.10, 95%
CI 2.96-5.24, P<0.001 and alkaline phosphatase, coefficient
0.06, 95% CI 0.03-0.09, P<0.001) and TE (fibrosis grade,
coefficient 7.16, 95% CI 5.43-8.89, P<0.001 and alkaline
phosphatase, coefficient 0.09, 95% CI 0.05-0.13, P<0.001).
Alcohol abstinence, smoking and age were all correlated with
higher rate of SWE failures in univariate analysis. However,
the only independent predictors of failure using SWE were
smoking (coefficient -0.07, 95% CI -0.14 to -0.004, P=0.039)
and age (coefficient -0.004, 95% CI -0.01 to -0.00, P=0.046).
BMI were the only predictor of TE failure in both uni- and mul-
tivariate analysis (coefficient -0.02, 95% CI -0.03 to -0.01,
P<0.001). Conclusions: In patients with alcoholic liver disease,
fibrosis grade and alkaline phosphatase influence elastogra-
phy measurements using SWE or TE. Ongoing alcohol abuse
does not impair liver stiffness measurements in patients with
alcoholic liver disease.
Disclosures:
Christian P. Strassburg - Advisory Committees or Review Panels: Novartis, Roche;
Speaking and Teaching: Novartis, Merz, MSD, Falk Pharma, BMS, Abbvie
The following people have nothing to disclose: Maja Thiele, Bjørn S. Madsen,
Christian Jansen, Jonel Trebicka, Aleksander Krag
443A
497
Noninvasive evaluation of portal hypertension by
spleen elastography
Karel Dvorak, Vaclav Smid, Renata Sroubkova, Jaromir Petrtyl,
Radan Bruha; 4th Internal Clinic, Charles University, 1st Faculty of
Medicine, Prague, Czech Republic
Introduction: Severity of portal hypertension is a crucial prog-
nostic factor in patients with liver cirrhosis. Invasive measure-
ment of hepatic venous pressure gradient (HVPG) is a standard
method used for the evaluation of portal hypertension. Although
generally safe and well tolerated, this invasive procedure is
not routinely available in all hospitals and it does not particu-
larly enable long-term monitoring. Recently, many noninvasive
approaches have been studied for evaluation of portal hyper-
tension and liver fibrosis. The efficacy of liver stiffness mea-
surement in evaluation of portal hypertension has been rather
controversial. The aim of our study was to assess the usefulness
of spleen elastography in the evaluation of portal hypertension
in patients with liver cirrhosis. Patients and methods: We exam-
ined 25 patients (18 men, 7 women), average age 56,7 years,
with liver cirrhosis (13 ethylic, 5 viral hepatitis, 5 NAFLD, 2
other). Diagnosis of cirrhosis was confirmed with liver biopsy
or with a presence of portal hypertension. Control group con-
sisted of 20 age-matched healthy individuals. Every patient
underwent standard biochemistry and blood count, abdominal
ultrasound and elastography of liver and spleen using ARFI
(Acoustic Radiation Force Impulse) measurement with ultra-
sound system Siemens Acuson S2000. HVPG was afterwards
measured in every patient. Results: Clinically significant portal
hypertension was diagnosed in 20 patients. The HVPG values
were (mmHg; median, IQ range) 16,0 (4-26), ARFI of liver
(m/s; median, IQ range), 2,817 (2,22-3,65), ARFI of spleen
3,140 (1,99-4,09). The value of ARFI of spleen significantly
correlated with the severity of portal hypertension (p=0,003),
ARFI of liver did not (p=0,163). Another parameter which cor-
related with HVPG was the length of spleen (p=0,033). Con-
clusion: Spleen elastography using ARFI is simple, reproducible
and easy to repeat noninvasive method for evaluation of portal
hypertension in cirrhotic patients. Supported by IGA MZCR NT
12290/4 a SVV 260032-2014.
Figure 1: Relationship between HVPG and ARFI of the spleen.
Disclosures:
The following people have nothing to disclose: Karel Dvorak, Vaclav Smid,
Renata Sroubkova, Jaromir Petrtyl, Radan Bruha
444A AASLD ABSTRACTS
498
Extracorporeal Shock Wave Lithotripsy for Diffi-
cult-to-Retrieve Common Bile Duct Stones: A Seven Year
Single Center Experience
Syed M. Hassan1, Kapeel Raja1, Asad A. Khan1, Nasir Hassan
Luck1, Munnawar Khaliq2, Muhammad Manzoor1, Zaigham
Abbas1; 1Hepatogastroenterology, Sindh Institute of Urology and
Transplantation, Karachi, Pakistan; 2Urology, Sindh Institute of
Urology and Transplantation, Karachi, Pakistan
Background: Extracorporeal shock wave lithotripsy (ESWL) is
emerging as a promising non-surgical treatment option for dif-
ficult-to-retrieve common bile duct (CBD) stones. We herein
report our seven year experience of ESWL in these patients.
Methods: All consecutive patients in whom ERCP failed to
retrieve CBD stones, even after mechanical lithotripsy, were
subjected to ESWL (using Modulith SLX-F2 by Storz Medical,
Germany) after obtaining informed consent. The naso-biliary
drain placed at the time of ERCP was used for fluoroscopic
guidance and flushing the stones during ESWL. The sessions
were performed mainly in prone position under mild intrave-
nous analgesia and sedation. The energy level and frequency
of the shocks were gradually increased from lowest to high-
est (1-9 Kilo Jules and 1-2 Hertz). The end point of a session
was dependent on achievement of predetermined maximum
number of shocks (6000), patient’s tolerance, stability of vital
signs, development of hemobilia or satisfactory fragmentation
of stones (5mm or less). Additional sessions were performed at
least 24 hours apart to rule out complications. Outcome was
assessed by CBD clearance. Both early and late complications
were noted. Results From January 2007 to May 2014, 58
patients aged between 9 to 82 years (mean 47.76 ± 14.65)
were treated by ESWL for CBD stones. Thirty one were female
(53.4%). Main indications for ESWL were; large size stone (≥
15mm) in 43 (74.1%), CBD stricture in 17 (29.3%) and incar-
cerated stone in 8 (13.8%) patients. The presenting complaints
include; abdominal pain in 50 (86.2%), jaundice in 40 (69%),
fever in 25 (43.1%) while 18 (31%) patients were diagnosed
to have cholangitis. A total of 115 ESWL sessions were per-
formed in 58 patients with an average of 1.98 sessions per
patient. The mean number of shocks was 4176 ± 1565. In
48 (82.8%) patients, the fragments were extracted endoscop-
ically after ESWL; spontaneous passage was observed in 10
(17.2%). The CBD clearance was label as complete in 46
(79.3%), partial (placement of stent followed by CBD clearance
at second ERCP) in 2 (3.4%) and failed in 10 (17.2%) patients.
Main adverse events included fever in 7 (12.1%), cholangitis in
6 (10.3%), hematuria in 1 (1.7%) and hemobilia in 1 (1.7%).
No procedure related death was observed. Naso-biliary drain
was displaced or removed in 6 (10.3%) cases. ESWL session
could not be completed or temporarily held in 10 (17.2%)
patients. Total hospital stay was 12 ± 7.26 days (range 1-42).
Conclusion: The ESWL for difficult-to-retrieve CBD stones is safe
and effective therapeutic option. It may be considered as an
alternative to surgical exploration of CBD.
Disclosures:
Kapeel Raja - Grant/Research Support: Sindh institute of Urology and transplan-
tation
The following people have nothing to disclose: Syed M. Hassan, Asad A. Khan,
Nasir Hassan Luck, Munnawar Khaliq, Muhammad Manzoor, Zaigham Abbas
HEPATOLOGY, October, 2014
499
The correlation between histology and the three elasto-
graphic techniques available in our department
Ioan Sporea, Oana Gradinaru Tascau, Alina Popescu, Madalina
Popescu, Roxana Sirli, Flavia Motiu; Department of Gastroenterol-
ogy and Hepatology, “Victor Babes” University of Medicine and
Pharmacy, Timisoara, Romania, Timisoara, Romania
Background and aim: In the last years many elastographic
techniques became available for assesing the severity of the
chronic liver disease and the number of liver biopsies (LB) has
decreased. The aim of this paper was to compare the histology
results obtained through LB with the values from the different
elastographic methods ( TE, ARFI, 2D-SWE ). Material and
methods: the study included patients with chronic hepatopa-
thies B or C that underwent LB and liver stiffness (LS) measure-
ments by three elastographic methods (TE, ARFI, 2D-SWE) in
our Department, between feb. 2013 –apr. 2014. Liver histol-
ogy was assessed according to the Metavir scoring. In these
patients for LS elastographic measurements, reliable measure-
ments were defined as: for TE and ARFI – the median value of
10 LS measurements with a success rate≥60% and an inter-
quartile range<30%, for SSI – the median value of 3 LS mea-
surements. All TE measurements were performed with M probe.
Results: 40 subjects underwent LB and all three elastographic
methods, 47.5% (19) were patients with chronic hepatitis B
and 52.5% (21) with chronic hepatitis C. Liver stiffness mea-
surements failures were in 5% (2/40) for 2D-SWE, in 10%
(4/40) for TE and in 2.5% (1/40) for ARFI. 2D-SWE, TE and
ARFI had a good corellation with the histological fibrosis (r=
0,72, P<0,0001; r= 0,65, P<0,0001; r= 0,52, P<0,0001,
respectively). Conclusions: All three shear wave elastographic
methods are corellated with liver histology in patients with
chronic viral hepatitis.
Disclosures:
Ioan Sporea - Advisory Committees or Review Panels: Siemens
The following people have nothing to disclose: Oana Gradinaru Tascau, Alina
Popescu, Madalina Popescu, Roxana Sirli, Flavia Motiu
500
Usefulness of Acoustic Noninvasive Assessment of Liver
Stiffness: Radiation Force Impulse (ARFI) Elastography
for staging of liver fibrosis and differential diagnosis of
hepatic tumor
Shunsuke Nakajima1, Takaaki Ohtake1, Takumu Hasebe1, Koji
Sawada2, Masami Abe1, Yasuaki Suzuki3, Mikihiro Fujiya1,
Yutaka Kohgo1; 1Asahikawa Medical University, Asahikawa,
Japan; 2Asahikawa Red Cross Hospital, Asahikawa, Japan; 3Nay-
oro City General Hospital, Nayoro, Japan
Purposes: Acoustic radiation force impulse (ARFI) elastography
is effective to evaluate the quantification of tissue elasticity at
arbitrary position. The aims of this study were to evaluate the
usefulness of liver stiffness measurement and differential diag-
nosis of hepatic tumors by ARFI. Methods: Eighty-three patients
whose liver tissues were diagnosed pathologically were stud-
ied (48 male, 35 female). The mean age of participants was
61.2 years (range, 10-80). The etiology of chronic liver dis-
ease were HBV related (n=15), HCV related (n=37), NASH
related (n=16), alcoholic (n=3), autoimmune (n=6) and others
(n=6). ARFI elastography data were correlated with histologic
data. The diagnostic performance of ARFI elastography (ACU-
SON S2000 or S3000, Siemens Japan) for predicting the
severity of hepatic fibrosis was determined from the area under
receiver operating characteristics (AUROC) curve analysis. Fur-
thermore, the stiffness of 5 hepatic tumors (1 hepatocellular
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
carcinoma (HCC), 3 cholangiocellular carcinomas (CCC), and
1 metastatic carcinoma) was evaluated by ARFI. We assessed
cell density by counting cell count ten pieces at random in a
range of 10,000 square micrometer of the tumor tissue slide.
We evaluated the correlation of cell density and ARFI elastog-
raphy of hepatic tumors. Results: The stage of hepatic fibrosis
was classified into 5 categories according to the New Inuyama
classification: F0, no fibrosis (n=4); F1, mild fibrosis (n=13);
F2, moderate fibrosis (n=23); F3, severe fibrosis (n=11); F4,
cirrhosis (n=32). The AUROC of ARFI elastography for pre-
dicting the severity hepatic fibrosis equal to or higher than F2,
F3, and equal to F4 were 0.84, 0.82, and 0.83, respectively.
The optimal cut-off values of ARFI elastography were 1.35m/s,
1.47m/s, and 1.59m/s, respectively. The dissociation of the
hepatic fibrosis stage was found in three patients between
ARFI and histologic data. We confirmed that varying degree
of fibrosis in the same biopsy specimen, local fatty deposition
in these cases. For liver tumors, the mean stiffness values were
0.87 m/s for HCC, 2.06 m/s (range, 1.42-2.70) for CCC,
and 2.31 for metastatic carcinoma. The correlation coefficient
between cell density and ARFI elastography.is 0.83 (p=0.29).
There variations could have been due to cell density, fibrosis,
and fatty deposition. Conclusion: ARFI elastography is use-
ful for evaluating liver stiffness and differential diagnosis of
hepatic tumors noninvasively.
Disclosures:
Yutaka Kohgo - Grant/Research Support: Novartis, Chugai-Roche, Asahikasei
Mecical, Mitsubishi Tanabe Pharm, Sapporo Beer Co
The following people have nothing to disclose: Shunsuke Nakajima, Takaaki
Ohtake, Takumu Hasebe, Koji Sawada, Masami Abe, Yasuaki Suzuki, Mikihiro
Fujiya
501
Assessment of hepatic fibrosis with Superb Micro-vascu-
lar Imaging: a preliminary report
Nobuko Koyama1, Jiro Hata2, Takeshi Sato3, Noriaki Manabe2,
Hiroshi Imamura2, Ken Haruma4, Keisuke Hino1; 1Hepatology
and Pancreatology, Kawasaki Medical School, Kurashiki, Japan;
2Endoscopy and Ultrasound, Kawasaki Medica School Hospital,
Kurashiki, Japan; 3Toshiba Medical Systems, Ohtawara, Japan;
4Gastroenterology, Kawasaki Medical School, Kurashiki, Japan
Background & Aim: Liver biopsy remains the current reference
standard for assessing hepatic fibrosis, despite limitations in
accuracy and adverse effects. Non-invasive alternatives include
ultrasound-based technique such as fibroscan or elastrography,
but each technique has its advantage and disadvantage. Very
recently new Doppler technology, Superb Micro-vascular Imag-
ing, that provides outstanding depiction of flow in very small
vessels and at lower velocities without motion artifact has been
developed. The aim of this study was to assess whether Superb
Micro-vascular Imaging can predict hepatic fibrosis by visualiz-
ing fine vessels present in the vicinity of liver surface. Methods:
A total of 29 patients with biopsy-proven chronic hepatitis C (6
in F1, 6 in F2 and 5 in F3) or liver cirrhosis C (12 in F4) and
36 healthy volunteers (control) were recruited from the Liver
Unit at Kawasaki Medical School between November 2012
and April 2014. Hepatic fibrosis was graded according to
the criteria for staging fibrosis (F1, F2, F3 and F4). We deter-
mined the vascular form score that is a number of irregular and
winding vessels among the randomly selected 5 vessels within
1.5 cm from liver surface, and measured vascular diverging
angle at different 5 points within 5 mm from liver surface, using
an Aplio 500 ultrasound machine (Toshiba Medical Systems,
Japan) with a 7 MHz or 12 MHz linear probe. Results: The
mean vascular score was significantly greater in patients with
advanced liver fibrosis (F3 or F4) (3.5 ± 1.1) than those with
445A
mild to moderate liver fibrosis (F1 or F2) (1.3 ± 1.4, P<0.01)
or control (0.6 ± 0.7, P<0.01). Similarly, the mean vascu-
lar diverging angle was significantly greater in patients with
advanced liver fibrosis (90.5 ± 14.3) than those with mild to
moderate liver fibrosis (68.0 ± 16.1, P<0.01) or control (62.2
± 10.5, P<0.01). The platelet count was negatively correlated
with vascular score (r=-0.701, P<0.001) and vascular diverg-
ing angle (r=-0.439, P=0.017), respectively. The area under
the receiver-operator curves (AUROC) of vascular score for
discriminating advanced liver fibrosis from mild to moderate
liver fibrosis was 0.88 with sensitivity of 76.5% and specificity
of 83.3%. Likewise the AUROC of vascular diverging angle
for discriminating advanced liver fibrosis from mild to mod-
erate liver fibrosis was 0.873 with sensitivity of 94.1% and
specificity of 75.0%. Conclusions: The present results indicated
that Superb Micro-vascular Imaging potentially predicts hepatic
fibrosis by detecting fine vessels present in the vicinity of liver
surface, even though further investigation is needed in a large
number of patients.
Disclosures:
Takeshi Sato - Employment: Toshiba Medical Systems Corporation
The following people have nothing to disclose: Nobuko Koyama, Jiro Hata,
Noriaki Manabe, Hiroshi Imamura, Ken Haruma, Keisuke Hino
502
Shear Wave Elastography and Hepatorenal Index for
the Assessment of Liver Fibrosis and Steatosis: a Novel
technique and its Predictive Accuracy and Optimal Mea-
surement Location
George Therapondos1, Michael T. Perry2, Neal Savjani2, Adri-
ana Dornelles3, Edward I. Bluth2; 1Multiorgan Transplant Institute,
Ochsner Clinic Foundation, New Orleans, LA; 2Department of
Radiology, Ochsner Clinic Foundation, New Orleans, LA; 3Biosta-
tistics, Ochsner Clinic Foundation, New Orleans, LA
Background: Liver biopsy is the gold standard used to diagnose
hepatic fibrosis/steatosis. Transient elastography which is used
in some centers is a non-invasive test preferred by patients. We
investigated the use of a novel technique called shear wave
elastography (SWE). Aims:To determine the optimal location
for obtaining SWE measurements, compare it with liver biopsy
and to investigate the accuracy of grayscale sonography hepa-
torenal index (HRI) in screening for hepatic steatosis. Meth-
ods:100 consecutive patients undergoing percutaneous liver
biopsy between Feb 2014 and May 2014 were recruited from
the outpatient clinics of Ochsner Medical Center. SWE mea-
surements were obtained in hepatic segments V/VI and VII/
VIII. HRI was calculated at the midportion of the right kidney.
A single liver pathologist determined liver fibrosis (METAVIR)
and steatosis. Analysis of Variance (ANOVA) was employed
to analyze the degree of fibrosis and SWE measurements and
Student’s t-test was used to analyze HRI and degree of steato-
sis. Results: Patient characteristics: We investigated 57 males
and 43 females- (40 OLT recipients). 54 patients had HCV
infection, 14 had hepatomegaly alone and 32 had a variety
of autoimmune liver diseases. SWE measurements: There was
no correlation found between SWE measurements and age,
gender, AST/ALT, bilirubin and the presence of steatosis. There
was however, a statistically significant difference in the mean
SWE seen in patients with a BMI<40 vs BMI>40 (p<0.0001).
OLT patients had similar SWE values to non-OLT patients. There
was no statistically significant inter-observer variation (3 tech-
nologists). SWE measurements and fibrosis: Segment VII/VIII
SWE was able to distinguish normal liver (p< 0.01) and stage
1 fibrosis (0.008) from stage 4 fibrosis. Similar results were
seen with segment V/VI SWE. When SWE measurements for
446A AASLD ABSTRACTS
both areas were combined, there was a significant difference
between stage 1 vs stage 3 (p<0.011), stage 1 vs stage 4
(p< 0.005) and stage 0 vs stage 4 (p< 0.033). HRI measure-
ments: HRI measurements for patients with <5% steatosis vs
those with >5% steatosis were different (P<0.0002). Summary:
a) SWE can distinguish normal liver/mild fibrosis from cirrhosis
in both non-OLT and OLT patents. b) BMI>40 may affect SWE
measurements. c) HRI can be used to identify patients with
clinically significant steatosis (>5%). Conclusions: SWE and
HRI measurements are non-invasive methods that can assist
in clinical decision making in the assessment of fibrosis and
steatosis in both OLT and non-OLT patients although caution
should be exercised over the interpretation of these measure-
ments in patients with a BMI>40.
Disclosures:
Edward I. Bluth - Advisory Committees or Review Panels: PHILLIPS; Grant/
Research Support: PHILLIPS
The following people have nothing to disclose: George Therapondos, Michael T.
Perry, Neal Savjani, Adriana Dornelles
503
Liver stiffness measurement in psoriatic patients: meta-
bolic factor, disease factor or methotrexate play import-
ant role?
Jamrus Pongpit1, Saneerat Porntharukchareon1, Wasana Stitchan-
trakul3, Ammarin Thakkinstian2, Piyaporn Kaewdoung1, Kwan-
napa Promson1, Supanna Petraksa1, Natta Rajatanavin1, Chomsri
Kositchaiwat1, Abhasnee Sobhonslidsuk1; 1Medicine, Ramathi-
bodi hospital, Bangkok, Thailand; 2Research center, Ramathibodi
hospital, Bangkok, Thailand; 3Section for Clinical Epidemiology
and Biostatistic, Ramathibodi hospital, Bangkok, Thailand
Background: Psoriasis is a chronic inflammatory immune-me-
diated skin disease which is showed to be associated with
metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD),
a hepatic manifestation of metabolic syndrome, can progress
to advanced fibrosis and cirrhosis. Liver biopsy is a gold stan-
dard method for assessing liver fibrosis; however it is invasive
with possible risks. Liver stiffness measurement (LSM) by tran-
sient elastography (TE), a noninvasive liver fibrosis assessment
tool, was evaluated in chronic liver diseases. We aimed to
investigate the prevalence of significant liver fibrosis by LSM
criteria and to identify the associate factors of significant fibro-
sis in psoriatic patients. Methods: A cross-sectional study was
conducted at psoriasis clinic from January 2013 to December
2013. Psoriatic patients were invited to participate with the
study. The subjects underwent laboratory tests for biochem-
istry, ultrasonography and TE (Fibroscan®) after overnight
fasting. LSM ≥7.1 kPa was defined as a significant liver fibro-
sis. The prevalence of significant fibrosis was calculated. Uni-
variate analysis was performed to identify factors associated
with significant fibrosis. Factors with p-value less than 0.10
were analyzed with multivariate logistic regression analysis.
A p-value <0.05 was taken as statistical significance. Results:
One hundred and sixty-eight patients were enrolled. TE could
not be performed in 3 patients due to obesity. Mean age was
49.22 (14.0) years. Ninety (54.5%) patients were female.
Mean body mass index was 24.76 (4.7) kg/m2. Eighty-eight
(53.3%), 55 (33.3%) and 31 (18.8%) patients had hyperten-
sion, dyslipidemia and diabetes mellitus (DM). According to
AHA/NHLBI criteria, metabolic syndrome was documented in
83 (50.3%) patients. Median duration of psoriasis was 13.00
(range: 0.4-68.0) years. Taking methotrexate over 1500 g in
accumulating dosage was found in 39 (23.6%) patients. Mean
LSM was 5.26 (2.9) kPa, and 18 (10.95%) patients had signif-
icant fibrosis. By multivariate analysis, DM (OR 17.65, 95%CI:
HEPATOLOGY, October, 2014
21.997-55.966; p=0.01), waist circumference (OR 1.24,
95%CI: 1.044-1.475; p=0.014) and AST level (OR 1.16,
95%CI: 1.052-1.288; p=0.003) were independently associ-
ated with significant fibrosis. Conclusions: Approximately 11%
of psoriatic patients have significant liver fibrosis defined by
transient elastography criteria. Diabetes is the strongest inde-
pendent factor associated with significant fibrosis, followed by
waist circumference and AST levels. The association of disease
factors and methotrexate use with significant fibrosis could not
be demonstrated in the study. Further research is required to
confirm our findings.
Disclosures:
The following people have nothing to disclose: Jamrus Pongpit, Saneerat Porn-
tharukchareon, Wasana Stitchantrakul, Ammarin Thakkinstian, Piyaporn Kaew-
doung, Kwannapa Promson, Supanna Petraksa, Natta Rajatanavin, Chomsri
Kositchaiwat, Abhasnee Sobhonslidsuk
504
Short Waiting Time Predicts Early Recurrence of Hepato-
cellular Carcinoma after Liver Transplantation: A Multi-
center Study Supporting the “Ablate and Wait” Principle
Neil Mehta1, Julie Heimbach2, Denise M. Harnois3, Jennifer L.
Dodge4, Justin M. Burns3, David Lee3, William Sanchez5, John P.
Roberts4, Francis Y. Yao1,4; 1Medicine, UCSF, San Francisco, CA;
2Transplantation, Mayo Clinic, Rochester, MN; 3Transplantation,
Mayo Clinic, Jacksonville, FL; 4Surgery, UCSF, San Francisco, CA;
5Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
The “ablate and wait” concept (Liver Transpl 2010;16:925)
for patients with hepatocellular carcinoma (HCC) awaiting liver
transplant (LT) is to allow a minimum observation period from
the time of loco-regional therapy (LRT) to LT, to avoid transplant-
ing tumors that progress rapidly over time despite LRT. Under
this principle, a short waiting time from HCC diagnosis to LT
would result in transplanting aggressive tumors at increased
risk for post-LT recurrence. To test this hypothesis, we undertook
a multi-center study involving 3 LT centers in regions with long,
median and short waitlist time, to evaluate the impact of waiting
time, defined as time from HCC diagnosis to LT, on post-LT out-
come. This study included 881 patients from 3 centers (median
waiting time of 3.4 months, 7.3 months, and 12.9 months,
respectively) with HCC meeting Milan criteria and receiving
MELD exception for LT from June 2002 to June 2012. Among
them, 91.3% received at least one LRT, and 81.8% underwent
LT after a median of 8.3 months (IQR 4.1-14.2) from HCC
diagnosis. The waiting time was < 6 months in 35.7%, 6-12
months in 31.4%, and > 12 months in 32.9%. Dropout from
the waiting list was observed in 14.5% at a median of 11.6
months (IQR 7.1-16.7) and 92.2% of dropout was from the
center with the longest waiting time. Median post-LT follow-up
was 4.2 years. The Kaplan Meier 1- and 5-year post-LT sur-
vival was 92.8% and 72.1% for waiting time < 6 months, ver-
sus 93.1% and 78.6% for waiting time ≥ 6 months (p=0.02).
Cumulative probabilities of HCC recurrence at 6 months, 1 and
5 years post-LT were 6.4%, 7.7% and 16.8% with waiting time
< 6 months versus 2.0%, 4.6% and 10.9% with waiting time
≥ 6 months, respectively (p=0.048). Predictors of HCC recur-
rence in multivariate analysis included microvascular invasion
(HR 3.8, 95% CI 2.2-6.4, p<0.001), explant tumor > Milan cri-
teria (HR 3.2, 95% CI 1.4-7.1, p=0.005), and alpha-fetopro-
tein >100 at transplant (HR 2.6, 95% CI 1.6-4.3, p<0.001).
Waiting time < 6 months was a predictor of HCC recurrence
in univariate (HR 1.5, 95% CI 1.001-2.4, p=0.049) but not in
multivariate analysis. However, waiting time < 6 months was
the only pre-LT factor predicting early HCC recurrence within
6 months after LT in multivariate analysis (HR 3.0, 95% CI
1.2-7.0, p=0.015). In conclusion, this large multi-center study
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
provides evidence of an association between short waiting
time and early HCC recurrence after LT. A minimal observation
of 6 months from HCC diagnosis and LRT to LT may select out
patients at increased risk for early post-LT HCC recurrence,
thus supporting the “ablate and wait” principle in candidate
selection while on the LT waiting list.
Disclosures:
The following people have nothing to disclose: Neil Mehta, Julie Heimbach,
Denise M. Harnois, Jennifer L. Dodge, Justin M. Burns, David Lee, William San-
chez, John P. Roberts, Francis Y. Yao
505
Biomarkers significantly improve the performance of the
Milan criteria in predicting Hepatocellular carcinoma
(HCC) recurrence post liver transplantation (LT)
Roongruedee Chaiteerakij1,2, Xiaodan Zhang1, Benyam D. Addis-
sie1, Essa A. Mohamed1, William S. Harmsen3, J Paul Theobald4,
Brian E. Peters4, Joseph Balsanek4, Melissa M. Ward4, Nasra H.
Giama1, Catherine D. Moser1, Abdul M. Oseini1, Naoki Umeda1,
Denise M. Harnois5, Michael Charlton1, Hiroyuki Yamada6, Shinji
Satomura6, Alicia Algeciras-Schimnich4, Melissa R. Snyder4, Terry
M. Therneau3, Lewis R. Roberts1; 1Division of Gastroenterology
and Hepatology, Mayo Clinic College of Medicine, Mayo Clinic
and Mayo Clinic Cancer Center, Rochester, MN; 2Department of
Medicine, Faculty of Medicine, Chulalongkorn University and King
Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bang-
kok, Thailand; 3Department of Biomedical Statistics and Informat-
ics, Mayo Clinic College of Medicine, and Mayo Clinic Cancer
Center, Rochester, MN; 4Division of Laboratory Medicine, Depart-
ment of Laboratory Medicine and Pathology, Mayo Clinic College
of Medicine, Rochester, MN; 5Mayo Clinic College of Medicine,
Mayo Clinic, and Mayo Clinic Cancer Center, Jacksonville, FL;
6Wako Life Sciences, Inc., Mountain View, CA
Background: HCC recurrence is a major impediment to effec-
tive treatment of HCC by LT. Despite using the Milan criteria
for candidate selection, up to 20% of HCC patients develop
recurrence after LT and consequently have poor survival. This
limits the benefit/risk ratio of LT for HCC patients compared to
patients with benign liver disease. In order to optimize organ
allocation strategies, other objective preoperative parameters
that can reliably predict the risk for recurrence post-LT are
needed. Aims: To determine the association between pre-LT
alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP
(AFP-L3) and des-gamma-carboxy prothrombin (DCP) alone,
or in combination with other biomarkers or Milan criteria
and risk of HCC recurrence after LT Methods: A retrospective
cohort study of HCC patients undergoing LT between 2000
and 2008 was conducted. Of the 313, 127 had available
serum samples drawn before LT. Serum AFP, AFP-L3% and
DCP were measured in a blinded fashion using the μTASWako
i30 immunoanalyzer. The hazard ratio (HR) and 95% confi-
dence interval (95%CI) were calculated using Cox Proportional
Hazards analysis. Results: Of the variables examined, tumor
size, the Milan criteria and high levels of biomarkers were
significantly associated with HCC recurrence. HRs (95%CI)
were 1.4 (1.1–1.7) for tumor size, 2.6 (1.4–4.7) for tumor
stage outside Milan criteria, 2.8 (1.4–5.4) for AFP ≥250 ng/
mL, 3.2 (1.7–6.1) for AFP-L3 ≥35% and 3.5 (1.9–6.7) for DCP
≥7.5 ng/mL; p=0.004, 0.003, 0.002, 0.0003 and <0.0001,
respectively. The HR (95%CI) increased to 5.2 (2.3–12.0) for
patients with both AFP ≥250 ng/mL and DCP ≥7.5 ng/mL,
p<0.0001. Among patients with tumors within the Milan crite-
ria, the HRs (95%CI) were 3.1 (1.3–7.5) for AFP ≥250 ng/mL,
4.3 (1.8–10.1) for DCP ≥7.5 ng/mL, and 4.5 (1.9–10.6) for
AFP-L3 ≥35%; p=0.01, 0.0008, 0.0005, respectively. The HR
447A
(95%CI) for tumors outside the Milan criteria increased from
2.6 (1.4–4.7) to 8.6 (3.0–24.6), and 7.2 (2.8–18.1) when
combined with AFP ≥250 ng/mL, and DCP ≥7.5 ng/mL respec-
tively (p<0.0001 for both). The concordance index (95%CI) of
the Milan criteria increased from 0.63 (0.56–0.70) to 0.68
(0.60–0.76), 0.70 (0.62–0.78) and 0.70 (0.62–0.78) when
combined with AFP, DCP and AFP-L3%, respectively, suggest-
ing that combining the biomarkers with the Milan criteria was
more predictive of recurrence than the Milan criteria alone.
Conclusions: HCC biomarkers significantly improved the per-
formance of the Milan criteria in predicting HCC recurrence
after LT. Our findings could potentially improve the organ allo-
cation algorithm for LT.
Disclosures:
Shinji Satomura - Board Membership: Wako Life Sciences, Inc
Lewis R. Roberts - Grant/Research Support: Bristol Myers Squibb, ARIAD Pharma-
ceuticals, BTG, Wako Diagnostics, Inova Diagnostics, Gilead Sciences
The following people have nothing to disclose: Roongruedee Chaiteerakij, Xia-
odan Zhang, Benyam D. Addissie, Essa A. Mohamed, William S. Harmsen, J
Paul Theobald, Brian E. Peters, Joseph Balsanek, Melissa M. Ward, Nasra H.
Giama, Catherine D. Moser, Abdul M. Oseini, Naoki Umeda, Denise M. Har-
nois, Michael Charlton, Hiroyuki Yamada, Alicia Algeciras-Schimnich, Melissa
R. Snyder, Terry M. Therneau
506
Injury of Peribiliary Glands of Donor Liver Bile Ducts
Plays a Pivotal Role in the Development of Non-anasto-
motic Biliary Strictures after Liver Transplantation
Negin Karimian1, Sanna op den Dries1,2, Pepijn D. Weeder1,2,
Andrie Westerkamp1, Fernanda Bomfati1, Janneke Wierse-
ma-Buist1, Bote G. Bruinsma4, Annette S. Gouw3, James F.
Markmann2, Ton Lisman1, Heidi Yeh2, Korkut Uygun4, Paulo N.
Martins2, Robert J. Porte1; 1Department of Surgery, Section of
Hepatobiliary Surgery and Liver Transplantation, University Med-
ical Center Groningen, Groningen, Netherlands; 2Department
of Surgery, Massachusetts General Hospital, Harvard Medical
School, Boston, MA; 3Department of Pathology, University Medi-
cal Center Groningen, Groningen, Netherlands; 4Center for Engi-
neering in Medicine/Surgical Services, Massachusetts General
Hospital, Harvard Medical School, Boston, MA
Injury of donor bile ducts may lead to the development of
non-anastomotic biliary strictures (NAS) after liver transplan-
tation. Peribiliary glands (PBG) provide a niche of progenitor
cells that contribute to regeneration of biliary epithelium of
large bile ducts. It is unknown whether PBG injury plays a
role in the development of NAS after transplantation. Aim of
this study was a) to determine the degree of PBG injury in
donor livers, b) to assess whether PBG injury is a risk factor
for the development of (NAS), and c) to identify risk factors for
PBG injury in donor livers. In 128 liver transplant procedures,
biopsies were taken from the extrahepatic bile duct (EHBD)
and injury was assessed using a systematic histological grad-
ing system. Histological injury was correlated with the occur-
rence of NAS. Donor characteristics and surgical variables
were correlated with PBG injury, using uni- and multivariable
regression analysis. . In another10 donor livers that were
declined for transplantation, proximal extension of bile duct
injury was assessed by obtaining biopsies from the EHBD and
the intrahepatic sectoral and segmental ducts. In 117 / 128
(91%) liver grafts, the biliary epithelial lining of the EHBD was
lost for >50%, yet NAS occurred in 16.4%. Periluminal PBG
were injured more severely than deep PBG located near the
fibromuscular layer (>50% epithelial cell loss in 56.9% and
17.5%, respectively; p<0.001). Injury of deep PBG was more
prevalent and more severe in livers that later developed NAS,
compared to uncomplicated grafts (>50% epithelial cell loss in
448A AASLD ABSTRACTS
50.0% versus 9.8%, respectively; p=0.004). After uni- and mul-
tivariable analysis, the following variables were independently
associated with injury of the deep PBG: DCD donor type (OR
6.337), prolonged cold ischemia time (OR 1.012), and donor
age >55 yr (OR 8.130). In the 10 livers that were declined
for transplantation, there was no significant difference in the
amount of histological injury of EHBD or the intrahepatic ducts.
Conclusions: a) The vast majority of donor livers suffer severe
bile duct injury, as characterized by a >50% loss of the luminal
biliary epithelium and the PBG of the larger bile ducts; b) Injury
of the deep PBG is strongly related with posttransplant occur-
rence of NAS; c) DCD donor type, prolonged cold ischemia
time, and donor age >55 yr are independently associated with
deep PBG injury. These data strongly suggest that PBG play a
pivotal role in the development of NAS. Severe injury of the
PBG may result in insufficient regeneration of biliary epithelium
which eventually leads to biliary strictures.
Disclosures:
Robert J. Porte - Advisory Committees or Review Panels: Organ Assist
The following people have nothing to disclose: Negin Karimian, Sanna op den
Dries, Pepijn D. Weeder, Andrie Westerkamp, Fernanda Bomfati, Janneke
Wiersema-Buist, Bote G. Bruinsma, Annette S. Gouw, James F. Markmann, Ton
Lisman, Heidi Yeh, Korkut Uygun, Paulo N. Martins
507
Early Post-Operative Neutrophil Gelatinase Associated
Lipocalin (NGAL)-Associated Acute Kidney Injury Pre-
dicts the Development of Chronic Kidney Disease and
Mortality Following Liver Transplantation
Elizabeth C. Verna1, Giuseppe Cullaro1, Joseph F. Pisa1, Robert
S. Brown1, Gebhard Wagener2; 1Center for Liver Disease and
Transplantation, Columbia University Medical Center, New York,
NY; 2Department of Anesthesiology, Columbia University Medical
Center, New York, NY
Background: Urinary NGAL (uNGAL) associated acute kid-
ney injury (AKI) is common following liver transplant (LT), but
whether early AKI predicts the onset of chronic kidney dis-
ease (CKD) and mortality remains uncertain. Methods: Adults
with LT from 2008-2010 in a previously published prospective
cohort evaluating post-LT uNGAL were retrospectively assessed
to evaluate uNGAL as a predictor of outcomes at 4 years. The
primary outcomes were CKD, defined as MDRD estimated glo-
merular filtration rate (GFR)<60 mL/min/1.73m2 for three con-
tinuous months, and death. Results: 92 patients were included,
mean age 54 years, 65% male. Pre-LT kidney function was
generally normal (mean GFR 103 mL/min/1.73m2 with CKD
v 112 mL/min/1.73m2 without CKD, p=0.34). One patient
was on peri-LT dialysis. Baseline characteristics were similar
between groups, including diabetes mellitus, MELD, cold isch-
emia time (CIT), donor age, immunosuppression, operative
length and estimated blood loss (EBL). Those who developed
CKD had a higher mean age (57 v 49 years, p=0.002) and
BMI (29 v 26, p=0.02), and higher rates of hypertension
(46% v 24%, p=0.046), HCV (63% v 21%, p<0.001), HCC
(49% v 26%, p=0.01) and deceased donor transplant (92% v
72%, p=0.01). Post-LT AKI by AKIN criteria was numerically
higher in the CKD group (48% v 28%, p=0.07), though similar
by RIFLE-R (41% v 38%, p=0.76) and RIFLE-I (16% v 14%,
p=0.80) criteria. The 4 year cumulative incidences of CKD
and death were 68.5% and 24.9%, respectively. uNGAL 24
hours post-LT was the most predictive time point for CKD (AUC
0.65), with uNGAL>93 ng/ml being highly predictive of CKD
(log rank p=0.002, PPV 100%, NPV 36%). The final multivari-
able model for the prediction of time to CKD included uNGAL
at 24 hours (HR1.09 per 100 ng/ml, p=0.03), age at LT (HR
1.41 per decade, p=0.048), HCV (HR 1.86, p=0.04), and
HEPATOLOGY, October, 2014
BMI (<30 ref, 30≤BMI>35 HR 1.04, p=0.92, 35≤BMI>40 HR
4.76, p=0.007, BMI≥40 HR 1.86, p=0.27). All patients who
died post-LT developed CKD prior to death (p<0.001). 24 hour
post-LT uNGAL>30 ng/ml was predictive of death (log rank
p=0.05, PPV 32%, NPV 87%). Additional predictors of time to
death in multivariable modeling included age at LT (HR 3.02
per decade, p=0.002), HCV (HR 3.0, p=0.048), BMI (<30
ref, 30≤BMI>35 HR 6.01, p=0.005, 35≤BMI>40 HR 1.12,
p=0.85, BMI≥40 HR 3.18, p=0.33), CIT (HR 1.21 per hour,
p=0.002) and EBL (HR 1.15 per liter, p=0.02). Conclusions:
uNGAL predicts not only early post-LT AKI, but also the devel-
opment of long-term CKD, in this cohort with preserved pre-LT
kidney function. Given the significant correlation between CKD
and death, such early predictors could be used to guide pre-
ventative interventions.
Disclosures:
Elizabeth C. Verna - Advisory Committees or Review Panels: Gilead; Grant/
Research Support: Salix, Merck
Robert S. Brown - Advisory Committees or Review Panels: Vital Therapies; Con-
sulting: Genentech, Gilead, Merck, Abbvie, Janssen; Grant/Research Support:
Gilead, Merck, Vertex, AbbVie, Salix, Janssen, Vital Therapies
The following people have nothing to disclose: Giuseppe Cullaro, Joseph F. Pisa,
Gebhard Wagener
508
The Impact of Deconditioning In Advanced Cirrhosis
Michael A. Dunn1,2, Deborah A. Josbeno5, Mark Sturdevant3,2,
Amy R. Schmotzer1, Elizabeth A. Kallenborn2, Jaideep Behari1,2,
Doug Landsittel1,2, Andrea DiMartini4,2, Anthony Delitto5; 1Med-
icine, University of Pittsburgh, Pittsburgh, PA; 2Starzl Transplant
Institute, University of Pittsburgh, Pittsburgh, PA; 3Surgery, Uinver-
sity of Pittsburgh, Pittsburgh, PA; 4Psychiatry, University of Pitts-
burgh, Pittsburgh, PA; 5Physical Therapy, University of Pittsburgh,
Pittsburgh, PA
BACKGROUND. Declining physical capacity, deconditioning,
is thought to cause poor outcomes among patients awaiting
liver transplantation. Very little is known about the ability of
tests of deconditioning to predict adverse pre-transplant end-
points, or whether measured deconditioning has predictive
value independent of MELD and Child scores. We hypothe-
sized that measured deconditioning would predict deaths and
morbidity expressed as inpatient hospital days caused by the
complications of cirrhosis. METHODS. We measured decon-
ditioning in 218 patients evaluated or listed for transplantation
using a simple test, dominant hand grip strength, known to pre-
dict outcomes in large chronic disease populations. We used
Poisson regression stratified by gender to determine whether
grip testing was associated with the number of inpatient days
between the test date and the end of a 6 month observation
period. A multivariable Poisson model was used to test grip
strength, MELD and Child scores as covariates against the out-
come of inpatient days. Age and 3 potential drivers of inactivity
and deconditioning—depression, narcotic use, and low vita-
min D level—were also tested for significance or confounding
against the model. RESULTS. Multivariable modeling showed
that weak grip strength predicted excess inpatient days (p <
0.001) independently of MELD and Child scores, which also
predicted this endpoint. Mean grip strength for 83 women was
18.9 ± 6.0 kg, range 7.6-34.1. Mean grip strength for 136
men was 27.4 ± 9.2 kg, range 1.6-49.2. The 218 patients
had 710 inpatient days during 17,645 days at risk. Women
with weaker than mean grip strength had 7.81 ± 3.04 inpa-
tient days/100 days at risk. Women with stronger than mean
grip had fewer than half those inpatient days, 3.21 ± 1.96
days/100 days at risk. Men with weaker than mean grip had
4.19 ± 2.23 inpatient days/100 days at risk compared with
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
only 1.55 ± 1.45 days/100 days at risk for men with stron-
ger than mean grip. The other covariates were not associated
with the grip strength results. Weak grip was associated with
higher mortality but the 11 deaths in the study period were
too few for multivariable modeling. CONCLUSION. Our data
show that an easily performed test of deconditioning strongly
predicts morbidity independently of MELD and Child scores in
patients with advanced cirrhosis awaiting transplantation. The
endpoint of increased hospital days can be directly translated
into a major human and financial care burden imposed by
deconditioning. Objective assessment of deconditioning should
become a standard of pre-transplant care. Interventions to sta-
bilize or improve measured deconditioning merit clinical study.
Disclosures:
The following people have nothing to disclose: Michael A. Dunn, Deborah A.
Josbeno, Mark Sturdevant, Amy R. Schmotzer, Elizabeth A. Kallenborn, Jaideep
Behari, Doug Landsittel, Andrea DiMartini, Anthony Delitto
509
Narcotics Increase Rate of Rejection and Mortality After
Liver Transplantation Regardless of Underlying Disease
Etiology
Mina Pirzadeh1,
Amir Prushani2,
Syed-Mohammed R. Jafri2,
Maria
C. Segovia2; 1Internal Medicine, Boston University, Boston, MA;
2Gastroenterology and Hepatology, Henry Ford Hospital, Detroit,
MI
. AIM We endeavored to examine the outcomes of primary
liver transplant patients utilizing long-term narcotics prior to
and post-transplant at an urban transplant center with spe-
cific attention to underlying disease etiology. METHODS We
reviewed charts of 276 patients receiving first liver transplants
from 2008-2010. Narcotic use was defined as positive or
negative at time of transplant (pretransplant) and 6 months
post-transplant (6PT). We evaluated demographics, moderate
to severe rejection rate and mortality for all patients as well as
based on disease etiology. RESULTS There were 276 patients
with primary liver transplant. 24% used narcotics at the time
of transplant. 107 had etiologies other than alcohol and hep-
atitis C (OAC). 63.4% were male. Survival in pre-transplant
narcotic group at one year was lower (86.4%) than controls
(90.5%)(p=0.34). This effect became more pronounced at
three years with 68.2% survival among narcotic users versus
81.9% among controls (p=0.02). This survival effect was seen
regardless of etiology. OAC patients on pretransplant narcotics
had 3 year survival rate at 63.3% versus 81.8% in controls
(p=0.042). 15.2% of pretransplant narcotic users suffered
moderate to severe rejection versus 6.2% of controls (p=0.02).
This trend was even more pronounced among OAC patients
with moderate to severe rejection in 23.3% of narcotic users
versus 3.9% of controls (p=0.002). At 6 months post-transplant
(t=6m), 27.3% were narcotic users including 25.7% of whites,
30.4% of blacks and 29.8% of others. Among patients alive
and on narcotics at t=6m, 91.7% of narcotic users survived
to 1 year versus 97.4% of controls (p=0.04). 75% of t=6m
narcotic users survived to 3 years post-transplant versus 88% of
controls (p=0.01). OAC patient group had increased mortality
when on narcotics at t=6m with 3 year survival of 81.8% ver-
sus 74.3 (p=0.172). In patients with hepatitis C on narcotics 3
year survival was 90.1% versus 76.9% in controls (p=0.76).
CONCLUSION Chronic narcotic use in the peri-liver transplant
period significantly decreases long-term survival and increases
moderate to severe rejection rates. Pretransplant narcotic use
had significant survival disadvantage regardless of etiology.
Post-transplant narcotic use was harmful in all patients, and
449A
most significantly in those with a history of alcoholic liver dis-
ease.
Disclosures:
Syed-Mohammed R. Jafri - Advisory Committees or Review Panels: Gilead
The following people have nothing to disclose: Mina Pirzadeh, Amir Prushani,
Maria C. Segovia
510
Positive impact of everolimus on regulatory T cells after
liver transplantation
Clement Barjon1, Kaldoun Ghazal1, Geraldine Dahlqvist1, Faouzi
Saliba3, Francois Durand4, Christophe Duvoux5, Lynda Aoudje-
hane6, Yvon Calmus1,2, Filomena Conti1,2; 1UMR_S 938, CDR
Saint-Antoine, Sorbonne Universités, UPMC Univ Paris 06, Paris,
France; 2Centre de Transplantation Hepatique, Hôpital Saint
Antoine, APHP, Paris, France; 3Hepato-Biliary Center, Hopital
Paul Brousse, Villejuif, France; 4Hepatology and Liver Intensive
Care Unit, Hopital Beaujon, Clichy, France; 5Hepatology and
Liver Transplantation unit, Hopital Henri Mondor, Creteil, France;
6Human HepCell, Paris, France
Background. Liver transplantation (LT) is the treatment for ter-
minal liver diseases. Long term survival is excellent, however
immunosuppressive drugs required for rejection prophylaxis
are responsible of side effects such as infections, malignan-
cies or renal failure. The modulation of host immune system to
induce tolerance is a promising new approach to reduce immu-
nosuppressive treatment. Particularly, the promotion of natural
CD4+ CD25+ FoxP3+ regulatory T cells (Tregs) could be cru-
cial for operational tolerance. Tacrolimus is usually included in
standard immunosuppression protocols after LT and has been
shown to have a deleterious effect on Treg population. In con-
trast, reports indicate that mTOR inhibitors, like everolimus,
may have a positive impact on Tregs and thus could favor the
establishment of operational tolerance. Aim of the study. In
this study, Tregs levels were evaluated in 30 liver transplant
recipients included in a prospective study comparing tacrolim-
us-based and everolimus-based immunosuppressive regimens.
Patients and methods. All study patients received tacrolimus
during the first month after LT, then, were randomized to con-
tinue tacrolimus or to be progressively converted to everolimus.
Blood samples were obtained before LT, one, three and six
months after LT. Flow-cytometry immunophenotyping of Tregs
(CD4+ CD25+ CD127- FoxP3+) was performed using freshly
isolated PBMC. Tregs were isolated from PBMC using magnetic
sorting to assess their immunosuppressive capacities. Results.
One month after LT, while all patients received tacrolimus, Treg
levels were significantly reduced (p<0,05) when compared to
pre-transplant levels. Three months after LT, when converted
patients received everolimus for at least one month a trend
increase of Tregs was observed when compared to patients
under tacrolimus (p=0.12). Six months after LT, when patients
had been converted to everolimus for at least four months, Treg
levels were significantly higher when compared to patients who
had continued tacrolimus (p<0,02). Additionally, we observed
a strong tendency (p = 0,057) for higher level of Tregs in
HCV-infected patients compared to non-infected patients three
months after LT. Functional assays demonstrated that Tregs con-
served their capacity to suppress the proliferation of activated
PBMC independently of the treatment and the time point. Con-
clusion. This is the first randomized study to demonstrate a
positive impact of everolimus on Treg levels when compared
to tacrolimus after LT maintaining Tregs suppressive activity. .
Disclosures:
Faouzi Saliba - Advisory Committees or Review Panels: Novartis, Roche, Gen-
zyme, Vital therapies; Grant/Research Support: Astellas; Speaking and Teach-
ing: Schering Plough, Gambro, MSD, Gilead
450A AASLD ABSTRACTS
Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis;
Speaking and Teaching: Gilead
Christophe Duvoux - Advisory Committees or Review Panels: Novartis, Roche,
Novartis, Roche, Novartis, Roche, Novartis, Roche; Speaking and Teaching:
Astellas, Astellas, Astellas, Astellas
The following people have nothing to disclose: Clement Barjon, Kaldoun Ghazal,
Geraldine Dahlqvist, Lynda Aoudjehane, Yvon Calmus, Filomena Conti
511
Predictors of excessive alcohol use following liver trans-
plantation for alcoholic liver disease: A nationwide
competing risks analysis of psychiatric comorbidity and
occupational status (1990-2013)
Gro Askgaard1,2, Janne S. Tolstrup2, Thomas A. Gerds3, Ole Ham-
berg1, Mette Kjær1; 1Department of Hepatology, Copenhagen Uni-
versity Hospital, Rigshospitalet, Copenhagen, Denmark; 2National
Institute of Public Health, University of Southern Denmark, Copen-
hagen, Denmark; 3Department of Biostatistics, Copenhagen Uni-
versity, Copenhagen, Denmark
Aim It has been shown that excessive alcohol intake after liver
transplantation decreases long-term survival. We evaluated pre-
dictors of excessive alcohol intake among patients transplanted
for alcoholic liver disease. Method Among all patients trans-
planted for alcoholic liver disease in Denmark 1990-2013,
we studied predictors of excessive alcohol consumption (20 g
alcohol/day for women, 30 g alcohol/day for men) after trans-
plantation. Information was obtained from medical records,
nationwide registries, and by interview. We calculated the
absolute risk of relapse of excessive alcohol consumption tak-
ing the competing risk of death into account, and associated
changes in the absolute risk with predictors assessed at time
of transplantation Results We included 156 patients with a
median follow-up time of 12.3 years. The overall absolute risk
of excessive alcohol consumption after 10 years was 24.4 %
(CI95%: 16.9 ; 31.9). The relative absolute risks of excessive
alcohol use after liver transplantation were 1.16 for depres-
sion (p=0.65), 2.39 for anxiety (p=0.04), 2.68 for personality
disorder (p=0.05), 0.88 for being married (p=0.72), 2.57 for
being retired (p=0.007) (Table 1). With each year of age, the
absolute risk of excessive alcohol use after liver transplanta-
tion decreased by a factor of 0.96 (p < 0.001). Conclusion
Regarding psychiatric comorbidity, anxiety and personality dis-
order increased the risk of excessive alcohol use following liver
transplantation for alcoholic liver disease. Younger age and
being retired were also both independent predictors. Careful
psychiatric assessment prior to liver transplantation is important
to identify patients at particular high risk of relapse.
Table 1. Relative absolute risks of relapse of excessive alcohol
consumption after liver transplantation according to changes in
psychiatric comorbidity and occupational status. All analyses
were adjusted for age, gender, and alcohol dependence
HEPATOLOGY, October, 2014
Disclosures:
The following people have nothing to disclose: Gro Askgaard, Janne S. Tolstrup,
Thomas A. Gerds, Ole Hamberg, Mette Kjær
512
Prevalence and prediction of major adverse cardiovas-
cular events after liver transplantation using a novel
database
Lisa B. VanWagner1,2, Marina Serper3, Raymond Kang4, Anton
I. Skaro5, Josh Levitsky1,5, Samuel Hohmann6,7, Donald M. Lloyd-
Jones8; 1Medicine, Division of Gastroenterology & Hepatology,
Northwestern University Feinberg School of Medicine, Chicago, IL;
2Preventive Medicine, Northwestern University Feinberg School of
Medicine, Chicago, IL; 3Medicine, Division of Cardiology, Univer-
sity of Pennsylvania School of Medicine, Philadelphia, PA; 4Center
for Healthcare Studies, Northwestern University Feinberg School of
Medicine, Chicago, IL; 5Department of Surgery, Division of Organ
Transplantation, Northwestern University Feinberg School of Med-
icine, Chicago, IL; 6University HealthSystem Consortium, Chicago,
IL; 7Health Systems Management Department, Rush University,
Chicago, IL; 8Department of Medicine, Division of Cardiology,
Northwestern University Feinberg School of Medicine, Chicago, IL
BACKGROUND: Accurate assessment of predictors of major
adverse cardiovascular events (MACE) after liver transplanta-
tion (LT) has been limited by the lack of a large, multi-center
study with detailed clinical information. Thus, we aimed to
develop a novel database to assess the prevalence and pre-
dictors of early MACE after LT. METHODS: Adult recipients
of primary LT (ICD9 50.5) were identified from the University
HealthSystem Consortium clinical database/resource manager
from 2/2002-12/2012 and matched to recipients in the Organ
Procurement and Transplantation Network registry. ICD9 codes
from billing claims assessed comorbidities and 30- and 90-day
MACE, defined as myocardial infarction, heart failure, atrial
fibrillation, cardiac arrest, pulmonary embolism and/or stroke,
not present on initial admission. Multivariate Poisson regression
analysis assessed factors associated with MACE and 1-year
patient survival. RESULTS: We identified 32,810 patients
(mean age 55.2 ± 9.9 years, 73.1% white, 67.4% male),
of which 4,440 were admitted within 30 days and 6,095
within 90 days of LT. MACE occurred in 330 (7.4%) and 429
(7.0%) patients at 30 and 90 days, respectively. Patients with
MACE were older (57.0 vs. 53.6 years, p<.0001), and more
likely to be white (81.2% vs. 73.5%, p=.03), have steatohep-
atitis (40.1% vs. 28.2%, p<.0002) and a history of ischemic
heart disease, myocardial infarction, heart failure, stroke, atrial
fibrillation, hepatopulmonary syndrome, and obstructive sleep
apnea (p<.01 for all). They also had higher mean creatinine
(1.9 vs. 1.4 mg/dL, p<.0001) and prevalence of chronic renal
disease (12.8% vs. 9.5%, p=.03). There was no significant
difference in simultaneous kidney transplant (9.3% vs. 7.0%,
p=0.08). In multivariate analysis, age > 45 [Incidence risk ratio
(IRR)=1.8 (1.2-2.7)], alcoholic cirrhosis [IRR=1.6 (1.2-2.2)],
nonalcoholic steatohepatitis [IRR=1.6 (1.2-2.2)], pretransplant
creatinine [IRR=1.1 (1.04-1.2), atrial fibrillation [IRR=6.9 (4.9-
9.6)] and stroke [IRR=6.3 (1.6-25.4)] remained independently
predictive of early MACE. Of note, those with an early MACE
had lower 1-year survival post-LT (65.2% vs. 75.6%) than those
without an event (p<.0001). CONCLUSIONS: Based on a
novel national database, MACE occurred in < 10% of inpatient
hospitalizations after LT. However, these events appear to have
a significant impact on early transplant survival. Pretransplant
atrial fibrillation and stroke, both modifiable risk factors, sub-
stantially increase risk of MACE. Future prospective studies
aimed at determining whether aggressive risk factor reduc-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS 451A

tion of these novel findings can decrease MACE and improve Disclosures:
post-LT outcomes are needed. Valerie Canva - Board Membership: ROCHE
Disclosures: Philippe Mathurin - Board Membership: Schering-Plough, Janssen-Cilag, BMS,
Gilead, Abvie; Consulting: Roche, Bayer, Boehringer
The following people have nothing to disclose: Lisa B. VanWagner, Marina
Serper, Raymond Kang, Anton I. Skaro, Josh Levitsky, Samuel Hohmann, Donald Sebastien Dharancy - Board Membership: NOVARTIS; Speaking and Teaching:
M. Lloyd-Jones ASTELLAS, ROCHE
The following people have nothing to disclose: Guillaume Lassailly, Franck
Saint-Marcoux, Juliette Boulanger, Alexandre Louvet, Odile Goria, Stephanie
Truant, Gilles Lebuffe, Emmanuel Boleslawski, François René Pruvot
513
Calcineurin inhibitor withdrawal following by myco-
phenolate mofetil monotherapy using therapeutic drug 514
monitoring in maintenance liver transplant recipients Alpha-fetoprotein Slope >7.5 ng/mL/month Predicts
Guillaume Lassailly1,3, Franck Saint-Marcoux5, Juliette Boulanger1, Post-transplant Tumor Recurrence and Micro-vascular
Valerie Canva1, Philippe Mathurin1,3, Alexandre Louvet1, Odile Invasion for Hepatocellular Carcinoma within Milan
Goria4, Stephanie Truant2, Gilles Lebuffe6, Emmanuel Bole- Criteria
slawski2, François René Pruvot2, Sebastien Dharancy1,3; 1Hepatol-
Jeanne-Marie Giard1, Neil Mehta1, Jennifer L. Dodge2, John P.
ogy, CHRU lille, Lille, France; 2Hepatic surgery, CHRU Lille, Lille,
Roberts2, Francis Y. Yao1,2; 1Medicine, University of California
France; 3U995, INSERM, Lille, France; 4hepatology, CHU Rouen,
San Francisco, San Francisco, CA; 2Surgery, University of Califor-
Rouen, France; 5pharmacology, CHU Limoges, Limoges, France;
6Anesthesiology, CHRU Lille, Lille, France nia San Francisco, San Francisco, CA
Rising alpha-fetoprotein (AFP) has been suggested to be a
Calcineurin inhibitors (CNI) induce chronic renal dysfunction.
marker of poor prognosis after liver transplant (LT) for hepato-
Switching CNI to mycofenolate mofetil (MMF) monotherapy
cellular carcinoma (HCC), but prior studies relied on only two
remains controversial due to an increased risk of acute rejec-
data points and were imprecise in assessing the AFP trend,
tion. To safely withdraw CNI, mycophenolic acid (MPA) should
and did not adequately account for random fluctuations of AFP
be monitored. Aims: 1) Define a safe MPA targeted exposure
in liver disease. The primary aim of this study was to examine
(AUC). 2) Study the benefit and efficacy of MMF monotherapy
the association between AFP slope and post-LT HCC recur-
under therapeutic drug monitoring. Methods: 1) To define a
rence, with AFP slope more precisely estimated from multiple
safe MPA targeted exposure, 18 stable LT recipients previously
data points over time. Our cohort included 336 consecutive
treated with MMF monotherapy, were selected. Algorithms
patients undergoing LT with MELD exception for HCC within
were used to determine AUC0-12h (0, H0.5, H2, H3 and H4).
Milan criteria between January 2003 and February 2013.
2) Patients that required CNI withdrawal were selected, and
Most (98%) had pre-LT loco-regional therapy (LRT). The AFP
prospectively followed. Before CNI withdrawal MMF, daily
slope was estimated by fitting a regression line to the AFP levels
doses were adjusted to reach the MPA targeted previously
over time. The median number of AFP data points was 6 (IQR
determined. Data as ALT, glomerular filtration rate (GFR) using
4-8) per patient and the median time interval was 64 days
MDRD formula were prospectively collected at CNI withdrawal
(IQR 36-97). The median post-LT follow-up was 4 years (range
(baseline), M1, and each year until M72. Results: 1) A wide
2-6.2 years). The 1- and 5-year patient survival was 94% and
variability in MPA concentrations was observed at any time,
77%; and 1- and 5-year recurrence-free probabilities were
with mean C0, C0.5, C2, C3 and C4 values at 2.4 (0.4 to
95% and 86%, respectively. In univariate analysis, significant
4.6), 15.2 (4.5 to 31.1), 5.2 (2.2 to 9.5), 3.3 (0.9 to 5.5)
predictors of HCC recurrence included microvascular invasion
and 2.9 mg/L (0.6 to 5.3). For C0 MPA a greater than 10-fold
(HR 13.1, 95% CI 6.8-25.2, p<0.001), tumor grade (HR 1.8,
range was observed. The mean estimated AUC0-12h value
95% CI 1.3-2.5, p<0.001), pathologic stage > Milan criteria
was 48.1±13 mg.h/L. MPA AUC0-12 did not correlate with
(HR 8.9, 95% CI 3.9-20.6, p< 0.001), 3 tumor nodules (HR
MMF daily dose (r= 0.27, p=0.2). 2) From dec 2000 to dec
5.4, 95% CI 2.2-13.4, p=0.002), AFP slope >7.5 ng/mL/
2013, 103 recipients (mean age 60.2±7.4 yrs) underwent
month (HR 3.9, 95% CI 1.5-10.2, p=0.005), and female gen-
MMF monotherapy after a mean of 6.3±3.9 yrs from LT. LT
der (HR 2.3, 95% CI 1.2-4.3, p=0.01). AFP at diagnosis at all
indication was alcoholic cirrhosis in 73% of cases, mean MPA
cutoffs (>100, >300, >400, >500, and >1000 ng/mL), age,
AUC was at 49.3±17.1 and GFR was 47.8±16.9 ml/kg/
race, liver disease diagnosis, waitlist time and number of LRT
min. Follow up: 4 patients had acute rejection and 2 required
were not significant predictors of HCC recurrence. When only
steroid bolus. Over time, patients did not have a significant
pre-transplant variables were included in multivariate analysis,
change in term of: ALT (23.2±13.4 vs 25.7±16.2) and weight
3 tumor nodules (HR 7.7, 95% CI 3.0-20.1, p<0.001), AFP
(80±18.2 to 80±19.1). Renal function improved significantly
slope >7.5 ng/mL/month (HR 3.0, 95% CI 1.1-7.9, p=0.03),
(GFR 47.7±15.7 to 53.7±19.6, p<0.001). This improvement
and female gender (HR 2.6, 95% CI 1.3-5.2, p=0.008) were
occurred the first year of MMF monotherapy (GFR: 45.8±14.9
significant predictors of HCC recurrence. Three tumor nodules
to 52.9±19.8 ml/kg/min; p<0.05), as shown by GFR evolu-
and a rising AFP slope were associated with microvascular
tion between 1 and 2 years: 50.8±17.1 vs 48.1±14.7 (ns),
invasion; with AFP slope >7.5 ng/mL/month being the most
and also concerned patients with a low GFR at baseline (<60)
significant (OR 6.2, CI 1.5-26.3, p=0.01). The 1- and 5-year
41.3±10 to 47.9±15.4 ml/kg/min p<0.05. GGT worsened
survival without recurrence for the 23 patients (7%) with pre-LT
(57.6±50.5 vs 79.6±92.5 p<0.001). Patients with elevated
AFP slope >7.5 ng/mL/month was 91% and 70%, respec-
GGT after MMF monotherapy did not differ at baseline from
tively, versus 96% and 87% for all others (p=0.01). Conclu-
other in terms of: age (60.3 vs 59.7), time after LT (6.9 vs 5.8),
sion: Rising AFP with slope >7.5 ng/mL/month despite LRT for
MPA AUC (50 vs 52) or weight (82 vs 78kg). Conclusion: In
HCC within Milan criteria predicts post-LT HCC recurrence,
maintenance LT recipients, MMF monotherapy regimen is safe
and may serve as a surrogate for microvascular invasion.
when a 45 mg.h/L AUC is targeted and improve renal function
These findings support incorporating changes in the AFP into
with low risk of acute rejection. However, GGT increase may
the “ablate and wait” principle of candidate selection while on
reflect a trend toward subclinical rejection and further studies
the LT waiting list.
are needed to exclude the risk of humoral rejection.
Disclosures:
452A AASLD ABSTRACTS
The following people have nothing to disclose: Jeanne-Marie Giard, Neil Mehta,
Jennifer L. Dodge, John P. Roberts, Francis Y. Yao
515
WITHDRAWN
516
Treatment of acute cellular rejection episodes does not
influence fibrosis progression rate in patients with recur-
rence HCV after liver transplantation
Pinelopi Manousou1, Emmanuel Tsochatzis1, Ioanna Parisi1, Fran-
cesca Saffioti1, Alexandra Mansell1, Silvia Aspite1, David W.
Patch1, James O’Beirne1, Douglas Thorburn1, Tu Vinh Luong2,
Amar P. Dhillon2, Massimo Pinzani1, Andrew K. Burroughs1;
1Royal Free Hospital, Liver Transplantation, London, United King-
dom; 2Department of Cellular Pathology, UCL Medical School,
Royal Free Campus, London, United Kingdom
Background/aim: It is known that steroids boluses for the treat-
ment of acute cellular rejection(ACR) greatly increase HCV
RNA levels after liver transplantation(LT), but results regard-
ing fibrosis progression rate are controversial. We evaluated
the effect of treatment of ACR in a large cohort of patients
transplanted for HCV. Methods: 271 consecutive patients
with follow up≥12months (median 9 years) were included.
ACR was graded using the Royal Free Hospital score which
incorporates eosinophilia with the Banff score: If moderate/
severe, we treated with 1g daily methylprednisolone intra-
venously for 3 days. Ishak stage≥4, collagen proportionate
area(CPA)≥12.5%, HVPG≥10mmHg and clinical decompensa-
tion were the endpoints evaluated with Cox regression. Results:
Baseline characteristics: median age/donor age 51/42 years,
genotype 1/3: 47%/35%, concomitant HCC in 83, antiviral
treatment in 78(24 with SVR were censored). 172 patients
received tacrolimus and 63 cyclosporine as main immunosup-
pression. Median tacrolimus levels up to day 30 were 6.9
ng/ml and cyclosporine levels were 132μg/l. These patients
had 906 biopsies at yearly interval as part of their routine
care. Another 532 biopsies were performed as protocol liver
biopsies between the 5th and 10th days post-LT, to assess ACR
episodes. Boluses steroids for treatment of ACR episodes were
given in 125/246(49%, SVR censored) patients; 121 received
a single or 2 courses and another 4 received three courses of
steroids in total: 35/121 with no ACR versus 42/121 with 1
or 2 episodes treated reached Ishak stage 4 (p=0.4), 17/87
vs 26/84 reached CPA 12.5% (p=0.1), 22/57 vs 34/79
reached HVPG 10mmHg (p=0.9) and 16/121 vs 25/121
decompensated (p=0.1) respectively. In Cox or Kaplan-Meier
analysis, steroids boluses were not significant for any of the end-
points examined: for Ishak stage 4(Chi square 0.13, p=0.99);
for CPA≥12.5%(Chi square 2.1, p=0.36), for HVPG≥10mmH-
g(Chi square 0.81, p=0.66), for clinical decompensation(Chi
square 1.3, p=0.5). 46% (69 with 1 episode, 24 with 2, 2
with ≥3 of 206 in total) of the patients with lower trough CNI
levels(TAC≤10ng/ml or CYA≤300μg/Lt) within the first month
post LT, were treated for rejection with steroids boluses com-
pared to 60% (23 with 1 episode, 6 with 2 and 1 with 3 of
53 in total) of those with higher CNI levels(p=0.2). Conclusion:
Treatment of ACR with steroid boluses was not associated with
fibrosis progression, portal hypertension or clinical decompen-
sation in recurrent HCV post-LT. Lower trough CNI levels within
the 1st month post LT, did not predispose to ACR.
Disclosures:
HEPATOLOGY, October, 2014
Massimo Pinzani - Advisory Committees or Review Panels: Intercept Pharmaceu-
tical, Silence Therapeutic, Abbot; Consulting: UCB; Speaking and Teaching:
Gilead, BMS
The following people have nothing to disclose: Pinelopi Manousou, Emmanuel
Tsochatzis, Ioanna Parisi, Francesca Saffioti, Alexandra Mansell, Silvia Aspite,
David W. Patch, James O’Beirne, Douglas Thorburn, Tu Vinh Luong, Amar P.
Dhillon, Andrew K. Burroughs
517
Pre-transplant Type 2 Hepatorenal Syndrome is Asso-
ciated with Persistently Impaired Renal Function after
Liver Transplantation
Hiang K. Tan1, Max Marquez2, Florence Wong1, Eberhard L.
Renner2; 1Division of Gastroenterology, Department of Medicine,
Toronto General Hospital, Toronto, ON, Canada; 2Liver Transplant
Unit, Multi-Organ Transplant Program, Toronto General Hospital,
Toronto, ON, Canada
BACKGROUND: Type 2 hepatorenal syndrome (HRS2) is a
form of functional renal impairment complicating end-stage
liver disease. While generally felt to be reversible after liver
transplantation, long-term outcomes after transplantation in
HRS2 patients remains ill-defined. METHODS: Retrospective,
matched case-control (1:2) study of all adult HRS2 patients
transplanted in our institution between 2000 and 2012. HRS2
patients were identified from our electronic transplant data-
base, and matched with controls for the following variables:
age, gender, etiology, diabetes mellitus and year of transplant.
RESULTS: Forty-two HRS2 patients were compared to 83 con-
trols. At the time of transplant, HRS2 patients had an estimated
glomerular filtration rate (eGFR) of 41±1ml/min/1.73m2 (vs.
96±4ml/min/1.73m2 among controls, p<0.0001). HRS2
patients required more intra-operative packed red blood cell
transfusion (p=0.002), and had a longer intensive care unit
(p=0.01) and total hospital length of stay (p=0.03). Reversal
of HRS2 occurred in 88.1% patients, on average 5.7±0.5
days post-transplantation. Although HRS2 patients had lower
initial exposure to calcineurin inhibitor, a greater proportion
of HRS2 patients had renal dysfunction, as defined by eGFR
<60ml/min/1.73m2, at three (53.8% vs. 28.4%, p=0.007)
and 12 months (59.5% vs. 38.2%, p=0.03) post-transplan-
tation compared to controls (Figure 1). One-year survival
was similar between the two groups (log-rank p=0.82). On
multivariate analysis, pre-transplant HRS2 was associated
with persistent renal dysfunction at three (OR 3.73, [95% CI
1.54-9.03], p=0.004) and 12 months (OR 3.23 [95% CI
1.37-7.64], p=0.007) post-transplant. CONCLUSION: Liver
transplantation reverses HRS2 in the majority of patients with
survival outcomes comparable to matched controls. However,
pre-transplant HRS2 is associated with persistently impaired
renal dysfunction post-transplant, despite calcineurin inhibitor
minimization.
Figure 1. Proportion of HRS2 and control patients with renal dys-
function (eGFR < 60ml/min/1.73m2) at a) 3 and b) 12 months
post-transplant
Disclosures:
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Florence Wong - Consulting: Gore Inc; Grant/Research Support: Grifols
Eberhard L. Renner - Advisory Committees or Review Panels: Vertex Canada,
Novartis, Astellas Canada, Roche Canada, Gambro, AbbVIe, BMS; Grant/
Research Support: Novartis Canada, Gilead; Speaking and Teaching: Novartis,
Astellas Canada, Roche Canada
The following people have nothing to disclose: Hiang K. Tan, Max Marquez
518
A Single-Center Experience with Preoperative Selective
Internal Radiation Therapy (SIRT) with Y-90 with or
without Transarterial Chemoembolization (TACE), as a
Bridging Procedure, in Liver Transplant Recipients (OLT)
with Unresectable Hepatocellular Carcinoma (uHCC):
Efficacy of Combination Therapy (Rx)
Carlos G. Fasola, Parvez S. Mantry, Bahar Madani, Jeffrey S.
Weinstein, Abdullah Mubarak, Hector Nazario, Adil Habib, Mai-
sha N. Barnes, Alejandro Mejia, Richard Dickerman, Edward A.
Dominguez, Stephen Cheng; Liver Institute, Methodist Dallas Med-
ical Center, Dallas, TX
Background: Radioembolization using Yttrium-90 is increas-
ingly being used as locoregional Rx in the US to treat HCC.
We report the use of SIRT by itself or associated with TACE to
improve outcome of our OLT-uHCC population. Methods: From
April 2007 to March 2013, OLT (n=15) with uHCC were eval-
uated by multiphasic MRI and treated with SIRT alone (n=8) or
in combination with TACE (n=7) to reduce tumor burden and/
or fulfill Milan criteria. MRI Follow up: at 6 weeks and then
every 3 months post Rx. Data analyses: laboratory tests, tumor
number, size and necrosis, at imaging and at explant; adverse
events and survivals. Statistics: t-test, Chi 2, Kaplan-Meier.
Results: Demographics (n, %): male (10, 67%), race (Cauca-
sian (7, 47%), AfroAmerican (5, 33%), Hispanics (2, 13%)
and Asian (1, 6%). Etiology: HCV (7, 47%), HBV (3, 20%),
Alcohol (2, 13%), Cryptogenic (2, 13%) and NASH (1, 6%).
Child’s class (A= 12, 80%; B= 3, 20%). Most tumors were mul-
tifocal. Four OLT-HCC had TACE initially and upon HCC pro-
gression, tumor growth was controlled with SIRT. Three other
OLT-HCC had SIRT first, then TACE. Follow up range: 10 to 78
months. No HCC recurrence has been observed in any patient
during this period. Most patients tolerated SIRT or combination
Rx well. Side effects of SIRT included abdominal pain (n=1)
and worsening ascites (n=1). In the TACE group: abdominal
pain and GI bleeding (n=1), ascites (n=1) and jaundice (n=1).
Two OLT-HCC recipients in the SIRT group died at 5 and 6
years respectively. One due to laryngeal CA and another due
to HCV recurrence. As per explant pathology, for SIRT alone
therapy no statistical differences were found between tumor
number reduction or tumor size reduction before and after OLT
(n = 0.0 ± 0.5 and 0.2 ± 0.7 cm, respectively). For SIRT +
TACE recipients, these differences were significant (n = 2.0 ±
1.9 and 3.6 ± 2.4 cm, respectively). The incidence of necrosis
was numerically higher with combination therapy, although not
significant (table). Conclusions: In selective OLT-uHCC patients,
the use of SIRT by itself - and especially in combination with
TACE - plays an important role in downstaging patients to
transplant criteria with a low risk of HCC recurrence after OLT.
Larger experience is needed to confirm these initial findings.
453A
Tumor Changes post Therapy
P value < 0.05: 3 vs 10; 6 vs 13; 8 vs 9; 11 vs 12.
P = N.S.: Other comparisons.
Disclosures:
Parvez S. Mantry - Consulting: Salix, Gilead, Janssen, Abbvie; Grant/Research
Support: Salix, Merck, Gilead, Boehringer-Ingelheim, Mass Biologics, Vital Ther-
apies, Santaris, Vertex, Bristol-Myers Squibb, Abbive, Bayer-Onyx; Speaking
and Teaching: Gilead, Janssen, Salix, Bayer-Onyx
Jeffrey S. Weinstein - Speaking and Teaching: Merck
Abdullah Mubarak - Speaking and Teaching: Salix Pharmaceuticals, Genetech,
Vertex, Merck
Hector Nazario - Advisory Committees or Review Panels: Gilead; Speaking and
Teaching: Gilead, Merck, Abbvie, Salix
Edward A. Dominguez - Advisory Committees or Review Panels: Gilead, Pfizer;
Grant/Research Support: Cubist; Speaking and Teaching: Amgen, Astelleas
The following people have nothing to disclose: Carlos G. Fasola, Bahar Madani,
Adil Habib, Maisha N. Barnes, Alejandro Mejia, Richard Dickerman, Stephen
Cheng
519
HMGB1 and nucleosomes as biomarkers of clinical out-
come in human liver transplantation
Antônio Márcio F. Andrade1, Marcus V. Andrade2, Agnaldo S.
Lima1,3, Luciana C. Faria1,2; 1Instituto Alfa de Gastroenterologia
- Liver Transplantation Unit, Hospital das Clinicas - Universidade
Federal de Minas Gerais, Belo Horizonte, Brazil; 2Departamento
de Clínica Médica, Faculty of Medicine - Universidade Federal de
Minas Gerais, Belo Horizonte, Brazil; 3Departamento de Cirurgia,
Faculty of Medicine - Universidade Federal de Minas Gerais, Belo
Horizonte, Brazil
This study aimed to investigate if High Mobility Group Box 1
(HMGB1) protein and extracellular nucleosomes (EN) released
by the donor and the recipient in human liver transplantation
(LT) may act as alarmins and be associated with an amplified
inflammatory response and its clinical consequences. Meth-
ods: The study involved adult cirrhotic patients who underwent
first LT at an University Hospital from 2011 to 2012 and their
donors. They were evaluated according to clinical protocol in
order to identify postoperative complications. Serum samples
were obtained from the donor and the recipient before, during
and early after surgery, at several times. In all samples, the
levels of cytokines, HMGB1 and EN were measured, and asso-
ciation between the results and outcomes was investigated.
Results: Twenty two patients were included. HMGB1 and EN
levels in the donors were low. A peak response enhancement
of HMGB1 and EN was observed in the recipient after reper-
fusion suggesting origin from the graft probably due to isch-
emia-reperfusion injury. In univariate analysis, HMGB1 and
EN levels after reperfusion and early after LT were associated
with acute renal failure, early allograft dysfunction and early
mor-tality post-LT. The multivariate analysis confirmed the asso-
ciation with early mortality after LT. Conclusion: Our results
showed that HMGB1 and EN levels after reperfusion and early
after LT are associated with early survival. To the best of our
knowledge there are no studies so far showing the kinetics of
454A AASLD ABSTRACTS
EN in LT. Consequently, HMGB1 and EN may be used as bio-
markers of occurrence of early complications and survival after
LT and help to clinically manage these patients.
Disclosures:
The following people have nothing to disclose: Antônio Márcio F. Andrade,
Marcus V. Andrade, Agnaldo S. Lima, Luciana C. Faria
520
Improved but persistent poor functional performance at
1 year after liver transplantation: Predictors of perfor-
mance and opportunities for intervention
Sarah Uttal1, Lisa B. VanWagner2,3, Brittany Lapin1, Amanda Jich-
linkski1, Joshua Lee1, Madeleine Heldman1, Brian Poole1, Tanvi
Subramanian1, Eduardo A. Bustamante1, Suvai Gunasekaran1,
Christopher S. Tapia 1, Annapoorani Veerappan 2, She-Yan
Wong2, Josh Levitsky1,2; 1Northwestern University Transplant Out-
comes Research Collaborative (NUTORC), Northwestern University
Feinberg School of Medicine, Chicago, IL; 2Medicine, Division of
Gastroenterology & Hepatology, Northwestern University Feinberg
School of Medicine, Chicago, IL; 3Preventive Medicine, Northwest-
ern University Feinberg School of Medicine, Chicago, IL
Background: Functional impairment is common in chronic liver
disease (CLD) and improvement is expected following liver
transplantation (LT). The 6-minute walk distance (6MWD) is
an objective measure of functional performance. Aim: To com-
pare 6MWD in LT recipients over time compared to healthy
controls (HC) and CLD patients. Methods: 6MWD was pro-
HEPATOLOGY, October, 2014
spectively measured in 162 ambulatory participants (50 HC,
62 CLD, 50 LT) using a standard protocol. Sex, age, and BMI
were used to calculate ideal 6MWD. Chi-square, ANOVA,
and Pearson coefficients compared actual and % predicted
6MWD (%6MWD) across groups. Multivariable mixed models
assessed predictors of 6MWD improvement. Results: Mean
participant age was 53.5 (13.0) years, 39.5% female, 39.1%
non-white. LT recipient %6MWD was 65.3 (22.8)% at a mean
of 71.8 (65.1) days, improving to 79.1 (19.9)% by 287.3
(138.2) days post-LT (p<0.01). At 1-year post-LT male, but
not female, %6MWD [80.4 (19.5)%] remained worse than
both CLD [93.3 (13.7)%] and HC [91.9 (14.3)%] participants
(p=0.03, Figure). LT recipient 6MWD was directly correlated
with male sex (r=0.47, p<0.05) and hepatitis C (r=0.59,
p<0.01) and inversely correlated with nonalcoholic steatohep-
atitis (NASH) (r=-0.52, p<0.01). 6MWD also showed strong
correlation with physical component score on the SF-36 in all
groups (r=0.51, p<0.01). In multivariate analysis, hepatitis C
remained an independent predictor of 6MWD improvement
(p=0.048). There was a trend towards worse 6MWD in NASH
recipients (p=0.06). At 1-month post-LT, only 5/46 (10.9%)
of recipients were enrolled in a rehabilitation program and at
1-year none were participating. Conclusions: 6MWD is lower
in male patients up to 1 year post-LT as compared to HC and
CLD patients. Among LT recipients, male sex and NASH are
associated with poorer 6-minute walk performance, which is a
simple and inexpensive measure of functional performance that
can be easily applied in clinical practice. A minority of LT recip-
ients are enrolled in a rehabilitation program highlighting the
opportunity for early lifestyle intervention to potentially improve
functional capacity after LT.
Figure: Percent predicted 6MWD over time stratified by group
and sex
Disclosures:
Josh Levitsky - Consulting: Transplant Genomics Inc; Grant/Research Support:
Novartis; Speaking and Teaching: Gilead, Salix
The following people have nothing to disclose: Sarah Uttal, Lisa B. VanWagner,
Brittany Lapin, Amanda Jichlinkski, Joshua Lee, Madeleine Heldman, Brian Poole,
Tanvi Subramanian, Eduardo A. Bustamante, Suvai Gunasekaran, Christopher S.
Tapia, Annapoorani Veerappan, She-Yan Wong
521
Younger Hepatitis C Virus (HCV) Liver Transplant (LT)
Recipients have Significantly Reduced Graft Survival
Varun Saxena, Jennifer L. Dodge, John P. Roberts, Norah Ter-
rault; Gastroenterology, University of California San Francisco,
San Francisco, CA
Background/Aim: Among HCV LT recipients, older recipient
age has been associated with graft loss, but the natural his-
tory of HCV among young (age <40y) adults undergoing LT is
unknown. Using MELD-era UNOS data, we evaluated young
HCV LT recipients and compared their outcomes to older age
cohorts. Methods: All US adult HIV(-), HCV-positive LT recipients
from 2002-2013 were included (N=25,968). Graft loss (re-LT
or death) was estimated using the Kaplan-Meier method and
the association between recipient age and survival assessed
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
with Cox regression. Results: Overall, recipients were 25%
female, 70% White, with mean age of 54.5y. Recipients <40y
(n=105, 0.4% 18-29y; n=459, 1.8% 30-39y) vs >40yrs, had
higher % female (31 vs 24), mean MELD at LT (24 vs 20), %
rejection (18 vs 10), and lower mean donor risk index (1.3
vs 1.4), and % HCC (11 vs 44). Overall, the 1-, 3-, and 5-yr
graft loss rates were 23%, 32%, and 40%. Using 40+y cohort
as reference (40% 5-y graft loss), 5-y graft loss was higher at
63% and 42% for recipient age cohorts 18-29 and 30-39y
respectively (p<0.001) (Fig). In adjusted analysis, recipient
age 19-29y had 81%(HR 1.81, CI 1.39-2.37, p<0.001) and
30-39 had 17%(1.17, 1.01-1.36, p=0.04) higher rate of graft
loss. In recipients 18-29, 30-39 and 40+y, re-LT occurred in
10% 10% and 5%; HCV-related death in 22%, 21% and 13%
(p<0.001 for both). Among patients <40y, recipient age/y (HR
0.95, CI: 0.94-0.98), donor age/y (1.02, 1.02-1.03), recip-
ient female (1.39; 1.06-1.83), MELD at LT per point (1.02,
1.00-1.03) were independent predictors of graft loss; treated
rejection (1.19, 0.80-1.78) was not. Conclusions: Younger
(<40y) HCV LT recipients have significantly reduced graft sur-
vival, higher rates of re-LT and HCV-related death than older
HCV recipients. This suggests a more aggressive natural history
for HCV disease post-LT and identifies a group in need of early
consideration of HCV therapy.
Disclosures:
Norah Terrault - Advisory Committees or Review Panels: Eisai, Biotest; Con-
sulting: BMS, Merck; Grant/Research Support: Eisai, Biotest, Vertex, Gilead,
AbbVie, Novartis, Merck
The following people have nothing to disclose: Varun Saxena, Jennifer L. Dodge,
John P. Roberts
522
Impact of portal vein thrombosis prior to liver transplan-
tation: a multi-center retrospective cohort study
Constantine J. Karvellas1,2, Filipe S. Cardoso1, Malcolm M. Wells3,
Fayaz A. Handoo2, Lukasz Kwapisz3, Mansour G. Alghanem3,
Norman Kneteman4, Paul Marotta3, Bandar Al-Judaibi3,5; 1Crit-
ical Care, University of Alberta, Edmonton, AB, Canada; 2Gas-
troenterology (Liver Unit), University of Alberta, Edmonton, AB,
Canada; 3Gastroenterology (Liver Unit), London Health Sciences
Centre, London, ON, Canada; 4Surgery/Transplant, University of
Alberta, Edmonton, AB, Canada; 5Gastroenterology (Liver Unit),
King Saudi University, Riyadh, Saudi Arabia
Background/Aims: To identify the impact of portal vein throm-
bosis (PVT) on post liver transplant (LT) outcomes along with
other covariates and assess factors associated with compli-
cations amongst PVT patients. Methods: Retrospective cohort
study of 621 adult LT recipients (University of Alberta, London
455A
Health Sciences Centre) between 01/2002-12/2012. PVT
was identified in 147 (24%) patients and 474 (76%) non-
PVT patients served as controls. Cox survival analysis was
performed to determine independent associations with overall
mortality. Results: Demographic factors (mean age 53, 69%
male) were similar between groups. There were also no dif-
ferences in mean MELD (PVT 19 vs. controls 19, p=0.9) and
Child Pugh scores (10 vs. 10, p=0.9) on the day of LT. Donor
factors (mean DRI:1.6 vs. 1.5, p=0.2) were similar. Using
Cox multivariable survival analysis, covariates independently
associated with overall mortality included Age (adjusted Haz-
ard ratio ~ aHR 1.02, p=0.015) and requiring ICU support
pre-LT (aHR 2.17, p=0.006), but not PVT (p=0.67). 5-year
survival was similar between PVT and controls (75%,p= 0.8).
In comparing PVT patients who did not survive (n=32) with PVT
survivors (n=115), non-survivors (n=32) were more likely to
have complete thrombus occlusion (38% vs. 13%, p=0.027)
and hepatofugal flow (31% vs. 13%, p=0.08). Non-survivors
were more likely require thrombectomy (69 vs. 31%, p=0.08)
and develop reocclusion post-LT (16% vs. 3%, p=0.024). Anti-
coagulation rates were similar between groups. Conclusion:
Well-selected LT patients who had PVT prior to LT have similar
post-LT outcomes with controls when adjusting for donor and
recipient factors. Subgroups of PVT LT patients who did worse
post-LT (complete thrombosis pre-LT, thrombectomy at LT and
reocclusion post-LT) warrant closer evaluation in listing and
management post-LT.
Adjusted survival (Cox) for PVT LT recipients vs. controls (p=0.67).
Disclosures:
Constantine J. Karvellas - Grant/Research Support: Merck; Speaking and Teach-
ing: Gambro
The following people have nothing to disclose: Filipe S. Cardoso, Malcolm M.
Wells, Fayaz A. Handoo, Lukasz Kwapisz, Mansour G. Alghanem, Norman
Kneteman, Paul Marotta, Bandar Al-Judaibi
456A AASLD ABSTRACTS
523
Treatment with mTOR inhibitors after liver transplanta-
tion enables a sustained increase in regulatory T-cells
while preserving their suppressive capacity
Kaldoun Ghazal2, Fabien Stenard2, Clement Barjon2, Lynda Aoud-
jehane3, Fabiano Perdigao1, Olivier Scatton1, Yvon Calmus1,2,
Filomena Conti1,2; 1Centre de Transplantation Hepatique, Hôpital
Saint Antoine, APHP, Paris, France; 2UMR_S 938, CDR Saint-An-
toine, Sorbonne Universités, UPMC Univ Paris 06, Paris,, France;
3Human HepCell, Paris, France
Background. The mammalian targets of rapamycin (mTOR)
inhibitors (sirolimus [SRL] and everolimus [EVR]) are used after
transplantation for their immunosuppressive activity. Evidence
has indicated that regulatory T-cells (Tregs) play a crucial role in
immune tolerance. mTOR inhibitors appear to preserve Tregs,
unlike Tacrolimus (Tac). The aim of this study was to evaluate
the number and function of Tregs in liver transplant recipients
before and after their conversion from Tac to mTOR inhibitors.
Patients and methods. Fifteen patients with stable graft function
where converted to SRL (n=5) or EVR (n=10). Tregs (CD4+C-
D25+FoxP3+CD127-) were analysed prospectively in blood
cells using flow cytometry, and a functional assay was per-
formed to test Treg activity. Results. All patients in both groups
displayed a sustained rise in Treg levels after the introduction
of mTOR inhibitors (Treg levels at 3 months: 6.45±0.38% of
CD4 T-cells, vs. a baseline level of 3.61±0.37%, p<0.001;
mean fold increase 2.04±0.73). In the SRL group, 3-month
Treg levels were 6.0±0.5 vs. 3.7±0.3; p=0.037, while in the
EVR group they were 6.6±0.6 vs. 3.5±0.5; P=0.001. By con-
trast, no statistical change was observed in an unconverted
Tac control group. Tregs also preserved their functional ability
to suppress activated T-cells. Conclusion. These results suggest
that mTOR inhibitors induce a significant increase in Tregs
while maintaining suppressive activity after LT.
Disclosures:
The following people have nothing to disclose: Kaldoun Ghazal, Fabien Stenard,
Clement Barjon, Lynda Aoudjehane, Fabiano Perdigao, Olivier Scatton, Yvon
Calmus, Filomena Conti
524
Cardiovascular Risk in Liver Transplant Patients
Tommaso Di Maira1, Lorena Puchades2, Angel Rubin2, Carmen
Vinaixa2, María García Eliz2, Fernando San Juan2, Rafael López
Andujar2, Erica Villa1, Martin Prieto2, Marina Berenguer2; 1Uni-
versity Hospital, Policlinico di Modena, Modena, Italy; 2University
Hospital La Fe, Valencia, Spain
Introduction: Cardiovascular (CV) diseases together with de
novo cancers represent major impediments to liver transplant
(LT) long-term survival, accounting for 13-14% and 10-18%
of long-term deaths, respectively. Aims: To assess whether the
Framingham score at transplantation can predict the develop-
ment of post-LT CV events. Patients and methods: Patients trans-
planted between January 2006 and December 2008 were
included. Baseline features (age, gender, LT indication, thera-
pies pre-LT, immunosuppression at hospital discharge, donor-re-
lated factors), history of risk factors for CV events (tobacco use,
arterial hypertension (AHT), diabetes (DM), dyslipidemia (DL),
renal insufficiency, obesity) and CV events occurring post-LT
(ischemic heart disease, stroke, heart failure, de novo arrhyth-
mias, peripheral arterial disease) were recorded. Results: 250
patients, 69.5% men, median age 56 (range 18-68) yrs, mostly
transplanted for viral or alcoholic cirrhosis (40% and 29%,
respectively), Child C 51% were included. Immunosuppression
was based on cyclosporine (CsA) or tacrolimus (Tac) (55% and
41%, respectively). Mycophenolate mofetil (MMF) and predni-
HEPATOLOGY, October, 2014
sone (PDN) were used in 44% and 88%, respectively. Median
donor age was 56 (range 13-81) yrs. Pre-LT cardiovascular
risk factors were: history of tobacco use 53%, DM 21%, hyper-
cholesterolemia 8.5%, hypertriglyceridemia 8%, AHT 27%,
estimated filtration rate < 90 ml/min 41%. At transplantation,
34.5%, 33% and 33% of patients respectively had a low, mod-
erate and high Framingham risk score. Fourteen percent of LT
recipients developed at least one CV event at a median of 2.5
(range: 0.005 – 7) yrs. An association was found between the
Framingham score at LT and the development of CV events (p=
.003 by Cox regression analysis). Moreover, an association
was also found between the Framingham score and overall
survival (p= .014 by Kaplan-Meier) with 1, 3 and 5 yrs survival
rates of 89.5%, 87% and 82.5% in the low-risk group, 90%,
79% and 78% in the moderate risk group, and 74.5%, 67.5%
and 61.5% in the high-risk group, respectively. Other variables
associated with the development of CV events included age
(p= .007), creatinine clearance (p= .020) and MMF use at
discharge (p=.011). By multivariate analysis, only creatinine
clearance (HR: .98, 95/CI: .97-1.00; p= .009) and Framing-
ham score (HR: 1.06, 95/CI: 1.02-1.10, p= .002) remained
in the model. Conclusions: In our series, the Framingham score
and renal function at LT were able to predict the development
of post-LT CV events. Studies with higher number of CV events
are needed to confirm these findings.
Disclosures:
Erica Villa - Advisory Committees or Review Panels: Abbvie, MSD, GSK; Grant/
Research Support: MSD, Roche
Marina Berenguer - Advisory Committees or Review Panels: Novartis, Astellas,
Janssen, BMS
The following people have nothing to disclose: Tommaso Di Maira, Lorena
Puchades, Angel Rubin, Carmen Vinaixa, María García Eliz, Fernando San
Juan, Rafael López Andujar, Martin Prieto
525
Long-Term Transplant Outcomes: The Role of Pre-Trans-
plant Depression
Shari S. Rogal1, Gautam Mankaney2, Viyan Udawatta2, Chris-
topher B. Hughes3, Amit D. Tevar3, Mark Sturdevant3, Abhinav
Humar3, Andrea DiMartini4; 1Division of Gastroenterology,
Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh,
PA; 2Department of Internal Medicine, University of Pittsburgh,
Pittsburgh, PA; 3Department of Surgery, University of Pittsburgh,
Pittsburgh, PA; 4Department of Psychiatry, University of Pittsburgh,
PIttsburgh, PA
Background: We aimed to assess potentially modifiable risk
factors for poor 10-year liver transplant outcomes. We hypoth-
esized that pre-transplant depression would be associated
with decreased survival. Methods: After excluding patients
transplanted for fulminant liver failure and with multi-organ
transplants, all primary hepatic transplants at a single cen-
ter between 2004-2014 were evaluated in this retrospective
cohort study. Factors associated with death were evaluated
with Cox Proportional-hazards models. Acute rejection and
graft failure were modeled using competing risk models, with
death as a competing risk. Potential covariates included recip-
ient demographics, donor age, MELD at transplant, etiology
of liver disease, cold and warm ischemia time, and graft type
including donation after cardiac death (DCD) vs. live-donor
vs. standard grafts. Pre-transplant depression (per the trans-
plant evaluation), substance use, and a Charlson Comorbidity
Index were also assessed for all patients. Results: Liver trans-
plant recipients (N=1095) were followed for a median of 4.6
years (IQR=1.8, 7.6). Of these, 313 experienced acute rejec-
tion, 66 required re-transplantation, and 347 died. The fac-
tors significantly associated with death in the final regression
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
model included race (HR for African-American vs. Caucasian
=1.11 CI=1.01,1.21), depression pre-transplant (HR=1.58,
CI=1.51,1.65), MELD (HR per point=1.02 CI=1.2,1.01), donor
type (HR for cadaveric vs. live donor=2.54 CI=2.28,2.86),
age at transplant (HR per year=1.04 CI=1.04,1.04), and
warm ischemia time (HR per hour=1.11, CI=1.06,1.16).
Additionally, etiology was also significant in the final model,
with HCV associated with the lowest survival. The only cause
of death that was significantly associated with pre-transplant
depression was death due to non-adherance or withdrawal of
care. Graft failure was significantly associated with DCD grafts
(HR=2.04, CI=1.00,4.17) and donor age (HR per year=1.02,
CI=1.00,1.03). Graft failure was inversely related to recipient
MELD (HR per point=0.96, CI=0.93,0.99) and age at trans-
plant (HR per year=0.96, CI=0.94,0.98). Acute rejection was
not associated with death or graft failure. Time to rejection was
significantly associated with autoimmune (AIH/PBC/PSC) etiol-
ogies of liver disease (HR=1.7, CI=1.03,2.30) and cadaveric
graft (vs. live donor) (HR=1.64, CI=1.17,1.64). Rejection was
inversely related to age (HR =0.98, CI=0.97,0.99). Conclu-
sion: Depression pre-transplant was the only modifiable risk
factor for long-term survival after liver transplantation and was
associated with non-adherance-related death.
Disclosures:
The following people have nothing to disclose: Shari S. Rogal, Gautam Mank-
aney, Viyan Udawatta, Christopher B. Hughes, Amit D. Tevar, Mark Sturdevant,
Abhinav Humar, Andrea DiMartini
526
C4d is Present in Portal Venules in Plasma Cell Hepatitis
and May Also be Used as a Predictor for its Develop-
ment
Anshu Trivedi1, Thomas D. Schiano1, Stephen C. Ward1, Swan
N. Thung1, M. Isabel Fiel1, Josh Levitsky2; 1Pathology, Mount Sinai
Medical Center, New York, NY; 2Pathology, 2Northwestern Uni-
versity Feinberg School of Medicine, Chicago, IL
Background: Plasma cell hepatitis (PCH) is a severe form of
post liver transplant (LT) allograft dysfunction considered a vari-
ant of rejection.In renal transplants, C4d immunohistochemical
(IHC) staining is a reliable marker of antibody mediated rejec-
tion (AMR), however its role in post-LT allograft dysfunction is
controversial. We hypothesize that PCH is a form of AMR.
The purpose of our study is to investigate the C4d IHC stain-
ing pattern in patients with PCH. Design: 21 post-LT hepati-
tis C (HCV) patients from 2 transplant centers were included;
16/21 had more than one liver biopsy; 11 control cases were
included- 5 post LT for HCV-3/5 with recurrent HCV and 2/5
with Acute cellular rejection (ACR) and 6 patients with post LT
for non-HCV-2/6 with recurrent AIH,3/6 with ACR and 1/6
with CR. IHC staining for C4d was performed on archival FFPE
tissue. H&E slides were reviewed to confirm the diagnosis of
PCH. C4d IHC staining was assessed by 2 liver pathologists.
Staining was scored semiquantitatively from 0-3+ based on
number and intensity of staining in portal venules(PV),central
venules (CV) and sinusoids(S). Results: Strong 3+ staining for
C4d was consistently observed in PV as opposed to CV and
S. Of PCH cases, 14/21 (67%) cases showed 3+ staining for
C4d in PV; 5/21 (24%) PCH cases had 2+ PV staining while
2/21 (9%) had 1+ PV staining. 16 of 21 PCH cases had liver
biopsies prior to developing PCH and 7/16 (44%) had 3+,
6/16 (37%) had 2+, and 3/16 (19%) had 1+staining. Of the
HCV control cases 1/5 (20%) showed strong 2+ staining; 4/5
(80%) showed either absent or weak staining. In the non- HCV
control cases 2/6 (33%) showed 2+ PV staining and 4/6
(67%) showed weak or absent staining. Donor specific anti-
457A
body (DSA) level in 1/21 patients with PCH was known and
correlated with strong C4d staining. Conclusion: C4d staining
in PVs is strongly expressed in majority of PCH cases and sug-
gests that AMR may play a role in post-LT HCV PCH cases. Fur-
thermore, our findings show that pre-PCH biopsies also show
significant C4d staining and may predict the occurrence of
PCH. One case of PCH with high DSA level had strong C4d
staining, thus emphasizing the measurement of DSA levels in
patients suspected to have PCH. Thus, the utility of C4d IHC
may be emphasized so that timely clinical intervention to pre-
vent the occurrence of PCH can be instituted.
Table 1: C4d staining intensity in PV
Disclosures:
Josh Levitsky - Consulting: Transplant Genomics Inc; Grant/Research Support:
Novartis; Speaking and Teaching: Gilead, Salix
The following people have nothing to disclose: Anshu Trivedi, Thomas D. Schi-
ano, Stephen C. Ward, Swan N. Thung, M. Isabel Fiel
527
Probiotic decreases post-liver transplant infection: A
meta analysis
Tarek Sawas1, Shadi Al Halabi2, Mubarak W. Sayyar1, Won
Kyoo Cho3; 1Internal Medicine, Georgetown University Medstar
Washington Hospital Center, washington, DC; 2Internal Medicine,
Cleveland Clinic, Cleveland, OH; 3Gastroenterology, Georgetown
University Medstar washington hospital center, washington, DC
Background: Post liver transplant infections contribute to signif-
icant morbidity, mortality and prolong hospital stay. Pre trans-
plant probiotics have been proposed as possible preventative
measure to decrease post transplant infections. It is believed
that probiotics decrease infection by preventing bacterial trans-
location. We aimed to do a meta-analysis and evaluate the
effect of pre-transplant probiotic on post transplant infection
rate. Method: We searched PubMed, Embase and Cochrane
databases for controlled trials evaluating the effect of probiotic
on post liver transplant infection rate. Quality for each included
study was assessed by CONSORT system. Heterogeneity was
analyzed by Cochran’s Q statistics. Mantel Haenszel relative
risks were calculated with a fixed effect model to combine
studies. Results: We included 4 randomized controlled trials
with 246 participants (123 probiotic, 123 control). In the 4
included studies, the intervention group received fiber with
probiotic and the control group received only fibers. Infection
rate was 7% in the probiotic group compared to 35% in the
placebo group (RR: 0.21, CI: 0.11 - 0.41). The number need
to treat (NNT) to prevent one infection was 4. A subgroup anal-
ysis of infection type showed significant decrease in urinary
tract infection with probiotic 2% compared to 16 % in the pla-
cebo (RR: 0.14, CI: 0.04 - 0.47) and intra-abdominal infection
2% in probiotic VS 11% in the placebo (RR: 0.27, CI: 0.09
- 0.78). Furthermore probiotics significantly decreased hospi-
tal stay with mean difference of stay (MD: -1.41, CI: -1.97,
-0.86), ICU stay (MD: -1.41, CI: -2.09, -0.73) and duration
of antibiotic use (MD: -3.89, CI: -4.17, -3.60). There was no
difference in mortality between the two-study groups (RR: 0.97,
CI: 0.21 – 4.47). There was no significant heterogeneity. Con-
clusion: Our findings show that the use of probiotics decreases
post liver transplant infection rate, shortens hospital stay, ICU
458A AASLD ABSTRACTS
stay and the duration of antibiotic use. The Use of probiotics
prior to liver transplant should be considered as a part of the
transplant protocol.
Disclosures:
The following people have nothing to disclose: Tarek Sawas, Shadi Al Halabi,
Mubarak W. Sayyar, Won Kyoo Cho
528
Should Patients Check (WWW.SRTR.ORG) Before They
Get a Liver Transplant?
Bashar M. Attar1,2, David Van Thiel2; 1Gastroenterology and
Hepatology, Cook County Health and Hospitals System, Chicago,
IL; 2Rush University Medical Center, Chicago, IL
Several factors have been reported to influence the survival
outcome following liver transplantation. The principal six iden-
tified variables that influence outcomes are the transplant cen-
ter’s experience and outcome statistics, recipient age, donor
age, gender, MELD score, and liver disease etiology. The aim
of this study was to compare the most recent outcome data from
United States liver transplant centers which have performed at
least 50 Liver Transplants (LT) per year. Methods/Results: Data
were collected from the Scientific Registry of Transplant Recip-
ients (www.SRTR.org) and the data was compared between
the liver transplant centers in the US. The parameters assessed
included but were not limited to: 3-year graft survival, 3-year
patient survival, wait list mortality, composite 3-year mortality.
Despite adjusting for all of the main variables, it was apparent
that major differences in the three-year patient survival at liver
transplant centers in the US varied widely and ranged from
60-94% with a national average of approximately 79%. Wait
list mortality also varied (10 folds) from a value 0.04% at the
better performing LT centers to 0.40% in the poorer performing
centers. Furthermore, the composite 3-year mortality rate range
varied from 17.6- 67.0%. This large variation in 3-year patient
survival outcome between US LT centers performing more than
50 LT per year could not be explained after adjusting for the
identified predictive variables and was not related to the level
of competitiveness between centers or the centers’ access to
organs. Importantly, performing < 50 liver transplantation per
year was not found to correlate negatively with the 3-year
patient survival data. Based upon these data obtained from the
SRTR, it can be concluded that: 1) post- transplant survival var-
ies widely between US liver transplant centers; 2) a favorable
outcome is not predicted by: a) the number of liver transplants
performed, b) the various patient and donor characteristics
examined, c) the MELD score, or d) the availability of organs
for the individual transplant center. 3) The practice of substi-
tuting less toxic immunosuppressive agents at some centers
was positively associated with a better overall 3-year survival
outcome. These data suggest that the hospital and transplant
team skills are the most important factors that contribute to the
marked variation in adjusted post- LT survival between cen-
ters. Factors that may reduce this variation between centers
in the future potentially consist of: 1) Standardization of the
protocols used for the management of pre- and post-LT care.
2) Consideration for the use of less toxic and lower doses of
immunosuppression.
Disclosures:
The following people have nothing to disclose: Bashar M. Attar, David Van Thiel
HEPATOLOGY, October, 2014
529
Liver allograft provides immunoprotection for the car-
diac allograft in combined heart-liver transplantation
Tina W. Wong1, John M. Stulak2, Mark D. Stegall3, Julie Heim-
bach3, Timucin Taner3; 1College of Medicine, Mayo Clinic, Roch-
ester, MN; 2Cardiovascular Surgery, Mayo Clinic, Rochester, MN;
3Transplantation Surgery, Mayo Clinic, Rochester, MN
When transplanted simultaneously, liver allograft has been
widely thought to have an immunoprotective role on other
organs. In fact, circulating HLA antibody titers are reduced
significantly after a liver transplantation. Detailed studies on
simultaneous heart-liver transplantation (SHLT) are lacking.
The goal of this study was to assess the patient outcomes and
ascertain the incidence of immune-mediated injury in SHLT vs.
isolated heart transplantation (IHT) based on protocol heart
allograft biopsies. Methods: 22 SHLT and 223 IHT were per-
formed between Jan 2004 and Dec 2013. Demographic, labo-
ratory, protocol heart biopsy and donor-specific HLA antibody
(DSA) (baseline, 1-wk, 4-mo, 1-yr, yearly thereafter) data were
reviewed. Survival was analyzed by Kaplan-Meier and cat-
egorical data by Fisher’s Exact tests. Results: At a mean fol-
low-up of 52.9 months, patient survival was similar (86.4% in
SHLT and 83.9% in IHT; P=NS). Five SHLT (22.7%) and 18 IHT
(18.1%) recipients had preformed DSA (MFI>2000) at the time
of transplant, of which 4 and 11 had a positive cross-match,
respectively. In SHLT the majority of the preformed DSA were
anti-class I while in IHT they were mostly anti-class II. Despite
identical immunosuppression, persistence of DSA post-trans-
plant was rarer in SHLT (1/5; 20%) compared to IHT (9/18;
50%). Cumulative incidence of heart allograft rejection was sig-
nificantly lower in SHLT (8/22; 36.4%) than in IHT (192/223;
86.1%) (P<0.001). Of the 8 rejection episodes in SHLT, 7 were
acute cellular (ACR) and 1 was antibody-mediated (AMR). The
latter was concomitant with ACR of the liver, and this liver
graft injury resolved after treatment with a steroid bolus. Sim-
ilarly, ACR was more common in IHT (159/223) than either
AMR (2/223) or mixed ACR-AMR (30/223). Post-transplant,
de novo DSA were found in 18.2% of SHLT and 18.8% of
IHT, and in both groups these were predominantly anti-class II
antibodies (100% and 88.1% in SHLT and IHT, respectively).
In 3 SHLT cases with a wide variety of high-titer (MFI>5000)
preformed DSA, liver was implanted first to utilize the protec-
tive effect of the former on the heart allograft, and these graft
functions remain excellent to date. Conclusions: Compared to
IHT, both ACR and AMR of the heart allograft appear to be less
common in SHLT. In addition, persistence of preformed DSA in
SHLT is rare. Taken together, these data suggest that in SHLT,
the liver appears to provide immunoprotection for the cardiac
allograft.
Disclosures:
Mark D. Stegall - Grant/Research Support: Millennium, Alexion
The following people have nothing to disclose: Tina W. Wong, John M. Stulak,
Julie Heimbach, Timucin Taner
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
530
Everolimus with early withdrawal or reduced dose Cal-
cineurin-Inhibitors (CNI) improves renal function in Liver
Transplant (LT) Recipients: A Meta analysis
Frahad Sahebjam1, Sahil Mittal2, Gagan K. Sood1,2; 1Department
of Surgery, Baylor College of Medicine, Houston, TX; 2Gastroen-
terology and Hepatology, Baylor college of Medicine, Houston, TX
Background: Calcineurin inhibitors (CNI) are the mainstay of
immune suppression after liver transplantation (LT), but CNI
are associated with significant nephrotoxicity. Recently, mTOR
inhibitors sirolimus and everolimus have been used with or
without CNI for their renal sparing effect in LT recipients. We
conducted a systematic review and Meta analysis of all ran-
domized controlled trials (RCT) to study if use of everolimus
along with CNI minimization or withdrawal improves the renal
function in LT recipients. Methods: We performed search of all
major databases through May 2014. We included studies of
primary adult LT recipients with GFR> 30ml/min with use of
everolimus either with reduced dose or complete withdrawal
of CNI. A random effect model was used to determine the
pooled estimate of the change in renal function at 1 year and
pooled estimate relative risk (RR) of adverse reactions associ-
ated with everolimus based therapy. Results: Six RCT and 6
observational studies reported the results of everolimus use in LT
recipients. Four randomized controlled trials met the inclusion
criteria. There were total 883 patients (Everolimus n= 465, con-
trol n= 428) with baseline GFR > 50 ml/min in all patients. In
3 RCT everolimus was initiated early at 4 weeks after LT (2 CNI
withdrawal and one CNI minimization), whereas in one study
mean time since transplantation was 3 years (CNI withdrawal).
At 12 months everolimus use was associated with significant
improvement in GFR 7.4 ml/min (095 % CI= 0.28-14.85). In
subgroup analysis of three studies with everolimus initiation at
4 weeks after LT improvement in GFR was 10.2 ml/min (95
% CI= 2.75-17.8). Everolimus use was not associated with
increased risk of biopsy proven acute rejection relative risk (RR)
=0.70 (95% CI 0.34-1.44)} or wound dehiscence (RR=1.22
T95% CI=0.93-1.61) or increased mortality (RR=1.54 95%CI-
0.82-2.88). There was no increased risk of hepatic artery
thrombosis (HAT). However, everolimus use was associated
with increased risk of infections (RR 1.18, 95% CI 1.04-1.34).
In conclusion in LT recipients’ everolimus use without CNI or
with reduced dose CNI results in improved renal function at
12 months. Everolimus was not associated with increased risk
of death or graft failure or wound dehiscence or hepatic artery
thrombosis.
Disclosures:
The following people have nothing to disclose: Frahad Sahebjam, Sahil Mittal,
Gagan K. Sood
531
Portal vein thrombosis is a risk factor for early mortality
and graft loss post liver transplantation: Analysis of the
UNOS database.
Marwan Ghabril1, Saurabh Agrawal1, Marco A. Lacerda1,
Eric S. Orman1, Raj Vuppalanchi1, Craig Lammert1, Howard C.
Masuoka1, Samer Gawrieh1, Suthat Liangpunsakul1, Naga P.
Chalasani1, A. Joseph Tector2, Paul Y. Kwo1; 1Gastroenterology
and Hepatology, Indiana University, Indianapolis, IN; 2Transplant
Surgery, Indiana University, Indianapolis, IN
Background: Portal vein thrombosis (PVT) is present in an esti-
mated 7.8% of patients undergoing liver transplantation (LT).
The decision to anti-coagulate a LT candidate for PVT requires
an understanding of the risk of LT with PVT. Aim: To analyze
459A
LT outcomes in patients with PVT. Methods: UNOS data (2002-
2013) was used to identify 50,393 adult recipients under-
going first LT (excluding patients with split grafts, donation
after cardiac death, live donor and multi-organ transplants).
PVT was reported as present at LT in 3321 (6.6%), absent in
45,249 (89.8%) and data missing in 1823 (3.6%) patients.
Demographic and clinical characteristics (% or mean± stan-
dard deviation) were compared in patients with and without
PVT. Patient and graft survival were analyzed by the Kaplan-
Meier method (log rank test). Simple/multiple logistic regres-
sion was performed to estimate the odds ratio (OR) of 90 day
outcomes. Results: Demographic and clinical characteristics in
patients with and without PVT are described in table 1. Post
LT patient survival with PVT vs. no PVT was 91.5% vs. 95.1%
at 90 days, 88.6% vs. 92.8% at 1 year, and 69.7% vs. 74%
at 5 years, p<0.0001. Graft survival was 88.4% vs. 92.8%
(90 days), 80.7% vs. 86.1% (1 year), and 65.3% vs. 69.7%
(5 years), p<0.0001. Patient and graft survival with and with-
out PVT diverged largely within 90 days post LT, and were
numerically and statistically similar in patients surviving >180
days. PVT was an independent predictor of 90 day mortality
(OR 1.68 95%CI 1.44-1.96, p<0.0001) and graft failure (OR
1.71, 95%CI 1.5-1.95, p<0.0001) on multiple logistic regres-
sions (covariate adjusted model including MELD and DRI). In
the top quartile of MELD (>27), 90 day mortality and graft
failure rates were 16.1% and 18.6% vs. 7.8% and 9.9% in
patients with and without PVT, p<0.0001. In ICU patients at
LT, 90 day mortality and graft failure rates were 21.4% and
25.2% vs. 12.4% and 15.4% in patients with and without
PVT, p<0.0001. These associations remained significant when
analyzed for confounding of MELD>27 and ICU status. Con-
clusions: PVT is an independent predictor of early mortality and
graft loss post LT, and studies of pre-LT interventions are war-
ranted. The poor outcomes in the subset of patients with PVT
and MELD>27 or requiring ICU care suggest that intervention
may be indicated at earlier disease stages in LT candidates.
Disclosures:
Marwan Ghabril - Grant/Research Support: Salix
Naga P. Chalasani - Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-
rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin
Paul Y. Kwo - Advisory Committees or Review Panels: Abbott, Novartis, Merck,
Gilead, BMS, Janssen; Consulting: Vertex; Grant/Research Support: Roche, Ver-
tex, GlaxoSmithKline, Merck, BMS, Abbott, Idenix, Vital Therapeutics, Gilead,
Vertex, Merck, Idenix; Speaking and Teaching: Merck, Merck
The following people have nothing to disclose: Saurabh Agrawal, Marco A.
Lacerda, Eric S. Orman, Raj Vuppalanchi, Craig Lammert, Howard C. Masuoka,
Samer Gawrieh, Suthat Liangpunsakul, A. Joseph Tector
532
The association between early anemia and the develop-
ment of renal insuffiency after liver transplantation
Dilip Moonka1, Wadih Chacra1, Mohammad Elbatta2, Aishwarya
Kuchipudi2, Alexander Weick2, Charlotte Burmeister3, George
Divine3; 1Division of Gastroenterology, Henry Ford Hospital,
Detroit, MI; 2Department of Internal Medicine, Henry Ford Hospi-
tal, Detroit, MI; 3Biostatistics and Research Epidemiology, Henry
Ford Hospital, Detroit, MI
PURPOSE To determine if the presence of anemia three months
after liver transplant (LT) can help predict the development of
460A AASLD ABSTRACTS
severe renal insufficiency after LT. METHODS: We evaluated
all 652 patients at our center who underwent an initial liver
alone transplant between 2000 and 2011 and who survived
one year. Patients were divided into three groups based on
hemoglobin (HGB) at 3 months after LT. Group 1 was no ane-
mia (HGB > 12 mg/dl for women and >13.5 for men): Group
2 was mild anemia (HGB 10.7-12 for women and 11.8-
13.5 for men): Group 3 was marked anemia (HGB < 10.7
for women and < 11.8 for men). The three anemia groups
were compared for baseline data and for primary outcomes
of death and development of severe renal insufficiency (RI)
defined by eGFR<30 ml/min (MDRD4), renal transplant or
renal replacement therapy. RESULTS: There were 213 patients
with no anemia, 230 with mild anemia and 209 with marked
anemia. Patients with marked anemia (compared to mild or no
anemia) were older in years (54.9 +/- 9.8 vs 53.7 +/- 10.2
vs 52.7 +/- 10.2: p=0.032), more likely to be male (71.3%
vs 68.2% vs 56.3%:p=0.003), had a lower GFR at LT (67.8
+/- 36.7 vs 78.0 +/- 40.0 vs 84.5 +/- 42.6: p<0.001) and
were more likely to have pre-LT diabetes (31.7% vs 21.8% vs
15.5%: p<0.001). There were marked differences in patient
survival and development of renal insufficiency over time using
Kaplan-Meier analysis. Patients with marked anemia had 5
year survival of 73.7% compared to 83.7% in the mild ane-
mia group and 91.4% in the no anemia group (p<0.001).
Differences in severe RI were even more pronounced. Patients
with marked anemia had rates of severe RI at 3 and 5 years
of 28.7% and 35.1% compared to 10.4% and 13.2% for
mild anemia and 8.8% and 11.4% for no anemia (p<0.001).
In multivariate analysis, marked anemia three months after LT
was significantly associated with both death and severe RI.
Compared to no anemia, the presence of marked anemia was
associated with severe RI with a hazard ratio (HR) of 2.39 (CI
1.46-3.91: p<0.001). In multivariate analysis, other variables
associated with severe RI were GFR at LT (HR 1.01 per ml/
min: p<0.001) female sex (HR 2.47: p<0.001) and diabetes
before LT (HR 1.97: p=0.003). Marked anemia (vs no anemia)
was associated with patient death with a HR of 2.16 (CI 1.28-
3.63: p=0.004). CONCLUSIONS: The presence of marked
anemia three months after LT is common and is an early, sig-
nificant and independent predictor of poor patient outcomes
after LT including death and the development of severe renal
insufficiency. The use of this variable along with other proven
variables, should help identity patients for aggressive renal
sparing measures.
Disclosures:
Dilip Moonka - Advisory Committees or Review Panels: Gilead; Grant/Research
Support: Bristol-Myers Squibb, Genentech; Speaking and Teaching: Merck,
Genentech, Gilead
The following people have nothing to disclose: Wadih Chacra, Mohammad
Elbatta, Aishwarya Kuchipudi, Alexander Weick, Charlotte Burmeister, George
Divine
533
Impact of mTOR inhibition on expression of immune
regulatory molecules by circulating dendritic cells and
regulatory T cells in stable liver transplant patients
Antonino Castellaneta1,2, Antonio Massaro1, Maria Rendina1,
Francesca D’Errico1, Sonia Carparelli1, Angus W. Thomson2,
Alfredo Di Leo1; 1Gastroenterology, University of Bari, Bari, Italy;
2Surgery, University of Pittsburgh, Pittsburgh, PA
Introduction: Everolimus, a mammalian target of rapamycin
(mTOR) inhibitor, is a ‘tolerance-sparing’ immunosuppressant
used in solid organ transplantation. mTOR regulates diverse
functions of professional antigen-presenting cells, in particular
dendritic cells (DCs), and has important roles in the activation
HEPATOLOGY, October, 2014
of conventional T cells and the function and proliferation of
regulatory T cells (Treg). Aim: currently, no data are avail-
able concerning the impact of everolimus on DC and Treg in
stable liver transplant patients. Therefore, the aim of this pilot
study was to analyze peripheral blood DC subsets and Treg
in 10 liver transplant patients exposed to everolimus (mTOR).
Material and Methods: Ten patients taking a calcineurin inhib-
itor (CNI; tacrolimus) served as controls group. Moreover, the
Expression of key co-stimulatory and co-regulatory molecules
on DC and Treg were examined by flow cytomeric analysis.
Results: our findings show that everolimus-treated liver trans-
plant patients maintain a stable DC subset distribution and
phenotype. Thus, expression of co-stimulatory and co-regula-
tory molecule (CD86, CD83, PD-L1 and ICOS-L) did not differ
between the 2 groups. Moreover, expression on DC subsets of
HLA-DR and human leukocyte antigen (HLA)-G, a non-classical
HLA class I molecule, and of its receptor, the immunoglobulin
(Ig)-like transcript (ILT)-4 did not differ between the mTOR and
CNI groups. Notably, however, expression of the ectonucleoti-
dase CD39 was significantly higher on myeloid DC in patients
taking everolimus compared with the CNI. Notably, in the ever-
olimus group the incidence of Treg was significantly higher
and the expression of Programmed death-1 (PD-1) on Treg
was significantly lower as compared with CNI group. Conclu-
sions: this preliminary study provides new information about
how mTOR inhibitor-based immnosuppression may influence
peripheral innate and adaptive immune cells in liver transplant
patients. Our findings also point out possible new biomarkers
of liver graft acceptance which could be monitored after trans-
plantation.
Disclosures:
The following people have nothing to disclose: Antonino Castellaneta, Antonio
Massaro, Maria Rendina, Francesca D’Errico, Sonia Carparelli, Angus W. Thom-
son, Alfredo Di Leo
534
Abusive drinking after liver transplantation for pure
alcoholic cirrhosis is associated with significant allograft
fibrosis
Marika Rudler1, Géraldine Rousseau2, Pascal Lebray1, Corinne
Vezinet3, Daniel Eyraud3, Jean-Christophe Vaillant2, Thierry
Poynard1, Dominique Thabut1; 1Hepatology, Pitié-Salpêtrière
Hospital, Paris, France; 2Hepato biliary surgery and liver trans-
plantation, Pitié-Salpêtrière Hospital, PARIS, France; 3Anesthesia,
Pitié-Salpêtrière Hospital, Paris, France
Background Progression of fibrosis after liver transplantation
(LT) is associated with a worse outcome. One study suggested
that abusive drinking after LT for pure alcoholic cirrhosis was
associated with liver fibrosis progression. Aims (1) to evaluate
alcohol consumption in France after LT for alcoholic cirrhosis
using carbohydrate deficient transferrin (CDT); (2) To assess
fibrosis progression using 2 non-invasive methods. Methods
Liver fibrosis progression was assessed using FibroTest (FT,
Biopredictive, France) and FibroScan (FS, Echosens, France) in
all patients who underwent LT for pure alcoholic cirrhosis in our
center, on the same day, once a year. Discordances between
the 2 methods were resolved by consensus, after repeating the
tests and analysing the files of each patients (clinical exam-
ination, biology, ultrasound exam). Excessive drinking was
defined by a CDT>1.8%. Parameters of metabolic syndrome
were assessed each year. Results Overall, 93 patients were
transplanted in La Pitié-Salpêtrière (Paris, France) for pure alco-
holic cirrhosis, all other causes of hepatopathy being ruled
out, between February 2000 and June 2012. Among them,
9 died within the first year after LT, and 9 were not evalu-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
ated (lost of follow-up or residing in a foreign country). 75
patients were prospectively analyzed (male gender: 77,3%;
age at LT: 55,4±7,2 years; indication for LT: hepatocellular
carcinoma 26,7%, end-stage liver disease 72%, or portal
hypertension 1,3%). Mean follow-up was 64 months (16-158).
Follow-up was at least of 1 year in all patients, 2 years in
96% of patients, 3 years in 86.7% and 4 years in 68% of
patients. FibroTest was applicable in 74/75 patients (98.6%)
and FibroScan in 68/75 patients (90.7%). Three patients
(4%) declared an excessive alcohol consumption, whereas 27
(36%) had a CDT>1.8%. Overall, 36% of patients developed
significant fibrosis (F≥2). Independent factors associated with
the development of significant fibrosis were weight at evalua-
tion (p=0.003), cold ischemia (p=0.05), and alcohol abuse
(p=0.04), but not the development of metabolic syndrome after
LT. Conclusion Alcohol consumption is underestimated after
LT for pure alcoholic cirrhosis and should be evaluated with
objective biomarkers such as CDT. Abusive drinking after LT is
associated with significant progression of fibrosis that should
be regularly assessed with noninvasive methods.
Disclosures:
Marika Rudler - Speaking and Teaching: Gilead
Pascal Lebray - Grant/Research Support: Merck, astellas; Speaking and Teach-
ing: Janssen, MSD, Gilead
Thierry Poynard - Advisory Committees or Review Panels: Merck; Grant/Research
Support: BMS, Gilead; Stock Shareholder: Biopredictive
The following people have nothing to disclose: Géraldine Rousseau, Corinne
Vezinet, Daniel Eyraud, Jean-Christophe Vaillant, Dominique Thabut
535
Early evaluation of regulatory T cells to predict severity
of HCV recurrence after liver transplantation
Kaldoun Ghazal2, Morales Olivier4, Clement Barjon2, Geral-
dine Dahlqvist2, Lynda Aoudjehane3, Laurissa Ouaguia4, Yvon
Calmus1,2, Delhem Nadira4, Filomena Conti1,2; 1Centre de Trans-
plantation Hepatique, Hôpital Saint Antoine, APHP, Paris, France;
2UMR_S 938, CDR Saint-Antoine, Sorbonne Universités, UPMC
Univ Paris 06, Paris, France; 3Human HepCell, Paris, France; 4Ins-
stitut de Biologie, Lille, France
Background: Immune response failure during HCV infection
has been associated with the activity of regulatory T cells.
Hepatitis C-related cirrhosis is the one of the main indication
for liver transplantation (LT). However, 80% of transplanted
patients present an accelerated recurrence of the disease.
This study aim was to assess regulatory T-cell subsets, and T
helper 1, 2 and 17 cells involvement in recurrent hepatitis C
after liver transplantation. Patients and Methods: Peripheral
blood mononuclear cells, obtained before and one month after
LT, from 22 liver transplant recipients have been analysed.
Forty four key molecules, related to Treg, T helper 1, 2 and
17 responses, were evaluated by using qRT-PCR analysis.
Liver transplant recipients have been classified on two groups
in function of fibrosis evaluation observed on the one year
follow-up biopsy. The severity of hepatitis C recurrence was
evaluated by the results METAVIR analysis on one year liver
biopsy (mild: F<1, severe F≥ 1). The results of patients that will
develop a severe hepatitis C recurrence (n=9) were compared
to those obtained in patients will develop a mild recurrence
(n=13). Results: Our results demonstrated a significant increase
in mRNA levels of Treg markers (CD4,CD25,TGFβ,CTLA-4,
GATA-3, and IL-10Rα/β) early after liver transplantation (one
month) in patients with a severe evolution of HCV recurrence.
Th1 markers (IL-2, IFNg, IL-23, T-bet), which could be impli-
cated in antiviral response, were also elevated in same group
of patients. This suggests that Tregs may play a role in the
suppression of an antiviral response, early after liver transplan-
461A
tation. No differences have been observed before LT. Conclu-
sion: Our findings showed that Tregs are enhanced, early after
liver transplantation, in patients who will develop a severe HCV
recurrence. High levels of Treg might be predictive of severe
recurrence, patients with this high expression warrant more
intensive management.
Disclosures:
The following people have nothing to disclose: Kaldoun Ghazal, Morales Olivier,
Clement Barjon, Geraldine Dahlqvist, Lynda Aoudjehane, Laurissa Ouaguia,
Yvon Calmus, Delhem Nadira, Filomena Conti
536
Predictors of Delirium after Liver Transplantation and its
Relationship to Outcomes
Koki Yamada, Max Marquez, Khalid Mumtaz, Eberhard L. Ren-
ner; Multi organ Transplant, Toronto General Hospital, University
Health Network, Toronto, ON, Canada
Introduction: Delirium has been reported to be common in
post-surgical patients. Data on delirium in post liver transplant
(LT) setting is growing but conflicting. Aims: We studied the
pre-, intra- & post-LT predictors of delirium. Moreover, we also
examined the relationship of delirium with length of stay (LOS)
and mortality. Methods: A retrospective, analytical study of
1237 consecutive, adult LT patients performed from Jan 2000
to Dec 2013. Data on pre-, intra-, and post-LT variables and out-
comes was obtained from the University Health Network data
base. Data were divided into groups with and without delirium.
We studied predictors of delirium and its relationship with LOS
and mortality. Patients who died within one week after LT on
whom delirium could not be assessed were excluded. We also
excluded patients with seizures and CVA. Statistical analysis:
Descriptive statistics were reported for all variables to explore
the distributions. To assess differences between groups, inde-
pendent-samples t- tests or Mann-Whitney U and chi-square or
Fisher exact tests were conducted where appropriate. Logistic
regression analysis was conducted to examine the relation-
ship between the predictors of delirium and mortality. Linear
regression analysis was performed to study the association
of delirium with length of stay (LOS). Results: A total of 102
(8.2%) patients develop delirium post- LT. Two pre-LT predic-
tors of delirium were high MELD score (MS) (OR: 1.03; 95%
CI: 1.008-1.051, p=0.008) and hepatic encephalopathy
(HE) (OR: 1.63; 95% CI: 1.05-2.52, p=0.029). Duct-to-duct
anastomosis have a protective effect on delirium (OR: 0.39;
95% CI: 0.22-0.68, p=0.001) as compared to roux-en-y. Anti-
body induction therapy increases chances of development of
delirium almost twice as compared to no induction (OR: 1.95;
95% CI: 1.19-3.19, p=0.007). Finally, delirium is 1.7 times
more common in patients with high (≥3/4) Clavien score as
compared to low (1/2) score (OR: 1.71; 95% CI: 1.10-2.66,
p=0.017). Generalized Linear Models showed that Clavien
score ≥3/4 contributed most (18.2 days; CI: 14.8 – 21.6, p<
0.001) followed by blood loss of ≥3L during surgery (5 days;
CI: 1.86 – 8.08, p=0.002) and delirium (5 days; CI: -0.55 –
10.38, p=0.052) to LOS. Conclusions: Incidence of delirium
in post-LT setting was 8.2 %. Pre-LT predictors of delirium are
presence of HE & high MS. Duct-to-duct anastomosis provides
protection against development of delirium as compared to
roux-en-y. Post LT predictors are use of thymoglobulin and high
Clavien score. Moreover, high Clavien score and blood loss
during surgery contributed more than delirium on LOS.
Disclosures:
Eberhard L. Renner - Advisory Committees or Review Panels: Vertex Canada,
Novartis, Astellas Canada, Roche Canada, Gambro, AbbVIe, BMS; Grant/
Research Support: Novartis Canada, Gilead; Speaking and Teaching: Novartis,
Astellas Canada, Roche Canada
462A AASLD ABSTRACTS
The following people have nothing to disclose: Koki Yamada, Max Marquez,
Khalid Mumtaz
537
Bacterial antigen translocation persists after liver trans-
plantation in peripheral blood of patients with decom-
pensated cirrhosis
Gonzalo Rodriguez-Laiz3, Pedro Zapater1,2, Paola Melgar3, Mari-
ano Franco3, Cándido Alcázar3, Sonia Pascual1,2, Pablo Bellot1,2,
Jose María Palazón1,2, Jose Such1,2, Félix Lluis3, Ruben Frances1,2;
1Liver Unit, Hospital General Universitario Alicante, Alicante,
Spain; 2CIBERehd, Instituto de Salud Carlos III, Madrid, Spain;
3General and Digestive Surgery Service, Hospital General Univer-
sitario Alicante, Alicante, Spain
Background&Aims: The translocation of bacterial antigens
into blood of patients with decompensated cirrhosis has been
related with poor prognosis and an increased inflammatory
outlook. The aim of this study was to evaluate the association
between liver transplantation and the systemic bacterial anti-
gen clearance in cirrhotic patients and also to determine the
relationship between bacterial antigen translocation in liver
transplant donors and recipients. Patients&Methods: Patients
with decompensated cirrhosis admitted for liver transplantation
at the Digestive Surgery Unit of Hospital General Universitario
de Alicante, Spain, were consecutively included. Peripheral
blood samples from the recipient were collected at the beggin-
ing of surgery and 72 hours after liver transplantation. A blood
sample was also collected from the donor. Bacterial genomic
translocation was identified by partial sequencing analysis of
amplified 16SrRNA gene of prokariotes. Results: Forty-nine
patients (40 male, mean age 55±9.5 years) were included
in the study. Etiology was mainly alcohol (n=18, 37%), HCV
(n=13, 26.5%) or alcohol+HCV (n=9, 18%). Twenty-eight
patients had hepatic carninoma. Thirteen patients had ascitic
fluid. MELD mean score was 18±6. Seventeen patients showed
blood bacterial DNA before surgery (34.7%). Of those, 14
patients showed blood bacterial DNA 72 hours after liver trans-
plantation (82.3%). Sequencing analysis identified the same
bacterial species in 11 out of 14 patients (78.5%). In the group
of patients without bacterial antigen translocation before sur-
gery, 10 patients showed blood bacterial genomic fragments
(31.2%). On the other hand, bacterial DNA was detected in
19 liver transplant donors (38.7%). Five out of 10 liver recip-
ients (50%) who had not bacterial DNA and 8 out of 17 liver
recipients who had bacterial DNA (47%) before surgery and
showed it after transplantation received the organ from a bac-
terial DNA-positive donor. Sequencing analysis identified the
same bacterial species as that found after surgery in 7 cases (5
without and 2 with bacterial DNA before surgery). Finally, 4
out of 5 patients with partial portal thrombosis before surgery
showed bacterial DNA fragments in blood. No other clinical
or analytical correlations were found. Conclusion: Circulating
bacterial antigens persist in blood of patients with cirrhosis
after liver transplantation. De novo bacterial DNA after sur-
gery might be related with bacterial translocation in liver trans-
plant donors. Longer series of cirrhotic patients undergoing
liver transplantation might identify an increased rate of adverse
events among patients with systemic bacterial antigen translo-
cation.
Disclosures:
Jose Such - Consulting: Sequana Medical, Sequana Medical, Sequana Medical,
Sequana Medical; Stock Shareholder: Sequana Medical, Sequana Medical,
Sequana Medical, Sequana Medical
The following people have nothing to disclose: Gonzalo Rodriguez-Laiz, Pedro
Zapater, Paola Melgar, Mariano Franco, Cándido Alcázar, Sonia Pascual,
Pablo Bellot, Jose María Palazón, Félix Lluis, Ruben Frances
HEPATOLOGY, October, 2014
538
Early Liver Transplantation in Severe Alcoholic Hepatitis:
the U.S. Experience
Brian P. Lee1, David W. Victor2, R. Mark Ghobrial3, Mary E.
Rinella4, Zhiping Li1; 1Department of Medicine, Johns Hopkins
University School of Medicine, Baltimore, MD; 2Department of
Medicine, Houston Methodist Hospital, Houston, TX; 3Department
of Surgery, Houston Methodist Hospital, Houston, TX; 4Department
of Medicine, Northwestern University Feinberg School of Medi-
cine, Chicago, IL
OBJECTIVE: The vast majority of liver transplant (LT) centers
require 6 months of alcohol abstinence before a patient is
considered for LT. Severe alcoholic hepatitis refractory to med-
ical treatment carries a 6-month mortality estimated at 70%.
In 2011, a French study reported early LT of severe alcoholic
hepatitis in a highly selected group of patients, yielding a 77%
6-month survival and a 12% recidivism rate, suggesting that
early LT could improve survival for severe alcoholic hepatitis.
The purpose of this study was to examine the outcomes of
early LT for severe alcoholic hepatitis in U.S. transplant cen-
ters. METHODS: 12 U.S. transplant centers were surveyed for
patients who underwent LT and met the following criteria: severe
alcoholic hepatitis as the first presentation of liver decompensa-
tion, and listing for LT prior to 6 months of alcohol abstinence.
4 of the 12 centers reported experience with patients who met
selection criteria, of which 3 centers submitted retrospective
data. All patients underwent LT between April 2012 to Novem-
ber 2013, except one patient who underwent LT in 2006. The
follow-up period extended until June 2014. Recidivism was
defined as any evidence of alcohol consumption following LT.
RESULTS: 19 patients underwent early LT for severe alcoholic
hepatitis. The median amount of alcohol consumption prior
to abstinence was 9 units of alcohol per day. The median
period of alcohol abstinence immediately prior to LT listing was
46 days. The median MELD at time of listing was 34. Prior
to transplant listing, six (32%) received steroids; three (16%)
received pentoxifylline; 10 (53%) received neither. 19 of the
19 patients (100%) were alive at 6-months. Five (26%) had
recidivism to alcohol within the follow-up period. CONCLU-
SIONS: For patients presenting with a first episode of severe
alcoholic hepatitis, early liver transplantation is feasible, and
confers high levels of survival. Compared to the French study,
our patients appeared to trend towards improved short-term
survival (100% vs. 77%) and a higher recidivism rate (26% vs.
12%). A larger study population and longer follow-up period
are needed to determine long-term survival and predictors of
recidivism, which could help guide a standardized selection
for patients best suited for early LT in severe alcoholic hepatitis.
Disclosures:
Mary E. Rinella - Advisory Committees or Review Panels: Gilead
The following people have nothing to disclose: Brian P. Lee, David W. Victor, R.
Mark Ghobrial, Zhiping Li
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
539
Deleterious Effect of Body Mass Index and Prior Abdom-
inal Surgery on Liver Transplant Complications
Angel Alsina1,6, Jian Zheng5, Alexia M. Makris4, Jason Shim3,
Edson S. Franco1,6, Chris Albers2, Nyingi M. Kemmer2; 1Trans-
plant Surgery, Tampa General Hospital, Tampa, FL; 2Hepatology,
Tampa General Hospital, Tampa, FL; 3Center of Research Excel-
lence, Tampa General Hospital, Tampa, FL; 4College of Public
Health, University of South Florida, Tampa, FL; 5Surgery, Boston
University, Boston, MA; 6Surgery, University of South Florida Mor-
sani College of Medicine, Tampa, FL
Background: The impact of body mass index (BMI) on out-
comes post liver transplant (LTx) is a challenge and results
inconclusive. BMI is still used by some centers as an absolute
contraindication to LTx and can influenced resource alloca-
tion decisions. Obesity has been associated with increased
post LTx complications, when controlled for cardiovascular
disease and diabetes. The negative impact of BMI and pre-
vious abdominal surgery on postoperative complications has
not been demonstrated. Hypothesis: We hypothesize that BMI
and prior abdominal surgery contribute to higher rates of any
grade of complications post LTx. Methods: Single-center, ret-
rospective review of 616 consecutive LTx patients undergoing
LTx between Feb 2002 and Dec 2013. Complications were
classified using Clavien-Dindo (2); only grades (Gr) II to V were
examined. BMI was dichotomized at 35 kg/m2, the cutoff
for severely obese (WHO). Only abdominal surgeries were
included (Surgery +) and compared to none (Surgery -). Cat-
egories were: BMI < 35, and Surgery (-) n= 450; BMI < 35
and Surgery (+), n=96; BMI > 35 and Surgery (-), n=46; and
BMI > 35 and Surgery (+), n=14. Statistical analysis involved
a multinomial logistic regression model. All statistical tests
were 2-tailed at a 5% significance level. Results: Compared
to patients with BMI <35, those with BMI >35 had signifi-
cantly higher complications in Gr II (OR 2.8, p-value<.0001),
Gr III (OR 1.7, p-value=0.0015), and Gr IV or V (OR 2.7,
p-value<.0001), when controlled for prior abdominal sur-
gery. Surgery + patients were more likely to have Gr II (OR 2,
p-value<0.0001), Gr III (OR 1.5, p-value=0.0015), or Gr IV or
V complications (OR 2.6, p-value<0.0001), when controlling
for BMI. Prior surgery was a significant predictor of mortality
(Gr V) (OR 2.5 p-value=0.0248) but BMI was not (p-value
0.163). Conclusion: Both BMI and prior abdominal surgery
are independent predictors of post LTx morbidity but only prior
abdominal surgery was a significant predictor of mortality.
Higher rates of Gr II to V complications were demonstrated
with BMI > 35, and prior abdominal surgery. Thus, both BMI
and prior abdominal surgery should be considered as indexes
of disease severity and risk prior to LTx. Given increasing prev-
alence of obesity and patients with prior abdominal surgery,
a larger multicenter data will be better able to evaluate their
impact. Meanwhile, their use in selecting transplant candidates
should be used with caution. Reference: (1) Clavien, P. A., et
al. Definition and classification of negative outcomes in solid
organ transplantation. Application in liver transplantation. Ann
Surg 1994; 220(2): 109-120.
Disclosures:
Angel Alsina - Advisory Committees or Review Panels: Bayer; Speaking and
Teaching: Bayer, Novartis
Edson S. Franco - Grant/Research Support: bayers, gilead, eisai
The following people have nothing to disclose: Jian Zheng, Alexia M. Makris,
Jason Shim, Chris Albers, Nyingi M. Kemmer
463A
540
Primary Non Function after liver transplant in children
in the PELD era: Analysis of UNOS database
Jaime Chu1,2, Rachel A. Annunziato3, Christie DiPietrantonio3,
Ailie M. Posillico3, Ronen Arnon1,2; 1Pediatrics, Mount Sinai Med-
ical Center, New York, NY; 2Surgery, RMTI, New York, NY; 3Psy-
chology, Fordham University, Bronx NY, NY
Primary non function (PNF) is irreversible early graft failure
with no evidence of vascular or immunological causes. It is a
life-threatening condition that requires urgent re-transplantation.
The etiology of PNF is largely unknown. Aim: To determine the
incidence and the risk factors for developing PNF among chil-
dren who underwent LT in PELD era. Methods: Children (age
0-18 years) who underwent first isolated LT between 2/2002
(the beginning of the PELD era) and 12/2012 were identified
from the UNOS database. Patients who underwent LT from
deceased cardiac death donors were excluded from the anal-
ysis. Children who developed PNF were compared to children
who did not experience early graft loss. Risk factors to develop
PNF were identified by multivariate logistic regression. Results:
Of 4,283 patients, 182 (4.2%) children developed PNF and
were compared to 4,101 children with intact graft functioning.
Table 1 displays characteristics of the sample. Patients with
biliary atresia had the highest incidence of PNF (4.6% or 70
patients) while patients with metabolic liver diseases had the
lowest incidence (2.6% or 16 patients).The incidence of PNF
in patients with acute liver failure was 3.7% or 17 children.
Younger recipient age, being on life support, older donor age
and longer cold ischemic time were identified as risk factors for
developing PNF. Transplant type (whole vs technical variation)
and donor BMI did not emerge as risk factors.Conclusions:
PNF is a significant cause for early graft failure in the PELD era.
Our study highlights concrete risk factors for pediatric PNF.
Given that it is a modifiable factor, special attention should be
paid to the cold ischemic time in patients vulnerable to PNF
with future research focused on minimizing cold ischemic time
and improving graft preservation.
Table 1.
Disclosures:
The following people have nothing to disclose: Jaime Chu, Rachel A. Annunziato,
Christie DiPietrantonio, Ailie M. Posillico, Ronen Arnon
464A AASLD ABSTRACTS HEPATOLOGY, October, 2014

541 The following people have nothing to disclose: Ravi Chhatrala, Mohammad B.
Siddiqui, R. Todd Stravitz, Carolyn Driscoll, Robert A. Fisher, Carol Sargeant,
Pro-Atherogenic Lipoproteins And Metabolic Biomakers Fareed R. Riyaz, Scott Matherly, Mohammad S. Siddiqui
Drive Serum Cardiovascular Risk In Liver Transplant
Recipients
Ravi Chhatrala1, Mohammad B. Siddiqui1, R. Todd Stravitz1, Car- 542
olyn Driscoll1, Arun J. Sanyal1, Robert A. Fisher2, Carol Sargeant1, Coronary artery calcium score in evaluating cardiovas-
Fareed R. Riyaz1, Velimir A. Luketic1, Scott Matherly1, Richard K. cular risk 1 and 4 years after liver transplant
Sterling1, Puneet Puri1, Mohammad S. Siddiqui1; 1Internal Medi-
Livia M. Linhares 1, Mario R. Alvares-da-Silva 3, Claudia P.
cine, VCU, Richmond, VA; 2Transplant Surgery, Virginia Common-
Oliveira1, José Tadeu Stefano1, Eloisa M. Gebrim2, Flair J. Car-
wealth University, Richmond, VA
rilho1, Luiz C. D`Albuquerque1; 1Department of Gastroenterology
Cardiovascular disease (CVD) is the leading cause of long- (LIM-07), University of Sao Paulo School of Medicine, São Paulo,
term mortality in liver transplant (LT) recipients. Although LT Brazil; 2Departament of Radiology, University of São Paulo School
is associated with dyslipidemia, the role of recently identified of Medicine, Sao Paulo, Brazil; 3Division of Gastroenterology,
biomarkers of CVD risk in LT recipients is unknown. Therefore, Universidade Federal do Rio Grande do Sul, School of Medicine,
the aim was to evaluate an extensive serum CVD risk profile Porto Alegre, Brazil
in LT recipients. Methods: Markers of CVD risk in 35 LT recip-
BACKGROUND AND AIMS: The prevalence of metabolic syn-
ients with no known history of diabetes mellitus (DM) or dys-
drome (MS) and cardiovascular (CV) disease is currently rising
lipidemia were compared to age-, gender-, and BMI-matched
as consequence of the increasing liver transplant recipients
controls with no known history of chronic medical disease. To
(LTR) life expectancy. Coronary artery calcium score (CACS),
determine the impact of DM on CVD risk profile, LT recipients
which was not appraised in LTR, is considered the most sensi-
with DM were subsequently compared to those without DM. To
tive method for assessing CV risk. Our aim was to evaluate a
avoid confounding effects of cirrhosis or steroids, LT recipients
cohort of LTR 4 years after transplant regarding MS, CV risk
on steroids or those with graft cirrhosis were excluded. Finally,
and CV disease. PATIENTS AND METHODS: Forty consecutive
to compare the effects of calcineurin inhibitors on the CVD
LTR outpatients, admitted between 2009 and 2010, were fol-
risk profile, a separate analysis was done in non-DM subjects
lowed-up by 1 and 4-year period, and consecutively enrolled.
who were either on Tacrolimus (Tac) or Cyclosporine (CsA).
The anthropometric data, liver enzymes, metabolic syndrome
Results: Non-DM LT recipients were well matched to controls
features, glucose and lipid profiles, and insulin resistance data
with regard to age (54±10 years vs. 58±12 years), gender
were collected. Framingham risk score (FRS) was calculated
(%male: 43 vs. 41) and BMI (28.3±4.6 kg/m2 vs 29.7±6.5
in both 1 and 4-year evaluation, and CACS was assessed in
kg/m2). Serum HDL-C was similar between the two groups,
the end of the follow-up period. Comparisons between 1 and
but LT recipients had higher serum TG, LDL-C and total choles-
4 years were done. RESULTS: The study population comprised
terol. Although serum LDL-particle concentrations (LDL-P) were
62.5% males, mean age 53.8 years and body mass index
similar between the two groups, pro-atherogenic small-dense
(BMI) 26.9 kg/m2. Regarding the components of MS, 65%
(sd) LDL-C (30.7±12.1mg/dL vs. 20.1±6.9mg/dL; p<.001)
patients had hypertension, 55% diabetes, 60% dyslipidemia
and percent sdLDL-C (28.1±9 vs. 23.6±6.8%; p=.02) were
and mean waist circumference was 96.7 cm. One year after
significantly higher in LT recipients. Compared to controls, LT
liver transplantation, 22.4% had MS and after 4 years, this
recipients had higher apolipoprotein-B (91.6±22.8mg/dL vs.
percentage increased to 47.5%. Besides, 20% of the patients
77.8±20.5mg/dL, p<.01), very low-density lipoprotein con-
developed CV disease after 4 years LT. The median FRS also
centrations (VLDL-P; 6.87±6.45nmol/L vs. 2.07±2.35nmo-
increased from 2% to 15.5% between the 1st and 4th year,
l/L p<.001), and VLDL-size (50.1±5nm vs. 45.1±5.9nm,
which ranks the cardiovascular risk in 10 years, as an inter-
p<.001). In LT recipients, VLDL-size and particle concentration
mediary. Medium CACS values were 166.03, which is mod-
was directly related to serum CsA levels (R=0.53 p=.09 and
erately altered. Patients with MS had higher values of CACS
R=0.63, p<.01; respectively) but not to Tac. Compared to con-
than others (p =0.018). When MS components were evaluated
trols, LT recipients had lower total serum HDL-particle concen-
separately, we found higher values of CACS for dyslipidemic
trations (HDL-P; 28.3±7.9nmol/L vs. 33.7±7.2nmol/L, p<.01).
patients when compared to non-dyslipidemic (p =0.011); and
Aside from lower serum vitamin D levels, other atherogenic met-
for hypertensive than non-hypertensive patients (p=0.004).
abolic (homocysteine, folate) and inflammatory factors (hs-CRP,
There was no difference in the values of CACS, when we
myeloperoxidase, fibrinogen) were similar between the two
assessed BMI and waist circumference. There was a statistically
groups. Progression to DM in LT recipients was associated with
significant correlation between FRS, CACS and GGT 4 years
worsening serum atherogenic risk profile characterized by
after transplantation. Individuals who never drank or smoked
elevated serum sdLDL-C, fibrinogen, and homocysteine levels.
had values of CACS significantly lower compared to patients
Conclusion: LT recipients have a pro-atherogenic metabolic
who drank/smoked. We sought a correlation between smok-
and lipoprotein profile that is not captured with a traditional
ing burden and values of CACS moderately or severely altered
lipid panel. Detailed serum atherogenic profile is needed to
(> or =100) and concluded that the former was significantly
truly assess CVD risk in LT recipients.
higher in these patients than in those with CACS lower value
Disclosures:
(28.95 x 17.29 pack-years; p=0.0015). CONCLUSIONS: MS
Arun J. Sanyal - Advisory Committees or Review Panels: Bristol Myers, Gilead,
Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Nimbus, Genentech, Echo-
and CV risk significantly increased from 1 to 4 years after LT.
sens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept, CACS is useful in evaluating CV risk in this population, and
Ikaria, Takeda, GalMed, Novartis, Gilead; Independent Contractor: UpToDate, correlated well with FRS, GGT and alcohol/tobacco consump-
Elsevier
tions.
Velimir A. Luketic - Grant/Research Support: Intercept, Merck, Idenix, Vertex,
Disclosures:
Gilead, BMS, Novartis, abbvie, Genfit, Takeda
The following people have nothing to disclose: Livia M. Linhares, Mario R. Alva-
Richard K. Sterling - Advisory Committees or Review Panels: Merck, Vertex, Salix,
res-da-Silva, Claudia P. Oliveira, José Tadeu Stefano, Eloisa M. Gebrim, Flair J.
Bayer, BMS, Abbott, Gilead; Grant/Research Support: Merck, Roche/Genen-
Carrilho, Luiz C. D`Albuquerque
tech, Pfizer, Gilead, Boehringer Ingelheim, Bayer, BMS, Abbott
Puneet Puri - Advisory Committees or Review Panels: Health Diagnostic Labora-
tory Inc.; Consulting: NPS Pharmaceuticals Inc.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
543
Control of Diabetes Mellitus in Liver Transplant Recipi-
ents:a multicentric spanish study
Beatriz Rodríguez-Medina1, Diego Alvarez de Sotomayor1, Carla
Satorres1, Jose Ignacio Herrero2,5, Trinidad Serrano3,5, Manuel
De la Mata4,5, Carmen Vinaixa1,5, Victoria Aguilera1,5, Angel
Rubin1,5, Martin Prieto1,5, Marina Berenguer1,5; 1Hepatology and
Liver Transplant Unit, Hospital La Fe, Valencia, Spain; 2Hepatol-
ogy and Liver Transplant Unit, Clínica Universitaria de Navarra,
Navarra, Spain; 3Hepatology and Liver Transplant Unit, Hospital
Lozano Blesa, Zaragoza, Spain; 4Hepatology and Liver Transplant
Unit, Hospital Reina Sofía, Córdoba, Spain; 5CIBERehd, Instituto
Carlos III, Madrid, Spain
BACKGROUND: Diabetes is a common complication after liver
transplantation (LT) that has shown to negatively impact trans-
plant outcome. There is however scarce information on the
quality of diabetes care in LT patients. AIM: To investigate the
rate and quality of diabetes care in LT patients. METHODS:
Prospective, cross-sectional, multicenter study including 312
LT patients fulfilling the following criteria: a) age 18 yr; b)
follow-up after LT 1 yr; c) periodic outpatient control in the 4
participating centers, and d) clinically stable condition. We
describe the prevalence of diabetes and the parameters indica-
tive of an adequate diabetes care according the recommended
international standards. RESULTS: 147 (47%) out of the 312
patients were patients with diagnosis of diabetes.There were
no differences between the DM (n=147) and non-DM group
(n=165) with respect to arterial hypertension (62% vs 53%)
and chronic renal failure (14%vs18%) prevalences. Dyslip-
idemia (44%DM-group vs 21% no-DM group,p=<0.01) and
cardiovascular disease (20% vs 9%,p=0.03) occurred more fre-
quently in the DM-group. 69% of diabetic patients were obese/
overweight and 85% had abdominal obesity. With regards to
diabetic care based on accepted international standards, it
included drug therapy (insulin in 54%, oral antidiabetic drugs
in 39.5%), exercise (moderate in 33%), diabetic diet (62)%,
and diabetic management education (40%). However, hemo-
globin A1c levels were adequately controlled in only 27% of
patients. A free diet was followed by 36% of the patients, and
a sedentary life and/ or light physical exercise was practised
by 65%. Moreover, screening for complications of diabetes
had never been performed in 50% of patients in terms of ret-
inopathy, nephropathy and cardiovascular disease., and less
than 10% had been screened for neuropathy and diabetic
foot. CONCLUSIONS: 1.Prevalence of diabetes and common
diabetes-associated conditions in LTR are high;2.Control of DM
in LTR is poor,with low control of risk factors associated withD-
M,a poor screening of DM complications and poor glycemic
control;3.Treatment is focused on the use of antidiabetic drugs
disregarding other treatments,such as exercise and diet;4.The
role of the LT team is important to improve control of DM but
ultimately a multidisciplinary approach is required.
Disclosures:
Jose Ignacio Herrero - Speaking and Teaching: Roche, Astellas, Novartis; Stock
Shareholder: Roche, Novartis, Abbott, GlaxoSmitthKline
Martin Prieto - Advisory Committees or Review Panels: Bristol, Gilead
The following people have nothing to disclose: Beatriz Rodríguez-Medina, Diego
Alvarez de Sotomayor, Carla Satorres, Trinidad Serrano, Manuel De la Mata,
Carmen Vinaixa, Victoria Aguilera, Angel Rubin, Marina Berenguer
465A
544
Non-coronary causes account for the majority of early
major adverse cardiac events after liver transplantation
Lisa B. VanWagner1,2, Bing Bing Weitner2, Tanvi Subramanian4,
Sarah Uttal3, Alfred W. Rademaker2, Josh Levitsky1,4, Donald M.
Lloyd-Jones2,5, Anton I. Skaro4; 1Medicine, Division of Gastroenter-
ology & Hepatology, Northwestern University Feinberg School of
Medicine, Chicago, IL; 2Preventive Medicine, Northwestern Univer-
sity Feinberg School of Medicine, Chicago, IL; 3Northwestern Uni-
versity Transplant Outcomes Research Collaborative (NUTORC),
Northwestern University Feinberg School of Medicine, Chicago,
IL; 4Surgery, Division of Organ Transplantation, Northwestern
University Feinberg School of Medicine, Chicago, IL; 5Medicine,
Division of Cardiology, Northwestern University Feinberg School
of Medicine, Chicago, IL
BACKGROUND: Over the past decade, cardiovascular dis-
ease has emerged as a major cause of long-term complications
after liver transplantation (LT). However, little is known about
early major adverse cardiac events (MACE) following trans-
plant. AIM: To determine the cumulative risk and predictive
factors for early (30-day and 1-year) MACE after LT. METH-
ODS: We identified all adult recipients of a first LT at our insti-
tution from 2/2002-12/2012. International Classification of
Diseases (ICD-9) codes were used to identify MACE, defined
as myocardial infarction, heart failure, atrial fibrillation, car-
diac arrest, pulmonary embolism and/or stroke. Cumulative
risk of 1-year MACE after LT was analyzed using Kaplan-Meier
method. Multivariate logistic regression analysis assessed fac-
tors associated with 30-day MACE and Cox proportional haz-
ard models assessed 1-year MACE post-LT. RESULTS: Of 1024
LT recipients (mean age 56.3 ± 9.7 years, 65.9% male, 71.6%
white), 322 (31.4%) had at least one MACE within 1 year of
LT; most events [238/322 (73.9%)] occurred within the first 30
days of transplant. The most common underlying cause of a
1-year MACE was heart failure [156/322 (48.4%)], followed
by atrial fibrillation (40.1%) and stroke (23.9%). Distribution
was similar for 30-day events. In multivariate analysis, inde-
pendent predictors of 30-day MACE were older age [Odds
ratio (OR): 1.04 (1.02-1.06)] and higher calculated model for
end-stage liver disease (MELD) score [OR: 1.05 (1.04-1.07)]
at transplant, non-Hispanic ethnicity [OR: 2.44 (1.34-4.42)],
and prior history of heart failure [OR: 2.3 (1.6-3.4)], isch-
emic heart disease [OR: 1.5 (1.09-2.1)], and stroke [OR: 2.4
(1.2-4.8)]. For 1-year MACE, only older age [Hazard Ratio
(HR)=1.05 (1.03-1.06)], higher MELD score [HR: 1.04 (1.03-
1.05), non-Hispanic ethnicity (HR: 1.74 (1.15-2.63), and prior
history of heart failure [HR=1.9 (1.5-2.4)] and stroke [HR: 1.8
(1.1-2.8)] remained predictive. The models showed moderate
discrimination (c-statistic 0.73, 95% CI: 0.69-0.77). CONCLU-
SIONS: Cardiac complications after liver transplant are com-
mon (over 1/3 of patients experience a MACE within 1 year
of LT) and the majority of events are related to non-coronary
causes. Pre-transplant heart failure, ischemic heart disease and
stroke, all modifiable risk factors, substantially increase risk
of an early MACE. Future prospective studies aimed at deter-
mining whether aggressive risk factor reduction of modifiable
factors can decrease non-coronary MACE and improve post-LT
outcomes are needed.
Disclosures:
The following people have nothing to disclose: Lisa B. VanWagner, Bing Bing
Weitner, Tanvi Subramanian, Sarah Uttal, Alfred W. Rademaker, Josh Levitsky,
Donald M. Lloyd-Jones, Anton I. Skaro
466A AASLD ABSTRACTS
545
Sphincter of Oddi Dysfunction after Liver Transplanta-
tion: Experience in a High Volume Transplant Center
Alejandro Fernandez Simon1, Diego S. Royg1, Oriol Sendino1,
Claudio Zulli1, Cristina Rodriguez de Miguel1, Domingo Balder-
ramo1, Gonzalo Crespo2, Jordi Colmenero2, Josep Llach1, Miquel
Navasa2, Andres Cardenas1; 1GI/Endoscopy Unit, Institut de
Malalties Digestives, Hospital Clinic, Barcelona, Spain; 2Liver Unit,
Institut de Malalties Digestives, Hospital Clinic, Barcelona, Spain
INTRODUCTION: Sphincter of Oddi dysfunction (SOD) in liver
transplant (LT) recipients can occur 3-16% of patients, however
there is scarce data regarding the specific characteristics, inci-
dence, and long term outcome of this condition. The aim of this
analysis was to estimate the incidence and outcome of SOD in
a cohort of LT recipients. METHODS: We reviewed 460 ERCP’s
performed in LT-patients with duct-to-duct biliary anastomosis
at Hospital Clinic, Barcelona from 2003 to 2013. Information
was obtained from electronic health records and a prospec-
tively collected database. SOD in LT recipients was defined as
the presence of cholestasis, elevated liver enzymes, dilated bile
duct and absence of alternative diagnosis at ERCP. Patients
with SOD underwent a biliary sphincterotomy with adequate
drainage of contrast and bile. Definite SOD was defined as
absence of alternative diagnosis in the following 12 months.
Laboratory and clinical findings were obtained immediately
before ERCP and 3 months post-ERCP to evaluate the effect of
sphincterotomy. Post-ERCP follow-up data was obtained for a
period of 48 months. RESULTS: 201 LT recipients underwent
460 ERCP’s during the study period. Twenty-three patients met
the initial criteria of SOD (11.4%). However during the 12
month follow-up, 10 patients (43%) developed other conditions
[biliary anastomotic stricture (n=1), biliary sludge or stones
(n=3), chronic graft rejection (n=4), HCV recurrence (n=1) and
chronic pancreatitis (n=1)]. Therefore 13 of the 201 patients
(6.5%) were diagnosed with definite SOD. Patients with defi-
nite SOD had a significant decrease in bilirubin and alkaline
phosphatase after sphincterotomy compared to those without
SOD (Table). There were no complications after ERCP. CON-
CLUSION: The estimated incidence of definite SOD in LT recipi-
ents was 6.5%. More than 40% of the patients with a suspected
diagnosis of SOD at ERCP developed other conditions that
accounted for cholestasis and abnormal liver enzymes. Biliary
sphincterotomy is a safe and effective procedure in these cases
as those with definite SOD had a resolution of cholestasis.
SOD, sphincter of Oddi dysfunction;; ALP, alkaline phosphatase
(IU/L); GGT, gamma-glutamyl transferase (IU/L); AST, aspartate
aminotransferase (IU/L); ALT, alanine transaminase (IU/L) .Biliru-
bin (mg/dl)
Disclosures:
Andres Cardenas - Board Membership: Frontline Gastroenterology- BMJ publish-
ing group; Consulting: Uptodate; Stock Shareholder: Limmedx LLC
The following people have nothing to disclose: Alejandro Fernandez Simon,
Diego S. Royg, Oriol Sendino, Claudio Zulli, Cristina Rodriguez de Miguel,
Domingo Balderramo, Gonzalo Crespo, Jordi Colmenero, Josep Llach, Miquel
Navasa
HEPATOLOGY, October, 2014
546
Hyperhomocysteinemia is Associated with Reduced Sur-
vival after Liver Transplantation
Rahima A. Bhanji, Mang M. Ma, Aldo J. Montano-Loza; Division
of Gastroenterology & Liver Unit, University of Alberta, Edmonton,
AB, Canada
Background/Aims: The clinical significance of hyperhomocys-
teinemia (HHcy) in patients with cirrhosis and outcomes post-
liver transplant is poorly documented. In this study we aimed to
determine the prevalence of HHcy in cirrhotic patients, evaluate
the association between HHcy and thrombosis, and determine
the impact of HHcy on graft/patient survival after liver trans-
plant. Methods: A total of 450 patients with cirrhosis who had
received a liver transplant over 1989 to 2010 were evaluated.
Homocysteine (Hcy) levels were measured as part of the pre-
liver transplant assessment. Results: Of the 450 patients 308
were males (68%), and mean age was 52±10 years. Cirrhosis
etiology was HCV (37%), autoimmune liver disease (22%),
alcohol (16%), NASH (8%), and others (17%). Mean Hcy level
was 14±13μmol/L, and 165 patients (37%) had HHcy. During
a mean follow-up of 58±40 months after liver transplantation,
90 patients (20%) had at least one episode of thrombosis;
however, there was no significant difference in the frequency
of thrombosis in patients with or without HHcy (18% vs. 21%,
P=0.5). Severity of liver disease before liver transplant assessed
by MELD (23±10 vs. 20±9 points, P<0.001), and Child-Pugh
scores (11±2 vs. 9±2 points, P<0.001) was worse in patients
with HHcy. Finally, HHcy was associated with a reduced graft
(95±5 vs. 109± 3 months; Log Rank P=0.007), and patient sur-
vival after liver transplantation (98±5 vs. 111±3 months; Log
Rank P=0.009), compared to patients with normal Hcy levels
(Figure 1). By Cox multivariate analysis (adjusted to age and
MELD score at transplant), HHcy was independently associated
with patient mortality after liver transplant (HR 1.46, 95% CI
1.03-2.10, P=0.03). Conclusion: HHcy is frequently detected
in patients with cirrhosis but is not associated with a higher risk
of thrombosis after liver transplantation. Nevertheless, HHcy is
associated with a reduced graft and patient survival after liver
transplantation.
Disclosures:
The following people have nothing to disclose: Rahima A. Bhanji, Mang M. Ma,
Aldo J. Montano-Loza
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
547
Use of mTOR inhibitor is associated with increased fre-
quency of late anastomotic biliary strictures and need
for repeat ERCP in Orthotopic liver transplant recipients.
Cheri Ogwo1, Satheesh Nair2,
Jason M. Vanatta2,
James Eason2,
Sanjaya K. Satapathy2; 1Medicine, University of Tennessee Health
Sciences Center, Memphis, TN; 2Department of Surgery, Method-
ist University Hospital Transplant Institute, University of Tennessee
Health Sciences Center, Memphis, TN
BACKGROUND:The mammalian target of rapamycin (mTOR)
inhibitors have been linked to inhibition of cholangiocyte
regeneration after orthoptic liver transplantation (OLT) resulting
in impaired healing and recovery of the biliary ducts, and
could potentially affect outcomes of anastomotic biliary stricture
(ABS) due to delayed healing at the anastomotic site. AIM:Eval-
uate association between mTOR inhibitor use (Rapamycin/
Everolimus) with anastomotic biliary strictures. METHODS: Med-
ical records of 806 recipients who underwent liver transplant at
the Methodist University Hospital Transplant institute from April
2006 to June 2014 were reviewed if they had undergone an
ERCP during their post-transplant period for anastomotic biliary
stricture. We categorized the patients into groups, Early ABS
(stenosis occurring less than < 90 days after OLT) and late ABS
(≥ 90 days after OLT). Patients were further grouped based on
their main immunosuppression regimen; Gr I: mTOR + (those
who received mTOR inhibitors starting in the first 3 months after
OLT), and mTOR – (those who received other immunosuppres-
sant). RESULTS: 159 recipients underwent a total of 291 ERCPs
during the observation period. A total of 40 (25.2) recipients
were grouped under the mTOR positive group, and 119 (74.8)
under the mTOR negative group. No significant difference in
the overall frequency of anastomotic [23(57.4) vs 60(50.4),
P=0.438] OR non-anastomotic biliary strictures [8(20%) vs.
12(10.1%), P=0.130] was noted between the mTOR positive
and negative groups. However mTOR positive group of patients
developed significantly higher number of late ABS [24(60%)
vs. 39(32.8%), P=0.002], and also needed significantly higher
number of repeat ERCPs [24(60%) vs. 46(38.7%), P=0.019].
CONCLUSION: Use of mTOR inhibitors is associated with
increased predisposition for late anastomotic biliary strictures
and is associated with increased need for repeat ERCPs.
Table 1. Clinical and demographic profile of the recipients with
ERCP
Disclosures:
Satheesh Nair - Advisory Committees or Review Panels: Jansen; Grant/Research
Support: Gilead; Speaking and Teaching: Bayer, Salix, Gilead
Sanjaya K. Satapathy - Advisory Committees or Review Panels: Gilead
The following people have nothing to disclose: Cheri Ogwo, Jason M. Vanatta,
James Eason
467A
548
Sexual Functioning in Patients With End-Stage Liver Dis-
ease Before and After Liver Transplantation (LT)
Beatriz Rodríguez-Medina1,2, Diego Alvarez de Sotomayor1,
Carla Satorres1, Agustin Ramos-Prol1, Carmen Vinaixa1, Angel
Rubin1, María García Eliz1, Victoria Aguilera1, Martin Prieto1,
Marina Berenguer1; 1Hospital Universitario La Fe, Valencia, Spain;
2Hospiten Clinica Roca, Las Palmas de Gran Canaria, Spain
Background-Aims:Data on Sexual Dysfunction(SD) in cirrhotic
patients are limited.Sexual function is a complex area of
human behavior with great impact on Quality-of-Life.Despite its
relevance,it is rarely evaluated in clinical practice in cirrhotic
patients.Our aim was to evaluate in detail the sexual function
of patients with end-stage liver disease in the waiting list for LT
and to compare it with the results after LT and with that of a
controlled group from the general population matched by age
and gender.Methods:Changes in Sexual Functioning Question-
naire were used to evaluate SD in cirrhotic patients awaiting
LT and in the post-LT setting 1 year after transplant.Clinical
data as well as a complete set of sexual hormonal profile were
obtained in the same periods.Controls were given the same
questionnaires.Results:58 patients,69% men with a median
MELD 19,were included and compared to 58 controls.92% of
men presented SD during the waiting period for LT compared
to 63% of controls(p<0.01).In women, of whom 88% were in
menopausal stage, SD was present in 94% compared to 72%
of controls(p=0.7).One year post-LT,SD decreased to 74% in
men(p=0.09),while no changes were detected in women.In
men,sex hormones showed a pattern of central hypogonad-
ism during the pretransplant period with a decrease in male
sex hormones(free testosterone in 83%,testosterone 53%)and
normal values of FSH and LH(in 72% and 81% of men).In
addition,an increase of estradiol and prolactin in 86% and
72 %,respectively,were observed.Levels of DHEA-Sulphate,an
androgen produced in the adrenal gland,were decreased in
97% of men. Sex hormones results one year after LT showed
FSH and LH values above the normal range, a significant
increase with respect to the pre-transplantation period(p=0.07
and 0.005,respectively);a descrease of prolactin to normal
levels (p=0.2),and estrogen levels, while still slightly above the
normal range, had decreased(p=0.2). There was an increase
in testosterone and free testosterone levels(P=0.05 and 0,2).
Levels of DHEA-Sulphate remained low after transplantation.
Conclusion:SD,an infra-estimated condition,is extremely com-
mon in cirrhotic patients awaiting LT.Besides central hypogo-
nadism,the reduced levels of DHEA,possibly due to adrenal
dysfunction,is an aspect that deserves further investigation:-
sexual dysfunction could,in part,be another manifestation of
the recently coined“hepatoadrenal syndrome”.LT improves SD
in men,demonstrated both subjectively (questionnaires) and
objectively,with a normalization in sex hormone levels in most
cases and the disappearance of central hypogonadism with
a compensatory increase of pituitary hormones synthesis(FSH
and LH).
Disclosures:
The following people have nothing to disclose: Beatriz Rodríguez-Medina, Diego
Alvarez de Sotomayor, Carla Satorres, Agustin Ramos-Prol, Carmen Vinaixa,
Angel Rubin, María García Eliz, Victoria Aguilera, Martin Prieto, Marina Ber-
enguer
468A AASLD ABSTRACTS
549
Adherence to Immunosuppressive therapy in Adult and
Adolescent Liver Transplant Recipients in a Multi-Ethnic
Asian Centre: A Questionnaire Survey
Kieron B. Lim1,2, Juanda Leo Hartono1, Yock Young Dan1, Maung
Aye Thwin1, Poh Seng Tan1, Charlene Soon3, Alfred W. Kow3,
Krishnakumar Madhavan3, Seng Gee Lim1; 1Gastroenterology &
Hepatology, National University Hospital, Singapore, Singapore,
Singapore; 2Liver Diseases, Ichan School of Medicine at Mount
Sinai, New York, NY; 3Hepatobiliary Surgery, National University
Hospital, Singapore, Singapore, Singapore
Background Immunosuppressive (IS) therapy in liver transplant
(LT) recipients is responsible for improved graft survival due to
prevention of acute and chronic allograft rejection. Non-adher-
ence to IS therapy leading to graft rejection is well-recognized.
We aim to study adherence to IS treatments and patient prefer-
ences in adolescent and adult liver recipients in a multi-ethnic
Asian centre. Methods Liver recipients (age >18) on IS therapy
on active follow up at our institution were identified. An anon-
ymous questionnaire form (available in English, Mandarin,
Malay, Arabic) was given to each patient during a clinic visit
(survey period Oct 2013 – Apr 2014). Completed forms were
returned in unmarked sealed envelope. Results One hundred
questionnaires were distributed; sixty-eight were returned fully
completed and included in the present analysis. Based on the
validated Morisky Adherence Score, only 5% of our cohort
were considered to have “high adherence”; while 31% had
“low adherence”. Liver recipients aged 20-39 were more likely
to have low adherence compared to those between 40-69
years. Respondents were predominantly male (84%), with high
school education (44%). Time from LT ranged from <1 year to
>10 years. 30% did not know the names of their current IS.
37% admitted to missing IS doses; 7% missed doses once in
2 weeks; 12% missed doses once in 3 months. Evening doses
were most commonly missed (18%). 57% felt once daily morn-
ing dosing regimen would improve IS adherence. Common
reasons for missed doses include “forgot” (19%), “too busy”
(13%). 68% prefer to have their number of doses reduced
and 28% found it difficult to take their evening dose on time.
Patient’s ethnicity and primary language used, education level,
occupation status, number of IS agents and amount spent on
IS were not associated with adherence. Conclusion Adherence
to immunosuppression is often under-reported by liver recipi-
ents. Extra vigilance and patient education by the transplant
team is needed to improve adherence among younger liver
recipients (20-39 years). Simplified immunosuppression dosing
regimens with once daily regimens and a reduced pill burden
may improve adherence to immunosuppressive therapy.
Disclosures:
Kieron B. Lim - Advisory Committees or Review Panels: Gilead, Sirtex; Consulting:
AstraZeneca, Novartis; Grant/Research Support: Astellas, Bayer
Yock Young Dan - Advisory Committees or Review Panels: Merck, Sharp and
Dohme, GIlead; Grant/Research Support: Novartis
Seng Gee Lim - Advisory Committees or Review Panels: Bristol-Myers Squibb,
Achillon Pharmaceuticals, Pfizer Pharmaceuticals, Janssen Pharmaceuticals,
Novartis Pharmaceuticals, Merck Sharp and Dohme Pharmaceuticals, Vertex
Pharmaceuticals, Boehringer-Ingelheim, Gilead Pharmaceuticals, Roche Pharma-
ceuticals, Tobira Pharmaceuticals; Speaking and Teaching: GlaxoSmithKline,
Bristol-Myers Squibb, Merck Sharp and Dohme Pharmaceuticals, Boehring-
er-Ingelheim, Gilead Pharmaceuticals, Novartis Pharmaceuticals
The following people have nothing to disclose: Juanda Leo Hartono, Maung Aye
Thwin, Poh Seng Tan, Charlene Soon, Alfred W. Kow, Krishnakumar Madhavan
HEPATOLOGY, October, 2014
550
Orthotopic liver transplantation for hepatocellular car-
cinoma after successful downstaging: results from the
Belgian multicentre cohort
Jonas Schreiber1, Jan P. Lerut2, Chris Verslype3, Hans Van Vlier-
berghe4, Valerio Lucidi1, Olivier Detry5, Luisa Vonghia6, Francesco
Puleo1, Eric Trépo1, Milton E. Inostroza2, Hélène Poels3, Roberto
Troisi4, Jean Delwaide5, Sven M. Francque6, Vincent Donckier1,
Christophe Moreno1; 1Department of Gastroenterology and
abdominal surgery, Erasme Hospital ULB, Brussels, Belgium; 2Unit
of abdominal transplantation, Saint Luc Hospital, Brussels, Bel-
gium; 3Department of Gastroenterology and abdominal surgery,
Gasthuisberg KUL, Leuven, Belgium; 4Department of gastroenterol-
ogy and abdominal surgery, UZ Gent, Ghent, Belgium; 5Depart-
ment of Gastroenterology and abdominal surgery, CHU Liège,
Liège, Belgium; 6Department of Gastroenterology and abdominal
surgery, UZA, Antwerp, Belgium
Purpose: Successful downstaging of hepatocellular carcinoma
(HCC) into the Milan criteria (MC) remains a controversial
indication for orthotopic liver transplantation (OLT). In Belgium,
successful downstaging of HCC is an accepted non-standard-
ized exception (NSE) for liver allocation. This NSE group rep-
resents a unique cohort to analyse if OLT can be safely offered
to patients with those extended allocation criteria. The aim
of this study is to compare the overall and recurrence free
survival after cadaveric OLT between patients with successful
downstaging (MILDOWN) and patients always inside the MC
(MILIN) from all Belgian transplant centres. Methods: We ret-
rospectively analysed all patients listed for OLT with HCC and
underlying cirrhosis between 12/2006 and 12/2011 from
all Belgian liver transplant centres. Successful downstaging
was defined as bringing a patient who was outside the MC
into the MC after locoregional therapy (LRT). Results: Overall
381 patients were listed in Belgium during the study period.
Of these, 320 received OLT. 248 were MILIN, 62 were MIL-
DOWN and 10 were transplanted outside MC. Downstaging
treatment included transarterial chemoembolization (TACE;
n=26), radiofrequency (RF; n=9), transarterial radioembolisa-
tion (TARE; n=4), resection (n=3), percutaneous ethanol injec-
tion (n=2) and a combination of the above-mentioned therapies
in 18 cases. In the MILIN group 67.3% received locoregional
therapy before transplantation, with no significant differences
in the distribution of treatment type compared to the MIL-
DOWN group. At listing there were no significant differences
between the MILIN and MILDOWN group for age, gender and
underlying liver disease. Median time on waiting list between
the two groups was similar (120 days vs. 115.5 days). Overall
survival at 1 year was not significantly different between MILIN
and MILDOWN (87.1% vs. 79%; p=0.120). 1.6% of patients
were lost to follow-up in both groups. Although not significant,
recurrence free survival at 1 year tended to be higher in the
MILIN group than in the MILDOWN group (83.9% vs. 74.2%;
p=0.073). Conclusion: In this large Belgian multicentre cohort,
overall and recurrence free survival at 1 year are not signifi-
cantly different between patients who have been downstaged
successfully and patients who were always inside the Milan
criteria. However, a longer follow up period will define, if the
trend of lower survival in the successfully downstaged group
becomes significant. Factors associated with HCC recurrence
have to be identified.
Disclosures:
Jan P. Lerut - Grant/Research Support: Fresenius Biotech, Astellas
Christophe Moreno - Consulting: Abbvie, Janssen, Gilead, MSD, Novartis, BMS;
Grant/Research Support: Janssen, Gilead, Roche, MSD, Novartis, Astellas
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
The following people have nothing to disclose: Jonas Schreiber, Chris Verslype,
Hans Van Vlierberghe, Valerio Lucidi, Olivier Detry, Luisa Vonghia, Francesco
Puleo, Eric Trépo, Milton E. Inostroza, Hélène Poels, Roberto Troisi, Jean Del-
waide, Sven M. Francque, Vincent Donckier
551
Outcomes for Patients with Decompensated Cirrhosis
Transferred from Outlying Hospitals to a Tertiary Care
Liver Transplant Center
Chad Cornish1, Michael Winter2, Thomas D. Rodgers2, Gopal A.
Ramaraju1, Benedict Maliakkal1, Jonathan Huang1; 1Gastroen-
terology & Hepatology, University of Rochester Medical Center,
Rochester, NY; 2Internal Medicine, University of Rochester Medical
Center, Rochester, NY
BACKGROUND: Tertiary care liver transplant centers frequently
receive requests from outlying hospitals to transfer patients
with acute decompensated cirrhosis for a higher level of care,
including evaluation for liver transplantation. There have been
no published studies looking at clinical outcomes for patients
with acute decompensated cirrhosis who are transferred to
a liver transplant center or barriers to efficient interhospital
transfer. AIM: To determine the rate of liver transplantation
and mortality for patients with acute decompensated cirrhosis
transferred from outlying hospitals to a tertiary care liver trans-
plant center and elucidate barriers to timely interhospital trans-
fer. METHODS: Patients 18 years of age or older transferred
from an outlying hospital to Strong Memorial Hospital (SMH)
for management of acute decompensated cirrhosis between
January 1, 2011 and July 31, 2013 were identified by interro-
gation of the hospital’s transfer request logs. Patients less than
18 years of age or those transferred for management of fulmi-
nant hepatic failure were excluded. RESULTS: 99 patients were
identified, including 7 patients who were transferred multiple
times. Mean length of stay (LOS) at the outside hospital (OSH)
was 6.8 days (range 0-38 days). Mean time from transfer
request to arrival at SMH was 1.2 days (range 0-18 days).
There were 30 cases of interhospital transfer delay in which
30% of cases were due to lack of bed availability while 13%
of cases were due to the patient being too unstable to trans-
fer. 13 of 99 (13%) patients were evaluated and listed for
liver transplantation; 3 (3%) of these patients underwent liver
transplantation during their admission while 7 others died in
the hospital. 29 of 92 (32%) patients died during their initial
admission after a mean LOS of 19.7 days (range 4-99 days).
2 additional patients died after being transferred on a sepa-
rate occasion. Mean peak OSH MELD score for patients who
died at SMH was 31.3 (range 20-41). CONCLUSIONS: Very
few patients with acute decompensated cirrhosis transferred
from an outlying hospital were suitable for liver transplantation
and an even smaller number of patients were transplanted. A
substantial number of patients died following a prolonged hos-
pitalization. The major reason for delay of transfer was lack of
bed availability. Given limited resources and costs associated
with transferring patients to a tertiary care liver transplant cen-
ter, patient selection for transfer is crucial in order to provide
optimal care and allocate resources appropriately. Further stud-
ies are needed which identify risk factors that help prioritize
patient transfers.
Disclosures:
The following people have nothing to disclose: Chad Cornish, Michael Winter,
Thomas D. Rodgers, Gopal A. Ramaraju, Benedict Maliakkal, Jonathan Huang
469A
552
MELD score does not impact the outcomes of simultane-
ous liver and kidney transplantation
Mohsen Hasanin1, Siddharth Bansal2, Yong-Fang Kuo3, Ashwani
K. Singal4, Russell H. Wiesner5; 1Internal Medicine, UAB Mont-
gomery, Montgomery, AL; 2Internal Medicine, UAB, Birmingham,
AL; 3Biostatistics, UTMB, Galveston, TX; 4Gastroenterology and
Hepatology, UAB, Birmingham, AL; 5Gastroenterology and Hepa-
tology, Mayo Clinic, Rochester, MN
Background and Aim: Outcomes after liver transplantation
are worse for patients with MELD score >40 compared to
MELD<40. We performed this study to assess impact of MELD
score on post-transplant outcomes after simultaneous liver kid-
ney (SLK) transplantation. Methods: The United Network for
Organ Sharing (UNOS) database from 1995 to 2011 was
queried for SLK transplants performed in adults. We excluded
participants who had previous liver or kidney and patients
receiving simultaneous organ other than kidney. Study popula-
tion was stratified based on MELD score at transplantation to
≤35, 36-40 and > 40. Kaplan-Meier curves were built for five
year outcomes (liver graft, kidney graft, and patient survival)
comparing three groups. Cox proportional hazard regression
analyses were performed to determine impact of MELD score
on outcomes after controlling for recipient characteristics and
donor risk index (DRI). P<0.025 was considered statistically
significant. Results: A total of 3,403 SLK transplants (77%
MELD <36, 10% MELD 36-40, and 13% MELD >40) were ana-
lyzed and differed for various recipient characteristics and DRI.
Over 90% of SLK transplants were performed in the MELD era
(Table). Five year outcomes were no different for three MELD
groups for liver graft (72%, 69%, and 71.7%; P=0.44), kidney
graft (71%, 69%, and 69.5%; P=0.47), and patient survival
(75%, 73%, and 74%; P=0.56). Compared to MELD ≤35, out-
comes of SLK transplants with MELD 36-40 were similar for liver
graft, kidney graft, and patient survival with hazard ratio (95%
confidence interval) of 1.08 (0.84-1.38), 1.02 (0.79-1.33),
and 1.02 (0.8-1.30) respectively. Similar respective figures
comparing MELD ≤35 and MELD >40 were 0.99 (0.71-1.40),
0.94 (0.66-1.34), and 0.99 (0.71-1.38). Recipient age, black
race, being on dialysis or ventilator, diabetes mellitus, and
DRI were predictors of outcomes. Conclusion: Frequency of
SLK transplantation is increasing. For patients selected for SLK,
MELD score did not impact the post-transplant outcomes. Fur-
ther studies are needed to assess role of SLK transplantation for
patients with MELD score above 40.
Baseline recipient characteristics and donor risk index of simulta-
neous liver kidney recipients comparing MELD ≤35, 36-40, and
>40 at the time of transplantation.
Disclosures:
The following people have nothing to disclose: Mohsen Hasanin, Siddharth Ban-
sal, Yong-Fang Kuo, Ashwani K. Singal, Russell H. Wiesner
553
WITHDRAWN
470A AASLD ABSTRACTS
554
Diabetes Mellitus is associated with Lower Survival fol-
lowing Simultaneous Liver Kidney Transplantation
Ryan B. Perumpail1, Robert Wong1, Andrew M. Su1, Jane Tan2,
John Scandling2, Aijaz Ahmed1; 1Division of Gastroenterology
and Hepatology, Stanford University Medical Center, Stanford,
CA; 2Division of Nephrology, Stanford University Medical Center,
Stanford, CA
Background: The prevalence of diabetes mellitus in the U.S.
population and among simultaneous liver kidney transplant
(SLKT) recipients is increasing. The effect of pre-transplant dia-
betes mellitus on outcomes following SLKT is not well estab-
lished. Aim: To evaluate the association of pre-transplant
diabetes mellitus on post-SLKT survival among patients in the
U.S. Methods: We conducted a retrospective cohort study
using population-based national data from the United Network
for Organ Sharing registry to evaluate the impact of diabetes
on long term survival following SLKT among U.S. adults from
2003 to 2012. Post-SLKT survival was evaluated with multivar-
iate Cox proportional hazards model adjusted for age, sex,
hepatitis C virus infection, body mass index, race/ethnicity,
hepatocellular carcinoma, ascites, hepatic encephalopathy,
Model for End-stage Liver Disease (MELD) score, and cardiac
disease. Results: Overall, 2,782 adult patients underwent
SLKT from 2003-2012, including 933 diabetic (33.5%) and
1,849 non-diabetic (66.5%) patients. In the multivariate Cox
proportional hazards model, patients with diabetes mellitus
had significantly lower post-SLKT survival than patients without
diabetes mellitus (HR 1.34, 95% CI, 1.13 – 1.58, p<0.001).
Conclusions: In the U.S. experience, pre-transplant diabetes
mellitus was an independent predictor of lower survival follow-
ing SLKT.
Disclosures:
Aijaz Ahmed - Consulting: Bristol-Myers Squibb, Gilead Sciences Inc., Roche,
AbbVie, Salix Pharmaceuticals, Janssen pharmaceuticals, Vertex Pharmaceuti-
cals, Three Rivers Pharmaceuticals; Grant/Research Support: Gilead Sciences
Inc.
The following people have nothing to disclose: Ryan B. Perumpail, Robert Wong,
Andrew M. Su, Jane Tan, John Scandling
HEPATOLOGY, October, 2014
555
Histological correlates of ERCP confirmed biliary anasto-
motic strictures
Fazal Yahya1, Pamela B. Sylvestre2, Saradasri Karri1, Satheesh
Nair3, Jason Vanatta3, James Eason3, Sanjaya K. Satapathy3;
1Medicine, University of Tennessee Health Science Center, Mem-
phis, TN; 2Gastroenterology and Hepatology, University of Tennes-
see Health Science Center, Memphis, TN; 3Department of Surgery,
Transplant Institute, University of Tennessee Health Science Center,
Memphis, TN
BACKGROUND:Suspicious findings of biliary obstruction on
allograft histology often prompt an ERCP for further evalua-
tion in OLT recipients with cholestatic liver test abnormalities.
No study has systematically evaluated histological correlates
of anastomotic biliary strictures in OLT recipients to provide
guidance or support for this approach. AIM: Retrospective eval-
uation of liver biopsy performed within 1 week of ERCP in
recipients of OLT with confirmed biliary strictures. METHODS:
Records of 806 adult liver transplant recipients, age > 18, who
underwent OLT at the Methodist University Hospital Transplant
Institute between April 6, 2006 and December 31, 2012,
were reviewed. Patients with PSC (n=24), and/or non-anas-
tomotic biliary stricture (n=10) were excluded. 25 recipients
with new or clearly defined recurrent ABS on ERCP with liver
biopsy performed within 1 week of ERCP were included.
RESULTS: Most prominent liver histology findings in recipients
with ABS included mononuclear portal inflammation (88%),
feathery degeneration of the hepatocytes (64%) and periportal
ductular reaction (52%). Moderate to marked mononuclear
inflammation was noted 36%, but portal neutrophilic infiltrate
is less commonly noted (24%). Cytological alteration of chol-
angiocytes, cholestasis, canalicular bile plugs each occurs in
about 1/3rd of the recipients with ABS. Definite bile duct loss
is an uncommon, noted in 8% of recipients. Periportal interface
activity, if noted, is usually minimal to mild. CONCLUSION: We
have described histological correlates of anastomotic biliary
strictures in OLT recipients which potentially could be useful in
the decision making process to proceed with ERCP particularly
if imaging modalities are equivocal.
Table 1. Histological findings in recipients with anastomotic bili-
ary strictures
Disclosures:
Satheesh Nair - Advisory Committees or Review Panels: Jansen; Speaking and
Teaching: Gilead
Sanjaya K. Satapathy - Advisory Committees or Review Panels: Gilead
The following people have nothing to disclose: Fazal Yahya, Pamela B. Sylvestre,
Saradasri Karri, Jason Vanatta, James Eason
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
556
Pre-operative renal failure predicts reduced survival
following liver transplantation but not liver specific graft
failure or death
Francis P. Robertson1,
Pulathis Siriwardana1,
Paul R. Bessell2,
Rafael Diaz-Nieto1, Nancy Rolando1, Brian R. Davidson1; 1Depart-
ment of Surgery, University College London, London, United King-
dom; 2University of Edinburgh, Edinburgh, United Kingdom
Liver transplantation is now accepted as the treatment of choice
for end stage liver failure. Pre-operative renal failure has been
previously been associated with increased post-operative mor-
bidity and mortality, and reduced graft survival after 2 years in
patients undergoing liver transplantation. Our aim was to anal-
yse pre-operative creatinine levels with overall graft survival and
liver specific failure up to 10 years following liver transplanta-
tion in a large single centre prospectively collected database.
Methods Data was reviewed for 1272 patients undergoing
liver transplantation between 1988 and 2012. Clinical out-
come was reviewed and their pre-operative creatinine level
was documented. Overall graft survival was calculated on
death from any cause or re-transplantation within 3 months,
1, 5 and 10 years. Liver specific death and failure (acute
and chronic rejection/primary graft non-function/non-throm-
botic infarction/biliary complications) was calculated at 10
years. Pre-operative creatinine levels were log transformed
and were analysed via a full cox proportional hazard model
and T-test. Results were corrected for age, cold ischaemic time
and post-operative aspartate transaminase (log transformed).
Results 1272 patients (640M/628F/4 Unspecified) were iden-
tified. 514 records were excluded from the cox proportional
hazard model due to missing creatinine level at day 30. The
mean age at time of transplantation was 47 years (Range
37-69). The mean pre-operative creatinine was 104.08g\L
(Range 16-999). At all time points the mean creatinine levels
pre-operatively were significantly greater in grafts that had
failed than those that were functioning (3 months p<0.001, 1
year p<0.001, 5 years p<0.001, 10 years p=0.017). When
corrected for contributing variables, high pre-operative cre-
atinine levels were associated with poorer overall survival at
3 months, 1, 5 and 10 years (p<0.001). Per unit increase
of the pre-operative creatinine value, the risk of overall graft
failure was calculated as 1.30 and 0.48 for liver specific fail-
ure. Pre-operative creatinine was not significant when analysed
against liver specific failure at 10 years (p=0.25). Conclusions
This retrospective review from a large single centre prospective
database has shown that grafts implanted into recipients with
higher pre-operative creatinine levels experience a significantly
poorer outcome at all measured time points up to 10 years. The
correlation between pre-operative creatinine levels and liver
specific graft failure did not reach significant values. These
results suggest that although the survival of these implanted
grafts is reduced, it is secondary to extra-hepatic factors.
Disclosures:
The following people have nothing to disclose: Francis P. Robertson, Pulathis Siri-
wardana, Paul R. Bessell, Rafael Diaz-Nieto, Nancy Rolando, Brian R. Davidson
471A
557
Long term outcomes of patients with new portal vein
thrombosis occurring after liver transplantation
Scott Duncan2, Laxmi B. Parsa1,3, Nader Dbouk1,3; 1Surgery,
University of Tennessee Health Science Center, Memphis, TN;
2Internal Medicine, University of Tennessee health Science Center,
Memphis, TN; 3Methodist University Hospital Transplant Institute,
Memphis, TN
Background: Portal vein thrombosis (PVT) occurs in 3-7% of
adult patients following orthotopic liver transplantation (OLT).
The long term consequences and potential impact on graft
and patient survival remain unknown. Methods: We identi-
fied seventeen patients who underwent a liver transplant at
our institution between January 2006 and December 2013
and developed PVT following OLT (PVT group) and compared
their outcomes to those of 51 controls who had received a
liver transplant during the same time period (non-PVT group).
Controls were matched to cases on the basis of age, gender,
body mass index (BMI) and etiology of liver disease. Graft
survival was defined as time from transplantation to death, last
follow-up or re-transplantation. Kaplan Meier survival analy-
sis was used to compare graft and patient survival between
both groups. Results: Baseline patient and donor characteristics
were similar between both groups. There was no statistically
significant difference in the incidence of biopsy proven acute
or chronic rejection and biliary complications (anastomotic
and non-anastomotic strictures) between both groups. Seven
patients (41%) in the PVT group had esophageal and/or gas-
tric varices detected endoscopically or on imaging, compared
to 7/51 (14%) of patients in the control group (p=0.016).
Variceal bleeding occurred in 12% of patients in the PVT group
compared to 4% of patients in the control group (p=0.06). Clin-
ically significant ascites occurred in 9/17 patients in the PVT
group (53%) compared to 10/41 patients in the control group
(19.6%) (p=0.0085). Overt hepatic encephalopathy occurred
in 2/17 patients in the PVT group (12%) compared to 1/51
(2%) of patients in the control group (p=0.09). Interestingly,
patients in the PVT group were also more likely to develop
hepatic artery thrombosis (HAT) compared to patients in the
control group (23.5% vs 5.9% respectively; p= 0.04). Seven
patients in the PVT group (41%) died compared to 11 in the
control group (21%) (p=0.11). The main cause of death in
both groups was sepsis, followed by cardiovascular disease
and malignancy. There was no statistically significant differ-
ence in graft and patient survival between both groups. Mean
duration of follow up was 976±707 days for the PVT group
and 1187±728 days for the control group (p=0.3). Conclu-
sion: New PVT following OLT did not impact graft or patient
survival, however patients with PVT post transplantation were
more likely to develop varices and clinically significant asci-
tes. Variceal bleeding and hepatic encephalopathy occurred
more frequently amongst PVT patients but the difference did not
reach statistical significance.
Disclosures:
The following people have nothing to disclose: Scott Duncan, Laxmi B. Parsa,
Nader Dbouk
472A AASLD ABSTRACTS
558
Evolving renal function in the post-operative period
correlates with over all graft survival following liver
transplantation
Francis P. Robertson1, Pulathis Siriwardana1, Paul R. Bessell2,
Rafael Diaz-Nieto1, Nancy Rolando1, Brian R. Davidson1; 1Depart-
ment of Surgery, University College London, London, United King-
dom; 2University of Edinburgh, Edinburgh, United Kingdom
Liver transplantation is now accepted as the treatment of choice
for end stage liver failure. Pre-operative renal failure has been
associated with increased post-operative morbidity and mortal-
ity and reduced graft survival at 2 years. Our own data has
shown that high pre-operative creatinine levels are associated
with a poorer overall survival at 3 months, 1, 5 and 10 years.
Renal function can improve or deteriorate following orthotopic
liver transplantation and our aim was to analyse changes in
renal function in the immediate post-operative period on long-
term graft survival following successful OLT in a large single
centre prospectively collected database. Methods Data was
reviewed for 1272 patients undergoing liver transplantation
between 1988 and 2012. Clinical outcome was reviewed and
the creatinine levels pre-operatively and at day 30 post opera-
tively were documented. A ratio was calculated. Patients were
placed in to 3 groups depending on their ratio. 1: patients
whose renal function improved post-operatively (<1) 2: patients
whose renal function was stable post-operatively (1-2) 3:
patients who suffered significant deterioration post-operatively
(>2). Graft survival was calculated for death from any cause
and liver failure requiring re-transplantation at 3 months, 1,5
and 10 years. Results were corrected for age, cold ischaemic
time, pre-operative creatinine and post-operative aspartate
transaminase (both log transformed) and a full cox propor-
tional hazard model was performed. A survival regression
curve was also calculated. Results 1272 patients were identi-
fied (640M/628F/4 Unspecified). 514 records were excluded
due to missing creatinine level at day 30. The mean age at
time of transplantation was 47 years (Range 37-69). Improv-
ing renal function in the post-operative period correlated with
improved survival at all time points (p<0.001) when compared
with patients whose renal function was stable. Similarly dete-
riorating renal function in the post-operative period correlated
strongly with deceased survival at all time points (p<0.001)
when compared with patients whose renal function was stable.
Conclusions This retrospective review from a large single centre
prospective database has shown that post-operative changes
in renal function correlate significantly with long term overall
graft outcome. Changes in post-operative renal function would
be an adequate outcome measure of trials aimed at improving
survival following liver transplantation.
Disclosures:
The following people have nothing to disclose: Francis P. Robertson, Pulathis Siri-
wardana, Paul R. Bessell, Rafael Diaz-Nieto, Nancy Rolando, Brian R. Davidson
559
Listing practices for Morbidly Obese Patients at Liver
Transplant Centers in the United States
Dina Halegoua-De Marzio1, She-Yan Wong1, Jonathan M. Fen-
kel1, Cataldo Doria2, David A. Sass1; 1Department of Medicine,
Division of Gastroenterology and Hepatology, Thomas Jefferson
University, Philadelphia, PA; 2Department of Surgery, Division of
Transplantation, Thomas Jefferson University, Philadelphia, PA
Introduction: Obesity affects more than one third of Ameri-
cans. Morbid obesity (body mass index (BMI) >35 kg/m2) has
been associated with multiple co-morbidities and perioperative
HEPATOLOGY, October, 2014
complications. The effect of morbid obesity on liver transplant
outcomes has yielded mixed results. The aim of this study is
to determine listing practices for morbidly obese patients in
United States (U.S.) liver transplant centers. Methods: A 19
item survey was created to assess liver transplant evaluation
and listing practices for morbidly obese patients. All U.S. adult
liver transplant medical and surgical directors were contacted
by email with a cover letter describing the study and an inter-
net link to the SurveyMonkey® website. A few questions had
a free-text section which allowed for comment. Five follow-up
emails were sent to encourage participation. Results: A total
of 187 surveys were emailed with responses received from
46 physicians (24.7% response rate). The responding cohort
consisted of 29 (63%) medical directors and 17 (37%) surgi-
cal directors, including respondents from all United Network
Organ Sharing (UNOS) regions, though regions 4 and 6 had
the fewest respondents (n=2). The majority of respondents
reported treating patients at an academic medical center
(73.3%) and performing more than 50 liver transplants a year
(60.8%). A policy on evaluation and listing of obese patients
was present at 70.5% of institutions with the majority (54.5%)
reporting their BMI cut off for transplant was 40 but a range
of 35 to unlimited was noted. The majority (61.4%) of respon-
dents agreed that there has been an increase in the number
of obese patients they have listed for liver transplant, however
75% of respondents’ reported that patients with high BMI were
less likely to be evaluated for transplantation. With regards
to complications in obese patients, 65.9% of respondents
reported experiencing an increased complication rate, with the
most frequently cited complications being poor wound healing
and increased infection rates. Despite the reported increased
complication rate, only 34.1% reported they had experienced
worse survival rates with obese patients. Conclusions: The
majority of medical and surgical liver transplant directors have
a strong appreciation of the possible morbidity risks associated
with morbidly obese patients post-transplant and have policies
in effect to minimize these risks. This is of specific concern due
to the need to provide more high quality and cost effective
transplant care in the current healthcare climate. More data
examining morbidly obese cirrhotic patient outcomes perioper-
atively, stratified by other co-morbidities, is needed.
Disclosures:
Jonathan M. Fenkel - Consulting: Gilead Pharmaceuticals, Janssen Therapeutics
The following people have nothing to disclose: Dina Halegoua-De Marzio, She-
Yan Wong, Cataldo Doria, David A. Sass
560
Racial/Ethnic Disparities in Simultaneous Liver Kidney
Transplantation: An Analysis from the UNOS Database
Ryan B. Perumpail1, Robert Wong1, Andrew M. Su1, Robert Isom2,
John Scandling2, Aijaz Ahmed1; 1Division of Gastroenterology
and Hepatology, Stanford University Medical Center, Palo Alto,
CA; 2Division of Nephrology, Stanford University Medical Center,
Stanford, CA
Background: Racial/ethnic disparities in liver transplantation
(LT) are well established. African Americans (AAs) are referred
for LT at lower rates, and there is significantly lower post-LT
survival among AAs compared to other groups. Significantly
higher rates of hepatitis C virus (HCV) infection and chronic
kidney disease are also seen in AAs. However, it is not clear
if these racial/ethnic disparities persist among LT patients with
impaired renal function requiring simultaneous liver kidney
transplantation (SLKT). Aim: To evaluate racial/ethnic dispar-
ities in the trends of SLKT and post-SLKT survival in the U.S.
Methods: We conducted a retrospective cohort study using
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
data from the United Network for Organ Sharing registry to
evaluate race/ethnicity-specific trends in adult patients under-
going SLKT in the U.S. from 2003 to 2012. Race/ethnicity-spe-
cific survival following SLKT was evaluated using Kaplan Meier
methods and multivariate Cox proportional hazards models.
Results: Overall, 2,782 adult patients underwent SLKT from
2003 to 2012. AAs received 15.5% (n=425) of SLKTs during
this time period and had the lowest overall 5-year post-SLKT sur-
vival (60.4%; 95% CI, 55.3-65.1%, p<0.01) (Figure). While
the majority of SLKT patients were non-Hispanic white (62.9%;
n=1,728), when stratified by HCV status, there were signifi-
cantly more AAs in the HCV SLKT group compared with the
non-HCV SLKT group (24.7% vs. 7.7%, p<0.001). Compared
to non-Hispanic Whites, there was a trend towards lower
post-SLKT survival among AAs (HR 1.16; 95% CI, 0.94-1.43;
p=0.15) and a trend towards better post-SLKT survival among
Hispanics (HR 0.81; 95% CI, 0.65-1.02; p=0.08). Conclu-
sions: Race/ethnicity leads to a non-significant trend towards
lower survival following SLKT in AAs, unlike other minority
groups. AAs are well represented among HCV SLKT recipients,
whereas less than a tenth of non-HCV SLKT recipients are AAs.
Disclosures:
Aijaz Ahmed - Consulting: Bristol-Myers Squibb, Gilead Sciences Inc., Roche,
AbbVie, Salix Pharmaceuticals, Janssen pharmaceuticals, Vertex Pharmaceuti-
cals, Three Rivers Pharmaceuticals; Grant/Research Support: Gilead Sciences
Inc.
The following people have nothing to disclose: Ryan B. Perumpail, Robert Wong,
Andrew M. Su, Robert Isom, John Scandling
561
The mTOR inhibitor everolimus is safe within the first
month after liver transplantation
Indhira Perez Medrano1, Manuel Rodríguez-Perálvarez1,2, Marta
Guerrero Misas1, Mercedes Muñoz Nuñez1, Víctor M. González
Cosano1, María Muñoz Garcia-Borruel1, Antonio Poyato1,2, Pilar
Barrera Baena1,2, Enrique Fraga Rivas1,2, Gustavo Ferrín1,2, Gua-
dalupe Costan Rodero1,2, Juan Carlos Pozo Laderas1,2, Marina
Sánchez Frías1,2, Ruben Ciria1,2, Javier Briceño1,2, Jose Luis Mon-
tero1,2, Manuel De la Mata1,2; 1Department of Hepatology and
Liver Transplantation, Reina Sofía University Hospital., Córdoba.,
Spain; 2Maimónides Institute of Biomedical Research of Córdoba
(IMIBIC), CIBERehd., Córdoba, Spain
BACKGROUND: Sirolimus should not be started within the first
month after liver transplantation (LT) because of an increased
risk of adverse outcomes. The evidence regarding everolimus is
scarce but the manufacturer’s recommendations transposed the
same warning. We aimed to evaluate the safety of everolimus
started within the first month after LT. METHODS: 187 consec-
473A
utive LT patients at the Reina Sofía University Hospital (2009-
2013) were included. Patients starting everolimus within the first
month after LT were compared with those starting everolimus
thereafter or not receiving this drug. Median follow up was 21
months (IQR 7-36). Kaplan-Meier curves and Log-rank test were
used to evaluate outcome. RESULTS: Everolimus was started
within the first month after LT in 33 patients (17.6%), with a
median interval from LT of 12 days (IQR 8.5-20.5). Twenty-five
patients (13.4%) started everolimus thereafter (median day 90;
IQR=37-365), and 129 patients (69%) did not receive evero-
limus. The incidence of hepatic artery thrombosis was reduced
in patients early treated with everolimus when compared with
the remaining cohort (0% vs 10.6%; p=0.036). Other vascular
complications occurred in 9.1% of patients with early evero-
limus vs 7.3% in the remaining cohort (p=0.72). No wound
healing complications were detected in the early everolimus
group. There were similar rates of incisional hernia (p=0.31),
infections (p=0.15), renal impairment (0.43), and histologi-
cally proven acute cellular rejection (p=0.32) between groups.
Hyperlipidemia rates were increased in the group early treated
with everolimus (42.6% vs 3.6% at 3 years; p=0.018). There
were neither differences in terms of graft loss (12.6% with early
everolimus vs 21.3% with late or no everolimus at 3 years;
p=0.25), nor regarding overall mortality (34.8% with early
everolimus vs 29.1% with late or no everolimus at 3 years;
p=0.88). CONCLUSION: Everolimus proved to be safe within
the first month after LT. Randomized controlled trials implement-
ing de novo everolimus after LT are warranted to confirm our
findings.
Disclosures:
Enrique Fraga Rivas - Speaking and Teaching: Gilead, Janssen, MSD, BMS
The following people have nothing to disclose: Indhira Perez Medrano, Manuel
Rodríguez-Perálvarez, Marta Guerrero Misas, Mercedes Muñoz Nuñez, Víc-
tor M. González Cosano, María Muñoz Garcia-Borruel, Antonio Poyato, Pilar
Barrera Baena, Gustavo Ferrín, Guadalupe Costan Rodero, Juan Carlos Pozo
Laderas, Marina Sánchez Frías, Ruben Ciria, Javier Briceño, Jose Luis Montero,
Manuel De la Mata
562
Magnetic Resonance Cholangiopancreatography is
Significantly Superior to Ultrasound in the Diagnosis of
Biliary Anastomotic Strictures After Liver Transplantation
Anoop Prabhu1, James Park2, Jawad Ahmad1; 1Division of Liver
Diseases, Icahn School of Medicine at Mount Sinai, New York,
NY; 2Division of Gastroenterology, NYU Langone Medical Center,
New York, NY
Introduction: Biliary anastomotic stricture (AS) is a common
complication after liver transplantation (LT). Therapeutic endo-
scopic retrograde cholangiopancreatography (ERCP) is the pre-
ferred management strategy but has potential complications
and the pre-ERCP probability of finding AS should be high. In
addition to laboratory studies, abdominal imaging is typically
required to make a diagnosis of biliary AS. There is highly vari-
able data on the effectiveness of different imaging modalities.
Ultrasound (USS) can be performed at the bedside but is oper-
ator dependent and computerized tomography (CT) and mag-
netic resonance imaging/cholangiopancreatography (MRI/
MRCP) are less operator dependent but more difficult to obtain
quickly and require a degree of patient co-operation. Aim:
To determine the effectiveness of different abdominal imaging
studies in the diagnosis of biliary AS after LT. Methods: Patients
who underwent ERCP demonstrating a biliary AS (defined by
the cholangiographic appearance and improvement in labo-
ratory parameters after stent therapy) at a single center were
included. Imaging tests (USS, CT or MRI/MRCP) in the 30
days prior to the ERCP were noted. A positive imaging study
474A AASLD ABSTRACTS
was defined by the presence of biliary ductal dilation and/
or the presence of biliary AS. Results: A total of 50 patients
were diagnosed with a biliary AS after LT at ERCP. The aver-
age age was 56.7 (+10.4) years and 80% were male. The
average time from LT to ERCP was 332 (+362) days (range
4-1998), although 40% of all strictures were found within 6
months of LT. All except 3 patients underwent abdominal imag-
ing prior to ERCP. Of these 47 patients, 22 underwent USS, 5
underwent CT and 35 underwent MRI/MRCP. Of the patients
with imaging, 41/47 (87%) had a positive test (USS 12/22
(54.5%), CT 4/5 (80%), MRI/MRCP 33/35 (94.3%)). Of the
10 patients who underwent USS with a normal biliary tree, 6
patients underwent an MRI/MRCP and 5/6 were positive, 2
had no further imaging and 1 had a positive CT. Of the 35
patients who underwent MRI/MRCP, 16/35 (45.7%) had bili-
ary dilation, 16/35 (45.7%) had biliary dilation and a biliary
AS, and 1/35 (2.9%) had no biliary dilation but a biliary AS.
Compared to the gold standard of ERCP the positive predictive
value of MRI/MRCP in making a diagnosis of biliary AS was
94.3% compared to 54.5% with USS (p<0.05). Conclusion:
MRI/MRCP is significantly superior to USS in diagnosing bil-
iary AS after LT. The poor positive predictive value of USS
suggests that alternative imaging modalities should be strongly
considered before performing ERCP in this patient population.
Disclosures:
James Park - Consulting: Bayer, BMS, Onyx
The following people have nothing to disclose: Anoop Prabhu, Jawad Ahmad
563
Primary Sclerosing Cholangitis is a Risk Factor for
Developing Intra-abdominal Thrombosis Following Liver
Transplantation
Paul Reynolds, Elnaz Jafarimehr, Xiao Jing Wang, Ram M. Subra-
manian; Emory University, Decatur, GA
Background: Intra-abdominal thrombosis (IAT) is an uncom-
mon event after liver transplantation (LT); however, the associ-
ated complications can be devastating, including mesenteric
ischemia and death. Based on our personal observations of
patients with primary sclerosing cholangitis (PSC) following LT,
we hypothesized that patients with PSC have a higher risk of
developing IAT following LT compared to other etiologies of
liver disease. Method: We performed a retrospective analysis
of patients transplanted at our center between 1987 and 2013,
and compared the following groups: 128 patients with PSC,
and a randomly selected control group of 189 patients with
Hepatitis C (70%) and NASH (30%). Patients with graft cirrho-
sis, post LT HCC, and post LT vascular or biliary interventions
were excluded. Rates of thromboses in the two groups were
compared using the Chi square test. Results: Twelve patients
(9.4%) in the PSC group had intra-abdominal thromboses (7
portal vein (PV), 1 superior mesenteric vein (SMV), 1 splenic
vein, 2 IVC, 1 hepatic artery). In comparison, 3 patients (1.6%)
in the control group developed IAT (2 PV, 1 SMV) (p=0.002).
Similarly, the prevalence of thromboses in all territories except
IAT was higher in those with PSC compared with controls [9
(7.1%) vs. 3 (1.6%), p=0.012]. The prevalence of inflamma-
tory bowel disease in the PSC group was similar between
those with and without IAT [5 (42%) vs. 58 (50%), p=0.76].
In a multivariate analysis, PSC was associated with a 7.2-fold
increased risk of having any form of thrombosis (p=0.003).
Conclusion: Our findings suggest that PSC is a risk factor for
thrombotic complications in the post LT period. Importantly, we
observed a higher prevalence of intraabdominal thromboses in
these patients, which can greatly compromise graft and patient
survival. Further investigation into this association is warranted
HEPATOLOGY, October, 2014
to determine whether anticoagulant therapy or surveillance
imaging is indicated in patients transplanted for PSC.
Disclosures:
The following people have nothing to disclose: Paul Reynolds, Elnaz Jafarimehr,
Xiao Jing Wang, Ram M. Subramanian
564
Prevalence and risk factors of metabolic syndrome after
liver transplantation: a single centre experience
Veronica Pepe1, Giacomo Germani1, Alberto Ferrarese1, Alberto
Zanetto1, Ilaria Bortoluzzi1, Elena Nadal1, Francesco P. Russo1,
Marco Senzolo1, Enrico Gringeri2, Umberto Cillo2, Patrizia Burra1;
1Surgery, Oncology and Gastroenterology, Multivisceral Trans-
plant Unit, Padua, Italy; 2Surgery, Oncology and Gastroenterol-
ogy, Hepatobiliary Surgery and Liver Transplantation Unit, Padua,
Italy
Introduction: Metabolic syndrome (MS) is a frequent condition
after liver transplantation (LT). However, most of the studies
are focused on the early years after LT, and only few data are
available on the long-term prevalence of this condition. Meth-
ods: Patients who underwent LT at Padua Liver Transplant Cen-
tre between January 2000 and March 2013 and who were
followed up at the Multivisceral Transplant Unit (Padova Univer-
sity Hospital) were included in the analysis. Patients <18 years
old, who underwent re-LT, and patients who underwent multi-or-
gan transplant were excluded from the study. MS has been
diagnosed according to the modified NCEP-ATP III criteria,
and only post-LT “de novo” MS has been evaluated. Results:
Overall, 165 patients were included in the analysis (74% male,
mean±SD age at LT 52±8 years). Underlying liver disease was:
HCV in 48.5% of patients, HBV in 11.5%, HBV and HCV in
3%, alcohol in 16.4%, alcohol and virus in 9.1%, and due
to other causes in 10.3%. HCC was diagnosed in 59/165
(35.7%). After a median follow-up time of 6.4 years, preva-
lence of post-LT MS was 87/165 patients (52.7%): 80.5%
male and with a mean±SD age at LT of 53.4±8.8 years. Under-
lying liver disease was HCV in 47% of patients, HBV in 12.6%,
HBV and HCV 2.3%, alcohol in 19.6%, alcohol and virus in
11.5%, and due to other causes in 6.9%. HCC was diagnosed
in 28/87 (32%) patients. Patients with post-LT MS had a sig-
nificantly higher pre-LT BMI (26.2±3.2 vs. 24±3; p<0.001),
and higher prevalence of pre-LT diabetes (22.9% vs. 9.5%;
p=0.039), post-LT hypertension (80.5% vs. 28.2%; p<0.001),
and post-LT diabetes (59.8% vs. 15.4%; p<0.001) compared
with patients without MS. Moreover, patients with post-LT MS
presented hypertriglyceridemia (185.2±92 vs. 110.9±42.3;
p<0.001) and significantly lower levels of HDL (38.8±14 vs.
53.3±16.9; p<0.001) compared with patients without MS.
No differences in terms of liver disease etiology was found
between patients with and without post-transplant MS, as well
as in terms of immunosuppressive regimen (steroid use vs. no
steroid use and cyclosporine-based vs. tacrolimus-based immu-
nosuppression). At the multivariate analysis pre-LT diabetes
(RR 9.16, 95% CI 1.09-76.9; p=0.04) and pre-LT BMI (RR
per 5 unit increase 2.05, 95% CI 1.04-4.03; p=0.003) were
identified as risk factors for post-LT MS. Conclusions: MS is a
condition affecting more than the half of recipients in the long-
term after LT. Pre-LT diabetes and pre-LT increased BMI are risk
factors for the development of post-LT MS. The identification
of patients at risk for post-LT MS is crucial in order to develop
specific medical strategies acting on modifiable risk factors
Disclosures:
Umberto Cillo - Grant/Research Support: Novartis, Bayer, Astellas
The following people have nothing to disclose: Veronica Pepe, Giacomo Ger-
mani, Alberto Ferrarese, Alberto Zanetto, Ilaria Bortoluzzi, Elena Nadal, Fran-
cesco P. Russo, Marco Senzolo, Enrico Gringeri, Patrizia Burra
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
565
20 year followup of liver transplantation for HCV+
patients. Rustgi V, Landsittel D, Humar A, Hughes C,
Malik S, Behari J, Jazwinski A, Chopra K. The Thomas
Starzl Transplant Institute, Univ of Pittsburgh
Vinod K. Rustgi, Doug Landsittel, Abhinav Humar, Christopher B.
Hughes, Shahid M. Malik, Jaideep Behari, Alison Jazwinski, Kapil
B. Chopra; the thomas starzl transplant institute, university of pitts-
burgh medical center, Pittsburgh, PA
Introduction: HCV-related end-stage liver disease is the most
common indication for liver transplantation. Previous studies
have shown poorer outcome in these recipients beyond 5
years. Few studies, however, report on data byeond a 10 year
followup. We report a single-center experience with a 20 year
followup Methods: All patients undergoing liver transplantation
for hepatitis C in the period from 1993 to 2013 (n=789) were
reviewed with respect to immunosuppression, recipient age at
transplant, time to organ failure, time to re-transplant and time
to death as well as genotype. Survival estimates were calcu-
lated using Kaplan-Meier estimates and differences in survival
were tested using the log-rank test Results: The average patient
age was 52.3 (SD=8.55), 44.6% were female adn 93.0%
were Caucasian. Of those with genotype available (n=421),
80.5%, 7.6%, 9.0% and 2.9% were genotype 1, 2, 3 and 4
respectively. The average MELD score at transplant was 20.0
(SD=8.90). Males had a statistically significant better survival
rate than females in the cohort (n=81) between 15 and 20
years of followup. Outcomes did not vary by genotype, age
beyond or below the median of 52 years, MELD scores above
or below the median of 18 CONCLUSION: An examination
of 20 year followup of 789 HCV+ patients undergoing liver
transplantation at a single center shows that just over half of
patients survive up to ten years with 42.4% and 32.9% surviv-
ing 15 and 20 years respectively. All-cause mortality may vary
by gender and deserves further study
Estimates of overall survival at 1-year and in 5-year increments
Disclosures:
Vinod K. Rustgi - Grant/Research Support: Abbvie, BMS, Gilead, Achillion
The following people have nothing to disclose: Doug Landsittel, Abhinav Humar,
Christopher B. Hughes, Shahid M. Malik, Jaideep Behari, Alison Jazwinski, Kapil
B. Chopra
566
Serum aspartate transaminase levels on the third
post-operative day correlate with overall survival and
liver specific survival at 10 years following liver trans-
plantation
Francis P. Robertson1, Paul R. Bessell2, Rafael Diaz-Nieto1, Nancy
Rolando1, Brian R. Davidson1; 1Department of Surgery, University
College London, London, United Kingdom; 2University of Edin-
burgh, Edinburgh, United Kingdom
Background Liver transplantation is now accepted as the treat-
ment of choice for end stage liver failure. Ischaemia reperfusion
(IR) injury remains a significant cause of post-operative mor-
bidity and mortality and post-operative graft dysfunction. Post
operative liver function tests specifically aspartate transaminase
475A
(AST) and alanine transaminase (ALT) are widely accepted to
represent the degree of IR injury to the hepatic parenchyma.
In animal models of interventions to reduce IR injury, reduced
levels of AST and ALT in the serum at 48 hours post-opera-
tively are often the primary end-points. Whether serum trans-
aminases are an accurate indicator of IR injury in human liver
transplantation remains controversial. Our aim was to analyse
AST levels following liver transplantation with long-term overall
graft survival and liver specific graft survival in a large single
centre prospectively collected database. Methods Data was
reviewed for 1272 patients undergoing liver transplantation
between 1988 and 2012. Clinical outcome was reviewed
and their AST level on the third post-operative day was doc-
umented. Overall graft survival was calculated on death from
any cause or re-transplantation within 3 months, 1, 5 and 10
years. Liver specific death and failure (acute and chronic rejec-
tion/primary graft non-function/non-thrombotic infarction/bili-
ary complications) was calculated at 10 years. The AST levels
were log transformed and results were analysed via a Full Cox
proportional hazard model and T-test. Results were corrected
for age, cold ischaemic time and pre-operative creatinine (log
transformed). Results 1272 patients 640M/628F/4 Unspeci-
fied) were identified. 514 records were excluded from the cox
proportional hazard model due to missing creatinine level at
day 30. The mean age at time of transplantation was 47 years
(37-69). The mean AST level on day 3 post operatively was
613IU/L (Range 18-18885). At all time points the mean AST
levels on day 3 were significantly greater in grafts that failed
than those that were still functioning (p<0.001) AST levels on
the third post-operative day were found to significantly cor-
relate with overall graft survival (p=0.001) and liver specific
failure (p<0.001). For every increase in 1 unit of AST at day 3,
the risk of liver specific failure increases by 0.875. Conclusions
This retrospective review from a large single centre prospective
database has shown that levels of AST on the third post-oper-
ative day correlate with long-term clinical outcome following
liver transplantation and would be an adequate outcome mea-
sure of trials aimed at reducing IR injury or improving organ
preservation.
Disclosures:
The following people have nothing to disclose: Francis P. Robertson, Paul R.
Bessell, Rafael Diaz-Nieto, Nancy Rolando, Brian R. Davidson
567
Clinical impact of cholestasis after liver transplantation:
a retrospective cohort study
Constantine J. Karvellas1,2, Filipe S. Cardoso2, Andrew Mason1,
Norman M. Kneteman3, Glenda Meeberg3, Aldo J. Monta-
no-Loza1; 1Hepatology, University of Alberta, Edmonton, AB, Can-
ada; 2Critical Care Medicine, University of Alberta, Edmonton,
AB, Canada; 3Transplantation, University of Alberta, Edmonton,
AB, Canada
Aims: To assess factors associated with cholestasis at 3-months
post-liver transplant (LT) and the impact of cholestasis on sur-
vival along with other covariates. Methods: Retrospective
cohort study of all (n=489) adult patients who underwent LT
at the University of Alberta between 01/2002-12/2012.
Cholestasis was defined as either an alkaline phosphatase
(ALP) level >2 times the upper limit of normal or a combined
elevation of both bilirubin and ALP. Logistic regression was per-
formed to determine independent associations with cholestasis
at 3-months post-LT and Cox survival analysis for independent
associations with overall survival. Results: 115 patients (24%)
had cholestasis at 3-months post-LT. Cholestatic patients were
older (54 vs. 52 years, p=0.004) and more likely to be signifi-
476A AASLD ABSTRACTS
cantly encephalopathic (70% vs. 58%, p=0.017) at the time
of LT. Using multivariable logistic regression, independent fac-
tors associated with cholestasis at 3-months post LT were age
(odds ratio ~ OR 1.03(1.01-1.06), p=0.018) and donor age
(OR 1.02(1.01-1.03), p=0.025), but not MELD at LT (p=0.13).
Median survival after LT was worse in cholestatic patients
(71 vs.102 months, Log Rank p<0.001, see Figure 1). Using
Cox multivariable survival analysis adjusting for covariates
(etiology, MELD, donor factors), age (OR 1.03(1.01-1.06),
p=0.015) and presence of cholestasis at 3 months post-LT (OR
1.47(1.01-2.15), p=0.04) were independently associated with
increased mortality but not MELD at LT (p=0.17) or donor age
(p=0.3). Conclusion: Patients who developed cholestasis at
3-months post-LT had worse survival post-LT after adjusting for
other patient and donor factors. Age was independently asso-
ciated with cholestasis and mortality. Donor age was inde-
pendently associated with cholestasis but not mortality.
Comparison of long-term survival post-LT for patients with
cholestasis (n=115) and controls (n=374); Log Rank < 0.001.
Disclosures:
Constantine J. Karvellas - Grant/Research Support: Merck; Speaking and Teach-
ing: Gambro
The following people have nothing to disclose: Filipe S. Cardoso, Andrew
Mason, Norman M. Kneteman, Glenda Meeberg, Aldo J. Montano-Loza
568
Analytic Morphomics Identifies Predictors of New-Onset
Diabetes After Transplantation
Valerie Vaughn-Sandler1, David C. Cron2,
Michael Terjimanian3,
Zachary Gala3, Stewart C. Wang2, Grace L. Su4, Michael Volk4;
1Internal Medicine, University of Michigan Health System, Ann
Arbor, MI; 2Department of Surgery, University of Michigan Health
System, Ann Arbor, MI; 3Medical School, University of Michigan,
Ann Arbor, MI; 4Division of Gastroenterology, University of Michi-
gan Health System, Ann Arbor, MI
Among liver transplant recipients, development of post-trans-
plant complications such as new-onset diabetes after transplan-
tation (NODAT) is common and highly morbid. Current methods
of predicting patient risk are inaccurate in the pre-transplant
period and therefore implementation of targeted therapies is
difficult. We sought to determine if analytic morphomics using
computed tomography scans obtained could be used to predict
the incidence of NODAT. We analyzed peri-transplant scans
from 216 patients with varying indications for liver transplan-
HEPATOLOGY, October, 2014
tation, among whom 61 (28%) developed NODAT. Combi-
nations of visceral fat, subcutaneous fat and psoas area were
considered in addition to traditional risk factors. On multivari-
ate analysis, subcutaneous fat thickness remained significantly
associated with NODAT (OR=1.43, 95% C.I. 1.00-1.88,
P-0.047). Sub-group analysis showed that patients with later
onset of NODAT had higher visceral fat whereas subcutaneous
fat thickness was more correlated with early onset of NODAT
(using 10 months post-transplant as the cut off). Conclusion:
Analytic morphomics can be used to help assess NODAT risk
in patients undergoing liver transplantation.
Disclosures:
The following people have nothing to disclose: Valerie Vaughn-Sandler, David
C. Cron, Michael Terjimanian, Zachary Gala, Stewart C. Wang, Grace L. Su,
Michael Volk
569
Everolimus treatment start POD 1 in combination with
low dose CNI is safe and effective post liver transplan-
tation
Martina Sterneck2,3, Antonio Galante2, Gesa Pamperin2, Mar-
tina Koch1, Jun Li1, Lutz Fischer1, Bjoern Nashan1; 1Department
of Hepatobiliary Surgery and Visceral Transplantation, Univer-
sity Medical Center Hamburg Eppendorf, Hamburg, Germany;
2Department of Medicine, University Medical Center Hamburg
Eppendorf, Hamburg, Germany; 3Transplant Outpatient Clinic,
University Medical Center Hamburg Eppendorf, Hamburg, Ger-
many
Introduction: Most transplant centers do not use Everolimus
directly post orthotopic liver transplantation (OLT) due to a
potentially increased risk for hepatic artery thrombosis and
impaired wound healing. In this retrospective analysis we
report our experience with EVR treatment initiated during the
first three post operative days after OLT. Methods: 33 adult
de novo OLT recipients were included in the analysis. Results:
All patients (mean age 54, 25 male, mean lab-MELD 16.5)
recieved initially a combination therapy of EVR with very-low
dose CSA (81.8%) or tacrolimus (18.2%). EVR treatment was
started on post op day 1, 2 and 3 in 23, 8 and 2 patients,
respectively. The EVR, CSA and TAC doses were adjusted to
aim at a trough target level between 3-8 ng/ml, 50-80 ng/ml
and 3-5 ng/ml, respectively. Other concommittant initial immu-
nosuppressive therapy included basiliximab in 13 patients
(39.4%), and prednisolone in all patients. Mean follow-up was
883 days. Indications for early treatment with EVR were renal
dysfunction (39.4%), prophylaxis for recurrent HCC 36.4%),
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
neurological problems (6%), other preexisting malignancies
(3%) or combined OLT/kidney transplantation (15%). During
follow-up CNI was stopped in 4/33 patients (12.1%). Alto-
gether only 2/33 patients (6%) experienced a mild episode
of BPAR (BANF score 4 and 5) 20 and 80 weeks post OLT.
Both patients responded well to steroids. No patient required a
retransplantation. No patient developed hepatic artery throm-
bosis. Impaired wound healing was an uncommon complica-
tion (9%). The 1- and 2- year patient survival rate was 90.9%
and 81.8%, respectively. HCC recurred in 2/12 patients. Post-
operatively 8/27 (29.6%) OLT recipients not undergoing kid-
ney transplantation required dialysis. At last follow-up only 1
of these patients had terminal renal insufficiency. In 8 (24.2%)
patients EVR treatment was stopped after a mean treatment
duration of 311.5 days for hematological side effects (9%),
infections (6%), dermatological side effects (6%), polyarthral-
gia (3%). Other side effects included hypercholesterolemia
(51.5%), anemia (12.1%), leukopenia (6%), edema (3%),
proteinuria (9%). During follow-up incisional hernias occurred
frequently (45.4%), but rarely required surgical repair (21.2%).
Conclusion: Everolimus treatment start directly post operative in
combination with very low-dose CNI is effective and safe post
OLT resulting in a low rejection rate.
Disclosures:
Martina Koch - Grant/Research Support: Novartis
Lutz Fischer - Advisory Committees or Review Panels: Novartis, Gilead; Grant/
Research Support: Astellas; Speaking and Teaching: Novartis
Bjoern Nashan - Advisory Committees or Review Panels: Novartis, Bristol-Myer
Squibb; Speaking and Teaching: Novartis, Bristol-Myer Squibb
The following people have nothing to disclose: Martina Sterneck, Antonio
Galante, Gesa Pamperin, Jun Li
570
Non-adherence related mortality in adolescents and
young people after Liver transplantation
Marianne Samyn, Nigel Heaton, Michael A. Heneghan, Anil Dha-
wan; Institute of liver studies, King’s College Hospital, London,
United Kingdom
Introduction: Young people with liver disease, aged 12-25
years, are a unique population that requires special attention
with respect to adherence to treatment and their subsequent
transition to adult services. Reports on long-term survival fol-
lowing liver transplantation (LT) show decreased patient and
graft survival in young adults with non-adherence (NA) as one
of the main contributory factors. Aim: The aim of our study
was to retrospectively describe a cohort of patients from the
paediatric liver service at King’s College Hospital who died
aged 12 years and over between 1984-2014. Results: On
our database of 16,525 patients, 629 died, of which 120
(19%) (58 male) were 12 years or older (median 16.5 yrs
(range 12-30 yrs)). A primary liver etiology was found in 62%
with biliary atresia (17), malignant liver tumours (17), autoim-
mune liver disease (AILD) (11) and cystic fibrosis (11) as the
most common conditions. 17 patients presented with fulminant
liver failure requiring urgent listing and LT. Overall 52 patients
(43%) underwent LT at a median age of 12.6 yrs (range 0.6-20
yrs), 18 (35%) required re-transplantation (re-LT) and 11 were
re-listed (2 after re-LT) (table). Median time between LT and
re-LT was 10.7 yrs (0-20.8 yrs). For 27 LTs performed between
1984-95, the incidence of re-LT was 54% and re-listing for LT
19% compared to 16% and 24% respectively for 25 patients
transplanted between 1996-2011. A further 9 patients were
listed for primary LT and 2 were assessed but not activated
(table). Median survival following listing was 2.2 mths (range
0.1-17.3 mths). NA was documented in 16 patients (9 male)
of which 14 LT patients (27%) and in the following conditions:
477A
biliary atresia (7/17), Wilson disease (4/7), autoimmune liver
disease (2/11), FIC disease (2/3) and Crigler Najjar type 1
(1/2). NA was more prevalent in patients who underwent re-LT
and who were re-listed (table). Fifty-six patients were recorded
to have died in hospital. 77% were admitted to a paediatric
or adult liver intensive care unit of which 16 were listed for LT.
Eight patients, 2 listed for LT, died unexpectedly at home. Con-
clusion: NA appears to be an important factor affecting graft
and patient survival in young people with liver disease and is
more common in patients who require re-LT or re-listing for LT.
Median survival on the waiting list is short with 80% of listed
patients dying in an intensive care setting.
Disclosures:
Nigel Heaton - Advisory Committees or Review Panels: Novartis, Roche; Speak-
ing and Teaching: Astellas
Michael A. Heneghan - Speaking and Teaching: Falk
The following people have nothing to disclose: Marianne Samyn, Anil Dhawan
571
Model to Predict Long-term Survival after Liver Trans-
plantation
Giuliano Testa, Giovanna Saracino, James F. Trotter, Greg J.
McKenna, Richard Ruiz, Nicholas Onaca, Tiffany Anthony, Peter
T. Kim, Marlon F. Levy, Robert M. Goldstein, Goran Klintmalm;
Annette C. and Harold C. Simmons Transplant Institute, Baylor
University Medical Center, Dallas, TX
Long-term Survival (LTS) prediction after Liver Transplant (LT) is
important and significantly contributes to LT listing. The literature
describes complications and poor outcome predictors but there
is no established model to predict LTS > 20 yrs. Methods: Long-
term (>20 years) and short-term survivors (< 1 and < 5 years)
were compared. Univariate and multivariate logistic regres-
sions were performed to identify variables associated with LTS.
Stepwise multivariable models were built using these variables.
Variables were organized in categories, each category was
assigned a reference value to create a referent risk factor pro-
file. A scoring system was created, 0 points were given to the
base category, unhealthier risk factors were assigned positive
points. Decision trees (DT) of LTS were created. Results: Of
3424 pts receiving a primary LT from 1984 to 2013, 211 sur-
vived > 20 yrs. LTS associated variables were: pts age 18-40,
MELD <20, no HCC, donor age <40, <5 PRBC transfusion. A
decision tree based on individual risk factor points and one
based on total points are represented in Figure 1 and 2. DT in
Fig 2 shows that 85.6% of pts with < 2 points achieve 20 yrs
survival. For each inner node, the Bonferroni-adjusted p-values
are given. Conclusions: This model allows LTS prediction post
LT. Information provided by the model can be of importance
for pts both during the evaluation and post LT. The model may
represent a support tool in the decision to list pts for LT in view
of maximizing efficiency of scarce donor availability.
478A AASLD ABSTRACTS
Fig 1: DT based on individual risk factor points. Fig 2: DT based
on total points.
Disclosures:
James F. Trotter - Speaking and Teaching: Salix, Novartis
Goran Klintmalm - Advisory Committees or Review Panels: Novartis; Grant/
Research Support: Astellas, Novartis, Opsona, Quark
The following people have nothing to disclose: Giuliano Testa, Giovanna Sara-
cino, Greg J. McKenna, Richard Ruiz, Nicholas Onaca, Tiffany Anthony, Peter T.
Kim, Marlon F. Levy, Robert M. Goldstein
572
Combined Heart and Liver Transplantation: Analysis of
a Single-Center Experience
Abimbola Aderinto1, Maha R. Boktour2, Mina Elnemr3, Andrea M.
Cordero-Reyes3, Jerry Estep3, Sherilyn Gordon Burroughs2, Ashish
Saharia2, Barry Trachtenberg3, Arvind Bhimaraj3, Rafik M. Gho-
brial2, Howard P. Monsour4; 1of Medicine, Methodist Hospital,
Houston, TX; 2of Surgery, Houston Methodist Hospital, Houston,
TX; 3of Cardiology, Houston Methodist Hospital, Houston, TX; 4of
Gastroenterology and Hepatology, Houston Methodist Hospital,
Houston, TX
Background: Combined heart and liver transplantation (CHLT)
is the treatment option for patients with end-stage heart and
liver disease. This is a review of nine patients who underwent
combined heart and liver transplant at a single center. Methods:
We conducted a detailed retrospective examination of nine
patients who underwent simultaneous combined heart and liver
transplantation at our institution from 2004 to 2013. Statistical
analysis was performed using descriptive and Kaplan-Meier
analyses. Results: Eight patients received combined heart and
liver transplantation and one patient received combined heart,
liver and lung transplantation. Mean age was 53.2 + 11.3
years, 8 (78%) were male and 8 (78%) were white. Median
biological MELD score was 13 (range, 6-20), and median BMI
was 27 (range 15-31). Cardiac transplant indications were
ischemic cardiomyopathy in 2 (22%), non-ischemic cardiomy-
opathy in 2 (22%), hemochromatosis in 3 (34%), ATTR-amyloi-
dosis in 1 (11%) and pulmonary hypertension with end stage
right heart failure in 1 (11%). All patients, but one with amyloi-
dosis, had documented cirrhosis on liver biopsy. Eight (88%)
patients had simultaneous heart and liver transplant within the
same operation, while one patient had a heart and lung trans-
HEPATOLOGY, October, 2014
plantation followed by a liver transplantation 24 hours apart.
Observed patient year to date survival rates at 1, 3 and 5
years were 100%, 88% and 88% respectively, compared to
our isolated heart transplant (n=222) at 91.6%, 77.5% and
71.1%. Among the nine patients who underwent CHLT, only
two patients (22%) had one cardiac rejection episode based
on biopsy (ISHLT grade 2R) in the presence of stable cardiac
allograft function, and there were no liver rejection events in all
nine patients. The mean left ventricular ejection fraction (LVEF)
at 1-year follow-up was 63 ± 3%. At 5-year follow-up (n=6),
there was no evidence of cardiac allograft vasculopathy by
direct angiography. Five patients (55.6%) developed acute kid-
ney injury requiring hemodialysis or renal replacement therapy
within 30 days post transplantation. No patient developed end-
stage renal failure at the mean follow up of 59 + 36 months.
Conclusion: With proper patient selection, favorable short and
long-term outcomes can be achieved in patients who receive
combined heart and liver transplantation. Post-transplant acute
kidney injury is not uncommon, however it is not associated
with long-term sequelae. MELD = Model for End-Stage Liver
Disease BMI = Body Mass Index ISHLT = International Society
for Heart and Lung Transplantation
Disclosures:
Jerry Estep - Consulting: Thoratec
The following people have nothing to disclose: Abimbola Aderinto, Maha R.
Boktour, Mina Elnemr, Andrea M. Cordero-Reyes, Sherilyn Gordon Burroughs,
Ashish Saharia, Barry Trachtenberg, Arvind Bhimaraj, Rafik M. Ghobrial, How-
ard P. Monsour
573
Clinical and prognostic relevance of albumin dimers in
patients with cirrhosis: a novel identified structural alter-
ation of the molecule
Maurizio Baldassarre1,2, Marco Domenicali1,2, Ferdinando A.
Giannone1,2, Marina Naldi2,3, Maristella Laggetta1,2, Daniela
Patrono4, Carlo Bertucci3, Mauro Bernardi1,2, Paolo Caraceni1,2;
1Department of Surgical and Medical Sciences, University of Bolo-
gna, Bologna, Italy; 2Center for Applied Biomedical Research
(C.R.B.A.), S.Orsola-Malpighi University Hospital, Bologna, Italy;
3Department of Pharmacology and Biotechnology, University of
Bologna, Bologna, Italy; 4Centralized Laboratory, S.Orsola-Mal-
pighi University Hospital, Bologna, Italy
Background. Beside the regulation of fluid distribution, human
serum albumin (HSA) carries several activities unrelated to its
oncotic power, such as binding, transport and detoxification of
many molecules. In patients with cirrhosis, HSA presents struc-
tural alterations likely affecting its function. It has been recently
reported that in pro-oxidant environments, HSA may undergo
homodimerization through a disulfide bond at the cysteine
34 (Cys-34) residue, the main antioxidant site. Whether HSA
homodimerization occurs also during cirrhosis is unknown.
Aims. This study aimed to assess the extent of HSA dimeriza-
tion in advanced cirrhosis and to evaluate its association with
specific clinical complications and patient survival. Methods.
133 cirrhotic patients hospitalized for an acute clinical compli-
cation and 44 age- and sex-comparable healthy controls were
enrolled. At study inclusion, HSA isoforms, including monomers
and dimers, were identified in peripheral blood samples by
using a HPLC-ESI-MS technique. Each isoform abundance was
expressed as relative amount over all HSA isoforms identified.
Clinical and biochemical parameters were also recorded and
patients were followed up to one year. Results. Among the sev-
eral monomeric isoforms identified, three of them, namely the
N- and C-terminal truncated and the native HSA, were found
to undergo homodimerization with an exact double molecular
weight compared to monomers. Although the three HSA dimers
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
can be detected at a very low level also in healthy controls,
their relative abundance was significantly greater in patients
with cirrhosis. As a result, the amount of the native, unchanged
monomeric HSA isoform was significantly reduced in cirrhotic
patients. All the three HSA dimers positively correlated with the
Child-Pugh and MELD scores, while only the dimeric N-terminal
truncated isoform was associated to the presence of ascites,
renal impairment, and bacterial infection independently of dis-
ease severity. Finally, the dimeric N-terminal truncated and the
native monomeric HSA isoforms were associated with lower
1-year survival. Conclusions. Homodimerization is a novel
described post-transcriptional structural change in patients
with cirrhosis, which correlates with disease severity and is
associated with specific clinical complications and survival.
As it occurs via the inactivation of the Cys-34 residue, homod-
imerization may alter the non-oncotic properties of HSA. Thus,
accumulating evidence indicate that only a proportion of the
circulating molecule maintain a fully active functional capacity,
as witnessed by the significant reduction of the native, mono-
meric HSA isoform.
Disclosures:
Mauro Bernardi - Consulting: CLS Behring GhmB, Baxter Healthcare; Speaking
and Teaching: CLS Behring GhmB, PPTA Europe
Paolo Caraceni - Advisory Committees or Review Panels: GSK; Speaking and
Teaching: Baxter, Kedrion
The following people have nothing to disclose: Maurizio Baldassarre, Marco
Domenicali, Ferdinando A. Giannone, Marina Naldi, Maristella Laggetta, Dan-
iela Patrono, Carlo Bertucci
574
The empirical antibiotic treatment of nosocomial spon-
taneous bacterial peritonitis in patients with decompen-
sated liver cirrhosis: results of a randomized controlled
clinical trial
Salvatore Piano1, Freddy Salinas2, Filippo Morando1, Marta Caval-
lin1, Antonietta Romano1, Silvia Rosi1, Marialuisa Stanco1, Silvano
Fasolato1, Antonietta Sticca1, Marco Senzolo3, Patrizia Burra3,
Enrico Gringeri4, Umberto Cillo4, Angelo Gatta1, Paolo Angeli1,5;
1Department of Medicine DIMED, University of Padova, Padova,
Italy; 2Division of General Medicine, Private Hospital “Giovanni
XXIII”, Monastier di Treviso, Italy; 3Multivisceral Transplant Unit,,
University of Padova, Padova, Italy; 4Unit of Hepatobiliary Sur-
gery and Liver Transpantation, University of Padova, Padova, Italy;
5Department of Medicine DIMED, Unit of Medical Emergencies in
Liver Transplantation, University of Padova, Padova, Italy
Background and aims: Spontaneous bacterial peritonitis (SBP)
is a common and life-threatening complication of liver cirrho-
sis. Third generation cephalosporins are the first line empiri-
cal treatment of SBP. In recent years it has been observed an
increasing rate of SBP due to third generation cephalosporins
resistant bacteria, in particular in nosocomial SBP. Up to now
a broader spectrum antibiotic regimen such as carbapenems
and glicopeptides or lipopeptides have never been compared
to third generation cephalosporins in the treatment of nosoco-
mial SBP. The aim of our study was to compare the efficacy of
meropenem plus daptomycin versus ceftazidime in the treat-
ment of nosocomial SBP. Methods: Consecutive patients with
cirrhosis, ascites and nosocomial SBP were randomized to
receive meropenem (1 g/8 hours) plus daptomycin (6 mg/kg/
day) or ceftazidime (2 g/8 hours) plus albumin in both groups
(1.5 g/kg on day 1 and 1 g/kg on day 3). A diagnostic
paracentesis was performed after 48 h of antibiotic treatment.
A reduction in ascitic fluid neutrophil count to less than 25%
of the pretreatment value and/or isolation of bacteria resistant
to the assigned treatment were considered a treatment failure
and antibiotic therapy was changed accordingly. The primary
479A
outcome was the efficacy of the treatment defined by the resolu-
tion of SBP after 7 days of treatment. Results: 32 patients were
randomized. The combination of meropenem plus daptomycin
was significantly more effective than ceftazidime in the treat-
ment of nosocomial SBP (86.7 vs 25 %; p<0.001). Third gen-
eration cephalosporin resistant bacteria and multidrug resistant
bacteria were isolated in 81.3% and 37.5% of positive cul-
tures, respectively. In the multivariate Cox regression analysis,
ineffective response to first line treatment (hazard ratio=20.6;
p=0.01), development of acute kidney injury during hospi-
talization (hazard ratio=23.2; p=0.01) and baseline mean
arterial pressure (hazard ratio= 0.92; p=0.01) were found
to be independent significant predictors of 90-day transplant
free mortality. The incidence of global adverse events (73.3
vs 81.3%; p= 0.68) and drug related adverse events (20.0 vs
25.0; p= 1.0) were similar between the two groups. Conclu-
sions: The combination of meropenem plus daptomycin is more
effective than ceftazidime in the treatment of hospital acquired
SBP. The effectiveness of the first line treatment is associated
with improved 90 day survival in these patients. ClinicalTrials.
gov Identifier: NCT01455246
Disclosures:
Umberto Cillo - Grant/Research Support: Novartis, Bayer, Astellas
Paolo Angeli - Advisory Committees or Review Panels: Sequana Medical
The following people have nothing to disclose: Salvatore Piano, Freddy Salinas,
Filippo Morando, Marta Cavallin, Antonietta Romano, Silvia Rosi, Marialuisa
Stanco, Silvano Fasolato, Antonietta Sticca, Marco Senzolo, Patrizia Burra,
Enrico Gringeri, Angelo Gatta
575
Determinants and prognostic significance of bacterial
infections occurring in patients with HBV- or HCV-re-
lated compensated cirrhosis. A multicenter prospective
cohort study in 1672 patients (ANRS CO12 CirVir)
Pierre Nahon1, Valérie Bourcier1, Richard Layese2, Nabila Tal-
mat1, Patrick Marcellin3, Dominique Guyader4, Stanislas Pol5,
Dominique G. Larrey6, Victor de Ledinghen7, Denis Ouzan8,
Fabien Zoulim9, Jean Claude Trinchet1, Françoise Roudot-Thora-
val2; 1Hôpital Jean Verdier, Bondy, France; 2Hôpital Henri Mon-
dor, Créteil, France; 3Hôpital Beaujon, Clichy, France; 4CHU
Pontchaillou, Rennes, France; 5Hôpital Cochin, Paris, France;
6Hôpital Saint Eloi, Montpellier, France; 7Hôpital Haut-lévêque,
Pessac, France; 8Institut Arnaud Tzanck, St Laurent du Var, France;
9Hôpital Hôtel Dieu, Lyon, France
Background: The incidence, characteristics and prognostic sig-
nificance of bacterial infections (BI) occurring in the course of
compensated viral cirrhosis are unknown. The aim of the CirVir
cohort was to assess the incidence and predictive factors of
complications in HBV- or HCV-related compensated cirrhosis.
Methods: This study involved 35 French centres. Inclusion cri-
teria were histologically proven HCV- or HBV-related cirrho-
sis, Child-Pugh A, no previous hepatic complication including
HCC. Patients were prospectively screened for HCC. Results: A
total of 1672 patients were consecutively enrolled from March
2006 to June 2012 [mean age 54.9 yrs, males 67.3%; HCV
1323, HBV 318, HCV-HBV co-infection 31]. During a median
follow-up of 43 months, 219 BI occurred in 180 patients
(5-yr cumulative incidence, cumI: 13.6%). Among them, 187
(94.4%) were symptomatic, 19 of which occurred as a septic
shock (8.7%). Main sites of BI were lung (66, 30.6%), urine
(55, 25.5%), skin (24, 11.1%), and peritoneum (SBP) (21,
9.7%) [50 others (23.1%), 3 missing data]. The risk of a first
BI occurrence was higher in HCV than in HBV patients (5-year
cumI: 15.8% vs 5.5%, Log-rank=0.0009). Among 159 HCV
patients who developed BI, 50 (31.6%) were infected while
480A AASLD ABSTRACTS
treated with an interferon-based regimen. HCV patients who
developed a first BI had a higher probability of subsequent
hepatic decompensation (5-yr cumI: 49.3% vs 11.7%, Log-
rank<0.0001) and death (5-yr cumI: 48.3% vs 8.3%, Log-
rank<0.0001). In HBV patients, an episode of BI only impaired
survival (5-yr cumI: 34.8% vs 1.9%, Log-rank<0.0001). In mul-
tivariate analysis, a higher probability of a first BI was associ-
ated with older age, higher AST level, lower prothrombin time
and a past history of hepatic decompensation in HCV patients,
whereas a BMI > 30kg/m2 was the only predictive factor in
HBV patients. Among the 136 patients who died during the
follow-up of the whole cohort, BI represented the third cause
of death (14.0%) after liver failure (20.6%) and primary liver
cancer (PLC, 19.8%). In the whole cohort, a first episode of
BI was selected by the multivariate model as an independent
predictor of death (HR=1.81, P=0.003), along with older age,
alcohol consumption, lower platelet count, a first episode of
liver decompensation and the occurrence of PLC during fol-
low-up. Conclusions: BIs represent critical events in the course
of compensated viral cirrhosis. Their occurrence is associated
with subsequent hepatic decompensation and death, and
thus should be taken into account in decision making process
regarding liver transplantation strategies.
Disclosures:
Pierre Nahon - Speaking and Teaching: BMS, GILEAD
Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen,
MSD, Abbvie, Alios BioPharma, Idenix, Akron; Grant/Research Support: Roche,
Gilead, BMS, Novartis, Janssen, MSD, Alios BioPharma; Speaking and Teach-
ing: Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Boehringer, Pfizer,
Abbvie
Dominique Guyader - Advisory Committees or Review Panels: ROCHE, GILEAD,
IRIS, ABBVIE; Board Membership: MERCK; Grant/Research Support: JANSSEN;
Speaking and Teaching: BMS
Stanislas Pol - Board Membership: Sanofi, Bristol-Myers-Squibb, Boehringer Ingel-
heim, Tibotec Janssen Cilag, Gilead, Glaxo Smith Kline, Roche, MSD, Novartis;
Grant/Research Support: Glaxo Smith Kline, Gilead, Roche, MSD; Speaking and
Teaching: Sanofi, Bristol-Myers-Squibb, Boehringer Ingelheim, Tibotec Janssen
Cilag, Gilead, Glaxo Smith Kline, Roche, MSD, Novartis
Dominique G. Larrey - Board Membership: ROCHE GENE, MSD, TIBOTEC/
JANSSEN, ABBOTT, BOEHRINGER, BMS, GILEAD; Consulting: BAYER, SANOFI,
PFIZER, SERVIER-BIG, AEGERION, MMV, BIAL-QUINTILES, TEVA, ORION, NEG-
MA-LERADS, ASTELLAS; Grant/Research Support: Roche, Boehringer, BMS, GIL-
EAD; Independent Contractor: ABBOTT
Victor de Ledinghen - Advisory Committees or Review Panels: Merck, Janssen,
Gilead, BMS, Abbvie; Grant/Research Support: Gilead, Janssen; Speaking and
Teaching: AbbVie, BMS
Fabien Zoulim - Consulting: BMS, Gilead, Roche; Grant/Research Support: BMS,
Gilead, Roche; Speaking and Teaching: BMS, Gilead
Françoise Roudot-Thoraval - Advisory Committees or Review Panels: Roche; Con-
sulting: LFB biomedicaments; Speaking and Teaching: gilead, Janssen, BMS,
Roche
The following people have nothing to disclose: Valérie Bourcier, Richard Layese,
Nabila Talmat, Denis Ouzan, Jean Claude Trinchet
576
The detection of bacterial DNA by in situ hybridization
method may prove the evidence of bacterial transloca-
tion in patients with decompensated liver cirrhosis
Shingo Usui1,3, Hirotoshi Ebinuma1, Po-sung Chu1, Nobuhito Tan-
iki1, Yuko Wakayama1, Nobuhiro Nakamoto1, Yoshiyuki Yam-
agishi1, Kazuo Sugiyama1, Hidetsugu Saito2,1, Takanori Kanai1;
1Division of Gastroenterology and Hepatology, Keio University,
school of medicine, Tokyo, Japan; 2Keio University, school of phar-
macy, Tokyo, Japan; 3Gastroenterology, National Hospital Orga-
nization Saitama hospital, Wako, Japan
Background and aims: Patients with decompensated cirrhosis
often suffer from various complications such as spontaneous
bacterial peritonitis (SBP). However, it is difficult to diagnose
SBP or bacteremia because bacteria in ascites or blood cannot
HEPATOLOGY, October, 2014
be detected accurately by conventional culture. It has been
showed that the method using in situ hybridization (ISH) for
detecting the gene of bacteria phagocytized by neutrophil
in ascites is possibly useful to diagnose SBP within one day
(Enomoto et al. J Hepatology 2012). It is thought that SBP is
developed following bacteremia after bacterial translocation
in the intestinal tract. Therefore we used the ISH method for
blood samples taken from patients with decompensated liver
cirrhosis and considered the significance of bacterial detec-
tion. Methods: Sixty peripheral blood samples were collected
from patients with ascites and were examined for bacteria
using both conventional blood culture and ISH method simul-
taneously. Thirty-five patients also underwent paracentesis of
ascites to search for SBP. The ISH method we used was the
kit provided by Fuso Pharmaceuticals (Tokyo, Japan). Results:
Thirty-seven of 60 blood samples (61.7%) showed a positive
result in using the ISH test while only 6 samples (10.0%) were
positive in using the blood bottle culture method (p<0.01). The
difference of detection ratio depended on the presence of fever
and more than 1 mg/dl of CRP level in the patients. No patient
had a positive blood culture and a negative ISH method. The
bacteria in the 37 samples detected by the ISH method were
30 samples of E. coli group (81.1%), 6 of E. faecalis (16.2%),
and 4 of P. aeruginosa (10.8%) with multiple identification
in a single sample. Eight of 35 patients were diagnosed with
SBP. Six of the 8 patients showed positive results using the
ISH method while bacteria were detected in only one case
by blood culture. Conclusion: The ISH method resulted in a
higher positive rate of bacterial detection than blood culture
in patients with decompensated cirrhosis. These results might
show that bacterial translocation which cannot be proved by
conventional culture occurs. Once patients with decompen-
sated cirrhosis are affected with infection such as SBP or bacte-
remia, they are thought to have poor prognosis. So it would be
better that these patients with the positive ISH method should
be treated soon. In patients with decompensated cirrhosis, the
ISH method can be helpful for rapid diagnosis and prevention
from bacteremia and SBP.
Disclosures:
The following people have nothing to disclose: Shingo Usui, Hirotoshi Ebinuma,
Po-sung Chu, Nobuhito Taniki, Yuko Wakayama, Nobuhiro Nakamoto, Yoshi-
yuki Yamagishi, Kazuo Sugiyama, Hidetsugu Saito, Takanori Kanai
577
‘Eastern type’ of Acute-on-chronic Liver Failure (ACLF) is
similar in pathophysiologic, diagnostic and prognostic
criteria to the ‘Western type’: A comparison of Chinese
hospitalized patients with Hepatitis B with CANONIC
data
Hai Li1, Marco Pavesi2, Bo Zeng1, Liu-Ying Chen1, Shu-Ting Li1,
De-Kai Qiu1, Richard Moreau3, Pere Gines4, Vicente Arroyo5,
Rajiv Jalan6; 1Dept. of Gastroenterology, Ren Ji Hospital, School
of Medicine, Shanghai Jiao Tong University; Shanghai Institute of
Digestive Disease, Shanghai, China; 2Data Management Center,,
EASL-CLIF Consortium, Barcelona, Spain; 3Hopital Beaujon, Cli-
chy, France; 4Hospital Clínic, Barcelona, Spain; 5EASL-CLIF Con-
sortium, Barcelona, Spain; 6Liver Failure Group, Institute for Liver
and Digestive Health, UCL, London, United Kingdom
The diagnostic criteria for ACLF were described from data
of1353 European patients (CANONIC study;Gastroenterology
2013). Two main observations of the study were that the CLIF-
SOFA score could be used to diagnose ACLF and classify its
severity and, inflammation was important in its pathogenesis.
Much debate in the literature has suggested that the ‘Eastern
type’ of ACLF, where the main underlying cause of liver dis-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
ease is Hepatitis B may not have the same pathophysiologic
characteristics and therefore requires different diagnostic and
prognostic criteria. The aim of this study was to validate the
CLIF-SOFA score to diagnose and classify ACLF and, determine
whether inflammation played a role in the pathogenesis of
ACLF in a population of patients in a single center in Shanghai,
China with HBV infection. METHODS: 890 consecutive hospi-
talized HBV-related chronic liver disease patients with acute
decompensation from 2005-2010 were included. Among them
243 (27%) patients underwent liver transplantation (LT). Pre-
disposition (cirrhosis), acute insult, inflammatory parameters
(leukocyte count), CLIF-SOFA score and short-term mortality
were used to evaluate the population. RESULTS: According to
the CLIF-SOFA score, 24% (211/890) patients had ACLF at
enrollment and 7% (62/890) developed ACLF within 28-days.
Their 28 and 90-day mortality were 41%, 37% and 46%,
45% respectively. 20%, 53% and 27% patients had ACLF-1,
ACLF-2 or ACLF-3. The 28 and 90-day mortality were 24% and
31%; 40% and 44%; 53% and 61% respectively. Non-ACLF
patients (69%; 617/890) had a 28 and 90-day mortality of
3% and 6% respectively (P<0.001 vs ACLF). ACLF patients had
a significantly higher white cell (10±6*109 vs 5±4*109/L;
P<0.001) compared with non-ACLF patients. No precipitat-
ing event was identifiable in 62% (130/211) ACLF and 45%
(305/679) non-ACLF patients. Both HBV reactivation (30%)
and bacterial infection (30%) were the most frequent acute
insult for precipitating events identifiable ACLF patients. CON-
CLUSION: The results confirm that the clinical characteristics of
ACLF patients in China, where the main cause is HBV infection
is similar to the clinical characteristics of European patients
where the main etiology is alcohol. CLIF-SOFA score allows
classification of ACLF into different prognostic groups; precipi-
tating factor is not necessary; infection is an important precipi-
tating factor and systemic inflammation is pathophysiologically
important. The data argue strongly that the ‘Eastern’ form of
ACLF follows similar diagnostic, prognostic and pathophysio-
logical characteristics to that of the ‘Western’ form suggesting
that the definition of ACLF should be harmonized world-wide.
Disclosures:
Pere Gines - Advisory Committees or Review Panels: Ferring ; Grant/Research
Support: Sequana Medical, Grifols
Vicente Arroyo - Speaking and Teaching: GRIFOLS
Rajiv Jalan - Consulting: Ocera Therapeutics, Conatus; Grant/Research Support:
Grifols, Gambro
The following people have nothing to disclose: Hai Li, Marco Pavesi, Bo Zeng,
Liu-Ying Chen, Shu-Ting Li, De-Kai Qiu, Richard Moreau
481A
578
Utility Of A Modified PIRO (Predisposition, Injury,
Response, Organ Failure) Model For Predicting Kidney
Failure In Patients With ACLF- A Multinational Cohort
Study
Rakhi Maiwall1, Shiv K. Sarin1, Chandan K. Kedarisetty1, Rich-
ard Moreau28,14, Suman Kumar29, Zaigham Abbas5, Deepak
N. Amarapurkar6, Ankit Bhardwaj2, Ajeet S. Bhadoria2, Chha-
gan Bihari3, Amna S. Butt7, Chan Albert8, Yogesh K. Chawla10,
Abdulkadir Dokmeci11, Hasmik Ghazinyan12, Saeed S. Hamid7,
Cho Mong13, George K. Lau15, Guan Huei Lee16, Laurentius A.
Lesmana17, Mamun A. Mahtab18, Qin Ning19, Viniyendra Pame-
cha4, Diana A. Payawal20, Archana Rastogi3, Salimur Rahman18,
Mohamed Rela21, Amrish Sahney1, Vivek A. Saraswat22, Samir
R. Shah23, Gamal Shiha24, Barjesh C. Sharma25, Manoj Kumar1,
Soek Siam Tan26, Chitranshu Vashishtha1, Ashok Choudhary1,
Man Fung Yuen9, Osamu Yokosuka27; 1Hepatology, ILBS, New
Delhi, India; 2Rsearch, ILBS, New Delhi, India; 3Pathology, ILBS,
New Delhi, India; 4Hepatobiliary Surgery, ILBS, New Delhi, India;
5Sindh Institute of Urology and transplantation, Karachi, Paki-
stan; 6Department of Gastroenterology and Hepatology, Bombay
Hospital and Medical Research, New Delhi, India; 7Department
of Medicine, Aga Khan University Hospital, Karachi, Pakistan;
8Department of Surgery, The University of Hong Kong, Hong Kong,
Chile; 9Department of Medicine, The University of Hong Kong,
Hong Kong, China; 10Department of Hepatology, Post Graduate
Institute of Medical Education and Research, Chandigarh, India;
11Department of Gastroenterology, Ankara University School of
Medicine, Ankara, Turkey; 12Department of Hepatology, Nork
Clinical Hospital of Infectious Diseases, Yerevan, Armenia; 13Hal-
lym University Chuncheon Sacred Heart Hospital, Gangwon-Do,
Republic of Korea; 14Liver Unit, Beaujon hospital, Paris, France;
15Department of Hepatology, Beijing 302 Hospital, Beijing,
China; 16National University Health system, Singapore, Singa-
pore; 17University of Indonesia, Jakarta, Indonesia; 18Department
of Hepatology, Bangabandhu Sheikh Mujib Medical university,
Dhaka, Bangladesh; 19Department of Infectious Disease, Tongji
Hospital of Tongji Medical College, Wuhan, China; 20Department
of Hepatology, Cardinal Santos Medical center, Manila, Philip-
pines; 21Institute of Liver diseases and Transplantation, Global
Health city, Chennai, India; 22Department of Gastroenterology,
Sanjay Gandhi Post Graduate Institute of Medical Sciences, Luc-
know, India; 23Department of Gastroenterology and Hepatol-
ogy, Global Hospitals, Mumbai, India; 24Department of Internal
Medicine, Egyptian Liver Research Institute and Hospital, Cairo,
Egypt; 25Department of Gastroenterology, GB Pant Hospital, New
Delhi, India; 26Department of Gastroenterology and Hepatology,
Selayang Hospital, Kuala Lumpur, Malaysia; 27Department of
Gastroenterology and Nephrology, Graduate School of Medicine,
Chiba, Japan; 28Center for Research in Inflammation (CRI), Inserm
and Paris Diderot University, Paris, France; 29Command Hospital,
Kolkata, India
Background and Aim: Kidney dysfunction is an ominous sign
in ACLF patients. There is however, limited data on predic-
tors of kidney dysfunction in ACLF. The PIRO classification
was developed to stratify patients with sepsis with different
outcomes. We developed a modified PIRO model (Predispo-
sition,Injury,Response,Organ failure) to identify variables for
predicting kidney failure in a multicentric, multinational cohort
of ACLF patients(APASL definition). Patients and Methods:
Prospectively collected data from 17 Asian countries using
the APASL ACLF Research Consortium (AARC) database was
analyzed and logistic regression models were developed to
assess the best set of covariates for each of the components
of PIRO and a combined PIRO model for predicting kidney
failure in patients with ACLF. Kidney failure was defined as an
482A AASLD ABSTRACTS
increase of serum creatinine ≥ 2 mg/dl or requirement of renal
replacement therapy. Factors considered for univariate analy-
sis for Predisposition included patient demographics, severity
and etiology of underlying liver disease, baseline biochem-
ical parameters, presence of ascites,comorbidities including
chronic kidney disease; for Injury- diuretic use, nephrotoxicity,
bacterial infections, variceal bleed; for Response-components
of systemic inflammatory response syndrome and for Organ
failure-extrarenal organ failures i.e. cerebral, circulatory and
respiratory defined according to CLIF-SOFA score. Results: Of
1365 patients with ACLF (age 44 ±12.9 years, 83% males)
with MELD score of 32.6 ± 9.4, 29% developed kidney failure.
Factors significant (p,OR, 95% CI) on multivariate analysis for
P component were high baseline MELD (≥30) (<0.001, 1.72,
1.34-2.2) and low serum sodium (<130mEq/l) (0.002, 1.4,
1.14-1.9); for I component, bacterial infections (0.02, 1.4,
1.04-1.96); for R component, leucocytosis (0.03, 1.3, 1.02-
1.71); for O component, circulatory failure (<0.0001, 4.6,
3.2-6.7) and cerebral failure (<0.001,2.7, 2.1-3.6). The com-
bination of these four components into a single-value predictor
of kidney failure in the combined PIRO model identified circu-
latory failure (OR 5.8, 95% CI 3.1-11.1) and cerebral failure
(OR 2.1, 95% CI 1.2-3.7) as the most significant predictors.
Amongst all organ failures, presence of circulatory failure at
baseline was the most significant predictor of mortality (OR
1.8, 95% CI 1.1-3.3). Conclusions: The PIRO model could
be a novel approach to identify and stratify ACLF patients at
risk of kidney failure. Kidney failure is commonly associated
with presence of extra-renal organ failures at baseline amongst
which circulatory failure predicts mortality independent of both
renal and other organ failures.
Disclosures:
George K. Lau - Consulting: Roche, Novartis, Roche, Novartis, Roche, Novartis,
Roche, Novartis
Qin Ning - Advisory Committees or Review Panels: ROCHE, NOVARTIS, BMS,
MSD, GSK; Consulting: ROCHE, NOVARTIS, BMS, MSD, GSK; Grant/Research
Support: ROCHE, NOVARTIS, BMS; Speaking and Teaching: ROCHE, NOVAR-
TIS, BMS, MSD, GSK
Diana A. Payawal - Advisory Committees or Review Panels: United Laboratories;
Consulting: Takeda Pharmaceutical; Speaking and Teaching: Fatima Medical
University Hospital
Soek Siam Tan - Advisory Committees or Review Panels: Abbvie
Osamu Yokosuka - Grant/Research Support: Chugai, Taiho, Bristol Myers
The following people have nothing to disclose: Rakhi Maiwall, Shiv K. Sarin,
Chandan K. Kedarisetty, Richard Moreau, Suman Kumar, Zaigham Abbas,
Deepak N. Amarapurkar, Ankit Bhardwaj, Ajeet S. Bhadoria, Chhagan Bihari,
Amna S. Butt, Chan Albert, Yogesh K. Chawla, Abdulkadir Dokmeci, Hasmik
Ghazinyan, Saeed S. Hamid, Cho Mong, Guan Huei Lee, Laurentius A. Les-
mana, Mamun A. Mahtab, Viniyendra Pamecha, Archana Rastogi, Salimur
Rahman, Mohamed Rela, Amrish Sahney, Vivek A. Saraswat, Samir R. Shah,
Gamal Shiha, Barjesh C. Sharma, Manoj Kumar, Chitranshu Vashishtha, Ashok
Choudhary, Man Fung Yuen
579
Gene-specific control of inflammation during lipopoly-
saccharide tolerance is altered in immune cells from
patients with advanced cirrhosis
Mikhael Giabicani 1, Emmanuel Weiss 1,3, Pierre-Emmanuel
Rautou2, Magali Fasseu1, Catherine Paugam-Burtz1,3, Dominique
Valla2, Francois Durand2, Sophie Lotersztajn1, Richard Moreau1,2;
1UMR_S1149 Center for Research in Inflammation (CRI), Inserm
and Paris Diderot University, Paris, France; 2DHU Unity, Liver unit,
Beaujon hospital, APHP, Clichy, France; 3Anesthesiology and
intensive care, Beaujon hospital, APHP, Clichy, France
Background: Excessive TLR4-mediated innate inflammatory
gene induction by lipopolysaccharide (LPS) may result in col-
lateral tissue damage (i.e., immunopathology) . To limit this
phenomenon, TLR4 induces mechanisms such as tolerance
HEPATOLOGY, October, 2014
aiming to control the inflammatory response. After a first LPS
stimulation, innate immune cells are tolerant to a second LPS
challenge. Tolerant cells are characterized by two categories
of genes: “tolerizable” genes that are transiently silenced and
“non tolerizable” genes that remain inducible at the same or
to a greater level. “Tolerizable” and “non tolerizable” are dif-
ferentially regulated through gene-specific epigenetic mecha-
nisms. In patients with cirrhosis the innate immune response to
a first LPS challenge is known to be altered but the response to
a second challenge has not yet been studied. This work aims
to study the LPS tolerance in peripheral blood mononuclear
cells (PBMCs) from patients with advanced alcoholic cirrhosis.
Patients and Methods: PBMCs from 9 patients (median MELD
score 17 [7.1-29.4]) and 10 healthy subjects have been iso-
lated and cultured for 24 hours with LPS or medium. After 24
hours, PBMCs have been washed and then received or not a
second LPS challenge during 4 hours. RNA was extracted and
the expression of 32 genes known to be involved in the innate
immune response has been studied by RT-qPCR. Results: After
the second LPS stimulation in healthy PBMCs, “tolerizable”
genes included proinflammatory genes (e.g., TNF), anti-inflam-
matory mediators (e.g., IL10, TNFAIP3, IL1RN, NFKBIA) and
interferon stimulated genes (ISGs, e.g., MX2, OAS2, IFIT1,
MOV10); “non tolerizable” genes included proinflammatory
genes (e.g., IL8, CXCL1, CXCL5) and antimicrobial peptide
(e.g., LCN2). “Cirrhotic” cells exhibited an enhanced tolerance
phenomenon: the expression of IL10, TNFAIP3 and LCN2 was
2.5 (p<0.01), 1.5 (p=0.04) and 2 times (p=0.01) lower as
compared to “healthy” cells; the expression of ISGs was also
lower (1.6-6.4 times lower, each p<0.05). Furthermore, the
second stimulation led to a 3 times stronger down-regulation of
IL10 (p<0.01) and an 11 times more pronounced up-regulation
of CXCL5 (p=0.02) in cirrhotic cells. Finally, while LCN2 was a
“non tolerizable” gene in healthy PBMCs, it was “tolerizable”
in cirrhotic PBMCs (p=0.02). Conclusions: Immune cells from
patients with advanced alcoholic cirrhosis exhibit alterations
of the gene-specific control of inflammation and antimicrobial
response during LPS tolerance phenomenon. The enhanced
LPS immune tolerance may explain increased risk of develop-
ing immunopathology and second infections in patients with
cirrhosis.
Disclosures:
Dominique Valla - Advisory Committees or Review Panels: Sequana medical;
Consulting: IRIS; Speaking and Teaching: MSD, Gilead
Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis;
Speaking and Teaching: Gilead
The following people have nothing to disclose: Mikhael Giabicani, Emman-
uel Weiss, Pierre-Emmanuel Rautou, Magali Fasseu, Catherine Paugam-Burtz,
Sophie Lotersztajn, Richard Moreau
580
Systemic Inflammatory Response Syndrome (SIRS) - a
potential clinical marker for early sepsis and survival
in Acute on chronic liver failure (ACLF)
Ashok K. Choudhury, Chitranshu Vashishtha, Chandan K. Kedar-
isetty, Shiv K. Sarin; Hepatology, Institute of Liver and Biliary Sci-
ences New Delhi, India, NEW DELHI, India
Bakground and Aims: Acute on chronic liver failure (ACLF)
is associated with high mortality ~ and sepsis contributes to
the worsening of liver failure. SIRS is an early marker of sep-
sis and ongoing inflammation. We investigated the clinical
profile, dynamicity, predictors, natural history and outcome
in hospitalized ACLF cohort. Patients and Methods: Consecu-
tive patients of ACLF were evaluated for components of SIRS,
development of sepsis and associated complications till liver
transplant, 90 days follow-up or death. The standard medical
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
care was continued as per institute policy and undergone peri-
odic sepsis screening for initial 15 days followed by ‘on suspi-
cion’ screening. Results: All (n=561)ACLF patients underwent
sepsis screening at admission. 360 (64.2%) patients had ≥2
components of SIRS; median age 42 years (IQR 35-54), 88%
male majority being alcoholic hepatitis (55%) with mean CTP
score 12.09 ±1.48 and median MELD 29.6, IOR=24.4-37.6.
At baseline, 33% and 4.5% patients had sepsis and septic
shock respectively. At Day 4 (D4), new onset SIRS occurred in
55.4% and resolution was seen in 44.7% cases. Persistence
of SIRS at D4 (85.2 vs. 50.7%, p=0.05) or D7 (6.4% vs.
39.5%, p=0.05), ≥2 organ failure (CLIF SOFA score) were
associated with high mortality and correlate with persistence
SIRS (p<0.05). Increasing number of organ failure seen with
increasing number of SIRS components (<2 vs. ≥ 2, 39% vs.
73%, p=0.01). Persistence hyperlactemia (median= 2.1 vs.
1.5 mmol/lit) at D4 was independent predictor of mortality (OR
=4, 95% CI 1.6-9.6). Serum procalcitonin >0.5 ng/ml was
associated with SIRS (p=0.05) supporting SIRS as a marker of
early sepsis. The mortality was higher in presence of SIRS at
baseline irrespective of sepsis compared to those without SIRS
(p<0.05). Conclusion: SIRS is an important predictor of early
sepsis, organ failure, survival in ACLF. The dynamic changes
in SIRS, serum lactate on D4 and persistence of SIRS even
irrespective of overt sepsis were associated with high mortality.
Onset of SIRS may be a clue for early or occult sepsis and
prompt use of prophylactic antibiotics is highly recommended.
Mortality in ACLF
Presence of SIRS irrespective of sepsis associated with high mor-
tality compared to those have no SIRS(p<0.05). Overall mortality
in SIRS or sepsis is equal.
Disclosures:
The following people have nothing to disclose: Ashok K. Choudhury, Chitranshu
Vashishtha, Chandan K. Kedarisetty, Shiv K. Sarin
581
Genetic polymorphism of mannose binding lectin 2: a
potential new risk factor for spontaneous bacterial peri-
tonitis in cirrhotic patients
Cornelius Engelmann, Janett Fischer, Sandra Krohn, Adam Her-
ber, Albrecht Boehlig, Danilo Deichsel, Stephan Boehm, Thomas
Berg; Gastroenterology/Hepatology, University Hospital Leipzig,
Leipzig, Germany
Background: Patients with liver cirrhosis are at high risk for
infectious complications, mainly appearing as spontaneous
bacterial peritonitis (SBP). As its impact on survival is consider-
able, reliable risk factors facilitating the early diagnosis need
to be established. Several genetic polymorphisms of pattern
recognition receptors such as Toll-like receptor (TLR)-subclasses
and nucleotide-binding oligomerization domain-containing pro-
tein 2 (NOD2) have been proven to independently increase the
risk for SBP. Variants of mannose binding lectin 2 (MBL2), that
is a soluble complement associated receptor, has been linked
to the susceptibility to infections. We therefore investigated the
association of receptor polymorphisms with the occurrence of
SBP in a single center cohort. Methods Ascites sample (AS)
collection was performed in the line of clinically indicated
paracentesis for therapeutic or diagnostic reasons. If multiple
483A
interventions were performed only the first paracentesis was
chosen for analysis. A leukocyte count of >500/mm3 in AS
was defined as SBP. Bacterial DNA (bactDNA) was detected
by using 16S rRNA gene based PCR methods. Genetic poly-
morphisms (SNP) of receptors such as TLR (subtypes 1,2,4,6),
CD14, NOD2 and MBL2 were identified by detecting and
amplifying corresponding genes. Data were correlated with
clinical and laboratory results. Results: 173 AS of cirrhotic
patients (ASH 72.8%, NASH 8.1 %, viral 2.3%, others 16.2%)
were collected between 02/2011 and 12/2012. Median
MELD was 16.05 (SBP 16.12, no SBP 15.95, p=0.296). In
total 13.3% (n=23) of patients had a SBP. The bilirubin-level
(58.09 ± 62.4 vs. 112.74±149.74, p=0.034) and the CrP-
level (32.15±30.84 vs. 50.74±36.83, p=0.019) was sig-
nificantly increased if infection occurred in ascites. BactDNA
could be detected in both, nonleukocytic AS (38.7%, median
707 copies/ml) as well as leukocytic AS (47.6% (p=0.439),
median 11950 copies/ml (p=0.006)). In contrast only 13% of
AS were positive using conventional culture techniques. SNPs of
TLR-subclasses, CD14 and NOD2 showed no association with
the occurrence of SBP in AS. But variants of two MBL2-SNPs
increased the risk for infections in ascites, rs11003125 C/G
(GG n=65, 7.7% SBP; CG/CC n=92, 18.5% SBP; p=0.058;
OR 2.7 for C allel) and rs5030737 C/T (CC n=136, 11.8%
SBP; CT/TT n=21, 28.6 % SBP; p=0.040; OR 3.0 for T allel)
but not for bactDNA detection. Conclusion: Mannose binding
lectin 2 is a soluble pattern recognition receptor of the com-
plement system that might resemble a new genetic risk factor
for infectious complications like SBP in cirrhotic patients. This
marker needs to be evaluated in a large prospective cohort.
Disclosures:
Sandra Krohn - Grant/Research Support: Pfizer
Thomas Berg - Advisory Committees or Review Panels: Gilead, BMS, Roche,
Tibotec, Vertex, Jannsen, Novartis, Abbott, Merck; Consulting: Gilead, BMS,
Roche, Tibotec; Vertex, Janssen; Grant/Research Support: Gilead, BMS, Roche,
Tibotec; Vertex, Jannssen, Merck/MSD, Boehringer Ingelheim, Novartis; Speak-
ing and Teaching: Gilead, BMS, Roche, Tibotec; Vertex, Janssen, Merck/MSD,
Novartis, Merck, Bayer
The following people have nothing to disclose: Cornelius Engelmann, Janett
Fischer, Adam Herber, Albrecht Boehlig, Danilo Deichsel, Stephan Boehm
582
Overexpression Of The Genetic Effector Pathway Of
Inflammasome In Peripheral Blood Mononucleated Cells
(Pbmc) Of Patients With Acute On Chronic Liver Failure
Elisabetta Gola1, Alessandra Brocca1, Salvatore Piano1, Antoni-
etta Sticca1, Filippo Morando1, Silvia Rosi1, Marta Cavallin1, Mari-
aluisa Stanco1, Antonietta Romano1, Silvano Fasolato1, Angelo
Gatta1, Paolo Angeli1,2; 1Department of Medicine DIMED, Univer-
sity of Padova, Padova, Italy; 2Department of Medicine DIMED,
Unit of Medical Emergencies in Liver Transplantation, University of
Padova, Padova, Italy
BACKGROUND AND AIMS Acute on chronic liver failure
(ACLF) is a severe complication of cirrhosis characterized by
organs failure and high short-term mortality. Inflammation may
be relevant in the pathophysiology and prognosis of ACLF but
the evidence of inflammation in patients with ACLF are rough
and its potential mechanism not studied yet. Inflammasome is
a multi-complex protein involved in the inflammatory immune
response. We aimed to investigate the expression of genetic
effector pathway of inflammasome in PBMCs of patients with
ACLF and its prognostic relevance. METHODS Seventy-two con-
secutive patients hospitalized for an acute decompensation of
cirrhosis were included in the study and followed prospectively
(group 1). Fifteen outpatients with uncomplicated cirrhosis were
also included (group 2). Clinical, laboratory data and blood
484A AASLD ABSTRACTS
sample were collected at the admission in patients of group 1
and during a scheduled visit in those of group 2. Plasma levels
of TNF-α, IL-6 were assessed by ELISA. Gene expression levels
of NF-kB, Caspase-3, Caspase-1, TNF-α and IL-1β in peripheral
blood mononucleated cells (PBMCs) was assessed by means of
real time PCR. RESULTS. ACLF was diagnosed in 21 (29.2%)
of patients in group 1. Patients with ACLF showed higher
MELD score (26.5vs14; p<0.01) and CTP (11vs10; p<0.05).
The plasma levels of TNF-α and IL-6 were found to be higher
patients in group 1 (25.76 pg,ml and, 30.59 pg/ml) than in
patients in group 2 (2.38 pg,ml and, 5.98 pg/ml, p<0.05 and
p<0.01, respectively). In group 1, the plasma levels of TNF-α
and IL-6 were found to be significantly higher in patients with
ACLF than in those without ACLF (38.9vs20.2 pg/mL p<0.05;
34.9vs15.4 pg/mL p<0.05, respectively). Gene expression
levels of NF-kB (35.3vs2.2; p<0.03), caspase-3 (29.6vs1.8;
p<0.03), caspase-1 (75.6vs3.3; p<0.05), TNF-α (95.0vs2.8;
p<0.05) e IL-1β (65.1 vs 18; p<0.05) were significantly higher
in PBMCs from ACLF vs no-ACLF patients. In group 1, the mor-
tality rate was significantly higher in patients with ACLF vs
patients without ACLF (77.8vs37.5%; p<0.01). In group 1,
gene expression levels of NF-kB (34.8vs2.2; p<0.01), Casp1
(69.6vs 3.3; p<0.03), Casp3(32.4vs1.9; p<0.005), TNFα
(71.8vs2.8; p<0.01), IL-1β (63.7vs15.6; p<0.03) were higher
in non survivors than in survivors. CONCLUSIONS. Our data
confirm that an excessive inflammation is involved in the patho-
physiology of ACLF in patients admitted to hospital for an acute
decompensation of cirrhosis. An overexpression of the genetic
effector pathway of inflammasome in PBMC is a relevant mech-
anism of the excessive inflammation in patients with ACLF with
a potential negative impact on survival.
Disclosures:
Paolo Angeli - Advisory Committees or Review Panels: Sequana Medical
The following people have nothing to disclose: Elisabetta Gola, Alessandra
Brocca, Salvatore Piano, Antonietta Sticca, Filippo Morando, Silvia Rosi, Marta
Cavallin, Marialuisa Stanco, Antonietta Romano, Silvano Fasolato, Angelo Gatta
583
CD64 Expression may be a Promising Marker for Early
Diagnosis of Sepsis in Hospitalized Patients with Cirrho-
sis
Sakkarin Chirapongsathorn1, Jody C. Olson3, Stacy C. League2,
Siddharth Singh1, Sarah Jenkins1, Roshini Abraham2, Patrick
Kamath1; 1Gastroenterology and Hepatology, Mayo Clinic, Roch-
ester, MN; 2Cellular and Molecular Immunology, Mayo Clinic,
Rochester, MN; 3Gastroenterology, University of Kansas Medical
Center, Kansas City, KS
Background: Patients with cirrhosis develop infections putting
them at risk for organ failure and mortality. Cultures are posi-
tive in about 50% of patients suspected to have infection. Early
diagnosis and treatment reduces mortality. Neutrophils play
an important role in the innate immune response to infection
through CD 64 which is a receptor on the surface of neu-
trophils. Flow cytometry for immunological markers may be
superior to cultures in diagnosing infection. Since results of flow
cytometry are available well before culture results, the aims of
this study were to determine if infections may be detected using
immunological markers. Methods: In a prospective study, hos-
pitalized cirrhotics were evaluated within 24 hours of admis-
sion. Blood, urine and ascitic fluid cultures were drawn; blood
was also drawn for multiparametric flow cytometry for potential
immunological markers. There were two control groups: unin-
fected outpatients with compensated cirrhosis (n=13 ); and a
group of healthy subjects (n=23). Data were analyzed using
SAS version 9. Results: 19 patients were included; 8 (mean
HEPATOLOGY, October, 2014
age 57.9; 62.5% male (M); MELD 27 ±11; etiology: 50%
NASH; 37.5% alcoholic liver disease (ALD); and other etiol-
ogies) had culture positive infection and 11 patients (mean
age 52.5; 54.5% M; MELD 18±7.etiology: 55% ALD; 27%
viral hepatitis (VH); 9.1% NASH; and other etiologies) had no
infection. The control group of out-patient cirrhotics had mean
age 59.5, 54% M; MELD 14.±6 and etiology 46% ALD; 23%
VH; 23 % PBC and other etiologies. Neutrophil CD64 expres-
sion (molecules per cell) was the most promising immunolog-
ical marker and was significantly higher in septic cirrhotics
than uninfected in-patient cirrhotics, outpatient cirrhotics, and
normal population (4256.5 vs 784.2 vs 677.2 and 453.9,
p value = 0.0002) (Table 1). Conclusions: Cirrhotic patients
with infection had CD64expression >1500/ neutrophils were
infected. Since these results may be obtained within 12 hours
and well before conventional bacterial cultures, neutrophil
CD64 expression may be used for early diagnosis of bacterial
infection.
Disclosures:
The following people have nothing to disclose: Sakkarin Chirapongsathorn, Jody
C. Olson, Stacy C. League, Siddharth Singh, Sarah Jenkins, Roshini Abraham,
Patrick Kamath
584
Improving survival for patients with cirrhosis admitted
to United Kingdom critical care units
Mark J. McPhail1,2, Francesca Parrott3, Julia Wendon1, David A.
Harrison3, Kathy M. Rowan3, William Bernal1; 1Institute of Liver
Studies, King’s College Hospital, London, United Kingdom; 2Hepa-
tology, Imperial College London, London, United Kingdom; 3Inten-
sive Care National Audit and Research Centre, London, United
Kingdom
Background and aims Survival rates for patients admitted to
general intensive care units (ICUs) have improved significantly
over the last two decades with an expectation that the majority
will now survive to hospital discharge. Patients with cirrho-
sis have had higher mortality rates but any improvements in
survival over recent years have not been quantified . Meth-
ods Patient data from ICUs in England, Wales and Northern
Ireland participating in the United Kingdom Intensive Care
National Audit and Research Centre (ICNARC) Case Mix
Programme (CMP) were interrogated for patients with hepatic
cirrhosis admitted between 1996 and 2012. Data on demo-
graphics, aetiology of cirrhosis (alcohol related liver disease
(ARLD) v non-ARLD), Acute Physiology and Chronic Health
Evaluation (APACHE) II score, critical care unit and hospital
outcome and level of organ support were collected. Results
31,921 patients with cirrhosis were identified in the study
period out of 1,208,336 total ICU admissions (2.6%). 11,090
patients were identified as having alcohol as an aetiological
factor (34%). 183 patients out of a total 14,200 identified ICU
admissions (1.3%) in 1996 had cirrhosis rising to 4,207 out
of 136,351 (3.1%, p<0.001) in 2012. Although coverage
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
in the CMP did increase over this time period, the extrapo-
lated numbers show an increase from 1,050 out of 79,800
(1.3%) to 4750 out of 153,600 (3.1%). The crude critical care
unit mortality of patients with cirrhosis was 45% in 1996 fall-
ing to 31% in 2012 (p<0.001). Crude hospital mortality was
59% in 1996 and fell to 46% in 2012 (p<0.001). Mean (SD)
APACHE II score in 1996 was 19.9(8.7) and was unchanged
at 19.5(7.1) in 2012. For patients with cirrhosis secondary
to alcohol, crude hospital mortality fell from 69% in 1996 to
58% in 2012 (p<0.001). Mean APACHE II score for patients
with ARLD in 2012 was 20.6 (7.0) but lower (19.0 (7.2)) for
patients with a non-ARLD. Patients with ARLD had higher peak
serum creatinine levels during the critical care unit stay (mean
(SD) 161(149) mmol/l v 142(130) mmol/l for non-ARLD in
2012). Conclusion The incidence of cirrhosis in ICU patients
is rising but the survival rates for these patients have improved
significantly during the last two decades. Patients with cirrhosis
secondary to alcohol excess have higher mortality rates which
may be partly explained by higher levels of organ failure sever-
ity (particularly renal dysfunction). Patients with cirrhosis and
organ failure warrant a trial of organ support and prognostic
pessimism is not justified.
Disclosures:
Julia Wendon - Consulting: Pulsion, Excalenz
William Bernal - Consulting: Vital Therapies Inc
The following people have nothing to disclose: Mark J. McPhail, Francesca Par-
rott, David A. Harrison, Kathy M. Rowan
585
The Economic Burden and Mortality of Patients with
Acute on Chronic Liver Failure (ACLF) in the United
States
Alina M. Allen1, W. Ray Kim2, James P. Moriarty3, Nilay Shah4,
Patrick S. Kamath1; 1Gastroenterology and Hepatology, Mayo
Clinic, Rochester, MN; 2Gastroenterology and Hepatology, Stan-
ford University, Stanford, CA; 3Science of Health Care Delivery,
Mayo Clinic, Rochester, MN; 4Health Care Policy and Research,
Mayo Clinic, Rochester, MN
Background: Acute on chronic liver failure (ACLF) in hospi-
talized patients with cirrhosis is associated with multi-system
organ failure and poor prognosis, with estimated mortality
rates as high as 50%. The nationwide prevalence of hospi-
talizations for ACLF in the US and the associated economic
burden are not known. We aim to determine the costs and
in-hospital mortality associated with ACLF in the US. Methods:
The National Inpatient Sample was queried between the years
2007-2011 and rates of hospitalization, mortality and costs
associated with ACLF were analyzed. ACLF was defined as
presence of any of the following diagnosis or tests (ICD-9) in
patients with cirrhosis: sepsis, septic shock, mechanical ven-
tilation, central venous/ arterial pressure monitoring, hepatic
coma, acute kidney failure or hemodialysis. Results: The rates
of hospitalization for cirrhosis and ACLF have increased over
time (figure). In 2011there were 1,065,019 hospitalizations in
the US for cirrhosis, with a total cost of over 20 billion dollars.
ACLF represents 18% of admissions in patients with cirrho-
sis. The mean cost per ACLF hospitalization (as opposed to
charges) is twice as high as that for patients with cirrhosis
without ACLF (approximately $32,000 for ACLF, compared to
$16,000 for cirrhosis without ACLF). While the costs per ACLF
hospitalization have not changed significantly over time, the
number of hospitalizations per patient has increased and the
in-hospital mortality in ACLF has decreased (from 28% in 2007
to 22% in 2011). Of 196,716 ACLF hospital admissions in
2011, 44,198 resulted in deaths. Conclusions: Cirrhosis and
485A
ACLF represent a substantial economic burden in the US. The
hospitalization rates and associated costs are increasing. The
in-hospital mortality rate for ACLF is lower than previously esti-
mated and has decreased, while the cost per hospitalization
has remained unchanged.
Disclosures:
W. Ray Kim - Consulting: Bristol Myers Squibb, Gilead Sciences
Patrick S. Kamath - Advisory Committees or Review Panels: Sequana Medical
The following people have nothing to disclose: Alina M. Allen, James P. Moriarty,
Nilay Shah
586
Mortality risk associated with Acute on Chronic Liver
Failure varies dependent on inciting event: a NACSELD
study
Patrick S. Kamath2, Jacqueline G. O’Leary3, K. Rajender Reddy4,
Florence Wong5, Siddharth Singh2, Michael B. Fallon6, Guada-
lupe Garcia-Tsao7, Scott W. Biggins8, Benedict Maliakkal9, Ram
M. Subramanian10, Heather M. Patton11, Leroy Thacker1, Jasmo-
han S. Bajaj1; 1VCU and McGuire VAMC, Richmond, VA; 2Mayo
clinic, rochester, MN; 3Baylor University Medical Center, Dallas,
TX; 4University of Pennsylvania, Philadelphia, PA; 5University of
Toronto, Toronto, ON, Canada; 6University of Texas, Houston, TX;
7Yale University, New Haven, CT; 8University of Colorado Denver,
Denver, CO; 9University of Rochester, Rochester, NY; 10Emory
University, Atlanta, GA; 11University of California, San Diego, CA
Acute-on-chronic liver failure (ACLF) is characterized by
hepatic and multi-organ failure following a precipitating event
in patients with chronic liver disease. It is uncertain whether
the type of precipitating event determines prognosis. Bacte-
rial infections and surgery are known precipitating events. The
mortality risk with multiple organ failure has been attributed
to the severity of liver disease; inciting event; inflammatory
response; and number of organ failures. Current studies assess-
ing prognosis in ACLF have pooled patients with varied pre-
cipitating events and conclude that liver disease severity and
organ failure are main mortality predictors. . We used a val-
idated model to predict short-term mortality after surgery in
patients with cirrhosis (Gastro 2007;132:1261) to determine
whether the observed mortality in patients with infection-related
ACLF was similar to mortality predicted by the surgery model.
Methods: Using the North American Consortium for Study of
End-stage Liver Disease (NACSELD) database, data from 18
North American centers were collected for survival analysis
of prospectively enrolled cirrhosis patients hospitalized with
an infection. We defined organ failure as shock, grade III/
IV hepatic encephalopathy, need for dialysis or mechanical
ventilation. The model for surgery-related ACLF was used for
infection-related ACLF with: age; MELD;ASA score (catego-
ries 3 or 4 depending on presence/absence of organ failure)
and etiology of cirrhosis (alcoholic/cholestatic versus viral/
486A AASLD ABSTRACTS
other) received identical weights in both models. Mortality pre-
dicted using this model was compared with observed mortal-
ity. Results: We included 366 cirrhotic patients admitted to a
hospital with infection (56y; 58% males, 29% and 25% with
alcoholic and HCV cirrhosis, respectively). Median (IQR) MELD
at admission was 16.5 (10-23); 66% of patients developed at
least 1 organ failure (18%, 7% and 8% with 2, 3 and 4 organ
failures, respectively). Observed 30- and 90-day mortality was
18.6% and 29.2%, respectively. Patients with higher predictive
model scores had higher mortality. However, the surgery model
overestimated mortality in patients at risk for infection-ACLF
(table). Conclusion: The observed 30- and 90-day mortality in
cirrhotic patients with infection–related ACLF is lower than that
predicted for surgery-related ACLFThis suggests that mortality in
ACLF depends not only on severity of liver disease and organ
failure but also on the precipitating event.
Observed ACLF mortality compared to predicted values
Disclosures:
Patrick S. Kamath - Advisory Committees or Review Panels: Sequana Medical
Jacqueline G. O’Leary - Consulting: Gilead, Jansen
K. Rajender Reddy - Advisory Committees or Review Panels: Genentech-Roche,
Merck, Janssen, Vertex, Gilead, BMS, Novartis, Abbvie; Grant/Research Sup-
port: Merck, BMS, Ikaria, Gilead, Janssen, AbbVie
Florence Wong - Consulting: Gore Inc; Grant/Research Support: Grifols
Michael B. Fallon - Grant/Research Support: Bayer/Onyx, Eaisi, Gilead, Grifolis
Jasmohan S. Bajaj - Advisory Committees or Review Panels: Salix, Merz, otsuka,
ocera, grifols, american college of gastroenterology; Grant/Research Support:
salix, otsuka, grifols
The following people have nothing to disclose: Siddharth Singh, Guadalupe Gar-
cia-Tsao, Scott W. Biggins, Benedict Maliakkal, Ram M. Subramanian, Heather
M. Patton, Leroy Thacker
587
The impact of nutritional status on infections in liver cir-
rhosis
Aung Kaung1, Ken D. Nguyen1, Amit Rajaram2, Phillip Zakowski1,
Tram T. Tran1, Vinay Sundaram1; 1Cedars-Sinai Medical Center,
Los Angeles, CA; 2Tuoro Medical School, Henderson, NV
Aims: Infection is associated with high mortality in cirrhosis.
Malnutrition is a known risk factor for infection, but the risk
associated with obesity is unknown. The study aim was to eval-
uate the association between infection and nutritional status in
cirrhotics. Methods: We reviewed the Nationwide Inpatient
Sample, years 2009-2011. Patients under age 18, with HIV,
or post-liver transplant were excluded. Patients and infections
were identified using International Classification of Diseases
9th revision (ICD-9) codes. Subjects were grouped as malnour-
ished, obese, and morbidly obese. Infections evaluated for
included bacteremia, sepsis, cellulitis, urinary tract infection
(UTI), lower respiratory infection (LRI), Clostridium diffiicile
infection (CDI), and spontaneous bacterial peritonitis (SBP). We
adjusted for patient co-morbidities using the Deyo modification
of the Charlson index and for liver decompensation using the
Baveno IV criteria. We evaluated for risk factors for infection
and mortality using multivariable logistic regression. Results: Of
316,161 cirrhotic patients identified, 8,208 (2.6%) were mal-
nourished, 13,945 (4.4%) were obese, and 11,909 (3.8%)
were morbidly obese. A total of 98,404 patients (31.1%) had
at least one infection during hospitalization. Infection was most
prevalent among malnourished patients (49.4%), followed by
morbidly obese (40.9%), and then obese patients (32.2%). In
HEPATOLOGY, October, 2014
multivariable analysis, malnutrition and morbid obesity pre-
dicted infection (Table 1). Among infected patients, risk factors
for mortality included malnutrition (OR=2.10; 95% CI 2.02-
2.20) and morbid obesity (OR=1.47; 95% CI 1.41-1.54).
Regarding specific infections, malnourished patients had great-
est prevalence of sepsis, UTI, LRI, SBP and CDI, while morbidly
obese patients had highest prevalence of cellulitis. Prevalence
of bacteremia was similar among all patient groups. Conclu-
sion: Malnutrition and morbid obesity are associated with
infection acquisition in cirrhosis and higher mortality among
infected cirrhotics. The prevalence of specific infections also
varies depending on nutritional status. Further study is needed
regarding the impact and optimization of nutritional status in
chronic liver disease.
Disclosures:
Tram T. Tran - Advisory Committees or Review Panels: Gilead, Bristol Myers
Squibb; Consulting: Gilead, AbbVie, Janssen; Grant/Research Support: Bristol
Myers Squibb; Speaking and Teaching: Bristol Myers Squibb, Gilead
Vinay Sundaram - Advisory Committees or Review Panels: Salix, Gilead, Jansen;
Speaking and Teaching: Salix
The following people have nothing to disclose: Aung Kaung, Ken D. Nguyen,
Amit Rajaram, Phillip Zakowski
588
Delay in appropriate antimicrobial therapy increases
mortality in cirrhotics with spontaneous bacterial perito-
nitis and septic shock
Constantine J. Karvellas1,2, Juan G. Abraldes2, Yaseen Arabi3,
Anand Kumar4; 1Critical Care Medicine, University of Alberta,
Edmonton, AB, Canada; 2Hepatology, University of Alberta,
Edmonton, AB, Canada; 3Critical Care Medicine, College of Med-
icine, King Saud bin Abdulaziz University for Health Sciences,
Riyadh, Saudi Arabia; 4Critical Care Medicine, University of Man-
itoba, Winnipeg, AB, Canada
Aim: To determine what clinical factors contribute to the high
mortality from septic shock among cirrhotics with spontaneous
bacterial peritonitis (SBP). Methods: From the CATTS Database
between 1996 and 2011, retrospective cohort study of all
cirrhotic patients with septic shock and evidence of SBP (neu-
trophils > 250 or positive tap). Results: Among 126 cirrhotics
(mean age 55, 60% male), in-hospital mortality was 82%. In
comparing survivors (n=23) with non-survivors (n=103), survi-
vors had lower mean admission APACHE II (22 vs. 32), MELD
(24 vs.34) and serum lactate (4.9 vs. 8.9, p<0.001 for all)
and were less likely to have co-existent bloodstream infection
(BSI) (22% vs. 50%, p=0.015). Survivors were more likely
to receive appropriate initial antimicrobial therapy (100%
vs. 75%, p=0.013) and receive therapy earlier (median 1.8
vs. 9.5 hours, p<0.001). Predicted death rates (regression)
according to APACHE II score, lactate and time to antimicrobi-
als are shown in Figure 1 . On multivariable analysis, APACHE
II (Odds Ratio 1.45 (1.04-2.02, p=0.03), lactate (OR 2.34
(1.04-5.29), p=0.04) and time delay to appropriate antimi-
crobials (OR 1.86 per hour (1.10-3.14), p=0.02) were all
significantly associated with increased mortality. Age, gender
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
and presence of co-existent BSI did not impact outcome. This
model performed well (c-statistic 0.98). Conclusions: Cirrhotic
patients with septic shock secondary to SBP have high mortal-
ity (> 80%). Each hour of delay in appropriate antimicrobial
therapy was associated with an 86% increase in the odds of
in-hospital mortality. Admission APACHE II and serum lactate
also significantly impacted mortality. Earlier identification of
septic shock and initiation of appropriate antimicrobial therapy
could potentially improve outcomes.
A,B,C: Predicted death according to APACHE II, lactate, time to
antimicrobials. D: Time to antimicrobials adjusted for APACHE II
scores.
Disclosures:
Constantine J. Karvellas - Grant/Research Support: Merck; Speaking and Teach-
ing: Gambro
Juan G. Abraldes - Speaking and Teaching: Gore, Janssen
The following people have nothing to disclose: Yaseen Arabi, Anand Kumar
589
Prognostic Value of Procalcitonin in patients with Spon-
taneous Bacterial Peritonitis: Preliminary Results from a
Multicenter Study in Argentina
Sebastian Marciano1,6, Natalia Sobenko1, Alfredo Martinez2,
Manuel Mendizabal3, Luis A. Gaite4, Federico Piñero3, Leila
Haddad1, Marcelo O. Silva3, Ezequiel Ridruejo6, Oscar G.
Mandó6, Diego H. Giunta5, Adrian Gadano1; 1Liver Unit, Hos-
pital Italiano, Buenos Aires, Argentina; 2Clinical Analysis Depart-
ment, Centro de Educación Médica e Investigaciones Clínicas
Norberto Quirno (CEMIC), Buenos Aires, Argentina; 3Hepatology
and Liver Transplant Unit, Hospital Universitario Austral, Buenos
Aires, Argentina; 4Liver Unit, Hospital José María Cullen, Santa
Fe, Argentina; 5Internal Medicine Research Unit, Hospital Italiano,
Buenos Aires, Argentina; 6Liver Unit, Centro de Educación Médica
e Investigaciones Clínicas Norberto Quirno (CEMIC), Buenos
Aires, Argentina
Identification of patients with Spontaneous Bacterial Peritonitis
(SBP) at risk of organ failure and death is challenging. Aims:
To evaluate the association of procalcitonin (PCT) with acute-
on-chronic liver failure (ACLF) or death in patients with SBP.
Methods: Adult cirrhotic patients with SBP were prospectively
included from October 2012 to March 2014 in 3 Liver Units.
Patients with a prior episode of ACLF (CLIF-Consortium) in the
30 days before the inclusion and patients with end-stage hepa-
tocellular carcinoma, organ transplantation, immunosuppres-
sion or active alcohol drinking were excluded. Procalcitonin
487A
(measuring range: 0.02-100 ng/mL) was collected at the time
of SBP diagnosis and before antibiotic initiation. Investigators
were blinded to PCT results. Primary outcome was ACLF or
death at 30 days of SBP diagnosis. Results: Forty one consecu-
tive patients with SBP were included. Overall, ACLF was diag-
nosed in 27 (66%) patients, 11 (27%) died. In the univariate
analyses, patients with ACLF or death had significantly higher
PCT, Child-Pugh score, MELD, INR and creatinine than patients
without ACLF or death (Table). The OR for ACLF or death for
every 0.1 ng/mL increase of PCT was 1.34 (CI 95% 1.07-
1.67, p 0.01). After adjusting for age, MELD, creatinine and
positive blood cultures, the OR was 1.75 (CI 95% 1.05-2.93,
p 0.033). From a receiver operating characteristic curve, a
PCT cut-off point of 0.95 ng/mL was identified with sensitiv-
ity 67% and specificity 100% for predicting ACLF or death.
Positive and negative predictive values were 100% and 61%,
respectively. Conclusion: In patients with SBP, PCT is a strong
predictor of bad outcomes. A PCT of ≥ 0.95 ng/mL at diag-
nosis of SBP identifies patients at high risk of ACLF or death.
*Median (IQR), **Mean ± SD, *** Hepatocellular Carcinoma,
**** Systemic Inflammatory Response Syndrome.
Disclosures:
The following people have nothing to disclose: Sebastian Marciano, Natalia
Sobenko, Alfredo Martinez, Manuel Mendizabal, Luis A. Gaite, Federico Piñero,
Leila Haddad, Marcelo O. Silva, Ezequiel Ridruejo, Oscar G. Mandó, Diego H.
Giunta, Adrian Gadano
590
CLIF-SOFA score and serum sodium are independent
predictors of short term survival in decompensated cir-
rhosis. A prospective study
Gustavo Pereira, Flavia F. Fernandes, Vanessa L. Zenatti, Camila
M. Alcântara, Tatiana Valdeolivas, Zulane D. Veiga, Daniela M.
Mariz, João Luiz Pereira; GastroHepatology Unit, Bonsucesso Fed-
eral Hospital, Ministry of Health, Rio de Janeiro, Brazil
Introduction: CLIF-SOFA score has recently been proposed as
diagnostic criteria for acute on chronic liver failure (ACLF).
Hyponatremia is a common finding in cirrhosis and associ-
ated with poor prognosis. There are few studies evaluating
the interaction between hyponatremia and CLIF-SOFA in
predicting survival in cirrhosis. Objectives: To evaluate the
association between CLIF-SOFA and hyponatremia and their
capacity in predicting survival in patients with decompensated
cirrhosis. Methods: prospective study with 145 consecutive
488A AASLD ABSTRACTS
patients hospitalized for treatment of complications of cirrho-
sis. CLIF-SOFA, presence of ACLF and hyponatremia (serum
sodium<130mEq/L) were determined at hospital admission.
Transplant-free survival was evaluated at 28 days. Results:
Mean age was 57±14 years, 51% were men and cirrhosis
was due to HCV/alcohol in 62%. Ascites, bacterial infections
and hepatic encephalopathy were the most common complica-
tions at admission, present in 72%, 48% and 40% of patients.
Child and MELD scores were 9±2 and 18±8. Mean CLIF-SOFA
was 5±3 (median 5, IQR 3-7). Mean serum sodium was 133±6
mEq/L and hyponatremia was diagnosed in 34 patients. At
admission, ACLF was diagnosed in 42 patients. Presence of
ACLF was associated with male gender, alcoholic etiology,
bacterial infections, and higher leucocyte count and C-reactive
protein values. Patients with hyponatremia more frequently had
ascites, hepatic encephalopathy and bacterial infections, as
well as lower MAP and higher INR. Hyponatremia was more
frequent in patients with ACLF (41 vs. 18%, p=0.004). ACLF
was diagnosed in 50% of patients with hyponatremia (vs. 25%
for patients without, p<0.001). On multivariate analysis, CLIF-
SOFA (OR 1.47 95%CI 1.20-1.80) and hyponatremia (OR
2.77 95%CI 1.05-7.30), but not MELD or presence of ACLF,
were independent predictors of survival. The best cut-off point
of CLIF-SOFA in predicting mortality was 7 (sensibility 71%,
specificity 82%). A high CLIF-SOFA (≥7) was not necessary
related to ACLF. 14 out of 42 patients with high CLIF-SOFA
did not have ACLF. Conversely, 30% of patients with ACLF
had low CLIF-SOFA. Presence of hyponatremia was associated
with lower survival in patients with high CLIF-SOFA (35% vs
46%). Nevertheless, the effect of hyponatremia on survival was
most marked in patients with low CLIF-SOFA (69% vs. 92%,
p<0.001 for all comparisons). Conclusions: In patients with
decompensated cirrhosis, CLIF-SOFA and serum sodium are
independently associated with prognosis. The predictive value
of CLIF-SOFA is not related to the presence of ACLF. Hypona-
tremia identifies a subgroup of patients with low CLIF-SOFA
with high short-term mortality.
Disclosures:
The following people have nothing to disclose: Gustavo Pereira, Flavia F. Fer-
nandes, Vanessa L. Zenatti, Camila M. Alcântara, Tatiana Valdeolivas, Zulane
D. Veiga, Daniela M. Mariz, João Luiz Pereira
591
Alpha 2a adrenergic receptor antagonism abrogates
innate immune dysfunction and hepatic inflammatory
cytokine generation in a rodent model of Acute-on-
Chronic Liver Failure (AoCLF): Proof of concept for a
new target for therapy
Vikram Sharma, Junpei Soeda, Jane MacNaughtan, Abeba
Habtesion, Pamela Leckie, Nathan Davies, Rajiv Jalan, Rajeshwar
Mookerjee; Institute of Liver and Digestive Health, London, United
Kingdom
Background: Organ failure and mortality in acute-on-chronic
liver failure (AoCLF) is commonly related to infection. Several
lines of investigation suggest innate immune dysfunction under-
pins the increased sepsis in AoCLF patients. We previously
reported significant neutrophil phagocytic dysfunction in patients
with alcoholic hepatitis. Studies in a model of sepsis, have
suggested that Alpha 2a adrenergic (ADRA 2a) receptors are
up-regulated in phagocytic cells (1) but this has not been further
characterized in liver disease. This study tested the hypothesis
that a highly selective ADRA 2a antagonist (BRL 44408) would
improve innate immune function in a rodent model of AoCLF.
Method: Male Sprague-Dawley rats were studied 4-weeks after
BDL or sham surgery and randomised to saline or the selective
HEPATOLOGY, October, 2014
ADRA2a antagonist, BRL 44408 (Sigma, 10mg/kg s.c) daily
for 10 days. Intra peritoneal LPS was administered 3 hours
prior to study termination to emulate the severe inflammatory
response in AoCLF. The following sub-groups were studied:
Sham (n=14), Sham+LPS (n=7), BDL (n=15), BDL+BRL (n=16),
BDL+LPS (n=9) and BDL+LPS+BRL (n=7). Neutrophil and macro-
phage characterization was studied through FACS, in multiple
sub-group analyses. Endotoxin measurement (Limulus amebo-
cyte lysate assay) and Cytokine measurement (BD cytometric
bead array) were also performed. Results: BDL+LPS animals
treated with BRL 44408 showed improvement in phagocytic
activity of hepatic neutrophils (p<0.005) and macrophages
(p<0.05) compared to saline treated BDL+LPS rats. BDL rats
treated with BRL 44408 also showed significantly reduced total
hepatic reactive oxygen species (ROS) production (p<0.001),
which was complimented by a reduced activated Kuppfer
cell population (CD163 gated CD68 cells) in both BDL+LPS
(p<0.05) and BDL rats (p<0.05). Moreover, ROS generation
from activated Kuppfer cells was abrogated by treatment with
BRL 44408 in both BDL+LPS (p<0.05) and BDL (p<0.05) rats
as compared to saline treated rats. BRL 44408 treated BDL+LPS
rats also showed significant reduction in absolute neutrophil
counts in the portal circulation compared to saline treated rats
(p<0.01), associated with decreased portal endotoxin levels
and significantly reduced hepatic TNFα and IL-6 production.
Conclusion: This study shows that treatment with a highly selec-
tive ADRA 2a antagonist significantly improves hepatic neutro-
phil and macrophage functional capacity in a rodent model of
AOCLF. This provides proof-of-concept for ADRA 2a as a target
for intervention in AoCLF to improve innate immune function
and thereby outcome. References: 1. Flierl,MA et al; Nature
2007,Oct 11;449(163):721-5
Disclosures:
Nathan Davies - Patent Held/Filed: UCL
Rajiv Jalan - Consulting: Ocera Therapeutics, Conatus; Grant/Research Support:
Grifols, Gambro
The following people have nothing to disclose: Vikram Sharma, Junpei Soeda,
Jane MacNaughtan, Abeba Habtesion, Pamela Leckie, Rajeshwar Mookerjee
592
Pathophysiological basis of Hepatic Encephalopathy
(HE) in patients with Acute-on-chronic liver failure
(ACLF): A prospective, longitudinal study determining
the role of ammonia, inflammation and cerebral oxy-
genation
Rohit Sawhney, Peter Holland-Fischer, Rajeshwar Mookerjee, Mat-
teo Rosselli, Banwari Agarwal, Rajiv Jalan; Institute of Liver and
Digestive Health, University College London/Royal Free Hospital,
London, United Kingdom
Background: HE is a defining feature of acute liver failure and
its presence is associated with high mortality in ACLF patients.
Although ammonia, inflammation, cerebral perfusion and oxy-
genation are known to be associated with HE in ALF, their
relative roles in ACLF patients are unknown. The aim of this pro-
spective, longitudinal observational study was to determine the
role of these key pathophysiological variables in ACLF patients
with or without associated HE. Methods: 101 patients (M/F:
69/32; mean age: 54; Alcohol: 78%) with ACLF admitted to
ICU were studied. The severity of ACLF was classified using the
CLIF-SOFA score and the severity of HE using the West-Haven
criteria. All patients were managed according to a pre-de-
fined protocol and organ support was provided as required.
Arterial ammonia, jugular venous oxygen saturation (JVO2),
white cell count (WCC) and CRP were measured at time of
enrolment, at days, 1, 3 and 7 or, until death or discharge.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Results: 51 patients died (50.5%). Mortality was higher in
ACLF patients with HE (ACLF-HE) irrespective of the severity
of ACLF (ACLF-HE: 35/53 (66%); ACLF-no HE: 16/48 (33%),
p = 0.001). Mortality was greater in patients with greater
severity of HE (Grade 0/1: 16/48 (33%) Grade 2: 19/32
(59%) Grade 3-4 16/21 (76%), p = 0.002). INR, creatinine,
WCC, low platelets at baseline, and ACLF severity were inde-
pendent predictors of death in the whole cohort and in the
ACLF-HE cohort. Baseline ammonia levels were higher in HE
patients (90 vs 73 μmol/L; p = 0.004) but did not predict
mortality. A decrease in ammonia level was associated with
better survival (p <0.001). Abnormal baseline JVO2 (deviation
by more than 5% from an optimal 75%) was associated with
both presence and severity of HE (ACLF-no HE: 22%; ACLF-HE
Grade 2: 47%; ACLF-HE Grade 3-4: 62%, p = 0.005). Wors-
ening JVO2 (low or high) was independently associated with
mortality (improved JVO2: 21% mortality; worsened 79%, p
<0.001). WCC did not differ between non-HE and HE groups
at baseline (p = 0.95) but WCC was higher in the group that
died (p = 0.007). A further increase was independently pre-
dictive of death (p <0.001). There was a strong interaction
between ammonia and JV02 in regards to predicting the sever-
ity of HE and mortality. Conclusions: The data in this study
describes potential mechanisms of HE in ACLF indicating that
ammonia and abnormal cerebral oxygenation are pathophysi-
ologically important. These findings suggest that ammonia and
JVO2 as well as WCC are important biomarkers for prognosis
and also important therapeutic targets. Whether the altered
JVO2 is independent of ammonia in the pathogenesis of HE in
ACLF requires future study.
Disclosures:
Rajiv Jalan - Consulting: Ocera Therapeutics, Conatus; Grant/Research Support:
Grifols, Gambro
The following people have nothing to disclose: Rohit Sawhney, Peter Hol-
land-Fischer, Rajeshwar Mookerjee, Matteo Rosselli, Banwari Agarwal
593
Inhibition of MER receptor tyrosine kinase in patients
with acute on chronic liver failure: a potential target for
immunotherapy?
Christine Bernsmeier1, Oltin T. Pop1, Evangelos Triantafyllou1,2,
Chris J. Weston2, Stuart M. Curbishley2, Vishal C. Patel1, Arjuna
Singanayagam1, Wafa Khamri3, Christopher Willars 1, Wil-
liam Bernal1, Georg Auzinger1, Michael A. Heneghan1, Yun
Ma1, Wayel Jassem1, Nigel Heaton1, David H. Adams2, Mark
R. Thursz3, Alberto Quaglia1, Julia Wendon1, Charalambos G.
Antoniades1,3; 1Institute of Liver Studies, King’s College Hospi-
tal, King’s College London, London, United Kingdom; 2Centre for
Liver Research and NIHR Biomedical Research Unit, University of
Birmingham, Birmingham, United Kingdom; 3Section of Hepatol-
ogy, St. Mary’s Hospital, Imperial College London, London, United
Kingdom
Background: Infection is a major cause of mortality in acute
on chronic liver failure (ACLF). Immuneparesis, monocyte
dysfunction, is postulated to account for the increased sus-
ceptibility to infection. MER receptor tyrosine kinase (MERTK),
expressed on monocytes and macrophages (mφ), plays a
pivotal role in dampening innate immune responses and pro-
motes resolution through inhibition of Toll-like-/cytokine recep-
tor pathways. We sought to establish the role of MERTK and
determine its candidacy as an immunotherapeutic target to
reverse immuneparesis in ACLF. Methods: Patients with ACLF
(n=30), cirrhosis (CLD; n=8) and healthy controls (HC; n=14)
were studied. Immunophenotyping and LPS-induced TNF/IL-6
production were assessed by flow cytometry. Plasma Gas-6
489A
levels were measured by ELISA (Abnova). Immunohistochem-
istry and multispectral imaging was done on liver (n=6 each)
and mesenteric lymph nodes (n=1 each) from ACLF and CLD
patients undergoing transplantation. Monocyte phenotype
was assessed following migration across hepatic endothe-
lial monolayers into collagen plugs (HC, n=4;ACLF, n=5).
MERTK inhibitor UNC569 (Millipore) was used. Purified HC
derived monocytes were conditioned with ACLF plasma (n=9
patients) for 16h prior to MERTK inhibition. Results: Compared
to HC and CLD, there was a marked expansion of circulat-
ing MERTK positive monocytes (MERTK+) in ACLF (mean
5.9/3.5vs.26.5%,p<0.0001/p<0.001). Levels of the MERTK
ligand Gas-6 were increased (633vs.3203pg/ml,p<0.01).
MERTK+ monocytes in ACLF revealed an anti-inflammatory
(CD163high,CX3CR1low,HLA-DRlow), lymph node homing
(CCR7high) phenotype. Pro-inflammatory responses to LPS chal-
lenge (TNF(mean MFI):14664vs.5496,p=0.0014) were atten-
uated. Culture of monocytes in ACLF compared to HC plasma
expanded the number of MERTK+, anti-inflammatory, LPS-tol-
erant cells (82.6vs.42.0%,p=0.0021). Compared to CLD,
multispectral analysis of ACLF tissue revealed a MERTK+ infil-
trate within hepatic sinusoids (33.8vs.105.3/10HPF,p<0.01)
and subcaspular/medullary areas of mesenteric lymph nodes
(23vs.309/10HPF). Following migration across the endothe-
lium a significant increase in MERTK+ monocytes was detected
in ACLF compared to HC (75.8%vs.63.3%,p=0.01). Remark-
ably, inhibition of MERTK signalling significantly increased
HLA-DR expression (p=0.0225) and improved LPS-induced TNF
production (p=0.0078). Conclusions: We have identified the
presence and marked expansion of a novel immunoregulatory
monocyte/mφ subset that suppresses innate immune responses
to microbial challenge in patients with ACLF. Thus, MERTK pro-
vides a promising immunotherapeutic target to reverse immune-
paresis and susceptibility to infection in ACLF.
Disclosures:
William Bernal - Consulting: Vital Therapies Inc
Michael A. Heneghan - Speaking and Teaching: Falk
Nigel Heaton - Advisory Committees or Review Panels: Novartis, Roche; Speak-
ing and Teaching: Astellas
Mark R. Thursz - Advisory Committees or Review Panels: Gilead, BMS, Abbott
Laboratories
Julia Wendon - Consulting: Pulsion, Excalenz
The following people have nothing to disclose: Christine Bernsmeier, Oltin T. Pop,
Evangelos Triantafyllou, Chris J. Weston, Stuart M. Curbishley, Vishal C. Patel,
Arjuna Singanayagam, Wafa Khamri, Christopher Willars, Georg Auzinger,
Yun Ma, Wayel Jassem, David H. Adams, Alberto Quaglia, Charalambos G.
Antoniades
594
Acquired Hemophagocytic Lymphohistiocytosis (HLH)
mimicking acute hepatic insult presenting as Acute on
chronic liver failure (ACLF) is associated with high mor-
tality
Ankur Jindal, Ashok Choudhary, Shiv K. Sarin; Hepatology, Insti-
tute of Liver and Biliary sciences, New Delhi, India, New Delhi,
India
Background: HLH is frequently fatal (overall mortality >50%)
and is often underdiagnosed. It involves a final common path-
way of hypercytokinemia. A timely diagnosis is imperative to
facilitate immunosuppressive therapy and decrease mortality.
HLH presenting as severe acute hepatitis or ACLF is extremely
rare and is not well recognized. We present our experience
of HLH in patients presenting with severe acute hepatic insult/
liver failure. Patients and Methods: Retrospective analysis of
admitted patients with systemic inflammatory response fulfilling
diagnostic HLH criteria (≥ 5/8).[Henter et al, 2004] Results
490A AASLD ABSTRACTS
Seventeen patients [M: F -14:3; Adults: Child- 14:3; median
age- 26 years (range-1 m to 66 yrs] were diagnosed with
acquired HLH at our hospital from year 2010 to 2012. Twelve
(70.6%) patients presented clinically as ACLF (n=7) and severe
acute hepatitis ( n=5) at admission. Viral associated HLH (8
patients; 47.1%) was most common (HAV-3, HEV-2, EBV-1,
Dengue-1, Parvovirus-1). Although, etiology remained undiag-
nosed in 7(41.2%) patients, rare presentations included lym-
phomatous infiltration of liver (1) & visceral leishmaniasis (1).
While fever [16 patients (94.2%); median duration- 30days
(4-90 days)] and jaundice [14 patients; mean bilirubin-20.34
± 8.6mg/dl] were most common presentations, clinical signs
such as presence of enlarged liver (76.4%), spleen (76.4%)
and ascites (58.8%) were most frequent. Five patients also had
AKI (serum creatinine >1.5 mg/dl) at admission. Important bio-
chemical parameters included hyperferritinemia [all patients;
mean- 16,064.7 ±7,652 ng/ml], hypertriglyceridemia (10
patients; mean-355 ± 145 mg/dl), raised LDH(mean- 2,953
± 726 IU/L) and low fibrinogen (12 patients; mean-146.1±
32.4 mcg/L) levels. The mean plasma haemoglobin was 8.08
± 1.33 g/L and total leucocyte count was 2.1 x 103 /cu mm.
Bone marrow aspiration was done in 12 patients; 11 of which
showed the presence of hemophagocytosed histiocytes. Ten
(58.8%) patients had in-hospital mortality and the main cause
was eventual sepsis and multiorgan failure. 12 patients (70.6%)
received specific immunosuppressive therapy (steroids-4, IV
immunoglobulin -4, plasmaphersis-3, cyclosporine-1) but these
therapies made no difference in clinical outcome compared to
those who did not receive these therapies (in-hospital mortal-
ity- 66.67% vs. 62.25%, respectively). Conclusions: HLH may
masquerade as acute hepatic insult, in patients presenting with
severe and rapidly progressive liver failure. It is important to
suspect and recognise this generally fatal entity early enough
in patients with unexplained acute hepatitis or ACLF, especially
in presence of severe anemia.
Disclosures:
The following people have nothing to disclose: Ankur Jindal, Ashok Choudhary,
Shiv K. Sarin
595
Prognosis of cirrhotic patients admitted in Intensive care
Unit: A Meta-analysis
Delphine Weil1, Heng-Chih Pan2, Eric Levesque3, Bertrand
Sauneuf4, Eleni Theocharidou5, Evangelos Cholongitas6, Con-
stantine J. Karvellas7, René Robert8, Arnaud Galbois9, Jérôme
Fichet10, Rodrigo Cavallazzi11, Jean Paul Cervoni1, Gaël Piton12,
Thierry Thevenot1, Gilles Capellier12, Vincent Di Martino1; 1Liver
Department, CHU Jean Minjoz, Besançon, France; 2Department
of Nephrology, Chang Gung Memorial Hospital, Taipei, Taiwan;
3Centre Hépato-Biliaire, CHU Paul Brousse, Villejuif, France; 4Med-
ical Intensive Care Unit, CHU de Caen, Caen, France; 5Royal Free
Sheila Sherlock Liver Centre, Royal Free Hospital, London, United
Kingdom; 6Liver Department, Aristotle University of Thessaloniki,
Thessaloniki, Greece; 7Gastroenterology (Liver Unit) and Critical
Care Medicine, University of Alberta, Edmonton, AB, Canada;
8Medical Intensive Care Unit, CHU de Poitiers, Poitiers, France;
9Medical Intensive Care Unit, Hôpital Saint Antoine, Paris, France;
10Medical Intensive Care Unit, CHU de Tours, Tours, France;
11Medical Intensive Care Unit, University of Louisville, Louisville,
KY; 12Medical Intensive Care Unit, CHU Jean Minjoz, Besançon,
France
Background/Aim The prognostic assessment of cirrhotic patients
in the ICU provides short-term and controversial results. The
objective of this meta-analysis was to evaluate the influence of
the characteristics of patients and their care on in-ICU mortality,
HEPATOLOGY, October, 2014
in-hospital mortality, 3 month and 6 month mortality. Patients
and methods. 12 studies including 2132 cirrhotic admitted
in ICU were analyzed after selection of original articles and
response to a standardized questionnaire by the corresponding
authors. The prognostic performance of 177 variables (includ-
ing reason for admission, organ replacement therapy, and
composite prognostic scores)were analyzed for each period
according to the method of Der Simonian and Laird (708 pooled
analysis). Results. In-ICU, in-hospital, 3 and 6 month-survival
were 55% (range 28-66%), 45% (27-61%), 23% (13-37%)
and 20% (13-35%), respectively. In-ICU survival was better
in recent studies (>yr2000) (OR=1.36,p=0.036), in centers
containing a liver transplant program (OR=1.82,p<0.0001)
in patients admitted for variceal bleeding (OR=1.80,
p<0.0001, PPV=0.67), with MELD<13 (OR=4.31, p<0.0001,
PPV=0.86), albumin>35g/L (OR=3.97, p<0.0001,
PPV=0.77), <2 organ failures (OR=4.81, p<0.0001,
VPP=0.70). In-ICU mortality was significantly associated
with 23 variables and better predicted by: a CLIF-SOFA≥22
(OR=5.94, p=0.005, PPV=1); ≥5 organ failures (OR=10.87,
p<0.0001, PPV=0.98); SOFA≥19 (OR=14.46, p<0.0001,
PPV=0.97), a fungemia (OR=4.61, p=0.0005,PPV=0.87),
ARDS (OR=4.48,p<0.0001,PPV=0.81), refractory oli-
guria (OR=9.17, p<0.0001, VPP=0.79), a MELD≥35
(OR=5.43, p<0.0001,PPV=0.77), sepsis-induced hypoten-
sion (OR=5.75, p<0.0001, PPV=0.77), an increased SOFA
at d3 (OR=4.57,p<0.0001,PPV=0.72), positive blood cul-
tures (OR=2.15, p=0.004, PPV=0.73), infection with GN
Bacilii (OR=2.24,p<0.0001,PPV=0.70),and the use of MARS
(OR=2.04,p=0.0081,PPV=0.64). The mSOFA, APACHE, alco-
hol consumption, direct admission in ICU, HRS, nosocomial
infection or infection with GP cocci had no impact. The results
were heterogeneous for the Pugh, creatinine, the use of intuba-
tion or norepinephrine. SBP was associated only with in-hospi-
tal mortality. Patients who received TIPS had better in-hospital,
3 and 6 month survival. The Pugh, MELD, SOFA, the presence
of SIRS, bacterial infection or ARDS, the need for haemodi-
alysis kept an impact on 3 and 6 month survival. Conclusion
The prognostic performance of general ICU scores decreases
over the long-term, unlike the Pugh and MELD scores. Some
events can be considered alone and have an excellent predic-
tive value for short-term and long-term prognosis, as well as
composite scores.
Disclosures:
Constantine J. Karvellas - Grant/Research Support: Merck; Speaking and Teach-
ing: Gambro
Vincent Di Martino - Board Membership: Gilead, France, MSD France; Consult-
ing: Gilead, France
The following people have nothing to disclose: Delphine Weil, Heng-Chih Pan,
Eric Levesque, Bertrand Sauneuf, Eleni Theocharidou, Evangelos Cholongitas,
René Robert, Arnaud Galbois, Jérôme Fichet, Rodrigo Cavallazzi, Jean Paul
Cervoni, Gaël Piton, Thierry Thevenot, Gilles Capellier
596
Chronic Liver Failure Sequential Organ Failure Assess-
ment (CLIF-SOFA) is better than the Asia-Pacific Associ-
ation for the Study of Liver (APASL) criteria for defining
Acute-on-Chronic Liver Failure (ACLF) and Predicting
Outcome
Radha K. Dhiman, Tarana Gupta, Swastik Agrawal, Ajay K.
Duseja, Yogesh K. Chawla; Hepatology, Postgraduate Institute of
Medical Education and Research (PGIMER), Chandigarh, India
ACLF is acute hepatic decompensation (AD) in patients with
chronic liver disease including cirrhotic or noncirrhotic who
also have organ failure(s) and carry high risk of short-term
death. There is a sharp East (APASL)–West (CLIF-SOFA)
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
divide with respect to the definition of ACLF (Sarin et al Hepa-
tol Int 2009;3:269–82; Moreau R et al Gastroenterology
2013;144:1426–37). Hence, we for the first time compared
the CLIF-SOFA and APASL definitions in Asian-Indian patients
with liver cirrhosis and AD with regards to the short-term mor-
tality. Consecutive patients with liver cirrhosis and AD were
prospectively included between July 2013 and April 2014.
They were classified into ACLF and no-ACLF groups as per
CLIF-SOFA and APASL criteria. Patients were followed up for
3-mo from inclusion or mortality whichever was earlier. Mor-
tality at 28-d and 90-d was compared between no-ACLF and
ACLF groups and also between different grades of ACLF as per
CLIF-SOFA criteria. Prognostic scores like CLIF-SOFA, Acute
Physiology and Chronic Health Evaluation (APACHE)-II, Child-
Pugh-Turcotte (CTP) and Model for End-Stage Liver Disease
(MELD) scores were evaluated for their ability to predict 28-d
mortality using area under receiver operating curves (AUROC).
Of 80 patients, 56(70%) had ACLF as per CLIF-SOFA crite-
ria and 36(45%) as per APASL criteria. Males (n=66,82.5%)
were predominant, alcoholic liver disease (n=53, 66.3%) was
the most common etiology, sepsis (n=39,48.8%) was the most
common cause of AD while infection (n=39,48.8%) was the
most common precipitant of AD. The 28-d mortality in no ACLF
and ACLF groups was 8.3% and 44.6% (P=0.002) as per
CLIF-SOFA and 36.4% and 30.6% (P=0.64) as per APASL
criteria. The 28-d mortality in patients with no ACLF (n=24),
ACLF grade 1 (n=18), ACLF grade 2 (n=22) and ACLF grade
3 (n=16) as per CLIF-SOFA criteria was 8.3%, 16.7%, 40.9%
and 81.2% (χ2 for trend, P=0.002) and 90-d mortality was
20.8%, 38.9%, 72.7% and 100% (χ2 for trend, P <0.0001)
respectively. Patients with prior decompensation had similar
28-d (36.4% vs 30.6%, P=0.64) and 90-d (52.3% vs 58.3%,
P=0.66) mortality as patients without prior decompensation.
AUROCs for 28-d mortality for CLIF-SOFA, APACHE-II, Child-
Pugh and MELD scores were 0.839, 0.800, 0.783 and 0.755
respectively. On multivariate analysis of these scores, CLIF-
SOFA and APACHE-II were the only significant independent
predictor of mortality with an odds ratio 1.561 (95% CI:
1.114-2.187) and 1.160 (1.021-1.318) respectively. Con-
clusion: CLIF-SOFA criteria are better than APASL criteria to
classify patients into ACLF based on their prognosis. CLIF-SOFA
and APACHE II are the best predictor of short-term mortality.
Disclosures:
The following people have nothing to disclose: Radha K. Dhiman, Tarana Gupta,
Swastik Agrawal, Ajay K. Duseja, Yogesh K. Chawla
597
Copeptin: a marker of circulatory derangement, is inde-
pendently associated with outcome in patients admitted
for acute decompensation of cirrhosis
Hein W. Verspaget1, Amorós Àlex2, Rajiv Jalan3, Daniel Benten4,
Francois Durand5, Johan van der Reijden1, Bart Van Hoek1, Min-
neke Coenraad1; 1Gastroenterology and Hepatology, Leiden
University Medical Centre, Leiden, Netherlands; 2Liver Unit /
EASL-CLIF Data Center, Hospital Clínic de Barcelona, Barcelona,
Spain; 3Liver Failure Group, UCL Institute for Liver and Digestive
Health, UCL Medical School, Royal Free Hospital, London, United
Kingdom; 4Department of Medicine, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany; 5Hepatology and Liver
Intensive Care Unit, Hospital Beaujon, Clichy, France
Background: Acute on chronic liver failure (ACLF) is character-
ized by the presence of organ failure and a very high risk of
short-term mortality. Systemic hemodynamic dysfunction and
activation of endogenous vasoconstrictor systems are thought
to contribute. We hypothesize that copeptin, a stable cleavage
491A
product of the C-terminal part of the vasopressin precursor, is
a marker of early diagnosis of ACLF and outcome. Methods:
From 198 cirrhotic patients hospitalized for acute decompen-
sation, clinical, laboratory and survival data from the Canonic
database were used. Presence of ACLF was defined according
to the modified CLIF-sequential organ failure assessment (SOFA)
score. Serum copeptin concentration was measured in samples
collected within 2 days after admission, using an assay in the
chemiluminescence/coated tube format (B.R.A.H.M.S. GmbH,
Hennigsdorf, Germany). Cox proportional hazard regression
analysis with liver transplantation and mortality as a combined
endpoint was used to evaluate the effect of age, copeptin con-
centration, laboratory and clinical data on outcome. MELD,
MELDNa and CLIF-SOFA score were separately evaluated
with copeptin to avoid redundancy. Parameters with p<0.10
in univariate analysis were included in multivariate analysis.
The effect of ACLF grading and mean arterial blood pressure
(MAP) on copeptin levels was analysed by an ANOVA model
adjusted for confounders. Results are shown as median (IQR).
P< 0.05 was considered significant. Results: Copeptin concen-
tration was significantly higher in patients with ACLF (49 (22-
76) pmol/l) than without ACLF (26 (11-56) pmol/l, p<0.001).
Serum copeptin was increased according to the grade of ACLF
(p<0.001) and inversely related to MAP (p=0.04). At 28 days
of follow-up (FU) 34 (17.2%) of patients had died and 7 (3.5%)
were transplanted. Serum copeptin was significantly higher
in patients who died or were transplanted than in those who
survived (56 (30-93) vs. 51 (19-83) vs. 21 (10-48) pmol/l,
p<0.001). Copeptin was an independent predictor of outcome
at 28 days of FU (HR 1.68 (95% CI 1.10-2.56), p=0.017),
corrected for hepatic encephalopathy, INR and creatinine con-
centration. Copeptin independently predicted outcome at 3, 6
and 12 months of FU, also when corrected for MELD, MELD Na
and CLIF-SOFA score. Conclusion: Serum copeptin concentra-
tion, as a marker of circulatory dysfunction, is significantly ele-
vated in patients with ACLF as compared to those with ‘mere’
acute decompensation of cirrhosis. Copeptin is independently
associated with short and long term outcome in patients with
acute decompensation of cirrhosis.
Disclosures:
Rajiv Jalan - Consulting: Ocera Therapeutics, Conatus; Grant/Research Support:
Grifols, Gambro
Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis;
Speaking and Teaching: Gilead
Bart Van Hoek - Advisory Committees or Review Panels: MSD, Janssen, BMS,
MSD, Janssen, BMS, MSD, Janssen, BMS, MSD, Janssen, BMS
The following people have nothing to disclose: Hein W. Verspaget, Amorós Àlex,
Daniel Benten, Johan van der Reijden, Minneke Coenraad
598
High enrichment of circulating mononuclear cells with
transcripts encoding CXCL neutrophil-attracting chemo-
kines is a predictor of death in patients with decompen-
sated cirrhosis
Emmanuel Weiss1,4, Rakhi Maiwall2, Pierre-Emmanuel Rautou3,
Magali Fasseu1, Mikhael Giabicani1, Francois Durand1,3, Dom-
inique Valla1,3, Didier Lebrec1,3, Sophie Lotersztajn1, Richard
Moreau1,3; 1UMR_S1149, Center for Research in Inflammation
(CRI), Inserm and Paris Diderot University, Paris, France; 2Liver
unit, Institute of Liver & Biliary Sciences, New Delhi, India; 3DHU
Unity, Liver unit, Beaujon hospital, APHP, Clichy, France; 4Anesthe-
siology and intensive care, Beaujon hospital, APHP, Clichy, France
Background: Changes in the innate immune response to patho-
gen-associated molecular pattern (PAMP) can cause organ
failure (i.e., acute-on-chronic liver failure, ACLF) and death
in patients with decompensated cirrhosis. However little is
492A AASLD ABSTRACTS
known about the expression of innate cytokines in naïve or
PAMP-stimulated immune cells in these patients. Moreover, the
relationship between cytokine gene expression and mortality
is unknown. Aims: To investigate ex-vivo gene expression of
innate cytokine genes in naïve and PAMP-stimulated immune
cells in a large prospective cohort of patients with decom-
pensated cirrhosis. Methods: At enrollment, peripheral blood
mononuclear cells (PBMCs) were obtained from 64 patients
(57 alcohol, 7 HCV) including 17 (27%) with ACLF (6 grade
1, 11 grade 2) and from 42 healthy subjects. Cells were stim-
ulated or not with the PAMP lipopolysaccharide (LPS). RT-qPCR
was used to monitor the expression of genes encoding pleio-
tropic cytokines (IL12B, IL6, IL1B, TNF), neutrophil-attracting
CXCL chemokines (IL8, CXCL1, CXCL2, CXCL3, CXCL5), and
the anti-inflammatory IL10. We measured gene expression lev-
els in naïve (unstimulated) cells and LPS-stimulated cells and
calculated fold changes over naïve. Cox proportional hazard
models were used to identify risk factors for mortality. Results:
Expression of CXCL3 and CXCL5 was significantly higher and
that of IL10 significantly lower in “cirrhotic” than in “healthy”
naïve cells. LPS significantly induced (>2-fold) each gene in
both groups but the LPS-induced level of expression of TNF,
CXCL2, CXCL3 and CXCL5 was higher in “cirrhotic” than in
“healthy” cells. There was a direct correlation between the
levels of expression of each gene in naïve cells with corre-
sponding post-LPS levels. Patients were followed-up for 5.7
months (IQR 0.8-11.6); 25 (39%) patients died. Multivariate
analysis identified 2 independent predictors of death: higher
CXL5 expression in naïve cells (OR=13.9, 95% CI 2.6 to 75.1;
P=0.002), and higher ACLF grade (OR=7.0, 95% CI 2.7 to
18.1; P<0.0001). Conclusions: This study shows that circulat-
ing mononuclear cells of patients with decompensated cirrhosis
are abnormally enriched in constitutive transcripts encoding
CXCL chemokines. PAMP-stimulated cirrhotic cells are even
more enriched with these chemokines. Moreover, the higher
the constitutive level of the master chemokine CXCL5 in cirrhotic
cells, the higher the risk of death. Therefore the influx of circu-
lating mononuclear cells expressing high constitutive levels of
neutrophil-attracting CXCL chemokines at sites of infection may
lead to organ failure and death.
Disclosures:
Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis;
Speaking and Teaching: Gilead
The following people have nothing to disclose: Emmanuel Weiss, Rakhi Maiwall,
Pierre-Emmanuel Rautou, Magali Fasseu, Mikhael Giabicani, Dominique Valla,
Didier Lebrec, Sophie Lotersztajn, Richard Moreau
599
Percutaneous Cholecystostomy (PC) for Acute Cholecys-
titis (AC) in Advanced Cirrhosis is Associated with High
Morbidity and Poor Survival
Caitlin Sullivan, Charles Gabbert, Melissa Saul, Kapil B. Chopra,
Adam Slivka, Dhiraj Yadav; University of Pittsburgh Medical Cen-
ter, Pittsburgh, PA
Background: PC for AC is performed in patients at high risk for
cholecystectomy (CCY) due to medical co-morbidities. Cirrhosis
poses unique challenges to PC due to associated ascites and
coagulopathy. Although several series have been reported,
none have focused on cirrhosis patients. Our aim was to eval-
uate the natural history after PC in cirrhosis patients. Methods:
We retrospectively identified 109 patients who underwent PC
for AC at our institution between 1999-2012. Medical records
were reviewed and detailed information collected on clinical
presentation and course. Comparisons were made between
patients who underwent PC due to underlying cirrhosis (n=13)
or other co-morbidities (n=96). For survival analyses, patients
HEPATOLOGY, October, 2014
were censored on the date of death or last contact. Results: Cir-
rhosis patients were younger (median 59 vs. 70 yrs, p<0.05),
similar in sex (male 31 vs. 43%), race (white 83 vs. 93%) and
BMI (26 vs. 27) when compared with non-cirrhotics. Etiology
of cirrhosis was alcohol (4), NAFLD (3), HCV (2) and other
(4). Most had advanced disease (Child’s B [5], C [7]), median
MELD score [21, IQR 19, 26]), and 6/13 had new onset jaun-
dice. AC was diagnosed both clinically and on imaging in
12/13 and 8/13 had calculous AC. Median duration of hos-
pitalization before PC, antibiotic use and survival after PC was
9, 15 and 32 (IQR 11, 403) days. Inpatient mortality/transfer
to hospice (7/13 vs. 27/96) and overall mortality during the
follow up period (11/13 vs. 43/96) was significantly higher
in cirrhotics when compared with non cirrhotic patients (multi-
variable HR 3.1, 95% CI 1.5-6.4; Fig 1). Clinical resolution
was seen in 0/7 patients who died and 6/6 who survived the
index hospitalization. PC related complications were observed
in 7/13 patients: dislodgement (4), bleeding (1), bile leakage
(1), peritonitis (4), and blockage (1). CCY was performed in 6
patients (in 5 with PC related complications). Among non cir-
rhotics, clinical success was noted in 75 patients (67 survivors
of index hospitalization) of whom 18 had recurrent cholecys-
titis and 23 underwent eventual CCY. Conclusions: While an
acceptable temporizing procedure in high risk non cirrhotic
patients with AC, PC in cirrhotic patients is associated with
high morbidity and mortality, and may not be suitable “bridge”
to CCY.
Figure 1: Cumulative Survival after PC
Disclosures:
Adam Slivka - Consulting: Boston Scientific; Grant/Research Support: Mauna
Kea Technology
Dhiraj Yadav - Consulting: Abbvie, Inc
The following people have nothing to disclose: Caitlin Sullivan, Charles Gabbert,
Melissa Saul, Kapil B. Chopra
600
Epidemiologic trends in mortality of cirrhosis in the
intensive care unit: a large, Australasian, multi-centre
cohort
Avik Majumdar1, Michael J. Bailey3, William W. Kemp1, Stuart
K. Roberts1, David Pilcher2,4; 1Department of Gastroenterology,
Alfred Hospital, Melbourne, VIC, Australia; 2Department of Inten-
sive Care, Alfred Hospital, Melbourne, VIC, Australia; 3Australian
and New Zealand Intensive Care Research Centre (ANZIC RC),
Department of Epidemiology and Preventative Medicine, Monash
University, Melbourne, VIC, Australia; 4Centre for Outcome and
Resource Evaluation (CORE), Australian and New Zealand Inten-
sive Care Society (ANZICS), Melbourne, Austria
Background There is little published population level data that
describes the outcomes of patients with cirrhosis in the intensive
care unit (ICU). The aims of this study were: 1) to describe trend
changes in mortality of patients with cirrhosis admitted to ICUs
across Australia and New Zealand, and 2) to investigate the
effect of increasing organ failures on mortality in this group.
Methods The Australian and New Zealand Intensive Care Soci-
ety Centre for Outcome and Resource Evaluation Adult Patient
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Database was examined. Readmissions to ICU and admissions
following liver transplantation were excluded. Patients admitted
to ICU with and without cirrhosis between January 1, 2000
and December 31, 2011 were compared. Severity of illness
on admission was assessed using number of organ failures and
the Acute Physiology and Chronic Health Evaluation (APACHE)
III scoring system (after removal of the coefficient for cirrho-
sis). Results Patients with cirrhosis accounted for 1.4% (13
379/958 853) of ICU admissions. In-hospital mortality in the
cirrhotic group was 31% compared to 12% in the non-cirrhotic
group (p<0.001). Cirrhotic patients had a higher mortality
rate with each increase in number of organ failures. Cirrhotic
patients with 1 organ failure had a comparable mortality to
non-cirrhotic patients with 3 organ failures (20 vs 21%). In-hos-
pital mortality decreased in both groups over time. The cirrhotic
group had a 10% absolute reduction in mortality between the
2000-2003 and 2008-2011 time cohorts compared to a 3.8%
reduction in the non-cirrhotic group (p <0.001). After adjusting
for baseline illness severity using logistic regression, a similar
reduction in the odds ratios for mortality over time was demon-
strated for both groups (Figure 1). Conclusion The mortality
of critically ill patients with cirrhosis has decreased over time.
Survival in this group is better than previous reports. Mortality
in cirrhosis increases with number of organ failures.
Disclosures:
Stuart K. Roberts - Board Membership: Jannsen, Roche, Gilead, BMS
The following people have nothing to disclose: Avik Majumdar, Michael J. Bai-
ley, William W. Kemp, David Pilcher
601
Bacterial translocation in liver failure: a possible
mechanism of impaired innate immune responses and
immuneparesis?
Vishal C. Patel1, Susanne Knapp2, Glory Y. Lai2, Christine Ber-
nsmeier1, Arjuna Singanayagam1, Mark J. McPhail1,2, Christo-
pher Willars1, William Bernal1, Georg Auzinger1, Michael A.
Heneghan1, Krishna Menon1, Wayel Jassem1, Parthi Srinivasan1,
Andreas Prachalias1, Hector Vilca-Melendez1, Nigel Heaton1,
Mark R. Thursz2, Julia Wendon1, Charalambos G. Antoniades2,1;
1Institute of Liver Studies, Kings College Hospital, King’s College
London, London, United Kingdom; 2Section of Hepatology, St.
Mary’s Hospital, Imperial College London, London, United King-
dom
Background: Monocyte (Mo) dysfunction is associated with sus-
ceptibility to infection in acute-on-chronic liver failure (ACLF).
Possible mechanisms include tolerance to persistent microbial
stimulation due to increased circulating levels of bacterial prod-
ucts as a consequence of (i) increased translocation of gut-de-
493A
rived bacteria in association with intestinal barrier dysfunction
and (ii) impaired hepatic clearance of these microbial ligands.
We sought to examine monocyte innate responses to micro-
bial challenges through diverse Toll-like receptor signalling
cascades, and the relationship to circulating levels of bacterial
DNA (bactDNA). Methods: Patients with ACLF (n=18), cirrho-
sis (CLD;n=4) and healthy controls (HC;n=9) were studied.
Whole blood (WB) was obtained for bactDNA and PBMCs. In
a subset of patients undergoing orthotopic liver transplantation
(n=8) WB was sampled concurrently from portal (PV), hepatic
veins (HV), and peripheral artery for ‘cross-liver’ bactDNA
analysis. DNA extraction was performed using QiAMP DNA
extraction kit, followed by real-time PCR with a TaqMan probe
targeting a 380bp region of bacterial 16s rDNA for bactDNA
relative quantification, expressed in pg/mL of WB. In a subset
of 7 ACLF, 5 CLD and 9 HC, PBMC production of TNF-α and
IL-6 was measured by Toll-like receptor (TLR) 2, 4 and 9 ligand
stimulation (5μg/mL, 100ng/mL and 10μg/mL, respectively;
InvivoGen™). Results are expressed as median percentage
of CD14+ Mo. Results: BactDNA levels in ACLF (2.24 IQR
1.33; p=0.0002) and CLD (1.94 IQR 1.34; p<0.04) were
significantly elevated compared to HC (1.08 IQR 0.59). Paired
cross-liver bactDNA levels (PV vs. HV) demonstrated no signif-
icant difference (1.043 vs. 1.291; p=0.11) in ACLF or CLD.
BactDNA levels were also similar in peripheral artery and HV
(1.162 vs 1.29; p=0.91). TLR stimulation of PBMCs in ACLF
patients revealed suppression of TNF-α and IL-6 production.
TNF-α production was supressed in response to TLR2 (16.8%
IQR 21.6 vs 1.2% IQR 5.5 (p=0.0002)) in HC vs ACLF as was
IL-6 ((4.7% IQR 10.3 vs 0.4% IQR 0.39 (p=0.002)). TNF-α
production was also significantly reduced in response to TLR4
(52.9% (HC) vs 8.7% (ACLF); p<0.0001) and to TLR9 (8.2%
(HC) vs 1.67% (ACLF); p=0.01). Discussion: Our data clearly
link attenuated monocyte responses to microbial challenge on
diverse signalling cascades with elevated levels of circulating
bactDNA in patients with ACLF. Persistent exposure to such
bacterial products due to translocation from the gut and other
epithelial beds, in combination with a failure of hepatic clear-
ance, might thus explain endotoxin tolerance, immuneparesis
and susceptibility to infection in ACLF.
Disclosures:
William Bernal - Consulting: Vital Therapies Inc
Michael A. Heneghan - Speaking and Teaching: Falk
Nigel Heaton - Advisory Committees or Review Panels: Novartis, Roche; Speak-
ing and Teaching: Astellas
Mark R. Thursz - Advisory Committees or Review Panels: Gilead, BMS, Abbott
Laboratories
Julia Wendon - Consulting: Pulsion, Excalenz
The following people have nothing to disclose: Vishal C. Patel, Susanne Knapp,
Glory Y. Lai, Christine Bernsmeier, Arjuna Singanayagam, Mark J. McPhail,
Christopher Willars, Georg Auzinger, Krishna Menon, Wayel Jassem, Parthi
Srinivasan, Andreas Prachalias, Hector Vilca-Melendez, Charalambos G. Anto-
niades
494A AASLD ABSTRACTS
602
Number Needed to reTap: Assessing the Utility of
Repeat Diagnostic Paracentesis in Spontaneous Bacterial
Peritonitis
Aparna Goel1, Mollie A. Biewald2, Gopi Patel2,3, Shirish Hupri-
kar2,3, Thomas D. Schiano1,3, Gene Y. Im1,3; 1Medicine, Division
of Liver Diseases, Icahn School of Medicine at Mount Sinai, New
York, NY; 2Medicine, Division of Infectious Diseases, Icahn School
of Medicine at Mount Sinai, New York, NY; 3Recanati-Miller Trans-
plantation Institute, Icahn School of Medicine at Mount Sinai, New
York, NY
Background: Current societal guidelines differ in their recom-
mendations for repeating diagnostic paracentesis (retap) for
the management of spontaneous bacterial peritonitis (SBP).
Increasing rates of antibiotic resistance suggest a need to
retap to guide therapy in SBP. Contemporary cohort studies
to assess this strategy and determine the number needed to
retap to detect initial treatment failure are lacking. Our aim
was to determine the utility of repeat diagnostic paracente-
sis in patients with SBP. Methods: Cirrhotic patients with SBP
hospitalized from 1/2010 to 9/2013 at a high volume liver
transplant center in New York City were retrospectively iden-
tified by ICD-9 code. Clinical and demographic data were
collected and analyzed. SBP was defined as ascitic fluid neu-
trophil count (ANC)>250/mm3. Initial treatment failure was
defined as <25% decrease in ANC after 48 hours of antibiotic
treatment. Results: Over almost 4 years, 186 patients with SBP
were identified and 144 (77%) underwent retap. The cohort
was 70% male, median age 59, the majority having hepatitis
C or alcohol-related cirrhosis (66%), high MELD (median 25)
and a median follow-up of 45 days from SBP diagnosis. Nearly
all were treated with conventionally dosed intravenous albumin
(87%) and antibiotics (100%, 3rd-generation cephalosporin
in 67%), reflecting a highly standardized treatment approach
at our institution. Sixty-three patients (34%) died and 5 under-
went liver transplantation within 30 days of SBP diagnosis.
Initial treatment failed in 26%, revealing the number needed
to retap to identify treatment failure as 4. On multivariate
analysis, peripheral white blood cell count (WBC)>11 x103
cells/mL was associated with treatment failure (2.5; 1.15-5.52;
p=0.02) whereas proton-pump inhibitor (PPI) use was inversely
associated with treatment failure (0.42; 0.18-0.99; p=0.05).
Individuals with treatment failure were 5-times more likely to
have antibiotics broadened than those without failure (p<0.01).
Conclusion: The number needed to retap to identify a single ini-
tial treatment failure was 4, suggesting good utility of repeat
diagnostic paracentesis in patients with SBP. Peripheral WBC
>11 x103 cells/mL is associated with treatment failure and may
identify a cohort of patients most likely to benefit from retap.
Individuals with treatment failure are 5-times more likely to have
antibiotics broadened, which may have an impact on mortality.
Additional cost-effectiveness analysis is required to determine
if retap is of health care value. The possible protective effect
of PPI use on treatment failure is unclear as acid-suppression
therapy has been positively associated with SBP.
Disclosures:
Thomas D. Schiano - Advisory Committees or Review Panels: vertex, salix, merck,
gilead, pfizer; Grant/Research Support: massbiologics, itherx
The following people have nothing to disclose: Aparna Goel, Mollie A. Biewald,
Gopi Patel, Shirish Huprikar, Gene Y. Im
HEPATOLOGY, October, 2014
603
Prognostic significance of Insulin-like growth factor-1
(IGF-1) serum levels in patients admitted for acute
decompensation of cirrhosis
Bruno S. Colombo1, Marcelo F. Ronsoni1, Pedro E. Soares e Silva1,
Leonardo Fayad1, Letícia M. Wildner2, Maria Luiza Bazzo2, Esther
B. Dantas-Correa1, Janaína L. Narciso-Schiavon1, Leonardo L.
Schiavon1; 1Department of Internal Medicine, Division of Gas-
troenterology, Federal University of Santa Catarina, Florianópo-
lis, Brazil; 2Department of Clinical Analysis, Federal University of
Santa Catarina, Florianópolis, Brazil
Introduction: Decreased IGF-1 serum levels have been reported
in patients with cirrhosis and seem to correlate with hepatic
dysfunction intensity. However, data about its prognostic signif-
icance is still lacking. We sought to investigate the relationship
between serum IGF-1 levels and short-term prognosis in patients
admitted for acute decompensation of cirrhosis. Methods: In
this prospective cohort study, patients admitted in the emer-
gency department were followed during their hospital stay and
90-day mortality was evaluated by phone call, in case of hos-
pital discharge. All subjects underwent laboratory evaluation
at admission. The acute-on-chronic liver failure (ACLF) criteria
were applied according to the EASL-CLIF Consortium definition.
Twenty-one patients were also evaluated in the outpatient clinic
after discharge and were compared in two moments (inpa-
tient and outpatient evaluation). Results: Between December
2011 and November 2013, 103 patients were included, with
a mean age of 54.2 ± 11.3 years, and a male predominance
(69.9%). Hepatitis C was the cause of cirrhosis in 40.8% of
the patients, alcohol abuse in 17.5% and hepatitis B in 3.9%.
The mean MELD score was 15.7 ± 6.1 and 36.9% of the indi-
viduals were Child-Pugh C. IGF-1 levels positively correlated
with albumin levels and negatively correlated with INR, CPR,
total bilirubin and MELD. Significantly lower IGF-1 levels were
observed in Child-Pugh C patients (P = 0.007) but not in sub-
jects with ACLF (P = 0.222). The 90-day mortality was 26.2%
and it was associated in the bivariate analysis with older age,
bacterial infection, presence of ascites, hepatic encephalop-
athy, Child-Pugh C and ACLF at admission. Concerning lab-
oratory data, 90-day mortality was associated with higher
creatinine, INR, CRP, venous lactate, total bilirubin, MELD and
lower sodium, albumin and IFG-1 at admission. Stepwise for-
ward logistic regression analysis including variables with P <
0.01 in the bivariate analysis showed that MELD score (OR
1.20, 95% CI 1.08-1.34, P = 0.001), ascites at admission
(OR 12.37, 95% CI 2.73-55.96, P = 0.001) and IGF-1 levels
(OR 0.91, 95% CI 0.84-0.99, P = 0.031) were independently
associated with 90-day mortality. The Kaplan-Meier survival
probability (figure) at 90-day was 87.8% in patients with IGF-1
≥ 10 ng/mL and 61.1% for subjects with IGF-1 < 10 ng/mL
(P = 0.003). Significantly lower IGF-1 levels were found at the
time of acute decompensation of cirrhosis as compared to the
outpatient evaluation (21.9 ± 23.3 ng/mL vs. 49.3 ± 33.3
ng/mL, P < 0.001). Conclusion: IGF-1 levels decrease during
acute decompensation of cirrhosis and were independently
associated with short-term prognosis.
Disclosures:
The following people have nothing to disclose: Bruno S. Colombo, Marcelo F.
Ronsoni, Pedro E. Soares e Silva, Leonardo Fayad, Letícia M. Wildner, Maria
Luiza Bazzo, Esther B. Dantas-Correa, Janaína L. Narciso-Schiavon, Leonardo
L. Schiavon
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
604
Prognostic value of C-reactive protein in patients with
cirrhosis: external validation from the CANONIC cohort
Jean Paul Cervoni1, Amorós Àlex2, Richard Moreau3, Vicente
Arroyo4, Rajiv Jalan8, Faouzi Saliba6, Francois Durand7, Julia
Wendon5, Thierry Gustot9, Paolo Angeli10, Pere Gines4, Thierry
Thevenot1, Vincent Di Martino1; 1Hopital Jean Minjoz, Besancon,
France; 2EASL CLIF Data Center, Hospital Clínic i Provincial de
Barcelona, Barcelona, Spain; 3INSERM CRB3 – Service d’Hépatol-
ogie, Hôpital Beaujon, Clichy, France; 4Liver Unit, Hospital Clínic
i Provincial de Barcelona, Barcelona, Spain; 5Institute of Liver
Studies, King’s College London, London, United Kingdom; 6Centre
Hépato-biliaire, Hôpital Paul Brousse, Villejuif, France; 7Fédéra-
tion médicochirurgicale d’hépato-gastroentérologie, Hôpital Beau-
jon, Clichy, France; 8lnstitute of Liver and Digestive Health, Royal
Free Hospital, London, United Kingdom; 9Service d’Hépatologie,
Erasme, Anderlecht, Belgium; 10Unit of Hepatic Emergencies and
Liver transplantation, University of Padua, Padua, Italy
Patients with end-stage liver disease candidates for liver trans-
plantation are sorted according to MELD score. The Systemic
Inflammatory Response Syndrome impacts on the prognosis of
these patients but is not taken into account by the MELD. In a
recent study CRP a marker of systemic inflammation, has been
reported to predict 6-month mortality in hospitalized cirrhotic
patients with Child-Pugh score>B7. This study demonstrated
the good prognostic value of a 3-variables model incorpo-
rating MELD score, extrahepatic comorbidities, and variation
of CRP levels within 15 days. Objectives: 1) to provide an
external validation of the pejorative influence of sustained high
CRP levels in cirrhotic patients;2) to optimize the prognostic
model without considering extrahepatic comorbidities to make
it more appropriate to the context of liver transplantation, 3)
to test the model for predicting 3 month mortality. Methods:
Data from cirrhotic patients without hepatocellular carcinoma
nor extrahepatic comorbidities, enrolled in CANONIC study
from February to September 2011 in eight European countries
were collected. Multivariate analyses of predictors of 3-month
and 6-month mortality used the Cox model. The prognostic
performance (AUROCs) of the model incorporating CRP vari-
ations within 15 days and MELD score was compared to that
of the MELD score alone. Results: 583 cirrhotic patients hospi-
talized for decompensation with Child-Pugh>B7 and available
CRP value at baseline and at day 15±6 were included. Of
them, 111 patients had baseline CRP≥29mg/L and 60 still
had CRP≥29mg/L at day 15 (group A). Multivariate analysis
(Cox) identified three predictors of 6-months mortality: high
MELD score (HR=1.12;95%CI:1.09-1.15;p<0.001), old age
(HR=1.04;95%CI:1.02-1.06;p<0.001), and CRP level (group
A) (HR=1.65 95%CI:.04-2.64;p=0.035). Multivariate analysis
(Cox) identified three predictors of 3-months mortality: high
MELD score (HR=1.14; 95%CI:1.11-1.17;p<0.001), old age
(HR=1.04;95%CI:1.02-1.06, p<0.001) and CRP level (group
A) (HR=1.69 95%CI:1.01-2.81,p=0.046). The performance
of the 3 variables taken together for predicting 3-months or
6 months mortality was 0.80 (AUROC) and was significantly
better than that of the MELD score (AUROC=0.77;p=0.002).
Conclusion In Pugh >B7 cirrhotic patients with decompensa-
tion, prognostic models incorporating variations in CRP within
15 days predict 3-month and 6-month mortality better than the
MELD score alone. Such models would thus be useful to sort
candidates for liver transplantation, particularly in the event of
intermediate MELD scores.
Disclosures:
Vicente Arroyo - Speaking and Teaching: GRIFOLS
Rajiv Jalan - Consulting: Ocera Therapeutics, Conatus; Grant/Research Support:
Grifols, Gambro
495A
Faouzi Saliba - Advisory Committees or Review Panels: Novartis, Roche, Gen-
zyme, Vital therapies; Grant/Research Support: Astellas; Speaking and Teach-
ing: Schering Plough, Gambro, MSD, Gilead
Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis;
Speaking and Teaching: Gilead
Julia Wendon - Consulting: Pulsion, Excalenz
Paolo Angeli - Advisory Committees or Review Panels: Sequana Medical
Pere Gines - Advisory Committees or Review Panels: Ferring ; Grant/Research
Support: Sequana Medical, Grifols
Vincent Di Martino - Board Membership: Gilead, France, MSD France; Consult-
ing: Gilead, France
The following people have nothing to disclose: Jean Paul Cervoni, Amorós Àlex,
Richard Moreau, Thierry Gustot, Thierry Thevenot
605
Factors associated with low cardiac T2* MRI in liver
transplant (LT) candidates at risk for iron overload
Moises Nevah Rubin1, Monika Sarkar1, Karen Ordovas2, Oren K.
Fix1, Neil Mehta1; 1Gastroenterolgoy and Hepatology, The Univer-
sity of California, San Francisco, San Francisco, CA; 2Radiology
and Biomedical Imaging, The University of California, San Fran-
cisco, San Francisco, CA
At our center, liver transplant (LT) candidates with concern for
iron overload based on ferritin > 1000 μg/L with transferrin
saturation > 50%, significant iron overload on liver biopsy,
or hereditary hemochromatosis must undergo cardiac MRI
T2* to assess for cardiac iron overload. While T2* <10ms is
considered a contraindication to LT, the significance of values
between 10-20ms, or factors associated with significant car-
diac iron overload and subsequent post LT heart failure (HF),
are not known. Methods: This was a retrospective single-center
cohort study of adult LT candidates that underwent cardiac MRI
T2* between January 2008 and May 2014. All patients also
had a transthoracic echocardiogram (TTE) performed prior to
MRI. Logistic regression was used to identify predictors of wait-
list and post LT outcomes. Results: Median age of the eligible
cohort (n=129) was 56 years (IQR 50-61). 71% were male
and 43% were Caucasian. Hepatitis C was the most common
etiology of liver disease (50%). Median MELD at time of T2*
was 24 and 67% of patients were Child-Pugh class C (CP-C).
Seventy-six patients had HFE gene mutation analysis tested,
7 (9%) of whom had high-risk mutations (C282Y/C282Y or
C282Y/H63D). Median ferritin was 1477 μg/L (IQR 1173-
2270) and median iron and transferrin saturation were 137.5
μg/dL and 86%, respectively. Median left ventricular ejection
fraction (LVEF) on TTE was 68% (IQR 64-73) and diastolic dys-
function was found in 28%. Median T2* was 29 ms and 28
patients (22%) had a value <20ms. On multivariate analysis,
CP-C (HR 4.9, 95% CI 1.4-16.4, p=0.01), ferritin>2000 μ/L
(HR 2.8, 95% CI 1.1-7.2, p=0.03), and LVEF on TTE (HR 1.5
(per 5% drop), 95% CI 1.1-1.9, p=0.01) were associated with
having a T2* ≤20ms. Overall, 62 patients (48%) received LT,
38% were delisted (7 due to T2*<10ms), and 12% are still
waiting. Thirteen patients with a T2* 11-20ms underwent LT
and 4 of these (31%) had immediate post LT HF whereas only
1 of 49 patients (2.0%) with a T2*>20ms experienced post
LT HF (p=0.01). Two of the 5 patients with post LT HF died. In
addition to T2* <20ms, lower LVEF on echocardiogram was
also associated with post LT HF (p=0.04). Conclusion: In LT
candidates at risk for iron overload, severity of liver disease,
lower TTE LVEF and ferritin levels>2000 μg/L were associated
with T2* ≤20ms, which in turn was associated with post LT HF.
As over 30% of patients with T2* values between 10-20ms
developed post LT HF, early involvement of HF specialists is
prudent for both pre-LT patient selection decisions and for close
management in the peri-transplant period.
496A AASLD ABSTRACTS
Disclosures:
The following people have nothing to disclose: Moises Nevah Rubin, Monika
Sarkar, Karen Ordovas, Oren K. Fix, Neil Mehta
606
Involvement of the TNF and FasL produced by CD11b
Kupffer cells/macrophages in CCl4-induced acute
hepatic injury
Hiroyuki Nakashima1, Atsushi Sato1, Masahiro Nakashima1,
Masami Ikarashi1, Kiyoshi Nishiyama2, Manabu Kinoshita1, Shuhji
Seki1; 1Immunology and Microbiology, National Defense Medical
College, Saitama, Japan; 2Department of Surgery 1, National
Defense Medical College, Saitama, Japan
Background: Hepatic injury induced by carbon tetrachloride
(CCl4) is a well-known chemical-induced hepatocyte injury.
However, the role of Kupffer cells in this model is still in con-
troversy. We previously reported that F4/80+ Kupffer cells
are subclassified into two subsets, the CD68+ population with
phagocytic, ROS producing and bactericidal capacities, and
CD11b+ population with cytokine-producing and antitumor
capacities in mice and humans. Based on this theory, the pres-
ent study investigated the immunological role of Kupffer cells/
macrophages in CCl4-induced hepatitis. Methods: C57BL6
mice were administered with CCl4 intra-peritoneally and exam-
ined dynamics of Kupffer cell populations, intracellular TNF
and surface Fas-ligand (FasL) expression by flow cytometry.
After clodronate liposome (c-lipo) pretreatment, hepatic injury
and Kupffer cell populations were examined. Hepatic injury
was also examined in mice after adoptive transfer of CD11b+
Kupffer cells/macrophages isolated from CCl4 administered
mice. Results: Severe hepatic injury was induced 24 h after
CCl4 administration, and simultaneously the population of
CD11b+ Kupffer cells/macrophages dramatically increased.
Consistent with our previous report, the immunohistochemical
analysis of the liver and the flow cytometry of the liver mono-
nuclear cells showed that c-lipo treatment greatly decreased
the spindle-shaped F4/80+ or CD68+ cells, while the oval-
shaped F4/80+ CD11b+ cells increased. Notably, hepatic
injury induced by CCl4 was further aggravated by c-lipo-pre-
treatment. The CD11b+ Kupffer cells expressed intracellular
TNF and surface FasL after CCl4 administration. Anti-FasL Ab
pretreatment or FasL deficient gld/gld mice attenuated the liver
injury. Furthermore, anti-TNF Ab pretreatment decreased the
FasL expression of CD11b+ Kupffer cells and ameliorated the
hepatic injury. The adoptive transfer experiment and cytotoxic
assay against primary cultured hepatocytes confirmed the role
of CD11b+ Kupffer cells in CCl4-induced hepatitis. Interest-
ingly, the serum MCP-1 level rapidly increased and peaked at
six hour after c-lipo pretreatment, suggesting that the MCP-1
produced by c-lipo-phagocytized CD68+ Kupffer cells may
recruit CD11b+ macrophages from the periphery and bone
marrow. Conclusion: The recruited CD11b+ Kupffer cells seem
to accelerate hepatocyte apoptosis by producing TNF and
FasL, and play a pivotal role in CCl4-induced acute hepatic
injury. Consideration of the phenotypical and functional differ-
ences of Kupffer cell/macrophage subpopulations contributes
to the better understanding of the immunological mechanisms
of experimental hepatitis and pathogenesis of liver diseases.
Disclosures:
The following people have nothing to disclose: Hiroyuki Nakashima, Atsushi
Sato, Masahiro Nakashima, Masami Ikarashi, Kiyoshi Nishiyama, Manabu
Kinoshita, Shuhji Seki
HEPATOLOGY, October, 2014
607
Acid sphingomyelinase inhibits growth of metastatic
liver tumor
Yosuke Osawa, Jun Imamura, Kiminori Kimura; Hepatology, Tokyo
Metropolitan Cancer and Infectious Diseases Center Komagome
Hospital, Tokyo, Japan
Acid sphingomyelinase (ASM) regulates the homeostasis of
sphingolipids, including ceramides and sphingosine-1-phos-
phate (S1P). These sphingolipids regulate carcinogenesis and
proliferation, survival, and apoptosis of cancer cells. However,
the role of ASM in host defense against liver metastasis remains
unclear. In this study, the involvement of ASM in liver metastasis
of colon cancer was examined using ASM–/– and ASM+/+
mice that were inoculated with SL4 colon cancer cells to pro-
duce metastatic liver tumors. ASM expression and ceramide
generation were increased by SL4 inoculation. ASM–/– mice
demonstrated enhanced tumor growth and reduced macro-
phage accumulation in the tumor. Tumor growth was increased
by macrophage depletion, but was decreased by ASM over-
expression in the liver accompanied with increased S1P pro-
duction. S1P stimulated macrophage migration in vitro. These
findings indicate that ASM in the liver inhibits tumor growth
through cytotoxic macrophage accumulation in response to
S1P. In addition, B16C2M melanoma cells formed small meta-
static lesions in the liver of ASM–/– mice (incidence: 44.4%),
whereas none of the ASM+/+ mice developed metastases,
suggesting that the anti-tumor effect of ASM is not specific for
colon cancer cells. In conclusion, ASM in hepatocytes inhib-
ited tumor growth via S1P formation and subsequent cytotoxic
macrophage accumulation. Thus, targeting ASM may represent
a new therapeutic strategy for treating metastatic liver tumor.
Disclosures:
The following people have nothing to disclose: Yosuke Osawa, Jun Imamura,
Kiminori Kimura
608
Dose-limiting toxicity of in vivo TLR7 ligation differs
according to the kinetics of systemic and hepatic inflam-
mation after LCMV infection
Thomas Vanwolleghem1, Dowty Movita1, Martijn D. van de
Garde1, Florence Herschke2, Gregory C. Fanning2, Harry L. Jans-
sen1,3, Andre Boonstra1; 1Department of Gastroenterology and
Hepatology, Erasmus MC University Hospital, Rotterdam, Neth-
erlands; 2Janssen Infectious Disease and Drug Safety Sciences,
Beerse, Belgium; 3Liver Clinic, University Health Network, Toronto,
ON, Canada
Background Limited information is available on the dynamics
of immune responses in the liver shortly after and during the
chronic phase of HBV and HCV infection. A better understand-
ing of these intrahepatic processes is essential since currently
the applicability of immunostimulants, such as Toll-like receptor
(TLR) agonists are being examined as an alternative antiviral
strategy to treat patients with chronic HBV or HCV. We stud-
ied the kinetics of viral hepatitis in the LCMV infection model
in C57Bl/6 mice, and evaluated intrahepatic immune effects
following treatment of LCMV-infected mice with a TLR7/8 ago-
nist. Methods C57Bl/6 mice, aged 4-6 weeks were infected
with LCMV-clone 13 via the intravenous route, and sacrificed
at different time points post-infection. Livers were isolated and
subjected to flowcytometry or mRNA analysis, and serum was
analysed by multiplex protein arrays. Therapeutic treatment
of R848 (intraperitoneal, 4-40 μg/mouse) was performed at
early (day 8-15) or chronic phase of LCMV infection (>day
15 post-infection). Results We observed that the early phase
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
of LCMV infection was characterized by a strong reduction of
body weight and mild discomfort. Moreover, during the early
phase high ALT levels, extensive leukocyte inflammation of the
liver, increased intrahepatic TLR7 mRNA expression, and high
serum TNF and IFNγ levels were observed. Therapeutic injec-
tion of R848 at the early phase of LCMV resulted in severe
pathology and lethality. Lethality was still observed at a dose
4 μg/mouse, which was 10-fold lower than tolerated by unin-
fected mice at this time point. In contrast, R848 treatment at a
chronic phase of LCMV infection (>day 15 post-infection) was
better tolerated, with only mild adverse effects. Importantly, at
the chronic phase of infection, next to serum pro-inflammatory
cytokines (IFNγ, TNF and IL-6), serum IFNα was induced by
R848 injection (up to 380-fold in uninfected mice compared
to 100-fold in LCMV-infected mice). At 3 hours after R848
treatment high ISG-15 mRNA levels were measured in the liver
in both LCMV-infected and control mice, while no intrahepatic
IFNα mRNA was induced. Conclusions Our findings highlight
the importance of understanding the kinetics of intrahepatic
immunity following viral infection, and acknowledge the impor-
tance of the narrow time-window and dose range that is crucial
for the ongoing development of therapeutic immunostimulants
to treat chronic HCV and HBV patients. Future studies will be
conducted that test whether the tolerated dose of R848 is suf-
ficient to clear the virus during the chronic phase of infection.
Disclosures:
Florence Herschke - Employment: Janssen Pharmaceutica
Gregory C. Fanning - Management Position: Tibotec, Tibotec, Tibotec, Tibotec
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sci-
ences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support:
Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck,
Medtronic, Novartis, Roche, Santaris
Andre Boonstra - Grant/Research Support: BMS, Janssen Pharmaceutics, Merck,
Roche
The following people have nothing to disclose: Thomas Vanwolleghem, Dowty
Movita, Martijn D. van de Garde
609
Cytotoxic CD4+ Cells Play a Pivotal Role in Cyclophos-
phamide-Mediated Cytotoxicity against Hepatoma with-
out Antigen Priming
Tatsushi Naito1, Tomohisa Baba2, Naofumi Mukaida2, Yasunari
Nakamoto1; 1Second Department of Internal Medicine, University
of Fukui, Fukui, Japan; 2Division of Molecular Bioregulation, Can-
cer Research Institute of Kanazawa University, Kanazawa, Japan
BACKGROUND: Hepatocellular carcinoma (HCC) frequently
recurs in patients with liver cirrhosis that is known to have
the high carcinogenic potentials, even after successful local
treatment. Thus, the development of multidisciplinary treatments
including immune therapy is needed. Accumulating evidence
indicated the potential roles of CD4+ T cells with a direct
cyototoxicity (CD4 + CTLs) in antitumor immunity. It was also
reported that the decrease in number of CD4+ CTLs was cor-
related with high mortality rate in patients with HCC. However,
the importance of CD4+ CTLs in patients treated with anticancer
chemotherapy remains to be elucidated. Hence, we examined
the role of CD4+ cells, particularly CD4+ CTLs, in chemother-
apy-induced tumor eradication in an animal model of HCC.
METHODS and RESULTS: We injected a murine hepatoma cell
line BNL 1ME A.7R.1 (BNL) subcutaneously into Balb/c mice
and performed a single intraperitoneal injection of 150 mg/kg
cyclophosphamide (CTX) after a tumor formed. CTX injection
eradicated tumors in wild-type mice (6 / 9 heads), whereas
none of the tumors disappeared in nude mice lacking T cells
(P<0.05). Moreover, depletion of CD4+ cells by antibody GK
1.5 abrogated CTX-induced tumor eradiation, while CD8+
497A
cell depletion by antibody 53. 6. 7. did not show the effects.
Consistently, CTX treatment increased intratumoral CD4+ CTLs
expressing cytolytic granule protein CD107a. When fluoro-
chrome-labeled congenic CD45.1 splenocytes were intrave-
nously transferred to tumor-bearing CD45.2 mice one day after
CTX treatment, adoptively transferred CD4+ CTLs accumulated
at tumor sites without proliferation on day 3 after transfer, and
the cells started to proliferate on day 6. CONCLUSIONS: The
cytotoxic effect of CTX treatment against HCC cells critically
depends on CD4+ CTLs in a mouse model, in which CD4+
cells infiltrate into tumor site without antigen priming and sub-
sequently exhibit the killing activity in an antigen-nonspecific
manner. The results suggest a novel strategy to enhance the
antitumor immunity by activating CD4+ CTLs in patients treated
with chemotherapeutic agents for HCC.
Disclosures:
The following people have nothing to disclose: Tatsushi Naito, Tomohisa Baba,
Naofumi Mukaida, Yasunari Nakamoto
610
Activation of cellular innate immunity during primary
Hepacivirus infection
Cordelia Manickam1,2, R. Keith Reeves1,2; 1Immunology, NEPRC,
Harvard Medical School, Southborough, MA; 2Center for virology
and vaccine research, Beth Israel Deaconess medical center, Bos-
ton, MA
Hepatitis C virus (HCV) is estimated to infect greater than 150
million people worldwide and is a major source of global mor-
bidity and mortality. Interestingly, many individuals clear the
virus after an acute viremia while others develop chronic dis-
ease, but the factors that dictate these two disease phenotypes
are poorly understood. In this study we utilized an understudied
model of HCV infection, GBV-B infection of common marmo-
sets to characterize innate immune responses to hepaciviruses.
During acute infection, the frequency of NK cells increased up
to 3-fold, generally peaking between day 7 and day 14. The
frequency of NK cells in circulation returned to pre-infection
levels by day 57 post-infection. Correspondingly, up to 3-fold
increases in intracellular Ki67 expression were observed as
early as day 7 and were elevated through day 28 post-in-
fection. Circulating NK cells also upregulated expression of
CXCR3, suggesting increased infiltration into tissues. However,
no increase in NK cells was found in the liver at day 14. Func-
tionally, NK cells in both the circulation and in the liver had
increased expression of intracellular perforin, but no change in
production of IFN-γ or TNF-α. Up to 2-fold increases in circulat-
ing antiviral plasmacytoid DCs (pDCs) were observed as early
as day 3 and peaked around day 7. In liver, the percentages
of total pDCs also increased significantly by day 14. Interest-
ingly, no changes were observed in T cell numbers or activa-
tion states during the first few weeks post-infection, but after
day 28, increases in perforin, Ki67 expression, and memory
cell subsets of both CD4 and CD8 T cells were observed. Thus,
GBV-B activates the innate immune system early after infection
before T and B cell responses are detectable. Additional stud-
ies will be needed to determine what role innate immune cells
might play in modulation of GBV-B infection and persistence.
Disclosures:
The following people have nothing to disclose: Cordelia Manickam, R. Keith
Reeves
498A AASLD ABSTRACTS
611
DSS-induced colitis and simultaneous hepatic inflamma-
tion lead to immunological tolerance in the murine liver
Nobuhito Taniki1, Nobuhiro Nakamoto1, Hirotoshi Ebinuma1,
Hiroko Murata1, Yuko Wakayama1, Po-sung Chu1, Shingo Usui1,
Akihiro Yamaguchi1, Takeru Amiya1, Hidetsugu Saito2, Takanori
Kanai1; 1Keio University, School Of Medicine, Tokyo, Japan;
2Keio University, School of Pharmacy, Tokyo, Japan
BACKGROUND & AIMS: The liver is continuously exposed to
gut-derived antigen stimulation such as short chain fatty acids
(SCFA) and Microbe-associated molecular patterns (MAMPs)
from intestinal tracts through portal vein. Specific subsets of
innate immune cells, such as macrophages and dendritic cells
play a role to eliminate these foreign antigens. On the other
hand, numerous phenomena such as persistent hepatotrophic
viral infections and Lipopolysaccharide (LPS) tolerance suggest
that liver is also an immunological tolerant organ. In this study,
we sought to clarify the role of innate immune cells that lead to
immunological tolerance through the gut-liver axis. METHODS:
We recently reported that mice treated with dextran sulfate
sodium (DSS) for 7 days, a common colitis model in mice, devel-
oped a mild hepatic inflammation with an infiltration of inflam-
matory cells. In this study, a sub-lethal dose of concanavalin A
(ConA), a common model of T cell-mediated hepatitis in mice,
was subsequently administered to DSS-treated mice or WATER-
treated mice. The severity of hepatitis and colitis, and a subset
of immune cells emerged in each organ were evaluated 12 h
after ConA injection, and compared between the following
groups (WATER-PBS, WATER-ConA, DSS-PBS, and DSS-ConA).
RESULTS: DSS-ConA treated mice developed a significantly
mild liver inflammation both in histology and serology com-
pared with WATER-ConA group (serum ALT level; 6867±1522
IU/ml vs.1130±226.2 IU/ml, p= 0.0003). Importantly, the
severity of the basal colitis level was inversely correlated with
a subsequent liver inflammation. We recently reported that
tumor necrosis factor (TNF)-producing CCR9+CD11b+ macro-
phages play a critical role in murine acute liver injury patho-
genesis following a single injection of ConA. In WATER-ConA
treated liver, TNF-producing CCR9+CD11b+ macrophages
(WATER-ConA mac) were increased as expected, whereas
CCR9-CD11b+ macrophages (DSS-ConA mac), a function-
ally distinct subset from WATER-ConA mac, were increased in
DSS-ConA treated liver. Sorted DSS-ConA mac had regulatory
characteristics and potentially produced IL-10, but less TNF or
interferon-gamma with LPS stimulation in vitro. Furthermore,
DSS-ConA mac showed a deficient ability to present antigens
to naïve CD4 T cells derived from ovalbumin (OVA)-specific
αβ-TCR transgenic mice. CONCLUSIONS: These results col-
lectively suggest that IL10-producing CCR9-CD11b+ macro-
phages migrated to the inflamed liver under DSS-induced colitis
contribute to immunological tolerance in the liver.
Disclosures:
The following people have nothing to disclose: Nobuhito Taniki, Nobuhiro Naka-
moto, Hirotoshi Ebinuma, Hiroko Murata, Yuko Wakayama, Po-sung Chu, Shingo
Usui, Akihiro Yamaguchi, Takeru Amiya, Hidetsugu Saito, Takanori Kanai
HEPATOLOGY, October, 2014
612
A novel mouse model of hepatocyte apoptosis-induced
sterile liver inflammation and wound healing response
Heng-Fu Bu1,2, Fangyi Liu1,2, Xiao Wang1,2, Pauline M. Chou3,2,
Catherine Marek2, Ke Tian1,2, Peng Wang1,2, Hua Geng2, M.
S. Rao3, Suhail Akhtar2, Monique E. De Paepe4, Xiao-Di Tan1,2;
1Department of Pediatrics, Feinberg School of Medicine, North-
western University, Chicago, IL; 2Center for Intestinal and Liver
Inflammation Research, Stanley Manne Children’s Research Insti-
tute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chi-
cago, IL; 3Department of Pathology, Feinberg School of Medicine,
Northwestern University, Chicago, IL; 4Department of Pathology,
Alpert Medical School of Brown University, Providence, RI
Massive hepatocyte apoptosis is a characteristic of acute
liver damage, whereas scattered apoptotic hepatocytes are
frequently found in various chronic liver diseases. To estab-
lish a mouse model of inducible apoptosis in a hepatocyte
specific manner, and to elucidate progression and resolution
of hepatocyte apoptosis-triggered liver injury, we generated
a triple transgenic mouse line, namely, 3xTg-iHAP (inducible
Hepatocyte specific Apoptosis Phenotype). The phenotype of
3xTg-iHAP mice was characterized by having doxycycline
(Dox)-induced Fas-ligand expression and apoptotic cell injury
in a dose-dependent and hepatocyte specific manner. Injection
of high-dose of Dox (10 mg/kg, s.c.) induced massive hepato-
cyte apoptosis in 3xTg-iHAP mice within 8 hrs, which caused
fulminant liver failure and hepatic encephalopathy. In contrast,
3xTg-iHAP mice treated with a low-dose of Dox (1.2 – 1.7 mg/
kg, s.c.) survived, but histological analysis showed scattered
apoptotic hepatocytes throughout the liver lobule. Within 24
hrs after low-dose Dox-initiated hepatic apoptotic injury, 3xTg-
iHAP mice developed asymptomatic transient sterile inflam-
mation characterized by mild neutrophil infiltration in the liver
and elevated TNF-α level in serum. The liver inflammation and
injury in 3xTg-iHAP mice were spontaneously resolved through
liver regeneration and restitution within 5 days after low-dose
Dox challenging. Taken together, we have developed and val-
idated a new murine model of hepatocyte apoptosis-induced
sterile liver inflammation and wound healing response. In a
pilot study, we further revealed that 3xTg-iHAP mice chronically
fed with alcohol-containing Lieber-DeCarli liquid diet devel-
oped profound steatohepatitis after treatment with a single low-
dose of Dox. This finding suggests that our novel mouse model
for sterile liver inflammation can be combined with other liver
disease models for studying the exact role of multi-hits in the
pathogenesis of numerous inflammatory liver diseases such
as alcoholic hepatitis and nonalcoholic steatohepatitis. Thus,
3xTg-iHAP mice is a novel in vivo research tool and may have
a broad range of applications from exploring insights into the
pathogenesis of sterile liver inflammation to testing new thera-
pies for various liver diseases and complications (Supported in
part by grants from the NIH).
Disclosures:
The following people have nothing to disclose: Heng-Fu Bu, Fangyi Liu, Xiao
Wang, Pauline M. Chou, Catherine Marek, Ke Tian, Peng Wang, Hua Geng,
M. S. Rao, Suhail Akhtar, Monique E. De Paepe, Xiao-Di Tan
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
613
Administration of antisense oligodeoxynucleotides to
nerve growth factor attenuates inflammation and liver
damage in acute liver damage models
Rafael Bruck1, Einav Hubel2, Isabel Zvibel2; 1Gastroenterology
and Liver, Tel Aviv Medical Center, Tel Aviv, Israel; 2Research
Gastro and Liver Center, Tel Aviv Medical Center, Tel Aviv, Israel
Background/Aims: Nerve growth factor (NGF) has pro-inflam-
matory effects in lung and skin inflammatory diseases. During
liver regeneration, NGF secreted by hepatocytes induces
hepatic stellate cell apoptosis. However, NGF involvement in
models of liver damage and inflammation has not yet been
assessed. We investigated the possible inflammatory effects of
NGF on isolated hepatic stellate cells (HSC), as well as the in
vivo effect of silencing NGF on acute liver damage and inflam-
mation. Methods: Primary HSC from rats and mice were iso-
lated and cultured for 7d and 14d to obtain activated and fully
activated HSC, respectively. HSC were treated with 100ng/
ml NGF and proNGF and inflammatory cytokine expression
was assessed by qRT-PCR and ELISA. Acute liver damage was
induced by two i.p. injections of CCl4 (1μl/g body weight) or
by bile duct ligation (BDL) and mice received daily treatment
with antisense oligodeoxynucleotide to NGF (ODN)(25mg/kg
body weight). Results: Both NGF and proNGF induced expres-
sion of pro-inflammatory cytokines TNFα and IL-6 in activated
and fully activated primary rat and murine HSC. Administration
of antisense ODN to NGF in the acute CCl4 and BDL mod-
els reduced liver damage, as demonstrated by significantly
reduced serum liver enzymes. In addition, antisense ODN to
NGF resulted in dramatically reduced (6- fold) hepatic mRNA
expression of pro-inflammatory cytokines IL-6, TNFα and MCP1
in the acute CCl4 model. In the BDL-induced acute liver injury,
administration of ODN resulted in a two-fold reduction in
TNFα, MCP-1 and CXCL1 expression. Conclusions: Silencing
NGF may have a beneficial, anti-inflammatory and protective
effect in acute hepatotoxicity models.
Disclosures:
The following people have nothing to disclose: Rafael Bruck, Einav Hubel, Isabel
Zvibel
614
High fat diet impairs hepatic microRNAs related to
inflammation and macrophage infiltration contributing
to nonalcoholic steatohepatitis in a mouse model with
metabolic syndrome
Priya Handa1,2, Vicki Morgan-Stevenson1,2, Bryan D. Maliken1,2,
Yu Li1,2, James E. Nelson1,2, Matthew M. Yeh3, Kris V. Kowd-
ley1,2; 1Liver Center of Excellence, Digestive Disease Institute, Seat-
tle, WA; 2Benaroya Research Institute, Virginia Mason Medical
Center, Seattle, WA; 3University of Washington Medical Center,
Seattle, WA
Aim: The goal of this study was to investigate the relationship
between inflammation-related microRNAs and NAFLD patho-
genesis in a rodent model with metabolic syndrome. Methods:
Leptin receptor deficient (Leprdb/db) mice were fed a high
fat diet or standard chow for 5 or 10 weeks. Liver histology
was scored for steatosis, ballooning, inflammation, fibrosis
and NAFLD activity score (NAS) by a hepatopathologist; and
classified into DM (diabetes mellitus), NAFL (nonalcoholic fatty
liver) and NASH (nonalcoholic steatohepatitis) groups. Serum
were analyzed for metabolic changes, and hepatic microRNA
(miR-122, -146a, -155, and -223) levels were determined.
Results: Greater than half of the mice fed high-fat diet devel-
oped NASH compared to controls. Mice with NAFL and NASH
499A
had elevated hepatic triglycerides, serum aminotransferases,
inflammatory cytokines (IL-6 and TNF-α), glucose and insulin
levels. Expression of miR-155 and -223 (p<0.01 for both)
were increased in NAFL and NASH mice, while miR-122 was
decreased, relative to DM. Expression of miR-146a were also
increased in the livers of NAFL and NASH mice compared to
DM mice (p<0.03), though the extent of increase was smaller
compared to miR155 and 223. Increased levels of miR155
correlated with upregulation of its transactivator and target,
NF-KB, in NASH livers, indicated by increased phosphoryla-
tion of the p65 subunit of NF-KB, and increased expression of
MCP-1, an NF-KB regulated chemokine and CCR2, its cognate
receptor. Consistent with the upregulation of miR-155 (and
down-regulation of miR-122), we observed increased infiltra-
tion of macrophages in NASH livers indicated by increased
F480 and Mac-2 staining; and elevated CD68, F480 and
CD11b gene expression levels in the NASH livers, relative
to DM. Also consistently, T cell markers such as CD3gamma,
IFN-gamma, MHCII and CD8 were upregulated in NASH
livers. Regression analysis revealed that correlating miR-155
versus miR-223 gave a Pearson r of 0.91. These miRs were
strongly associated with %mass increase (r=0.61, p<0.0001
for both), ALT & AST (r>0.56, p<0.001 for all), adiponectin
(r<-0.50 for both, p<0.001), and NAS (Spearman r=0.50,
p<0.001 for both). Conclusions: MicroRNAs associated with
inflammation, especially miR155 and its known targets, were
significantly altered in this mouse model of NASH, suggesting
their involvement in cytokine/chemokine induction and immune
cell recruitment and activation. The significant Pearson’s cor-
relation between MiR-155 and miR-223 indicated that these
microRNAs are involved in similar inflammatory cascades in
NASH progression. These studies emphasize a key role for
these microRNAs in NASH pathogenesis.
Disclosures:
Kris V. Kowdley - Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research
Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria,
Janssen, Merck, Mochida, Vertex
The following people have nothing to disclose: Priya Handa, Vicki Morgan-Ste-
venson, Bryan D. Maliken, Yu Li, James E. Nelson, Matthew M. Yeh
615
Murine natural killer cells transiting through the liver
demonstrate hyporesponsiveness to activation receptor
mediated stimulation
Claire Meyer, Sandeep K. Tripathy; Division of Gastroenterology,
Department of Medicine, Washington University in St. Louis, St.
Louis, MO
Purpose: The healthy liver appears to maintain relative immu-
notolerance, where significant inflammation is absent despite
exposure to antigen-rich blood from the portal vein. Defining
the scope of this tolerance, and how it is maintained, pro-
vides a foundation for understanding diseases in which it may
be altered. The purpose of this study is to determine if the
hepatic microenvironment contributes to natural killer (NK)
cell tolerance using a mouse model. Methods: Hepatic and
splenic NK cells were harvested from C57BL/6-background
mice, stimulated with plate-bound antibodies to NK1.1 and
Ly49D, and assessed for interferon-γ production. To assess for
differences in Ly49 receptor repertoire, hepatic and splenic NK
cells were stained for Ly49A, Ly49C, Ly49D, Ly49G2, Ly49H,
and Ly49I. Previous studies describe two populations of hepatic
NK cells differentiated by CD49a expression, thus hepatic NK
cells in this study were further subdivided into liver-resident
(CD49a+) and liver-transiting (CD49a-). Results: Following
stimulation through NK1.1, 20.4% of total hepatic NK cells
500A AASLD ABSTRACTS
produced interferon-γ, compared with 52.2% of splenic NK
cells (p<0.0001, n=6); among the hepatic NK cells, 23.6%
of CD49a+ cells and 19.5% of CD49a- cells produced inter-
feron-γ (p=0.558, n=6). Following stimulation through Ly49D,
5.0% of total hepatic NK cells produced interferon-γ, compared
with 22.8% of splenic NK cells (p<0.0001, n=6); among the
hepatic NK cells, 3.2% of CD49a+ cells and 5.7% of CD49a-
cells produced interferon-γ (p=0.055, n=6). Liver-transiting and
splenic NK cells expressed similar levels of Ly49A, Ly49C and
Ly49I, Ly49D, Ly49G2, Ly49H, and Ly49I (n=3). Conclusions:
Hepatic NK cells produced significantly less interferon-γ than
did splenic NK cells when stimulated through activating recep-
tors NK1.1 and Ly49D. Liver-resident and liver-transiting NK
cells showed similar levels of interferon-γ production, suggest-
ing that the overall defect in interferon-γ production by total
hepatic NK cells was not due to the presence of a hypofunc-
tional liver-resident population. No significant differences in
Ly49 receptor expression were found between liver-transiting
and splenic NK cells, suggesting that differences in expression
of these inhibitory or activating receptors were not responsible
for the altered responsiveness. These results demonstrate that
the liver microenvironment decreases activation receptor-medi-
ated responses in transiting NK cells. Further work is needed
to determine the mechanisms by which this occurs. An under-
standing of these mechanisms might allow us to modify NK cell
function for use in the treatment of viral infections and malig-
nancies of the liver.
Disclosures:
The following people have nothing to disclose: Claire Meyer, Sandeep K. Trip-
athy
616
Characterization of the liver:lung axis in alcohol-in-
duced lung damage
Veronica L. Massey1,2, Lauren G. Poole1,2, Edilson Torres-Gonza-
lez3,4, Robin H. Schmidt1,2, Michael L. Merchant5, Keith C. Falk-
ner2, Jeffrey D. Ritzenthaler3, Jesse Roman3,4, Gavin E. Arteel1,2;
1Pharmacology and Toxicology, University of Louisville School of
Medicine, Louisville, KY; 2University of Louisville Alcohol Research
Center, University of Louisville School of Medicine, Louisville, KY;
3Department of Medicine, Division of Pulmonary, Critical Care,
and Sleep Disorders Medicine, University of Louisville School of
Medicine, Louisville, KY; 4Veterans Affairs Medical Center, Louis-
ville, KY; 5Department of Medicine, Division of Nephrology, Uni-
versity of Louisville School of Medicine, Louisville, KY
Background. It is well known that liver and lung injury can
occur simultaneously during severe inflammation (e.g. multiple
organ failure). However, whether these are parallel or interde-
pendent (i.e. liver:lung axis) mechanisms is unclear. Previous
studies have shown that chronic alcohol consumption greatly
increases the risk of mortality caused by acute respiratory dis-
tress syndrome (ARDS). The potential contribution of subclini-
cal liver disease driving this effect of ethanol on the lung has
not been determined. Therefore, the purpose of this study was
to develop a model of concomitant liver and lung injury in
the setting of chronic alcohol exposure, followed by an acute
inflammatory stimulus. Methods. Male mice were exposed to
ethanol-containing Lieber-DeCarli diet or pair-fed control diet
for 6w. At the end of the feeding period, some animals were
administered LPS to induce ARDS-like lung damage and sac-
rificed either 4 or 24 h after LPS exposure. The expression of
cytokine mRNA in lung and liver tissue were determined by
real-time PCR. Cytokine levels in the BAL and plasma were
determined by Luminex assay. Changes in the ECM proteome
of the liver and lung were determined by LC-MS. Results. As
HEPATOLOGY, October, 2014
expected, the combination of EtOH and LPS caused liver injury,
as indicated by significantly increased levels of ALT/AST in
the plasma. EtOH preexposure also increased the number and
size of inflammatory foci in the liver tissue caused by LPS. In
the lung, EtOH preexposure enhanced pulmonary inflammation
and alveolar hemorrhage caused by LPS exposure. The combi-
nation of EtOH and LPS resulted in a unique pro-inflammatory
mRNA expression profile in the two organs. As expected, eth-
anol preexposure significantly increased hepatic TNFα mRNA
expression and increased TNFα levels in the systemic circula-
tion. In contrast, EtOH preexposure significantly increased pul-
monary mRNA expression of the TNFα responsive genes MIP-2
and KC in the lung in the absence of a significant increase in
TNFα mRNA or protein in lung tissue or BAL fluid, respectively.
Additionally, EtOH exposure caused dynamic, transitional
changes in the expression of ECM components (e.g. fibrin and
fibronectin) in both the liver and lung. Conclusions. EtOH pre-
exposure enhanced both liver and lung injury caused by LPS.
Enhanced organ injury corresponded with unique changes in
the expression of pro-inflammatory cytokines in the liver (i.e.
TNFα) and the lung (i.e. MIP-2, KC). EtOH preexposure also
contributed to transitional changes in the ECM profile and
increased expression of extracellular matrices which may play
direct role in enhanced inflammation and injury in the two
organs.
Disclosures:
Jesse Roman - Advisory Committees or Review Panels: Cellgene; Grant/Research
Support: Actelion, Intermune, Novartis
The following people have nothing to disclose: Veronica L. Massey, Lauren G.
Poole, Edilson Torres-Gonzalez, Robin H. Schmidt, Michael L. Merchant, Keith C.
Falkner, Jeffrey D. Ritzenthaler, Gavin E. Arteel
617
DSS-induced Chronic Colitis Aggravates Inflammation
and Fibrogenesis in Mice with CCl4-induced Hepatic
Fibrosis
Xiaolan Zhang, Yufeng Liu, Guochao Niu, Libo Zheng; Dept of
Gastroentology, The Second Hospital of Hebei Medical University,
Shijiazhuang City, China
Background: Fatty liver patients were found to have bacterial
overgrowth and increased permeability in gut, patients with
inflammatory bowel disease were also found to have hepa-
tobiliary disorders frequently, indicating the importance of
gut-liver axis. However, the effects of colitis on liver fibrosis
remain unclear. The aim of this study is to investigate the role
of murine chronic colitis induced by dextran sodium sulfate
(DSS) in hepatic fibrogenesis. Methods: Male C57BL/6 mice
were randomly divided into five groups: Control group (n=10),
DSS group (n=10), Olive oil group (n=10), CCl4 group (n=10)
and CCl4+DSS group (n=10). Severity of colitis was evaluated
by disease activity index (DAI), gross score, myeloperoxidase
(MPO) activity and histology. Bacterial translocation and serum
LPS level were also checked. Pro-inflammatory cytokines includ-
ing TNF-α, IFN-γ, IL-17A and tight junction (TJ) proteins in the
colon mucosa were also checked by immunohistochemistry,
western blot and real-time Q-PCR, respectively. Haematoxylin
and eosin staining (H&E staining), Sirius red staining and Mas-
son’s trichrome staining (MT staining) were used to evaluate
liver histopathology and fibrosis. Serological tests were used to
observe liver function. The protein and mRNA expressions of
TNF-α, IFN-γ, IL-17A, TGF-β1, α-SMA, collagen type I and III,
MMP-2, TIMP-2, TLR4, TRAF6 and NF-κB in liver tissues were
observed by immunohistochemistry, western blot and real-time
Q-PCR, respectively. Results: DSS administration increased DAI
score, gross score and MPO activity, and worsened histologic
inflammation. The histological analysis revealed that hepatic
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
inflammation in CCl4+DSS group was significantly aggra-
vated. Meanwhile, increased hepatic fibrosis was observed,
especially in the CCl4+DSS group, accompanied by higher lev-
els of TGF-β1, α-SMA, collagen type I and III, TIMP-2 and low-
ered MMP-2. Enhanced pro-inflammatory cytokines, bacterial
translocation and LPS were also found in the DSS group. And
they were significantly higher in the CCl4+DSS group. In line
with this, TLR4, TRAF6 and NF-κB were markedly increased in
liver tissues. Conclusions: The intestinal inflammation promotes
hepatic inflammation and fibrogenesis, probably through LPS/
TLR4 signaling pathway.
Disclosures:
The following people have nothing to disclose: Xiaolan Zhang, Yufeng Liu, Guo-
chao Niu, Libo Zheng
618
Beta-hydroxybutyrate and niacin protect the murine
liver from acute inflammatory injury via activation of
the Gpr109 receptor
Rafaz Hoque1, Ahmad Farooq1, Fred Gorelick1,2, Wajahat Z.
Mehal1; 1Section of Digestive Diseases, Yale University, New
Haven, CT; 22. Section of Digestive Diseases, Department of
Veterans Affairs Connecticut Healthcare, West Haven, CT
Introduction: Inflammation is an important component of many
forms of acute liver injury. Beta-hydroxybutyrate (BHB) and
niacin are ligands for the plasma membrane receptor GPR109
which is expressed on Kupffer cells (KC). Some GPRs have
immunomodulatory actions but a role for GPR109 in hepatic
inflammation has not been investigated. Aim: Assess the
role of GPR109 as a regulator of inflammation in acute liver
injury, and the potential for therapy by its ligands BHB or nia-
cin. Methods: WT (C57BL/6), Gpr109 null, and WT siRNA
Gpr109 treated male mice were subject to LPS/d-Gal induced
acute liver injury with/without sodium BHB or niacin (one i.p.
dose 380 mcg and 30 mcg per g body weight respectively).
WT mice were subject to APAP induced liver injury +/- saline,
BHB, or niacin (two i.p. doses). Plasma ALT, H&E, neutrophil
staining, liver inflammatory gene transcripts, and mortality
were quantified. Inflammatory peritoneal macrophages and
KC were isolated from WT and Gpr109 null mice and acti-
vated with LPS and ATP, +/- BHB or niacin. Pro-inflammatory
gene transcripts, and IL1β release was quantified. NF-KB GFP
reporter transgenic mice were treated with LPS and BHB or
saline, livers isolated, and GFP expression quantified in KC.
Results: Gpr109 null and Gpr109 siRNA treated WT mice
had lethality from LPS/D-gal (5/7 and 6/6, respectively). No
deaths in WT control, scramble siRNA treated animals (0/10
and 0/6, respectively). BHB or niacin versus saline supplemen-
tation protected WT mice from LPS/D-gal and APAP induced
acute liver injury with reduced ALT (1010 +/- 905 and 1090
+/-1069 versus 8806 +/-1600 IU/L in APAP model P<0.05)
and liver neutrophil infiltration (11.4 +/- 2.3 and 22.5 +/-
5.8 versus 76.5 +/- 8.9 cells per 40 x magnified high power
field P<0.05 in APAP model), as well as hepatic expression of
nlrp3, casp1, and pro-il1β . BHB did not protect Gpr109 null
or Gpr109 siRNA treated mice. In macrophages, BHB and
niacin dose dependently decreased LPS induced intracellular
Pro- IL1β and IL1β release in a GPR109 dependent manner.
BHB or niacin suppressed LPS mediated pro-inflammatory gene
transcription in KC in vitro and in vivo in NF-KB GFP reporter
mice. Conclusions: BHB and niacin have potent anti-inflamma-
tory effects via the GPR109 plasma membrane receptor on
Kupffer cells. This pathway is endogenously active, and can
be additionally stimulated to provide hepatoprotection in a
numbers of forms of liver disease.
501A
Disclosures:
Wajahat Z. Mehal - Management Position: Gloabl BioReserach Partners
The following people have nothing to disclose: Rafaz Hoque, Ahmad Farooq,
Fred Gorelick
619
Type III interferons, including IFNL4, drive interfer-
on-stimulated gene (ISG) pre-activation and the interfer-
on-refractory state
Jordan J. Feld1, Vera A. Cherepanov1, Nicholas Anand1, Sonya
A. MacParland1, Tawnya Hansen1, Harry L. Janssen1, Matthew
Kowgier1, Ian McGilvray2; 1Toronto Centre for Liver Disease, Uni-
versity Health Network, University of Toronto, Toronto, ON, Can-
ada; 2Surgery, University Health Network, University of Toronto,
Toronto, ON, Canada
Background Baseline upregulation of hepatic interferon-stim-
ulated genes (ISGs) is associated with non-response to inter-
feron-based antiviral therapy, however the cause of ISG
preactivation remains unknown. Interferon lambda 4 (IFNL4)
was recently described as a possible functional explanation for
the association of the IL28B genotype and treatment response.
Aim To determine whether expression of IFNL4 or other interfer-
ons correlates with intrahepatic ISG expression and treatment
response. Methods RNA was extracted from pre-treatment liver
biopsies from patients with known treatment outcome. Follow-
ing DNAse 1 treatment, mRNA expression of IFN-alpha, IFN-
beta, IFNL1 (IL29), IFNL2 (IL28A), IFNL3 (IL28B), IFNL4, the
IFN-lambda receptor and selected ISGs (IP10, RSAD, IFI27,
USP18, ISG15, MxA) were measured by qPCR. Genotyping
for rs12979860 (CC vs non-CC) and ss469415590 (TT vs
non-TT) was performed by sequencing. The correlation between
expression of ISGs and the various interferons was assessed by
the Spearman rank test and using non-hierarchical clustering.
Results Of 66 patients, 17 (27%) achieved sustained virolog-
ical response (SVR), 18 (28%) relapsed (REL) and 29 (45%)
were non-responders (NRs) to peginterferon and ribavirin. The
IFNL4 genotype was: TT (32%), TT/dG (50%) and dG/dG
(18%). Although ISG expression was higher in future NRs than
SVR/REL (p<0.0001), the expression levels of all interferons
were similar by response. Similarly, ISG expression was higher
in patients with a non-TT IFLN4 genotype but there were no
differences in expression of interferons by genotype. There was
no correlation between expression of ISGs and Type I interfer-
ons (alpha or beta). By cluster analysis, IL28a and IL29, but not
IL28B, clustered with ISGs, but only in patients with the non-TT
IFNL4 genotype or in NRs to therapy. Expression of IL28A and
IL29 correlated most strongly with expression levels of ISG15
and UPS18, whereas there was a weak correlation between
ISGs and IL28B. IFNL4 expression was very low in all patients
and undetectable in 10 samples with no difference in expres-
sion level by IFNL4 genotype or treatment response. Expression
of IFNL4 correlated with USP18 but only in patients with a
non-TT IFNL4 genotype (non-TT: rho=0.48, p=0.0009 vs TT:
rho=0.13, p=0.60) and in NRs (NRs: rho=0.58, p=0.0007,
SVR/REL: rho=0.18, p=0.31). IFNL4 expression did not cor-
relate with expression of other ISGs. Conclusion Despite similar
levels of interferon expression, ISG preactivation appears to be
driven by type III interferons, including IFNL4, but only in those
with a non-TT IFNL4 genotype suggesting that it may be the
functional explanation for the ‘IL28B’ genotype.
Disclosures:
Jordan J. Feld - Advisory Committees or Review Panels: Idenix, Merck, Janssen,
Gilead, AbbVie, Merck, Theravance, Bristol Meiers Squibb; Grant/Research
Support: AbbVie, Boehringer Ingelheim, Janssen, Gilead, Merck
502A AASLD ABSTRACTS
Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sci-
ences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support:
Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck,
Medtronic, Novartis, Roche, Santaris
The following people have nothing to disclose: Vera A. Cherepanov, Nicholas
Anand, Sonya A. MacParland, Tawnya Hansen, Matthew Kowgier, Ian McGil-
vray
620
Iron decreases IL-4- mediated STAT6 phosphoryla-
tion, Arginase-1 production and M2 activation, while
increasing NF-KB phosphorylation, INOS protein levels
and M1 activation in primary murine macrophages
Priya Handa1,2, Vicki Morgan-Stevenson1,2, Kris V. Kowdley1,2;
1Liver Center of Excellence, Digestive Disease Institute, Seattle,
WA; 2Benaroya Research Institute, Virginia Mason Medical Cen-
ter, Seattle, WA
Background and Aim: We have previously demonstrated that
hepatic iron overload in the reticuloendothelial system (RES)
is associated with severe nonalcoholic steatohepatitis (NASH)
and advanced fibrosis in nonalcoholic fatty liver disease. In
this study, we hypothesized that iron loading of primary murine
macrophages could influence their activation status and con-
tribute to inflammation via promoting NF-KB activation and
by diminishing M2 activation via impairing STAT6 activation.
Methods: Mouse bone marrow derived macrophages (BMDM)
were treated with either ferric ammonium citrate (FAC) alone,
or cotreated with FAC/IL-4 (to prime macrophages for M2
polarization) for 4-24 hours to determine the effect of iron on
iron homeostasis pathways, activation status of NF-KB, induc-
ible nitric oxide synthase (iNOS) protein, phosphorylation of
STAT-6 (a key regulator of M2 activation), and gene expres-
sion markers of proinflammatory (M1) or alternative (M2) path-
ways. Further, we assessed the effect of iron in concert with
cytokines such as interferon-gamma, TNF-α or IL-1β on M1
activation. Results: Treatment of BMDMs with iron led to an
increased expression of iron homeostasis genes such as hepci-
din, ferritin and ferroportin and downregulated the transferrin
receptor gene expression. We assessed the effect of iron on
M1 activation pathway. Iron–treated macrophages showed
elevated levels of phospho-p65 (a subunit of NF-KB) and INOS
protein and had increased gene expression of INOS, MCP-
1, TNF-α, IL-6 and CD14. This effect could be reversed by
Super Oxide Dismutase (SOD, an anti-oxidant), consistent
with iron’s known role as a pro-oxidant. We also observed
increased levels of proinflammatory activation when iron was
coadministered with cytokines such TNF-α or IL-1β, leading
to a synergistic upregulation of IL-6, TNF-α and iNOS genes.
While IL-4 promoted activation of STAT6, iron treatment in
conjunction with IL-4 decreased the phosphorylation of STAT6.
It also reduced expression of IL-4-mediated upregulation of M2
markers such as Arginase-1, Ym1, Fizz-1/RELMα, TGF-β, IL-4R
and Mgl-1. Interestingly, it also led to a downregulation in the
fatty acid β-oxidation-related gene expression (the machinery
that fuels M2 activation), evidenced by decreased PGC1β and
Ppar gamma mRNA levels. Conclusions: Iron impacts macro-
phage activation by enhancing NF-KB activation and promot-
ing M1 activation, while impairing IL-4/p-STAT6-mediated M2
pathway in primary murine macrophages. This study highlights
the direct role for iron in influencing critical innate M1 and
M2 immune responses, providing useful insights into molecular
pathways governing NASH pathogenesis.
Disclosures:
Kris V. Kowdley - Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research
Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria,
Janssen, Merck, Mochida, Vertex
HEPATOLOGY, October, 2014
The following people have nothing to disclose: Priya Handa, Vicki Morgan-Ste-
venson
621
Role of NADPH oxidase 4 in hepatic inflammation and
TGFβ response mediated by Toll-like receptor 4
Bhargav Koduru1, Rui-Ming Liu2, Nicole L. Corder1, Katrin Schro-
der3, Ralf P. Brandes3, Jinah Choi1; 1School of Natural Sciences,
UC Merced, Merced, CA; 2School of Medicine, University of Ala-
bama at Birmingham, Birmingham, AL; 3Department of Cardiovas-
cular Physiology, Goethe Universität, Frankfurt am Main, Germany
Chronic Inflammation is an important factor in liver diseases.
Toll-Like receptors (TLRs) play an important role in innate immu-
nity, and TLR4 and intestinal microbiota have been associated
with the promotion of hepatocellular carcinoma and other liver
diseases. Studies indicate that TLR responses are modulated by
NADPH oxidase (Nox) family enzymes in various cell types.
Nox family enzymes consist of Nox proteins and dual oxidases
(Duox) that catalyze the transfer of electrons from NAD(P)H to
O2 to produce reactive oxygen species (ROS). Nox enzymes
are expressed in the liver, but whether these proteins function in
TLR4 responses of hepatocytes is unknown. Therefore, we eval-
uated the role of Nox4 in TLR4 responses stimulated by lipo-
polysaccharides (LPS) in vitro, using Huh7 human hepatoma
cells as well as hepatocytes isolated from control wildtype and
Nox4 knockout (Nox4-/-) mice. In addition, hepatic responses
to LPS were compared in the wildtype versus Nox4KO mice
exposed to weekly i.p. injection of LPS (1mg/kg body weight)
or saline only for up to six weeks. We found that LPS increased
Nox activity and Nox4 as well as tumor necrosis factor alpha
(TNFα) expression in Huh7 cells. In addition, diphenyleneiodo-
nium, an inhibitor of Nox proteins and other flavoproteins, and
Nox4 siRNA suppressed TNFα elevation induced by LPS in
these cells. The LPS-induced TNFα elevation was MyD88-de-
pendent. The LPS-stimulated increase in TNFα was also atten-
uated in primary hepatocytes isolated from Nox4KO mice,
compared to control wildtype mice. In addition, LPS increased
the level of proliferating cell nuclear antigen in Huh7 cells in
a Nox4-dependent manner. With six weeks of repeated LPS
stimulation in vivo, hepatic TNFα response also subsided more
in the Nox4KO mice compared to the wildtype mice, such
that TNFα mRNA was not elevated in the liver of LPS-injected
Nox4KO mice compared to saline-injected controls, whereas
the wildtype animals continued to show elevated TNFα with LPS
at 24 hrs. Likewise, the LPS-stimulated increase in transforming
growth factor beta1 mRNA in the liver was reduced in the
Nox4KO group, compared to the wildtype control group. How-
ever, the effect of Nox4 deletion on in vivo LPS responses was
time-dependent. Therefore, Nox4 mediates TLR4 responses in
human hepatoma cells and murine hepatocytes in vitro. Nox4
may also play a role in hepatic responses to repeated LPS
stimulation in vivo.
Disclosures:
The following people have nothing to disclose: Bhargav Koduru, Rui-Ming Liu,
Nicole L. Corder, Katrin Schroder, Ralf P. Brandes, Jinah Choi
622
MicroRNA-155 deficiency attenuates chronic alcohol
induced hepatic and intestinal inflammation in mice
Shashi Bala, Dora Lippai, Timea Csak, James V. Zatsiorsky, Donna
Catalano, Karen Kodys, Gyongyi Szabo; UMass Medical School,
Worcester, MA
Purpose: MicroRNAs (miRNAs) are small non-coding regula-
tory RNAs that play an essential role in almost all cellular pro-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
cesses. miRNA-155 is a multifunctional miRNA that regulates
immune and non-immune biological processes. Previously, we
showed increased expression of miR-155 in alcoholic liver dis-
ease (ALD), where it contributes to inflammation via TNF alpha.
To elucidate the biological function of miR-155 in ALD, we
employed miR-155 deficient (KO) mice. Methods: Wild type,
WT (C57/BL6J) or miR-155 KO and TLR4 KO female mice
(n=8-10) were fed the Lieber-DeCarli diet containing ethanol or
control diet for 5 weeks. Results: We found that miR-155 KO
mice were protected from alcohol-induced liver and intestinal
inflammation. Alcohol metabolism was comparable between
WT and miR-155 KO mice as measured by serum alcohol lev-
els and hepatic Cyp2e1 expression. A significant attenuation
in liver TNF alpha, IL-1 beta, and MCP1 was found in alco-
hol-fed miR-155 KO compared to WT mice administered with
or without TLR4 ligand, LPS. Alcohol-induced increase in WT
mice in hepatic CD68 (a macrophage activation marker) and
MMP2, a remodeling protein, was dampened in miR-155 KO
mice. Further, liver steatosis as evidenced by histological scores
of H&E and Oil-Red-O staining was significantly decreased
in alcohol-fed miR-155 KO compared to WT mice. Alcohol
feeding resulted in a significant induction of oxidative stress
(measured by TBAR assay) in the livers of WT mice, which was
attenuated in miR-155 KO mice. Further, compared to WT,
alcohol-induced decrease in hepatic miR-122 was prevented
in miR-155 KO mice, suggesting a causative role for miR-155
in ALD. Remarkably, there was no increase in plasma endo-
toxin levels in miR-155 deficient mice after alcohol feeding,
revealing intact gut barrier function. MiR-155 KO mice were
also protected from alcohol induced increases in intestinal TNF
alpha and NF-kappaB activation. Mechanistically, SHIP1, a
miR-155 target that regulates inflammation was decreased in
WT mice after alcohol feeding and this decrease in SHIP1
was prevented in miR-155 KO mice in the intestine. Also miR-
155 KO mice were protected from alcohol-induced decrease
in antimicrobial peptide, Reg3Beta in the intestine. Our results
indicate that alcohol induces miR-155 via the TLR4 pathway.
Compared to WT mice, TLR4 KO mice showed no increase
in hepatic miR-155 expression after alcohol feeding. Conclu-
sion: In conclusion, our results suggest that miR-155 plays an
essential role in the gut-liver axis in ALD and that therapeutic
inhibition of miRNA-155 might be an attractive strategy to ame-
liorate ALD.
Disclosures:
Gyongyi Szabo - Consulting: Idenix; Grant/Research Support: BMS, GSK, Cona-
tus, Idera, Johnson&Johnson, Novartis, Ocera, Roche, Shering - Plough, Wyeth,
Integrated Therapeutics, Idera
The following people have nothing to disclose: Shashi Bala, Dora Lippai, Timea
Csak, James V. Zatsiorsky, Donna Catalano, Karen Kodys
623
Human Mucosal Associated Invariant T cells express
high levels of MDR-1 and maintain innate effector func-
tion following exposure to immunosuppressive MDR-1
substrates
Joannah R. Fergusson2, Lucy J. Walker1,2, Paul Klenerman2; 1Insti-
tute of Cellular Medicine, Newcastle University, Newcastle upon
Tyne, United Kingdom; 2Peter Medawar Building for Pathogen
Research, University of Oxford, Oxford, United Kingdom
Background Mucosal associated invariant T (MAIT) cells repre-
sent 20% of CD3+ lymphocytes within the human liver. They
are defined by an invariant T cell receptor (Va7.2+/Vb2 or
13.2) and innate-like activation by microbial-derived vitamin
B metabolites presented by the highly evolutionarily conserved
non-classical MHC class 1 related molecule (MR1). MAIT cells
display marked cross-reactivity and express high levels of the
503A
multi-drug resistance protein 1 (MDR1). MAIT cells are resistant
to and rapidly efflux chemotherapeutic MDR1 substrates such
as duanorubicin. Tacrolimus, mycophenolic acid (MPA) and
corticosteroids are all MDR1 substrates. The effect of these
compounds on MAIT cell function, proliferation and apoptosis
is not known. Aim The aim of this study was to establish the
effect of exposure of MAIT cells in-vitro to tacrolimus, MPA and
prednisolone on proliferation, apoptosis and innate effector
function. Methods Peripheral blood mononucleocytes (PBMCs)
from healthy donors obtained via NHS Blood and Transplant
(Oxford, UK) were cultured in the presence of tacrolimus
(20ng/ml;10ng/ml;5ng/ml), MPA (8mg/L;4mg/L;2mg/L) or
prednisolone (100ng/ml;50ng/ml;25ng/ml) with cell trace
violet (CTV) proliferation dye. On day 4 of culture a mono-
cyte cell line (THP-1) was incubated over night with either
formalin-fixed E.coli or a sterile control. On day 5 cultured
PBMCs were either retained for annexin V/CTV staining or
co-incubated for 5 hours with the E.coli exposed THP-1 line
+/-anti-MR1 blocking antibody prior to intracellular cytokine
staining and analysis by flow-cytometry. Results MAIT cells
express very high levels of MDR-1 compared to non-MAIT T
cell subsets (p<0.001). Amongst PBMCs MAIT cells uniquely
produce IFN-γ on co-culture with THP-1 monocytes pre-exposed
to fixed E.coli in an MR1-dependent manner. Following 5 days
of culture in the presence of tacrolimus, MPA and prednisolone
such innate effector function of MAIT cells was maintained
with no significant differences in IFN-γ production observed
on comparison between the drug treated, untreated and sol-
vent-only treated controls. MAIT cells were equally inhibited in
their ability to proliferate compared to other non-MAIT T cell
subsets and underwent similar levels of apoptosis. Conclusions
MAIT cells are an abundant hepatic human T cell subset and
due to marked MR1-mediated cross reactivity may represent
important mediators of allograft rejection. In this context it is a
significant observation that their innate-effector function is main-
tained following exposure to agents used in standard immuno-
suppression regimens.
Disclosures:
The following people have nothing to disclose: Joannah R. Fergusson, Lucy J.
Walker, Paul Klenerman
624
Circulating monocytes from chronic HCV-infected
patients display a pro-fibrotic phenotype mediated by
IL-1β and correlates with liver fibrosis
Banishree Saha, Karen Kodys, Gyongyi Szabo; Medicine, UMASS
Med School, Worcester, MA
Introduction: Innate immune cells including monocytes and
macrophages play an important role in the pathogenesis of
chronic Hepatitis C Virus (HCV) infection. Pro-inflammatory
cytokines; TNF-α, IL-1β and pro-fibrotic cytokine, TGFβ are
increased in chronic HCV patients. Though monocyte and mac-
rophage activation contributes to the pathogenesis of HCV
infection and liver fibrosis, mechanisms involved in the interac-
tions between circulating monocytes/tissue macrophages, HCV
and HCV-infected hepatocytes are not fully understood. We
hypothesized that HCV signals circulating monocytes to differ-
entiate into pathogenic, pro-fibrotic macrophages. Methods:
Immunostaining of monocytes from HCV-infected patients and
co-culture of healthy monocytes with HCV-infected Huh7.5 cells
were performed. Results: In patients with chronic HCV infec-
tion we identified a unique population of circulating M2-po-
larized monocytes expressing high levels of CD14, CD206,
CD163 and collagen. The frequency of circulating pro-fibrotic
CD14+ monocytes expressing M2 markers and collagen in
504A AASLD ABSTRACTS
HCV-infected patients positively correlated with the extent of
liver fibrosis and with increased expression of M2 macrophage
markers in the liver. To further gain mechanistic insights into the
interactions of circulating monocytes and HCV, we performed
long-term co-culture of healthy monocytes with HCV-infected
Huh7.5 cells or HCV alone and observed an increased expres-
sion of collagen in the monocytes. Also we found that mono-
cytes differentiated into macrophages in the presence of HCV
and had increased expression of CD14, CD68 (macrophage
markers), preferential expression of M2 markers (CD206,
CD163 and DC-SIGN) and produced both pro- and anti-in-
flammatory cytokines. HCV-induced IL-1β secretion promoted
TGFβ production and polarization to an M2-like macrophage
phenotype, which was prevented in the presence of the IL-1
receptor antagonist. Furthermore, IL-1β stimulation, indepen-
dent of HCV, led to polarization of monocytes to M2-like mac-
rophages and increased expression of collagen. Monocytes
stimulated with IL-1β secreted large amounts of TGFβ that led
stellate cell activation indicated by increased expression of
collagen, α-SMA and TIMP-1. Conclusion: We identified the
presence of a pro-fibrotic CD14+ monocyte population in the
circulation of HCV-infected patients with liver fibrosis. These
monocytes display the phenotypic characteristics of fibrocytes
and alternatively activated M2 macrophages. We show that
HCV induces monocyte differentiation into macrophages via
autocrine IL-1β secretion with mixed M1/M2 cytokine profile
and M2 surface phenotype that promotes stellate cell activation
via TGFβ.
Disclosures:
Gyongyi Szabo - Consulting: Idenix; Grant/Research Support: BMS, GSK, Cona-
tus, Idera, Johnson&Johnson, Novartis, Ocera, Roche, Shering - Plough, Wyeth,
Integrated Therapeutics, Idera
The following people have nothing to disclose: Banishree Saha, Karen Kodys
625
Glycine minimizes hepatic innate immune responses
and autoimmunity caused by double-stranded RNA
Akira Uchiyama, Kenichi Ikejima, Kumiko Arai, Kazuyoshi Kon,
Kyoko Fukuhara, Tomonori Aoyama, Shunhei Yamashina, Sumio
Watanabe; Department of Gastroenterology, Juntendo University
Graduate School of Medicine, Tokyo, Japan
Background: Glycine has been shown to be protective against
a variety of liver injuries caused by ischemia-reperfusion, endo-
toxin, and ethanol, where macrophage activation through TLR4
is mainly involved. Recently, we demonstrated that dietary gly-
cine prevents metabolic syndrome-related steatohepatitis, in
which innate immune responses also play a pivotal role. In
this study, we evaluated the effect of glycine on hepatic innate
and autoimmune responses caused by double-stranded RNA,
a TLR3 ligand. Methods: Female, 8 week-old C57Bl6 mice
were fed a diet containing 5% glycine or casein as controls for
1 week, and then given a single, intra-peritoneal injections of
poly I:C (5 μg/g BW). Some mice were given repeated injec-
tions of poly I:C (twice/week) for 24 weeks in combination
with glycine-diet. Serum alkaline phosphatase (ALP) levels were
measured, and liver histology was assessed. Serum anti-mito-
chondria (AMA)-M2 antibody was detected by ELISA. Hepatic
mRNA levels for TNFα, IL-1β, IL-6, IFNα, IFNβ, IFNγ, and TLR3
were quantified by real time RT-PCR. Results: A single injection
of poly I:C caused trivial necro-inflammatory changes in the
liver; however, poly I:C elicited swift elevations in hepatic TNFα,
IL-1β, and IL-6 mRNA levels in 1 hr. Further, mRNA levels for
IFNα and IFNβ were increased transiently in 6 hr after injection
of poly I:C, while the levels for IFNγ were almost unchanged.
All of these transient inductions in cytokines were significantly
HEPATOLOGY, October, 2014
blunted in mice pre-fed a diet containing glycine. Hepatic
expression levels of TLR3 mRNA were not altered by dietary
pretreatment. On the other hand, long-term treatment with poly
I:C resulted in development of autoimmune cholangitis with
positive AMA-M2 antibody, resembling human primary biliary
cirrhosis (PBC). Interestingly, simultaneous dietary treatment
with glycine prevented the formation of cholangiopathy almost
completely. Indeed, dietary glycine blunted not only elevations
in serum ALP levels but also induction levels of AMA-M2. More-
over, poly I:C-induced cholangitis were markedly ameliorated
even when glycine-diet were given only for 8 weeks, starting
from 16 weeks after repeated poly I:C injections with con-
trol diet-feeding. Conclusions: These findings clearly indicated
that dietary glycine attenuates TLR3-mediated innate immune
responses elicited by double-stranded RNA. Further, glycine
minimizes development of hepatic autoimmunity involving
alterations in innate immune responses and molecular mimicry,
thereby ameliorating induction of cholangitis. It is postulated
that glycine is a promising immune-nutrient for prevention and
treatment for autoimmune liver diseases including PBC.
Disclosures:
The following people have nothing to disclose: Akira Uchiyama, Kenichi Ikejima,
Kumiko Arai, Kazuyoshi Kon, Kyoko Fukuhara, Tomonori Aoyama, Shunhei
Yamashina, Sumio Watanabe
626
Neutrophil toll-like receptor 9 expression and plasma
lactoferrin in acute alcoholic hepatitis and the suscepti-
bility to fungal infection
Jennifer M. Ryan1, Godhev K. Manakkat Vijay1, (Robin) Daniel
Abeles1, Thomas Tranah1, Laura J. Blackmore1, Victoria T. Kro-
nsten1, Lee J. Markwick2, Antonio Riva2, Nikhil Vergis3, Nicholas
J. Taylor1, Shilpa Chokshi2, Yun Ma1, John G. O’Grady1, Deb-
bie Shawcross1; 1Institute of Liver Studies, King’s College London,
London, United Kingdom; 2Foundation for Liver Research, 69-75
Chenies Mews, London, United Kingdom; 3Hepatology Research
Unit, St Mary’s Hospital, Imperial College London, London, United
Kingdom
Introduction: Acute alcoholic hepatitis (AAH) has a high mortal-
ity. Sepsis and resultant organ failure are frequently the cause
of death. Fungal infection in this group of patients is increas-
ingly recognized as a contributor to poor outcome. A balance
between pro- and anti-inflammatory pathways are thought to
be important but, overall, disease drivers in AAH and the sub-
sequent impact on ability to survive infection are poorly under-
stood. Neutrophil toll-like receptor (TLR) 9 detects fungal DNA
and results in the release of pro-inflammatory cytokines that aid
in the containment and clearance of fungi. Aims: We examined
circulating neutrophil TLR9 expression and plasma lactoferrin
(an antimicrobial lipopolysaccharide-binding protein released
from neutrophils) in17 patients with AAH (discriminant factor
>32), 20 patients with alcohol-related cirrhosis (ARC) and 10
healthy controls (HC). Methods: Neutrophil phenotype was
characterized in peripheral blood using fluorochrome conju-
gated monoclonal antibodies anti-CD16, -CD11b, -TLR2, -TLR4
and TLR9. Plasma cytokines and lactoferrin were measured
using CBA and ELISA, respectively. Results: Median MELD
scores for the AAH and ARC cohorts were 25 and 11, respec-
tively. 28-day mortality for the AAH cohort was 18%. Fungal
or candida species were isolated from 6/17 AAH patients and
4/20 ARC patients. TLR9 expression was increased in both the
AH and ARC patients compared to HC (p<0.05). Plasma lacto-
ferrin was significantly elevated in AAH compared to cirrhotics
and HC (p<0.01 and p<0.001, respectively). The circulating
AAH neutrophils had reduced TLR2 expression (p=0.02) and
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
showed a trend towards reduced TLR4 expression (p=0.05)
compared to HC. Neutrophil TLR9 expression was found to
inversely correlate with plasma lactoferrin (p=0.03; spearman
r-0.7) in AAH supporting the role of TLR9 in ‘non-sterile’ inflam-
mation thought to be of importance in AAH. There were no
differences however in TLR9 or lactoferrin between those AAH
patients that had confirmed fungal/candida infection com-
pared to those who did not. Lactoferrin levels on day 7 (n=6)
were significantly reduced compared to day 1 in the AAH
patients (p=0.04). Conclusion: Neutrophil TLR9 expression is
increased in AAH whereas expression of TLR2 and TLR4 is
reduced. As TLR2 and TLR4 provide critical innate antifungal
immune signals and TLR9 detects fungal DNA these findings
may explain the susceptibility to fungal invasion in AAH. With
regard to lipopolysaccharide-binding, lactoferrin may initially
suppress endotoxin-related biological activity which may con-
tribute to the reduction in TLR2 and 4 expression and account
for the development of bacterial sepsis in AAH.
Disclosures:
John G. O’Grady - Advisory Committees or Review Panels: Astellas, Novartis;
Speaking and Teaching: Astellas, Roche
Debbie Shawcross - Advisory Committees or Review Panels: Norgine; Grant/
Research Support: Norgine; Speaking and Teaching: Norgine
The following people have nothing to disclose: Jennifer M. Ryan, Godhev K.
Manakkat Vijay, (Robin) Daniel Abeles, Thomas Tranah, Laura J. Blackmore,
Victoria T. Kronsten, Lee J. Markwick, Antonio Riva, Nikhil Vergis, Nicholas J.
Taylor, Shilpa Chokshi, Yun Ma
627
TLR3/4 Signaling is Mediated via the MyD88-NF-κB-
CXCR4/7 Pathway in Human Alcoholic Hepatitis and
Non Alcoholic Steatohepatitis, Where Mallory-Denk
Bodies Form
Samuel W. French, Hui Liu, Barbara A. French, Brittany C. Tillman,
Jun Li; Pathology, LABioMed at Harbor UCLA, Torrance, CA
Activation of Toll-like receptor (TLR) signaling which stimulates
inflammatory and proliferative pathways is the key element
in the pathogenesis of Mallory-Denk bodies (MDBs) in mice
fed DDC. However, little is known as to how TLR signaling
regulates MDB formation during chronic liver disease devel-
opment. The first systematic study of transcript regulation in
human archived formalin-fixed, paraffin-embedded (FFPE)
liver biopsies and frozen liver sections from DDC re-fed mice
with MDB formation is presented here. When compared to
the activation of Toll-like signaling of Kupffer cells in alcoholic
liver disease, striking similarities and obvious differences were
observed. Similar TLRs (TLR3 and TLR4, etc.), TLR downstream
adaptors (MyD88 and TRIF, etc.) and transcript factors (NF-κB
and IRF7, etc.) were all up regulated, in both DDC re-fed mice
livers and patients’ livers. MyD88, TLR3 and TLR4, however,
were significantly induced in alcoholic hepatitis (AH) and Non
alcoholic steatohepatitis (NASH) compared to normal subjects,
while TRIF and IRF7 mRNA were only slightly up regulated. This
is a different pathway from the induction of the TLR4-MyD88-in-
dependent pathway in the AH and NASH patients with MDBs
present. The subunits of the NF-κB family p65 and p50 which
induce the proinflammatory cytokines were also significantly
up regulated both in the AH and NASH biopsies. Importantly,
chemokine receptor 4 and 7 (CXCR4/7) mRNA were found
to be significantly up regulated both in the patients livers and
mice fed DDC in FAT10 positive hepatocytes. The CXCR7 path-
way was up regulated in patients with AH and the CXCR4 was
up regulated in patients with NASH, indicating that CXCR4/7
is crucial in liver MDB formation. This data constitutes the first
demonstration of the up regulation of the MyD88-dependent
TLR4/NFκB pathway in AH and NASH where MDBs formed,
505A
via the MyD88- NF-κB -CXCR4/7 pathway, and provides fur-
ther insight into the investigation of the human liver disease
development mechanism of MDB formation.
Disclosures:
The following people have nothing to disclose: Samuel W. French, Hui Liu, Bar-
bara A. French, Brittany C. Tillman, Jun Li
628
Liver Injury and Inflammation Leads to Profound Hepatic
Natural Killer Cell Dysfunction and Predisposes the Liver
to Metastatic Disease
Justin B. Mendel1,2, Aryn Price2, Arash Grakoui1,2; 1Division of
Digestive Diseases, Emory University, Atlanta, GA; 2Emory Vac-
cine Center, Emory University School of Medicine, Atlanta, GA
Background and Methods: Natural Killer (NK) cells comprise
30-50% of the lymphocyte pool in the human liver, yet their role
in maintaining hepatic immune homeostasis remains poorly
understood. Their abundance in the liver - compared to 10-15%
frequency in the blood - suggests an important role for these
cells during hepatic inflammatory responses. As NK cells have
been proposed as a therapeutic option for liver fibrosis and
cancer, we sought to define the effects of hepatic inflammation
on NK cell function. B6 mice were given a singe dose of the
hepatotoxic drug carbon tetrachloride (CCl4) to induce liver
inflammation and injury. Three days post injection, hepatic NK
cell function was evaluated by assessing cytokine secretion and
cytotoxic capacity. To demonstrate the in vivo consequences of
hepatic inflammation and injury on NK cell function, mice were
given an I.V. injection of GFP bearing B16 melanoma cells,
which have previously been shown to metastasize to the liver
in the setting of global NK cell depletion. Results: Three days
post injection of CCl4 the frequency of (CD3-NK1.1+) NK cells
in the liver remained unaltered. However, functional analysis
revealed significantly reduced cytotoxic potential as assessed
by expression of CD107a, a marker of degranulation. Fur-
thermore, we observed a significant decrease in IFN-γ and
TNF-α production when NK cells were stimulated with PMA/
Ionomycin directly ex vivo. As B16 melanoma cells metasta-
sis to the liver in the setting of NK cell depletion, we sought
to investigate whether the observed ex vivo compartmental
defect in NK function allowed for increased metastatic disease.
Accordingly, mice that received a single dose of CCl4 had
more GFP bearing B16 metastatic lesions compared to control
animals. Our data demonstrates that hepatic inflammation and
injury leads to hypofunctional NK cells with consequent failure
to prevent tumor metastasis. Conclusions: While the timing and
capacity for functional NK cells to repopulate the liver after
inflammation and injury will need to be further explored, our
work demonstrates that a prolonged compartmental defect in
NK cell function - as measured by inadequate cytokine secre-
tion and cytotoxic capacity - leads to increased potential for
metastatic disease. Understanding the mechanisms leading to
NK dysfunction secondary to inflammation from hepatitis and
acute injury may help reveal novel pathways to prevent tumor
metastasis and development of hepatocellular carcinoma.
Disclosures:
The following people have nothing to disclose: Justin B. Mendel, Aryn Price,
Arash Grakoui
506A AASLD ABSTRACTS
629
Role of interactions of circulating monocytes in vascular
sprouting during liver regeneration in mice
Pedro Melgar-Lesmes1, Elazer R. Edelman1,2; 1Edelman Lab, Insti-
tute for Medical Engineering and Science, Massachusetts Institute
of Technology, Cambridge, MA, USA, Cambridge, MA; 2Car-
diovascular Division, Brigham and Women’s Hospital, Harvard
Medical School, Boston, MA
Background and aims: Liver regeneration is a complex process
that requires the sequential activation of multiple pathways and
different cell types. Understanding the regulation of the inter-
actions that allow hepatocyte expansion is of vital importance
for developing clinical approaches toward liver repair. How-
ever the role of recruited monocytes in vascular and hepatic
regeneration is not yet well-defined. We aimed to investigate
the role of circulating monocytes in vascular and liver regen-
eration after partial hepatectomy in mice. Methods: Vascular
architecture and the location of macrophages were analyzed
using simultaneous angiography and macrophage staining
with Texas-red dextran 70 kDa in the whole mouse liver by
fluorescent multiphoton microscopy throughout the regenera-
tive process. Tri-dimensional segmentation of z-stack images
was used to determine macrophage position and contacts in
vascular network. CD14 staining in liver sections followed the
rate of recruited monocytes. The gene expression profiles of
monocyte adhesion molecules, monocyte chemotactic protein
type 1 (MCP-1) and inducible nitric oxide synthase (iNOS)
were quantified by Real-Time PCR from 16h to 7 days after
hepatectomy. To investigate the role of infiltrated monocytes
in priming sprouting, Wnt5a, Notch1 and angiopoitein-1
(Ang-1), together with F4/80 as macrophage marker, were
examined by immunofluorescence. Moreover protein phosphor-
ylation of vascular endothelial (VE)-cadherin was compared to
the amount of monocyte-vessel interactions. Results: Vasodila-
tion begins after 16 hours of hepatectomy and correlates with
iNOS expression. Kupffer cells in the space of Disse do not
migrate to interact with vessels while infiltrating monocytes sur-
round initial sprouting points. Infiltrated macrophages deliver
Wnt5a, angiopoietin 1 and Notch-1 in contact points and are
positively correlated with phosphorylation and disruption of
VE-cadherin. MCP-1 and the intercellular adhesion molecule
1 expression are sequentially up-regulated at 16h and 72h
after hepatectomy preceding the waves of hepatocyte prolif-
eration. Conclusions: Direct vascular interactions of infiltrating
monocytes, but not Kupffer cells, are responsible for driving
vascular sprouting preceding parenchymal expansion. These
outcomes provide new mechanistic insight and potential targets
to develop new strategies for hepatic regeneration.
Disclosures:
The following people have nothing to disclose: Pedro Melgar-Lesmes, Elazer R.
Edelman
630
Distinctive phenotypic features of human mucosal-asso-
ciated invariant T cells in the liver
Kentaro Tominaga, Toru Setsu, Satoshi Yamagiwa, Naruhiro
Kimura, Hiroki Honda, Hiroteru Kamimura, Masaaki Takamura,
Minoru Nomoto; Division of Gastroenterology and Hepatology,
Niigata university Graduate School of Medical and Dental Sci-
ences, Niigata, Japan
BACKGROUND/AIM: The functional profile and preferential
localization of mucosal-associated invariant T (MAIT) cells in
the gut and liver indicate that these cells may play a major role
in controlling the pathogens that could escape the gut mucosal
HEPATOLOGY, October, 2014
barrier. MAIT cells constitute a unique subset of innate-like T
lymphocytes characterized by a semi-invariant T cell receptor
(TCR) repertoire (made of an invariant Vα7.2-Jα33 TCRα chain)
capable of recognizing bacterial products. Although MAIT cells
are abundant in the human liver, the characteristics of human
MAIT cells in the liver remains to be further elucidated. METH-
ODS: Heparinized peripheral blood and surgically removed
liver tissues were collected from 8 patients with metastatic
liver tumors and 2 patients with focal nodular hyperplasia. All
the patients did not have any previous liver disease, and the
liver tissues distant from the tumor were examined. Mononu-
clear cells were separated by Ficoll-gradient, and then various
surface markers were investigated by flow cytometry. mRNA
expression was quantified by real-time PCR. Cytokine produc-
tion was investigated using peripheral blood MAIT cells after
stimulation with anti-CD3/CD28-coupled beads in the pres-
ence or absence of IL-7. We also investigated the distribution
of Vα7.2+ CD161+ cells in the liver by immunohistochemical
staining. RESULTS: CD3+ TCR-γδ- CD161high Vα7.2+ MAIT
cells comprised 6.8% (median) (range 1.1-17.9) of the total T
cells in the liver but only 1.6% (0.1-6.7) of the total T cells in the
blood. The proportions of activated CD69+ MAIT cells were
significantly increased in the liver (82.8%, 27.6-99.4) com-
pared to the blood (25.2%, 7.1-42.9). Although the expression
of the NK cell receptor, NKG2D, was similar between the
liver (44.8%, 27.6-89.2) and blood (55.8%, 39.4-70.9), an
inhibitory NK cell receptor, NKG2A, was significantly higher
in the liver (12.4%, 3.-32.30) than in the blood (0.3%, 0-6.1).
The median proportion of IL-18 receptor (IL-18R) + and IL-7R+
cells in the MAIT cells were 97.9% (94.6-100) and 75.5%
(23.1-93.7) in the liver but 99.0% (64.5-99.8) and 90.8%
(38.5-98.6) in the blood, respectively. Although MAIT cells
exhibited high levels of the chemokine receptor CCR6, the
expression of CCR5 was heterogeneous. We also confirmed
that the functions of MAIT cells were dynamically regulated by
the presence of IL-7. CONCLUSIONS: Intrahepatic MAIT cells
exhibit an activated phenotype and preferentially express the
Th17-associated chemokine receptor CCR6. Our results indi-
cate that MAIT cells are a specialized cell population highly
adapted to exert specific immune functions in the liver.
Disclosures:
The following people have nothing to disclose: Kentaro Tominaga, Toru Setsu,
Satoshi Yamagiwa, Naruhiro Kimura, Hiroki Honda, Hiroteru Kamimura,
Masaaki Takamura, Minoru Nomoto
631
Large scale biomarker profiling reveals distinct cytokine
and chemokine signatures distinguishing different acute
and chronic hepatitis virus infections
Svenja Hardtke1, Julia Hengst1, Katja Deterding1, Michael P.
Manns1, Falk S. Christine2, Markus Cornberg1, Heiner Wede-
meyer1, Verena Schlaphoff1; 1Gastroenterology,Hepatology and
Endocrinology, Hannover Medical School, Hannover, Germany;
2Transplant Immunology, IFB-Tx, Hannover Medical School, Han-
nover, Germany
Infections with hepatotropic viruses can cause acute and
chronic hepatitis. The detailed immuno-pathophysiological
events leading to inflammation and fibrosis progression are
not well understood. In order to investigate the effects of dif-
ferent hepatitis viruses on systemic cytokine and chemokine
expression, we performed a large scale multianalyte profiling
of samples from 163 individuals with acute hepatitis (12 acute
HAV, 5 acute HBV, 21 acute HCV) or chronic viral hepatitis
(12 HBV, 14 HBV/HDV coinfection, 51 HCV). In addition, 25
subjects who had recovered from acute hepatitis C and 22
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
healthy controls were studied. 50 serum cytokine, chemokines
and angiogenic factors were studied using multiplex technol-
ogy (Bio-Plex System). Moreover, various clinical parameters
were included in the statistical analysis including viral load,
ALT,AST, gamma GT and blood counts. Principal component
analysis (PCA) was performed by ANOVA/t-test testing using
Qlucore Omics Explorer software(Qlucore Lund, Sweden).
Results: Profiling revealed distinct signatures by of 31 mark-
ers differentiating acute hepatitis from healthy controls as well
as chronic hepatitis patients from controls (32 parameters).
Similarly, acute and chronic infections could be separated by
biomarkers (9 parameters). Interestingly, signatures differed for
distinct viruses as HAV infections caused a much more upreg-
ulation of various pro-inflammatory cytokines as compared to
acute hepatitis C. In contrast, chronic hepatitis C was asso-
ciated with a broad upregulation of various cytokines and
chemokines including IP-10, IL-18, IL12, SDF-1a, and VCAM-1
compared to chronic hepatitis B patients while RANTES (CCL5)
appears as the only cytokine/chemokine upregulated in HBV
and HBV/HDV. No significant markers could be identified to
differentiate between HBV monoinfection and hepatitis delta.
Interestingly both groups showed a cluster of markers which
are clearly less expressed compared to controls including
IL-2RA,IL-3,IL-5, IL-15, IL-17 and G-CFS. Discussion: Acute and
chronic liver inflammation is characterized by distinct cytokine
signatures which differ between different hepatitis viruses. This
large-scale profiling reveals novel insights in the immunopatho-
genesis and host pathogen interactions.
Disclosures:
Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim,
Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/
Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim,
BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK,
Novartis
Markus Cornberg - Advisory Committees or Review Panels: Merck (MSD Ger-
mamny), Roche, Gilead, Novartis, Abbvie, Janssen Cilag, BMS; Grant/Research
Support: Merck (MSD Germamny), Roche; Speaking and Teaching: Merck (MSD
Germamny), Roche, Gilead, BMS, Novartis, Falk, Abbvie
Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD,
Roche, Gilead, Abbott, BMS, Falk, Abbvie, Novartis, GSK; Grant/Research
Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS,
MSD, Novartis, ITF, Abbvie, Gilead
The following people have nothing to disclose: Svenja Hardtke, Julia Hengst,
Katja Deterding, Falk S. Christine, Verena Schlaphoff
632
Functional features of antigen-specific T-cell receptors
reflected clinical responses of α-fetoprotein-derived
peptides vaccine treatment for advanced hepatocellular
carcinoma
Hidetoshi Nakagawa1, Eishiro Mizukoshi1, Eiji Kobayashi2,
Takeshi Terashima1, Masaaki Kitahara1, Noriho Iida1, Hiroyuki
Kishi2, Atsushi Muraguchi2, Shuichi Kaneko1; 1Department of Dis-
ease control and Homeostasis, Kanazawa University, Kanazawa
city, Japan; 2Department of Immunology, University of Toyama,
Toyama city, Japan
BACKGROUND/AIM: In the past decade, several clinical stud-
ies of immunotherapy for hepatocellular carcinoma (HCC)
using tumor-associated antigens (TAAs) have proceeded.
In these studies, the advents of TAA-specific T-cells in the
patients were monitored using cytokine-secretion assays or
peptide-MHC multimers. However, functional features of the
antigen-specific T-cell receptors (TCRs) in HCC immunotherapy
remain unclear. In this study, we revealed the TCR repertoire
landscape of the vaccinated patients and its role on the clini-
cal response. METHODS: Fifteen patients who underwent more
than 3 times of vaccinations were analyzed among the par-
507A
ticipants of the phase I clinical trial using HLA-A24-restricted
α-fetoprotein (AFP)-derived peptide vaccines for advanced HCC
(trial registration: UMIN000003514). AFP-specific cytotoxic
T lymphocytes (CTLs) were induced and analyzed using the
hTEC10 (human TCR efficient cloning within 10 days) system
that we had developed for rapid TCR cloning (Kobayashi et
al. Nat Med. 2013). Finally, the avidities of obtained TCRs
were estimated by comparing the cytotoxicity against C1R-
A24 cells loaded with various concentrations of peptides and
the EC50 values were calculated. RESULTS: Of 15 vaccinated
patients (male, 60%; median age, 73; LCSGJ stage III/IVa/
IVb, 9/2/4), one patient (6.7%) achieved complete response
(CR), and stable disease (SD) and progressive disease (PD)
were recorded in 8 patients (55.3%) and in 6 patients (40%),
respectively. Median time to progression (TTP) was 79 days
(Mizukoshi et al. AASLD2013). AFP-specific CTLs were induced
in 4 patients whose clinical responses were CR (no recurrence
until day 1,336), long SD (TTP, 812 days), SD (91 days) and
PD (46 days), respectively (long SD is defined as SD over 6
months). Totally, 347 specific TCR clones that consisted of 10
kinds of TCR gene rearrangements (3 from the CR patient; 4
from the long SD patient; 2 from the SD patient and 1 from the
PD patient) were amplified. From the CR patient and the long
SD patient, TCRs possessing higher avidities (0.0058 μM and
0.0168 μM, respectively) were obtained; meanwhile the SD
patient and the PD patient had weaker TCRs (0.2811 μM and
0.0613 μM, respectively). CONCLUSION: AFP-derived pep-
tide vaccine treatment for advanced hepatocellular carcinoma
induced antigen-specific CTLs with diverse TCR repertoires in
the vaccinated individuals. Furthermore, the inductions of TCRs
with high avidities reflected the favorable clinical responses.
TCR repertoire analysis could be a potent tool for immunomon-
itoring in HCC immunotherapy.
Disclosures:
Atsushi Muraguchi - Consulting: SCW
Shuichi Kaneko - Grant/Research Support: MDS, Co., Inc, Chugai Pharma.,
Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co.,
Inc, Ajinomoto Co., Inc, MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co.,
Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc, Ajinomoto Co.,
Inc, Bayer Japan
The following people have nothing to disclose: Hidetoshi Nakagawa, Eishiro
Mizukoshi, Eiji Kobayashi, Takeshi Terashima, Masaaki Kitahara, Noriho Iida,
Hiroyuki Kishi
633
Immunomodulatory Effects of OK432-Stimulated Mono-
cyte-Derived Dendritic Cell Injection into Hepatocellular
Carcinoma after Radiofrequency Ablation
Masaaki Kitahara, Eishiro Mizukoshi, Hidetoshi Nakagawa,
Noriho Iida, Hajime Sunagozaka, Kuniaki Arai, Tatsuya
Yamashita, Shuichi Kaneko; Kanazawa Univercity, Kanazawa,
Japan
BACKGROUND: Dendritic cell (DC)-based immunotherapies
are expected to contribute to the eradication of the resid-
ual and recurrent tumor including hepatocellular carcinoma
(HCC). We have developed the combined therapy of radiofre-
quency ablation (RFA) with infusion of OK432, a Streptococ-
cus-derived anticancer immunotherapeutic agent, stimulated
monocyte-derived DCs (MoDCs) for HCC, and indicated that
patients treated with RFA and OK432-stimulated DC transfer
had prolonged recurrence-free survival compared with the his-
torical controls that had been treated with RFA alone (Hepatol-
ogy 58(S1):1265,2013). In the present study, we analyzed
immunobiological responses in peripheral blood monocytes
(PBMCs) before and after DC infusion into HCC following RFA.
METHODS: MoDCs were derived from PBMCs of hepatitis
508A AASLD ABSTRACTS
C-related HCC patients (n=30) in the presence of 50ng/ml IL-4
and 100ng/ml GM-CSF for five days. The cells were cultured
for two additional days in the medium and stimulated with
0.1 KE/ml OK432. On day 7, DCs were harvested for injec-
tion, 5×106 cells suspended in 5ml normal saline containing
1% autologous plasma, and injected into HCC with a needle
percutaneously after RFA. The immune responses were evalu-
ated by NK cell activity, intracellular cytokine production (IFN-γ
and IL-4) and IFN-γ enzyme-linked immunospot (ELISPOT) assay
using PBMCs. NK cell cytotoxity against K562 erythroleukae-
mia target cells measured using the 51Cr-release assay. ELIS-
POT assay was performed in HLA-A24 positive patients using
HLA-A24 restricted peptides derived from AFP, MRP3, SART2,
SART3 and hTERT, which we previously identified as HCC-spe-
cific tumor associated antigen (TAA). RESULTS: The level of NK
cell activity was unaltered following treatment. There were no
significant changes in terms of cytokine production capacity in
the CD4+, CD8+ and CD56+ subsets in the patients follow-
ing treatment. After HCC treatment, positive T cell responses
against at least one TAA-derived peptide were observed in 6
of 17 (35%) patients. The increase of the frequency of TAA-spe-
cific T cells after treatment was detected in 5 of 9 (56%) pep-
tides. In addition, the length of HCC recurrence-free survival
in patients with T cell responses against 2 and more peptides
after treatment was longer than that of the patients without the T
cell responses (p=0.042). CONCLUSIONS: OK432-stimulated
DC infusion into HCC following RFA newly induced immune
responses to unprimed tumor antigens, implying that anti-
gen-non-specific DC injection into the treated tumor enhanced
tumor immunity.
Disclosures:
Shuichi Kaneko - Grant/Research Support: MDS, Co., Inc, Chugai Pharma.,
Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co.,
Inc, Ajinomoto Co., Inc, MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co.,
Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc, Ajinomoto Co.,
Inc, Bayer Japan
The following people have nothing to disclose: Masaaki Kitahara, Eishiro Mizu-
koshi, Hidetoshi Nakagawa, Noriho Iida, Hajime Sunagozaka, Kuniaki Arai,
Tatsuya Yamashita
634
Identification of a Novel HLA-A2 Restricted Immunother-
apeutic Target Derived from an EGFR Mutated Antigen
for the Treatment of Metastatic Liver Tumors
Kazuya Ofuji1,2, Toshiaki Yoshikawa2, Yoshitaka Tada2, Manami
Shimomura2, Yasunari Nakamoto1, Tetsuya Nakatsura2; 1Sec-
ond Department of Internal Medicine, University of Fukui, Fukui,
Japan; 2Division of Cancer Immunotherapy, Exploratory Oncol-
ogy Research & Clinical Trial Center, National Cancer Center,
Kashiwa, Chiba, Japan
BACKGROUND: Metastatic liver tumors are originated from
various malignancies including lung. Since the phenotypes of
metastatic tumor cells are often altered from the original cancer
cells, we observe the difference in susceptibility to chemother-
apy at metastatic lesions. The efficacy of EGFR-tyrosine kinase
inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, against
non-small cell lung cancer (NSCLC) with activating EGFR-mu-
tation is dramatic. However, almost all patients developed
acquired drug resistance to EGFR-TKI. EGFR T790M mutation is
the most common acquired resistance mutation in patients with
NSCLC. Mutation-derived antigens associated with tumor cell
progression and drug resistance may provide a candidate tar-
get in the future strategies of immunotherapy. Here, we evalu-
ated the immunogenicity of antigen derived from EGFR T790M
point mutation that is associated with drug resistance. METH-
ODS: The computer-based epitope prediction programs BIMAS
HEPATOLOGY, October, 2014
was used for the prediction of peptides binding to HLA-A2. T2
binding assay was done to evaluate the binding capability of
selected candidate peptides to HLA-A2. To the induction of
peptide-specific cytotoxic T lymphocytes (CTL), CD8 + cells of
healthy donors were stimulated by peptide-pulsed DCs for one
week and subsequently, stimulated twice per week by pep-
tide-pulsed artificial-APC-A2 (K562/HLA-A2/CD80/CD83).
By IFN-γ ELISPOT assay, CD107a assay, and cytotoxic assay,
reactivity of established peptide specific CTLs against pep-
tide-pulsed or non-pulsed target cells was assessed. RESULTS: 9
or 10-mer five peptides were selected as candidate sequences.
Peptide binding assay showed that EGFR T790M-derived five
peptides had relatively high affinity to HLA-A2 molecules. By
stimulation with peptide-pulsed DCs and artificial APC-A2,
T790M-A (789-797) (IMQLMPFGC)-specific CTLs were induced
from PBMCs of all four donors, and peptide-specific CTL lines
were established. T790M-A specific CTL line was able to spe-
cifically recognize T2 cells pulsed with T790M-A peptide but
not pulsed with T790M-A (789-797) wild-type (ITQLMPFGC) pep-
tide. Finally, this CTL line showed the reactivity against NCSLC
cell line, H1975-A2 (HLA-A2+, T790M+), but not H1975 (HLA-
A2-, T790M+) by IFN-γ ELISPOT assay and CD107a assay.
This CTL line also demonstrated the peptide-specific cytotox-
icity against H1975-A2. CONCLUSIONS: We determined
the immunogenicity of an HLA-A2 restricted, EGFR T790M
mutation-derived antigen. Immunotherapy targeting to the cur-
rent mutation epitope may be a treatment option for patients
with metastatic liver tumors originated from EGFR-TKI resistant
NSCLC.
Disclosures:
Tetsuya Nakatsura - Consulting: Ono Pharmaceutical co.Ltd.; Grant/Research
Support: Ono Pharmaceutical co.Ltd., MEDINET co.Ltd.
The following people have nothing to disclose: Kazuya Ofuji, Toshiaki Yoshi-
kawa, Yoshitaka Tada, Manami Shimomura, Yasunari Nakamoto
635
The dynamic changes of Th1/Th2/Th17 cytokines in
serum of patients with acute-on-chronic liver failure
Li Jin, Yingli He, Dan Du, Yuanyuan Li, Ruitian Yi, Jing Wang,
Tianyan Chen, Yingren Zhao; Infectious Disease, the First Affili-
ated Hospital of Medical College, Xi’an Jiaotong University, Xi’an,
China
Aims: Overwhelming evidence suggests that acute-on-chronic
liver failure (ACLF) is an inflammatory disease mediated by
innate and adoptive immune systems. Cytokines are import-
ant mediators during immune responses. The purpose of this
study was to quantify Th1, Th2 and Th17 cytokines in serum
of patients with ACLF and to analyze their dynamic changes
in the progression of ACLF. Methods: Dynamic blood samples
were taken from 15 patients with HBV related ALCF, whose
liver and anticoagulation function recovered during the fol-
low-up. 27 patients with chronic HBV infection (CHB) were
enrolled as control. Th1 cytokines (IL-2, IFN-γand TNF), Th2
cytokines (IL-4, IL-6 and IL-10) and Th17 cytokine (IL-17A) were
detected in serum using cytometric bead array. Results: The
concentrations of IFN-γ, TNF, IL-6, IL-10 and IL17A as well as
MELD scores were higher in ACLF patients than those in CHB
patients on admission. With the development of ACLF, the con-
centrations of Th1, Th2 and Th17 cytokines were slightly raised
during the peak ACLF severity (MELD score peak), although the
differences were not statistically significant except MELD scores
(P=0.004). During the 3th week of follow-up, all the concentra-
tions of the cytokines as well as MELD scores were declined.
The concentrations of IFN-γ, TNF, IL-10 and IL17A were even
declined to the same levels as the CHB patients (p>0.05),
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
while IL-6 and MELD scores were still higher than CHB patients
(p=0.000). In addition, on the peak ACLF severity, the con-
centrations of IFN-γ, IL-6 and IL-10 were positive correlation
with MELD scores (R=0.514, P=0.05; R=0.518, P=0.048;
R=0.629, P=0.012, respectively), while the rates of IFN-γto
IL-10 and IFN-γto IL-6 were negative correlation to MELD scores
(R=-0.564, P=0.028; R=-0.531, P=0.042, respectively). Con-
clusions: Th1/Th2/Th17 the cytokines were raised in the acute
phase of ACLF and exhausted quickly, which were paralleled
with MELD scores. Th2 cytokines such as IL6 and IL10 were
associated with aggravation of ACLF.
Disclosures:
The following people have nothing to disclose: Li Jin, Yingli He, Dan Du,
Yuanyuan Li, Ruitian Yi, Jing Wang, Tianyan Chen, Yingren Zhao
636
Regulation of hepatic inflammation by the macro-
phage-expressed, sulfated steroid transporter, Slc10a6
Astrid Kosters1, Demesew Abebe1, Julio Felix2, Saul J. Karpen1;
1Pediatrics, Emory University, Atlanta, GA; 2Pediatrics, Baylor Col-
lege of Medicine, Houston, TX
The interplay of resident hepatic macrophages (Kupffer Cells,
KCs) and neighboring hepatocytes in the liver plays a major
role in innate and adaptive immune responses by mutual
responses to small molecules shuttling between the cell types,
and affecting the release of various cytokines and acute-phase
proteins. The full extent of the roles and intercellular communi-
cations between hepatocytes and KCs as a model for hepatic
inflammation has not been explored in detail. To address this
gap, RNA microarray analysis was performed on livers of mice
treated with 2 mg/kg LPS or saline by ip for 16 hrs. We dis-
covered that Slc10a6 (an incompletely characterized mem-
ber of the SLC10A Na+-dependent bile acid [BA] transporter
family) was the most-induced transcript (~500-fold), confirmed
independently by qPCR (>50 fold) in the array. Slc10a6 RNA
levels were upregulated in mouse liver at 2 hrs (7-fold) and 4
hrs (100-fold) after LPS treatment and 35-fold after treatment
with the cytokine IL-1β (5mg/kg) for 4 hrs. In silico promoter
analysis suggests the presence of adjacent binding sites for
NFkB and RXRα heterodimers, whereby previous studies indi-
cate that RXRα agonists and NFκB/JNK inhibitors can serve
as anti-inflammatory agents. Upregulation of Slc10a6 RNA
by LPS (16 hrs) was attenuated by ~60% when mice were
pretreated for 5 days with the synthetic RXRα ligand LG268
(30 mg/kg/day). In vitro, Slc10a6 RNA was induced 30-fold
(p<0.05) by LPS in macrophages (mouse RAW264.7 cells) in
a time-dependent manner (max. at 6-8 hrs), but not in multiple
hepatocyte, cholangiocyte, stellate and endothelial cell lines.
This induction was abrogated in the presence of either NFkB or
JNK inhibitors. Slc10a6 differs from well-characterized Slc10a
509A
family members, the BA-uptake transporters Slc10a1 (Ntcp)
and Slc10a2 (Asbt), as its substrates are sulfated steroids. The
Slc10a6 substrate dehydroxyepiandrosterone sulfate (DHEAS)
enhanced the LPS-induced CCL5 expression in Raw264.7 cells
after 24h by 50% (p<0.05), which was abrogated in the pres-
ence of the RXRα ligand 9cisRA (p<0.05). Upregulation of
Slc10a6 RNA by LPS and enhancement of the LPS-mediated
upregulation of CCL5, a pro-inflammatory neutrophil-attracting
chemokine, by the Slc10a6 substrate DHEAS in macrophages,
suggests that Slc10a6 is a significant component of the inflam-
matory response of KCs and suggests the presence of DHEAS
in an ongoing inflammatory state has additional pro-inflamma-
tory effects. Further characterization of regulation of expression
and transporter function of Slc10a6 in KCs under inflamma-
tory conditions will expand our understanding of, and provide
means for curtailing the hepatic immune response.
Disclosures:
The following people have nothing to disclose: Astrid Kosters, Demesew Abebe,
Julio Felix, Saul J. Karpen
637
Living donor liver transplantation in high model for end-
stage liver disease score
Murat Dayangac1, Murat Akyildiz1,2, Yalcin Erdogan1, Gokhan
Gungor1, Yaman Tokat1; 1Liver Transplantation Unit, Florence
Nightingale Hospital, Istanbul, Turkey; 2Department of Gastroen-
terology, Istanbul Bilim University, Istanbul, Turkey
Statistical models suggest that the sickest patients are those who
derive the highest benefit from living donor liver transplantation
(LDLT) (1). However, previous studies have shown that high
model for end-stage liver disease (MELD) scores were associ-
ated with adverse outcomes (2). In this retrospective analysis
of 450 adult patients, who underwent right lobe LDLT between
August 2004 and May 2013, we examined the impact of
pre-transplant MELD score on post-transplant outcome. Patients
were divided into three MELD categories: MELD<15 (n=193),
MELD between 15-25 (n=215), and MELD>25 (n=42) (Table
1). The median follow-up was 30 (15-58) months. There
was a significant difference between the groups in terms of
perioperative mortality (6.2%, 9.3%, and 31.0%, respectively;
p<0.001), which showed a significant positive correlation
with the MELD score (p<0.001, Spearman’s correlation coef-
ficient=0.188). Patient survival at 1 and 3 years were both
significantly higher in the MELD<15 and MELD 15-25 groups
than that of the MELD>25 group (Wilcoxon test, p=0.007;
88%, 86%, and 64% at 1 year and 82%, 78%, and 64% at
3 years, respectively). In LDLT, disease severity is the most sig-
nificant factor that determines recipient outcomes. Our results
indicate that LDLT being performed for candidates with high
MELD scores have a significantly higher risk of dying from the
procedure. To justify the risk incurred by the donor, the timing
of LDLT should be done to avoid high pre-transplant MELD
scores. 1. Durand F, Belghiti J, Troisi R, et al. Living donor liver
transplantation in high-risk vs. low-risk patients: optimization
using statistical models. Liver Transpl. 2006; 12(2): 231-9. 2.
Kaido T, Egawa H, Tsuji H, Ashihara E, Maekawa T, Uemoto
S. In-hospital mortality in adult recipients of living donor liver
transplantation: experience of 576 consecutive cases at a sin-
gle center. Liver Transpl. 2009; 15(11): 1420-5.
510A AASLD ABSTRACTS
Clinical features of 450 adult LDLT recipients
GRWR, graft-to-recipient weight ratio
Disclosures:
The following people have nothing to disclose: Murat Dayangac, Murat Akyildiz,
Yalcin Erdogan, Gokhan Gungor, Yaman Tokat
638
Priming hepatocytes to G2 enhances liver regeneration
in elderly mice
Fatima K. Rehman1, Toshiyuki Hata1, Zhaoyu Li2, Guojun Bu3,
Justin H. Nguyen1; 1Department of Transplantation/Division of
Transplant Surgery, Mayo Clinic, Jackosnville, FL; 2Cancer Biol-
ogy, Mayo Clinic, Jacksonville, FL; 3Neuroscience, Mayo Clinic,
Jacksonville, FL
Introduction: Priming is essential for hepatocytes to proceed
and complete the cell cycle culminating in mitosis and repli-
cation. It remains poorly understood how hepatocytes fail to
regenerate promptly in elderly animals following a two-third
partial hepatectomy (PH). Since γ-aminobutyric acid (GABA)
promotes hepatocytes into G2 phase of cell cycle, we hypoth-
esized that by priming old hepatocytes to G2 phase, the liver
remnants of old mice regain their regenerative capacity. Meth-
ods: We used 24-month (old) and 4-month (young) C57BL/6
mice and evaluated cell cycle distribution by immunohisto-
chemistry for cyclin D1 (G1 phase), cyclin A (S phase), cyclin
B1 (G2 phase), Ki67 and pHH3 (M phase). Results: Marked
increase of Cyclin B1 positive hepatocytes was seen in aged
mice following 7 days of GABA pretreatment, while control
mice had mostly quiescent and Cyclin D1 positive cells (Figure
1A). The GABA treated livers regained similar mitotic activity
to young controls as seen by pHH3 and Ki67 staining at 36 h
after PH. The results were confirmed with western and further
explored through gene expression analyses (data not shown).
In a separate experiment, mice with and without GABA pre-
treatment were followed daily through day 7 post PH to estab-
lish cell cycle profile by IHC. We found that Old-GABA mice
had proliferative Ki-67 and mitotic pHH3 profiles that were sim-
ilar to those of young mice (Figure 1B). Conclusion: Our results
indicate that hepatic regenerative capacity after PH in elderly
mice can be restored by priming hepatocytes to G2 state prior
to PH. Improvement in liver regeneration in elderly will impact
quality of liver grafts from elderly donors.
HEPATOLOGY, October, 2014
Disclosures:
The following people have nothing to disclose: Fatima K. Rehman, Toshiyuki
Hata, Zhaoyu Li, Guojun Bu, Justin H. Nguyen
639
Cadaveric versus Living donor Liver Transplant Survival
in Relation to MELD Score
Mohammed Al Sebayel1, Almoutaz Hahim2, Faisal A. Abaalkhail1,
Hussien Elsiesy1, Hamad M. Al-bahili1, Saleh Alabbad1, Mohamed
Shoukri1, Markus U. Boehnert1, Dieter C. Broering1; 1Liver Trans-
plantatio, King Faisal Specialist Hospital-D, Riyadh, Saudi Arabia;
2Gastroenterology, King Abdulaziz University, Jeddah, Saudi Ara-
bia
Introduction: MELD score (Model for End Stage Liver Disease)
is universally used to priorities patients on the liver transplant
waiting list. It is potentially used to predict survival as well.
There has been conflicting evidence on using living donor liver
transplantation (LDLT) in patients with high MELD score. We
herein showing a retrospective analysis of survival data in these
two categories of patients and comparing survival between
LDLT and Deceased Donor liver Transplantation (DDLT) in a
single center experience. Patient & Method: We retrospectively
reviewed our records from 2001 to April 2014 for LDLT and
DDLT of KFSH. Date reviewed includes the number of patients
for LDLT and DDLT, age, sex, MELD score and survival. Only
Adults are included in this analysis. Patients were categorized
into MELD score above and below 25. Kaplan Meier analysis
was used for survival and log rank chi square test was used for
comparison with p value of below .05 used for significance.
Results: Total number of transplanted patients at KFSH was
491. There were 222 patients for LDLT and 269 patients for
DDLT. Age ranges between 15 and 80 with a median of 53.
For DDLT, there were 290 males and 201 females. The overall
1, 3 and 5 years Kaplan Meier survival of LDLT & DDLT is
shown below: (table 1) When comparing the Kaplan Meier
survival experience of the 2 groups (MELD above and below
25), there was no significance difference (Log-rank Chi-Square
test, p-value= 0.177). There were also no significance differ-
ence in survival of the 2 groups of LDLT (p-value = 0.097)
and DDLT (p-value=0.923) Conclusion: Our survival data indi-
cates that there is not difference between the survivals of the
two groups (DDLT vs LDLDT), nor that high meld score has a
negative impact on survival. Larger cohort of patients may be
needed to confirm these findings.
Table 1
Disclosures:
Hussien Elsiesy - Speaking and Teaching: ROCHE, BMS, JSK
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
The following people have nothing to disclose: Mohammed Al Sebayel, Almoutaz
Hahim, Faisal A. Abaalkhail, Hamad M. Al-bahili, Saleh Alabbad, Mohamed
Shoukri, Markus U. Boehnert, Dieter C. Broering
640
Hepatocellular Carcinoma is associated with Lower Sur-
vival following Living Donor Liver Transplantation in the
U.S
Ryan B. Perumpail1,Robert Wong1,
Andrew M. Su1,
Clark A.
Bonham2, Carlos O. Esquivel2, Aijaz Ahmed1; 1Division of Gastro-
enterology and Hepatology, Stanford University Medical Center,
Stanford, CA; 2Department of Surgery, Stanford University Medi-
cal Center, Stanford, CA
Background: Although liver transplantation is often recom-
mended for patients with hepatocellular carcinoma (HCC) who
fall within Milan criteria, availability is limited. Living donor
liver transplantation (LDLT), well studied in Asia, may address
the gap between available donor organs and the growing
waiting list for liver transplantation. However, concern exists
regarding potential increased HCC recurrence following LDLT.
Nevertheless, large studies examining the association of HCC
on long-term survival post-LDLT in the U.S. are lacking. Meth-
ods: We conducted a retrospective cohort study using popula-
tion-based national data from the United Network for Organ
Sharing registry to evaluate the impact of HCC on long-term
survival among adult patients undergoing LDLT in the U.S.
from 2003 to 2012. Post-LDLT survival was evaluated with
Kaplan Meier methods and multivariate Cox proportional haz-
ards model adjusted for age, gender, obesity, hepatitis C virus
(HCV) infection, hepatic encephalopathy (HE), and diabetes
mellitus (DM). Results: Overall, 2,258 adult patients underwent
LDLT from 2003-2012, including 234 with HCC (10.4%) and
2,024 without HCC (89.6%), 687 HCV positive (30.4%) and
1,571 HCV negative (69.6%), 261 with DM (11.6%) and
1,997 without DM (88.4%). Compared with patients without
HCC, overall 5-year survival in patients with HCC following
LDLT was lower (65.8% vs. 81.0%, p<0.001). On multivariate
Cox proportional hazards modeling, patients with HCC had
significantly lower post-LDLT survival compared with non-HCC
patients (HR 1.03, 95% CI, 1.02 – 1.04, p<0.001). HCV pos-
itivity (HR 1.42, 95% CI, 1.10 – 1.83, p<0.01) and DM (HR
1.52, 95% CI, 1.09 – 2.11, p<0.02) were similarly associated
with significantly lower survival following LDLT. Patients with HE
(HR 1.27, 95% CI, 0.97 – 1.65, p=0.08) had a non-significant
trend toward lower survival, whereas obesity (HR 1.08, 95%
CI, 0.82 – 1.43, p=0.58) was not associated with survival
following LDLT. Conclusions: In the U.S. experience of LDLT,
HCC is an independent predictor of lower survival. Increased
age, HCV positivity, and DM are also associated with lower
survival following LDLT. These findings may enable optimiza-
tion of patient selection for LDLT.
Disclosures:
Aijaz Ahmed - Consulting: Bristol-Myers Squibb, Gilead Sciences Inc., Roche,
AbbVie, Salix Pharmaceuticals, Janssen pharmaceuticals, Vertex Pharmaceuti-
cals, Three Rivers Pharmaceuticals; Grant/Research Support: Gilead Sciences
Inc.
The following people have nothing to disclose: Ryan B. Perumpail, Robert Wong,
Andrew M. Su, Clark A. Bonham, Carlos O. Esquivel
511A
641
Effect of Fully Laparoscopic Left Hepatectomy on Donor
Interest in Living Donor Liver Transplantation (LDLT)
Anna Yegiants, Darby Santamour, Tarek Mansour, Joseph F. Pisa,
Jean C. Emond, Benjamin Samstein; Center for Liver Disease and
Transplantation, NewYork-Presbyterian Hospital/Columbia Univer-
sity Medical Center, New York, NY
Purpose: In kidney donation, application of laparoscopy has
led to a marked increase in unrelated donor interest. Laparos-
copy was extended to liver donation to reduce invasiveness
and our center has offered selected patients fully laparoscopic
procurement since 8/12. We sought to determine the impact
of offering laparoscopic donation on donor interest in LDLT.
Methods: We examined a retrospective cohort of 244 potential
donors and their 206 recipients who underwent evaluation
between 1/10 and 3/14. We separated our patients into two
groups, based on date of evaluation of the donor (prior to or
after 8/12). We analyzed percentage of waitlisted candidates
with potential donors, relationships between donors and recipi-
ents and evaluations that resulted in donation. Potential donors
were informed that the application of full laparoscopy to donor
hepatectomy was novel and all consented to our IRB-approved
observational protocol. Results: An insignificant decrease in
the percentage of waitlist candidates with a potential donor
was observed between 2010-12 and 2013, from 17% to 16%
(P=0.75). However, total candidates on our waitlist increased
by 26% leading to a 27% increase in donor evaluations per
month (P=0.07). When controlling for the rise in candidate
listings, only a 1.4% increase in evaluations per month was
observed. We also noted an insignificant 3.7% increase in
average potential donors per recipient (P=0.52). Unrelated
donors (those with a non-biological relationship to the recipi-
ent, excluding spouses) increased from 18% to 29% (P=0.04)
and the biggest increase was seen in 2013 (17% to 35%,
P=0.002). There was an increase in unrelated donors going
on to donate from 14% to 23%, but this did not reach signifi-
cance (P=0.31). We also saw an increase in female recipient
candidates with a donor coming forward from 37% to 48%
(P=0.04). Conclusions: Overall, there was no increase in the
percentage of waitlist candidates with a potential donor and
an insignificant increase in total donors. The average number
of potential donors per recipient increased slightly. However,
the composition of the donor and recipient pool changed with
an increase in unrelated donors and an increase in female
recipients with a potential donor. This may reflect the percep-
tion that laparoscopic donor hepatectomy has less morbidity
and a shorter recovery time. More study is needed to see if
perception matches outcomes.
Evaluations and donations before and after offering laparoscopy.
Disclosures:
The following people have nothing to disclose: Anna Yegiants, Darby Santamour,
Tarek Mansour, Joseph F. Pisa, Jean C. Emond, Benjamin Samstein
512A AASLD ABSTRACTS
642
“Patient positioning” in living liver donors – reinventing
the wheel each time
Daniela Ladner1,2, Robert A. Fisher3, James V. Guarrera4, Eliza-
beth A. Pomfret5, Mary Ann Simpson5, Donna Woods2; 1Depart-
ment of Surgery, Division of Organ Transplantation, Northwestern
University, Chicago, IL; 2Center for Healthcare Studies, Feinberg
School of Medicine, Northwestern University, Chicago, IL; 3Hume-
Lee Transplant Center, Virginia Commonwealth University, Rich-
mond, VA; 4Surgery, Columbia University Medical Center, New
York, NY; 5Transplantation and Hepatobiliary Diseases, Lahey
Clinic, Burlington, MA
Purpose A comprehensive Failure Modes and Effects Analy-
sis (FMEA) was performed focusing on the OR setup period
and the risks leading to preventable complications in living
donors related to the OR set-up process. Patient positioning
was among the highest risk processes to the patient among
those related to OR set-up, which if not done correctly prior to
the surgery and maintained during the surgery leads to neu-
ropraxia in 3% of living donors. Study objective: To examine
the positioning process of living donors and identify areas for
improvement to reduce the risk of neuropraxia. Methods A
targeted literature review was conducted to identify Guideline
recommendations related to patient positioning. The identified
elements were reviewed with clinicians at four large transplant
centers (TCs) to determine importance and relevance of each
element and specific methods for implementation. Participants
included anesthesiologist, surgeons, OR nurses and OR techni-
cians along with system engineers and patient safety experts.
In-person and video observations were also applied to assess
the positioning. Results The literature review revealed little high
level evidence focused on patient positioning. Twenty, Guide-
line recommended elements were identified related to patient
positioning (e.g., positioning of arms, securing of patient,
placement of protective foam). The most important and relevant
positioning elements related to prevention of neuropraxia were
arm position. There was substantial variation in the methods
for applying the recommended positioning elements across
the four TCs and within TCs. Of the twenty recommended ele-
ments, only 35% were applied in similar ways across the TCs.
Agreement was reached on positioning roles and responsibili-
ties across the teams: Anesthesiologists are responsible for the
pre-operative assessment and initial upper body positioning,
Nurses are responsible for the lower body elements, and Anes-
thesiologists are responsible for final positioning. Communica-
tion and coordination is necessary for a smooth and accurate
positioning process and for continuous monitoring. Conclusions
Patient positioning leads to an unacceptable incidence of neu-
ropraxia in living liver donors. The process at high volume
living donor liver TCs is variable within and across TCs. Apply-
ing the evidence that does exist, a standardized positioning
protocol is being developed. Understanding and implementing
optimal supine patient positioning applies to many abdominal
surgical patients, not only living liver donors. A standardized
evidence-based approach has the potential to have wide-reach-
ing impact, in an effort to reduce the incidence of neuropraxia.
Disclosures:
James V. Guarrera - Grant/Research Support: Organ Recovery Systems
The following people have nothing to disclose: Daniela Ladner, Robert A. Fisher,
Elizabeth A. Pomfret, Mary Ann Simpson, Donna Woods
HEPATOLOGY, October, 2014
643
Liver regeneration after right lobe donor hepatectomy:
serial changes of HGF, TNF α, IL6, Interferon α, Inter-
feron γ, TGF β1 and Thrombopoietine
Shridhar Sasturkar1, Shreya Sharma2, Paul David2, Shiv K. Sarin3,
Nirupma Trehanpati2, Viniyendra Pamecha1; 1Hepato Pancreato
Biliary Surgery, Institute of Liver and Biliary Sciences, New Delhi,
India; 2Clinical and Cellular Transplant Immunology and Research,
Institute of Liver and Biliary Sciences, New Delhi, India; 3Hepatol-
ogy, Institute of Liver and Biliary Sciences, New Delhi, India
Methods: 15 donors (9 males & 6 females) with median age
of 23 years (range: 18 to 45 years) undergoing right lobe
donor hepatectomy for living related liver transplantation are
included in the study. Peripheral venous blood samples were
taken before surgery and 1, 3, 7, 14 and 42 post operative
day (POD) after donor hepatectomy. HGF, IL-6, TNF α, Throm-
bopoietine, TGF β1, Interferon α and Interferon γ levels were
detected. Sandwich ELISA assay were performed in the plasma
after separation of cells. Paired sample t test was used for sta-
tistical analysis and p value of < 0.05 was considered signifi-
cant. Results: The statistically significant observations (P<0.05)
are described. HGF and TNF α levels increased transiently on
POD 1 after donor hepatectomy. IL6 and Thrombopoietine lev-
els increased after donor hepatectomy and remained elevated
till POD 42. IFN α and IFN γ levels decreased on POD 1 and
then increased to significant level at POD 14 and POD 42
respectively. TGF β1 levels increased at POD 42. Conclusion:
The biological markers of liver regeneration have shown dis-
tinct patterns after right lobe donor hepatectomy.
Table 1: Mean values of growth factors and cytokines (pg/ml)
Disclosures:
The following people have nothing to disclose: Shridhar Sasturkar, Shreya
Sharma, Paul David, Shiv K. Sarin, Nirupma Trehanpati, Viniyendra Pamecha
644
Donor Safety in Live Left-Lobe Liver Donation
Roger Patron-Lozano, Manuel Rodriguez Davalos, James E.
Tooley, Armando Salim Munoz-Abraham, Peter S. Yoo, Brett E.
Fortune, Stephen M. Luczycki, Michael L. Schilsky, David C. Mul-
ligan, Sukru Emre; Surgery - Division of Organ Transplantation &
Immunology, Yale School of Medicine, New Haven, CT
Objective: Compare the incidence and severity of post-oper-
ative complications of left lobe (LL) versus right lobe (RL) live
liver donation (LLD) in a single institution. Methods: Retro-
spectively analyzed LLD charts and evaluated patient demo-
graphics, post-operative complications, and length of stay
(LOS). We combined left lateral segment (LLS) resections with
LL resections under the LL group. All the data was obtained
from patients who underwent hepatectomies for LLD at our insti-
tution. We analyzed the post-operative complications in left
versus RL living donor hepatectomies. Results: Post-operative
complications using the Clavien-Dindo Classification. 58 liv-
ing donor liver transplants (LDLTx) were done at our institution
from 03/08-03/14. 29(50%) were male and the average
age was 38.2(+/-10.5 years). 19(32.76%) were RL donations
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
and 39(67.24%) were either LLS (n=17,29.31%) or LL dona-
tions(n=22,37.93%). The mean LOS was 7.05+/-2.66 days
for right hepatectomies and 6.92+/-3.26 days for the LL group
(p=0.881). The incidence of Grade II or greater complications
was 17.9%(n=7) for the LL group and 47.37%(n=9) for the RL
group (p=0.029). The odds of being a RL donor with a grade
II or higher complication was 4.11 (95% CI [1.22-13.89]
p=0.023). The distribution of these complications is reported
in Table-1. Conclusions: Even though the majority of transplant
centers in the United States prefer RL over LL for LDLTx, we
didn’t observe a difference in LOS when the donors were sub-
jected to a LL or LLS hepatectomy. However, we observed that
the incidence and severity of complications of RL LLD are higher
and more severe when compared to their left counterparts. This
study, although small, should prompt an impulse towards LL
LLD, an almost abandoned practice in the western world.
Table 1. Complications by Severity
Disclosures:
The following people have nothing to disclose: Roger Patron-Lozano, Manuel
Rodriguez Davalos, James E. Tooley, Armando Salim Munoz-Abraham, Peter
S. Yoo, Brett E. Fortune, Stephen M. Luczycki, Michael L. Schilsky, David C.
Mulligan, Sukru Emre
645
Impact of Donor Minimal Histological Changes on the
Outcome of Living Donor Liver Transplantation
Naglaa A. Allam1, Wael Abdel-Razek1, Nermine Ehsan2, Asmaa
Gomaa1, Deena El-Azab2, Imam Waked1; 1Hepatology, National
Liver Institute, Menoufiya, Egypt; 2Pathology, National Liver Insti-
tute, Menoufiya, Egypt
Background: Apparently healthy individuals occasionally have
minimal hepatic histological changes that do not alter liver
tests. In living donor liver transplantation (LDLT), the limitation of
donor availability often makes a donor with minimal histologic
changes the only available donor, and the only chance to save
the patient, and is frequently accepted for donation. The impact
of donor minimal histological changes on donor and recipi-
ent outcome has not been extensively analyzed. Methods: In
this study we analyzed unexpected histological changes in
donors for LDLT, and the effects of accepted minimal changes
on outcome of the donors and their recipients. Post-operatively,
donors’ and recipients’ labs [(ALT, AST, bilirubin, INR) on post-
operative days 1 (POD1), 7, 14, 30 and days of ICU and
hospital discharge]; length of ICU and hospital stay; compli-
cations and morbidities; recipients’ portal vein velocity and
hepatic artery resistivity index on POD1 and 7, and 1-year
survival were correlated to different minimal changes in donor
histology. Results: Of 380 related donors who consented for
right lobe liver donation, 252 (66.3%) were rejected because
of abnormal liver tests or imaging, or unsuitable volumetry, and
only 128 (33.7%) underwent liver biopsy. Based on biopsy
results, 20 donors (15.6%) were rejected, due to expanded bil-
harzial portal fibrosis in 12 (60%), steatohepatitis with steatosis
513A
>30% in 6 (30%) (2 of whom were >60%), and prominent lob-
ular necroinflammation in 2 (10%). The 108 acecepted donors
included 77 males (71.3%), had mean age 28.2±7 years;
mean BMI 24±3.6. Forty-two donors (38.9%) had minimal
changes: 10%-20% steatosis was present in 4 donors; minimal
portal fibrosis in 24; mild hepatitic changes in 11; ductular
proliferation in 2 and minimal lobular hepatitis in 1. Thus 62
of the 128 donors with normal liver tests and imaging (48.4%)
had histological changes on biopsy, which were severe and
prevented donation in (15.6%). The recipients included 96
males (88.9%), their mean age was 47.3±7.5 years, mean
MELD score 16.5 (range 11-25), hepatitis C underlying etiol-
ogy of cirrhosis in 92.5%. None of these changes had signif-
icant impact on donors’ or recipients’ parameters, including
no effect on acute rejection and HCV recurrence, or on 1-year
survival [donor steatosis (p=0.9), portal fibrosis (p=0.44), hep-
atitic changes (p=0.73)]. Conclusion: Grafts from living donors
with minimal histologic changes were the only available option
for 39% of the patients. Nevertheless, accepting these donors
did not affect donor outcome, and had no negative impact on
recipient outcome and one-year survival, even for recipients
with MELD score up to 25.
Disclosures:
Imam Waked - Advisory Committees or Review Panels: Janssen; Speaking and
Teaching: Hoffman L Roche, Merck, Bayer, BMS, Gilead
The following people have nothing to disclose: Naglaa A. Allam, Wael Abdel-
Razek, Nermine Ehsan, Asmaa Gomaa, Deena El-Azab
646
Surgical and Percutaneous Ablation are Both Safe and
Effective in Patients with Small Hepatocellular Carci-
noma
Jonathan M. Schwartz1, Corbett Shelton1, Aws Aljanabi2, Mustafa
A. Alani1, Dina Ginzberg1, Akiva J. Marcus1, Javier Chapoch-
nick-Friedmann2, Sarah Bellemare2, Yosef Golowa3, Jacob Cyna-
mon3, Andreas Kaubisch5, Nitin Ohri4, Milan Kinkhabwala2;
1Gastroenterology and Liver Diseases, Albert Einstein College
of Medicine/Montefiore Medical Center, Bronx, NY; 2Surgery,
Albert Einstein College of Medicine/Montefiore Medical Center,
Bronx, NY; 3Interventional Radiology, Albert Einstein College of
Medicine/Montefiore Medical Center, Bronx, NY; 4Radiation
Oncology, Albert Einstein College of Medicine/Montefiore Med-
ical Center, Bronx, NY; 5Medical Oncology, Albert Einstein Col-
lege of Medicine/Montefiore Medical Center, Bronx, NY
Background: Thermal tumor ablation is an established treat-
ment for early stage hepatocellular carcinoma (HCC), but it is
unclear if surgical and percutaneous approaches have equiv-
alent safety and efficacy. Aim: To compare the safety and effi-
cacy of surgical or percutaneous thermal ablation in patients
with early stage HCC. Methods: Adult patients with early BCLC
stage HCC who underwent surgical or percutaneous ablation
were identified from a prospective clinical database at a ter-
tiary medical center in the U.S. Patient demographics, etiology
of liver disease, pre-treatment AFP, Child-Turcotte-Pugh score
(CTP), MELD score, BCLC stage, tumor location and history of
prior chemoembolization were recorded. Patient safety was
assessed with the five point Clavien Scale and local recur-
rences were noted using the modified RECIST criteria. Patient
mortality was recorded. Comparisons between the surgical
and percutaneous patient groups were made using Student’s
t test, Mann-Whitney U test, Fisher’s exact test, and Pearson’s
chi-squared test, as appropriate. Rates of freedom from local
recurrence and overall survival were calculated using the
Kaplan-Meier method, and compared using the Log rank test.
Cox Proportional hazards models were used to identify pre-
514A AASLD ABSTRACTS
dictors of local recurrence. The study was approved by the
Institutional Review Board. Results: 105 patients underwent
tumor ablation (63 percutaneous and 42 surgical). The groups
were similar with regard to age, gender, etiology of liver dis-
ease, co-morbid medical conditions, pre-treatment CTP score,
MELD, AFP, BCLC Stage, and follow-up duration (all p-values
>0.05). Percutaneous patients had higher rates of pre-ablation
chemoembolization (49/63 vs 21/42 (p=0.003)), and hos-
pital length of stay was longer after surgery (median 2 days
(IQR 2-4) Vs 1 day (IQR 0-2); p<0.001). Differences in the
Clavien Morbidity Scores were not observed. One percutane-
ously ablated patient had tumor seeding. Fifteen patients died
(14.3%) during follow up, however mortality did not differ
according to ablative technique (p=0.896). There were no
treatment related deaths. Local tumor recurrence occurred in
13/63 (21%) of percutaneously treated patients and 12/42
(29%) of surgical patients (p=0.335). Univariate and multivari-
ate Cox regression analyses did not identify statistically signifi-
cant predictors of local recurrence. Summary and Conclusions:
Surgical and percutaneous ablation for early stage HCC have
similar safety and efficacy. Patients treated surgically had lon-
ger hospital length of stay. The choice of ablative technique
should thus be determined by tumor specific factors in addition
to center expertise and resources.
Disclosures:
Jacob Cynamon - Advisory Committees or Review Panels: Foresight imaging;
Employment: Delcath; Speaking and Teaching: Angiodynamics
The following people have nothing to disclose: Jonathan M. Schwartz, Corbett
Shelton, Aws Aljanabi, Mustafa A. Alani, Dina Ginzberg, Akiva J. Marcus, Javier
Chapochnick-Friedmann, Sarah Bellemare, Yosef Golowa, Andreas Kaubisch,
Nitin Ohri, Milan Kinkhabwala
647
Role of Portocaval Shunt for Patients with Glycogen
Storage Disease Type I in the Era of Liver Transplanta-
tion : Reappraisal of Portocaval Shunt for Growth
YoungRok Choi1, Nam-Joon Yi2, Suk-won Suh2, Jeong-moo Lee2,
Hyeyoung Kim2, Hae Won Lee2, Kwang-Woong Lee2, Kyung-Suk
Suh2; 1Surgery, Seoul National University Budang Hospital, Seoul,
Republic of Korea; 2Surgery, Seoul National University College of
Medicine, Seoul, Republic of Korea
[Background] Instead of dietary modification, surgical manage-
ment was considered for correcting growth retardation, poor
metabolic control, and hepatic adenoma in glycogen storage
disease type I. The role of portocaval shunt (PCS) has been
decreased by advent of liver transplantation (LT) with excellent
outcomes. In the respect of organ shortage, outcome of PCS
was reassessed as a curative intent treatment. [Patients and
Methods] Fifty-five patients with GSD type I were retrospectively
reviewed. Thirty-two patients were managed by only dietary
modifications (Group D). Seventeen patients underwent PCS,
and 13 patients underwent LT (Group S). Changes of growth
pattern during 14 years in Group S were analyzed using a lon-
gitudinal Z-score and its variations from mean Z-scores based
on group D by the age, changes of clinical features including,
taking cornstarch, hypoglycemic seizure, metabolic profiles
(glucose, cholesterol, uric acid, urine calcium, pH, white blood
cell, and creatinine), and development of de novo adenoma
were assessed. [Results] Patients in group S had average effect
of + 0.3765 Z-score compared to group D; in subgroup anal-
ysis, patients of LT group had additional + 0.7523 effect to
those of PCS group (p<0.0001). In LT group, all metabolic pro-
files have been improved, but there was no significant improve-
ment in PCS group. Adenoma has been detected in 4 patients
(13%) of group D, 12 patients (100%) after PCS, but in no
one after LT. Adenoma associated complication was noted in
HEPATOLOGY, October, 2014
2 patient (6.3%) of group D (each one of hepatocellular car-
cinoma (HCC) and hemorrhages and 4 patients (23.5%) after
PCS [fig.1]. [Conclusions] Growth pattern has been improved
in group S beyond the effect of Group D for patients with GSD
type I. However, metabolic and adenoma control were better
in LT group. PCS can be an alternative procedure to catch
up growth under close observation for laboratory results and
adenoma with malignant potency in the aspect of the shortage
of donors.
Disclosures:
Kwang-Woong Lee - Grant/Research Support: ChongGeunDang, Astellas,
GreenCross
Kyung-Suk Suh - Grant/Research Support: Green Cross, Chong Kun Dang Pharm,
Novartis, SK chemical; Speaking and Teaching: Bayer, Novartis
The following people have nothing to disclose: YoungRok Choi, Nam-Joon Yi,
Suk-won Suh, Jeong-moo Lee, Hyeyoung Kim, Hae Won Lee
648
Success of meso-Rex bypass in the management of
extrahepatic portal vein obstruction in children
Andrew Wehrman1, Nadia Ovchinsky1, Adam Griesemer2, Steven
J. Lobritto1, Mercedes Martinez1, Tomoaki Kato2, Jean C. Emond2;
1Pediatrics, Columbia University Medical Center, New York, NY;
2Surgery, Columbia University Medical Center, New York, NY
Extrahepatic portal vein obstruction (EPVO) is a known cause
of portal hypertension in children, frequently resulting in hyper-
splenism and variceal bleeding. The purpose of this study was
to analyze outcomes of meso-rex bypass (MRB) in the manage-
ment of idiopathic EPVO as well as in late-onset portal vein (PV)
obstruction in liver transplant (LT) recipients. We retrospectively
reviewed a database of all children who underwent MRB at our
institution between 1998 and 2013. Details of patient demo-
graphics, preoperative evaluation, and post-operative compli-
cations were collected. We included both idiopathic EPVO as
well as LT recipients with late-onset PV complications. Success
rates were defined as shunt patency at one year follow-up. 28
pediatric patients underwent MRB at our institution. 42.8% of
the patients were male, the mean age at the time of the opera-
tion was 7 y (range 1.75-17.2 y). Twenty-five percent (7/28)
were LT recipients with late-onset PV complications. Indications
for performing MRB included history of variceal hemorrhage
in 46% of patients, large esophageal varices in 78.5%, and
hypersplenism with thrombocytopenia in 42.8%. Pre-operative
assessment of the intrahepatic PV was accomplished by MRI or
CT. The MRB was successful in 24/28 (85%) of all patients.
In the LT recipients, 7/7 (100%) MRB remained patent at 1
year follow up. Of the subset of patients who experienced
variceal bleeding before operation, 13/13 (100%) had no fur-
ther episodes of bleeding. The improvements in platelet count
(+58 ±87.7 thousand/mL, p=0.001), AST (-11.6±20.2 U/L,
p=0.003, ALT (-1.8±31.5 U/L, p=0.3), INR (-0.05±30.12,
p=0.0.08) were noted after MRB. Significant improvement in
weight-for-age percentile was achieved as well (+9.3±19%,
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
p=0.04). Peri-operative complications included return to the
OR for evacuation of MRB thrombosis after a gastrointestinal
bleed in one patient (MRB remained patent long-term), bowel
perforation requiring repair in 1 patient, and neck hematoma
from internal jugular harvest in 1 patient. In an attempt to refine
the technique, 4 successful MRB were performed using intra-ab-
dominal vessels identified at the time of exploration avoiding
the need for jugular vein (JV) sacrifice. In conclusion, he MRB
is a safe and effective treatment option for children with idio-
pathic EPVO as well as for liver transplant recipients with
late-onset PV complications. Intra-abdominal collateral vessels
may be used successfully for MRB avoiding the need for JV sac-
rifice. MRB effectively relieves symptoms of portal hypertensive
bleeding and hypersplenism and may improve growth param-
eters in children by restoring normal portal venous circulation.
Disclosures:
Tomoaki Kato - Grant/Research Support: Novartis
The following people have nothing to disclose: Andrew Wehrman, Nadia
Ovchinsky, Adam Griesemer, Steven J. Lobritto, Mercedes Martinez, Jean C.
Emond
649
PET/CT Positivity Has Lower Survival in Adult Living
Donor Liver Transplantation for Hepatocellular Carci-
noma
Murat Akyildiz1,2, Arzu Oezcelik2, Gokhan Gungor2, Nergis
Ekmen1, Necdet Guler2, Onur Yaprak2, Yalcin Erdogan2, Gulen
B. Dogusoy2, Murat Dayangac2, Yildiray Yuzer2, Yaman Tokat2;
1Gastroenterology, Istanbul Bilim University, Istanbul, Turkey;
2Organ Transplantation Center, Sisli Florence Nightingale Hospi-
tal, Istanbul, Turkey
Background The role of the PET-CT for clinical staging of HCC,
patient selection for liver transplantation, recurrence and pre-
diction of survival is controversial. Aim To evaluate the rela-
tion between FDG positivity and recurrence, survival and
histopathology in living donor liver transplantation. Methods
All patients with HCC who underwent living donor liver trans-
plantation (LDLT) between June 2011 and December 2013
were retrospectively analyzed. Imaging data, differantiation,
AFP, number of tumors and size, recurrence and survival were
reported and correlated to FDG-PET CT scanning. Results There
were 62 patients, in a mean age of 54 years and the mean
follow-up of all patients was 20.4±11.9 months. The com-
parison of the results between PET-CT negative and positive
patients have shown that the maximum tumor size was larger
in PET-CT positive vs negatives (p= 0.04), PET-positive patients
had higher mortality and recurrence rates than PET-CT negative
patients (p<0.05), figure 1. One-year survival was significantly
lower in PET-CT positive patients vs negatives (82% vs 100%,
p=0.04), figure 1. However, there were no differences accord-
ing to AFP, grade and microvasculare invasion (p>0.05). Con-
clusion The present study has shown that pre-transplant PET-CT
positivity is a marker of poor prognosis of HCC and shows
lower survival and higher tumor recurrence rates after LDLT.
However, especially in pre-transplant setting, its role should be
studied with higher number of patients.
515A
Disclosures:
The following people have nothing to disclose: Murat Akyildiz, Arzu Oezcelik,
Gokhan Gungor, Nergis Ekmen, Necdet Guler, Onur Yaprak, Yalcin Erdogan,
Gulen B. Dogusoy, Murat Dayangac, Yildiray Yuzer, Yaman Tokat
650
Adult Living Donor Liver Transplantation From Donors
with Gilbert’s Syndrome: is it Safe?
Murat Akyildiz1,2, Gokhan Gungor2, Necdet Guler2, Arzu Oezce-
lik2, Tonguc Utku Yilmaz2, Onur Yaprak2, Yalcin Erdogan2, Murat
Dayangac2, Yildiray Yuzer2, Yaman Tokat2; 1Gastroenterology,
Istanbul Bilim University, Istanbul, Turkey; 2Organ Transplantation
Center, Sisli Florence Nightingale Hospital, Istanbul, Turkey
Background: Gilbert’s syndrome is a benign inherited status,
which is characterized by mild unconjugated hyperbilirubin-
emia episodes in absence of haemolysis or liver disease. The
data in the literature is very limited to answer the question
whether is it safe to accept donors with Gilbert’s syndrome
for living donor liver transplantation or not. Aim: The aim of
our study was to evaluate the safety of donors with Gilbert’s
syndrome and to compare the outcome of their recipience with
recipience of none-Gilbert’s donors. Methods: Between 2004
and May 2014, 600 living donor liver transplantation were
performed in our center. The pre-, intra- and postoperative
data of these patients and theirs donors were retrospectively
analyzed. Donors with serum bilirubin level greater than 1,2
mg/dL (20,5 mmol/L) were identified as a Gilbert’s syndrome.
All donors with a complete follow-up of at least one year were
identified as control group. Postoperative complications of the
donors were graded according to the Clavien classification.
Results: There were 45 donors (7%) with Gilbert’s syndrom in a
mean age of 33 years. The control group consist of 99 donors
by a mean age of 32 years. All patients received the right lobe
of their donor. There were no intraoperative complications. The
comparison of the two groups have shown that there are no
significant differences in age, remnant ratio, intra- or postoper-
ative complications, AST-, ALT-, INR- levels, hospital stay or sur-
vival. However the postoperative bilirubin levels at day 1-7, the
maximal peak bilirubin level and the level one and six month
after transplantation are significantly higher in donors with Gil-
bert’s syndrome compared to non-Gilbert’s donors (Table 1).
There were no donor death in our series. Conclusion: Although
the bilirubin levels are significantly higher in donor with Gil-
bert’s syndrome compared to non-Gilbert’s group, the results
do not show any clinical importance. Based on the results of
our study we can conclude that donor with Gilbert’s syndrome
can be accepted safely for living donor liver transplantation
without increased risk.
Table 1. Bilirubin Levels
p:0.000, student T test, for all
Disclosures:
The following people have nothing to disclose: Murat Akyildiz, Gokhan Gungor,
Necdet Guler, Arzu Oezcelik, Tonguc Utku Yilmaz, Onur Yaprak, Yalcin Erdo-
gan, Murat Dayangac, Yildiray Yuzer, Yaman Tokat
516A AASLD ABSTRACTS
651
Laparoscopic Liver Resection in the Pediatric Population:
A Single Center Case Series
Ashley Walther, Shrawan Gaitonde, Greg Tiao, Maria H. Alonso,
Jaimie D. Nathan; Division of Pediatric General & Thoracic Sur-
gery, Cincinnati Children’s Hospital Medical Center, Cincinnati,
OH
Purpose: Laparoscopic liver resection (LLR) has been shown to
be safe and efficacious in the management of liver masses in
adults, however, little literature exists describing the feasibility
of and approaches to LLR in children. Additionally, the indi-
cations for LLR have typically excluded large lesions (>5 cm)
and masses in the posterior and superior segments of the liver,
due to technical limitations. We present our experience with
LLR for liver lesions in the pediatric population, including large
tumors, masses in difficult locations, and major hepatic resec-
tion. Methods: After IRB approval, we retrospectively reviewed
LLR patients treated at our institution from 2009 – 2012. Data
collected included demographics, clinical presentations, radio-
graphic studies, intraoperative details, and postoperative
complications and outcomes. Results: Six LLR procedures were
performed in children (2 males, 4 females) presenting between
5 – 21 years of age. Maximal tumor diameter ranged from
3.1 – 10 cm (mean, 5.7 cm). Indications for resection included
enlarging mass and/or right upper quadrant pain. Operative
approaches included pure laparoscopy (n = 3) and hand-as-
sisted laparoscopy (n = 3). Laparoscopic ultrasound was uti-
lized in all patients to delineate resection margins and major
intrahepatic vasculature. Techniques utilized for parenchymal
transection included electrocautery, Harmonic scalpel, CUSA
ultrasonic dissection, and endoscopic surgical staplers. LLR
procedures included left hemihepatectomy (n = 1), segment 7
resection (n = 1), and total or partial left lateral sectionectomy
(n = 4). Median operating time was 199 minutes, and median
estimated blood loss was 150 mL. No patients required trans-
fusion or conversion to laparotomy. There were no mortalities,
reoperations, or postoperative complications. Median length
of postoperative stay was 4 days (range, 3 – 5 days). Pathol-
ogy demonstrated focal nodular hyperplasia (n = 3), hepatic
adenomatosis with HNF-1 mutation (n = 2), and congenital
hemangioma (n = 1). There has been no recurrence of mass or
symptoms, over median follow-up of 3.1 years. Conclusions:
LLR can be an effective and safe technique in children even in
the setting of large tumor size, tumor location in the right pos-
terosuperior hepatic segment, and formal hemihepatectomy.
Complex laparoscopic liver resections are feasible in the pedi-
atric population with careful patient selection, the development
of individualized surgical strategies for patient positioning and
trocar placement, the use of specialized equipment, and an
understanding of three-dimensional hepatic anatomy with rou-
tine use of intraoperative ultrasound.
Disclosures:
The following people have nothing to disclose: Ashley Walther, Shrawan Gai-
tonde, Greg Tiao, Maria H. Alonso, Jaimie D. Nathan
HEPATOLOGY, October, 2014
652
Novel colonoscopy preparation of organic coconut
water with Miralax and Dulcolax in split doses for
decompensated cirrhotics. A randomized double
blinded open labelled clinical pilot single centered
observational study. COSMIC Study
Patrick Basu1,2, Niraj J. Shah3, David Lee2, M. Aloysius2, Frank G.
Gress1; 1Columbia University School of Physicians and Surgeons,
New York, NY; 2King’s County Hospital Medical Center, Brooklyn,
NY, New York, NY; 3James J. Peters VA Medical Center, Icahn
School of Medicine at Mount Sinai, NY, New York, NY
Background: Screening colonoscopy is routine for patients
been evaluated for OLT. Most aqueous colonoscopy prepara-
tions are poorly tolerated, cause gross dyselectrolytemia and
even renal dysfunction. This ultimately leads to poor compli-
ance affecting diagnosis. This pilot study evaluates the efficacy,
safety and utility of coconut water as a vehicle for colon cleans-
ing with Miralax for decompensated cirrhotics being evalu-
ated for OLT undergoing screening colonoscopy. Methods:
Sixty (n=60) patients aged 45-69 (MELD 16-20, with moderate
ascites and MHE on Diuretics, Lactulose and Xifaxan) were
recruited. Single center, one gastroenterologist, anesthesiol-
ogist, nurse and medical assistant. All were on Lasix (mean
dose of 60 mg daily), Aldactone 100 mg, Lactulose 30 ml and
Xifaxan 550 mg BID. All were placed on total liquids of 1200
cc along with a semi solid diet: 2 grams sodium, 120 grams
protein, 2300 cal/day, ice cream, 1 liter of natural coconut
water with 8 oz of Miralax from 4:00 pm till 10:00 pm and 4
tablets of Dulcolax 5 mg each (at bed time). Total mean noctur-
nal bowel movements were 3-5 in am from 7:00 am till 10:00
am with Miralax 8 oz and 1 liter of coconut water. All diuretics
were stopped 2 days prior to the initiation of the spilt doses
of prep. Questionnaire was taken post prep in the morning
and then again post procedure Results: table Conclusions: This
study postulates a novel organic coconut water preparation
with Miralax compared to traditional preparation to be safe
(lesser dyselectrolytemia), well tolerated with wide satisfactory
score and greater retention. It has greater efficacy with no
side events in special population (decompensated cirrhotics
awaiting OLT)
Results
Disclosures:
The following people have nothing to disclose: Patrick Basu, Niraj J. Shah, David
Lee, M. Aloysius, Frank G. Gress
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
653
The technical success rate and clinical efficacy of
Hepatic Vein Stenting of Hepatic Vein Outflow Stenosis
complicating Orthotropic Liver Transplant
Faiz Francis, Thomas Lowe, Matthew Johnson, David Agarwal,
Daniel E. Wertman, Sabah Butty, Thomas Casciani; Internvetional
Radiology, Indiana University, Indianapolis, IN
Purpose: To evaluate retrospectively the safety, technical suc-
cess and clinical efficacy of hepatic vein stenting in the man-
agement of clinically evident hepatic venous outflow obstruction
complicating orthotopic liver transplantation. Material and
methods: From 2003 to 2013, 24 patients ( 8 female and
16 male), including 23 adults and one adolescent (17 years
of age) underwent hepatic vein stent placement for hepatic
venous outflow obstruction after orthotopic liver transplant. Pre
and post stent deployment pressure gradients were measured.
Results: Reduction of pressure gradient was achieved in 23 of
24 patients . Reduction of post stent placement to 3mmHg or
below was achieved in 15 of 24 patients. Mean pressure gra-
dient before stenting was 15.5 mmHg with SD of 3.5 mmHg
and mean pressure gradient after stenting was 2 mmHg with
SD of 2.8 mmHg with mean reduction in pressure of 13.5
mmHg with SD of 6.4 mmHg. There were no immediate major
complications in our population. Mean interval from transplan-
tation to stenting was 570 days. Mean follow-up was 618
days. Analysis of pre and post liver function values is ongoing.
Conclusion: Hepatic vein stenting for the treatment of post liver
transplant clinically evident hepatic venous outflow obstruction
is a safe and technically successful procedure.
post stent placement venogram demonstrates resolution of stricture
and rapid flow
Disclosures:
Matthew Johnson - Advisory Committees or Review Panels: Boston Scientific,
Guerbet; Consulting: BTG, Bayer, Endoshape; Grant/Research Support: Argon,
Bard, B Braun, BTG, ALN, Cook, Cordis; Speaking and Teaching: BTG, Bayer,
Cook, Argon; Stock Shareholder: Endoshape
The following people have nothing to disclose: Faiz Francis, Thomas Lowe, David
Agarwal, Daniel E. Wertman, Sabah Butty, Thomas Casciani
517A
654
Elevated plasma DNA in patients with NASH and
reduced liver injury in mice with absence of TLR9 on
Kupffer cells
Irma Garcia-Martinez1, Xinshou Ouyang1, Nicola Santoro2, Mark
J. Shlomchik3, Wajahat Z. Mehal1; 1Section of Digestive Diseas-
es,Department of Internal Medicine, Yale University, New Haven,
CT; 2Section of Endocrinology, Department of Pediatrics, Yale Uni-
versity, New Haven, CT; 3Department of Immunobiology, Univer-
sity of Pittsburg, Pittsburg, PA
Introduction: Hepatic steatotic and inflammatory changes
in NASH are known to be significantly dependent of TLR9.
However the cellular requirement for TLR9 expression, and the
presence of the TLR9 ligand is not known. Our aim was to
determine the cellular requirement for TLR9 and to identify its
ligand (DNA) in plasma. Methods: Eight week-old wild-type
(wt) mice (C57BL/6), total TLR9 deficient (TLR9-/-), and mice
lacking TLR9 on lysozyme expressing cells (TLR9floxLysCre)
were fed with regular (chow) or high-fat diet (HFD) for 12
weeks. Food intake and body weight were monitored weekly.
At 12 weeks the following was quantified: Plasma ALT, cho-
lesterol, TGs and plasma DNA. NAFLD activity score, hepatic
mRNA for TNFα, IL-6, and IL-1β. Plasma from 27 age and
sex matched patients in three groups was available. Group
1 Control (n=9); Group 2 NASH low ALT (mean 18 +/- 3)
(n=9), Group 3 NASH high ALT (mean 110+/- 28) (n=9). From
the plasma of the patients the following was quantified: ALT,
DNA. Results: All mice gained more weight on HFD than chow.
HFD induced hepatic steatosis and inflammation in all mice.
TLR9-/- and TLR9floxLysCre mice had less steatohepatitis than
WT mice. The NAFLD activity score (steatosis, inflammation,
and ballooning) and serum ALTs were significantly lower in
TLR9 -/- and TLR9floxLysCre mice than WT mice (239+/-101,
107+/-11, 34+/-8, P<0.05). Plasma cholesterol and TGs
were significantly less in TLR9floxLysCre than wt (cholesterol
132+/-27, 49+/-8, TGs 79+/-16, 55 +/- 2, P<0.05). TLR-
9floxLysCre mice on HFD had reduced hepatic expression of
Pro-IL-1β, TNFα and IL6. Plasma DNA concentration in mice on
a HFD was significantly higher than on regular chow (3.9+/-
0.5, 2.6 +/- 1.1, P<0.05); and DNA concentration in patient
groups 2 and 3 was significantly higher than in control group
1 (3.4+/-0.9, 4.1+/-1.1, 2.7+/-0.5, P<0.05). Mitochondrial
and bacterial DNA in NASH patients with high ALT (Group 3)
was higher compared with control Group 1 (p<0.05). Con-
clusions: Plasma DNA is elevated in patients and mice with
NASH. The requirement of TLR9 for the development of NASH
is on LysMCre-expressing cells—most likely Kupffer cells. This
has identified removal of plasma DNA, and antagonism of
TLR9 on Kupffer cells as novel therapies for NASH.
Disclosures:
Wajahat Z. Mehal - Management Position: Gloabl BioReserach Partners
The following people have nothing to disclose: Irma Garcia-Martinez, Xinshou
Ouyang, Nicola Santoro, Mark J. Shlomchik
518A AASLD ABSTRACTS
655
Thalidomide Pretreatment Improves Cell Engraftment
and Liver Repopulation Independently of Chemokines/
Cytokines/Receptors Expressed after Neutrophil or
Kupffer cell Activation
Preeti Viswanathan1, Sorabh Kapoor2,
Brigid Joseph2,
Ekaterine
Berishvili2, Sanjeev Gupta2; 1Pediatric Gastroenterology and
Hepatology, Childrens Hospital at Montefiore, Bronx, NY; 2Medi-
cine and Pathology, Albert Einstein College of Medicine, Yeshiva
University, Marion Bessin Liver Research Centre, Bronx, NY
Optimizing liver-directed cell therapies requires superior cell
engraftment since this is the initial critical step for liver repop-
ulation. Recently, major roles were identified in transplanted
cell clearance of neutrophils (PMN) and Kupffer cells (KC)
via cytokines/chemokines/receptors that was abolished by
prior TNF-α blockade, and of COX1/2 pathways sensitive to
naproxen or celecoxib. Therefore, we hypothesized that potent
anti-inflammatory effects of Thalidomide (Thal), including inhi-
bition of TNF-α, IL6, NF-kB and COX activity, could improve
cell engraftment, and studied this possibility in DPPIV- rats trans-
planted with freshly isolated syngeneic F344 rat hepatocytes
via spleen. Rats were given 10-40 mg/kg Thal before cells.
We examined cell engraftment with morphometric analysis of
livers stained for DPPIV activity. Groups of control and drug-
treated rats were established with tissue analysis 1, 2, 4 and 7
d or 1 mo after cells. Thal was more effective since transplanted
cell numbers increased by 2.5-3.5-fold, p<0.001. However,
transplanted cell numbers did not increase over time in Thal-
treated rats, excluding hepatic damage. To elicit whether Thal
will permit induction of liver repopulation, we used retrors-
ine/PH-conditioned rats. In these recipients, liver repopula-
tion was accelerated through superior initial transplanted cell
engraftment after Thal, p<0.001. We then examined potential
mechanisms by which Thal benefited cell engraftment. In Thal
pretreated rats, cell transplantation did not alter PMN or KC
activation. This agreed with qRT-PCR array results showing
2-40-fold upregulation of 13 out of 84 cytokine/chemokine/
receptors, including CCL1, CCL2, CXCL2, CXCL4, which are
associated with PMN or KC. These chemokine changes were
abolished when TNF-α receptor was neutralized by Etanercept.
To dissect the role of PMN in this context, we pretreated rats
with Repertaxin (Rep), a small molecule inhibitor of CXCR1
and CXCR2, to block recruitment and activation of PMN by
CXCL1 or CXCL2 after cell transplantation. In Rep-treated rats,
transplanted cell numbers increased at most by 2-fold, which
was less than after Thal, p<0.001. Finally, we tested cell prim-
ing before transplantation with Thal plus or minus bosentan to
block endothelin-1 A/B receptors. Liver repopulation increased
in retrorsine/PH-conditioned rats after bosentan-primed but not
after Thal-primed cells, p<0.05. Conclusions: Transplanted cell
engraftment and liver repopulation benefited from Thal pre-
treatment independently of PMN or KC-mediated inflammation.
The synergism with ET1 receptor blockade and Thal indicates
this combined drug approach will advance cell therapy appli-
cations.
Disclosures:
The following people have nothing to disclose: Preeti Viswanathan, Sorabh
Kapoor, Brigid Joseph, Ekaterine Berishvili, Sanjeev Gupta
HEPATOLOGY, October, 2014
656
Low dose digoxin protects from NASH and alcoholic
hepatitis in mice by inhibiting a ROS-HIF-1α-inflam-
masome pathway
Xinshou Ouyang1, Ji-Yuan Zhang1, Dechun Feng2, Shi-Ying Cai1,
Irma Garcia-Martinez1, Fu-Sheng Wang3, Bin Gao2, Wajahat Z.
Mehal1; 1Digestive Diseases, Yale University, New Haven, CT;
2NIAAA, NIH, Bethesda, MD; 3Institute of Translational Hepatol-
ogy, Beijing 302 Hospital, Beijing, China
Introduction: The inflammasome plays a crucial role in the
pathogenesis of NASH and alcoholic hepatitis, and HIF1α
is required for sustained inflammasome activity. Digoxin was
identified with potent HIF1α antagonist but its role in liver dis-
ease is unexamined. Aim: To assess whether a low dose of
digoxin has therapeutic effects in NASH and alcoholic hepatitis
in mice, and investigate the molecular mechanisms. Methods:
C57BL/6J male mice were placed on a 45% high fat diet
(HFD) for 11weeks with and without digoxin (ip 1mg/kg twice
a week). Digoxin 1mg/kg ip daily in mice results in the thera-
peutic serum levels achieved in humans (0.5-2 ng/ml). Plasma
ALT, liver histology, neutrophil staining, leukocytes profiling,
mitochondrial reactive oxygen species (ROS) generation, and
gene transcriptome microarrays were analyzed. The ability of
digoxin to inhibit inflammasome in mouse and human macro-
phages was tested. The chronic plus binge model of alcoholic
hepatitis and LPS/D-GalN hepatitis models were also per-
formed. Results: In all three models digoxin resulted in reduced
histological injury, neutrophilic infiltrate and lower serum ALT’s
(417 +/- 398 U/L in HFD vs 91 +/- 73 U/L in HFD+DIG, P<
0.001). Starting digoxin after 4 weeks HFD still showed signif-
icant reduction in liver inflammation (neutrophil 24.6% in HFD
vs 14.3% in HFD+DIG; monocytes 31.6% in HFD vs 19.1% in
HFD+DIG) without a reduction in food intake. In LPS/D-GalN
hepatitis a dose titration of twice, a quarter and a twentieth
of the human equivalent dose resulted in improvement of liver
hemorrhage and necrosis, reduction in liver HIF-1α and Pro-
IL-1β transcripts as well as the proteins of IL-1β, HIF-1α, pro-
IL-1β and cleaved (P10) caspase-1. Microarray analysis in HFD
liver revealed significant changes of signal genes that digoxin
down-regulated ROS metabolism, antioxidant pathway and
glycolysis, and up-regulated fatty acid β-oxidation pathway. In
vitro data showed that digoxin dose-dependently inhibited mito-
chondrial ROS production under TLR and hydrogen peroxide
stimulation in mouse and human macrophages. Digoxin also
inhibited IL-1 β secretion and caspase-1 activation in mouse
macrophages. Conclusions: Low doses of digoxin reduce liver
steatosis, and inflammation in experimental models of NASH
and alcoholic hepatitis via a ROS-HIF1α-inflammasome path-
way. Low dose digoxin may have significant utility in the treat-
ment of NASH and alcoholic hepatitis.
Disclosures:
Wajahat Z. Mehal - Management Position: Gloabl BioReserach Partners
The following people have nothing to disclose: Xinshou Ouyang, Ji-Yuan Zhang,
Dechun Feng, Shi-Ying Cai, Irma Garcia-Martinez, Fu-Sheng Wang, Bin Gao
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
657
A distinct role for the TLR9 pathway in immune activa-
tion and tolerance during acute liver injury in mice
Nobuhiro Nakamoto1, Hirotoshi Ebinuma1, Nobuhito Taniki1,
Yuko Wakayama1, Po-sung Chu1, Akihiro Yamaguchi1, Takeru
Amiya1, Hidetsugu Saito2,1, Takanori Kanai1; 1Department of Inter-
nal Medicine, Keio University, School of Medicine, Tokyo, Japan;
2Keio Unversity, School of Pharmacy, Tokyo, Japan
BACKGROUND & AIMS: Hepatic antigen-presenting cells
with toll-like receptors (TLRs) bind to PAMPs and DAMPs and
are involved in immune activation and tolerance. We recently
reported that CCR9+CD11b+ macrophages play a critical role
in murine acute liver injury pathogenesis following a single
injection of concanavalin A (ConA). Repetitive ConA adminis-
tration induces immune tolerance and emergence of CCR9low-
CD11c+ dendritic cells (DCs), resulting in reduced injury in
the liver. In this study, we sought to clarify the underlying
mechanisms of immune activation and tolerance in the liver.
METHODS: Male C57BL/6 mice were given a sub-lethal dose
of ConA after an initial injection to induce immunological tol-
erance. Liver mononuclear cells were separated 12 h after the
final ConA injection. Cytokine production from each immune
cell subset with TLR ligand stimulation was evaluated, as was
the composition of intestinal bacterial flora by T-RFLP and
quantitative PCR. RESULTS: A single ConA injection induced
severe liver inflammation and an increase in CCR9+CD11b+
macrophages within 24 h (D1-mac). ConA administration 7
days after the initial injection, but not at earlier time point,
resulted in immunological tolerance; CCR9+ macrophages
were no longer apparent and CCR9lowCD11c+ DCs (D7-cDC)
emerged in the liver. D1-mac had the potential to produce
tumor necrosis factor and interferon-γ, with TLR2/6, 4, and 9
ligand stimulation, and differentiated naïve CD4 T cells into
Th1 cells in vitro. D7-cDC had regulatory characteristics and
potentially produced interleukin-10, transforming growth fac-
tor-β (TGF-β) with TLR9 ligand stimulation, and differentiated
CD4 T cells into Foxp3+CD4+ regulatory T cells (Treg) in a
TGF-β dependent manner. Pre-transferred D7-cDC protected
mice from ConA hepatitis in vivo. Treatment of wild-type mice
with TLR9 antagonist ODN2088 prior to the initial ConA injec-
tion ameliorated liver inflammation. In contrast, treatment with
ODN2088 prior to the second ConA injection worsened liver
damage, suggesting that the TLR9 pathway plays a distinct role
in immune activation and tolerance. The composition of intesti-
nal bacterial flora changed and a ratio of Clostridium subclus-
ter XIV increased following a single ConA injection. Treatment
with broad-spectrum antibiotics after the initial ConA injection
resulted in less TGF-β-producing CD11c+ DC migration into the
liver. CONCLUSIONS: The TLR9 pathway plays a distinct role
in immune activation and tolerance in murine acute hepatitis.
Severity of hepatic injuries and changes in intestinal bacterial
flora might regulate the balance between immunity and toler-
ance through TLR9 in a time-dependent manner.
Disclosures:
The following people have nothing to disclose: Nobuhiro Nakamoto, Hirotoshi
Ebinuma, Nobuhito Taniki, Yuko Wakayama, Po-sung Chu, Akihiro Yamaguchi,
Takeru Amiya, Hidetsugu Saito, Takanori Kanai
519A
658
Sonic hedgehog in microparticles from apoptotic T cells
modulate vascular endothelial function via a rho-kinase
pathway
Samantha A. Canipe1, Nicole Feilen1, Didier Dréau1,2, Mark G.
Clemens1,2; 1Department of Biological Sciences, University of
North Carolina at Charlotte, Charlotte, NC; 2Center for Biomedi-
cal Engineering and Science, University of North Carolina at Char-
lotte, Charlotte, NC
Impaired vascular regulation contributes to liver injury in
hepatic pathologies including sepsis/inflammation. Sinusoidal
endothelial cell dysfunction is a major cause in sepsis; how-
ever, the mechanisms are not fully understood. Sonic hedgehog
(shh) in microparticles (MP) has been shown to modulate liver
injury. Since sepsis is associated with T cell apoptosis and
apoptotic T cells shed (MP) containing shh, we tested whether
MP from apoptotic T cells might modulate endothelial function.
MPs containing shh (confirmed by Western blot) were pro-
duced by inducing apoptosis in human CEM T cell line. Human
umbilical vein endothelial cells (HUVEC) were used as a model.
We first tested the effect of MP on endothelin (ET)-stimulated
eNOS. ET increased eNOS activity and this was inhibited by
endotoxin (LPS). Pretreatment with MP alone resulted in a more
than 2x increase in ET-stimulated eNOS activity. However,
with MP + LPS, ET-stimulated eNOS was inhibited even more
than with LPS alone, indicating an interaction between LPS
and MP. We next tested the effect of MP on HUVEC wound
healing / proliferation. Without MP pretreatment 74 +/- 4 %
of the wound healed at 12 hours; with MP, only 44% healed.
This was duplicated using the smoothened activator purmor-
phamine (Pur, 43% p<.05) indicating a role for shh. We next
tested whether MP affected the response to oxidative stress.
HUVECS were pretreated for 6 or 24 hours with MP followed
by two hours of H2O2 or cotreatment with MP and H2O2.
Viability was assessed by MTT. H2O2 alone caused no signifi-
cant loss of viability, but it was decreased by 40% to 75% with
each treatment indicating that MP sensitize to oxidative stress.
Finally, we tested the effect of MP on morphology. Untreated
cells showed a typical cobblestone appearance. MP resulted
in a more elongated, spindle-shape. Aspect ratio (long axis/
short axis) for untreated was 2.4 +/- 0.1 and with MP, 3.9
+/- .24 (p< .001). This was duplicated by Pur indicating impli-
cating shh. While the canonical pathway for shh involves gli,
we were unable to demonstrate gli induction by MP or Pur.
Shh may activate rho kinase in endothelial cells. Therefore we
tested whether a rho-kinase inhibitor would prevent the change
in morphology caused by MP. Y27632 prevented the morpho-
logical change (aspect ratio 2.1 +/- 0.1, p >.05 vs untreated)
indicating that this effect depends on rho-kinase activation. In
conclusion, shh in MP from apoptotic T cells has significant
effects on vascular endothelial that are mediated by activation
of rho-kinase. We propose that MP may be a significant mod-
ulator of impaired hepatic vascular regulation in inflammation
and sepsis.
Disclosures:
Mark G. Clemens - Management Position: HepatoSys Inc; Stock Shareholder:
HepatoSys Inc
The following people have nothing to disclose: Samantha A. Canipe, Nicole
Feilen, Didier Dréau
520A AASLD ABSTRACTS
659
Chronic dietary iron overload in genetically obese
mice causes nonalcoholic steatosis, whereas acute iron
excess leads to increased inflammation and reduced
steatosis
Priya Handa1,2, Vicki Morgan-Stevenson1,2, Bryan D. Maliken1,2,
James E. Nelson1,2, Matthew M. Yeh3, Kris V. Kowdley1,2; 1Liver
Center of Excellence, Digestive Disease Institute, Seattle, WA;
2Benaroya Research Institute, Virginia Mason Medical Center,
Seattle, WA; 3University of Washington Medical Center, Seattle,
WA
Aim: To examine the differential effects of chronic dietary
iron overload and acute iron excess on nonalcoholic steatosis
(NASH) pathogenesis in a genetically obese animal model.
Methods: Leprdb/db mice were fed either a normal or iron-sup-
plemented (2% carbonyl iron) chow for 8 weeks. A subset of
chow-fed mice were administered a single dose of 1.25 mg/g
wt Fe-dextran by IP injection prior to resuming NC feeding.
The treatment groups are: 1) NC 2) Dietary iron (DI) 3) Par-
enteral iron (PI). After 16 weeks, blood and liver tissue were
collected. Histological features of NASH and iron deposition
were scored by a hepatopathologist using NASH CRN criteria.
Liver transaminase levels, glucose and iron parameters were
measured in serum; whereas triglyceride levels, malondialde-
hyde (MDA), TUNEL staining, immunohistochemistry for 4HNE
and changes in gene expression were assessed in liver tissue.
Results: Administration of iron by either route (oral or paren-
teral), resulted in increased liver enzymes (AST and ALT), glu-
cose and hepatic MDA. Administration of iron by either route
also resulted in reduced body mass, increased hepatic iron
stores and hepatic hepcidin expression. PI mice had a mixed
pattern of hepatocellular (HC) and reticuloendothelial cell sys-
tem (RES) iron deposition, while DI mice had an exclusively RES
localization. PI mice had higher grades of HC and RES iron,
decreased steatosis but high inflammation scores. Consistent
with the NASH histology, livers of PI mice demonstrated a
decrease in the lipid metabolism genes such as TFAM, ACOX,
CPT1α, SREBP1c and SCD1, and an increase in inflammatory/
immune markers such as TLR4, MCP-1, CD68, CD4 and MHCII.
Livers from PI mice showed elevated levels of 4-HNE staining.
Hepatocellular ballooning was not observed in PI mice, but
was significantly elevated in DI mice. DI mice exhibited signifi-
cantly higher hepatic triglycerides and elevated expression for
HO-1 and Gpx-1 anti-oxidant genes. TUNEL staining revealed
that PI caused significant apoptosis, higher levels of cleaved
caspase-8 protein and increased levels of Bcl2 and Bax genes,
relative to NC. Conclusions: Iron supplementation results in an
exacerbated diabetic phenotype, increased aminotransferases
and oxidative stress in the liver. Thus, in a genetically obese
mouse model, acute iron excess leads to increased inflamma-
tion and apoptosis with reduced steatosis, whereas chronic
dietary iron overload exhibits hepatic RES localization, hepato-
cellular ballooning injury and NASH. This study highlights the
role of chronic iron overload, not acute parenteral injection, as
a ‘second hit’ in the development of NASH in a mouse model
with metabolic syndrome.
Disclosures:
Kris V. Kowdley - Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research
Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria,
Janssen, Merck, Mochida, Vertex
The following people have nothing to disclose: Priya Handa, Vicki Morgan-Ste-
venson, Bryan D. Maliken, James E. Nelson, Matthew M. Yeh
HEPATOLOGY, October, 2014
660
NLRP3 inflammasome driven liver injury and fibrosis:
roles of IL- 17 and TNF-alpha
Alexander Wree1, Matthew D. McGeough1, Maria E. Inzauga-
rat2, Carla A. Pena1, Alejandra Cherñavsky2, Hal M. Hoffman1,
Ariel E. Feldstein1; 1Pediatrics, UCSD, La Jolla, CA; 2Institute of
Immunology, Genetics and Metabolism, CONICET-UBA, Buenos
Aires, Argentina
Background: The NLRP3 inflammasome, a caspase-1 activation
platform critical for processing key pro-inflammatory cytokines,
is of great importance in innate immunity. While its activation
has been linked to the development acute and chronic liver
diseases, regulatory pathways that mediate this process are
poorly understood. Therefore, our AIM was to investigate the
role of IL-17 and TNF-α in NLRP3 dependent liver damage.
Methods: Nlrp3A350VneoR knock-in mice were bred onto
IL-17 and TNF-α knockout backgrounds. The resultant mice
were then crossed with IL-17 or TNF-α knockout mice express-
ing a Cre recombinase under the Lysozyme promoter allow-
ing for mutant Nlrp3 expression in myeloid derived cells in
mice deficient in IL-17 or TNF-α. Results: Mice expressing the
Nlrp3A350V mutation in myeloid derived cells were smaller
than non-mutant littermates, showed a marked inflammatory
infiltrate in liver samples and had elevated levels of IL-17 and
TNF-α when compared to littermate controls. Mutants lacking
IL-17 showed a slight improvement in weight differential, while
TNF-α knockout mutants were not distinguishable from their
non-mutant knockout littermates. Livers of intact Nlrp3A350V
mutants showed strong neutrophilic infiltrations, while IL-17
loss of function mutants showed fewer neutrophils when com-
pared to intact Nlrp3A350V mutants, but still significantly more
than their non-mutant IL-17 knockout littermates. The amount
of neutrophils and regulating chemokines in TNF-α deficient
mutants did not differ from non-mutant knockout littermates. An
increase in hepatic macrophages was only present in intact
Nlrp3A350V mutants, while values in IL-17 and TNF-α defi-
cient mutants were similar to corresponding littermates. How-
ever, inflammatory macrophage polarization with increased
mRNA levels of TNF-α and iNOS was present in inact Nlr-
p3A350V mutants and IL-17 lacking mutants. Moreover, intact
Nlrp3A350Vmutants showed fibrosis, as evidenced by Sirius
red staining and increased mRNA levels of CTGF and TIMP-
1. IL-17 lacking mutants exhibited amelioration of the afore-
mentioned fibrosis, while TNF-α deficient mutants showed no
signs of fibrosis when compared to littermate controls. In addi-
tion, an attenuation of the inflammatory parameters discussed
above was also seen in mutants heterozygous for TNF-α loss
of function when compared to intact Nlrp3A350V mutants.
Conclusion: Our study uncovers key roles for IL-17 and TNF-α
as mediators of liver inflammation and activation of hepatic
stellate cells in NLRP3 inflammasome activated myeloid cells.
These findings may lead to novel therapeutic strategies aimed
at halting the progression of liver injury and fibrogenesis.
Disclosures:
The following people have nothing to disclose: Alexander Wree, Matthew D.
McGeough, Maria E. Inzaugarat, Carla A. Pena, Alejandra Cherñavsky, Hal M.
Hoffman, Ariel E. Feldstein
661
PAD4-mediated neutrophil extracellular trap formation
increases liver ischemia/reperfusion injury in mice
Samer Tohme, Hai Huang, Allan Tsung; Surgery, University of
Pittsburgh, Pittsburgh, PA
Liver ischemia and reperfusion (I/R) injury can be a detrimental
consequence encountered during major liver resection, trans-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
plant, massive trauma and hypovolemic shock. The initiation
of liver sterile inflammation results in the release of damage
associated molecular patterns (DAMPs) such as HMGB1 and
histones, in addition to the rapid recruitment of neutrophils to
the site of injury. Neutrophil infiltration and accumulation in the
ischemic liver lobe after reperfusion contributes to the damage
observed during liver I/R injury. Upon activation, neutrophils
have been shown to release fibers composed of chromatin and
protein to form neutrophil extracellular traps (NETs). Whether
NETs participate in liver I/R and the subsequent consequences
remain unknown. Therefore, the purpose of our work is to elu-
cidate whether NETs are formed during liver I/R and their
role. In vitro, treatment of neutrophils isolated from the femur
of mice with media from hypoxic hepatocytes, HMGB1 or
histones resulted in significant NET formation by immunofluo-
rescence. This was inhibited by adding peptidylarginine deimi-
nases (PAD) 4 (a nucleoprotein that mediates NET formation
by citrullinating histones) inhibitor or DNase1 to either inhibit
or disrupt NET formation, respectively. In vivo, mice were sub-
jected to a non-lethal partial (70%) warm liver I/R model. We
found abundant NET formation in ischemic liver lobes after
I/R as evidenced by confocal immunofluorescence, increased
citrullinated histone in the liver tissue, and increased levels of
serum free DNA and nucleosomes. Treatment with either PAD4
inhibitor or DNAse conferred significant protection compared
to controls after liver I/R evidenced by decreased AST and
ALT levels, significantly less hepatic necrosis by histology, and
decreased levels of circulating inflammatory cytokines, free
DNA, and nucleosomes. In summary, our study reveals that
NETs are formed during liver I/R and subsequently increase
the injury. Targeting NET formation may be a new therapeutic
strategy to reduce ischemia-related liver damage.
Disclosures:
The following people have nothing to disclose: Samer Tohme, Hai Huang, Allan
Tsung
662
Visceral Adipose Levels of mRNA Encoding GATA3 and
FOXP3 Transcription Factors and CSF1 Marker of Mac-
rophage Infiltration Negatively Correlate with Histologi-
cally Assessed Inflammatory Scores in Liver Biopsies
Maria Keaton2, Katherine Doyle2,
Lei Wang2,
Zahra Younoszai1,3,
Rohini Mehta1,3, Zachary D. Goodman1,3, Aybike Birerdinc1,2,
Ancha Baranova1,2, Zobair Younossi1,3; 1Betty and Guy Beatty
Center for Integrated Research, Inova Health System, Falls Church,
VA; 2Center for the Study of Genomics in Liver Diseases, George
Mason University, Fairfax, VA; 3Center for Liver Disease, Depart-
ment of Medicine, Inova Fairfax Hospital, Falls Church, VA
Expansion of the visceral adipose tissue (VAT) volume can
lead to the hypoxic death of adipocytes. The contents released
from dying cells may trigger the macrophage infiltration of
immune cells into adipose tissue and inflammatory pathway
activation. Aim: We assessed whether the subsequent systemic
release of proinflammatory cytokines plays a role in the spec-
trum of Non-Alcoholic Fatty Liver Disease (NAFLD). Methods:
Liver biopsies and VAT samples were collected after informed
consent from 84 morbidly obese patients (BMI>35) under-
going gastric bypass surgery. RNA was extracted with the
Bio-Rad Aurum Total RNA Fatty and Fibrous Tissue Kit from
VAT samples, reverse transcribed into cDNA for qRT-PCR using
the SABiosciences’ RT2 First Strand Kit with primers for genes
encoding transcription factors involved in T-cell differentia-
tion (GATA3, TBX21, FOXP3), macrophage markers (CSF1,
CSF1R, and TIMP1), and potassium channel regulators (KCN-
RGv1 and KCNRGv2). Relationships between the expression
521A
levels of these mRNAs and histological scores in the liver were
assessed using Spearman’s rank sum correlation. Results:
A total of 84 VAT samples were processed (38.6% NASH,
33.7% NAFLD-Non-NASH, 2.4% Cirrhosis, 36.1% with type 2
diabetes, age 42.62 +/- 11.55 years, AST 27.20 +/- 20.25
U/L, ALT 35.85 +/- 29.18 U/L, BMI 47.23 +/- 9.99). Levels
of mRNA encoding for CSF1 were negatively correlated with
the infiltration of Kupffer cells (r=-0.2325, p<0.03554), portal
fibrosis (r=-0.2228, p<0.04424), and portal triad inflamma-
tion (r=-0.2277, p<0.03964), while the levels of KCNRGv2
were negatively correlated with infiltration of polymorphoneu-
trophils (PMN) (r=-0.3907, p<0.0002843) and Kupffer cell
(r=-0.3352, p<0.002079) related inflammation. The mRNA
levels for GATA3 and FOXP3 were negatively correlated with
presence of Mallory-Denk bodies (r=-0.2425, p<0.03023) and
(r=-0.2938, p<0.00858) respectively, while FOXP3 mRNA
levels were also negatively correlated with bridging fibrosis
(r=-0.2234, p<0.04784). Conclusion: These data suggest that
expression of the transcription factors involved in T-cell differen-
tiation in VAT may influence the local and global inflammatory
state of the liver in an anti-inflammatory manner. Additional
studies with larger cohorts have to be performed to further
evaluate these findings.
Disclosures:
Zachary D. Goodman - Consulting: Gilead Sciences, Abbvie; Grant/Research
Support: Gilead Sciences, Fibrogen, Galectin Therapeutics, Merck, Vertex, Syn-
ageva, Conatus
The following people have nothing to disclose: Maria Keaton, Katherine Doyle,
Lei Wang, Zahra Younoszai, Rohini Mehta, Aybike Birerdinc, Ancha Baranova,
Zobair Younossi
663
A novel method for anti-TNF based-oral immunother-
apy: Oral administration of a plant cell-expressed
recombinant anti-TNF fusion protein for treating of fatty
liver disease
Yoseph Shaaltiel1, Yehudit Shabat2, Ami Ben Ya’acov2, Sveta
Gingis-Velitski1, Einat Almon1, David Aviezer1, Yaron Ilan2; 1Prota-
lix, Carmiel, Israel; 2Hebrew University Hadassah Medical Center,
Jerusalem, Israel
Orally administered BY-2 plant cell-expressed recombinant
anti-TNF fusion protein (PRX-106) consists of the soluble form of
the human TNF receptor (TNFR) fused to the Fc component of
a human antibody IgG1 domain. In vitro PRX-106 was shown
to bind TNF alpha, thereby inhibiting it from binding to cellular
TNF receptors, and preventing its downstream effects, such as
TNF-induced apoptosis and inflammation, in a dose-depen-
dent manner. Aim: Evaluation the immune modulatory effect
of oral administration of plant cells expressing PRX-106 in the
high fat diet (HFD) model. Methods: Four groups of C57B1/6
HFD fed mice were orally treated daily for 22 weeks with
BY-2 cells expressing PRX-106, equivalent to 0.5mg (1X) or
10mg (20X), for groups A and B, respectively. Mice in control
groups C and D were treated with the same orally admin-
istered volumes of BY-2(-) plant cells, or saline. The immune
modulatory effect of PRX-106 was determined by serum liver
enzymes and triglycerides levels, liver histology and intrahe-
patic and systemic FACS analysis for Tregs and NKT cells.
Results: Oral administration of BY-2 cells expressing PRX-106
is biologically active in the gut exerting a systemic immune
modulatory effect and alleviating the liver disease. Intrahepatic
NKT cells increased to 2.83% and 3.58% in treated mice in
groups A and B, respectively, (p=0.01 for group B vs. control).
A positive trend was noted for the intrahepatic/intrasplenic
CD4+CD25+FoxP3+ Tregs ratio that decreased to 0.3 and
0.25 in groups A and B, respectively, along with alteration of
522A AASLD ABSTRACTS
the CD4/CD8 lymphocyte distribution. The immune modula-
tory effects were associated with alleviation of several disease
parameters. Serum triglycerides levels decreased significantly
to 186 and 124 mg/dL as compared with 214 and 260 mg/
dL in control groups (p <0.02 for both treated groups vs. con-
trols). A positive trend was noted for hepatic triglyceride con-
tent that decreased to 26.65 mg in group B, as compared with
32.61 and 32.5 in control groups C and D; and for serum
AST levels that decreased to 370 and 296 u/L, respectively,
in mice from groups A and B, as compared with 454 and 496
u/L, for untreated controls in groups C and D. Conclusions:
Oral administration of plant cells expressing recombinant anti-
TNF fusion protein shows biological activity, and exerts an
immune modulatory effect alleviating the liver damage in the
HFD model. The data suggests that it may serve as a novel and
effective mode for oral immune therapy for NASH.
Disclosures:
Yoseph Shaaltiel - Employment: Protalix biotherapeutics
Sveta Gingis-Velitski - Employment: protalix
Einat Almon - Employment: Protalix
David Aviezer - Management Position: Protalix ; Speaking and Teaching: Bar Ilan
U. ; Stock Shareholder: Protalix
Yaron Ilan - Board Membership: Exalenz, Plantylight; Consulting: Immuron, Pro-
talix, ENZO, Abbott, Taxon, Teva
The following people have nothing to disclose: Yehudit Shabat, Ami Ben Ya’acov
664
Liver lymphocytes from NLG4-/- (KO) mice showed
chronic oxidative stress with reduced respiratory burst
response
Johnny Amer, Sarit Doron, Ahmad Salhab, Rifaat Safadi; Liver
& Gastroenterology Units, Hadassah Hebrew University Medical
Center, Jerusalem, Israel
Background: The production is free radicals are part of normal
host defenses against infectious diseases. The generation of
ROS in the respiratory burst is mediated by the multi-component
mitochondrion enzyme, NADPH oxidase. Natural Killer (NK)
cell impairment leads to fibrosis progression; accompanied
with NLG4 over expressions in human Nonalcoholic-Fatty-Liv-
er-Disease (NAFLD) and animal models of liver injury. Aims:
We assessed the role of NLG4 in respiratory burst response
of NK cell killing and fibrosis outcome using a murine model
of knockout human NLG4-/- (reported as a genetic model for
Autism). Methods: Liver lymphocytes isolated from WT and
NLG4-/- mice were incubated with 5 μmol/l 2-7-dichlorofluo-
rescin diacetate (DCF). After incubation for 15 min, lymphocytes
washed and stimulated for 20 min with 100 ng/ml phorbol
12-myristate-13-acetate (PMA). Results: Flow cytometry liver
lymphocytes profile showed anti-fibrotic patterns; increased
NK cells (from 9.2±2.1 in WT to 13.4±2.6% in NLG4-/- ani-
mals, p=0.001) with decreased CD8 cells (from 20.3±3.6 in
WT to 9.1±2.5% in NLG4-/- animals, p=0.002). The increase
in NK cells was associated with elevated ROS productions;
5-fold higher in NLG4-/- as compared to NK cells from WT
mice (p=0.0001). Upon PMA stimulations, total lymphocytes
together with each sub-populations (CD8, CD4, and NK cells)
from the WT animals showed increase in their oxidative burst
(P<0.02), however, lymphocytes from the NLG4-/- counter-
parts showed no response to the PMA stimulations. Conclusion:
At basal level, NLG4-/- lymphocytes have a higher ROS levels
but a reduced response to PMA. Chronically stressed lympho-
cytes, e.g. NLG4-/-, have reduced capacity to elicit a respira-
tory burst, which may compromise their antibacterial capacity
suggesting that NLG4 receptor is necessary for mitochondria
HEPATOLOGY, October, 2014
integrity while its loss although exert anti-fibrotic profile but is
susceptibility to infections.
Disclosures:
The following people have nothing to disclose: Johnny Amer, Sarit Doron, Ahmad
Salhab, Rifaat Safadi
665
Warm ischemia and reperfusion causes liver microcircu-
latory injury and acute endothelial dysfunction. Simvas-
tatin prevents these deleterious events
Diana Hide1, Marti Ortega-Ribera1, Sergi Vila1, Carmen Peralta2,
Juan Carlos Garcia-Pagan1, Jaime Bosch1, Jordi Gracia-Sancho1;
1Barcelona Hepatic Hemodynamic Lab, IDIBAPS - Hospital Clinic
de Barcelona, Barcelona, Spain; 2IDIBAPS, Barcelona, Spain
Warm ischemia reperfusion (WIR) injury causes hepatic
damage and may lead to graft dysfunction. The mechanisms
involved remain partially unknown. We demonstrated that
simvastatin, inducing the expression of the vasoprotective
transcription factor KLF2, improves/prevents hepatic vascular
damage in experimental models of cirrhosis and cold storage.
We herein aimed at characterizing the microcirculatory status
and endothelial phenotype of livers undergoing WIR, and eval-
uate the applicability of simvastatin to ameliorate/prevent WIR
injury. Methods Healthy rats received simvastatin, or vehicle,
30min before undergoing 60min of partial warm ischemia
followed by 2h of reperfusion (early damage) or 24h (late
damage). Afterwards, systemic and hepatic hemodynamics
(mean arterial pressure-MAP, portal pressure-PP, portal blood
flow-PBF and hepatic vascular resistance-HVR), hepatic injury
(ALT, AST, LDH), endothelial function (response to acetylcho-
line) and phenotype (KLF2-eNOS pathway), and inflamma-
tion (neutrophil and macrophage infiltration) were evaluated.
Results Livers undergoing WIR exhibited higher PP and reduced
PBF compared to sham group, indicating a marked increase in
HVR (+77% at 2h; +49% at 24h), without differences in MAP.
This was accompanied by hepatic damage, marked endothe-
lial dysfunction (-42% in vasodilatation capability at 2h; -75%
at 24h), reduced expression/activity of KLF2-eNOS pathway
(2h: -48% in KLF2, -50% in p-eNOS, -73% in cGMP, +130%
in nitrotyrosine; 24h: -28% in KLF2) and a markedly increased
inflammatory component (infiltration at 2h: neutrophils +100%,
macrophages +20%; and at 24h: neutrophils 14 fold increase,
macrophages +19%) Simvastatin pre-treated animals showed
less hepatic damage (AST:-55%, ALT:-66%, LDH:-49%) and
reduced HVR (2h: -32%; 24h: -21%) leading to increased
hepatic perfusion level (2h: PBF +34%, 24h: +21%). Endothe-
lial function (2h: +66%, 24h: +60%) and phenotype markers
(2h: KLF2:+100%, p-eNOS:+98%, cGMP: +42%, nitrotyro-
sine: -77%, 24h: KLF2: +38%) were markedly improved, being
comparable to sham rats. Inflammation both at 2 and 24h
of reperfusion was totally prevented. Conclusions This study
demonstrates that a brief period of warm-ischemia has delete-
rious effects on liver microcirculation and endothelial function
both in the acute and late phases of reperfusion. Simvastatin
prevents liver damage and maintains a correct microcirculatory
status, which confers protection against inflammatory burst.
Preservation of endothelial function and hepatic microcircula-
tion should be considered as a key factor to reduce warm-isch-
emia+reperfusion injury.
Disclosures:
Juan Carlos Garcia-Pagan - Grant/Research Support: GORE
Jaime Bosch - Consulting: Falk, Gilead Science, Norgine, ONO-USA, Intercept
pharma, Exalenz, Almirall, Conatus; Grant/Research Support: Gore
The following people have nothing to disclose: Diana Hide, Marti Ortega-Ribera,
Sergi Vila, Carmen Peralta, Jordi Gracia-Sancho
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS 523A

666 3 IE); PELD>19 were 3 PFIC2/PEBD. Summary/Conclusion:

Analysis of surgical interruption of the enterohepatic
circulation as a treatment for pediatric cholestasis: a ret-
rospective, multi-institutional study
Kasper S. Wang1, Benjamin L. Shneider2, Colleen G. Azen1,
Ronen Arnon3, Lee M. Bass4, Molly A. Bozic5, Mary L. Brandt6,
Matthew S. Clifton7, Patrick A. Dillon8, Annie Fecteau9, Paula M.
Hertel6, Shinjiro Hirose10, Kishore Iyer3, Binita M. Kamath9, Saul
J. Karpen7, Frederick M. Karrer11, Nanda Kerkar1, Kathleen M.
Loomes12, Cara Mack11, Peter Mattei12, Alexander G. Miethke13,
Douglas Mogul14, Philip Rosenthal10, Kyle A. Soltys2, Riccardo
Superina4, Dylan Stewart14, Greg Tiao13, Yumirle P. Turmelle8,
Karen West5; 1Children’s Hospital Los Angeles, Los Angeles, CA;
2Children’s Hospital of Pittsburgh, Pittsburgh, PA; 3Mount Sinai
School of Medicine, New York, NY; 4Lurie Children’s Hospital,
Chicago, IL; 5Riley Children’s Hospital, Indianapolis, IN; 6Baylor
College of Medicine, Houston, TX; 7Emory University, Atlanta, GA;
8Washington University School of Medicine, St. Louis, MO; 9The
This is the first multi-center analysis of nontransplant surgical
approaches to intrahepatic cholestasis. Approaches vary, are
well tolerated, and generally result in improvement of pruritus
and cholestasis. Disease specific responses may exist.
Disclosures:
Benjamin L. Shneider - Consulting: Bristol Myers Squibb, Vertex; Grant/Research
Support: Hyperion Therapeutics; Stock Shareholder: Bristol Myers Squibb
Lee M. Bass - Advisory Committees or Review Panels: Kadmon Pharmaceuticals
Alexander G. Miethke - Grant/Research Support: Lumena, Pharmaceutical Inc.
Philip Rosenthal - Advisory Committees or Review Panels: Ikaria, Gilead, Merck,
General Electric; Consulting: Roche; Grant/Research Support: Roche, Bristol
MyersSquibb, Gilead, Vertex
The following people have nothing to disclose: Kasper S. Wang, Colleen G.
Azen, Ronen Arnon, Molly A. Bozic, Mary L. Brandt, Matthew S. Clifton, Patrick
A. Dillon, Annie Fecteau, Paula M. Hertel, Shinjiro Hirose, Kishore Iyer, Binita
M. Kamath, Saul J. Karpen, Frederick M. Karrer, Nanda Kerkar, Kathleen M.
Loomes, Cara Mack, Peter Mattei, Douglas Mogul, Kyle A. Soltys, Riccardo
Superina, Dylan Stewart, Greg Tiao, Yumirle P. Turmelle, Karen West

Hospital for Sick Children, Toronto, ON, Canada; 10University of

California at San Francisco, San Francisco, CA; 11Children’s Hos- 667
pital Colorado, Denver, CO; 12Children’s Hospital of Philadelphia, Oxidative Stress Caused by Nocturnal Hypoxia is
Philadelphia, PA; 13Cincinnati Children’s Hospital Medical Center, Related to the Severity of Pediatric Non-Alcoholic Fatty
Cincinnati, OH; 14Johns Hopkins School of Medicine, Baltimore, Liver Disease
MD
Shikha Sundaram1,2, Ann C. Halbower1,2, Zhaoxing Pan2, Kristen
Purpose: Evaluate the efficacy of nontransplant surgery in N. Robbins1, Kelley E. Capocelli1,2, Jelena Klawitter2, Ronald J.
Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Sokol1,2; 1Pediatrics, Children’s Hospital Colorado, Aurora, CO;
Cholestasis (PFIC)-1 & -2. Methods/Results: At 14 Childhood 2University of Colorado School of Medicine, Aurora, CO
Liver Disease Research and Education Network centers, 57 chil-
Enhanced reactive oxygen species (ROS) generation with sub-
dren (20 ALGS, 16 PFIC1, 15 PFIC2, & 6 others with GGT<100
sequent lipid peroxidation contributes to Non-Alcoholic Fatty
U/L) were identified. Mean ages at surgery were 65±65 months
Liver Disease (NAFLD) pathogenesis. Emerging evidence sug-
(ALGS) & 28±37 months (PFIC). Data were retrospectively col-
gests obstructive sleep apnea (OSA), mediated by intermittent
lected: pre-op (0), 6-12 months post-op (12m), 12-24 months
hypoxia, is associated with NAFLD. Objective: To determine
post-op (24m), & >24m. Longitudinal lab data were analyzed
the relationship between nocturnal hypoxia, ROS generation
using repeated measures mixed models. Symptom data were
and severity of pediatric NAFLD. Methods: Adolescents (10-18
analyzed using McNamara’s test. 39 patients (15 ALGS, 12
yrs) with biopsy proven NAFLD and lean age-matched controls
PFIC1, 10 PFIC2, 2 GGT<100) underwent partial external
(BMI <85%; normal AST/ALT) were studied. Clinical and lab-
biliary diversion (PEBD). Serum total bilirubin decreased post-
oratory tests were obtained. Urine F(2)-isoprostanes (F2iso), a
PEBD in PFIC1 (0=8.1±4.0, 24m=2.9±4.1 mg/dL, p<0.0001)
measure of oxidative injury, were analyzed by LC/LC-MS/MS
but not in ALGS (0=5.3±5.4, 24m=4.9±4.1 mg/dL) or PFIC2
and normalized to urine creatinine. NAFLD subjects underwent
(0=2.7±2.9, 24m=2.1±2.5 mg/dL). Total serum cholesterol
standard sleep study. Results: We studied 35 NAFLD (mean
decreased in ALGS patients (0=695±465, 12m=365±152,
age 13.0 yrs; mean BMI z score 2.2, 66% male, 88% His-
24m=457±319 mg/dL, p<0.05). Alanine aminotransferase
panic) and 14 lean controls (mean age 13.1 yrs; mean BMI
levels were higher in ALGS (0=182±70, 24m=260±73 IU/L)
z score -0.04, 50% male, 36% Hispanic). NAFLD subjects
compared to PFIC1 (0=113±134, 24m=56±32) and PFIC2
had significantly elevated AST/ALT and labs consistent with
(0=123±112, 24m=99±83)(p<0.01). ALGS patients experi-
the Metabolic Syndrome compared to lean controls, p<0.02.
enced less severe pruritus (0=100%, 12m=7%, 24m=12%,
OSA/hypoxia was present in 74% of NAFLD subjects. NAFLD
>24m=8%, p<0.001) and greater freedom from pruritus
with OSA/hypoxia had higher mean Apnea Hypopnea Index
(0=0%, 12m=21%, 24m=35%, >24m=46%, p<0.001).
(AHI) (8.2 ± 7.7 vs 1.0 ± 0.6) and % time oxygen satura-
PFIC1 & 2 patients similarly were less pruritic (p<0.001). Xan-
tion (SaO2) <90% (2.3 ± 3.6 vs 0.1 ± 0.2) and lower SaO2
thoma-free ALGS patients increased (0=37%, >24m=69%,
nadir (83.3 ± 6.0 vs 88.3 ± 2.7) than without OSA/hypoxia,
NS). 11 patients (4 ALGS, 2 PFIC1, 3 PFIC2, 2 GGT<100)
p=<0.03. The % time SaO2 <90% correlated with liver histo-
underwent ileal exclusion (IE). Severe pruritus trended down-
logic grade (r-0.32, p=0.06), steatosis (r=0.43, p=0.01) and
ward in ALGS patients (0=4/4,12m=1/4) without change in
NAFLD activity score (r=0.33, p=0.05). NAFLD with OSA/
xanthomas (4/4 at 0&12m). No trend in severe pruritus was
hypoxia had more severe fibrosis (62% Stage 0-2; 38% Stage
seen in PFIC (0=3/5, 12m=1/3, & 24m=1/2). 2 patients
3) than without OSA/hypoxia (100% Stage 0-2), p=0.03.
with GGT<100 required conversion from IE to PEBD due
F(2)iso correlated with degree of hepatic steatosis (r=0.37,
to persistent severe pruritus. Both improved post-revision. 7
p=0.04) and were higher (753 ± 308 pg/mg creatinine) in
patients underwent gallbladder to colon diversion (GBC; 1
subjects with definitive NASH (NAS ≥ 5) than those with NAS
ALGS, 2 PFIC1, 2 PFIC2, 2 GGT<100) and had less postop
score <5 (548 ± 204), p =0.06. F(2)iso were also higher in
pruritus (0=7/7, 12m=0/6, 24m=3/6). Complications were
NAFLD with (725 ± 53) and without OSA/hypoxia (573 ± 85)
few (PEBD: 4 electrolyte abnormalities/dehydration, 2 bowel
than lean controls (310 ± 77), p=<0.04. F(2)iso correlated with
obstructions, 1 bowel ischemia, 2 stoma prolapses, 4 stoma
AHI (r=0.4, p= 0.02), % time SaO2 <90% (r= 0.47, p=0.006)
revision; IE: 2 electrolyte abnormalities/dehydration; GBC: 2
and inversely with SaO2 nadir (r=-0.42, p=0.02), suggesting
electrolyte abnormalities, 1 intestinal obstruction, 1 bowel isch-
hypoxia caused the oxidative stress. Conclusions: Pediatric
emia). 12 liver transplants were subsequently performed: 3
NAFLD patients commonly have significant OSA and nocturnal
ALGS (2 PEBD, 1 IE), 3 PFIC1 (2 PEBD, 1 IE), 6 PFIC2 (3 PEBD,
hypoxia and have increased urine F(2)iso levels compared to
524A AASLD ABSTRACTS
lean children. Excess hepatic steatosis may lead to increased
ROS generation and lipid peroxidation. Hypoxia/reoxygen-
ation adds further to this oxidative injury, potentially mediated
through activation of hypoxia inducible factor-1. These data
support the notion that chronic intermittent nocturnal hypoxia,
propagated through ROS generation, is an important factor in
the severity of pediatric NAFLD.
Disclosures:
Ronald J. Sokol - Advisory Committees or Review Panels: Yasoo Health, Inc.,
Ikaria, Yasoo Health, Inc., Ikaria; Consulting: Roche, Roche; Grant/Research
Support: Lumena
The following people have nothing to disclose: Shikha Sundaram, Ann C. Hal-
bower, Zhaoxing Pan, Kristen N. Robbins, Kelley E. Capocelli, Jelena Klawitter
668
Monitoring of bile acid urine profile with Liquid Chro-
matography-Tandem Mass Spectrography (LC-MS/
MS) allows achievement and maintenance of metabolic
control with minimal doses of chenodeoxycholic acid in
patients affected by 3β-hydroxy-Δ5-C27-steroid dehy-
drogenase/isomerase deficiency
Giorgia Curia1, Paola Gaio1, Francesca Parata1, Giuseppe
Giordano2, Graziella Guariso1, Mara Cananzi1; 1Unit of Gas-
troenterology, Digestive Endoscopy, Hepatology and care of the
Child with Liver Transplantation, University Hospital of Padova,
Padova, Italy; 2Mass Spectrometry Laboratory, University Hospital
of Padova, Padova, Italy
Background. Inborn errors of bile acid metabolism are rare
genetic disorders that can lead to end-stage liver disease.
3b-hydroxy-D5-C27-steroid dehydrogenase/isomerase (3b-
HSD) deficiency, is the most common of these diseases, is
corrected by the administration of cholic (CA) and chenodeoxy-
cholic acid (CDCA). Aim. To demonstrate that the monitoring
of bile acid urine profile with Liquid Chromatography-Tandem
Mass Spectrography (LC-MS/MS) permits achievement of met-
abolic control with minimal doses of CDCA in 3b-HSD defi-
ciency. Methods. Bile acid profile was determined by LC-MS/
MS employing a MICROMASS QUATTRO II interfaced with
HPLC HT Waters 2790 by electrospray ionization. The efficacy
of the treatment was evaluated on the urinary concentration
of 3b-7 alfa-glyco-dihydroxy-5-cholenoic acid (u-3b-D-OH-5C).
The genetic diagnosis of 3b-HSD deficiency was confirmed by
DNA sequencing of the HSD3B7 gene. The charts of all patients
were retrospectively reviewed. Results. 5 cases, belonging to
two distinct families (A and B), were diagnosed with 3b-HSD
deficiency in 16 years. Family A: 2 brothers (patient 1 and 2)
of Italian origin. Patient 1 presented at age of 2.5 months with
a low GGT cholestasis and a liver biopsy showing a giant cell
transformation of hepato-cytes with porto-portal fibrosis. Patient
2 was diagnosed at birth. Family B: 3 siblings (patient 3, 4
and 5) of Moroccan origin. Patient 3 presented at the age of
5.5 years with cryptogenic cirrhosis. Patient 4 presented at 3
years with a biliary cirrhosis. Patient 5 was diagnosed at birth.
All patients were treated with a starting dose of 7-10 mg/kg/
day of CDCA, which was subsequently reduced to an average
dose of 2-3mg/kg/day. Median follow up was 9.5 years per
patient. In patients 1, 3 and 4 a complete resolution of clini-
cal, biochemical, radiological and histological signs of liver
disease was observed. In patients 2 and 5 CDCA treatment
prevented the onset of liver disease. Conclusions. Treatment
with CDCA allows complete reversal of liver disease in patients
affected by 3b-HSD deficiency as well as prevention of hepatic
damage in pre-symptomatic carriers of the genetic defect. Mon-
itoring of the bile acid urine profile with LC-MS/MS not only is
necessary to establish the initial diagnosis but also represents
HEPATOLOGY, October, 2014
an essential guide to modulate the treatment. It allows, in fact,
per-sonalized adjustment of CDCA to the minimal effective
dose (i.e. able to suppress the metabolic path-way causing
liver injury), thus reducing the risk of potential bile acid toxicity.
Disclosures:
The following people have nothing to disclose: Giorgia Curia, Paola Gaio, Fran-
cesca Parata, Giuseppe Giordano, Graziella Guariso, Mara Cananzi
669
Predictive factors of response to non-transplant treat-
ment strategies in progressive familial intrahepatic
cholestasis type II
Sharat Varma1, Xavier Stephenne1, Nicole Revencu2, Isabelle
Scheers1, Raymond Reding3, Françoise Smets1, Etienne M. Sokal1;
1Pediatric hepatology and gastroenterology, Cliniques universi-
taires St Luc, Brussels, Belgium; 2Genetics, Cliniques universitaires
St Luc, Brussels, Belgium; 3Pediatric surgery and liver transplanta-
tion, Cliniques universitaires St Luc, Brussels, Belgium
Purpose: Progressive familial intrahepatic cholestasis type II
(PFIC-II) is a defect of bile salt exporter protein (BSEP) at the
canalicular surface of the hepatocytes. The defect of BSEP
leads to progressive liver injury and eventually cirrhosis. Thet-
reatment for PFIC-II includes liver transplantation (LT), UrsoDe-
oxyCholic Acid (UDCA) and biliary diversion (BD). There are
no predictive factors to assess the responsiveness of patients
to non-transplant modalities. Methods: Retrospective analysis
of 33 PFIC-II patients was done. Diagnostic criteria were com-
patible clinical presentation with either confirmatory genetic
analysis or the absence of BSEP on immuno-histochemistry. The
need for LT was taken as a poor outcome while maintenance
on non-LT treatment was as good. The UDCA and BD response
was assessed on the following parameters. Normalisation –
Remission of clinical manifestations, normal liver enzymes and
serum bile acids. Time to normalization (TTN) – Duration from
start of UDCA or BD until biochemical normalization Duration
of normalization (DOR) - Duration of time for which normal-
ization was sustained Results: 33 PFIC-II children included, LT
(n=20) and non-LT (n=13) groups comparable in terms of age
and sex. The two groups differed significanty for the age at first
presentation, history of neonatal jaundice & ALT levels. 4 of 5
(80%) with homozygous mutations needed a LT. BSEP staining
positive was seen only in 6 and canalicular in 3. 1/6 with
cytoplasmic staining needed LT. 7/33 responded to UDCA,
3 of these transiently and 4 with ongoing response. The mean
TTN was 16.7 +/- 3.3 months and there was no significant
difference between the transient and sustained responders. The
mean DOR in the sustained responders is 41.2+/-9.4 months
while in the transient responders it was 70+/-7.5 months. Con-
clusions: 30% of PFIC – II patients achieve normalization with
non-LT treatment, while disease progress may not be affected.
Prognostic factors identified for good response to non-LT man-
agement in PFIC-II are age at presentation >1 year, no neo-
natal jaundice, high ALT, absence of homozygous mutation
and presence of BSEP on immuno-histochemistry. The trial with
UDCA to assess response should be minimum 2 years. The
response that is seen may not be permanent.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Disclosures:
Etienne M. Sokal - Board Membership: Promethera Biosciences; Management
Position: Promethera Biosciences; Patent Held/Filed: Promethera Biosciences
The following people have nothing to disclose: Sharat Varma, Xavier Stephenne,
Nicole Revencu, Isabelle Scheers, Raymond Reding, Françoise Smets
670
Phase I/II clinical trial of Heterologous Human Adult
Liver-derived Progenitor Cells (HHALPC, hepastem) in
urea cycle disorders (UCD) and Crigler-Najjar syndrome
(CN): six months follow-up results
Etienne M. Sokal1,13, Patrick J. McKiernan2, Emmanuel Jacque-
min3, Giuliano Torre4, Pierre Broue5, Francois Eyskens6, Dries Dob-
belaere7, Carlo Dionisi-vici8, Paul Gissen9, Philippe Clapuyt10,
Daniele Pariente11, Marc Yudkoff12, Doreen Dekker13, Joelle J.
Thonnard13, Beatrice A. De Vos13, Françoise Smets1; 1Pediatric
Gastro-enterology and Hepatology, Saint-Luc University Hospital,
Brussels, Belgium; 2Liver Unit, Birmingham Children’s Hospital,
Birmingham, United Kingdom; 3Pediatric hepatology and trans-
plantation, Kremlin-Bicetre Hospital, Paris, France; 4Hepatology
Gastro-enterology & Nutrition, Bambino Gesu Pediatric Hospital,
Roma, Italy; 5Gastro-enterology Hepatology Nutrition and Dia-
betology Service, CHU Toulouse, Toulouse, France; 6Depatment
of metabolic diseases in children, University Hospital Antwerp,
Antwerp, Belgium; 7Service of hereditary metabolic diseases,
CHU Lille, Lille, France; 8Division of Metabolism, Bambino Gesu
Pediatric Hospital, Roma, Italy; 9Metabolic Medicine Department,
Great Ormond Street Children’s Hospital, London, United King-
dom; 10Pediatric Radiology, Saint-Luc University Hospital, Brussels,
Belgium; 11Pediatric Radiology, Kremlin-Bicetre Hospital, Paris,
France; 12Department of Pediatrics, Children’s Hospital Philadel-
phia, Philadelphia, PA; 13Clinics department, Promethera Biosci-
ences, Mont-Saint-Guibert, Belgium
Heterologous Human Adult Liver-derived Progenitor Cells
(HHALPC, hepastem, Mont-St-Guibert, Belgium) synthesize urea
and conjugate bilirubin in vitro. In animal models, cells engraft
and differentiate into hepatocyte-like cells expressing OTC
enzyme. HHALPC improve bilirubin levels in Gunn rats. Hepas-
tem was investigated in an open label, phase I/II safety study
in patients with urea cycle disorders (UCD) and Crigler-Najjar
syndrome (CN) with preliminary efficacy secondary endpoints.
Methods: Primary objective was safety at 6 months and second-
ary objectives, beside safety at 12 months, included efficacy
at 6 and 12 months. Readouts included measure of de novo
urea production in UCD patients based on 13C incorporation
into urea up to 120 minutes after 1 dose of oral Na [1-13C]
acetate (expressed as [13C] blood urea Area Under the Curve
or AUC-120), measures of blood ammonia and glutamine in
UCD patients, natural protein intake in UCD patients, blood
total bilirubin in CN patients, as well as evaluation of quality
of life (QoL) by PedsQL™ for both diseases. A dose equivalent
to 0.4 to 6.1% of the liver mass was infused in the portal vein
through a transhepatic catheter placed under radioguidance.
Over 1 to 4 consecutive days, 1 cycle of cells was infused to
14 UCD patients (1.5m to 17yrs, 8 boys, 6 girls, ) and 6 CN
patients (3.5yrs-9yrs, 2 boys, 4 girls). Results: Adverse events
were more frequent during the infusion cycle and within 14 fol-
lowing days, e.g. abnormal lab values, non-specific symptoms,
and transient metabolic decompensations. Two patients had
a thrombotic event: one had a non-occlusive portal thrombus
resolving after 1 month; one had a left portal vein thrombosis
with stable liver function tests during 6 month follow-up. Rate
of infection was within the expected incidence for the stud-
ied population. [13C] blood urea AUC-120, highly variable
between patients at baseline, increased in all but one patient
525A
between baseline and six months (101 % increase (95%CI
Lower Limit: 28%, Upper Limit 217%, p value: 0.004). Com-
pared to 1 year pre-infusion available data, median ammonia
post-infusion tended to decrease in <12yo UCD patients. Four
patients increased slightly their natural protein tolerance. In CN
patients median bilirubin values decreased in 3/6 CN (~-40,-
30 & -10%). Overall, QoL results remained stable. Conclusion:
One cycle of hepastem (dose 0.4% to 6.1% of liver mass) is
safe and preliminary data show functional metabolic changes
in UCD and CN patients.
Disclosures:
Etienne M. Sokal - Board Membership: Promethera Biosciences; Management
Position: Promethera Biosciences; Patent Held/Filed: Promethera Biosciences
Patrick J. McKiernan - Advisory Committees or Review Panels: Swedish Orphan
Biovitrum AB
Paul Gissen - Advisory Committees or Review Panels: Synageva; Speaking and
Teaching: Swedish orphan, Actelion
Doreen Dekker - Employment: Promethera Biosciences
Joelle J. Thonnard - Employment: Promethera Biosciences
Beatrice A. De Vos - Management Position: Promethera Biosciences
The following people have nothing to disclose: Emmanuel Jacquemin, Giuliano
Torre, Pierre Broue, Francois Eyskens, Dries Dobbelaere, Carlo Dionisi-vici,
Philippe Clapuyt, Daniele Pariente, Marc Yudkoff, Françoise Smets
671
Post-Developmental Genetic Screening for Zebrafish
Models of Inherited Liver Diseases
Seok-Hyung Kim1, Simon Wu2, Josh Gamse2, Kevin Ess1; 1Pedi-
atric Neurology, Vanderbilt University School of Medicine, Nash-
ville, TN; 2Biological Sciences, Vanderbilt University, Nashville,
TN
Hepatomegaly and steatosis are often manifestations of under-
lying problems such as metabolic disorders and infections.
To establish zebrafish models of inherited liver diseases due
to functional problems rather than liver specification defects
during development, we screened 250 ethyl-N-nitrosourea
(ENU) mutagenized zebrafish lines for fatty liver and/or hep-
atomegaly phenotypes at 6 to 8 days post fertilization (dpf).
We identified 21 novel mutants showing liver specific defects
after completion of normal liver development, which have not
been identified during the previous two decades of zebraf-
ish mutant screening. Twelve of mutants (vul02, vul03, vul04,
vul05, vul08, vul09, vul12, vul13, vul15, vul16, vul17, 7579)
showed hepatomegaly and fatty liver, 5 of mutants (vul01,
vul06, vul18, 7580, 7539) have a hepatomegaly phenotype
without steatosis symptom, and 4 mutants (vul04, vul07, vul10,
vul14) have fatty liver phenotype without hepatomegaly (Fig-
ure 1). Remarkably, 8 of mutants (vul02, vul03, vul09, vul12,
vul13, vul16, vul17, vul18) developed ballooning degener-
ation of hepatocytes resembles steatohepatitis symptom in
human and two mutants with severe liver defect (vul03, vul16)
showed acute liver necrosis phenotype at 7 to 8 dpf. We also
identified that 4 mutants (vul02, vul03, vul09, vul10) have
decreased number of intrahepatic bile ducts. We first identified
a nonsense mutation in vul02 among mutants showing hepato-
megaly and steatosis symptoms. The mutated gene encodes
electron transfer flavoprotein alpha subunit (Etfa) which is an
essential protein for mitochondrial beta oxidation and reca-
pitulates most of symptoms observed in patients with Multiple
Acyl-CoA Dehydrogenase Deficiency (MADD). Furthermore,
molecular identification of these novel liver mutants will also
enhance our understanding of genetic variations which could
increase risk for alcoholic/non-alcoholic fatty liver disease
development in adulthood.
526A AASLD ABSTRACTS
Figure 1. Three types of liver specific mutants
Disclosures:
The following people have nothing to disclose: Seok-Hyung Kim, Simon Wu, Josh
Gamse, Kevin Ess
672
Genetic, clinical, and histopathologic features of inter-
mediate tight junction protein 2 deficiency
Melissa Sambrotta1, A. S. Knisely2, Richard J. Thompson1,2; 1Insti-
tute of Liver Studies, King’s College London, London, United King-
dom; 2Institute of Liver Studies, King’s College Hospital, London,
United Kingdom
Tight junction protein 2 (TJP2) is a cytoplasmic component of
several cell-cell junction complexes. We recently showed that
protein-truncating mutations in TJP2 underlie infant-onset severe
cholestatic liver disease. We have now identified individuals
with TJP2 deficiency first manifest after infancy and with a
relapsing course, broadening the disease spectrum. Mecha-
nisms of such disease are difficult to explain. To understand
them better, clinical features and liver-biopsy findings were
reviewed, with routine, immunohistochemical, and ultrastruc-
tural study. The same missense mutation, c.2363A>T, p.(His-
788Leu), was found in homozygous state in 4 individuals from
3 families; it is predicted to replace a polar, charged amino
acid with an aliphatic, uncharged amino acid in the conserved
guanylate kinase-like domain. Three patients homozygous for
this mutation manifested pruritus and became icteric aged
14 months, 9 years, and 13 years. The remaining patient
is asymptomatic so far. As measured by levels of serum bile
acids and bilirubin, degrees of cholestasis varied, though
transaminase activities were almost normal. GGT activity was
always normal. The patient presenting earliest also had bouts
of cholestasis aged 4 and 5 years, both following administra-
tion of antibiotics. All have recovered, without signs of chronic
liver disease. In liver-biopsy material obtained during the first
2 cholestatic episodes in 1 patient and from the single episode
in the others, staining for TJP2 at canalicular margins was dra-
matically reduced vs controls, in all 4 specimens. However,
hepatocyte nuclei marked strongly. Claudin-1, a transmem-
brane protein with known cytoplasmic binding to TJP2, failed
in these patients to localise at canalicular margins, instead
clustering within the cytoplasm. This contrasts with severe TJP2
deficiency, in which cytoplasmic claudin-1 is not observed.
Electron microscopy found elongation, broadening, and irreg-
ular contour of tight junctions, with variable loss of canalicular
microvilli. Intermediate TJP2 deficiency is a new entity. It may
be precipitated by drug exposure. Although the reduction of
canalicular TJP2 expression was expected, nuclear marking
was not. Intracellular accumulation of Claudin-1 is novel. These
findings highlight the importance of these proteins in patholog-
ical mechanisms within the liver.
HEPATOLOGY, October, 2014
Disclosures:
The following people have nothing to disclose: Melissa Sambrotta, A. S. Knisely,
Richard J. Thompson
673
The Burden of Pruritus on Patients with Alagille Syn-
drome: Results from a Qualitative Study with Pediatric
Patients and their Caregivers
Linda Abetz-Webb1, Ciara Kennedy2, Bonnie Hepburn2, Mar-
tha Gauthier3, Nathan Johnson3, Sharon Medendorp4, Alejan-
dro Dorenbaum2, Benjamin L. Shneider5,7, Binita M. Kamath6,7;
1Patient-Centred Outcomes Assessments, Ltd, Bollington, Cheshire,
United Kingdom; 2Lumena Pharmaceuticals, San Diego, CA; 3End-
point Outcomes, Boston, MA; 4Premier Research, Philadelphia,
PA; 5Children’s Hospital of Pittsburgh, UMPC, Pittsburgh, PA; 6Hos-
pital for Sick Children, Toronto, ON, Canada; 7Childhood Liver
Disease Research and Education Network, Washington, DC
Background: Alagille Syndrome (ALGS) is an autosomal dom-
inant, highly variable, multisystem disorder with cholestasis as
a central feature. ALGS-associated pruritus is among the most
severe seen in any chronic liver disease; to date, no qualita-
tive research has been conducted to explore ALGS-associated
pruritus. Objective: To explore symptoms, signs and burden of
pruritus in children with ALGS. Methods: Recruited through the
ALGS Alliance, patients and caregivers participated in qualita-
tive interviews about their experiences with ALGS and pruritus.
To meet FDA guidance for patient qualitative research, con-
cepts were derived from the data rather than by pre-conceived
hypotheses, thus grounded theory formed the basis of the qual-
itative analysis and saturation was assessed. Results: 26 chil-
dren were included; 13 patients (median age: 6 yrs; range
<1-35 yrs) and 24 caregivers were interviewed. Based on
caregiver reports, 4 (15%) patients had severe itching; 8 (31%)
had moderate, 7 (27%) had mild, and 7 (27%) had very mild
itching, as reported by caregivers. 18 (69%) patients received
treatment for itching; 12 (46%) with rifampin and 7 (27%)
with hydroxyzine. Itching was the most bothersome symptom
reported by all patients and caregivers, across all ages. Other
symptoms included xanthomas (n=6; 18%), poor nutrition/
growth (n=11; 33%), jaundice (n=9; 27%), GI/heart problems
(n=6; 18%; n=5 (15%)) bone density (n=4; 12%) and pain
(n=4; 12%). The most important and relevant itching impact
concepts were skin damage (10 (76%) patients; 16 (80%)
caregivers), difficulty staying asleep (3 (23%) patients; 16
(80%) caregivers); difficulty falling asleep (7 (54%) patients; 11
(55%) caregivers), and mood disturbances (7 (54%) patients;
13 (65%) caregivers). To ascertain itching severity, caregivers
used observation of behaviors (frequency or intensity of scratch-
ing or rubbing), impacts (sleep disturbance, skin damage due
to scratching, mood changes) and reports by the children about
their symptoms to their parents. The caregiver observations
were particularly valuable for children from infancy through
8 years of age, as patients in these age groups had difficulty
adequately reporting symptoms. By the final three interviews,
limited new information was gained about the majority of itch-
ing, impact and observation concepts, thereby indicating that
saturation was achieved. Conclusions: In these ALGS patients
with pruritus, itching was the most impactful and bothersome
symptom. Based on these data, a new instrument to assess
itch severity in ALGS, the ItchRO, has been developed and is
currently being validated in the context of treatment response
to novel therapies.
Disclosures:
Linda Abetz-Webb - Consulting: Lumena
Ciara Kennedy - Employment: Lumena Pharmaceuticals
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Bonnie Hepburn - Consulting: Lumena Pharmaceuticals
Nathan Johnson - Consulting: Endpoint Outcomes
Sharon Medendorp - Consulting: Lumena Pharmaceuticals
Alejandro Dorenbaum - Employment: Lumena Pharmaceutical, Stanford Univer-
sity; Stock Shareholder: BioMarin Pharmaceutical
Benjamin L. Shneider - Consulting: Bristol Myers Squibb, Vertex; Grant/Research
Support: Hyperion Therapeutics; Stock Shareholder: Bristol Myers Squibb
The following people have nothing to disclose: Martha Gauthier, Binita M.
Kamath
674
A Comparison of Controlled Attenuation Parameter and
Liver Biopsy to Assess Hepatic Steatosis in Pediatric
Patients
Nirav K. Desai1, Sarah Harney1, Roshan Raza1, Paul D. Mitchell2,
Maureen M. Jonas1; 1Division of Gastroenterology, Hepatology
& Nutrition, Boston Children’s Hospital, Boston, MA; 2Clinical
Research Center, Boston Children’s Hospital, Boston, MA
Background: NAFLD is the most common chronic liver disease
in children. Liver biopsy remains the standard for assessing
steatosis but is limited by invasiveness, cost, and the potential
for sampling error. FibroScan® (Echosens, Paris, France) is an
ultrasound-based technology used to assess fibrosis using tran-
sient elastography (TE). Recently, a new FibroScan® measure-
ment called “controlled attenuation parameter” (CAP) has been
developed to detect and quantify steatosis. CAP represents
the ultrasonic attenuation coefficient during TE, expressed as
dB/m. There are no data regarding use of CAP in the pediatric
population. Objective: To assess whether the degree of steato-
sis as determined by liver biopsy correlates with CAP measure-
ments in a pediatric and young adult cohort. Methods: This
was a cross-sectional study in patients undergoing liver biopsy
between 1/25/12 and 5/27/14 at Boston Children’s Hospi-
tal. Eligible patients, with a variety of liver diseases and tho-
racic perimeter >75 cm, had liver biopsy within 1 year prior to
CAP measurement (76% within 75 days). Patients with BMI>40
kg/m2 were excluded. Each liver biopsy was interpreted by
an experienced pathologist. Steatosis was reported as none
(<5%), mild (5-30%), moderate (31-60%), or marked (>60%).
The reported CAP value was the median of 10 measurements
using the M (medium) probe, and is compared across steato-
sis grades using rank-sums. Results: 49 patients (mean age
15.7±3.3 yrs, 67% male, 14%≥18 yrs) were studied. Subjects
had a variety of liver diseases (29% autoimmune hepatitis,
25% viral hepatitis, 14% NAFLD, 6% metabolic disease, 2%
cholestasis, 2% allograft rejection, and 22% other). 13/49
subjects had steatosis on liver biopsy (4 mild, 9 marked).
Median CAP value (dB/m) for subjects with no steatosis was
192 (IQR 168, 210) compared with 302 (IQR 286, 321)
for subjects with steatosis (P<0.0001). Median CAP value for
mild steatosis was 266 (IQR 224, 309) and marked steatosis
305 (IQR 286, 337). There were statistically significant differ-
ences between CAP values in individuals with no steatosis vs.
mild steatosis (P=0.01) and no steatosis vs. marked steatosis
(P<0.0001). There was no statistically significant difference in
comparison of CAP values between mild and marked steatosis
(P=0.21). Conclusion: CAP may be a useful non-invasive tool
to detect hepatic steatosis in children. This study demonstrated
a difference in CAP between no steatosis vs. mild steatosis, as
well as no steatosis vs. marked steatosis. The lack of distinc-
tion between mild and marked steatosis may be due to small
sample size in the steatosis groups. Further studies with larger
sample size are needed.
Disclosures:
Nirav K. Desai - Grant/Research Support: Synageva BioPharma; Speaking and
Teaching: Synageva BioPharma
527A
Maureen M. Jonas - Advisory Committees or Review Panels: Gilead Sciences;
Consulting: Eisai; Grant/Research Support: Bristol Myers Squibb, Roche, Merck
Schering Plough
The following people have nothing to disclose: Sarah Harney, Roshan Raza,
Paul D. Mitchell
675
Hepatic mast cell infiltration is associated with progres-
sion of congenital hepatic fibrosis in the PCK rat
Pingping Fang1, James Weemhoff1, Seth Septer2, Briana Holt1,
Udayan Apte1, Michele Pritchard1; 1Pharmacology, Toxicology
and Therapeutics, University of Kansas Medical Center, Kansas
City, KS; 2Gastroenterology, Children’s Mercy Hospital, Kansas
City, MO
Congenital hepatic fibrosis (CHF), the most common extra-renal
manifestation of autosomal recessive polycystic kidney disease
(ARPKD), is the hepatic response to biliary cystogenesis and
cyst growth in periportal areas of diseased liver. Patients with
this disease who survive the early postnatal period develop
portal hypertension and esophageal varices secondary to
progressive pericystic fibrosis. Despite recent advances in our
understanding of disease pathogenesis, therapeutic options
for CHF patients remain elusive and quality of life remains
poor. Recently, hepatic mast cells (MCs), innate immune effec-
tor cells and mediators of inflammation, were implicated in the
pathogenesis of biliary liver disease. Here, using the polycys-
tic kidney (PCK) rat which recapitulates human CHF/ARPKD,
we explored whether or not MCs were associated with cys-
togenesis and pericystic fibrosis from postnatal day (PND) 0
- 90 when compared to control, Sprague Dawley, rats. MCs,
visualized using toluidine blue, were rare and not different
between control and PCK rats PND 0 - 15. However, MCs
abruptly increased 35-fold from postnatal day (PND) 15 to
30 in PCK rats; MC numbers remained increased to the end
of the study (PND 90). MCs were also found in livers from
CHF patients, suggesting relevance of these findings to human
disease. Consistent with increased MC infiltration in livers from
PCK rats, MC markers, chymase, tryptase and FcεR1, were
increased PND 20 - 90. MC infiltration was also associated
with increased numbers of hepatic cysts and increased liver
to body weight ratios. Hepatic markers of fibrosis (αSMA,
COL1A1) assessed using real-time PCR were greatest in PCK
rats at PND 15, before infiltration of MC. In contrast, extracellu-
lar matrix (ECM) content, measured by morphometric analysis
of Sirius red-stained liver sections, increased robustly from PND
20 - 90 in parallel with MC infiltration. Collectively, these data
suggest that MCs contribute to CHF progression, not initiation,
and do so through stimulating cyst growth and promoting ECM
maintenance. These studies were supported by grants to U.A.
(NIH 5P50DK057301-11) and M.T.P. (P20 GM103549, R00
AA017918, P20 GM103418 and UL1TR000001).
Disclosures:
The following people have nothing to disclose: Pingping Fang, James Weemhoff,
Seth Septer, Briana Holt, Udayan Apte, Michele Pritchard
528A AASLD ABSTRACTS
676
Silent progression of liver disease and development of
cirrhosis in children several years after cranial tumor
resection
Anita K. Pai1, Shengmei Zhou2, Mark Krieger3, Sophoclis Alexo-
poulos4, Yuri Genyk4, Nanda Kerkar5; 1Department of Pediatrics,
Children’s Hospital Los Angeles, Los Angeles, CA; 2Department
of Pathology, Children’s Hospital Los Angeles/Keck School of
Medicine of USC, Los Angeles, CA; 3Division of Neurosurgery,
Children’s Hospital Los Angeles/Keck School of Medicine of USC,
Los Angeles, CA; 4Department of Surgery, Division of Hepatobi-
liary Surgery and Abdominal Organ Transplantation, Children’s
Hospital Los Angeles/Keck School of Medicine of USC, Los Ange-
les, CA; 5Department of Pediatrics, Division of Gastroenterology,
Hepatology and Nutrition, Children’s Hospital Los Angeles/Keck
School of Medicine of USC, Los Angeles, CA
Patients with hypothalamic and pituitary tumors can become
obese, insulin resistant, and dyslipidemic, increasing the risk
of liver disease. The following cases were seen in our center
from 1998-2014. Patient 1 was an 8 y.o. girl who developed
panhypopituitarism, obesity, and type II DM after craniophar-
yngioma resection. Six years later, she presented with mildly
elevated liver enzymes and severe hypoxemia; she was diag-
nosed with hepatopulmonary syndrome secondary to NASH.
She received a liver transplant and recovered from HPS, but
struggled with non-adherence and weight gain. She developed
recurrent NASH after six months. Patient 2 was an 11 y.o. boy
with a history of a resected suprasellar germinoma, chemo-
therapy, and radiation, with subsequent panhypopituitarism,
type II DM, and morbid obesity. He presented six years later
in hemorrhagic shock after variceal bleeding. Despite multiple
banding and TIPS procedures, he succumbed to liver failure
before transplantation. Autopsy confirmed advanced cirrho-
sis with steatosis. Patient 3 was a 6 y.o. girl who underwent
fenestration of a hypothalamic pilocytic astrocytoma and a
hepatotoxic chemotherapy regimen. She developed obesity,
hypothyroidism, type II DM, and dyslipidemia. She presented
four years later with elevated liver enzymes that remained
high after chemotherapy concluded, with some improvement
during periods of glycemic control and worsening with statin
exposure. Liver biopsy revealed steatohepatitis and cirrhosis,
attributed to NASH and drug-induced liver injury. Patient 4
was a 3 y.o. boy with onset of type II DM, OSA, obesity,
and panhypopituitarism after craniopharyngioma resection.
After thirteen years of normal liver enzymes on metformin ther-
apy, he was found to have thrombocytopenia, hypersplenism,
and mildly elevated liver enzymes. Liver histology showed
advanced fibrosis without steatosis, consistent with burned-
out NASH. Discussion: Children who endure hypothalamic/
pituitary tumor resections may be at increased risk of NAFLD.
Features of metabolic syndrome were recognized early in our
pediatric patients, but liver disease was identified much later.
Screening for liver disease early and at regular intervals may
be indicated in this population, but screening parameters have
not been validated. It is well known that liver enzymes may not
be sensitive indicators of NAFLD, but new serologic biomarkers
and emerging radiologic modalities (e.g., transient liver elas-
tography) need exploration. Our report underscores the need
for multicenter data to elucidate the natural history of NAFLD in
this vulnerable patient population to determine who is at risk of
rapid progression to advanced fibrosis.
Disclosures:
The following people have nothing to disclose: Anita K. Pai, Shengmei Zhou,
Mark Krieger, Sophoclis Alexopoulos, Yuri Genyk, Nanda Kerkar
HEPATOLOGY, October, 2014
677
Serial Enhanced Liver Fibrosis Test (ELF) to monitor dis-
ease progression in Pediatric Non-Alcoholic Fatty Liver
Disease
Jeremy K. Rajanayagam1,2, Andrew W. Lee1,2, Patrick J. McKier-
nan1; 1Hepatology, Birmingham Children’s Hospital, Birmingham,
United Kingdom; 2University of Queensland, Brisbane, QLD, Aus-
tralia
Background: Pediatric Non-Alcoholic Fatty Liver Disease
(NAFLD) is a leading cause for chronic liver disease in chil-
dren and adolescents1. The Enhanced Liver Fibrosis (ELF) test
has demonstrated validity as a non-invasive marker for liver
fibrosis in paediatric NAFLD1. There is limited data regarding
the natural history of paediatric NAFLD. Objective: Investigate
serial ELF measurements in a cohort with paediatric NAFLD.
Methods: Serial ELF measurements were collected prospectively
in a cohort of children with NALFD. ELF scores were calculated
using a validated algorithm3 and compared to anthropometry,
biochemistry, and PELD/MELD scores measured at diagnosis
and follow-up. The diagnosis of NAFLD was based on liver
histology or the triad of obesity, deranged liver function tests,
and suggestive ultrasound findings. Patients were provided
consistent dietary and lifestyle advice. Results: 22 children
(9M, 13F), median age 12 years (range 4 -17 years) and BMI
29 (range 20- 41kgs), were diagnosed with NALFD. Median
duration of follow-up was 2.1years (range: 1-5years). Mean
ELF at diagnosis was 9.06 (n=4 ≥stage1, n=1 ≥stage2, n=3
≥stage3 fibrosis), and on follow-up 8.76 (n=3 ≥stage1, n=1
≥stage2, n=2 ≥stage3 fibrosis)(P=0.13). Mean BMI-Z score
at assessment was 2.04 and follow-up 2.07 (P=0.7). Mean
MELD score was 7 and 7.3, and PELD -13 at diagnosis and
follow-up, respectively (P=0.23). Conclusion: Serial ELF scores
and MELD/PELD suggest there is no significant progression
of chronic liver disease in children with NAFLD over a 2year
period. Further long-term follow-up studies are required to vali-
date ELF as a monitoring tool.
Disclosures:
Patrick J. McKiernan - Advisory Committees or Review Panels: Swedish Orphan
Biovitrum AB
The following people have nothing to disclose: Jeremy K. Rajanayagam, Andrew
W. Lee
678
Predicting future outcome in infancy-acquired chronic
hepatitis B – importance of quantitative HBeAg and
HBsAg plasma levels, HBV DNA viral load and IP10
plasma levels
Mary Horner, Matthew J. Bruce, Sanjay Bansal, Sarah Tizzard,
Diego Vergani, Phillip M. Harrison, Kosh Agarwal, Giorgina Mie-
li-Vergani, Ivana Carey; Institute of Liver Studies and Transplanta-
tion, King’s College Hospital, London, United Kingdom
Chronic hepatitis B (CHB) is a variable, dynamic disease and
accounts for significant morbidity and mortality. Long-term
disease outcome data in infancy-acquired patients stratified
according to HBV genotype, HBeAg status, HBV DNA and
HBsAg levels are limited. Plasma levels of chemokine IP10 pre-
dict HBeAg/HBsAg seroconversion in CHB adults. This retro-
spective longitudinal cross-sectional observational single centre
cohort study aims to investigate whether levels of serological
(HBeAg, and HBsAg), virological (HBV DNA) and immunologi-
cal (IP10) markers at time of diagnosis and HBV genotype can
predict long-term disease outcome in children with infancy-ac-
quired CHB. Patients: 422 patients with infancy-acquired CHB
were diagnosed between January 1999-May 2011, but only
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
169 untreated patients (91 males, median age 9.9years) had
at least 3 years consecutive follow-up (median 8years) with
samples available for testing. Methods: At diagnosis HBV DNA
was measured by real-time PCR [log10IU/ml], semiquantita-
tive HBeAg and HBsAg plasma levels by Abbott ARCHITECT®
assay [S/CO & log10IU/ml], IP10 plasma levels by ELISA [pg/
ml] and compared with CHB stage at last visit (range 3-15
years). HBV genotype was determined by direct sequencing.
Results: At diagnosis 138 (82%) patients were HBeAg+ and 72
(43%) had normal ALT (≤19 female/≤30IU/l male). The geno-
type distribution was as follows: A 9%, B 12%, C 14%, D 49%
and E 16%. At last follow-up visit 52 (38%) patients achieved
HBeAg seroconversion, 7 (4%) HBsAg seroconversion and
109 (65%) had normal ALT. At diagnosis only 14 (8%) of
patients were HBeAg-/HBV DNA<1000IU/ml/normal ALT
(HBeAg- carrier stage); at last visit (median follow-up 8years)
this proportion had increased to 49 (29%) patients. At diag-
nosis future HBeAg- carriers and patients with HBsAg loss had
significantly lower HBeAg, HBsAg and HBV DNA levels and
higher IP10 levels than persistently HBeAg+ patients (HBeAg:
1071vs.1324; HBsAg: 4.36vs.4.89; HBV DNA: 7.14vs.8.26
and IP10: 206vs.125, all p<0.05). Age at time of diagnosis
and ALT levels were similar between future HBeAg- carriers
and persistently HBeAg+ patients (age: 9.8vs.10.4, p=0.58;
ALT: 35vs.34, p=0.93). High IP10 at diagnosis (>250pg/ml)
predicted future HBeAg loss/carrier stage (PPV86%). HBeAg
seroconversion rate and subsequent HBeAg- carrier status were
similar across of all genotypes, but HBsAg loss was predom-
inant in genotype A (71%) patients. Conclusions: In children
with infancy-acquired CHB low HBeAg and HBsAg plasma
levels, low HBV DNA viral load and high IP10 plasma levels
at diagnosis predict future CHB outcome (HBeAg loss/HBeAg-
carriers stage). Genotype A was associated with HBsAg loss.
Disclosures:
Kosh Agarwal - Advisory Committees or Review Panels: Gilead, Novartis,
Abbott; Grant/Research Support: Roche, MSD; Speaking and Teaching: BMS,
Astellas, Janssen
Ivana Carey - Grant/Research Support: Gilead, BMS, Roche; Speaking and
Teaching: BMS
The following people have nothing to disclose: Mary Horner, Matthew J. Bruce,
Sanjay Bansal, Sarah Tizzard, Diego Vergani, Phillip M. Harrison, Giorgina
Mieli-Vergani
679
Association Between Hepatitis C Virus Infection with
Insulin Resistance and Total Cholesterol Levels in Chil-
dren and Youth
Aymin Delgado-Borrego1,2, Roshan Raza2, Michelle Godbee1,
Andrea Barreto1, Elsa Yumar1, Betania Negre1, David A. Ludwig1,
Maureen M. Jonas2, Raymond Chung2; 1Pediatric Gastroenterol-
ogy, Pediatric Clinical Research, Miami, FL; 2Harvard Medical
School, Boston, MA
Background and Aims: Hepatitis C virus (HCV) infected adults
have been found to face a significantly higher risk of insu-
lin resistance (IR) than the uninfected population. In addition,
HCV has been associated with lower total cholesterol (TC)
levels, suggesting a possible HCV-host lipid interaction. How-
ever, adults often possess multiple comorbidities that act as
confounders. The association between HCV infection and IR
or TC has not been previously addressed in children. We per-
formed a cross-sectional study to compare IR and TC between
HCV infected (+) children and uninfected (-) controls. Methods:
A total of 88 children and young adults (mean age=17.0,
SD=5.6) from Boston Children’s Hospital and the University of
Miami were included. Of these, there were 47 HCV infected
subjects and 41 uninfected controls matched by age and body
529A
mass index (BMI) category. Forty-seven percent of the HCV+
subjects and 34% of the HCV- controls were male. Subjects
were excluded if they were undergoing antiviral therapy or if
they had other chronic illnesses. HCV viremia was assessed
by HCV ribonucleic acid testing. Logistic regression analysis
was used to discriminate between HCV+ and HCV- subjects.
Independent effects included age, gender, body mass index
(BMI), IR estimated using the homeostasis model assessment
(loge HOMA2-IR), and TC. Results: After multivariate adjust-
ment for age, BMI, and gender, HCV status was independently
associated with loge HOMA2 IR (χ2(1) = 8.21, p=0.0042).
Mean loge HOMA2 IR for HCV+ and HCV- were 0.33 and
0.03, respectively. Total cholesterol was also associated with
HCV status (χ2(1) = 4.83, p=0.0279). Mean TC was lower for
HCV+ (139mg/dL) than HCV- (154 mg/dL) subjects. Eleven
percent of the variance was unique to loge HOMA2-IR and 9%
to TC. Total area under the curve was 71% and the full model
generalized R2 explained 20% of the HCV between group
variance. Positive (65%) and negative (61%) predictive values
were approximately equal. Conclusions: HCV infection is inde-
pendently associated with increased IR and lower total choles-
terol among children and young adults even when accounting
for potential confounding factors such as age, gender and BMI.
Currently, HCV infected children are not routinely evaluated
for IR or TC levels. These results support the notion of an HCV
associated dysmetabolism that manifests itself even at a young
age. Based on our findings, clinicians should strongly consider
the possibility of assessing for IR and lipid status among HCV
infected children and young adults.
Disclosures:
Maureen M. Jonas - Advisory Committees or Review Panels: Gilead Sciences;
Consulting: Eisai; Grant/Research Support: Bristol Myers Squibb, Roche, Merck
Schering Plough
Raymond Chung - Grant/Research Support: Gilead, Mass Biologics, Salix,
Ocera
The following people have nothing to disclose: Aymin Delgado-Borrego, Roshan
Raza, Michelle Godbee, Andrea Barreto, Elsa Yumar, Betania Negre, David A.
Ludwig
680
Differences in clinical characteristics of children with
chronic hepatitis B (CHB) by adoption status: findings
from the Hepatitis B Research Network (HBRN)
Simon C. Ling1, Yona K. Cloonan8, Philip Rosenthal3, G. John-
son8, Karen F. Murray4, Sarah J. Schwarzenberg7, Norberto
Rodriguez-Baez5, Jeffrey Teckman6, Kathleen B. Schwarz2; 1Uni-
versity of Toronto, Toronto, ON, Canada; 2Johns Hopkins Medical
Institutions, Baltimore, MD; 3University of California San Francisco,
San Francisco, CA; 4University of Washington, Seattle, WA; 5Uni-
versity of Texas South Western, Dallas, TX; 6St Louis School of
Medicine, St Louis, MO; 7University of Minnesota, Minneapolis,
MN; 8University of Pittsburgh, Pittsburgh, PA
Aims (1) To describe characteristics of adopted children with
CHB compared to children living with their birth parents
(“not-adopted”). (2) To determine if adoption status is asso-
ciated with differences in CHB disease phenotype, suggest-
ing the importance of early environmental influences on later
disease course. Methods We analyzed baseline data from
children enrolled in the HBRN pediatric cohort study at 7 sites
in N. America. Stepwise logistic regression was used to inves-
tigate associations with investigator-assigned CHB disease
phenotype. Results Of 335 children, 187 were adopted at
median age 27m (IQR 14-62m) after birth in Asia (n=132,
73%), Europe (24, 13%) or Africa (15, 8%). In univariate
analysis compared to not-adopted, adopted were younger
(median 9.7 v 12.3y), less likely to be Asian (74% v 83%),
530A AASLD ABSTRACTS
more likely to be female (75% v 45%) and immigrants to North
America (97% v 48%), with parents with higher education
and employed mothers, & to have been treated for HBV (18%
v 8%). Adopted had lower height (median percentile 30th v
56th) and BMI (47th v 66th). HBV genotype B was most com-
mon in adopted (B=49%, C=26%, Other=25%) v not-adopted
(36%, 40%, 24%). HBeAg+ (76% vs 72%), anti-HBe+ (29% v
29%) and HBV DNA viral load (8.2 vs 8.1 log10 IU/ml) were
similar, but ALT was lower in adopted (35 IQR 23-47, v 42
IQR 30-59 IU/l). Adopted were more likely to be immune-tol-
erant (IT) (51% v 30%). After controlling for genotype in a mul-
tivariable model, adoption & ht-for-age were associated with
CHB phenotype. The association with height held true when
only Asian children were included in analysis, but dropped out
when treated children were excluded. Conclusion IT disease
phenotype is associated with adoption status independent of
viral genotype and host variables (e.g. age, sex, race). Future
studies should further investigate the influence of environmental
factors on the course of CHB infection.
Multivariable Logistic Regression Model of Selected Variables in
Association with IT Phenotype
Odds ratio (OR) >1 = increased odds of being IT
REF = reference group
Disclosures:
Simon C. Ling - Grant/Research Support: Bristol Myers Squibb
Philip Rosenthal - Advisory Committees or Review Panels: Ikaria, Gilead, Merck,
General Electric; Consulting: Roche; Grant/Research Support: Roche, Bristol
MyersSquibb, Gilead, Vertex
Karen F. Murray - Grant/Research Support: Roche, Gilead, Vertex; Stock Share-
holder: Merck
Sarah J. Schwarzenberg - Consulting: SparkHealth Consultants, Cystic Fibrosis
Foundation; Grant/Research Support: BristolMeyerSquibb
Jeffrey Teckman - Consulting: Dicerna, Isis Pharmaceuticals, Vertex, Proteostasis,
Genkyotex, The Alpha-1 Project; Grant/Research Support: Alnylam, Arrowhead,
Alpha-1 Foundation
Kathleen B. Schwarz - Consulting: Novartis, Novartis; Grant/Research Support:
Bristol-Myers Squibb, Gilead, Roche/Genentech, Bristol-Myers Squibb, Vertex,
Roche
The following people have nothing to disclose: Yona K. Cloonan, G. Johnson,
Norberto Rodriguez-Baez
HEPATOLOGY, October, 2014
681
APRI, FIB-4 and Fibroscan in Prediction of Significant
Fibrosis in Adolescent Cancer Survivors in a Resource
Limited Country
Manal H. El-Sayed1, Dalia N. Toaima1, Fatma A. Marzouk1, Amira
Mohsen2, Aisha Elsharkawy3, Gamal E. Esmat3, Alaa El-Haddad4;
1Department of Pediatrics, Ain Shams University, Cairo, Egypt;
2Department of Public Health, National Research Center, Cairo,
Egypt; 3Department of Tropical Medicine, Cairo University, Cairo,
Egypt; 4Department of Pediatric Oncology, National Cancer Insti-
tute, Cairo, Egypt
Background/Aim: Egyptian children undergoing chemotherapy
are at a high risk for HCV infection due to immunesuppression
and multiple blood transfusions. The aim of this prospective
study was to evaluate the feasibility of liver stiffness measure-
ment and to compare Fibroscan to AST to platelet ratio index
(APRI) and FIB-4 (combining platelets, ALT, AST and age) in
diagnosis of advanced fibrosis in adolescent cancer survivors
with chronic HCV. Methods: Fifty one cancer survivors (mean
age: 13.41± 4.14 yrs; range 14-19 yrs; male predominance:
76.5%) with chronic HCV were prospectively recruited from the
National Cancer Institute. All underwent noninvasive tests for
fibrosis: Fibroscan, APRI and FIB-4 score, in addition to ALT,
ALP, serum bilirubin, albumin, PT, ferritin, ultrasound and liver
biopsy when necessary (n=6). Results: Patients were grouped
according to Fibroscan liver stiffness into 2 groups; group
1: patients with fibrosis stage F0-F2 (no significant fibrosis;
80.4%) and group 2: patients with fibrosis stage F3-F4 (signif-
icant fibrosis and cirrhosis; 19.6%). There was a highly signifi-
cant difference between the 2 groups regarding serum bilirubin
(p=0.001), AST (p=0.007) and APRI (p=0.001). In addition to
a significant difference regarding the FIB-4 score (p=0.03), ALT
(p=0.01) and platelet count (p=0.01). Liver stiffness showed
positive correlation with duration of chemotherapy, height,
ALT, ALP, ferritin, APRI and FIB-4 (r=0.37, 0.31, 0.28, 0.45,
0.52, 0.32 and 0.40 respectively). The AUROC curves for
APRI and FIB-4 for prediction of significant fibrosis (F3-4) was
0.85 and 0.712, respectively. As far as APRI is concerned,
a cut off value of 0.86 was selected for the best prediction of
mild and severe fibrosis (sensitivity: 80%, specificity: 90.2%,
PPV: 66.7% and NPV: 94.9%). The best predictive cut off value
for FIB-4 was 0.52 (sensitivity: 70%, specificity: 85.4%, PPV:
53.8% and NPV: 92.1%). APRI was more accurate than FIB4
in detecting of significant fibrosis. Conclusions: The results indi-
cate that liver stiffness measurement by Fibroscan is feasible
for identifying the stage of hepatic fibrosis in Pediatric can-
cer survivors with chronic HCV. However, APRI and FIB-4 are
noninvasive alternatives for assessment of hepatic fibrosis in
resource-limited countries. APRI is more preferred than FIB4 in
detecting significant fibrosis.
Disclosures:
Gamal E. Esmat - Advisory Committees or Review Panels: MSD &BMS compa-
nies, MSD &BMS companies; Grant/Research Support: Gilead Sc; Speaking and
Teaching: Roche & GSK companies, Roche & GSK companies
The following people have nothing to disclose: Manal H. El-Sayed, Dalia N.
Toaima, Fatma A. Marzouk, Amira Mohsen, Aisha Elsharkawy, Alaa El-Haddad
682
Pegylated Interferon Therapy in Chronic Hepatitis B
Infection- Is it the best option available in Children?
Vikrant Sood, Sanjeev K. Verma, Seema Alam, Rajeev Khanna,
Dinesh Rawat; Department of Pediatric Hepatology, Institute of
Liver and Biliary Sciences, New Delhi, India
Introduction: Hepatitis B infection, usually a benign disease in
children, holds importance due to impending complications in
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
adulthood including cirrhosis and hepatocellular carcinoma.
High viral load as seen in majority of children is associated with
a low T-cell activation and poor response to interferon. Com-
bining interferon and nucleosides could be a novel approach
with synergic immunomodulatory and antiviral action. Aim:
To prospectively evaluate the efficacy and safety of sequential
therapy of Peg IFN and oral nucleoside in Chronic Hepatitis B
Patients between 2-18 years age in Pediatric Hepatology Unit
at a Tertiary care specialized center. Methods: Chronic Hep-
atitis B infected children fulfilling criteria for immunotolerant
and immunoclearance phases, after informed parental consent,
were treated with sequential therapy of oral nucleoside and
pegylated interferon (Lamivudine 3 mg/kg/day once a day for
<12 years age or Tenofovir 300 mg once a day for > 12 years
age for 8 weeks followed by addition of Pegylated Interferon
Alpha-2b at 1.5 ug/kg/week for 24 weeks along with contin-
uation of nucleoside till end of therapy) for 52 weeks. Monitor-
ing included Hepatitis B profile (HbsAg, HbeAg, Anti-Hbe, HBV
DNA levels) and safety assessment (hematology, thyroid profile
and growth assessment). Results: A total of 33 chronic hepatitis
b patients (20 in immunotolerant and 13 in immunoclearance
phase) were enrolled in the study. 10 immunotolerant and 5
immunoclearance children agreed to participate in the study
and were given the sequential therapy. Mean age of the chil-
dren was 10.16 + 4.58 years. Of 11 patients with available
genotype data, 8 belonged to genotype D with 2 patients of
genotype A and 1 of genotype B. In Immunoclearance group
(3 in lamivudine and 2 in tenofovir group), all 5 patients (100
%) cleared HbeAg after completion of therapy and 2 out of
5 (in lamivudine group) cleared HbsAg with appearance of
anti-Hbs suggestive of cure. In the immunotolerant phase, none
out of the 10 patients had HbeAg clearance after 52 weeks
of therapy. Side effects included mild cytopenias (4 patients),
transient flu-like illness (all patients) and interferon dose reduc-
tion in 2 patients. Conclusion: In immunoclearance phase,
sequential therapy allows HbeAg seroconversion in all cases
and around half of the cases may be amenable to apparent
cure with HbsAg loss. Six months of Pegylated Interferon ther-
apy preceded by nucleoside therapy is not sufficient enough
to allow response in immunotolerant phase which may be due
to predominance of Genotype D in our population. Overall,
therapy was well tolerated by all children
Disclosures:
The following people have nothing to disclose: Vikrant Sood, Sanjeev K. Verma,
Seema Alam, Rajeev Khanna, Dinesh Rawat
683
Can expression of interferon-stimulated genes in
pre-treatment liver biopsy of chronic hepatitis B patients
predict therapy response and long-term HBV infection
outcome?
Ivana Carey, Kate Childs, Sanjay Bansal, Sarah Tizzard, Matthew
J. Bruce, Mary Horner, Diego Vergani, Kosh Agarwal, Giorgina
Mieli-Vergani; Institute of Liver Studies, Kings College School of
Medicine at King’s College Hospital, London, United Kingdom
Data on long-term outcomes after interferon (IFN) based ther-
apy in chronic hepatitis B (CHB) are limited. mRNA expression
of interferon-stimulated genes (ISG) in pre-treatment liver biopsy
in immunotolerant CHB patients prior to IFN therapy showed
that lower mRNA CXCL10 expression in the liver was associ-
ated with therapy response, but there was wide variability in
mRNA ISG expression results in therapy non-responders. We
aimed to assess whether different viral (genotype, precore)
factors at baseline and long-term post-therapy responses might
contribute to variability in ISG expression and can predict long-
531A
term CHB outcome. Patients: 23 patients (8 males, median age
10.2 years) with infancy-acquired CHB, treated for 52 weeks
[lead-in LAM (3mg/kg/d) for 9 weeks; add-on IFN-α (5MU/
m2TIW) from week 9] were followed-up 13 years post-stop-
ping therapy. Post-therapy results - 6 months post-stopping
therapy: 5 responders (R=HBsAg loss) and 18 non-respond-
ers (NR). All R remained anti-HBs+ during follow-up. 3 years
post-stopping: 17/18 NR were HBeAg+ (13 with normal ALT
vs. 4 with elevated ALT), only 1 patient was HBeAg-. 5 years
post-stopping: 15/16 NR were HBeAg+ (7 had normal ALT
vs. 8 with ALT elevation) and only 1 patient was HBeAg-. 10
years post-stopping: 7/13 NR were HBeAg+ (4 normal ALT
vs. 3 had ALT elevation) and 6 achieved HBeAg seroconver-
sion. 13 years post-stopping: 7/13 NR patients were HBeAg+
(only 1 had normal ALT) vs. 6 HBeAg- with HBeAg<1000IU/
ml and normal ALT. 5 HBeAg+ NR received/ing therapy. Meth-
ods: Total RNA was extracted from pre-treatment biopsies in
patients and 5 healthy controls. HPRT1 and 7 interferon-induc-
ible genes (ISG15, USP18, MxA, OAS2, OAS3, viperin and
CXCL10) mRNA expression was measured by quantitative real-
time RT-PCR. HBV genotypes and pre-core region mutations
were tested by direct sequencing. The results were compared
according to genotypes, presence/absence pre-core mutations
and outcome 10 years post-stopping therapy (responders vs.
HBeAg+ vs. HBeAg-). Results: R had higher viperin mRNA
expression and lower CXCL10 expression than NR (viperin:
16.8 vs.0.4, p<0.05; CXCL10: 0.62 vs. 1.4,p<0.05). ISG
expression was similar across HBV genotypes and irrespec-
tive of presence/absence of pre-core mutations. HBeAg+
NR had higher ISG15 and CXCL10 mRNA expression than
HBeAg- (ISG15: 1.96 vs. 0.41, p<0.05; CXCL10: 3.18 vs.
1.2, p<0.05), but lower viperin mRNA expression (0.52 vs.
2.63, p<0.05). Conclusions: High viperin and low CXCL10
mRNA expression in pre-treatment liver biopsy were predicting
therapy response and 10 years follow-up outcomes post-IFN
based therapy in immunotolerant CHB patients.
Disclosures:
Ivana Carey - Grant/Research Support: Gilead, BMS, Roche; Speaking and
Teaching: BMS
Kosh Agarwal - Consulting: Boehringer-Ingelheim
The following people have nothing to disclose: Kate Childs, Sanjay Bansal, Sarah
Tizzard, Matthew J. Bruce, Mary Horner, Diego Vergani, Giorgina Mieli-Vergani
532A AASLD ABSTRACTS
684
Impact of EGF, IL28B, and PNPLA3 polymorphisms on
the outcome of allograft hepatitis C: a multicenter study
Jessica L.Mueller1, Lindsay Y. King1,2,Kara B. Johnson1,2,
Tian
Gao7, Lauren D. Nephew8, Darshan Kothari2,3, Mary Ann Simp-
son4, Lan Wei5, Kathleen E. Corey1,2, Joseph Misdraji6, Joon
Hyoek Lee9, Bryan C. Fuchs2,5, Kenneth K. Tanabe2,5, Frederic D.
Gordon2,4, Michael P. Curry2,3, Raymond T. Chung1,2; 1Depart-
ment of Medicine, Division of Gastroenterology, Massachusetts
General Hospital, Boston, MA; 2Harvard Medical School, Boston,
MA; 3Department of Medicine, Division of Gastroenterology, Beth
Israel Deaconness Medical Center, Boston, MA; 4Department of
Medicine, Division of Gastroenterology, Lahey Hospital & Medi-
cal Center, Burlington, MA; 5Department of Surgery, Division of
Surgical Oncology, Massachusetts General Hospital, Boston, MA;
6Department of Pathology, Massachusetts General Hospital, Bos-
ton, MA; 7Department of Medicine, Division of Gastroenterology,
Boston Medical Center, Boston, MA; 8Department of Medicine,
Division of Gastroenterology, University of Pennsylvania Health
System, Philadelphia, PA; 9Department of Medicine, Sungkyunk-
wan University School of Medicine, Samsung Medical Center,
Seoul, Republic of Korea
Purpose: Allograft hepatitis C is accelerated following liver
transplantation (LT). Factors associated with disease progres-
sion include viral, demographic, and genetic characteristics of
recipients and donors. Single nucleotide polymorphisms (SNPs)
near the EGF (rs4444903), IL28B (rs12979860), and PNPLA3
(rs738409) loci are associated with treatment response, fibro-
sis, and hepatocellular carcinoma in nontransplant hepatitis C.
No study has examined the role of EGF genotype, and only
one study has examined the role of PNPLA3 genotype in LT
recipients. IL28B genotype is associated with IFN-based treat-
ment response in LT recipients, although data differ regarding
its association with allograft disease course. We sought to
determine whether these SNPs predict cirrhosis development
and graft survival in a multicenter population. Methods: HCV
patients who underwent LT at MGH, Beth Israel Deaconess, and
Lahey Clinic between 1990 and 2008 were studied. Geno-
types were determined from donor wedge or allograft biopsies
and recipient explants. Cox proportional hazards regression
model was used to assess time to cirrhosis, liver-related death,
and re-LT, adjusting for donor age and sustained virologic
response (SVR) as a time-dependent covariate. Logistic regres-
sion was used to assess SVR in patients receiving antiviral ther-
apy. Results: The cohort comprised 257 LT recipients followed
for a median of 6.9 years. We observed a trend towards a
higher rate of progression to cirrhosis among recipients with
an EGF non-AA vs. AA donor genotype (adjusted HR 2.02;
95%CI 0.93–4.37; p=0.07). No association was observed
between recipient EGF, IL28B, and PNPLA3 or donor IL28B
and PNPLA3 genotypes and cirrhosis. Additionally, no associa-
tion was observed between these genotypes and graft survival.
Among treated patients, the presence of the CC IL28B variant
in either the recipient (R) or donor (D) liver was associated with
increased rate of SVR (R-CC/D-CC 8/12 [67%], R-non-CC/
D-CC 19/42 [45%], R-CC/D-non-CC 3/9 [33%], R-non-CC/D-
non-CC 12/45 [27%], p=0.07). Conclusions: Recipient EGF,
IL28B, and PNPLA3 and donor IL28B and PNPLA3 genotypes
do not predict adverse outcomes in LT recipients with HCV. A
potential association exists between donor EGF genotype and
cirrhosis. Since the EGF GG genotype produces higher serum
and liver levels of EGF than the non-GG genotype, and since
the EGF receptor is involved in HCV entry, this finding is bio-
logically plausible. Future efforts will be directed at investigat-
ing this relationship in larger cohorts. The results also suggest
HEPATOLOGY, October, 2014
that IL28B and PNPLA3 genotypes do not play a major role in
determining the natural history of allograft hepatitis C.
Disclosures:
Jessica L. Mueller - Employment: NIDDK
Kathleen E. Corey - Advisory Committees or Review Panels: Gilead; Speaking
and Teaching: Synageva
Kenneth K. Tanabe - Patent Held/Filed: EGF SNP and risk for HCC, EGFR inhibi-
tion and HCC, gene signature for prognosis in cirrhosis
Michael P. Curry - Grant/Research Support: Gilead Sciences, Mass Biologics,
Merck, Salix, Conatus; Stock Shareholder: Achilion, Idenix
Raymond T. Chung - Consulting: Abbvie; Grant/Research Support: Gilead, Mass
Biologics
The following people have nothing to disclose: Lindsay Y. King, Kara B. Johnson,
Tian Gao, Lauren D. Nephew, Darshan Kothari, Mary Ann Simpson, Lan Wei,
Joseph Misdraji, Joon Hyoek Lee, Bryan C. Fuchs, Frederic D. Gordon
685
Genetic polymorphisms of toll–like receptors 1 and 9
are associated with increased risk of severe hepatitis C
virus recurrence after liver transplantation
Ana Maria Duca1, María J. Cítores2, Sara de la Fuente2, Isolina
Baños1, Ana B. Cuenca2, Valentin Cuervas-Mons1; 1Liver Trans-
plant Unit, Department of Internal Medicine, Hospital Puerta de
Hierro Majadahonda, Majadahonda, Spain; 2Department of Inter-
nal Medicine, Hospital Universitario Puerta de Hierro Majada-
honda, Majadahonda, Spain
The recurrence of hepatitis C virus (HCV) infection on the graft
is universal after liver transplantation (LT) in patients with HCV
RNA detectable at time of transplantation, although the severity
of recurrence is variable. Toll-like receptors (TLRs) are patho-
gen recognition receptors that orchestrate the innate immune
response and subsequent adaptive immune response. TLRs are
critical to innate antiviral response and HCV alters TLRs func-
tions to evade immune clearance. Whether TLRs play a role in
the severity of HCV recurrence after LT is unknown. The aim of
this study was to investigate whether genetic polymorphisms of
TLRs are associated with more aggressive recurrence of HCV
after LT for cirrhosis due to HCV infection. In this study 118
patients were included (age 54,6±9 years, 72% males) who
underwent LT because of HCV cirrhosis, with at least six months
of follow-up and with available DNA sample. We examined
15 single nucleotide polymorphisms of TLRs and genotyping
was carried out by real-time PCR and analysis of the melt-
ing curves with the LightCycler 480 system (Roche Diagnostics
GmbH, Mannheim, Deutschland). Sixty-five (63,6%) patients
developed severe recurrence of HCV after LT In the univariate
analysis, TT genotype for TLR1 Asp248Ser and TT genotype for
TLR9 -1486T>C were associated with a higher risk of severe
recurrence of HCV versus non-TT genotypes [(p=0,02; OR:
2,83; CI: 1,25-6,44) and (p=0,028; OR: 2,68; CI: 1,18-6,10)
respectively]. Donor age of more than 40 years and initial
immunosuppression with tacrolimus versus cyclosporine were
also found as risk factors for severe recurrence [(p=0,004;
OR: 3,39; CI: 1,53-7,52) and (p=0,017; OR: 2,82; CI: 1,27-
6,21) respectively]. In the multivariate analysis, only TT gen-
otype for TLR1 Asp248Ser, TT genotype for TLR9 -1486T>C
and donor age were confirmed as independent risk factors of
severe recurrence of HCV and their association increased the
risk [(p=0,01; OR: 3,28; CI: 1,32-8,12), (p=0,036; OR: 2,65;
CI: 1,06-6,60) y (p=0,028; OR 2,7; CI: 1,11-6,58) respec-
tively]. The overall survival of the graft was significantly lower
in patients with severe recurrence of HCV in comparison with
patients with non-severe recurrence (p< 0,001). Patients with
the three risk factors had a poor survival than those without
any, one or two risk factors (p=0,001; p=0,007 and p=0,034
respectively). In conclusion, the TT genotype TLR1 Asp248Ser
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
and TT genotype TLR9 -1486T>C are independent risk factors
of severe recurrence of HCV in patients with LT for cirrhosis
due to HCV.
Disclosures:
The following people have nothing to disclose: Ana Maria Duca, María J. Cítores,
Sara de la Fuente, Isolina Baños, Ana B. Cuenca, Valentin Cuervas-Mons
686
The influence of mTor-Inhibitors on HCV replication after
liver transplantation
Eva-Maria Ecker1,2, Alexandra Frey1, Katja Piras-Straub1,2,
Andreas Walker3, Guido Gerken1, Kerstin Herzer1,2; 1Gastroen-
terology and Hepatology, Universitätsklinikum Essen, Essen, Ger-
many; 2General, Viszeral and Transplantation Surgery, University
Hospital Essen, Essen, Germany; 3Institute for Virology, University
Hospital Essen, Essen, Germany
Background: HCV associated cirrhosis is still one of the leading
causes for liver transplantation (LT) in the western world. How-
ever, reinfection of the liver graft occurs in virtually all patients
typically followed by an accelerated course of progressive liver
damage. The influence of immunosuppressants (IS), in partic-
ular mTor-inhibitors, on HCV reinfection is not clarified yet.
Methods: We used a luciferase-coupled HCVcc replicon-system
to compare calcineurin inhibitors (CNIs; Tacrolimus, Cyclospo-
rin A) and mTor inhibitors (Everolimus, Sirolimus) concerning
their influence on HCV replication in vitro. Replication was
determined in luciferase assays. To exclude an effect of IS on
cell proliferation we performed carboxyfluorescein succinimidyl
ester (CFSE) analysis. To further identify factors which influence
replication, IS-treated HCVcc replicon cells as well as patient
liver biopsies underwent gene array analysis. In addition,
clinical characteristics of all patients who received liver trans-
plantation at our center during the past 5 years were retrospec-
tively analyzed and the course of viral load under different IS
regimes was compared with the in vitro results. Results: While
CNIs did not significantly influence HCV GT1 replicon activity,
we saw a significant reduction of replication of HCV GT2a
and GT3 after treatment with mTor inhibitors, applying doses
equivalent to the therapeutic range. In contrast, mTor inhibitors
rather increased activity of HCV GT1b and GT1a replicons. An
influence of mTor-Inhibitors on cell viability could be excluded.
Gene array analyses provided several interesting factors poten-
tially involved in the molecular mechanism of impairment of
replication. Moreover, analysis of the patient data revealed a
decrease in viral load in patients with HCV GT2 and 3 after
switch of IS from an CNI-based to an EVR-based regime, while
patients with HCV GT1-infection did not show a change in viral
load. Conclusions: Our results suggest a benefit of an mTor-
based immunosuppressive regimen in patients with HCV GT 2
or 3 reinfection after liver transplantation.
Disclosures:
The following people have nothing to disclose: Eva-Maria Ecker, Alexandra Frey,
Katja Piras-Straub, Andreas Walker, Guido Gerken, Kerstin Herzer
533A
687
Hepatitis C Treatment Does Not Affect Waiting Time for
Liver Transplantation in Hepatitis C Positive Patients
Mohannad Dugum1, Nizar N. Zein2, Naim Alkhouri2, Rocio
Lopez4, Brigette Bevly2, Charles M. Miller3, Teresa Diago3, Ibrahim
A. Hanouneh2; 1Internal Medicine, Cleveland Clinic Foundation,
Cleveland, OH; 2Gastroenterology and Hepatology, Cleveland
Clinic Foundation, Cleveland, OH; 3Transplantation Center, Cleve-
land Clinic Foundation, Cleveland, OH; 4Quantitative Health Sci-
ences, Cleveland Clinic Foundation, Cleveland, OH
Background: A growing demand for liver transplantation (LT)
with concomitant scarcity of livers has increased the need for
using hepatitis C virus (HCV) positive donor allografts in HCV
positive patients awaiting LT. Herein we hypothesize that treat-
ment of HCV in patients on the LT waiting list may affect the
organ allocation from HCV positive donors to HCV positive
recipients and therefore prolong the wait for an organ. Aim:
To assess the effect of HCV treatment on waiting time for LT in
HCV positive patients. Methods: Adult patients initiated on the
LT waiting list in the United States between 2008 and 2012
were identified from the United Network for Organ Sharing
database. A simulation study was performed to assess the
potential impact of HCV treatment on LT waiting time. Different
treatment rates (0, 30, 60 and 90%) along with estimated
HCV cure at 4 and 12 weeks were explored. For each treat-
ment scenario, each HCV patient on the waiting list was ran-
domly assigned to receive treatment or not commencing at the
time of waiting list registration. It was assumed that all treated
patients would be HCV-free within the treatment effectiveness
time. New donors were then assigned to each recipient by
choosing the next available donor in the same Organ Pro-
curement and Transplantation Network region. If the recipi-
ent received HCV treatment and was cured by the time his/
her first possible match was available then donors who had
HCV were deemed incompatible and the patient remained
on the waiting list. Patients that were removed from the wait-
ing list because of death or other reasons were competing for
donors until the time of their removal. This process was repli-
cated 100 times for each scenario. Results: A total of 53,390
patients were included in the analysis and 23% of those were
HCV positive. Average age for HCV positive patients was 56
years and 26% had hepatocellular carcinoma (HCC). 83.9%
of HCV positive patients were transplanted versus 34.1% of
non-HCV patients (p<0.001). Among the liver donors, 5.8%
were positive for HCV. Assuming that HCV cure is achieved
within 12 weeks of treatment initiation: 54.5% of HCV positive
patients will be transplanted if treatment rate is 30%, 54.4%
will be transplanted if treatment rate is 60% and 54.3% will
be transplanted if treatment rate is 90%. Results were similar
for the other treatment rates. Conclusion: In a large simulation
study utilizing a national database, there was no evidence to
suggest that HCV treatment prior to LT would have an impact
on LT waiting time. Effective treatment of HCV is unlikely to
affect liver organ allocation from HCV positive donors to HCV
positive recipients.
Disclosures:
Naim Alkhouri - Advisory Committees or Review Panels: Gilead Sciences
The following people have nothing to disclose: Mohannad Dugum, Nizar N.
Zein, Rocio Lopez, Brigette Bevly, Charles M. Miller, Teresa Diago, Ibrahim A.
Hanouneh
534A AASLD ABSTRACTS
688
Sofosbuvir and ribavirinin in hcv-infected patients listed
for liver transplantation: a cost-effectiveness analysis
Paolo A. Cortesi1, Lorenzo G. Mantovani2, Antonio Ciaccio3, Mat-
teo Rota4, Giancarlo Cesana1, Mario Strazzabosco5,3, Luca S
Belli6; 1Research Centre on Public Health (CESP), University of
Milan-Bicocca, Milan, Italy; 2Department of Clinical Medicine and
Surgery, University Federico II of Naples, Naples, Italy; 3Depart-
ment of Surgery and Translational Medicine, University of Milan-Bi-
cocca, Milan, Italy; 4Department of Health Sciences, Centre of
Biostatistics for Clinical Epidemiology, University of Milan-Bicocca,
Milan, Italy; 5Yale University, Section of Digestive Diseases, New
Haven, CT; 6Department of Hepatology and Liver Unit, Niguarda
Hospital, Milan, Italy
Post-liver transplant recurrent hepatitis C virus (HCV) infection
severely limits the prognosis of HCV-infected patients. Sofosbu-
vir in combination with ribavirin (SOF/RBV) is a novel interfer-
on-free treatment able to suppress HCV viremia when applied
to HCV patients listed for transplant, thereby preventing HCV
recurrence. Aim of this study was to assess the cost-effective-
ness of this regimens in patients listed for transplant for cirrho-
sis (HCV-cirrhosis) or for hepatocellular carcinoma in cirrhosis
(HCV-HCC). A semi-Markov model was developed to assess
the cost-effectiveness of pre-transplant SOF/RBV treatment in
patients listed for HCV-cirrhosis and HCV-related HCC. The
model simulates the progression of HCV-cirrhosis or HCV-HCC
patients from the time of listing until death considering the risk
of HCV recurrence post-transplant. The model compared 2 dif-
ferent strategies: 1) SOF/RBV up to a maximum of 24 weeks or
until OLT if performed before the 24th week from the initiation
of treatment, 2) No antiviral treatment. The model estimated the
costs related to the treatment with SOF/RBV, the costs associ-
ated to each health state, the life-years (LYSs), the quality-ad-
justed life-years (QALYs), and the incremental cost-effectiveness
ratio (ICER) expressed as € per QALY gained. The analysis was
performed from the Italian National Health System perspective
with a lifetime time horizon and one-month Markov cycles.
Future costs and clinical benefits, expressed as QALYs, were
discounted at 3% per year. Results: in the base-case analysis
the ICER for 24 weeks of SOF/RBVR was €30,518 per QALY
gained in HCV-cirrhosis patients and €41,610 in HCV-HCC
patients. The reliability of our results was confirmed by the one
way sensitivity-analysis and by the cost-effectiveness accept-
ability curve that reported 97.5% probability of SOF/RBV to
be cost-effective at a willingness to pay threshold of €60,000 in
the HCV–cirrhosis scenario, and 88.1% in the HCV-HCC sce-
nario. Further, SOF/RBV cost-effectiveness was clearly sensitive
to the duration of treatment; assuming 12 weeks SOF/RBV
treatment duration, the ICER decreased to €19,317 in HCV-Cir-
rhosis and €29,540 in HCV-HCC. In conclusion, our study
shows that treating patients with HCV-cirrhosis or HCV-HCC in
the transplant waiting list with SOF/RBV is cost-effective and
may become the new standard of care for these patients. How-
ever a well-defined prospective study is needed to confirm the
value of the parameters assumed in the model and the results.
Furthermore, associations of direct acting antivirals will soon
appear into the horizon also in the transplant setting and bring
new challenges and opportunities.
Disclosures:
Lorenzo G. Mantovani - Advisory Committees or Review Panels: Bayer; Grant/
Research Support: Jansen, Merck and Co; Speaking and Teaching: Bayer
The following people have nothing to disclose: Paolo A. Cortesi, Antonio Ciac-
cio, Matteo Rota, Giancarlo Cesana, Mario Strazzabosco, Luca S Belli
HEPATOLOGY, October, 2014
689
Hepatitis E Virus (HEV) Infection is Rare Cause of Hepa-
titis Among US Liver Transplant Recipients
Norah Terrault1, Ronald E. Engle2, Jennifer L. Dodge1, Chris
Freise1, Averell H. Sherker3, Patrizia Farci2, Robert H. Purcell2;
1University of California, San Francisco, CA; 2Laboratory of Infec-
tious Diseases,NIAID-NIH, Bethesda, MD; 3Liver Diseases Branch,
NIDDK-NIH, Bethesda, MD
Background: In studies predominantly from Europe, chronic
HEV infection has been shown to be an important cause of
chronic and progressive hepatitis among solid organ trans-
plant recipients. Limited data indicate that HEV is endemic in
the United States, but the prevalence, incidence and signifi-
cance of HEV infection among US transplant patients is largely
unknown. Methods: This A2ALL-approved ancillary study,
evaluated liver transplant (LT) recipients with deceased and
living donors in 9 LT programs from geographically diverse
regions of the US between 1998 and 2009. A total of 255
recipients with stored serum samples from before and after
(median 362 days) LT and an additional 260 transplant recip-
ients with post-LT samples only were tested for HEV IgG with
an EIA that uses a truncated 55 kDa recombinant HEV capsid
protein Positive samples were further tested for HEV-IgM with
a class-capture EIA that also employs the HEV capsid protein
and an antigen-specific monoclonal antibody. The majority
(82%) of post HEV-IgG and all seroconverters samples were
tested for HEV RNA. Borderline positive and negative samples
were designated as positive and negative, respectively. Donor
specimens were not available for testing. Results: Among the
255 pre-LT samples 97 (38%, 95% CI 32-44%) were anti-HEV-
IgG positive and none were positive for anti-HEV IgM. Age,
gender, race, and etiology of cirrhosis were not significantly
different in patients with or without anti-HEV. All 97 patients
with anti-HEV IgG before transplant remained positive on the
post-LT sample and 1 was IgM anti-HEV positive 4 yrs post-LT.
Among the158 LT recipients who tested negative for IgG anti-
HEV before transplant, 3 (1.9%, 95% CI: 0.4-5.4%) became
anti-HEV IgG positive during follow up (median 114 days, IQR
85-133), one of whom was also anti-HEV IgM positive. The
3 incident infection cases were all females, median age 57
yrs, Hispanic White (n=2) or Black (N=1), received deceased
(N=1) or living (N=2) donors and were transplanted for non-vi-
ral causes of cirrhosis. All 3 cases were HEV RNA negative.
Conclusions: In this geographically diverse LT population, prev-
alent HEV infection was common among patients undergoing
LT — present in 38%. Incident infections after LT were rare, with
only 1.9% (3 cases) identified and none with persistent infec-
tion. This natural history contrasts sharply with the reports from
Europe and suggests unique epidemiologic risks in Europe. We
conclude that HEV is not a major cause of unexplained chronic
hepatitis in US liver transplant populations.
Disclosures:
Norah Terrault - Advisory Committees or Review Panels: Eisai, Biotest; Con-
sulting: BMS, Merck; Grant/Research Support: Eisai, Biotest, Vertex, Gilead,
AbbVie, Novartis, Merck
The following people have nothing to disclose: Ronald E. Engle, Jennifer L.
Dodge, Chris Freise, Averell H. Sherker, Patrizia Farci, Robert H. Purcell
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
690
Characteristics of Post Transplantation Hepatitis E Virus
Infection Among Solid Organ Transplant Recipients at a
North American Transplant Center
Paul K. Sue1, Nora Pisanic2,
Christopher D. Heaney2,3,
Kenrad
Nelson3, Kathleen B. Schwarz4, Alexandra Valsamakis5, Michael
Forman5, Annette M. Jackson6, John R. Ticehurst3, Robert A.
Montgomery7, Wikrom Karnsakul4; 1Division of Pediatric Infec-
tious Diseases, Department of Pediatrics, Johns Hopkins University,
Baltimore, MD; 2Department of Environmental Health Sciences,
Johns Hopkins University Bloomberg School of Public Health, Balti-
more, MD; 3Department of Epidemiology, Johns Hopkins University
Bloomberg School of Public Health, Baltimore, MD; 4Division of
Pediatric Gastroenterology, Department of Pediatrics, Johns Hop-
kins University, Baltimore, MD; 5Department of Pathology & Clin-
ical Microbiology, Johns Hopkins Medical Institutions, Baltimore,
MD; 6Department of Immunogenetics, Johns Hopkins University
School of Medicine, Baltimore, MD; 7Department of Surgery, Johns
Hopkins University School of Medicine, Baltimore, MD
Background: Hepatitis E virus (HEV) is an emerging cause of
autochthonous infections among immunocompromised individ-
uals in developed nations. Among solid organ transplant (SOT)
recipients, HEV infection has been associated with acute hep-
atitis, liver graft dysfunction, cirrhosis, and chronic infection
in up to 65% of cases. While thrombocytopenia, leukopenia,
and tacrolimus use have been associated with the development
of chronic HEV infection among SOT recipients in Europe, risk
factors for HEV infection among SOT recipients in North Amer-
ica have not been previously characterized. Methods: We con-
ducted a nested case-control study of 16 SOT recipients at our
institution with evidence of post-transplant HEV infection (evi-
denced by anti-HEV IgM, IgG seroconversion, or positive PCR
at 6 months post-transplant), to determine risk factors for HEV
infection following SOT. Categorical variables included age
(by quartile), gender, immunosuppressive regimen, leukopenia
(WBC< 4.5K/mm3), lymphopenia (ALC< 1100), thrombocyto-
penia (platelets< 140k/mm3), and graft rejection. HEV cases
were matched by year and transplant type to negative controls
in a 1:3 ratio, and assessed by Chi square and multivariable
conditional logistic regression. Results: Of 311 subjects (271
kidney, 33 lung, 5 heart, 2 liver) in our cohort, 16 (13 kidney,
2 lung, 1 liver) demonstrated evidence of post-transplant HEV
infection (4 by HEV PCR, 2 by anti-HEV IgM,10 by anti-HEV
IgG seroconversion) and were matched to 48 controls. Univar-
iate analysis revealed significant associations between post
transplant HEV infections, cyclosporine use (p=0.015), and
leukopenia (p=0.007). In the multivariable model, leukopenia
(OR 4.15), thrombocytopenia (OR 2.24) and tacrolimus use
(OR 1.09) were associated with increased risk of HEV infection
post SOT, though only leukopenia was statistically significant
(p=.04). No subjects developed chronic HEV infection. Con-
clusions: Leukopenia was associated with an increased risk of
post-transplant HEV infection in our cohort. Associations with
other variables suggest a relationship between immunosuppres-
sion and risk of infection, but were not statistically significant.
In contrast to previous studies, we did not identify any chronic
HEV infections. Our findings suggest that while important,
immunosuppression and exposure alone may be insufficient for
the establishment of chronic HEV infection among SOT recip-
ients.
Disclosures:
Kathleen B. Schwarz - Consulting: Novartis, Novartis; Grant/Research Support:
Bristol-Myers Squibb, Gilead, Roche/Genentech, Bristol-Myers Squibb, Vertex,
Roche
The following people have nothing to disclose: Paul K. Sue, Nora Pisanic, Chris-
topher D. Heaney, Kenrad Nelson, Alexandra Valsamakis, Michael Forman,
Annette M. Jackson, John R. Ticehurst, Robert A. Montgomery, Wikrom Karnsakul
535A
691
Validation of The Hepatitis Aggressiveness Score in a
Liver Transplant Population with Recurrent Hepatitis C
Alberto Unzueta1, Roger K. Moreira2, Giovanni DePetris3, Max-
well L. Smith3, Yu-Hui H. Chang4, Meng-Ru Cheng4, Angela
Eyshou6, Juan F. Gallegos-Orozco5, Bashar Aqel6, Hugo E. Var-
gas6; 1Hospital Internal Medicine, Mayo Clinic, Scottsdale, AZ;
2Laboratory Medicine and Pathology, Mayo Clinic, Rochester,
MN; 3Laboratory Medicine and Pathology, Mayo Clinic, Scotts-
dale, AZ; 4Health Sciences Research, Mayo Clinic, Scottsdale, AZ;
5Gastroenterology, Hepatology and Nutrition, University of Utah
School of Medicine, Salt Lake, UT; 6Hepatology, Mayo Clinic,
Scottsdale, AZ
Histological recurrence of hepatitis C (HCV) post-liver trans-
plantation (LT) is still an important event even in the era of
more effective HCV treatments. The Hepatitis Aggressiveness
Score (HAS) is a histologic classification system that has been
recently developed to assess the recurrence of HCV. Objective:
the main outcome of the study was to evaluate graft survival
time based on HAS and to assess pathologist inter-observer
agreement. Methods: we reviewed the clinical records of HCV
liver transplant recipients in our facility from June 1999 to June
2012. We included those patients who had >30 day survival.
Clinical and histologic characteristics were obtained. Biopsies
were independently evaluated by 3 pathologists. All biopsies
were assessed for the presence of the following features, which
comprise the basis of the HAS: 1) prominent ductular reaction
2) prominent hepatocyte ballooning 3) cholestasis (including
at least focal canalicular cholestasis of any degree) and 4)
periportal sinusoidal/pericellular fibrosis. The final HAS was
assigned as follows: HAS 1, presence of 0 criterion; HAS 2,
presence of 1 to 2 criteria; HAS 3, presence of 3 to 4 criteria.
Results: 340 HCV-infected patients had LT at our center during
the study period, a total of 255 patients were included in the
final analysis. 79.9% were male, 73.9% (184) Caucasian,
19.3% (48) Hispanic, mean(SD) age at LT 54.6(6.4) years,
mean(SD) MELD at LT 21.5 (8.7) and mean donor age was
38.6 years. Viral genotype breakdown was 78.6%, 5.7%
and 15.1% for genotypes 1,2 and 3 respectively. Mean cold
ischemia time was 6.2 hours. Tacrolimus was the immunosup-
pressor in 87.2% of patients. 224 patients were scored to
have a HAS of 1 (87.8%), 24 HAS 2 (9.4%) and 7 HAS 3
(2.7%). In a univariate Cox model HAS 2 vs 1 had HR of 4.06,
CI (2.06-8.01) and HAS 3 vs 1, HR 5.86, CI (2.08-16.54).
Kaplan-Meier survival analysis revealed 1 year graft survival
of 94.6% for HAS 1; 66.7% for HAS 2 and 42.9% for HAS
3. The Fleiss’ Kappa coefficient for inter-observer agreement
among the 3 pathologist was moderate. Conclusions: the HAS
classification includes relevant prognostic features that predict
graft survival in patients with recurrent HCV. We identified a
moderate agreement among pathologists that could make this
new classification useful in the routine evaluation of recurrent
HCV.
Agreement among pathologists
Disclosures:
Hugo E. Vargas - Advisory Committees or Review Panels: Eisai; Grant/Research
Support: Merck, Gilead, Idenix, Novartis, Vertex, Janssen, Bristol Myers, Ikaria,
AbbVie
536A AASLD ABSTRACTS
The following people have nothing to disclose: Alberto Unzueta, Roger K.
Moreira, Giovanni DePetris, Maxwell L. Smith, Yu-Hui H. Chang, Meng-Ru
Cheng, Angela Eyshou, Juan F. Gallegos-Orozco, Bashar Aqel
692
Living donor liver transplantation for hepatitis C
virus-positive recipients in Japan: a nationwide survey
Tomohiro Tanaka1, Nobuhisa Akamatsu2, Yasuhiko Sugawara2,
Junichi Kaneko2, Sumihito Tamura2, Taku Aoki2, Yoshihiro Saka-
moto2, Kiyoshi Hasegawa2, Norihiro Kokudo2; 1Organ Transplan-
tation Service, The University of Tokyo Hospital, Tokyo, Japan;
2The Artificial Organ and Transplantation, Department of Surgery,
Graduate School of Medicine, The University of Tokyo, Tokyo,
Japan
A nationwide survey of living donor liver transplantation (LDLT)
for hepatitis C virus (HCV)-positive recipients was performed
in Japan by the end of 2012, to review the outcome, details
of the antiviral treatment and prognostic factors in those popu-
lations. A total of 514 recipients from 12 Japanese transplant
centers are reported and included in the study: 194 (38%)
were female, 404 (79%) were infected with HCV genotype 1b
and 330 (64%) were complicated with pretransplant hepato-
cellular carcinoma. Median MELD score was 15, and donor /
recipient age were 57 / 35 years old, respectively. The cumu-
lative patient survival rate at 5 and 10 years was 72% and
63%, respectively. 142 patients (28%) died until the end of
the observation, among which the leading cause was recurrent
hepatitis C (42 cases). Out of all the 514 recipients, 361 have
undergone antiviral treatment mainly with pegylated-interferon
and ribavirin (preemptive treatment in 211 and treatment for
confirmed recurrent hepatitis in 150). The dose reduction rate
and discontinuation rate were 40% and 42%, respectively,
with a sustained virologic response (SVR) rate of 43%. Accord-
ing to Cox regression multivariate analysis, donor age (>40
years old), non-right liver graft, acute cellular rejection (ACR)
episode, and absence of an SVR were independent prognostic
factors (Figure: the Kaplan-Meier of each variable). In conclu-
sion, patient survival of HCV-positive recipients after LDLT was
feasible. In addition to the consideration for known risk factors
such as older donor, episodes of ACR and absence SVR, right
liver graft could be preferable for HCV positive recipients in an
LDLT setting.
Disclosures:
The following people have nothing to disclose: Tomohiro Tanaka, Nobuhisa
Akamatsu, Yasuhiko Sugawara, Junichi Kaneko, Sumihito Tamura, Taku Aoki,
Yoshihiro Sakamoto, Kiyoshi Hasegawa, Norihiro Kokudo
HEPATOLOGY, October, 2014
693
Performance Characteristics of the Procleix HEV Assay
on the Fully Automated Procleix Panther System
Edgar Ong1, Alanna Janssen1, Robin Cory1, Maria Babizki1, Tim
Shin1, Andre Lindquist1, Ngoc-Anh Hoang1, Lee P. Vang1, Lisa
Danzig2, Jeffrey M. Linnen1; 1Research & Development, Hologic
Inc., San Diego, CA; 2Scientific & Medical Affairs, Grifols Inc.,
Emeryville, CA
Background: The Procleix HEV assay is a qualitative in vitro
nucleic acid test for the detection of hepatitis E virus (HEV)
RNA. The assay is currently under development and runs on
the Procleix Panther system, a fully automated instrument that
allows random access of samples and continuous loading of
reagents during processing. Aims: Studies were performed to
characterize the sensitivity, specificity, and reproducibility of
the Procleix HEV assay on the Panther system. Methods: Stud-
ies were conducted to assess the analytical sensitivity using
the HEV WHO International Standard (PEI code 6329/10)
and RNA transcripts of all 4 clinically relevant HEV genotypes
(1, 2, 3a, 3b, 3f and 4c), and clinical specificity of the assay
using multiple lots of reagents. Clinical sensitivity was assessed
by testing 40 HEV positive blood donor specimens with viral
load titers ranging from 10 to 1,000,000 IU/mL. Assay repro-
ducibility, performance in plasma and serum samples from
cadaveric specimens, and the effect of potentially cross-con-
taminating infectious agents, interfering substances, and donor
and donation factors were determined. Results: The Procleix
HEV assay showed a 95% limit of detection (LOD) of 7.9 IU/
mL (95% CI: 6.63-9.83 IU/mL) using the WHO Standard and
detected all the HEV genotype transcripts with 95% LOD values
ranging from 7.9 to 17.7 copies/mL. A total of 4,494 plasma
samples obtained from volunteer whole blood donations were
screened for HEV RNA with a resulting clinical specificity of
99.98% (95% CI: 99.87-100%). The 40 HEV positive blood
donor specimens were detected at a rate of 98.75% when
tested undiluted. When tested over three days with multiple
instruments, reagent lots, and operators, the assay showed
reproducible results with the intra-run factor contributing the
largest source of variability. The assay showed 100% specific-
ity and sensitivity in the presence of potentially cross-contam-
inating infectious agents, interfering substances, donor and
donation factors, and for cadaveric samples. Summary/Con-
clusions: Preliminary results indicated that the assay was sensi-
tive (95% LOD: 7.9 IU/mL) and specific (99.98% specificity).
The assay was also shown to detect the 4 clinically relevant
HEV genotypes and was highly reproducible. Furthermore, per-
formance was not affected by potentially cross-contaminating
infectious agents, donor and donation factors, and interfering
substances, including those that may be present in cadaveric
specimens. In conclusion, based on the performance demon-
strated in this study, the Procleix HEV assay on the fully auto-
mated Panther System may be useful for both blood screening
and diagnosis of HEV infection.
Disclosures:
Alanna Janssen - Employment: Hologic
Lisa Danzig - Employment: Grifols
Jeffrey M. Linnen - Employment: Hologic, Inc.; Stock Shareholder: Hologic, Inc.
The following people have nothing to disclose: Edgar Ong, Robin Cory, Maria
Babizki, Tim Shin, Andre Lindquist, Ngoc-Anh Hoang, Lee P. Vang
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
694
Sofosbuvir as the backbone of treatment for HCV after
liver transplantation: a real-life multicenter experience
Rohit Satoskar1, Joseph Ahn4, Helen S. Te2, Adam Deising1,
Andrew Aronsohn2, Suzanne Robertazzi1, Thomas D. Schiano3;
1Transplant Institute, MedStar Georgetown University Hospital,
Washington, DC; 2Center for Liver Diseases, Department of Med-
icine, University of Chicago Medicine, Chicago, IL; 3Division of
Liver Diseases/MGTI, The Mount Sinai Medical Center, New York,
NY; 4Oregon Health and Science University, Portland, OR
INTRODUCTION: There is limited data about the safety and
effectiveness of sofosbuvir (SOF)-based therapies in “real-life”
patients with HCV recurrence after liver transplantation (LT).
AIM: To evaluate the safety and effectiveness of SOF-based
therapies in patients with HCV recurrence after LT. METH-
ODS: This is a retrospective, multi-center study of patients
with post-transplant HCV recurrence who received pegylated
interferon (IFN) + ribavirin (RBV) + SOF (group 1) ; simepre-
vir (SMV) + SOF (group 2); SMV + SOF + RBV (group 3);
or SOF + RBV (group 4). Treatment response by HCV RNA,
cell counts, and adverse events (AE) were compared between
groups. RESULTS: 59 patients (88% genotype 1a /1b, 51%
F3/F4 fibrosis, 71% previously treated) were included in the
analysis. Median time from transplant was 1297d (56-6209).
There were no statistical differences in demographics, geno-
type, weight, fibrosis or laboratory parameters between the
groups. Analysis of undetectable HCV RNA (UD) is shown in
Table 1. Overall, 76% had generalized AE including fatigue,
musculoskeletal complaints, headache and nausea, but the fre-
quency of AE was similar between groups (p = 0.74). Serious
AE including 1 death were reported in 14 patients (6 anemia/
cytopenia, 2 infection, 6 unrelated to therapy). Hgb decrease
by >2 g and development of significant anemia (Hgb <10 g/
dL) was more frequent in patients receiving RBV [85.7%(1),
10.5%(2), 80%(3), 73.1%(4) p=<0.0001] and [71.4%(1),
10.5%(2), 20%(3), 57.7%(4) p=0.003], respectively. Leukope-
nia and thrombocytopenia were more common in patients who
received IFN. (p=<0.0001 and 0.002, respectively). The need
for growth factors was higher in the IFN and RBV containing
groups (p=0.005) and blood transfusions were more common
in RBV containing groups (p=0.028). No changes in immuno-
suppression doses were needed during treatment for any of
the groups. SVR data will be presented. CONCLUSIONS: On
treatment response using SOF based regimens in the treatment
of HCV post-transplant appears promising. Treatment is well
tolerated overall, but side effects are increased with RBV or IFN
use. No immunosupression changes are needed when using
SOF or SIM. Longer term data will help confirm safety and
effectiveness in “real-life” patients.
No significant difference between groups at week 2 and 4.
Disclosures:
Joseph Ahn - Advisory Committees or Review Panels: gilead; Grant/Research
Support: bms
Helen S. Te - Advisory Committees or Review Panels: Gilead Sciences, Jansenn
Pharmaceuticals; Grant/Research Support: Abbvie, BMS
The following people have nothing to disclose: Rohit Satoskar, Adam Deising,
Andrew Aronsohn, Suzanne Robertazzi, Thomas D. Schiano
537A
695
The Impact of Pre-Transplant Obesity and Diabetes on
Survival Following Liver Transplantation among Hepa-
titis C Virus Patients With and Without Hepatocellular
Carcinoma
Robert J. Wong1,2, Ramsey Cheung1,2, Edward W. Holt3, Aijaz
Ahmed1; 1Gastroenterology and Hepatology, Stanford University
Medical Center, Stanford, CA; 2Gastroenterology and Hepatol-
ogy, Veterans Affairs Palo Alto Health Care System, Palo Alto,
CA; 3Division of Transplant Hepatology, California Pacific Medical
Center, San Francisco, San Francisco, CA
Background: The growing proportion of hepatitis C virus (HCV)
patients with obesity and diabetes increases the risk of compli-
cations associated with undiagnosed nonalcoholic steatohepa-
titis among HCV patients undergoing liver transplantation (LT).
Aim: To evaluate the impact of pre-transplant obesity and dia-
betes on post-LT survival among HCV patients with (HCV-HCC)
and without hepatocellular carcinoma (HCV-nonHCC). Meth-
ods: Using the United Network for Organ Sharing 2003-2013
registry, four categories were created to evaluate the impact of
obesity and diabetes on post-LT survival among HCV patients:
non-obese and non-diabetic (NO-ND), obese and non-dia-
betic (O-ND), non-obese and diabetic (NO-D), and obese and
diabetic (O-D). Survival was evaluated using Kaplan Meier
and multivariate Cox proportional hazards models. Results:
Overall, 17,844 HCV-HCC and 5,962 HCV-nonHCC patients
underwent LT. Among the HCV-HCC cohort, O-ND patients had
significantly higher 5-year post-LT survival when compared to
NO-ND (73.0% vs. 70.6%, p=0.01), whereas NO-D (63.3%
vs. 70.6%, p<0.001) and O-D (64.9% vs. 70.6%, p<0.01)
had lower survival (Figure). Among the HCV-HCC cohort,
NO-D patients had lower 5-year post-LT survival when com-
pared to NO-ND. When compared to NO-ND patients with
HCV-nonHCC, O-ND was associated with improved survival
(HR, 0.90; 95% CI, 0.83–0.98) and NO-D with lower survival
(HR, 1.23; 95% CI, 1.10–1.36). However, the concurrence of
obesity and diabetes (O-D) seemed to mitigate the detrimen-
tal effect of diabetes alone (HR, 1.11; 95% CI, 0.97–1.26).
This same trend was seen among HCV-HCC patients. Con-
clusion: Among HCV patients with or without HCC, diabetes
was associated with lower post-LT survival. However, obesity
was associated with improved survival, and when concurrent
with diabetes, mitigated the detrimental effects of diabetes on
post-LT survival.
Disclosures:
Ramsey Cheung - Grant/Research Support: Gilead Sciences
538A AASLD ABSTRACTS
Aijaz Ahmed - Consulting: Bristol-Myers Squibb, Gilead Sciences Inc., Roche,
AbbVie, Salix Pharmaceuticals, Janssen pharmaceuticals, Vertex Pharmaceuti-
cals, Three Rivers Pharmaceuticals; Grant/Research Support: Gilead Sciences
Inc.
The following people have nothing to disclose: Robert J. Wong, Edward W. Holt
696
Long-Term Results of Prophylaxis of De Novo Hepatitis
B Virus (HBV) Infection With Lamivudine in HBsAg-nega-
tive Naive Recipients of anti-HBc-positive Liver Grafts: A
13-year Single-center Experience
Martin Prieto, María García Eliz, Ana M. Braithwaite, Angel Rubin,
Victoria Aguilera, Salvador Benlloch, Marina Berenguer, Carmen
Vinaixa; Hepatology Unit, Hospital Universitario y Politécnico La
Fe and CIBERehd, Valencia, Spain
Currrent Guidelines recommend the use of lamivudine (LAM) in
HBsAg-negative recipients of liver grafts from anti-HBc positive
donors. However, this recommendation is mainly based on
the results of studies with short follow-up and limited number
of naive recipients. The aim of this study was to assess the
long-term efficacy of LAM in HBsAg- naive recipients of anti-
HBc+ liver grafts. We aimed also to assess the relative contri-
bution of LAM resistance in cases of de novo HBV infection.
Methods: The study population consisted of 52 HBsAg- naive
recipients (median age 59 yrs, 73% male) of HBcAb+ livers
who underwent liver transplantation (LT) between 1/1/1999
and 12/31/2011. All of them had received LAM to prevent
HBV infection, defined as detection of HBsAg on at least two
consecutive occasions. Results: After a median post-LT follow-up
of 3.8 years (range: 0.1-11.6 yrs), 7 (13.5%) patients devel-
oped HBV infection at a median of 2 years (range: 1-6.5 yrs)
after LT: in 3 cases after accidental LAM withdrawal (8, 9,
and 12 months after LT) and while on continued LAM therapy
in the remaining 4 cases. The cumulated probability rates of
HBV infection were 2%, 13%, 17%, and 23% at 1, 3, 5, and
10 years, respectively. HBsAg positivity was accompanied by
elevated serum HBV DNA levels in six cases and by increased
ALT levels in 2 cases. LAM-specific mutations were found only
in the 4 patients who developed HBV infection while on con-
tinued LAM therapy. Initial HBV therapy consisted of tenofovir
+/- LAM (n=4), LAM +/- ADV (n=2), and entecavir (n=1),
respectively. Mean time from HBV infection to start of HBV ther-
apy was 64 days (range: 1-321 days). In addition, persistent
seroreversion of anti-HBc after LT was detected in four (11%)
of the 45 patients who remained HBsAg- after LT. Overall, 17
(33%) of the 52 patients died. Patient survival rates were 94%,
74%, and 55% at 1, 5, and 10 years, respectively, with no
deaths due to hepatitis B. Conclusions. HBV infection either
overt or cryptic is frequently observed with prolonged follow-up
in HBsAg-negative naive recipients of HBcAb+ grafts treated
with lamivudine. Based on these findings, alternative agents,
such as entecavir or tenofovir, should be used as HBV prohy-
laxis in these patients.
Disclosures:
Martin Prieto - Advisory Committees or Review Panels: Bristol, Gilead
The following people have nothing to disclose: María García Eliz, Ana M.
Braithwaite, Angel Rubin, Victoria Aguilera, Salvador Benlloch, Marina Beren-
guer, Carmen Vinaixa
HEPATOLOGY, October, 2014
697
Reinfection prophylaxis with entecavir monotherapy
is successful and safe in patients with hepatitis B virus
infection after liver transplantation
Kerstin Herzer1, Ingmar Mederacke2, Guido Gerken1, Frank Leh-
ner3, Juergen Klempnauer3, Michael P. Manns2, Karsten Wurst-
horn2,4; 1University Clinic Essen, Essen, Germany; 2Department
of Gastroenterology, Hepatology and Endocrinology, Hannover
Medical School, Hannover, Germany; 3Department of Surgery,
Hannover Medical School, Hannover, Germany; 4Asklepiosklinik
St. Georg, Liver Center Hamburg IFI Institute, Hamburg, Germany
Background Before the introduction of combined reinfection
prophylaxis in patients after liver transplantation (LTX) for hep-
atitis B survival rates were low. This was mainly due to a high
rate of HBV recurrence. Current reinfection prophylaxis consists
of hepatitis B immunoglobuline (HBIG) in combination with a
nucleos(t)ide analog (NUC). However, high costs of HBIG,
laborious administration and repeated testing of anti-HBs titers
are restrictive. Aim The aim of this prospective single-arm
open label pilot study was to investigate the effect of early
HBIG withdrawal within 3 months following LTx and continued
entecavir mono therapy on HBV reinfection after 48 and 96
weeks. Methods & Patients 20 HBV-positive patients with LTx
at two centers were recruited prospectively between 2010 and
2013. Perioperative care was performed according to local
standard. Intravenous HBIG administration was discontinued
during the first 3 months with entecavir mono therapy as the
only reinfection prophylaxis. Primary endpoint was HBsAg
recurrence 48 weeks after LTx. Secondary endpoints include
HBsAg recurrence after 96 weeks, recurrence of replicative
HBV and safety, among others. The study was performed with
the approval of the local ethics committee, each patient signed
an informed consent. All values are given as median (range).
Results 15 male and 5 female patients with chronic hepatitis B
were included. 5 patients had Delta coinfection, 8 patients had
hepatocellular carcinoma at the time of liver transplantation.
LabMELD score was 15. At study entry, anti-HBs was 206 U/
mL (28 – 2247). One year after transplantation, all patients
were alive. 20 of 20 patients were HBsAg negative and HBV
DNA negative. Only 2 patients were still positive for anti-HBs,
18 were anti-HBs negative. Median ALT was 22 U/lL (10 –
177). Serious adverse events were common but not related
to study procedures. Conclusion Reinfection prophylaxis with
entecavir after early withdrawal of HBIG did not lead to HBsAg
recurrence 48 weeks after liver transplantation. The regime
was safe and well tolerated in transplanted, immunosuppressed
patients. Monotherapy with a potent nucleos(t)ide analog has
the potential to simplify HBV reinfection prophylaxis following
perioperative care with HBIG.
Disclosures:
Frank Lehner - Advisory Committees or Review Panels: Astellas Pharma, Novartis
Pharma; Board Membership: Sanofi; Speaking and Teaching: Roche Pharma,
BMS Pharma
Juergen Klempnauer - Advisory Committees or Review Panels: Novartis Pharma,
Astellas, Roche, BMS, Genzyme; Grant/Research Support: Novartis Pharma,
Astellas
Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim,
Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/
Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim,
BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK,
Novartis
Karsten Wursthorn - Grant/Research Support: Novartis Pharma, BMS
The following people have nothing to disclose: Kerstin Herzer, Ingmar Meder-
acke, Guido Gerken
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
698
Accessibility to Liver Transplantation for HIV-HCV Coin-
fected Patients with End Stage Liver Disease: the French
Prospective Multicenter ANRS HC EP 25 PRETHEVIC
COHORT
Maria Ostos1, Moana Gelu-Simeon1,2, Johnson1,
Laetitia A. Elina
Teicher3,17, Hélène Fontaine4, Pierre Tattevin5, Isabelle Poizot-Mar-
tin6, Stephanie Dominguez7, David Zucman8, Julie Chas9, Pascal
P. Crenn10, Anne Gervais11, Karine Lacombe12, Philippe Morlat13,
Rodolphe Anty14, Faroudy Boufassa15, Inga Bertucci19, Georg-
es-Philippe Pageaux16, Laurence Meyer15, Jean-Charles Duclos-
Vallée1,18; 1AP-HP Hôpital Paul Brousse, Villejuif, France; 2CHU
de Pointe-à-Pitre, Pointe-à-Pitre, France; 3AP-HP Hôpital de Bicêtre,
Le Kremlin-Bicêtre, France; 4AP-HP Hôpital Cochin, Paris, France;
5CHU de Rennes, Hôpital Pontchaillou, Rennes, France; 6AP-HM,
Hôpital Sainte-Marguerite, Marseille, France; 7AP-HP Hôpital Henri
Mondor, Créteil, France; 8Hôpital Foch, Suresnes, France; 9AP-HP
Hôpital Tenon, Paris, France; 10AP-HP Hôpital Raymond Poincaré,
Garches, France; 11AP-HP Hôpital Bichat, Paris, France; 12AP-HP
Hôpital Saint-Antoine, Paris, France; 13CHU de Bordeaux, Bor-
deaux, France; 14CHU de Nice, Nice, France; 15U1018, Inserm,
Villejuif, France; 16CHU de Montpellier, Hôpital Saint Eloi, Mont-
pellier, France; 17U785, Inserm, Villejuif, France; 18Univ Paris-Sud,
Villejuif, France; 19ANRS, Paris, France
Describing the accessibility to liver transplantation (LT) in HIV/
HCV coinfected patients (pts) with end stage liver disease is
of crucial importance to analyze the factors influencing the
decisions for referring to LT. Aim: To determine the accessi-
bility to LT for HIV/HCV coinfected pts after a first episode of
decompensation (DC) and/or pts with hepatocellular carci-
noma (HCC). Patients and methods: A prospective and multi-
centric French cohort study was conducted since 2009 to study
all pts with DC and/or HCC within the year before the date of
inclusion. The eligibility of LT was evaluated every three months
during the follow-up. Results: 92 consecutive pts, 68 (74%) with
a first episode of DC and 24 (26%) with HCC, were included
in the study, males 71 (77%), mean age 49 years. At inclusion,
characteristics were: mean HIV viral load 5432 copies/mL,
mean HCV viral load 4.9 logIU/mL, mean CD4 cell count 375
cells /mm3. The distribution of Child-Pugh score was A: 58%,
B: 38% and C: 4% for pts with HCC and A: 24%, B: 47% and
C: 29%, for pts with DC. Median Meld score at inclusion was
9.7 [7.4-11.9] and 13.3 [10.61 - 16.3] for pts with HCC and
DC, respectively. During a median follow-up of 18.6 months
[9.2 - 35.3], 36 (39%) pts were contraindicated for LT. The
reasons were in 24 (35%) pts with DC: active alcoholism in
13%, respiratory failure in 1.5%, cancer in 1.5%, HIV profile
in 6%, outside Milan criteria in 3%, social reasons in 3%, psy-
chiatric disease in 3%, patient refusal in 4%. Fourteen (58%)
of these pts died, due to non-AIDS infection in 46%, HCC in
4% and DC in 4%. Concerning pts with HCC, LT was contra-
indicated in 12 (50%) due to beyond of Milan criteria in 33%,
other cancer in 4%, social reasons in 13% pts. Eleven (92%)
of these pts died, 58% due to HCC and 33% due to cirrhosis
DC. Twenty-six (28%) pts were registered on the waiting list
(WL), 8 (9%) and 18 (19%), in HCC and in DC groups, respec-
tively. Thirteen (14%) pts were transplanted, 4 and 9 in the
HCC group and in the DC group, respectively. The mean delay
between WL inscription and LT was 8 months. Eight (31%) pts
died on WL, 15% due to non-SIDA infection, 12% due to HCC
and 4% due to brain hemorrhage. Conclusions: Almost 40% of
HIV/HCV pts with end-stage liver cirrhosis are contraindicated
for LT because alcoholism or HCC beyond Milan criteria. Even
the short duration on WL, 30% died, because of progression
liver disease. Individualization of prognostic factors and a rein-
539A
forcement of therapeutic strategies for HIV/HCV candidates to
LT are mandatory.
Disclosures:
Hélène Fontaine - Independent Contractor: gilead, BMS, MSD, Roche, Janssen
Isabelle Poizot-Martin - Board Membership: Janssen, MSD, Bristol Myers Squibb,
ABBOTT; Consulting: ViiV Healthcare
Karine Lacombe - Advisory Committees or Review Panels: Janssen, MSD, Gilead
Philippe Morlat - Board Membership: GILEAD; Consulting: ViiV health Care
Georges-Philippe Pageaux - Advisory Committees or Review Panels: Roche,
Roche, Roche, Roche; Board Membership: Astellas, Astellas, Astellas, Astellas
The following people have nothing to disclose: Maria Ostos, Moana Gelu-Sim-
eon, Laetitia A. Johnson, Elina Teicher, Pierre Tattevin, Stephanie Dominguez,
David Zucman, Julie Chas, Pascal P. Crenn, Anne Gervais, Rodolphe Anty,
Faroudy Boufassa, Inga Bertucci, Laurence Meyer, Jean-Charles Duclos-Vallée
699
Hepatitis C Virus Infection is an Independent Predictor
of Post-Liver Transplant Diabetes: Data from the U.S.
Scientific Registry of Transplant Recipients
Zobair Younossi1,3, Maria Stepanova1,3, Sammy Saab2, Gregory
Trimble1,3, Alita Mishra1,3, Shirley K. Kalwaney3, Zahra Youno-
szai3, Fatema Nader1,3, Linda Henry1; 1Center for Liver Disease,
Department of Medicine, Inova Fairfax Hospital, Falls Church, VA;
2Departments of Medicine and Surgery, David Geffen School of
Medicine at University of California at Los Angeles, Los Angeles,
CA; 3Betty and Guy Beatty Center for Integrated Research, Inova
Health System, Falls Church, VA
BACKGROUND AND AIM: Hepatitis C virus (HCV) is asso-
ciated with insulin resistance and type 2 diabetes through
various viral and host mechanisms. Whether HCV infection is
associated with an increased risk of post-transplant diabetes in
liver transplant recipients is unclear. METHODS: All adult liver
transplant recipients mono-infected with hepatitis C (exposed
cohort) or hepatitis B (controls) from the Scientific Registry of
Transplant Recipients (SRTR) with annually recorded post-trans-
plant diabetes status, without other causes of chronic liver dis-
ease who were discharged alive post-transplant were included
(2002-2012). RESULTS: A total of 17,121 liver transplant
recipients with HCV and 1,450 HBV controls were included.
Patients with HCV were older (54.2±7.0 vs. 52.3±10.8 years),
predominantly Caucasian (71.6% vs. 35.7%), less likely Asian
(2.2% vs. 42.1%), and less likely male (74.5% vs. 78.8%) (all
p<0.0005). HCV patients were also more likely to be obese
at time of transplant (BMI ≥30: 32.5% vs. 20.2%, p<0.0001).
However, the rate of pre-transplant diabetes was similar
between HCV (13.7%) and HBV (15.1%) (p>0.05). Pre-trans-
plant MELD scores and post-transplant immunosuppressive
regimens were also similar between the two cohorts. In the
post-transplant follow-up (mean 27.6 months), 32.5% of HCV
and 27.5% of HBV patients developed diabetes (p<0.0001).
This difference was observed starting as early as 6 months
post-transplant: 22.5% HCV and 18.9% HBV (p=0.0043).
With longer follow-up, both cumulative and incidental risks of
developing post-transplant diabetes were consistently higher
in HCV patients. In particular, by 5 years post-transplant,
both the relative risk of having diabetes (RR (95% CI) = 1.18
(1.08-1.29), p=0.0002) and the hazard ratio for the time to
develop diabetes (HR = 1.27 (1.15-1.41), p<0.0001) were
higher in HCV compared to HBV. Long-term diabetes (diabetes
that did not resolve after the first year of transplant) was also
more prevalent with HCV infection: RR = 1.29 (1.04-1.60),
p=0.0209. Hepatitis C infection was independently asso-
ciated with development of post-transplant diabetes: aHR =
1.55 (1.34-1.79), p<0.0001 in multivariate analysis. Other
predictors of post-transplant diabetes included older age at
transplant, non-Caucasian race/ethnicity, being obese, having
540A AASLD ABSTRACTS
diabetes before transplant, and the use of steroids for immuno-
suppression (p<0.05). CONCLUSIONS: Hepatitis C infection
is associated with higher risk of post-transplant diabetes. Care-
ful assessment and management for post-transplant diabetes
must be considered for patients infected with HCV.
Disclosures:
Sammy Saab - Advisory Committees or Review Panels: BMS, Gilead, Merck,
Genentech; Grant/Research Support: Merck, Gilead; Speaking and Teaching:
BMS, Gilead, Merck, Genentech, Salix, Onyx, Bayer, Janssen; Stock Share-
holder: Salix, Johnson and Johnson, BMS, Gilead
The following people have nothing to disclose: Zobair Younossi, Maria Ste-
panova, Gregory Trimble, Alita Mishra, Shirley K. Kalwaney, Zahra Younoszai,
Fatema Nader, Linda Henry
700
Sustained Virologic Responses with Nitazoxanide Ther-
apy in Recurrent Hepatitis C (genotype 1) Infection Post
Liver Transplantation
Marshall E. McCabe1, Saurabh Agrawal2, Marco A. Lacerda2,
A. Joseph Tector3, Paul Y. Kwo2, Marwan Ghabril2; 1Medicine,
Indiana University, Indianapolis, IN; 2Gastroenterology and Hepa-
tology, Indiana University, Indianapolis, IN; 3Transplant Surgery,
Indiana University, Indianapolis, IN
Background: Pegylated interferon/Ribavirin (PEG-IFN/RBV)
based therapy for hepatitis C infection (HCV) recurrence post
liver transplantation (LT) had limited efficacy. Prior to the advent
of direct acting agents, there was a critical need to improve
treatment responses. Nitazoxanide (NTZ) has demonstrated
efficacy in genotype 4 infection. Despite significant interest
in its role at the time, there has been very limited data on its
use in genotype 1 infection, or in post LT recurrence. Aim: To
describe our centers experience with NTZ in post LT HCV recur-
rence. Methods: When used at our center, NTZ was prescribed
off-label in prior non-responders or in patients with aggres-
sive disease, such as early cholestatic HCV recurrence. NTZ
was mainly used as lead in therapy for PEG-IFN/RBV. Demo-
graphics, clinical, immunosuppression and virologic data in LT
recipients treated with NTZ/PEG-IFN/RBV were collected for
descriptive analysis. The primary endpoint was sustained viro-
logic response (SVR). Results: Nineteen patients were treated
with NTZ, 2 were excluded for introduction of telaprivir to the
course of treatment. The study group included 17 patients,
mean age 50±4 years, including 13 (76%) males (13 (76%
) Caucasian, 2 (12%) Black, and 2 (12%) Hispanic), all had
HCV genotype 1. NTZ was used in 13 (76%) prior non-re-
sponders and in 4 (23%) patients as part of their first course
of HCV treatment post LT. Of the 13 non-responders, 9 (69%)
were converted from tacrolimus to cyclosporine due to severity
of HCV recurrence and 6 (46%) had advanced fibrosis prior
to NTZ therapy. NTZ was introduced at 4.9±3.4 years post
LT, as 4 week lead-in 10 (77%) and extended a further 4-16
weeks in 3 (23%) cases. Five (38%) patients previously had
a <1 log and 4 (31%) had a >2log drop in viral load, none
had cleared virus on prior PEG-IFN/RBV, and 5 (38%). With
NTZ/PEG-IFN/RBV 1 (8%) patient had <1 log and 5 (38%)
had >2 log drop in viral load, with the latter 5 clearing HCV
on treatment and 4 achieving SVR (31%), 2 with advanced
fibrosis. Of the 4 treatment naïve patients post-LT receiving 4
week lead-in NTZ and PEG-IFN/RBV, 2 (cyclosporine) were
treated for cholestatic HCV infection with <2 log response. Two
patients (on tacrolimus) were treated 4-5 years post LT, without
advanced fibrosis. Both cleared HCV on therapy, but 1 died
before completing therapy (due to de novo malignancy) and 1
died after completing therapy but before SVR was established
(due to pulmonary hemorrhage). Conclusion: LT recipients with
HCV genotype 1 recurrence but without access to or success
HEPATOLOGY, October, 2014
of direct acting agents, who are being considered for PEG-IN/
RBV may benefit from NTZ lead-in therapy.
Disclosures:
Paul Y. Kwo - Advisory Committees or Review Panels: Abbott, Novartis, Merck,
Gilead, BMS, Janssen; Consulting: Vertex; Grant/Research Support: Roche, Ver-
tex, GlaxoSmithKline, Merck, BMS, Abbott, Idenix, Vital Therapeutics, Gilead,
Vertex, Merck, Idenix; Speaking and Teaching: Merck, Merck
Marwan Ghabril - Grant/Research Support: Salix
The following people have nothing to disclose: Marshall E. McCabe, Saurabh
Agrawal, Marco A. Lacerda, A. Joseph Tector
701
Early Safety and Efficacy Profiles of Renal Transplant
Recipients with Chronic Hepatitis C Treated with Sofos-
buvir and Ribavirin
Genevieve Huard1, Brian Kim1, Anna Patel1, Badr Aljarallah1,
Ponni Perumalswami1,2, Joseph A. Odin1,2, Sara Geatrakas2,3,
Jawad Ahmad1,2, Douglas Dieterich1, Vinay Nair2,3, Thomas
D. Schiano1,2, Gene Y. Im1,2; 1Medicine, Division of Liver Dis-
eases, Icahn School of Medicine at Mount Sinai, New York, NY;
2Recanati-Miller Transplantation Institute, Icahn School of Medicine
at Mount Sinai, New York, NY; 3Medicine, Division of Nephrol-
ogy, Icahn School of Medicine at Mount Sinai, New York, NY
Introduction: Treatment (Tx) of Hepatitis C Virus (HCV) infection
in kidney transplant (KT) recipients with interferon (IFN)-based
regimens has been contra-indicated. IFN-free therapies with
good safety profiles offer the opportunity of HCV Tx after KT
for the first time. Aim: To determine the safety and efficacy of
sofosbuvir (SOF) and ribavirin (RBV) in KT recipients. Methods:
All HCV positive patients who underwent a KT from January
2000 to December 2013 at Mount Sinai Medical Center were
identified and offered referral to a hepatologist. KT recipients
with negative HCV viral load (VL), GFR <30 ml/min and hemo-
globin <10 g/dl were excluded. Tx guidelines were devised
by the authors and distributed to KT and hepatology providers.
Eligible patients received SOF 400 mg daily and renally dosed
RBV for 24 weeks. Baseline and on-Tx clinical data were pro-
spectively gathered. Results: Of the 67 identified KT recipients
eligible for HCV Tx, 48 (72%) agreed to be referred for Tx con-
sideration and 34 (51%) were evaluated by a hepatologist. Tx
plan was initiated for 21/34 (62%) patients. Tx was deferred
in 11 patients due to non-adherence (n=2, 6%) or early dis-
ease (n=9, 27%). Two patients (6%) are being considered for
Tx at another facility. All patients had HCV genotype 1 (1a:
63%, 1b: 37%) with a median pre-Tx VL of 2.8 million IU/ml.
Among, the 21 Tx patients, SOF/RBV was started in 8 (38%)
and 13 (62%) are in the process of SOF/RBV acquisition.
Among the 8 Tx patients, the median age was 65 years, time
since KT was 46.7 months, and pre-Tx GFR was 57.8 ml/min.
One patient had a combined liver-KT, 1 had a previous liver
transplant and 3 patients had cirrhosis based on imaging. In 5
patients with Tx week 2 data, the median VL was 794 IU/mL.
One patient is currently at Tx week 8 with undetectable VL. Two
(25%) patients stopped Tx: one at week 3 due to pruritus and
another at day 9 due to myalgia. One patient required RBV
dose reduction and erythropoietin injection for anemia. No
serious adverse events have been observed thus far. In the 5
patients with week 2 data, there was no statistically significant
difference in median hemoglobin levels (p=0.121), creatinine
(p=0.563) or tacrolimus troughs levels (p=0.222) at the start of
Tx as compared to Tx week 2. No patient required tacrolimus
dose adjustment. Conclusion: With use of a recommended
treatment guideline, this single-center study demonstrates the
good early safety and efficacy profiles of SOF and RBV in
patients with chronic HCV after KT. While low rates of adverse
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS 541A

events and dose adjustments have been seen early in treat- Figure1 shows expression of Tregs, TGF-β, IL-10 and IFN-γ in
ment, long-term follow-up results will be reported. peripheral blood in AVH-B and DNVH-B-OLT patients. Figure2
Disclosures: shows expression of intrahepatic T lymphocyte subsets. Figure3
Joseph A. Odin - Advisory Committees or Review Panels: Bristol Meyers Squibb, shows correlations between the frequencies of the Tregs and HBV
AbbVie DNA, ALT, HAI scores and prognosis.
Douglas Dieterich - Advisory Committees or Review Panels: merck, Idenix, Jans-
sen ; Consulting: Gilead, BMS
Thomas D. Schiano - Advisory Committees or Review Panels: vertex, salix, merck,
gilead, pfizer; Grant/Research Support: massbiologics, itherx
The following people have nothing to disclose: Genevieve Huard, Brian Kim,
Anna Patel, Badr Aljarallah, Ponni Perumalswami, Sara Geatrakas, Jawad
Ahmad, Vinay Nair, Gene Y. Im

702
T Regulatory Cells in De Novo Hepatitis B Virus Infection
after Liver Transplantation
Yinjie Gao1, Min Zhang1, Jingmin Zhao2, Hanwei Li3; 1Department
of liver transplantation and research center. internal medicine, Bei-
jing 302 hospital, Beijing, China; 2Department of Pathology and
Hepatology, Beijing 302 hospital, Beijing, China; 3Department of
Liver Cirrhosis, Beijing 302 hospital, Beijing, China
Objective To observe the expression of T lymphocyte subsets
including CD3+, CD4+, CD8+ and CD4+CD25+ T regulatory
cells (Tregs) in De Novo Hepatitis B Virus infected patients after
orthotopic liver transplantation (DNVH-B-OLT), and analyze the
correlation between the expression and inflammatory activity.
Methods Liver biopsies were collected from 12 DNVH-B-OLT,
12 acute Hepatitis B Virus Infected patients (AVH-B) and 12
health controls (HC). Use Flow cytometry and ELISA kit to detect
Tregs, IL-10, TGF-β and IFN-γ in peripheral blood. Immunohis-
tochemistry was used to analyze intrahepatic T lymphocyte
subsets. Results Compared to AVH-B patients, Tregs, TGF-β
and IL-10 clearly increased, IFN-γ decreased in peripheral
blood, and intrahepatic CD3+, CD4+, CD8+T cells decreased
and Tregs expression enhanced in DNVH-B-OLT patients. The
differences were statistically significant. Tregs were positively
correlated with HBV DNA load, and negatively correlated
with HAI scores and ALT. The Tregs level in HBV-clearance
patients was obviously lower than that in non-HBV-clearance
patients. Conclusion In DNVH-B-OLT patients, the quantity of
Tregs increased in liver tissues and peripheral blood, which
suppressed immune inflammation reaction; the number of
CD3+, CD4+, CD8+T cells decreased, which on the other
hand inhibited ability of specific HBV clearance and led to
immune escape and chronicity.

Disclosures:
The following people have nothing to disclose: Yinjie Gao, Min Zhang, Jingmin
Zhao, Hanwei Li
542A AASLD ABSTRACTS
703
The long-term efficacy of combination of nucleos(t)ide
analogue treatment and low dose hepatitis b immuno-
globulin on posttransplant HBV recurrence
Ramazan Idilman1, Murat Akyildiz2, Onur Keskin1, Ali Tuzun1,
Tonguc U. Yilmaz2, Necdet Guler2, Onur Yaprak2, Gokhan Gun-
gor2, Yalcin Erdogan2, Murat Dayangac2, Deniz Balci3, Kubilay
Cinar1, Acar Tuzuner3, Selcuk Hazinedaroglu3, Yaman Tokat2,
Sadik Ersoz3, Abdulkadir Dokmeci1; 1Gastroenterology, Ankara
University School of Medicine, Ankara, Turkey; 2Istanbul Bilim Uni-
versity Faculty of Medicine, Sisli Florence Nightingale Hospital
Organ Transplantation Center, Istanbul, Turkey; 3Ankara Univer-
sity School of Medicine, Ankara, Turkey
Aim and Background: The aim of the present study was to
determine the long-term efficacy of nucleos(t)ide analogue
(NUC) treatment and low dose hepatitis B immunoglobulin
(HBIG) combination therapy for preventing posttransplant hep-
atitis B virus (HBV) recurrence. Material and Methods: Between
January 1, 1990 and December 31, 2012, a total of 296
HBV-infected patients (M/F: 246/50; median age: 52 years),
who underwent liver transplantation (LT) in two different Trans-
plantation Units, was included. Immunosuppressive protocol
consisted of tacrolimus, mycophenolate mofetil and steroid.
Steroids were gradually tapered for 24 weeks and discon-
tinued for 48 weeks after LT. HBV recurrence was defined as
reappearance of HBsAg positivity and HBV DNA detectability
during post-LT period. A combination of a daily single NUC
treatment and intravenous (i.v.) hepatitis B immunoglobulin
(HBIG) was used in an attempt to eliminate the HBV recurrence.
HBIG was initiated at a dose of 4.000-10.000 IU i.v during
anhepatic phase maintained at dose of 1.000-2.000 IU for 7
days, followed 2.000 IU weekly. After the patient discharged,
HBIG was adjusted to maintain the hepatitis B surface antibody
(antiHBs) titer at more than 100 IU/L (average doses of 2.000
IU monthly). Results: Median follow-up period after liver trans-
plantation was 46 months. Causes of LT were HBV-induced
cirrhosis in 191 patients (65%), HBV-induced acute liver failure
in 10 patients (3%), and delta virus-induced cirrhosis in 95
patients (32%). At the time of the LT, 9% of the patients were
HBeAg positive, 33% had detectable serum HBV DNA level,
43% had hepatocellular carcinoma (HCC), and median MELD
score was 15. After LT, 65% of the patients were treated with
lamivudine (LMV), 9% adefovir dipivoxil (ADV), 12% entecavir
(ETV), 28% tenofovir disoproxil fumarate (TDF). The majority of
the patients (75%) were on tacrolimus based triple combination
therapy (Tacrolimus+MMF+ Prednisone). HBV recurrence was
occurred in 8 patients (2.7%). HBV recurrent patients were
older (p=0.005) and had longer post transplantation period
(p= 0.031). Among them, 7 had HCC, 1 had HDV coinfec-
tion, and 2 had detectable serum HBVDNA levels prior to LT.
Four patients were on LMV, 2 LMV+ADV, 1 ADV and 1 ETV.
Overall, 44 patients died due to post-transplant complications
or HCC recurrence and its progression. Two of them had HBV
recurrence. The overall survival rate was 85%. No patients
underwent re-transplantation because of HBV-induced graft fail-
ure. In conclusion, based on the result of the present study, a
combination of NUC treatment and low dose HBIG is efficient
in long-term prophylaxis of HBV recurrence after LT.
Disclosures:
The following people have nothing to disclose: Ramazan Idilman, Murat Akyildiz,
Onur Keskin, Ali Tuzun, Tonguc U. Yilmaz, Necdet Guler, Onur Yaprak, Gokhan
Gungor, Yalcin Erdogan, Murat Dayangac, Deniz Balci, Kubilay Cinar, Acar
Tuzuner, Selcuk Hazinedaroglu, Yaman Tokat, Sadik Ersoz, Abdulkadir Dokmeci
HEPATOLOGY, October, 2014
704
Efficacy of protease inhibitor in combination with
pegylated interferon and ribavirin to treat hepatitis C
after living donor liver transplantation
Satoshi Miuma, Tatsuki Ichikawa, Hisamitsu Miyaaki, Naota
Taura, Kazuhiko Nakao; Department of Gastroenterology and
Hepatology, Nagasaki university hospital, Nagasaki, Japan
Background and Aim The pegylated interferon plus ribavirin
(PEG-IFN/R) therapy against hepatitis C virus (HCV) reinfection
in living donor liver transplantation (LDLT) patients is difficult.
Recently PEG-IFN/R plus protease inhibitor (teraprevir or sime-
previr) therapy has been used and produced excellent results
for non-transplanted patients with HCV. However there are
limited data on treatment of HCV reinfection with PEG-IFN/R
plus protease inhibitor in LDLT patients. Our aim of this study is
to evaluate the prognosis-improving of patients who achieved
Sustained viral response (SVR) by IFN therapy and present
the possibility that PEG-IFN/R plus protease inhibitor therapy
might contribute to prognosis-improving by their strong anti-
viral effects. Methods This study included eighty-six patients
underwent HCV-related LDLT from Aug 2000 to Jan 2013
in Nagasaki university hospital. Thirty patients were treated
with PEG-IFN/R therapy, four patients with PEG-IFN/R plus
teraprevir therapy and eight with PEG-IFN/R plus simeprevir
therapy. Other thirty-four patients didn’t receive IFN therapy.
The prognosis of patients who had achieved SVR was com-
pared with that of non-SVR to assess the prognosis-improving
in the LDLT patients with SVR. Furthermore, the therapy effect
of PEG-IFN/R with or without protease inhibitor was examined
at 4 weeks and 12 weeks after treatment. Results Eight of thirty
(26.6%) achieved SVR by PEG-IFN/R. Their mean duration of
therapy for SVR was 747 days. Survival rate of patients who
achieved SVR was higher than non-SVR significantly (p=0.046)
(3-years survival rate: SVR 100.0%, non-SVR 75.4%, 5-years
survival rate: SVR 100.0%, non-SVR 53.8%). Rapid virologi-
cal response (RVR) and Complete early virological response
(cEVR) were obtained in 5.9% (3/51 therapy sessions) and
13.7% (7/51) of patients treated with PEG-IFN/R. On the
other hand, RVR rate was 100.0% (4/4) with PEG-IFN/R plus
teraprevir and 100.0% (8/8) with PEG-IFN/R plus simepre-
vir, and cEVR rate was 100.0% (4/4) with PEG-IFN/R plus
teraprevir and 80.0% (4/5) with PEG-IFN/R plus simeprevir.
Conclusion The achievement of SVR by PEG-IFN/R therapy in
HCV-related LDLT patients bring good prognosis after LDLT and
the PEG-IFN/R plus protease inhibitor indicate strong anti-viral
effect compared with PEG-IFN/R. It is expected that PEG-IFN/R
plus protease inhibitor improve the prognosis of HCV-related
LDLT patients.
Disclosures:
The following people have nothing to disclose: Satoshi Miuma, Tatsuki Ichikawa,
Hisamitsu Miyaaki, Naota Taura, Kazuhiko Nakao
705
Post-transplant Treatment of Severe Recurrent Hepatitis
C (HCV) with Daclatasvir and Sofosbuvir Plus or Minus
Ribavirin
Natalie H. Bzowej, Shobha Joshi, George Therapondos, Nigel
Girgrah, Gia Tyson, Inna Goldvarg-Abud, Jennifer B. Scheuer-
mann, Humberto E. Bohorquez, Ari J. Cohen, Ian C. Carmody,
Trevor W. Reichman, David S. Bruce, George E. Loss; MultiOrgan
Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA
Background: Recurrent HCV is universal after liver transplant
(OLT) and progression to cirrhosis is rapid. Fibrosing choles-
tatic hepatitis (FCH) is a rare form of HCV recurrence associ-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
ated with graft failure/death and its treatment with pegylated
interferon is rarely successful and difficult to tolerate. Aims:
To describe the use of an IFN-free regimen in severe recurrent
hepatitis C post-OLT. Methods: One retransplant (A) and 5
primary OLT recipients (B-F) were treated: 3 with FCH(A-C),
1 with decompensated recurrent cirrhosis (D), 1 with acute
lobular hepatitis (E), 1 with cholestatic lobular hepatitis. Sofos-
buvir (SOF) 400 mg/day, plus Daclatasvir (DCV) 60 mg/day,
were co-administered for 24 wks. Patient C also received a
lead-in with peg-IFN plus ribavirin (RBV) and RBV was con-
tinued for an additional 24 wks. Pt E received one month of
SOF/RBV prior to initiating SOF/DCV. Pre-treatment MELD
scores ranged 12-19. All had G1a. Results: Interim analysis
(see table): Within 2 wks of initiating treatment with SOF/
DCV serum HCV RNA levels fell dramatically. Within 4 wks,
hyperbilirubinemia improved and liver enzymes normalized.
Blood levels of tacrolimus remained stable and therapy was
well tolerated. Conclusion: The rapid suppression of HCV with
novel oral antiviral regimens post-OLT, reverses the changes of
FCH and liver decompensation and provides great promise for
severe recurrent HCV.
HCV Viral Loads During Treatment
*qualitative HCV RNA positive; **qualitative HCV RNA nega-
tive; NYD=not yet done
Disclosures:
Natalie H. Bzowej - Grant/Research Support: Gilead Sciences, Ocera Thera-
peutics
Shobha Joshi - Grant/Research Support: Salix, Eisai; Speaking and Teaching:
Merck, Gilead, Bristol-Myers Squibb
George Therapondos - Grant/Research Support: Gilead, Biotest
Nigel Girgrah - Speaking and Teaching: Merck, Bayer, Vertex, Gilead, Merck,
Bayer, Vertex, Gilead, Merck, Bayer, Vertex, Gilead, Merck, Bayer, Vertex,
Gilead
Jennifer B. Scheuermann - Advisory Committees or Review Panels: Gilead, Jans-
sen, AbbVie, Vertex; Speaking and Teaching: Gilead, Janssen, AbbVie, Merck,
Vertex
The following people have nothing to disclose: Gia Tyson, Inna Goldvarg-Abud,
Humberto E. Bohorquez, Ari J. Cohen, Ian C. Carmody, Trevor W. Reichman,
David S. Bruce, George E. Loss
706
Sofosbuvir + Simeprevir is Safe in Liver Transplant
Recipients
Fredric D. Gordon, Andreana L. Kosinski, Sheila J. Coombs, Pau-
line Goucher, Emad S. Aljahdli, Elizabeth A. Pomfret; Department
of Hepatobiliary Surgery/Liver Transplant, Tufts Medical School,
Lahey Clinic Medical Center, Burlington, MA
An interferon-free treatment regimen, sofosbuvir (Sof) + sime-
previr (Sim), has been shown to be highly effective in hepatitis
C infected patients, curing over 94% of those treated for 12
weeks with minimal toxicities. Neither Sof nor Sim are antici-
pated to have significant drug-drug interactions with the stan-
dard immunosuppressive agents used for liver transplant (LT)
recipients. In this pilot study we sought to determine the safety
and efficacy of 12 weeks of Sof/Sim in a group of LT recipi-
543A
ents. The student t-test was applied where appropriate. METH-
ODS: 17 LT recipients with HCV genotype 1 were started on
Sof 400mg daily and Sim 150mg daily between January and
May, 2014. Patients were seen 2, 4, 8, and 12 weeks after
initiating treatment. The median followup was 8 weeks (range
2-12 weeks). The median pre-treatment fibrosis score was
2 (range 0-4) and there was 1 cirrhotic patient. 14 patients
were on tacrolimus, 2 on cyclosporine, and 1 on rapamycin.
RESULTS: Pre-treatment tacrolimus levels were 6.7 ± 2.05 and
on-treatment levels were 5.72 ± 2.35, p=NS. Immunosuppres-
sion doses remained unchanged in all except one patient who
required a dose reduction in tacrolimus from 2mg bid to 1mg
bid. Creatinine levels remained unchanged (pre-treatment:
1.31 ± 0.40 vs. on-treatment: 1.39 ± 0.44, p=NS) throughout
treatment. The largest increase in creatinine was 0.3 mg/dl.
Similarly, hemoglobin did not change (pre-treatment: 13.3 ±
2.21 vs. on-treatment: 13.3 ± 2.12, p=NS) throughout treat-
ment. The largest decrease in hemoglobin was 1.9 g/dl. 8 of
17 (47%) reported no side effects at all during treatment. 4
patients (24%) had gastrointestinal side effects, 2 (12%) had
headache, 2 (12%) had pruritus, 2 (12%) had myalgias, and
2 (12%) had non-life-threatening hyperkalemia. No patient
stopped treatment prematurely. 5/5 (100%) are HCV RNA
undetectable at end of treatment. CONCLUSIONS: 1) Sof/Sim
is well tolerated in liver transplant recipients. 2) Sof/Sim had
no impact on tacrolimus levels, creatinine, or hemoglobin. 3)
Complete efficacy data is pending but further investigation of
Sof/Sim in liver transplant recipients is warranted.
Disclosures:
The following people have nothing to disclose: Fredric D. Gordon, Andreana
L. Kosinski, Sheila J. Coombs, Pauline Goucher, Emad S. Aljahdli, Elizabeth A.
Pomfret
707
Telbivudine is associated with improvement of renal
function in patients after liver transplantation
Evangelos Cholongitas1, Themistoklis Vasiliadis1, Ioannis Goulis1,
Ioannis Fouzas2, Vasileios Papanikolaou2, Evangelos A. Akriv-
iadis1; 14th Department of Internal Medicine, Medical School of
Aristotle University, Thessaloniki, Greece; 2Department of Trans-
plant Surgery, Aristotle Uuniversity of Thessaloniki, Thessaloniki,
Greece
Background: Recent studies showed that telbivudine-treated
patients with hepatitis B virus (HBV) infection improved their
renal function (Gane E, Gastroenterology 2013), but data
regarding the impact of telbivudine on renal function in liver
transplant recipients are very limited. Aim: to evaluate the effi-
cacy, safety and impact on renal function of telbivudine in
patients who underwent liver transplantation (LT) for HBV cirrho-
sis Methods: 17 consecutive recipients (group 1; 14 men, age:
58±5 years, 4.2±2.1 years after LT) without HBV recurrence
after LT received at baseline nucleos(t)ide analogue(s) (NAs)
other than telbivudine (lamivudine±adefovir: 4, tenofovir:13
patients) for 12 months and then they were switched to telbivu-
dine monoprophylaxis for another 12 months. In each patient,
laboratory data including evaluation of eGFR (using MDRD
and CKD-EPI formulae) were prospectively recorded. The
changes GFR (ΔGFR) between baseline and after 12 months
(1st period) and between telbivudine initiation and 24 months
(2nd period) were evaluated. Results: all patients remained
with normal liver function tests, HBsAg negative and undetect-
able serum HBV DNA by PCR. None of the patients developed
adverse event related to antiviral prophylaxis. eGFRs based
on MDRD at baseline, 12 months and last follow up were
72±18, 67.8±16 and 71.5±17mL/min, respectively (p=0.039
544A AASLD ABSTRACTS
for comparison between 12 months and 24 months). Improve-
ment in eGFR (ΔGFR>0) was observed in 7 (41%) and 13
(76%) of the 17 recipients in the 1st and 2nd period, respec-
tively (p=0.06). ΔGFR at the 1st period was significantly lower,
compared to ΔGFR at the 2nd period [mean ΔGFR based on
MDRD: -4.2 (range: -24 – 9) vs 3.7 (range: -8 – 19) mL/min,
p=0.022; mean ΔGFR based on CKD-EPI: -4.7 (range: -19 –
10) vs 5 (range: -6 – 26) mL/min, p=0.004]. These differences
remained significant when the % changes at 1st and 2nd peri-
ods were evaluated [ΔGFR based on MDRD: -3.8% vs 3.1%,
p=0.02; ΔGFR based on CKD-EPI: -5% vs 6.6%, p=0.002],
although the serum levels of CNIs were similar between the two
periods (cyclosporine: 108±42 vs 106±35ng/mL, respectively,
p=0.85; tacrolimus: 6.2±2.1 vs 5.8±2.5ng/mL, respectively,
p=0.42). Conclusion: we showed for the first time that telbivu-
dine administration in LT recipients for HBV cirrhosis was asso-
ciated with significant improvement in renal function, but this
remains to be confirmed in larger well-designed studies.
Disclosures:
The following people have nothing to disclose: Evangelos Cholongitas, The-
mistoklis Vasiliadis, Ioannis Goulis, Ioannis Fouzas, Vasileios Papanikolaou,
Evangelos A. Akriviadis
708
Survey on Pre- and Post-Transplant Management of
Hepatitis C: Response from Medical Directors of US
Transplant Programs
Paul J. Gaglio, Carly E. Glick, John F. Reinus; Medicine, Albert
Einstein College of Medicine, Bronx, NY
Introduction: End-stage liver disease from hepatitis C (HCV)
remains the most common indication for liver transplantation
in the United States, with graft infection occurring universally
in patients who are viremic at the time of transplantation.
Strategies to manage HCV are evolving; we hypothesize that
pre- and post-transplant management of HCV infection differs
significantly among US liver transplantation centers. Methods:
An electronic survey designed to collect information about pre-
and post-transplantation hepatitis-C management was sent to
the Medical Directors of all US liver-transplantation programs.
The survey was sent prior to FDA approval of Simeprevir and
Sofosbuvir. Results: 37 of 110 (34%) responded to the survey.
65% stated that they routinely treat hepatitis C prior to liver
transplantation; 25% required HCV-RNA negativity pre-op.
95% of respondents stated that they would use a liver from an
HCV-positive donor for an HCV-positive recipient, and 93%
would re-transplant a patient with graft failure due to hepatitis
C, although most respondents would not re-transplant a patient
less than one year after initial transplant. 62% used an alter-
native immunosuppression strategy in HCV-infected patients,
most commonly a smaller post-operative steroid bolus and a
rapid steroid taper. 64% preferred tacrolimus to cyclosporine
for immunosuppression in patients with hepatitis C. 87% per-
formed protocol biopsies at specific time points after trans-
plantation. The trigger to treat HCV was > stage 2 (Metavir)
fibrosis (97%), cholestatic hepatitis C (81%), and increased
liver enzymes (19%). Treatment included antiviral therapy
(97%), discontinuing or decreasing the prednisone and myco-
phenolate doses (35 and 32% respectively), and conversion
from tacrolimus to cyclosporine (30%). Post transplant anti-viral
therapies included a protease inhibitor/peg/riba (72%) and
peg/riba (28%). Regarding use of sofosbuvir (sof) or simepre-
vir (sim) pre-transplantation, 62% of respondents would use
sof/riba, 32% sof/peg/riba and 8% sim/peg/riba pre-trans-
plant in a patient with genotype-1 infection. Related to all-oral
HCV treatment regimens; 78% would use such a regimen; 51%
HEPATOLOGY, October, 2014
pre-transplant, 19% immediately post-transplant and 30% in
patients with clinically significant HCV recurrence in the graft.
Conclusions: Pre- and post-transplantation management of hep-
atitis C varies significantly. Respondents appear willing to use
both recently FDA-approved and future interferon-free therapies
to reduce HCV replication pre-and post-transplantation.
Disclosures:
Paul J. Gaglio - Advisory Committees or Review Panels: Merck, Vertex, Salix, BI,
BMS, Janssen; Grant/Research Support: Merck, Gilead, Vertex, Otsuka, Genen-
tech, BI; Speaking and Teaching: Merck, Gilead, Vertex, Salix, Otsuka, Janssen
The following people have nothing to disclose: Carly E. Glick, John F. Reinus
709
Liver transplantation for patients with HCV-related end-
stage liver disease and undetectable HCV-RNA: the
Turin Centre experience
Alessandro Risso1, Francesco Tandoi2, Silvia Martini1, Renato
Romagnoli2, Mauro Salizzoni2; 1Gastroenterology and Hepatol-
ogy Unit, AOU Città della Salute e della Scienza di Torino, Turin,
Italy; 2Liver Transplantation and General Surgery Unit, AOU Città
della Salute e della Scienza di Torino, Turin, Italy
BACKGROUND: End-stage liver disease caused by hepatitis
C virus (HCV) is a leading indication (40%) for liver trans-
plantation (LT) in Western Countries. Viral recurrence in the
graft is considered “universal” and represents a major cause
of mortality and morbidity after LT. METHODS: We retrospec-
tively analyzed data from the last 14 years regarding patients
with HCV-related liver disease who underwent LT in our Centre
showing undetectable HCV-RNA at blood tests. We looked for
pre-LT predictors of HCV recurrences (both histological and
virological) and we conducted grafts and patients follow-up
until April 2014. RESULTS: 50 patients were included in the
study, 22/50 (44%) being HBV-HCV co-infected. We observed
HCV-RNA recurrence in 8/50 (16%) patients, and histological
recurrence at liver biopsy in 6/50 (12%). At univariate anal-
ysis, co-infection with HBV showed a “protective role” against
HCV recurrence in our patients: 0% had histological recurrence
versus 6/23 (26%) not co-infected patients (p=0.03) and 0%
showed virological recurrence verus 8/21 (38%) not co-in-
fected (p=0.01). Other possible predictors of recurrence (pre-
vious therapies for HCV, patients, grafts and donors conditions
at LT, time of HCV-RNA undetectability…) did not show any sig-
nificance. Nevertheless, at logistic regression the only param-
eter significantly associated with lower histological recurrence
rate was pre-LT HCV-RNA undetectability > 6 months (p=0.02),
irrespective of previous therapies for HCV. Graft was lost in
9/50 (18%) patients: graft survival was 86% at 1 year from LT,
81% at 2, 5 and 10 years. 4/50 (8%) patients died: survival
was 96% at 1 year from LT, 91% at 2, 5 and 10 years. No
significant predictors of mortality and lost of graft were found
among HCV-related variables. CONCLUSIONS: In patients
with HCV-related liver disease and undetectable HCV-RNA at
LT the HCV recurrence rates are far lower than those observed
in HCV-RNA positive patients. The only variable strongly asso-
ciated with lower HCV recurrence rate seems to be a pre-LT
period of HCV-RNA undetectability > 6 months, irrespective of
previous therapies for HCV. In our cohort, grafts and patients
survival rates after LT are comparable to those observed in
patients without an history of HCV infection, and no HCV-re-
lated variable affect these rates. A curious issue is the hypo-
thetical “protective role” from HCV recurrence that some data
suggest for HBV-HCV co-infection.
Disclosures:
The following people have nothing to disclose: Alessandro Risso, Francesco
Tandoi, Silvia Martini, Renato Romagnoli, Mauro Salizzoni
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
710
Safety and Efficacy of Hepatitis C Therapy with Sofosbu-
vir and Simeprevir after Liver Transplantation
Julio A. Gutierrez1,2, Alla Grigorian1,2, Andres F. Carrion1,2,
Michael D. Schweitzer1, Danny J. Avalos1, Kalyan R. Bhami-
dimarri1,2, Adam Peyton1,2; 1Hepatology, University of Miami,
Miami, FL; 2Miami Transplant Institute, Miami, FL
Introduction: Treatment of the hepatitis C virus (HCV) post-liver
transplantation has been notoriously difficult. In this population,
drug-drug interactions often have serious consequences and
immunosuppressant therapy may make viral eradication more
difficult. The interferon-free regimen used in the COSMOS
study combined two Direct Acting Antivirals (DAAs), sofosbuvir
and simeprevir. Early data suggests that it appears safe and
effective in non-cirrhotic and cirrhotic individuals. Little data is
available on the safety and efficacy of this treatment in patients
post-liver transplant. Here we describe our experience using
sofosbuvir and simeprevir in patients after liver transplant.
Methods: This was an IRB approved retrospective analysis.
Thirty-two patients who underwent liver transplantation were
started on a 12-week course of sofosbuvir and simeprevir. Two
patients were also given ribavirin. Basic laboratory data, viral
kinetics, side effects, and changes in immune suppression were
recorded. Only patients infected with GT 1a (55%) or 1b (45%)
were included. SVR 12 data will be available at time of presen-
tation. Statistics performed using JMP SAS with non-paramet-
ric, parametric or multivariate analysis as deemed necessary.
Results: The mean patient age was 61 years and 63% were
males. The mean time since transplant was 5.6 years and the
median HCV RNA at baseline was 2,604,118 IU/mL. Early
data suggested that this regimen was well tolerated, except in
one patient when simeprevir was discontinued for severe rash.
Another patient required 50% reduction of Prograf because
of elevated serum levels and worsening renal function. End of
treatment (EOT) data was available in 15 patients. All were
negative except one patient with detectable low-level viremia
throughout treatment. Week 4 of treatment data was avail-
able in 26 individuals. 53% of patients had a detectable HCV
RNA was seen and 42% (N=6) of those patients had HCV
RNA levels greater than the lower limit of quantification (LLQ).
Conclusion: Anti-HCV treatment with sofosbuvir and simeprevir
appears generally well tolerated and effective after transplant.
There appears to be delayed viral kinetics post-transplant com-
pared to what has been reported in patients not on immunosup-
pressant therapy. SVR 12 will be key in determining whether
longer treatment courses will be needed. Management of HCV
after transplant may remain a challenge, and more studies are
needed to determine the optimal treatment regimens for this
group of patients.
Disclosures:
The following people have nothing to disclose: Julio A. Gutierrez, Alla Grigorian,
Andres F. Carrion, Michael D. Schweitzer, Danny J. Avalos, Kalyan R. Bhamidi-
marri, Adam Peyton
711
The Combination of Simeprevir and Sofosbuvir for the
Treatment of HCV Infection in Patients Post Liver Trans-
plant With Significant Fibrosis
Idrees Suliman, Renee Pozza, Yaseen Kady, Catherine Hill,
Thomas A. Couturier, Preeti Reshamwala, Tarek Hassanein; South-
ern California Liver Centers, Coronado, CA
HCV infection accounts for >30% of yearly liver transplants
performed in the United States. Post transplant HCV recurrence
is universal and over 10% of patients will develop rapidly pro-
gressive fibrosis of the graft. The combination of Simeprevir
545A
(SIM) and Sofosbuvir (SOF) is recommended by AASLD for
genotype 1. Aim: To evaluate the safety, tolerability, and effi-
cacy of combined therapy with SIM/SOF in improving hepa-
titis (evidenced by improved liver enzymes) and eradicating
HCV (evidenced by negative PCR and SVR12). Subjects:
Ten patients have commenced and seven have completed
the course of treatment. Mean age was 60.7±13.7 with six
males (60%), four patients were treatment experienced, and
all patients had genotype 1A. Prior to treatment mean ALT and
AST were 79.0±44.0 IU/L and 72.4±41.0 IU/L respectively;
mean creatinine was 1.23 mg/dL, and average total bilirubin
was 0.99±0.3 mg/dL. Average Fibrosis score (METAVIR) by
biopsy in the treatment group was 2.5±0.5. Mean time since
liver transplantation was 9.7±5 years with all patients currently
on immunosuppressive regimes that included Tacrolimus with
or without Mycophenolic Acid. Methods: Patients started on
treatment with SIM 150mg daily and SOF 400mg daily for
12 weeks. Results: All patients on treatment had undetectable
levels of HCV RNA by week 4. For patients who completed the
12 week course, SVR4 rates are 100% (table). Further SVR12
data is still pending. In all patients transaminase levels returned
to reference values within 4 weeks after treatment onset. Thus
far treatment courses have been well tolerated and unremark-
able with no significant changes in total bilirubin, and minimal
increase in creatinine. Tacrolimus serum level increased by
25% in three patients. Conclusions: Following transplant the
combination of SIM/SOF treatment has been 1) safe; 2) tolera-
ble; and 3) efficacious in both eliminating HCV and improving
severe hepatitis. Liver transaminases returned to normal limits
in all patients. Although the regime increased Tacrolimus serum
levels by 25% in three patients there were no clinically relevant
toxic side effects.
Disclosures:
Tarek Hassanein - Advisory Committees or Review Panels: AbbVie Pharmaceuti-
cals, Bristol Myers Squibb; Grant/Research Support: Janssen R&D, Bristol-Myers
Squibb, Salix Pharmaceuticals, Sundise Traditional Chinese Pharmaceuticals,
Boehringer-Ingelheim, Vertex Pharmaceuticals, Ikaria Pharmaceuticals, Idenix
Pharmaceuticals, Eiasi Pharmaceuticals, Gilead Sciences, Inc., AbbVie Pharma-
ceuticals; Speaking and Teaching: Bristol Myers Squibb, Gilead Sciences, Inc.,
Baxter, Salix
The following people have nothing to disclose: Idrees Suliman, Renee Pozza,
Yaseen Kady, Catherine Hill, Thomas A. Couturier, Preeti Reshamwala
546A AASLD ABSTRACTS
712
The Mortality of Acute-on-Chronic Liver Failure by
APASL vs. EASL-CLIF definition: A Multicenter, Retro-
spective Cohort Study in Korea (KACLiF Study)
Tae Yeob Kim1,
Dong Joon Kim2,
Do Seon Song3,
Dong Hyun
Sinn4, Eileen L Yoon5, Joo Hyun Sohn1, Chang wook Kim3, Young
Kul Jung6, Ki Tae Suk2, Jin Mo Yang3, Heon Ju Lee7; 1Depart-
ment of Internal Medicine, Hanyang University Guri Hospital,
Guri, Republic of Korea; 2Department of Internal Medicine, Hal-
lym University, Chunchon Sacred Heart Hospital, Gangwon-Do,
Republic of Korea; 3Department of Internal Medicine, Colege of
Medicine, The Catholic University College of Korea, Seoul, Repub-
lic of Korea; 4Department of Internal Medicine, Samsung Medical
Center, Seoul, Republic of Korea; 5Department of Internal Med-
icine, Inje University Sanggye Paik Hospital, Seoul, Republic of
Korea; 6Department of Internal Medicine, Korea University Ansan
Hospital, Ansan, Republic of Korea; 7Department of Internal Med-
icine, Yeungnam University College of Medicine, Daegu, Republic
of Korea
Background: Acute-on-chronic liver failure (ACLF) is defined
differently between Eastern (APASL) and Western countries
(EASL-CLIF). This study aimed to investigate the prevalence
of ACLF according to the APASL vs. EASL-CLIF definitions as
well as short-term mortality and associated factors in patients
with acute decompensation (AD). Methods: We collected
data for 1022 hospitalized patients (male 756, median age
55±12 years) with chronic liver disease (CLD) and AD from
January 2013 to December 2013 from 16 academic hospi-
tals in Korea. The Kaplan-Meier method with log-rank test was
used to calculate short term mortality (28-day and 90-day).
Results: The most common underlying cause of CLD was alco-
hol (63.3%) and the main forms of AD were variceal bleeding
(29.2%), more than one events (20.3%), and ascites (17.2%).
The prevalence of ACLF development based on the APASL and
EASL-CLIF definitions were 158 (15.5%) and 132 (12.9%) at
admission, and 69 (6.8%) and 41 (4.0%) within 28 days of
enrollment, respectively. The 28-day and 90-day mortality were
higher in patients with ACLF at enrollment than in those without
ACLF at enrollment (by APASL definition: 18.4% vs. 4.6%,
and 29.5% vs. 8.6%, respectively, P < 0.001; by EASL-CLIF
definition: 27.3% vs. 3.7%, and 41.7% vs. 7.8%, respectively,
P < 0.001). At the time of admission, of the 242 patients who
satisfied the APASL or EASL-CLIF definition, only 48 (19.8%)
patients satisfied both definitions, while the remaining patients
(81.2%) satisfied only one (with APASL definition, 110 patients;
with EASL-CLIF definition, 84 patients). In patients with ACLF,
the 28-day and 90-day mortality in patients who satisfied both
definitions were higher than in those who satisfied just one
definition (45.8% and 51.3%, respectively). Patients with ACLF
by the APASL definition were significantly different from those
defined by the EASL-CLIF definition in terms of patient charac-
teristics, including higher bilirubin, lower creatinine, frequent
ascites, less frequent encephalopathy, higher Child-Pugh score,
and lower CLIF-SOFA score. Conclusions: The development of
ACLF is associated with high short-term mortality. However,
patient characteristics are significantly different when ACLF is
defined by the two different APASL vs. EASL-CLIF definitions.
Thus refinement of the two ACLF definitions or a consensus
definition is urgently needed.
Disclosures:
Dong Hyun Sinn - Speaking and Teaching: Gilead, Yuhan pharmacy
The following people have nothing to disclose: Tae Yeob Kim, Dong Joon Kim,
Do Seon Song, Eileen L Yoon, Joo Hyun Sohn, Chang wook Kim, Young Kul Jung,
Ki Tae Suk, Jin Mo Yang, Heon Ju Lee
HEPATOLOGY, October, 2014
713
Predicting Progression from Acute Liver Injury to Acute
Liver Failure Using a Machine Learning Algorithm
Jaime L. Speiser1, David G. Koch2, William M. Lee3; 1Public
Health Sciences, Medical University of South Carolina, Charleston,
SC; 2Medicine, Medical University of South Carolina, Charleston,
SC; 3Internal Medicine, University of Texas Southwestern at Dallas,
Dallas, TX
Background: Acute liver injury (ALI) is characterized by severe
liver injury resulting in coagulopathy without encephalopathy
in patients without prior chronic liver diseases. While there are
several prognosis models for acute liver failure (ALF) patients,
there are none available to help identify ALI patients that are
at the highest risk of progressing to ALF. We use the random
forest (RF) statistical procedure to build a prediction model for
ALI patients. A novel machine learning algorithm, RF can better
distinguish important predictors of a given outcome than many
traditional modeling procedures such as logistic regression.
Aim: To derive a model to predict the risk that a patient with
ALI will progress to ALF. Methods: 386 ALI subjects were pro-
spectively enrolled in the ALF Study Group database between
January 2008 and October 2013, defined as follows: INR
≥ 2.0 and ALT ≥ 10x ULN for acetaminophen (APAP) ALI,
or INR ≥ 2.0, ALT ≥ 10x ULN, and bilirubin ≥ 3.0mg/dL for
non-APAP ALI. 82 clinical variables from the database were
entered into the RF for predicting ALI progression to ALF. A
selection procedure which minimizes the prediction error rate
was implemented to determine variables for inclusion in the
model. Analyses were carried out using R software. Results:
Of the 82 variables entered into the model, etiology, INR,
bilirubin, and jaundice days prior to hospital admission were
the most predictive of progression to ALF. The resulting model
yielded an overall prediction accuracy of 73%, sensitivity of
76%, specificity of 73%, and area under the receiver operat-
ing curve of 0.82. Etiologies with higher likelihood of progress-
ing to ALF were autoimmune hepatitis, drug induced liver injury
and indeterminate. APAP overdose, hepatitis B and shock/
ischemia were not as likely to progress to ALF. High values of
INR, bilirubin, and jaundice days prior to hospital admission
were associated with higher likelihood of progressing to ALF.
Conclusions: RF analysis using four readily available clinical
and biochemical variables accurately and efficiently provides
estimates for the probability that ALI patients will progress to
ALF, which will help drive clinical decision making for these
patients. Apart from a patient’s biochemical profile, etiology
still remains an important predictor of outcome. A web applica-
tion of the prediction model is being developed for clinical use.
Future work will need to evaluate the efficacy of treatments that
may prevent progression to ALF and determine their impact on
our predictive model.
Disclosures:
William M. Lee - Consulting: Eli Lilly, Novartis; Grant/Research Support: Gilead,
Roche, Vertex, BI, Anadys, BMS, merck; Speaking and Teaching: Merck
The following people have nothing to disclose: Jaime L. Speiser, David G. Koch
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
714
Development and Validation of the CLIF-C AD score for
the prognosis of patients with acute decompensation
(AD) of cirrhosis not fulfilling diagnostic criteria for
acute-on-chronic liver failure (ACLF)
Rajiv Jalan1, Marco Pavesi2, Faouzi Saliba3, Alex Amorós2, Javier
Fernandez4, Peter Holland-Fischer1, Rohit Sawhney1, Rajesh-
war Mookerjee1, Paolo Caraceni5, Tania M. Welzel6, Richard
Moreau7, Pere Gines4, Francois Durand3, Paolo Angeli8, Carlo
Alessandria9, Wim Laleman10, Jonel Trebicka11, Didier Samuel3,
Stefan Zeuzem6, Thierry Gustot12, Alexander L. Gerbes13, Julia
Wendon14, Mauro Bernardi15, Vicente Arroyo15; 1Institute of
Liver and Digestive Health, Royal Free Hospital, London, United
Kingdom; 2Data Management Center, EASL-CLIF Consortium, Bar-
celona, Spain; 3Hôpital Paul Brousse, Villejuif, France; 4Hospital
Clínic, Barcelona, Spain; 5Policlinico St Orsola Malpighi, Bolo-
gna, Italy; 6J.W Goethe University Hospital, Frankfurt, Germany;
7Hopital Beaujon, Clichy, France; 8University of Padua, Padova,
Italy; 9University of Turin, Torino, Italy; 10University Hospital Gast-
huisberg, Leuven, Belgium; 11University Hospital Bonn, Bonn, Ger-
many; 12Erasme Hospital Brussels, Brussels, Belgium; 13University
of Munich, Klinikum der LMU, Munich, Germany; 14King’s College
Hospital, London, United Kingdom; 15EASL-CLIF Consortium, Bar-
celona, Spain
The CLIF organ failure score (CLIF-C OFs) was developed
to diagnose ACLF and the CLIF-C ACLF score to define their
prognosis (Jalan et al. J Hepatol 2014). Although the 28-day
mortality of the non-ACLF cirrhotic patient with acute decom-
pensation (AD) was only 4.6% in the CANONIC study, the
3, 6 and 12-month mortality were 12.6%, 18.3% and 27.6%
respectively. The aims were to develop and validate the CLIF-C
AD score (CLIF_C ADs) to prognosticate on the patients with
AD but without ACLF and, compare this with the Pugh score,
MELD and MELD-Na scores. METHODS: The derivation set
included 1,016 CANONIC study patients who did not have
ACLF at enrollment. Proportional-hazards models considering
liver transplantation as a competing risk (PH-CR) was used to
identify score parameters. PH-CR models were fitted applying a
forward step-wise selection method. The coefficients estimated
for each factor were used as relative weights to compute the
CLIF-C ADs. Validation was performed on a random sample of
500 patients from the CANONIC non-ACLF group and in 225
non-ACLF cirrhotic patients (London and Barcelona) comparing
the C-index estimates with those obtained for MELDs, MELD-
NAs and CPs. CLIF-C ADs was also validated for sequential
use. RESULTS. Age, serum sodium, Ln white-cell count, Ln creat-
inine and Ln INR were selected as the best predictors of mortal-
ity and used to compute the CLIF-C ADs. The C-index (95%CI)
for prediction of mortality was significantly better for CLIF-C
ADs (Table) in both the derivation (table) and internal vali-
dation sets. CLIF-C ADs also performed better than the Pugh,
MELD and the MELD-Nas at predicting 3- and 12-month mortal-
ity in the external dataset. CLIF-C ADs improved in its ability to
predict 3-month mortality using data from days 2, 3-7 and 8-15
(C-index: 0.72; 0.75 and 0.77 respectively). CONCLUSIONS.
This study describes and validates a new score, the CLIF-C ADs
for sequential use that accurately defines 3-month and 1-year
mortality of non-ACLF hospitalized cirrhotic patients with AD.
The combination of CLIF-C OFs for diagnosis of ACLF, and of
CLIF-C ACLFs and CLIF-C ADs for prognosis provides a novel
algorithm to accurately determine the mortality of a hospital-
ised cirrhotic patient that can be updated sequentially.
547A
Predictive discrimination ability of CLIF-C AD score (derivation
set).
*** p-values: <0.001 compared with Child-Pugh, MELD and
MELD-Na
Disclosures:
Rajiv Jalan - Consulting: Ocera Therapeutics, Conatus; Grant/Research Support:
Grifols, Gambro
Faouzi Saliba - Advisory Committees or Review Panels: Novartis, Roche, Gen-
zyme, Vital therapies; Grant/Research Support: Astellas; Speaking and Teach-
ing: Schering Plough, Gambro, MSD, Gilead
Paolo Caraceni - Advisory Committees or Review Panels: GSK; Speaking and
Teaching: Baxter, Kedrion
Tania M. Welzel - Advisory Committees or Review Panels: Novartis, Janssen,
Gilead, Abbvie, Boehringer-Ingelheim+
Pere Gines - Advisory Committees or Review Panels: Ferring ; Grant/Research
Support: Sequana Medical, Grifols
Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis;
Speaking and Teaching: Gilead
Paolo Angeli - Advisory Committees or Review Panels: Sequana Medical
Didier Samuel - Consulting: Astellas, MSD, BMS, Roche, Novartis, Gilead, LFB,
Janssen-Cilag, Biotest, Abbvie
Stefan Zeuzem - Consulting: Abbvie, Boehringer Ingelheim GmbH, Bristol-Myers
Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen,
Roche Pharma AG, Vertex Pharmaceuticals
Julia Wendon - Consulting: Pulsion, Excalenz
Mauro Bernardi - Consulting: CLS Behring GhmB, Baxter Healthcare; Speaking
and Teaching: CLS Behring GhmB, PPTA Europe
Vicente Arroyo - Speaking and Teaching: GRIFOLS
The following people have nothing to disclose: Marco Pavesi, Alex Amorós,
Javier Fernandez, Peter Holland-Fischer, Rohit Sawhney, Rajeshwar Mookerjee,
Richard Moreau, Carlo Alessandria, Wim Laleman, Jonel Trebicka, Thierry Gus-
tot, Alexander L. Gerbes
715
Hyperammonaemia and systemic inflammation is asso-
ciated with intracellular lactate accumulation
Anne M. Witt, Fin Stolze Larsen, Peter N. Bjerring; Department of
Hepatology, Rigshospitalet, Copenhagen OE, Denmark
Background and aim: In acute liver failure (ALF) cerebral
oedema and high intracranial pressure (ICP) are potentially
deadly complications. In vitro studies of astrocyte cultures have
shown mitochondrial dysfunction under hyperammonaemic
conditions and in rat brain of in vivo liver failure models de
novo lactate production has been observed. These findings
support the hypothesis of a compromised brain metabolism
during ALF. Yet, normal lactate levels are found in cerebral
microdialysate of ALF patients and the oxygen to glucose
ratio of cerebral metabolic rates remains normal. We there-
fore wanted to investigate the relationship between the extra-
cellular and total tissue lactate levels in brain cortex of a rat
model with hyperammonaemia and systemic inflammation.
Furthermore we assessed the mitochondrial function in brain
tissue with high-resolution respirometry. Methods: Sedated and
mechanically ventilated male Wistar rats were given either:
ammonia (NH3)+lipopolysaccharide (LPS): NH3+saline;
saline+LPS; or saline+saline. Ammonia/saline was infused for
120 minutes while extracellular brain lactate was measured
with enzymatic biosensors (Sarissa Biomedical). After the ani-
mals were sacrificed the total lactate concentration in cerebral
cortex was measured. In a separate series of animals, respira-
tion of cerebral cortex was studied with respirometry (Orob-
oros Instruments), concretely the function of complex I (state
2+3), complex I+II and after uncoupling. Results: Injection of
548A AASLD ABSTRACTS
NH3 and LPS resulted in hyperammonaemia (1550±147mM
vs. control 48±5mM, p<0.01). This was associated with a
significantly elevated intracranial pressure (6.8±2.1mmHg
vs. control 2.0±0.4mmHg, p<0.05). The total cerebral lac-
tate level increased (20.0±3.4mM vs. control 12.3±1.7mM,
p<0.05). There was no increase in the extracellular lactate,
but a tendency towards lower levels in rats given ammonia
and LPS (63.5±22.2mM vs. control 83.8±7.9mM, NS). We
did not find a significant reduction in the respiratory capacity
of brain cortex in any of the studied respiratory states. Con-
clusion: Hyperammonaemia and systemic inflammation in rats
was associated with increased total brain lactate and elevated
ICP. We observed that the extracellular lactate levels remained
normal and thereby indirectly demonstrated that the lactate
accumulation was intracellular. Apparently, the pathophysiol-
ogy did not involve reduced respiratory capacity indicating
that the mitochondrial function was preserved.
Disclosures:
The following people have nothing to disclose: Anne M. Witt, Fin Stolze Larsen,
Peter N. Bjerring
716
Alginate biocompatibility for use in tissue engineering
and cell therapy applications: biological responses to
hydrogel-encapsulated HepG2 cells in vitro - leukocyte
cytokine release and peripheral blood mononuclear cell
proliferation
Jordi G. Molina1, Graham Wright3, Sam Coward1, Hardeep
Kalsi1, Eloy Erro1, Barry Fuller2, Clare Selden1; 1UCL Inst for Liver
& Digestive Health, UCL Royal Free Campus, London, United King-
dom; 2Surgery, UCL, London, United Kingdom; 3Institute of Immu-
nity and Transplantation, UCL, Royal Free Hospital, London, United
Kingdom
Cell scaffolds used for tissue engineering and cell therapies
must have proven biocompatibility, demonstrating low biolog-
ical responses from blood cells encountered in vivo. Using a
bioartificial liver machine biomass (7x10*10 cells), we inves-
tigated cytokine release in response to the hydrogel, alginate,
containing encapsulated a liver-derived cell line (AELCs).
AELCs were cultured for 12d in fluidised bed bioreactors to
form the bioartificial liver biomass (n=3). At cell densities of
~3x10*7 cells/ml, beads were exposed to normal human
plasma, or liver failure plasma for 8h at 37C. Conditioned
plasma was presented to normal leukocytes for 24h to assess
cytokine release, and to peripheral blood mononuclear cells
to assess proliferation over 24h. Pro-inflammatory (IL6, IL8,
IL1β, IL2,TNFα, IL17a, IL5, IL12p70 IFNγ) and growth factors/
anti-inflammatory cytokines (IL10, IL4, GMCSF) were deter-
mined using multiplex cytokine FACS analysis CBA/CBA-flex
kits (pg/ml). PBMCs were cultured at 5x10*5/ml in condi-
tioned plasma assessing DNA synthesis with 3Hthymidine
incorporation. At likely in vivo ratios of liver-derived cells of the
biomass to blood leukocytes (2.86:1), only IL8 was increased
(263 pg/ml) compared with unstimulated (174 pg/ml) cells
or LPS stimulated positive control (22475 pg/ml). This was
cell number dependent: an increased ratio of ~28:1 of liver
cells to leukocytes IL8 reached 4923 pg/ml. In contrast there
was no increase in any other cytokines measured even at a
28:1 ratio. PBMC proliferation was not stimulated by normal
plasma (3631cpm/ml), or biomass-conditioned plasma (5414
cpm/ml), but was by ConA (134299 cpm/ml). Normalised to
normal human plasma, ConA in culture medium stimulated cells
37-fold; biomass conditioned plasma by 1.5-fold. The cytokine
blood levels in liver failure patient demonstrated increased lev-
els of IL-8 (419pg/ml), Interleukin-6 (1483pg/ml) and Inter-
HEPATOLOGY, October, 2014
leukin-10 (37pg/ml), cytokines that have been previously
reported to increase in Acetaminophen overdose patients. IL-8
is implicated in liver regeneration and protects from apoptosis
in hepatocytes. In conclusion, using alginate to encapsulate
cells leading to 3D cell spheroids in a biomass suitable for
a bioartificial liver device, we demonstrated acceptable bio-
compatibility with respect to blood cell exposure. The small
increase in IL8 expression may be beneficial in promoting liver
regeneration in patients being treated with a bioartificial liver
device. Alginate is utilised for both scaffolds used in extracor-
poreal cell therapies, as well as, in direct cell transplantation
therapies. This bio-inert material should therefore meet criteria
for clinical use.
Disclosures:
The following people have nothing to disclose: Jordi G. Molina, Graham Wright,
Sam Coward, Hardeep Kalsi, Eloy Erro, Barry Fuller, Clare Selden
717
Implanted human bone mesenchymal stem cells rescue
fulminant hepatic failure within one week through para-
crine and transdifferentiation in pigs
Jun Li1, Dongyan Shi1, Jianing Zhang2, Ding Wenchao3, Jiaojiao
Xin1, Qian Zhou1, Hongcui Cao1, Xin Chen2, Lanjuan Li1; 1State
Key Laboratory for Diagnosis and Treatment of Infectious Diseases,
Collaborative Innovation Center for Diagnosis and Treatment of
Infectious Diseases., The First Affiliated Hospital, School of Medi-
cine, Zhejiang University., Hangzhou, China; 2College of Life Sci-
ences, Zhejiang University, Hangzhou, China; 3Systems Biology
Division, Zhejiang-California International Nanosystems Institute,
Zhejiang University, Hangzhou, China
Previously, we have demonstrated the safety and effectiveness
of human bone marrow mesenchymal stem cells (hBMSCs)
transplantation to treat fulminant hepatic failure (FHF) in pigs
via proliferation and transdifferentiation within two weeks.
Here we further indicated that the first one week, even the first
three days after hBMSCs transplantation, is a key time for FHF
treatment, which were improved by the change of cytokine
profiling in FHF pigs and the recovery of liver functions. Immu-
nohistochemistry staining of hBMSCs-specific marker CD90
and human hepatocyte specific antigen in pig liver tissues indi-
cated that hepatocyte differentiation of hBMSCs started within
three days and completed within one week, and human cells
proliferated about 33.33~94.33 times via analysis of mRNA
sequencing (mRNA-seq). Functional classification of the sig-
nificantly differentially expressed cytokines at different stage
showed that 80% of the cytokines detected at day 3 were
related with inflammatory immunity (40%) and tissue regener-
ation (40%), such as CCL-28 and Oncostatin-M. Then the ratio
of inflammatory immunity cytokines increased at week 1 (69%)
and decreased at week 2 (50%), while tissue regeneration
related cytokines increased from 16% at week 1 to 37% at
week 2. Bioinformatics analysis showed that 63 human genes
increased from week 1 to week 2 in liver tissues were mainly
related with pro-regeneration. And 232 pig genes increased at
week 1 in liver tissue were mainly related with basic survival
functions and inflammatory immune responses, rather than
development, while 160 genes increased from week 1 to week
2 were mainly related with neurological disease and regener-
ation, accompanied by inflammation and immunity. All these
results indicated that the paracrine effects of anti-inflammatory
immunity of hBMSCs mainly functioned within week 1 and
the pro-regeneration mainly functioned between week 1 and
week 2. In conclusion, this research firstly demonstrated that
transplanted hBMSCs could rescue FHF pigs within one week
through transdifferentiation and paracrine effects of anti-in-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
flammatory, immunoregulation and pro-regeneration, and it
also showed the interaction between stem cells and recipient’s
microenvironment. These findings not only improve our under-
standing of the mechanisms underlying stem cell transplanta-
tion, but also possibly direct the clinical treatment of FHF in
future clinical therapy.
Disclosures:
The following people have nothing to disclose: Jun Li, Dongyan Shi, Jianing
Zhang, Ding Wenchao, Jiaojiao Xin, Qian Zhou, Hongcui Cao, Xin Chen, Lan-
juan Li
718
Assessment of adrenal function in patients with severe
acute hepatitis: a growing interest of serum free cortisol
and salivary cortisol. A prospective observational multi-
center study
Thibault Degand1,2, Elisabeth Monnet1,2, Francois Durand3, Emilie
Grandclement4, Philippe Ichai5, Franck Schillo6, Arnaud Agin7,
Alexandre Louvet8, Jérôme Dumortier9, Gilles Dumoulin4, Vincent
Di Martino1,2, Thierry Thevenot1,2; 1hepatology, university hospital
Jean Minjoz, Besancon, France; 2EA UPRES 3186, university of
Franche comté, Besançon, France; 3hepatology, Beaujon hospi-
tal, clichy, France; 4biochemistry, university hospital Jean Min-
joz, Besançon, France; 5hepatology, paul brosse APHP hospital,
Villejuif, France; 6endocrinology, university hospital Jean Minjoz,
Besançon, France; 7Laboratoire d’Explorations Fonctionnelles par
les Isotopes, university hospital of strasbourg, strasbourg, France;
8hepatogastroenterology, university hospital of Lille, Lille, France;
9hepatogastroenterology, university hospital Edouard herriot, Lyon,
France
Background/aims: A high frequency of adrenal dysfunction
(AD) has been reported in patients with severe acute hepatitis
(SAH) using the dosage of serum total cortisol (STC). Because
90% of the circulating cortisol in serum is bound to cortisol bind-
ing globulin (CBG) and albumin, which are altered in SAH, we
aimed to compare STC, serum free cortisol (SFC) and salivary
cortisol (SalivCort) in patients SAH to patients with non-severe
acute hepatitis (NSAH) and healthy controls (HC). Patients and
methods: We prospectively enrolled 43 SAH, 31 NSAH and
29 HC. STC, SFC and SalivCort concentrations were mea-
sured before (T0) and after (T60) a short corticotrophin stim-
ulation test dosed at 250 mg. Eight patients with known AD
have been included to provide a lower limit of normal range of
SFC. Cortisol values are expressed as median with IQRs and
comparisons between the three groups were performed by the
Kruskal-Wallis one-way analysis of variance. Results: Mean
age (39±14 years) and sex (male 59%) were similar between
SAH, NSAH and HC. The main cause of acute hepatitis was
drug-induced hepatitis (55.4%). T0 and T60 STC did not differ
between SAH, NSAH and HC. Conversely, we observed a
significant increase in SFC (KW: p=0.012 at T0 and p<0.001
at T60) and in SalivCort (KW: p=0.39 at T0 and p<0.0008 at
T60) from HC to SAH, together with a decrease in CBG (KW:
p<0.001) and albumin concentrations (KW: p<0.001). In
patients with acute hepatitis (n=74), the differences in SFC and
in SalivCort concentrations were especially marked for CBG
<28 mg/L (T0 SFC <28 vs ≥28 mg/L: 103.1 [61.2 to 157] vs
56.6 [43.6 to 81.9] nM, p=0.0024; T0 SalivCort <28 vs ≥28
mg/L: 61 [40-123] vs 32 [23-47] nM, p=0.0017). Analysis
of covariance showed that the regression lines differed sig-
nificantly between the three patient groups at T0 (p<0.0001).
This model was well fitted to our data set (R2=0.70). At equal
concentration of T0 STC, the T0 SFC concentration was sig-
nificantly higher in SAH than in NSAH (p<0.001) or in HC
(p<0.001). The correlations between T0 SalivCort and T0
549A
SFC increased alongside the severity of illness (HC: r=0.43,
p=0.02; NSAH: r=0.76, p<0.001; SAH: r=0.88, p<0.001).
Based on the 5th and 10th percentiles (specificity of 90-95%)
of the distribution of SFC in SAH, a lower limit of normal for
SFC might be assumed to be in the range of 32-34 nM at T0
and of 78-90 nM at T60. Conclusions: In SAH, the decrease
in CBG and in albumin makes the diagnosis of AD hazardous.
SFC better reflects adrenal function than STC does in SAH.
SalivCort is well correlated with SFC and could more easily
guide the clinician. Further studies are needed to confirm the
thresholds we provide herein.
Disclosures:
Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis;
Speaking and Teaching: Gilead
Jérôme Dumortier - Board Membership: Novartis, Astellas, Roche; Consulting:
Novartis; Grant/Research Support: Novartis, Astellas, Roche, MSD, GSK
Vincent Di Martino - Board Membership: Gilead, France, MSD France; Consult-
ing: Gilead, France
The following people have nothing to disclose: Thibault Degand, Elisabeth Mon-
net, Emilie Grandclement, Philippe Ichai, Franck Schillo, Arnaud Agin, Alexandre
Louvet, Gilles Dumoulin, Thierry Thevenot
719
Characterization of Acute-on-Chronic Liver Failure And
Prediction of Mortality in Patients with Alcoholic Hepa-
titis
Hwi Young Kim, Yong Jin Jung, Byeong Gwan Kim, Kook Lae Lee,
Won Kim; Department of Internal Medicine, Seoul National Uni-
versity Boramae Medical Center, Seoul, Republic of Korea
BACKGROUND: Alcoholic hepatitis(AH) often evolves to acute-
on-chronic liver failure(ACLF) which raises the risk of (multi-)
organ failure as well as mortality. The aims of the present study
were to investigate development and features of ACLF among
hospitalized patients with alcoholic hepatitis and to validate a
recently developed prognosticator of ACLF. METHODS: A total
of 1191 consecutive patients were evaluated for eligibility,
who were hospitalized with AH between 1999 and 2012.
Patients with the following conditions were excluded in further
analysis: serious cardiovascular diseases (n=13); presence
of malignancies (n=5); co-existence of viral hepatitis (n=16);
Child-Pugh class A (n=102); use of corticosteroid/pentoxifylline
(n=44). Finally, 1011 patients were included for the analysis.
CLIF-SOFA scoring system was used as the diagnostic criteria
for ACLF(Moreau R, et al. Gastroenterology 2013;144:1426–
1437). CLIF-consortium(CLIF-C) ACLF score was used to pre-
dict mortality(Jalan R, et al. J Hepatol 2014;60:s239), and
was compared with MELD, MELD-Na, and Child-Pugh score.
RESULTS: Median age was 52 years, and male patients were
88.7%. Median clinical scores at the time of admission were as
follows: Maddrey’s discriminant function(MDF), 20.2; model
for end-stage liver disease(MELD), 17.1; MELD-Na, 20.7. Sys-
temic inflammatory response syndrome(SIRS) was present in
574(56.8%). A total of 269(26.6%) patients were diagnosed
with ACLF: grade 1, 98(36.4%); grade 2, 108(40.1%); grade
3, 63(23.5%). Patients with ACLF had higher clinical scores
including MDF, MELD, MELD-Na than those without ACLF.
There was no difference in the frequency of ACLF between
cirrhotic vs. non-cirrhotic patients(16.7% vs. 27.1%, P=0.088).
From multiple logistic regression analysis, predictive factors
at admission for the development of ACLF were presence
of SIRS(odds ratio(OR), 2.714(95% confidence interval(CI),
1.582-4.657); P<0.001), bacterial infection(OR, 1.698(95%
CI, 1.176-2.451); P=0.005), high c-reactive protein(OR,
1.679(95% CI, 1.100-2.561); P=0.016), and low mean arte-
rial pressure(OR, 0.985(95% CI, 0.972-0.999); P=0.032).
For prediction of 90-day mortality in patients with ACLF, areas
550A AASLD ABSTRACTS
under the receiver-operating curve were 0.731 with CLIF-C
ACLF score, 0.688 with Child-Pugh score, 0.634 with MELD,
and 0.635 with MELD-Na, respectively. CONCLUSION: Infec-
tion and SIRS may play an important role in the development
of ACLF in patients with alcoholic hepatitis. CLIF-C ACLF score
was shown to be useful in predicting mortality compared with
other liver-specific scoring systems in this external validation.
Disclosures:
The following people have nothing to disclose: Hwi Young Kim, Yong Jin Jung,
Byeong Gwan Kim, Kook Lae Lee, Won Kim
720
Acute Liver Decompensation Following Radioemboliza-
tion For Liver Cancer: A Retrospective Study
Michael Min1,2, Totianna Prudhomme3, Eduardo Ehrenwald3, Jill
May3, Kai Hanson1, Andrew J. Henn1, Joseph Leach4, Coleman
Smith5,2; 1Medicine, Abbott Northwestern Hospital, Minneapolis,
MN; 2Hepatology, Abbott Northwestern Hospital, Minneapolis,
MN; 3Interventional Radiology, Abbott Northwestern Hospital,
Minneapolis, MN; 4Oncology, Abbott Northwestern Hospital,
Minneapolis, MN; 5Hepatology, University of Minnesota Medical
School, Minneapolis, MN
Introduction: Radioembolization (RE) is an emerging treatment
option for both primary and secondary hepatic malignancies
with promising tumor control rates. Infrequently, therapy can
lead to acute liver decompensation, which is characterized
by combination of new ascites and/or jaundice (bilirubin ≥ 3
mg/dL) in the absence of malignancy progression and biliary
obstruction, appearing <2 months after the initial RE. This proj-
ect aims at identifying and studying the risk factors associated
with this phenomenon, as well as the natural progression of the
disease. Methods: This retrospective study included all patients
with biopsy or imaging diagnosed primary liver cancer (HCC)
or metastatic disease who received Yttrium-90 RE with glass
beads at Abbott Northwestern Hospital in Minneapolis, MN
from 2012 to 2014. Demographic and pre- and post emboli-
zation variables were recorded and analyzed. Chi-square tests
and simple logistic regression were used to test association
between development of acute liver decompensation and cat-
egorical and continuous variables, respectively. The variables
that were independently associated with the disease were
then plugged into a backwards stepwise logistic regression
test to show which variables best modeled the development
of liver disease. Results: A total of 134 patients was identified
who had received RE; 12 (9%) patients experienced acute
liver decompensation based on the definition as above. There
was a higher percentage of portal vein thrombosis (42% vs.
9.0%, P<0.006) in the identified disease group. Overall, 9/12
(75%) patients in the acute liver decompensation group died,
compared to 27/127 (22%) in the nondecompensation group
(P<0.0001). Demographic/laboratory data that showed cor-
relation with developing liver decompensation included higher
alkaline phosphatase, ALT, bilirubin,, lower albumin, and asci-
tes measured on day of RE. Backward stepwise regression test
showed that presence of portal vein thrombosis (PVT) prior to
therapy (0.48 to 3.2 for 95% CI) had highest coefficients pre-
dictability (1.8) for acute liver decompensation. Conclusion:
Our study showed that acute liver decompensation following
radioembolization has a significant mortality. There is a trend
toward developing liver decompensation in patients with worse
initial hepatic function. Importantly, presence of PVT is a strong
predictor for developing acute liver decompensation follow-
ing radioembolization. Unlike previous studies, prior systemic
chemotherapy did not predispose to the development of liver
decompensation.
HEPATOLOGY, October, 2014
Disclosures:
Coleman Smith - Advisory Committees or Review Panels: Vertex, Gilead, Janssen;
Grant/Research Support: Gilead, Abbvie, Janssen, Salix, BMS, Merck, Intercept
Pharma, Lumena Pharma; Speaking and Teaching: Merck, Vetex, Gilead, Bayer/
Onyx, BMS, Abbvie, Janssen
The following people have nothing to disclose: Michael Min, Totianna Prud-
homme, Eduardo Ehrenwald, Jill May, Kai Hanson, Andrew J. Henn, Joseph
Leach
721
Improved survival of hepatocytes in co-culture with mes-
enchymal stromal cells following exposure to acute liver
failure serum: the role of paracrine factors
Emer Fitzpatrick1,2, Sunitha Vimalesvaran2, Celine Filippi2, Ragai
R. Mitry2, Tracey Dew3, Charalambos G. Antoniades2,4, Anil Dha-
wan1,2; 1Paediatric Liver, GI and Nutrition Centre, King’s College
London School of Medicine at King’s College Hospital, London,
United Kingdom; 2Institute of Liver Studies, King’s College London
School of Medicine at King’s College Hospital, London, United
Kingdom; 3Dept. of Biochemistry, King’s College Hospital, Lon-
don, United Kingdom; 4Section of Hepatology, Imperial College
London, London, United Kingdom
Objectives: Human hepatocyte (HC) transplantation has prom-
ise as a bridge to organ transplantation or spontaneous recov-
ery in acute liver failure (ALF). The survival and function of
transplanted hepatocytes is limited however. Mesenchymal
stromal cells (MSC) have been shown to enhance the survival
and function of co-cultured HC in addition to having additional
anti-inflammatory/anti-apoptotic properties. The mechanism of
this is unknown. The aim of this study was to investigate this
mechanism by examining cytokine and growth factor produc-
tion in vitro using human cells and serum to mimic in vivo
conditions. Methods: Human HCs were isolated from donor
organs and MSC from umbilical cord. Cells were plated in
monoculture or co-culture at a ratio of 6:1 (HC:MSC). After 24
hr, serum from patients with ALF, normal control or fetal calf
serum (FCS) was added and then removed 24 hours later, cells
were washed and standard culture medium added. Cytotox-
icity (MTT/SRB), specific hepatocyte death and albumin pro-
duction were measured 24 and 48 hours following medium
change. Thirteen cytokines/growth factors were measured
in medium using a multiplex array (Biochip Array, Randox,
UK). Results: At both time points, MSC monoculture had higher
cytotoxicity following exposure to ALF serum versus control
(>50% reduction in MTT activity/cell attachment, p<0.001).
HC monoculture maintained MTT activity and cell survival and
also increased albumin production in ALF serum versus FCS
medium (482 v 54 ng/24hr/well). Co-cultured HC and MSC
demonstrated improved MTT activity in ALF serum compared to
HC or MSC monoculture (p<0.05). IL6, IL8 and Monocyte Che-
moattractant Protein 1 (MCP1) were secreted by MSC but not
HC monoculture and there was a significant increase in pro-
duction in co-culture following culture in ALF serum (p<0.05):
MCP1 production in co-culture was increased 8x (mean 234
v 25ng/l) and IL8 production 14x (219 v 14ng/l) following
culture with ALF serum versus control. Hepatocyte Growth Fac-
tor (HGF) secretion was detected in MSC and HC monoculture
in all 3 conditions but was highest following co-culture in ALF
serum. IL1Receptor antagonist (IL1Ra) was also increased in
all 3 co-culture conditions versus HC monoculture (p<0.05).
Conclusion: ALF serum has toxic effects on MSC which may
be reversed by co-culture with HC. The increased production
of IL6, IL8 and MCP1, HGF and IL1Ra in HC:MSC co-culture,
further increased after ALF serum exposure, may contribute to
this effect. These data also suggest that direct cell to cell contact
may be necessary to induce HC and MSC to produce these
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
cytokines, which may potentially have relevance for therapeutic
application.
Disclosures:
The following people have nothing to disclose: Emer Fitzpatrick, Sunitha Vimales-
varan, Celine Filippi, Ragai R. Mitry, Tracey Dew, Charalambos G. Antoniades,
Anil Dhawan
722
Alpha fetoprotein: A biomarker for the recruitment of
progenitor cells in the liver of the patients with acute
liver injury/acute liver failure
Keisuke Kakisaka, Kojiro Kataoka, Yuji Suzuki, Yasuhiro Miya-
moto, Yasuhiro Takikawa; Hepatology, Iwate medical university,
Morioka, Japan
Background & Aims: The optimal conditions for hepatocyte
proliferation should be clarified to address the impaired liver
regeneration in cases of acute liver failure (ALF). The donors
of living donor liver transplantation (LDLT) demonstrate rapid
liver regeneration and seem to have optimal conditions for
liver regeneration, while ALF patients demonstrate impaired
liver regeneration. We evaluated the significance of the serum
AFP level and PT-INR level as markers for the induction of liver
stem/progenitor cells (LPC) and mature hepatocyte (MH) prolif-
eration, respectively, by comparing the levels of these markers
in LDLT donors and ALF patients. Methods: The serum AFP and
PT-INR levels were serially determined in 73 patients with ALI/
ALF and 11 donors who underwent LDLT. The LPC induction
was histologically evaluated using CK-19 staining in 20 ALI/
ALF patients. Results: The PT-INR peaked on postoperative day
3 (POD3) and then was normalized by POD7 in the donors.
The level of AFP was not apparently elevated during the obser-
vation period in the LDLT donors, while the serum AFP levels
were substantially elevated in the patients with ALI/ALF, and
this correlated with the extension of hepatocyte necrosis, and
was significantly correlated with the number of CK19-positive
cells in the liver. Three of the 11 non-surviving patients and all
of the surviving patients demonstrated a later peak AFP level
than the PT-INR level, while all of the patients with an ear-
lier peak AFP level before PT-INR elevation died. Conclusions:
The serum AFP level in ALI/ALF patients may reflect the sever-
ity of hepatocyte necrosis and the reactive induction of LPC.
The substantial and persistent induction of LPC until sufficient
regeneration of the MH may be necessary for the recovery
from ALF. We demonstrated that the serum AFP level in the
patients with ALI/ALF may be serum marker of LPC induction.
An early decrease of serum AFP level and delayed elevation
of the PT-INR level in patients with ALI/ALF may indicate a
poor prognosis due to both impaired proliferation of LPC and
retarded regeneration of the MH.
Disclosures:
The following people have nothing to disclose: Keisuke Kakisaka, Kojiro Kata-
oka, Yuji Suzuki, Yasuhiro Miyamoto, Yasuhiro Takikawa
723
The Safety of Therapeutic Plasma Exchange in Pediatric
End Stage Liver Disease
Amy S. Arrington1, Moreshwar S. Desai1, Ayse Akcan Arikan1,2,
Jun Teruya3, Poyyapakkam R. Srivaths2; 1Pediatric Critical Care,
Baylor College of Medicine / Texas Children’s Hospital, Houston,
TX; 2Pediatric Nephrology, Baylor College of Medicine / Texas
Children’s Hospital, Houston, TX; 3Clinical Pathology, Baylor Col-
lege of Medicine / Texas Children’s Hospital, Houston, TX
End stage liver disease (ESLD) in pediatric patients is an often
fatal disease, and in cases of irreversible liver injury, necessi-
551A
tates the need for liver transplantation. These children develop
life-threatening complications, including refractory coagulopa-
thies, hepatic encephalopathy, multi-organ failure and death.
Therapies for patients awaiting transplant are merely sup-
portive, including large volumes of blood products to correct
coagulopathy, resulting in volume and protein overload and
citrate toxicity. Therapeutic plasma exchange (TPE) allows for
a bridge to either recovery or transplant by correcting coag-
ulopathies, clearing toxins, and improving cytokine balance.
There are no published pediatric studies describing the safety
of TPE in children with hepatic failure. Methods: Charts of ESLD
patients from 2010-2013 at Texas Children’s Hospital who
received TPE for hepatic encephalopathy, severe coagulopa-
thy, or ABO mismatch liver transplant (n=20) were reviewed.
TPE was performed by replacing 1.5 total plasma volume with
fresh frozen plasma, and anticoagulation was regional with
citrate. A protocol for TPE was used for all patients in 2013 (n
= 10), and included 5 daily TPE treatments, followed by every
other day treatments until recovery, transplant or death. Prior to
this protocol, TPE was used randomly on a physician-directed
basis. Data: Over 4 years, 20 patients with ESLD were sup-
ported with TPE for a total of 102 treatments. Patients received
5 treatments on average. No infectious complications or deaths
were associated with TPE. TPE was done in tandem with CRRT
in the majority of patients (85%). Citrate lock, defined as a
total calcium to ionized calcium ratio of ≥ 2.4, was seen in
the majority of patients (85%), and improved by increasing
calcium chloride. 60% of patients experienced hypotension
requiring increased inotropic support, and 60% experienced
complications with catheters including bleeding and/or clot-
ting (67%). Despite these side effects, no treatment interruption
was necessary, even in patients on multiple vasoactive agents.
In the 10 patients subject to the 2013 TPE protocol, 4 were
successfully bridged to liver transplantation, and 1 had sponta-
neous resolution of disease. Prior to the 2013 protocol, 4/10
patients were successfully bridged to transplant. Conclusion:
These data demonstrate the safety of TPE in children with ESLD.
Despite commonly experiencing severe citrate lock, hemody-
namic instability, and catheter complications, TPE was well
tolerated and did not result in cessation of therapy or death.
The benefits of TPE as a therapeutic bridge allows for longer
survival while awaiting liver transplant.
Disclosures:
The following people have nothing to disclose: Amy S. Arrington, Moreshwar S.
Desai, Ayse Akcan Arikan, Jun Teruya, Poyyapakkam R. Srivaths
724
Acetaminophen (APAP)-induced Acute Liver Failure (ALF)
Leads to Activation Of Endogenous Hepatic Stem/Pro-
genitor Cells with Inability to Complete Hepatic Regen-
eration
Nicole Pattamanuch1, Preeti Viswanathan1, Sriram Bandi2, Leslie
E. Rogler2,3, Charles E. Rogler2,3, Sanjeev Gupta2,4; 1Pediatrics
Gastroenterology and Hepatology, Children’s Hospital at Monte-
fiore, Albert Einstein College of Medicine, Bronx, NY; 2Medicine,
Albert Einstein College of Medicine, Marion Bessin Liver Research
Center, Bronx, NY; 3Microbiology and Immunology, Albert Ein-
stein College of Medicine, Bronx, NY; 4Pathology, Albert Einstein
College of Medicine, Bronx, NY
Background: Acetaminophen hepatotoxicity is the leading
cause of ALF and can be fatal when liver fails to regenerate.
If hepatic stem/progenitor cells were recruited in ALF efforts to
amplify such cells could offer novel therapies. Recently, markers
were defined for pluripotency and lineage specification, com-
mitment and maturation within intact fetal or adult tissues. We
552A AASLD ABSTRACTS
hypothesized that activation of hepatic stem/progenitor cells in
APAP-induced ALF should be identified in tissues with markers
of pluripotency (e.g., OCT4), early hepatic specification (e.g.,
FoxA2), lineage fate, and lobular position (e.g., coexpression
of albumin – Alb - or CK-19 for hepatic or biliary identity and
acinar or ductal position, respectively). Methods: Liver samples
were from healthy subjects (n=3) or liver explanted after OLT
in APAP-induced ALF (n=6). Fetal human liver and pluripotent
human embryonic stem cells (hESC) were used as controls.
Tissues were immunostained for OCT4, FoxA2, Alb and CK-19
in various combinations. For genome-wide gene expression
profiling, replicate paraffin-embedded samples were analyzed
by Affymetrix U133 2.0 Plus arrays with standard methods for
data normalization and Ingenuity Pathway Analysis. Results:
Morphology of healthy livers was normal but after APAP injury
livers showed extensive necrosis, inflammation, steatosis, and
ductular reactions. Occasional Alb+ hepatocytes as well as
CK-19+ biliary cells showed proliferative activity in injured
livers. We observed Alb+/CK-19+ cells in ductal structures
suggesting appearance of bipotent hepatic progenitor cells.
Moreover, FoxA2 was expressed in large numbers of Alb+ or
CK-19+ cells. Colocalization showed FoxA2+/Alb+/CK-19+
cells, similar to fetal livers, indicating these were early-stage
stem/progenitor cells. As fetal, adult or APAP-injured liver cells
did not express OCT4, these cells were fetal- and not pluripo-
tent stem cell-like. Gene expression analysis established APAP
injury caused differences in multiple metabolic or inflammatory
pathways, along with upregulation of biliary markers (KR19,
NOTCH ligand, JAG1), in agreement with ductular prolifer-
ation. Proliferation markers (PCNA, Ki67) were upregulated
but growth inhibitory genes, e.g., PTCH2, TGFB1, PTTG1 and
WNT signaling inhibitors, e.g., BICC1, were simultaneously
upregulated. Conclusions: APAP-induced ALF resulted in acti-
vation of endogenous FoxA2+ stem/progenitor cells located
in acinar and ductular niches. Failure of liver regeneration was
likely explained by mechanisms inhibiting proliferation and/or
further differentiation of these stem/progenitor cells. This offers
therapeutic directions for regenerating the injured liver.
Disclosures:
The following people have nothing to disclose: Nicole Pattamanuch, Preeti Viswa-
nathan, Sriram Bandi, Leslie E. Rogler, Charles E. Rogler, Sanjeev Gupta
725
TNF-α Induces Receptor Interacting Protein-3 Kinase to
Mediate Necrotic Cell Death in Acute-on-Chronic Liver
Failure
Arshi Khanam1, Nirupma Trehan Pati1, Archana Rastogi2, Shiv
K. Sarin1,3; 1Research, Institute of liver and biliary sciences, New
Delhi, India; 2Pathology, Institute of Liver and Biliary Sciences,
Delhi, India; 3Hepatology, Institute of Liver and Biliary Sciences,
Delhi, India
Background:Molecular mechanism of tumor necrosis fac-
tor(TNF-α) and IFN-γ induced necrotic cell death in ACLF
remains largely unknown.Methods:Intrahepatic TNF-α and
IFN-γ producing CD8T cells, activation(CD69) and inhibitory
marker(PD-1), TNF-α, IFN-γ, CXCL-9,10 and STAT-1 gene
expression, plasma TNF-α, IFN-γ levels were analyzed in
hepatitis B virus-related ACLF(GroupI,n=14), alcohol–related
ACLF(GroupII,n=40), and chronic hepatitis B(GroupIII:n=42)
patients.Receptor interacting protein kinase-3(RIP-3) expression
was evaluated.Correlations of TNF-α and IFN-γ with clinical
parameters of severity was assessed.Results:Intrahepatic TNF-α
producing CD8T cells(p<0.04, 0.05), TNF-α gene (p<0.00,
0.00) and plasma TNF-α level(p<0.05, 0.05) were high in Gr.I
and II than Gr.III with high CD69 (p<0.05, 0.03) and PD-1
HEPATOLOGY, October, 2014
(p<0.04, 0.05). Strong CD69 staining to the necrotic vicinity
of liver tissue was seen. No change in TNF-α level was seen
with PD-1 blockade.Intrahepatic RIP-3 gene expression was
higher in Gr.I and II(p<0.00. 0.00), more so in hepatocyte
cytoplasm with intense staining towards necrotic areas. Fur-
thermore intracellular(p<0.00, 0.00), plasma(p<0.03, 0.03)
and gene expression of IFN-γ(p<0.03, 0.00) was higher in
Gr.I and II than III. IFN-γ also induced proinflammatory genes;
CXCL-9,10 and downstream signaling molecule STAT-1. TNF-α
and IFN-γ were positively correlated with serum ALT(p<0.00,
0.00), INR(p<0.02, 0.00), CTP(p<0.03, 0.02) and SOFA
score(p<0.04, 0.00).Conclusions:Increased intrahepatic
CD8T cells in ACLF lead to enhanced TNF-α, inducing RIP-3
pathway to mediate hepatocellular necrosis.In addition, IFN-γ
promoted proinflammatory pathway induces inflammation and
disease progression. High PD-1 expression is not sufficient in
controlling TNF-α and IFN-γ induced liver damage.These data
could help in developing new single or combined molecular
targets to prevent progressive liver injury in ACLF
Disclosures:
The following people have nothing to disclose: Arshi Khanam, Nirupma Trehan
Pati, Archana Rastogi, Shiv K. Sarin
726
The Usefulness of Prognostic Factors of Acute-on-
Chronic Liver Failure in Patients with Liver Cirrhosis: A
Multicenter, Retrospective Cohort Study in Korea (KAC-
LiF Study)
Do Seon Song1, Dong Joon Kim2, Tae Yeob Kim3, Dong Hyun
Sinn4, Eileen L Yoon5, Joo Hyun Sohn3, Chang wook Kim1, Young
Kul Jung6, Ki Tae Suk2, Jin Mo Yang1, Heon Ju Lee7; 1Department
of Internal Medicine, College of Medicine, The Catholic Univer-
sity College of Korea, Seoul, Republic of Korea; 2Department of
Internal Medicine, Hallym University, Chunchon Sacred Heart Hos-
pital, Gangwon-Do, Republic of Korea; 3Department of Internal
Medicine, Hanyang University Guri Hospital, Guri, Republic of
Korea; 4Department of Internal Medicine, Samsung Medical Cen-
ter, Seoul, Republic of Korea; 5Department of Internal Medicine,
Inje University Sanggye Paik Hospital, Seoul, Republic of Korea;
6Department of Internal Medicine, Korea University Ansan Hospi-
tal, Ansan, Republic of Korea; 7Department of Internal Medicine,
Yeungnam University College of Medicine, Daegu, Republic of
Korea
Background /Aims: The concept of acute-on-chronic liver fail-
ure (ACLF) associated with organ failure and high mortality is
emerging. This study aimed to validate the CLIF-SOFA score
recently proposed by the EASL-CLIF Consortium in cirrhotic
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
patients with acute decompensation (AD). Methods: Clinical
data of 946 hospitalized cirrhotic patients [male 703, median
age 54 (IQR 47-63) years] with AD were consecutively collected
from January 2013 to December 2013 in 16 academic hospi-
tals in Korea. The diagnostic performance between CLIF-SOFA
and well-known prognostic factors (Child-Pugh score, MELD
score, MELD-Na score) for short-term mortality were analyzed
by the area under the receiver operating characteristics curve
(AUROC). The Kaplan-Meier method with log-rank test was
used to calculate survival. Results: The median follow-up period
was 200 days (range: 1-491) and 175 patients (18.5%) died
[28-day mortality 66/946 (7.0%), 90-day mortality 103/839
(12.3%)]. AUROCs of Child-Pugh, MELD, MELD-Na, and CLIF-
SOFA scores for predicting 28-day mortality were 0.769,
0.837, 0.832, and 0.856, respectively (all P < 0.001). Sig-
nificantly lower AUROC was observed for Child-Pugh score as
compared to MELD (P = 0.016), MELD-Na (P = 0.038), and
CLIF-SOFA scores (P=0.002). AUROCs of Child-Pugh, MELD,
MELD-Na, and CLIF-SOFA scores for predicting 90-day mor-
tality were 0.784, 0.813, 0.829, and 0.833, respectively
(all P < 0.001). Significantly higher AUROC was observed for
CLIF-SOFA vs. Child-Pugh score (P = 0.034) and there was a
tendency towards higher AUROC for CLIF-SOFA as compared
to MELD-Na score (P = 0.068). The best overall performance
for CLIF-SOFA score was observed at a cutoff of 7. The mortal-
ity rate at 28-day, 90-day, and 1-year were 2.1%, 4.3% and
15.8% with CLIF-SOFA < 7, and 21.2%, 31.3%, and 53.5%
with CLIF-SOFA ≥ 7, respectively (log rank P < 0.001). Con-
clusions: CLIF-SOFA score is better than Child-Pugh score for
predicting short term mortality in cirrhotic patients with acute
decompensation. Although CLIF-SOFA score tend to be better,
further studies are needed to verify that CLIF-SOFA score is
more useful than MELD or MELD-Na scores in evaluating cir-
rhotic patients with acute decompensation.
Disclosures:
Dong Hyun Sinn - Speaking and Teaching: Gilead, Yuhan pharmacy
The following people have nothing to disclose: Do Seon Song, Dong Joon Kim,
Tae Yeob Kim, Eileen L Yoon, Joo Hyun Sohn, Chang wook Kim, Young Kul Jung,
Ki Tae Suk, Jin Mo Yang, Heon Ju Lee
727
Acute Liver Failure related to Drug reaction with eosin-
ophilia and systemic symptoms (DRESS): Outcome and
Predictive Factors for improvement
Philippe Ichai1,2, Camille Besch1, Catherine Guettier3,4, Claire
Francoz5, Laurence Valeyrie-Allanore6, Sylvie Roussin-Bretagne7,
Olivier Roux5, Alexia Letierce1, Faouzi Saliba1,3, Florent Artru1,
Marc Boudon1, Teresa Maria Antonini1, Francois Durand5, Didier
Samuel1,2; 1Centre Hepato-Biliaire, AP-HP Hopital Paul Brousse,
Villejuif, France; 2U785, Inserm, Villejuif, France; 3Univ Paris-Sud,
Villejuif, France; 4AP-HP Hôpital de Bicêtre, Le Kremlin-Bicêtre,
France; 5AP-HP Hôpital Beaujon, Clichy, France; 6AP-HP Hôpital
Henri Mondor, Créteil, France; 7Centre Hospitalier de Versailles,
Le Chesnay, France
DRESS is an acute and severe drug reaction. Several organs
can be involved with liver disturbance occurring in the majority
of cases. The outcome of DRESS is not well known in Acute
Liver Failure (ALF). The aim of this study is to determinate the
outcome of patients with ALF and predictive factors of a sponta-
neous improvement. Patients: From 1996 to 2013, 15 patients
with ALF related to DRESS syndrome (10F, 5M, mean age:
39+17.2 years) were reviewed. The drugs implicated were:
allopurinol (2), raltegravir (2), carbamazepine (2), levetirace-
tam (1), nevirapine (1), fluindrone (1), isoniazide or pyrazin-
amide (2) sulfasalazine (1) and unknown (2). At admission,
553A
all patients were febrile and all presented cutaneous signs.
Median prothrombin time (PT), total bilirubin, ALT and cre-
atinin values were 34.5% (5-66), 69 mmol/l (8-353), 1569
IU/L (360-5176) and 107 mmol/L respectively. 5 patients pre-
sented more 2 visceral involvement. Liver histology (7 patients)
identified lesions following: portal and sinusoidal infiltration
by activated T cells mainly with cytotoxic phenotype mixed
with a variable number of eosinophils; severe periportal activ-
ity; spotty or confluent hepatocellular necrosis; Kupffer hyper-
plasia with frequent erythrophagocytosis. After admission, 8
patients received corticosteroid therapy and all were treated
by N-Acetyl-Cysteine. The median duration of corticosteroid
therapy was 14 days (2-101d). 7 patients were mechanically
ventilated, 2 were placed on hemofiltration and 1 on albumin
dialysis. A HSV6 and CMV reactivation were found in 3 and
1 patient respectively. Results: Of these 15 patients, 8 (53%)
improved spontaneously and 7 (47%) worsened. Among these
last, 5 underwent liver transplantation (LT) and 2 died. 3 of
7 (43%) of them, received corticosteroid therapy. The delay
between admission and LT and death were 3 days and 5.5
days respectively. The two patients died both of multi organ
failure. After liver transplantation (LT), 2 patients presented a
reversible recurrence of the liver disease. In improved patients,
median PT nadir values was 31.5% (16-50%). In one of these
patients, a recurrence of the liver disease was observed. The
overal survival and the survival after LT were 80% respectively.
Patients with both PT <40% at Day 0 and a rising of PT supe-
rior to 20% at Day 1 improved significantly (p:0.012). Cor-
ticosteroids therapy was not significatively associated with a
spontaneous improvement. Conclusion: Prognosis of patients
with ALF related DRESS sd is poor. Corticosteroid therapy
doesn’t improve the spontaneous prognosis. The rising of PT at
D 1 (superior to 20% of Day 0 PT) is predictif of spontaneous
improvement.
Disclosures:
Faouzi Saliba - Advisory Committees or Review Panels: Novartis, Roche, Gen-
zyme, Vital therapies; Grant/Research Support: Astellas; Speaking and Teach-
ing: Schering Plough, Gambro, MSD, Gilead
Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis;
Speaking and Teaching: Gilead
Didier Samuel - Consulting: Astellas, BMS, Gilead, Janssen-Cilag, LFB, MSD,
Novartis, Roche, Biotest
The following people have nothing to disclose: Philippe Ichai, Camille Besch,
Catherine Guettier, Claire Francoz, Laurence Valeyrie-Allanore, Sylvie Rouss-
in-Bretagne, Olivier Roux, Alexia Letierce, Florent Artru, Marc Boudon, Teresa
Maria Antonini
728
A non-invasive method for enumerating cell number in
three dimensional cell cultures; the integrated variable
cell count, a tool for regenerative medicine, enabling
quality assurance of cell therapy applications
Eloy Erro2,1, Hyun Woo Yu2,1, Dominic Davis2,1, James T.
Bundy2,1, Aurelie Le lay2,1, Humphrey Hodgson2,1, Barry Fuller3,
Clare Selden2,1; 1Medicine, UCL, London, United Kingdom; 2UCL
Institute fro Liver & Digestive Health, UCL Royal Free Campus,
London, United Kingdom; 3Surgery, UCL, London, United Kingdom
Optimising per cell performance is key to defining a regen-
erative medicine therapeutic, eg in the biomass function for
a bioartificial liver machine. Current methods require direct
cell counting, are destructive and introduce the possibility of
contamination, a serious concern for any cell therapy: Aim: To
develop a non-invasive methodology to quantify cell numbers
in 3D cultures. HepG2 cells encapsulated in alginate were
grown in MEM containing 10% FBS and 24.9mM glucose in
fluidised bed 100L bioreactors (n=9) Cell numbers were enu-
554A AASLD ABSTRACTS
merated with a nucleocounter, counting nuclei after Propidium
iodide staining. Alginate encapsulated cell spheroids harvested
after 12 days, were analysed for glucose and lactate using glu-
cose and lactate oxidases. Viabilities were determined using
Fluorescein diacetate (alive) and Propidium Iodide (dead). The
QGL (cumulative flux of glucose and lactate combined) and
integrated variable cell count (IVCC :million cells-day = (xt
+xt−1)/2*Δt + IVCDt−1 were determined and correlated with
cell number. There was a linear correlation between cell num-
ber and cumulative flux (QGL), and between QGL and IVCC,
and IVCC and cell number that enabled determination of a
relationship between IVCC and cell number independent of
culture conditions (Figure 1). The slopes were constant during
cell proliferation. Correlations of cumulative flux vs. cell number
within each experiment were always greater than r2= 0.95;
correlations of IVCC vs cell number were always greater than
0.98. In conclusion measurement of the combined metabolic
fluxes of glucose and lactate can be correlated with cell num-
ber independent of culture conditions, and used as a non-in-
vasive tool to determine cell number in large scale bioreactor
runs. This has important implications for 3-dimensional cell cul-
tures when estimating per cell performance in potential cell
therapy applications.
Disclosures:
The following people have nothing to disclose: Eloy Erro, Hyun Woo Yu, Dominic
Davis, James T. Bundy, Aurelie Le lay, Humphrey Hodgson, Barry Fuller, Clare
Selden
729
Arterial ammonia concentration determined by point of
care testing in acute liver failure; clinical associations
and utility in prediction of complications and outcome
Vishal C. Patel, Beatriz Mateos Muñoz, Elizabeth Sizer, Charalam-
bos G. Antoniades, Christopher Willars, Georg Auzinger, Julia
Wendon, William Bernal; Liver Intensive Therapy Unit, Kings Col-
lege Hospital, London, United Kingdom
Background. Though ammonia is implicated as a toxin cen-
tral to the pathogenesis of hepatic encephalopathy (HE) and
cerebral edema (CE) in acute liver failure (ALF), there is limited
data on the clinical relevance of point of care (POC) measure-
ment of its arterial concentration (AAC), and changes with
therapeutic interventions. In a large cohort of patients with
ALF we examined the clinical associations of AAC and utility
in prediction of complications. Patients and Methods Patients
with ALF admitted to a single intensive therapy unit (ITU) over
a 10 year period were studied. AAC was measured on and
after admission using the POC PocketChem BA Blood Ammo-
nia Analyser. Its relation to development of HE, CE and sur-
vival was assessed. Changes in AAC following introduction of
hemofiltration for renal replacement and after liver transplan-
HEPATOLOGY, October, 2014
tation (LT) were examined, as was relation to progression of
HE and development of CE. Results 729 patients of median
age 37 years (IQR 28-49) were studied; 59% were female.
413 (57%) had acetaminophen (APAP) and 316 (43%) non-
APAP etiologies. 496 (68%) had or developed HE grade ≥3
(high-grade), in 81 (16%) with evidence of CE. 400 survived
with medical management alone, 176 underwent LT and 155
died without LT. Median AAC was 102 (66-156) in those with
high-grade HE and 73 (45-103) in those without (p<0.001).
In those admitted without HE, AAC on admission was higher
in those who progressed to high-grade (n=97) than those who
did not (n=221) 88 (60-146) vs. 65 (43-89) (p<0.001). In
patients with high grade HE who developed CE (n=81) AAC
was higher than those who did not (n=396) on admission (132
(99-203) vs. 84 (64-144)) and on ITU day 2 (122 (71-156) vs.
82 (61-124)) (both p<0.001). AAC was the best laboratory
measure for prediction of HE progression (AUROC 0.730) and
development of CE (AUROC 0.660). In those with HE, admis-
sion AAC did not differ between survivors and non-survivors
(87 (56-134) vs.93 (64-145) p=0.16) but did at day 3 (68
(49-101) vs. 98 (66-139) (p<0.001)) In those with high-grade
HE, hemofiltration on admission was associated with a median
16% fall in AAC on day 2 and 25% on day 3 as compared to
5% and 13% when not treated in this way (p<0.03). LT was
associated with a fall in AAC by 70% from 116 (77-170) to 38
(19-55) (p<0.0001). Conclusions Elevations of AAC, particu-
larly if sustained, relate closely to the development and severity
of cerebral complications of ALF. POC testing may assist in
the prediction of HE progression and the development of CE.
Elevated AAC is rapidly reversed by transplantation and to a
lesser degree by standard hemofiltration.
Disclosures:
Julia Wendon - Consulting: Pulsion, Excalenz
William Bernal - Consulting: Vital Therapies Inc
The following people have nothing to disclose: Vishal C. Patel, Beatriz Mateos
Muñoz, Elizabeth Sizer, Charalambos G. Antoniades, Christopher Willars,
Georg Auzinger
730
Impaired Neutrophil Function Aggravates Liver Injury
and Correlates with Clinical Severity Indices in Acute-
on-Chronic Liver Failure
Arshi Khanam1, Nirupma Trehan Pati1, Peggy Riese2, Archana
Rastogi3, Carlos A. Guzman2, Shiv K. Sarin1,4; 1Research, Insti-
tute of liver and biliary sciences, Delhi, India; 2Vaccinology and
Applied Microbiology, Helmholtz Centre for Infection Research,
Braunschweig, Germany; 3Pathology, Institute of Liver and Biliary
Sciences, Delhi, India; 4Hepatology, Institute of Liver and Biliary
Sciences, Delhi, India
Background: Impaired neutrophil function has been demon-
strated in acute liver failure and serves as a biomarker involved
in organ dysfunction and increase susceptibility to sepsis. How-
ever, its role in acute-on-chronic liver failure (ACLF) remains
completely unknown. Patients and methods: We assessed
phenotypic and functional alterations of neutrophils and their
contribution in hepatic injury in 17 hepatitis B virus-related
ACLF (HBV-ACLF), 19 alcohol–related ACLF (alcoholic-ACLF),
and 42 chronic hepatitis B (CHB) patients in comparison to
18 healthy controls (HC).Neutrophil phagocytic activity (NPA)
was determined by the uptake of opsonized E. coli and reac-
tive oxygen species (ROS) production with or without E. coli
stimulation.CXCR-1 and CXCR-2 expression was analyzed
by flowcytometry, immunohistochemistry (IHC) and qRT-PCR.
Results: Percentage of neutrophils was higher in both HBV and
alcoholic-ACLF patients than CHB and HC (Table). Contrarily,
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
NPA was significantly impaired in ACLF along with significant
increase in ROS. Flowcytometry and IHC showed up-regulated
CXCR-1 and 2 in ACLF. In ACLF, intrahepatic CXCR-1 and 2
gene expression was higher more than 6 fold (p<0.00) with a
significant increase in pro-inflammatory cytokines (IL-6, IL-17,
IL-23, CXCL-8, CCL-20 and GM-CSF). Role of neutrophils in
hepatic injury was determined by co-culturing of LPS stimulated
neutrophils or their supernatant with HepG2 cells. As com-
pared to controls, activated neutrophils from ACLF significantly
induced early apoptosis (p<0.04, 0.05) and necrosis (p<0.00,
0.00) of HepG2 cells by direct contact as well as cytokine/
ROS dependent mechanisms. Conclusions: ACLF patients have
increased frequency of neutrophils, with high expression of
migration receptors CXCR1/CXCR2. These activated neutro-
phils produce high ROS but have impaired phagocytic activ-
ity with high pro-inflammatory cytokine propagating hepatic
injury and liver failure. Neutrophil functional markers represent
a powerful tool for drug targets and clinical management of
ACLF patients.
Phenotypic and functional characterization of neutrophils in differ-
ent diseased groups
Disclosures:
The following people have nothing to disclose: Arshi Khanam, Nirupma Trehan
Pati, Peggy Riese, Archana Rastogi, Carlos A. Guzman, Shiv K. Sarin
731
Genome editing with Cas9 in adult mice corrects a liver
disease mutation and phenotype
Hao Yin; MIT, Cambridge, MA
The type II bacterial clustered, regularly interspaced, palin-
dromic repeats (CRISPR)-associated (Cas) system has been
engineered into a powerful genome editing tool consisting
of the Cas9 nuclease and a single guide RNA (sgRNA). The
sgRNA targets Cas9 to genomic regions that are complemen-
tary to the 20-nucleotide (nt) target region of the sgRNA and
that contain a 5ʹ-NGG-3ʹ protospacer-adjacent motif (PAM).
Double-stranded DNA breaks generated by Cas9 at target
loci are repaired by nonhomologous end-joining or homolo-
gy-directed repair (HDR). CRISPR-Cas9 genome editing has
been applied to correct disease-causing mutations in mouse
zygotes and human cell lines for cataract and cystic fibrosis,
but delivery to adult mammalian organs to correct genetic
disease genes has not been reported to our knowledge. We
demonstrate CRISPR-Cas9–mediated correction of a fumarylac-
etoacetate hydrolase (FAH) mutation in hepatocytes in a mouse
model of the human disease hereditary tyrosinemia. Delivery of
components of the CRISPR-Cas9 system by hydrodynamic injec-
tion resulted in initial expression of the wild-type Fah protein
in ~1/250 liver cells. Expansion of Fah-positive hepatocytes
rescued the body weight loss phenotype. Our study indicates
that CRISPR-Cas9–mediated genome editing is possible in adult
555A
animals and has potential for correction of human genetic dis-
eases.
Disclosures:
The following people have nothing to disclose: Hao Yin
732
LDH in the determination of cause in acute liver failure,
revisited
Michelle Gottfried1, Kurt Kleinschmidt2, William M. Lee2; 1Medical
University of South Carolina, Charleston, SC; 2University of Texas
Southwestern Medical Center at Dallas, Dallas, TX
Clinicians, often mention lactic dehydrogenase (LDH) as a
serum enzyme to be measured to help determine whether a
particular acute liver injury is due mainly to necrosis (high LDH,
high aminotransferases) or apoptosis (low LDH, high amino-
transferases). This wisdom draws upon an earlier observation
20 years ago by Telfer Reynolds (J Clin Gastro 1994;19:118),
suggesting that an ALT/LDH ratio > 1.5 discriminated between
viral hepatitis (an example of apoptotic cell death) and isch-
emia or acetaminophen (APAP) overdoses (primarily charac-
terized by necrosis). Methods: We measured serum LDH in 77
patients with acute liver failure (ALF) secondary to causes asso-
ciated with necrosis: APAP (N=31), ischemic injury (12); or
apoptosis: hepatitis A (8) or B (4), autoimmune (12) or drug-in-
duced hepatic injury (10). All patients had signs/symptoms of
ALF including prolonged INR (≥ 1.5) and encephalopathy and
available AST/ALTs. Results: Using a CART analysis to derive
the effectiveness of ALT/LDH ratio of > 1.5 as well as any ratio,
we were unable to discriminate effectively between the etiol-
ogy groups (accuracy 0.69, sensitivity 0.90, specificity 0.41,
AUROC 0.65). The same CART approach achieved an even
simpler model, namely an LDH value of >420 IU/L = necrosis,
which discriminated between apoptosis and necrosis with an
accuracy of 82%, sensitivity 0.79, specificity 0.85, AUROC
0.82. Conclusion: LDH is still of some value in separating isch-
emic and APAP liver injury from that due to various other cir-
cumstances in patients with ALF. However, unlike Reynolds’
work, it was not the ratio but an absolute value. These data
are limited currently to an ALF population. In settings where the
diagnosis eludes, knowing the LDH value may help narrow the
scope of subsequent investigation.
Disclosures:
William M. Lee - Consulting: Eli Lilly, Novartis; Grant/Research Support: Gilead,
Roche, Vertex, BI, Anadys, BMS, merck; Speaking and Teaching: Merck
The following people have nothing to disclose: Michelle Gottfried, Kurt Klein-
schmidt
556A AASLD ABSTRACTS
733
Liver failure determines the extra-hepatic organ failure
and outcome in patients with acute-on-chronic liver fail-
ure: Analysis of 1363 patients of AARC Data Base
Chandan K. Kedarisetty1, Shiv K. Sarin1, Lovkesh Anand1,
Zaigham Abbas4, Deepak N. Amarapurkar5, Ankit Bhardwaj2,
Ajeet S. Bhadoria2, Chhagan Bihari3, Amna S. Butt6, Ashok
Choudhary1, Chan Albert7, Yogesh K. Chawla9, Abdulkadir
Dokmeci10, Hitendra K. Garg1, Hasmik Ghazinyan11, Saeed S.
Hamid6, Ankur Jindal1, Naveen Kumar1, Avinash Kumar1, Guan
Huei Lee12, Laurentius A. Lesmana13, Mamun A. Mahtab14, Rakhi
Maiwall1, Qin Ning15, Devraj Rangegowda1, Archana Rastogi3,
Amrish Sahney1, Samir R. Shah16, Gamal Shiha17, Barjesh C.
Sharma18, Manoj Kumar1, Saggere M. Shasthry1, Soek Siam
Tan19, Chitranshu Vashishtha1, Man-Fung Yuen8, Osamu Yoko-
suka20; 1Hepatology, Institute of Liver and Biliary Sciences, New
Delhi, India; 2Research, Institute of Liver and Biliary Sciences, New
Delhi, India; 3Pathology, Institute of Liver and Biliary Sciences,
New Delhi, India; 4Hepatogastroenterology, Sindh Institute of Urol-
ogy and transplantation, Karachi, Pakistan; 5Gastroenterology and
Hepatology, Bombay Hospital and Medical Research, Mumbai,
India; 6Medicine, Aga Khan university hospital, Karachi, Pakistan;
7Surgery, University of Hong Kong, Hong Kong, China; 8Medi-
cine, University of Hong Kong, Hong Kong, China; 9Hepatology,
Post Graduate Institute of Medical Education and Research, Chan-
digarh, India; 10Gastroenterology, Ankara University School of
Medicine, Ankara, Turkey; 11Hepatology, Nork Clinical Hospital
of Infectious Diseases, Yerevan, Armenia; 12Gastroenterology and
Hepatology, National University Health system, Singapore, Singa-
pore; 13Hepatology, University of Indonesia, Jakarta, Indonesia;
14Hepatology, Bangabandhu Sheikh Mujib Medical university,
Dhaka, Bangladesh; 15Infectious Disease, Tongji Hospital of Tongji
Medical College, Wuhan, China; 16Gastroenterology and Hepa-
tology, Global Hospitals, Mumbai, India; 17Internal Medicine,
Liver Research Institute and Hospital, Cairo, Egypt; 18Gastroen-
terology, GB Pant Hospital, New Delhi, India; 19Gastroenterology
and Hepatology, Selayang Hospital, Selayang, Malaysia; 20Gas-
troenterology and Nephrology, Graduate School of Medicine,-
Chiba University, Chiba, Japan
Background and Aims: Acute-on-chronic liver failure (ACLF) is
a distinct syndrome characterized by an acute insult on under-
lying chronic liver disease culminating in extra-hepatic organ
failure and high mortality.The only definitive treatment is liver
transplantation. It is likely that interventions may be helpful, if
employed before extra-hepatic organ failure develop as there is
a potential of reversibility. We aimed at defining and grading
liver failure in ACLF patients, its impact on extra-hepatic organ
failure and patient outcome. Patients and Methods: It was a
retrospective- prospective data collection of 1363 patients from
17 university hospitals across Asia- Pacific from October 2012
to December 2013. Results: The overall mortality on day 28
was 52.1% and day 90 was 59.7%; 34.8% occurring in the
first 2 weeks. The common hepatotropic acute insults were
alcohol (563, 41.3%), viral infections (452, 33.1%), drug
induced liver injury (93, 6.82%) and flare of autoimmune (35,
2.6%) and Wilson’s disease (22, 1.6%). The chronic etiologies
included alcohol (645, 47.3%), viral (335, 24.6%), nonalco-
holic fatty liver disease (NAFLD)/cryptogenic (277, 20.2%)
and others (106, 7.9%). The CLIF SOFA score was evaluated
to assess organ failure in the Asian cohort. Even in the absence
of any extra-hepatic organ failure, 39% mortality was observed
in 28 days, primarily due to liver failure. The AARC grading
of liver failure (Class I,II and III), based on bilirubin, INR and
grade of hepatic encephalopathy correlated with mortality;
25.5% (75/ 106) in Class 1, 52.8% (336/636) in Class II
and 78.8% (167/212) in Class III (AUROC 0.72, p-0.000).
HEPATOLOGY, October, 2014
Conclusions: Our results provide conclusive evidence that ACLF
should be defined based on liver failure. Extra-hepatic organ
failure (s) is likely to be a consequence of worsening liver fail-
ure. The proposed AARC grading of liver failure needs to be
further validated.
Kapler Meier showing survival according to Class of liver failure
according to AARC grading
Disclosures:
Qin Ning - Advisory Committees or Review Panels: ROCHE, NOVARTIS, BMS,
MSD, GSK; Consulting: ROCHE, NOVARTIS, BMS, MSD, GSK; Grant/Research
Support: ROCHE, NOVARTIS, BMS; Speaking and Teaching: ROCHE, NOVAR-
TIS, BMS, MSD, GSK
Soek Siam Tan - Advisory Committees or Review Panels: Abbvie
Man-Fung Yuen - Advisory Committees or Review Panels: GlaxoSmithKline,
Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer,
GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-My-
ers Squibb, Pfizer; Grant/Research Support: Roche, Bristol-Myers Squibb,
GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmith-
Kline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead
Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science
Osamu Yokosuka - Grant/Research Support: Chugai, Taiho, Bristol Myers
The following people have nothing to disclose: Chandan K. Kedarisetty, Shiv K.
Sarin, Lovkesh Anand, Zaigham Abbas, Deepak N. Amarapurkar, Ankit Bhard-
waj, Ajeet S. Bhadoria, Chhagan Bihari, Amna S. Butt, Ashok Choudhary, Chan
Albert, Yogesh K. Chawla, Abdulkadir Dokmeci, Hitendra K. Garg, Hasmik
Ghazinyan, Saeed S. Hamid, Ankur Jindal, Naveen Kumar, Avinash Kumar,
Guan Huei Lee, Laurentius A. Lesmana, Mamun A. Mahtab, Rakhi Maiwall,
Devraj Rangegowda, Archana Rastogi, Amrish Sahney, Samir R. Shah, Gamal
Shiha, Barjesh C. Sharma, Manoj Kumar, Saggere M. Shasthry, Chitranshu
Vashishtha
734
Higher thyroid-stimulating hormone, triiodothyronine
and thyroxine values are associated with better out-
come in acute liver failure
Olympia Anastasiou1, Jan-Peter Sowa1, Paul P. Manka1, Chris-
tian D. Fingas2, Wing-Kin Syn3, Antonios Katsounas1, Dagmar
Führer4, Robert K. Gieseler1, Lars Bechmann1, Guido Gerken1,
Lars C. Moeller4, Ali Canbay1; 1Department of Gastroenterology
and Hepatology, University Hospital Essen, Essen, Germany;
2Department of General, Visceral and Transplantation Surgery,
University Hospital Essen, Essen, Germany; 3Regeneration and
Repair Group, The Institute of Hepatology London, London, United
Kingdom; 4Department of Endocrinology and Metabolism, Univer-
sity Hospital Essen, Essen, Germany
Background & Aims: Changes in thyroid-stimulating hormone
(TSH) and thyroid hormone levels, mostly in the form of non-thy-
roidal illness syndrome (NTIS), have been described in many
disease entities including myocardial infarction and sepsis.
However, the relationship of acute liver failure (ALF) and thy-
roid hormone levels has not yet been clarified. The objective
of our present study was to evaluate potential correlations of
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
select thyroid functional parameters with ALF. Methods: On
admission TSH, free thyroxine (fT4), free triiodothyronine (fT3),
total thyroxine (TT4), and total triiodothyronine (TT3) were
determined in 84 consecutively recruited ALF patients. Patients
were divided in groups according to the outcome of ALF (spon-
taneous recovery: SR; transplantation or death: NSR). NTIS
was defined as low or normal TSH, low fT3 or low fT4 without
known pre-existing thyroid illness. Results: More than 50% of
patients with ALF presented with abnormal thyroid parameters.
These patients had a greater risk for an adverse outcome than
euthyroid patients. Patients in the SR group had significantly
higher TSH, TT4, and TT3 (but not fT4) concentrations than
NSR patients. Albumin concentrations were significantly higher
in SR than in NSR. Conclusion: In patients with ALF, TSH and
total thyroid hormone levels differed significantly between SR
patients and NSR patients. Moreover, in more than 50% of
patients with ALF various degrees of NTIS were apparent upon
initial presentation. Therefore, thyroid parameters may serve as
additional indicators for severity of ALF.
Disclosures:
Robert K. Gieseler - Management Position: Rodos BioTarget GmbH; Stock Share-
holder: Rodos BioTarget GmbH
The following people have nothing to disclose: Olympia Anastasiou, Jan-Peter
Sowa, Paul P. Manka, Christian D. Fingas, Wing-Kin Syn, Antonios Katsounas,
Dagmar Führer, Lars Bechmann, Guido Gerken, Lars C. Moeller, Ali Canbay
735
Ambient temperature short-term preservation of liver
cells for bioengineering applications using perfluoro-
decalin as an oxygen source
Darren L. Scroggie2,1, Eloy Erro1, James T. Bundy1, Aurelie Le lay1,
Dominic Davis1, Sunil R. Modi1, Barry Fuller2,1, Clare Selden1;
1Institute of Liver and Digestive Health, University College London,
London, United Kingdom; 2Division of Surgery and Interventional
Science, University College London, London, United Kingdom
The short-term storage of three-dimensional liver cell spher-
oids at ambient temperature provides a convenient method
for transportation of cell constructs used in tissue engineer-
ing and bioartificial liver devices. The solubility of oxygen in
perfluorodecalin is approximately 20 times that of in water;
subsequently it functions as an oxygen source to support cell
metabolism and proliferation by releasing the dissolved gas
over time. The aim of this study was to optimise the geometry
and chemical composition of a preservative solution for short
term preservation at ambient temperature of tissue engineered
constructs. A biomass useful for a bioartificial liver device was
used as a model to define the relevant parameters that main-
tain cell number and functional viability. HepG2 cells encap-
sulated within alginate beads were cultured for 12 days in a
bioreactor, producing three-dimensional cell spheroids. Per-
fluorodecalin was oxygenated for 30 minutes prior to use.
Alginate-encapsulated HepG2 cell spheroids, customised tissue
culture medium and oxygenated perfluorodecalin were placed
in 40ml sterile glass containers in varying ratios, and stored at
room temperature for 48 hours. The number of cells per ml of
alginate was measured using an automated nucleus counter,
and viability determined by fluorescence microscopy using flu-
orescein diacetate and propidium iodide staining. The mean ±
SD number of cells per ml of alginate beads at the start of the
experiment was 2.74 × 107 ± 2.9 × 106 (n = 5). After 48h at
ambient temperature, a statistically significant (p < 0.05, Bon-
ferroni correction) increase in cell number was observed at a
3 to 1 ratio of perfluorodecalin to encapsulated cells, to 3.42
× 107 ± 3.4 × 106 (n = 4) cells/ml. There was a tendency for
higher perfluorodecalin proportions to result in higher cell num-
bers; however the differences between ratios did not achieve
557A
statistical significance. Mean viabilities after 48h ranged from
92.30% ± 3.1pp (n = 20) to 94.80% ± 2.2pp (n = 20), from
a starting viability of 100% ± 0.02pp (n = 5). At the 3 to 1
ratio, viable cell number increased from 2.74 × 107 ± 2.87
× 106 to 3.23 × 107 ± 3.26 × 106. It can be concluded that
three-dimensional spheroids of hepatocyte-derived epithelial
cell lines can be stored at ambient temperature for 48 hours
using perfluorodecalin as an oxygen source, with continuing
proliferation. This technique offers a simple and convenient
method of transporting metabolically active cells worldwide for
bioengineering applications. It is surprising that perfluorodeca-
lin supported continuing cell proliferation at ambient tempera-
ture; this finding merits further investigation.
Disclosures:
The following people have nothing to disclose: Darren L. Scroggie, Eloy Erro,
James T. Bundy, Aurelie Le lay, Dominic Davis, Sunil R. Modi, Barry Fuller, Clare
Selden
736
Hepatocyte Krüppel-Like-Factor 6 expression is upreg-
ulated in acute liver injury and represses hepatocyte
proliferation
Svenja Sydor1, Jan Best1, Paul P. Manka1, Martin Schlattjan1,
Thomas Schreiter1, Diana Vetter2, Andreas Paul3, Scott L. Fried-
man4, Guido Gerken1, Ali Canbay1, Lars Bechmann1; 1Depart-
ment of Gastroenterology and Hepatology, University Hospital
Essen, Essen, Germany; 2Department of Surgery, University Hospi-
tal Zurich, Zurich, Switzerland; 3Department of General, Visceral
and Transplantation Surgery, University Hospital Essen, Essen,
Germany; 4Division of Liver Diseases, Mount Sinai School of Med-
icine, New York, NY
Background: Krüppel-like factor 6 (KLF6) is a ubiquitously
expressed, multifunctional transcription factor and tumor sup-
pressor gene. In previous studies, we identified KLF6 as an
important transcription factor in hepatocyte glucose and lipid
homeostasis, and downregulation of KLF6 was associated with
accelerated tumor-growth of hepatocellular cancer. So far, no
data is available on the role of KLF6 in acute liver injury and
regeneration. Here, we aimed to investigate the expression pat-
tern of hepatocyte KLF6 in patients with acute liver failure (ALF),
in a human ex-vivo perfusion model of acetaminophen induced
liver injury and to study the effects of hepatocyte specific KLF6
depletion in mice undergoing partial hepatectomy (PHx). Meth-
ods: Liver samples from 10 patients with drug-induced ALF
were obtained (either liver biopsy or explanted liver in patients
who underwent liver transplantation) and KLF6 expression was
quantified via immunohistochemistry (IHC) and compared to
liver samples from 10 non-cirrhotic NAFLD patients with simple
steatosis as controls. In another setting, non-cirrhotic liver tissue
was obtained from partial liver resection for metastatic surgery
in 6 patients. In an established ex-vivo perfusion model, these
samples were treated with acetaminophen (APAP) up to 30
hours. KLF6 mRNA expression was quantified before and after
APAP treatment. In a murine model of PHx (n=6 mice/group),
we assessed KLF6 expression before and at different timepoints
after PHx. Also, hepatocyte specific KLF6 knockout mice under-
went PHx and we performed PCNA staining at different time-
points to assess hepatocyte proliferation, compared to controls
(n=6 mice/group). Results: IHC in ALF patients revealed sig-
nificant upregulation of KLF6 protein within hepatocytes com-
pared to controls. APAP perfusion of non-cirrhotic liver tissue
significantly induced KLF6 expression (4.4-fold, p=0.006). In
mice, PHx also led to significant induction of KLF6 expression
at different timepoints (3.8-fold, p=0.03). In hepatocyte spe-
cific KLF6 knockouts, hepatocyte proliferation, as assessed with
558A AASLD ABSTRACTS
PCNA staining was significantly induced at early timepoints
(p<0.05). Conclusion: Here, we were the first to study KLF6
expression in ALF. Our findings suggest an important role for
KLF6 in liver regeneration, as KLF6 expression is upregulated in
different models of acute liver injury and ALF patients. Hepato-
cyte proliferation following PHx was induced in mice with KLF6
knockdown, compared to controls, suggesting a role for KLF6
in hepatic regeneration. Further studies and data analysis will
be needed to identify the individual mechanisms for KLF6 medi-
ated effects in acute liver injury.
Disclosures:
Jan Best - Speaking and Teaching: BTG
Scott L. Friedman - Advisory Committees or Review Panels: Pfizer Pharmaceutical,
Sanofi-Aventis; Consulting: Conatus Pharm, Exalenz, Genenetch, Glaxo Smith
Kline, Hoffman-La Roche, Intercept Pharma, Isis Pharmaceuticals, Melior Dis-
covery, Nitto Denko Corp., Debio Pharm, Synageva, Gilead Pharm., Ironwood
Pharma, Alnylam Pharm, Tokai Pharmaceuticals, Bristol Myers Squibb, Takeda
Pharmaceuticals, Nimbus Discovery, Bristol Myers Squibb, Intermune, Astra Zen-
eca, Abbvie, Intermune; Grant/Research Support: Galectin Therapeutics, Tobira
Pharm, Vaccinex Therapeutics, Tobira; Stock Shareholder: Angion Biomedica
The following people have nothing to disclose: Svenja Sydor, Paul P. Manka,
Martin Schlattjan, Thomas Schreiter, Diana Vetter, Andreas Paul, Guido Gerken,
Ali Canbay, Lars Bechmann
737
Impaired monocyte and macrophage function in Hepa-
titis E Virus (HEV) infected pregnant women with Acute
Liver Failure
Rashi Sehgal1, Paul David1, Ashish Vyas1, Arshi Khanam1, Ankit
Bhardwaj1, Preety Rawal1, Syed Hissar1, Sharda Patra2, Shubha
S. Trivedi2, Shyam Kottilil3, Shiv K. Sarin1, Nirupma Trehanpati1;
1Research, Institute Of Liver and Biliary Sciences, New Delhi,
India; 2Lady Harding Medical College & Smt. S. K. Hospital, New
Delhi, India; 3Laboratory of Immunoregulation, National Institute
of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, Maryland, MD
Purpose: Hepatitis E virus (HEV) causes acute viral hepatitis
(AVH-E). AVH-E is more serious infection in pregnant females
and is often complicated by acute liver failure (ALF). Little
is known about the immunological factors that contribute to
development of ALF in pregnancy. Here,we investigated both
innate and adaptive immune cells, including expression of
TLRs,downstream signaling molecules and phagocytic capaci-
ties of innate immune cells. Patients and Methods: PBMCs from
patients Gr.1(healthy pregnant females), Grs. 2 & 3 (AVH-E
pregnant females with or without ALF) were used for surface
and intracellular immunophenotyping for various immune cells:
monocytes(CD14+),mcrophages(CD11b+CD163+),DC’s(DC-
SIGN),B-cells(CD19+ CD38+ CD24+) and T-cells (CD45RA+
CCR7+ on CD4+ and CD8+). The expression of TLR 3,7 &
9 was also studied on monocytes, macrophages & DC’s.
Gene expression of downstream signaling pathway MyD88
& it molecules MyD88, IRF3 and IRF7 was studied by qRT-
PCR. Phagocytic activity of monocytes & macrophages was
determined by uptake of opsonized E.coli. Reactive oxygen
species (ROS) production by macrophages & monocytes was
determined, with and without stimulation of fMLP, E.coli and
PMA. Results:Gr.2 and Gr.3 had increased monocyte derived
macrophages (%age of CD11b+CD163+macrophages;Gr2.
1.1 ± 0.4%;Gr3. 0.8 ± 0.3% vs. Gr1. 0.6 ± 0.2%, P=0.03,
P=0.02) and dendritic cells (DCSIGN MFI; Gr2. 40±5.3, Gr3.
38±7 vs. Gr1. 15±1.2, P=0.0004,P=0.002). However, Gr2.
patients showed significantly decreased phagocytic activity of
macrophages (38±5 vs 80.2±4,p=0.01) as well as decreased
ROS production of macrophages (Resting, p=0.001, E Coli,
p=NS, fMLP, p=0.0001 & PMA p=0.0001) respect to Gr.1 but
it is non-significant compared to Gr.2, while expression of TLRs
HEPATOLOGY, October, 2014
and its MYD88 signaling molecules show impaired response in
Gr.2 compared to Gr.1 and Gr.3. There was significant reduc-
tion of CD4+ and CD8+ effector T cells (CCR7-CD45RA+) in
Gr.2 than Gr.3 and 1(1 ± 0.5% vs. 12.5 ± 3.5% and 10.4
± 2%, P=0.002; 11± 3% vs. 30.3 ±4% and 13.2 ±2.6%,
P< 0.05). Conclusions: Our results demonstrate an impaired
innate immunity. The expression of TLR 3, 7 and 9 was reduced
in AVH-E-ALF patients and also the expression of downstream
signaling molecules was reduced. The frequency of effector
T-cells was reduced with a Th1 shift which is associated with
AVH-E-ALF patients. Therefore, we conclude their is a defect
in TLR-mediated activation of innate immune system resulting
in flawed innate-adaptive cross-talk which leads to the devel-
opment of ALF in pregnant females with HEV infection. Further
studies with TLR modulation can be explored in AVH-E-ALF to
enhance survival rates.
Disclosures:
The following people have nothing to disclose: Rashi Sehgal, Paul David, Ashish
Vyas, Arshi Khanam, Ankit Bhardwaj, Preety Rawal, Syed Hissar, Sharda Patra,
Shubha S. Trivedi, Shyam Kottilil, Shiv K. Sarin, Nirupma Trehanpati
738
Increased neutrophil actin production and translocation
of myeloperoxidase in patients with acetaminophen-in-
duced acute liver failure may contribute to multiorgan
failure
Godhev K. Manakkat Vijay1, Gema Vizcay-Barrena2, Thomas Tra-
nah1, Leanne Glover2, Vishal C. Patel1, Christine Bernsmeier1,
Jennifer M. Ryan1, Laura J. Blackmore1, Xiaohong Huang1, Vic-
toria T. Kronsten1, Nicholas J. Taylor1, William Bernal1, Georg
Auzinger1, Christopher Willars1, Julia Wendon1, Yun Ma1, Bar-
bara Bain3, Alice Warley2, Debbie Shawcross1; 1Institute of Liver
Studies, King’s College London, London, United Kingdom; 2Centre
for Ultrastructural Imaging, Guy’s, King’s and St. Thomas’ School
of Medicine, King’s College London, London, United Kingdom;
3Haematology Department, St Mary’s Hospital, Imperial College
London, London, United Kingdom
Background: There is a marked propensity for patients with
acetaminophen-induced acute liver failure (AALF) to develop
bacterial and fungal infections which may not only hasten the
development of brain edema, but also precipitate multiorgan
failure (MOF) and death. Neutrophil dysfunction has recently
been shown to be an important biomarker of poor prognosis
in AALF. Myeloperoxidase (MPO) is abundantly expressed in
neutrophil azurophilic granules and generates reactive oxygen
species (ROS) which kill invading pathogens but during AALF
also induce bystander damage and MOF. Actin, a cytoskeletal
globular protein, plays a key role in neutrophil degranulation.
Therefore we sought to determine the neutrophil spontaneous
oxidative burst (SOB), MPO degranulation and actin produc-
tion in AALF (n=11) compared to healthy controls (HC) (n=10).
Methods: Neutrophil SOB was measured by the conversion of
dihydrorhodamine to rhodamine by peroxidase. Leukocytes
were stained with fluorochrome-bound anti-CD16/CD11b/
MPO antibodies to determine the neutrophil extracellular (EC)
and intracellular (IC) (after permeabilisation) changes following
the addition of E. coli, by flow cytometry. Transmission elec-
tron microscopy (TEM) was performed on isolated leukocytes
from whole blood and stained with primary mouse (anti-actin
and anti-MPO) antibodies independently and then with sec-
ondary gold-conjugated antibodies. Stained sections were
viewed using TEM and images were acquired with a digital
camera. The gold particles present in the cells were counted
using ImageJ software and relative labelling index (RLI) was
calculated to determine the specificity of the stain (<1-random
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS 559A

and non-specific labelling). Plasma cytokines were also mea- use of G-CSF for the treatment of patients with ACLF signifi-
sured. Results: SOB was increased in AALF neutrophils com- cantly reduced short-term mortality.
pared to HC (p<0.0001). Baseline EC MPO was increased in
Forest Plot: G-CSF vs. placebo or no intervention: all cause mor-
AALF patients compared to HC (p<0.0001). Following E. coli
tality
stimulation, EC MPO was increased in HC compared to base-
line (p<0.05) but not in AALF. There was no difference in the
baseline or post stimulation IC MPO between AALF and HC.
TEM revealed no difference in the MPO labelling in AALF com-
pared to HC. However, actin was increased in the cytoplasm
of neutrophils (RLI>1) in AALF compared to HC (p<0.005;
degree of freedom 1). Plasma IL-6 and IL-8 were increased in Disclosures:
AALF compared to HC (p<0.0001). Conclusion: These data The following people have nothing to disclose: Victoria J. Ornelas-Arroyo, Desiree
show that there is no deficiency in the production of MPO in Vidaña-Pérez, Guadalupe Delgado-Sánchez, Indira R. Mendiola Pastrana,
AALF. However the increase in neutrophil SOB, degranulation Camilo Noreña-Herrera, Tonatiuh Barrientos-Gutierrez, Eva Juárez Hernández,
Nahum Méndez-Sanchéz, Misael N. Uribe-Esquivel, Norberto C. Chavez-Tapia
as measured by actin and EC MPO in AALF implies that gran-
ules translocate to the cell surface releasing ROS into the tissues
thereby contributing to bystander damage and organ failure.
Disclosures: 740
William Bernal - Consulting: Vital Therapies Inc Etiology, Clinical Features and Outcome of Acute Liver
Julia Wendon - Consulting: Pulsion, Excalenz Failure in Japan
Debbie Shawcross - Advisory Committees or Review Panels: Norgine; Grant/ Nobuaki Nakayama1, Hirohito Tsubouchi2, Satoshi Mochida1;
Research Support: Norgine; Speaking and Teaching: Norgine 1Department of Hepatology and Gastroenterology, Saitama Med-
The following people have nothing to disclose: Godhev K. Manakkat Vijay, ical University, Moroyama-Machi, Japan; 2Kagoshima City Hospi-
Gema Vizcay-Barrena, Thomas Tranah, Leanne Glover, Vishal C. Patel, Christine
Bernsmeier, Jennifer M. Ryan, Laura J. Blackmore, Xiaohong Huang, Victoria T. tal, Kagoshima, Japan
Kronsten, Nicholas J. Taylor, Georg Auzinger, Christopher Willars, Yun Ma, [Aims] Novel diagnostic criteria for “acute liver failure (ALF)”
Barbara Bain, Alice Warley
were established in 2011 in Japan, which include the disease
entity of “fulminant hepatitis”. Based on these, a nationwide
survey was executed to clarify the etiology, clinical features
739 and outcome of ALF patients seen between 2010 and 2012.
Granulocyte-colony stimulating factor for acute-on- [Methods] Total of 757 ALF patients were enrolled from 742
chronic liver failure: systematic review and meta-analy- institutes. All patients showed a prothrombin time (INR) of 1.5
sis of randomized control trials or more within 8 weeks after the onset of deaese symptoms.
Victoria J. Ornelas-Arroyo1, Desiree Vidaña-Pérez2, Guada- [Results] (1) Disease Types: 757 patients were classified into
lupe Delgado-Sánchez2, Indira R. Mendiola Pastrana2, Camilo 385 patients (50.9%) without hepatic coma and 372 patients
Noreña-Herrera2, Tonatiuh Barrientos-Gutierrez2, Eva Juárez (49.1%) with hepatic coma, and the later patients were further
Hernández1, Nahum Méndez-Sanchéz1, Misael N. Uribe-Es- subclassified into 2 disease type; 218 patients (28.8%) with
quivel1, Norberto C. Chavez-Tapia1; 1Medica Sur Clinic & Foun- the acute type and 154 patients (20.3%) with the subacute
dation, Mexico City, Mexico; 2National Institute of Public Health, type, in whom hepatic encephalopathy developed within 10
Mexico City, Mexico days and between 11 and 56 days, respectively, after the
onset of disease symptoms. Also, they were classified into 617
Background: Acute-on-chronic liver failure (ACLF) is associated
patients (81.5%) with histological findnings of hepatitis and
with increased short and long-term mortality. Currently, orth-
140 patients (18.5%) without hepatitis. (2) Etiologies: The
otropic liver transplantation remains the only definitive ther-
most prominent etiology was hepatitis viral infection; 30.4%
apy for patients with ACLF. Several animal models of liver
(117/385) of ALF without hepatic coma and 39.0% (85/218)
failure have demonstrated that granulocyte-colony stimulat-
and 26.6 % (41/154) of acute type and and subacute type,
ing factor (G-CSF) accelerates the liver regeneration process
respectively, and HBV infection was responsible for 69.5%
and improves survival. The objective of this systematic review
(169/243) of them. Autoimmune hepatitis and drug aller-
was to assess the benefits and harms of G-CSF in patients
gy-induced hepatitis were found in 42 patients (10.9%) and
with acute-on-chronic liver failure. Material and methods: The
38 patients (9.9%), respectively, without hepatic coma and
research was made in The Cochrane Central Register of Con-
in 26 patients (7.0%) and 46 patients (12.4%), respectively,
trolled Trials (CENTRAL), MEDLINE, EMBASE and LILACS until
with hepatic coma. Circulatory disturbance was the most pre-
November 2013. Additionally, the references from the iden-
dominant as an etiology of ALF without hepatitis (68 patients:
tified studies were handsearched. Randomized clinical trials
48.6%). Drug toxicity-induced liver injury including acetamino-
comparing the use of G-CSF against placebo or no interven-
phen intoxication was found only in 11 patients. Indeterminate
tion in patients with ACLF were selected. Three authors inde-
etiology accounted for 93 patients (24.2%) in ALF patients
pendently assessed the quality of the studies, evaluated the risk
without hepatic coma and 106 patients (28.5%) in those with
of bias, and extracted the data. Results: Two trials with a total
hepatic coma. (3) Therapies and the Outcome: Although 308
of 102 patients were included. One trial compared the use
patients (82.1%) without hepatic coma survived without liver
of G-CSF against placebo. The second trial compared G-CSF
transplantation (LT), only 101 patients (27.2%) with hepatic
against no intervention. Compared with the control group, the
coma were rescued after treatment of artificial liver support
group that received G-CSF presented a significant reduction
with plasma pharesis and hemodiafiltration without receiving
in short-term mortality (RR 0.56; 95% CI 0.39 to 0.80). There
LT. Total of 85 patients (22.5%) received LT, and 63 patients
is not enough evidence to show an effect of G-CSF therapy
(74.1%) were rescued. [Discussion & Conclusion] Hepatitis
on mortality secondary to gastrointestinal bleeding (RR 1.45;
virus infection, mainly HBV infection, was predominant as an
95% CI 0.50 to 4.27). The adverse effects reported included:
etiology of ALF in Japan, while ALF without the histological find-
fever, rash, zoster, headache and nausea. Conclusions: The
ings of hepatitis, such as acetaminophen intoxication, reraly
560A AASLD ABSTRACTS HEPATOLOGY, October, 2014

found. Although the survival rates of patients without hepatic
coma were excellent, the prognosis of those with coma was
unfavorate due to shortage of donors for LT.
Disclosures:
Hirohito Tsubouchi - Grant/Research Support: MSD, Chugai Pharmaceutical, Kan
Research Institute, Daiichi-Sankyo, Eisai, Tanabe Mitsubishi
Satoshi Mochida - Grant/Research Support: Chugai, MSD, Tioray Medical,
BMS; Speaking and Teaching: MSD, Toray Medical, BMS, Tanabe Mitsubishi
The following people have nothing to disclose: Nobuaki Nakayama
innate immune responses, augmenting pro-resolution/efferocy-
tosis responses and may be of therapeutic utility in offsetting
liver injury and promoting resolution responses in ALF.
Disclosures:
Mark R. Thursz - Advisory Committees or Review Panels: Gilead, BMS, Abbott
Laboratories
Julia Wendon - Consulting: Pulsion, Excalenz
The following people have nothing to disclose: Evangelos Triantafyllou, Oltin T.
Pop, Evaggelia Liaskou, Christine Bernsmeier, Wafa Khamri, Zania Stamataki,
Yun Ma, Alberto Quaglia, Chris J. Weston, Stuart M. Curbishley, David H.
Adams, Charalambos G. Antoniades

741
Secretory Leukocyte Protease Inhibitor (SLPI) promotes 742
hepatic resolution responses in acute liver failure (ALF) Characterization of disease-specific biomarkers in hep-
Evangelos Triantafyllou1,2, Oltin T. Pop1, Evaggelia Liaskou3, atitis B virus-related acute-on-chronic liver failure and
Christine Bernsmeier1, Wafa Khamri2, Zania Stamataki3, Yun their predictive value for mortality
Ma1, Mark R. Thursz2, Julia Wendon1, Alberto Quaglia1, Chris
Jun Li1, Jiaojiao Xin1, Ding Wenchao2, Qian Zhou1, Longyan
J. Weston3, Stuart M. Curbishley3, David H. Adams3, Charalam-
Jiang1, Dongyan Shi1, Lanjuan Li1; 1State Key Laboratory for Diag-
bos G. Antoniades1,2; 1Institute of Liver Studies, King’s College
nosis and Treatment of Infectious Diseases, The First Affiliated Hos-
London, London, United Kingdom; 2Section of Hepatology, Impe-
pital, School of Medicine, Zhejiang University, Hangzhou, China;
rial College London, London, United Kingdom; 3NIHR Biomedical 2Systems Biology Division, Zhejiang-California International Nano-
Research Unit and Centre for Liver Research, University of Birming-
systems Institute, Zhejiang University, Hangzhou, China
ham, Birmingham, United Kingdom
The establishment of disease-specific biomarkers to predict the
Background: Activation of innate immune responses is central
severity and mortality of hepatitis B-related acute-on-chronic
to the pathogenesis and outcome of acute liver failure (ALF).
liver failure (HBV-ACLF) is critical for identifying patients who
SLPI is a pivotal mediator of anti-inflammatory responses in
require early liver transplantation. In this study, novel sero-
ALF, through modulation of monocyte (Mo) function. Here,
logical biomarkers of HBV-ACLF were initially screened using
we aimed to determine the effects of SLPI on hepatic innate
a human cytokine antibody microarray that contained 274
immune and pro-resolution responses in ALF. Methods: Anal-
known cytokines. These biomarkers were then validated by
ysis of circulating Mo and hepatic macrophages (h-Mφ) was
enzyme-linked immunosorbent assay (ELISA) using the sera
performed in ALF patients (n=24) and healthy volunteers
from 304 HBV-ACLF subjects; this analysis revealed that 15
(HC; n=14) using a panel of 15 markers for flow cytometry.
cytokines were significantly differentially expressed in subjects
Immunohistochemistry and multispectral imaging (n=10) were
with HBV-ACLF and chronic hepatitis B (CHB). Bioinformat-
used to determine the h-Mφ MerTK expression in ALF explants
ics analysis indicated that these proteins are involved in the
and pathological control tissue (n=10). h-Mφ phenotype and
systemic dysregulation of hepatocyte repopulation, inflamma-
LPS-induced (100ng/ml) cytokine secretion were determined
tion, apoptosis and the immune response in HBV-ACLF. Six
following administration of 0.5 ug/ml of recombinant human
of these cytokines, hepatocyte growth factor (HGF), macro-
(rh)-SLPI (n=5). Using ELISAs, LPS-stimulated cytokine levels
phage inflammatory protein 3α (MIP-3α), carcinoembryonic
were determined in rh-SLPI (0.5 ug/ml) conditioned healthy
antigen-related cell adhesion molecule 1 (CEACAM1), growth
neutrophil and NK cell culture supernatants (n=10). SLPI effects
differentiation factor 15 (GDF15), E-selectin and osteopontin,
on CD14+ Mo uptake of apoptotic neutrophils and MerTK
were significantly increased in the HBV-ACLF group compared
expression (efferocytosis marker) were assessed by confocal
with the CHB group by significance analysis of microarray
microscopy and flow cytometry (n=5). Apoptosis was quanti-
(SAM) and predictive analysis of microarray (PAM) analy-
fied in neutrophils cultured in vitro ± rh-SLPI conditioned Mo
ses. These results were confirmed by ELISA analysis of the six
cell culture supernatants (n=10). Results: Compared to HC,
cytokines in 304 HBV-ACLF, 40 CHB patients and 20 normal
circulating Mo in ALF exhibited increased MerTK expression
adults. High expression levels of HGF and GDF15 (44.4- and
(10.72vs52.09 %; p<0.0001), typified by an anti-inflam-
84.8-fold change, respectively) could be used to distinguish
matory phenotype (HLA-DRlow CD163high). An expansion of
MerTK+ h-Mφ was detected within areas of necrosis of ALF subjects with HBV-ACLF and CHB. Meanwhile, bioinformatics
liver explants, compared to pathological controls (428vs34 # analysis demonstrated that MIP-3α was closely associated with
cells/10 HPF; p=0.0002); flow cytometry confirmed the h-Mφ the severity and mortality of HBV-ACLF. Immunohistochemis-
anti-inflammatory phenotype HLA-DRlow(66.73vs91.66 %) try confirmed that HGF, GDF15 and MIP-3α were positive in
CD163high(23.73vs7.07 %) MerTKhigh(42.35vs25.99 %). SLPI HBV-ACLF-derived liver tissues and negative in CHB and nor-
significantly increased h-Mφ CD163 (19.7vs30 %; p=0.0081) mal control-derived liver tissues. Conclusion: HGF and GDF15
and MerTK (29.15vs36.43 %; p=0.0492) expression whereas represent potential novel biomarkers for the early diagnosis of
decreased CCR5 (47.42vs35.6 %; p=0.0076) expression. HBV-ACLF, and MIP-3α might be useful as a novel biomarker
TNF-α, IL-6 and IFN-γ levels were decreased in SLPI-treated for predicting the severity and mortality of HBV-ACLF.
Disclosures:
h-Mφ (6031vs4888; 2619vs2403; 89.6vs43.3 pg/ml respec-
The following people have nothing to disclose: Jun Li, Jiaojiao Xin, Ding Wen-
tively; p< 0.05) but remained unaffected in SLPI-treated NK cells chao, Qian Zhou, Longyan Jiang, Dongyan Shi, Lanjuan Li
and neutrophils. Compared to untreated Mo, SLPI increased
MerTK expression (22.57vs28.90 %; p=0.0078) and uptake
of apoptotic neutrophils (25.34vs30.34 %; p=0.0156). Neu-
trophils cultured with SLPI-treated Mo supernatants showed
increased apoptosis, compared to untreated (25.09vs20.14
%; p=0.002). Conclusions: Our data indicate that SLPI is a piv-
otal microenvironmental mediator that suppresses h-mφ driven
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
743
Traditional prognostic factors do not differentiate
between survivors and non-survivors in pediatric liver
failure patients on renal support
Ayse Akcan Arikan2,3, Keila L. de la Garza1, Poyyapakkam
R. Srivaths3, Alyssa Riley3, Kathleen Thompson2, Ryan Himes4,
Moreshwar S. Desai2; 1Baylor College of Medicine, Houston, TX;
2Pediatric Critical Care, Baylor College of Medicine, Houston, TX;
3Pediatric Renal, Baylor College of Medicine, Houston, TX; 4Pedi-
atric Liver, Baylor College of Medicine, Houston, TX
Critically ill pediatric patients with acute and acute-on-chronic
liver failure (LF) requiring renal support (CRRT) have high mor-
bidity and mortality. Traditional adverse outcome predictors
such as peak bilirubin and international normalized ratio (INR)
values have been reported not to perform well in critically ill
adult LF patients. Factors associated with adverse outcomes
in pediatric critically ill liver failure patients remain largely
unknown, although hypoalbuminemia and ascites were assoc-
ited with mortality in biliary atresia. We hypothesized that
peak total bilirubin, peak INR, platelet (plt) count nadir, and
hyponatremia would differentiate survivors from nonsurvivors
in pediatric LF patients on renal support. Retrospective chart
review was performed in patients with LF who received CRRT
between2011-2013. 44 patients, 31 % male; mean age was
6.7 ± 7.2 years were included. All pts were mechanically ven-
tilated with mean length of ventilation 18.5 ± 14.5 days. CRRT
was provided as continuous venovenous hemodiafiltration
(CVVHDF) with regional citrate anticoagulation for a mean of
15.7±16.8 days.The mean length of hospital stay was 52.8
± 44.5 days. 26/44 patients died. There were no differences
between peak total bilirubin, peak INR, serum sodium nadir,
plt count nadir, lowest albumin levels between survivors and
nonsurvivors.Severe hyponatremia (<130 mEq/L) was present
in 15/27 survivors and 11/17 nonsurvivors (p=0.36). Cumu-
lative fluid overload at CRRT start indexed to ICU admission
weight was not different between survivors and nonsurvivors
(19.2± 21.4% vs 21.6 ± 18.7%, p 0.34). None of the param-
eters tested were predictors of mortality.Survivors did have a
longer CRRT course than nonsurvivors (22.5± 20.9 days vs
11± 10.9 days, p=0.01). There were more survivors in the
transplanted group compared to not-transplanted pts (13/20
vs 5/23, p=0.01). LF-related AKI requiring CRRT has a very
high mortality and morbidity.Traditional prognostic factors do
not differentiate between survivors and nonsurvivors in critically
ill pediatric LF pts. Additional studies are needed to identify
candidate prognostic factors that might be applied to this spe-
cific patient population.
Disclosures:
The following people have nothing to disclose: Ayse Akcan Arikan, Keila L. de la
Garza, Poyyapakkam R. Srivaths, Alyssa Riley, Kathleen Thompson, Ryan Himes,
Moreshwar S. Desai
561A
744
Inclusion of Admission Red Cell Distribution Width
(RDW) and Mean Corpuscular Volume (MCV) improves
predictive accuracy of prognostic models of Acute Liver
Failure (ALF)
Kimberly A. Forde1,2, Thure Caire3, Craig Newcomb4, R. Todd
Stravitz3; 1Gastroenterology, University of Pennsylvania, Phila-
delphia, PA; 2Center for Clinical Epidemiology and Biostatistics,
University of Pennsylvania, Philadelphia, PA; 3Gastroenterology,
Hepatology and Nutrition, Virginia Commonwealth University,
Richmond, VA; 4Biostatistics and Epidemiology, University of Penn-
sylvania, Phialdelphia, PA
Background: Prognostic models to predict outcome in ALF
lack diagnostic accuracy, and may lead to death without liver
transplantation (LT) or unnecessary LT with lifelong health impli-
cations. The presence of the systemic inflammatory response
syndrome (SIRS) is associated with increased mortality in
patients with ALF. Sensitive markers of SIRS include changes
in erythrocyte size and distribution of width, are available on
every automated complete blood count (CBC), and may serve
as potential surrogates for SIRS. Aims: To determine whether
erythrocyte indices on admission CBC improve the accuracy
of prognostic models in patients with ALF alone, and in combi-
nation with known predictors of poor prognosis in ALF. Meth-
ods: 205 consecutive patients with ALF admitted to Virginia
Commonwealth University Medical Center from 2001 through
2011 were included as an ancillary study of the ALF Study
Group (ALFSG). ALFSG registry data included demographics,
etiology, admission laboratory values and clinical outcomes.
Specific parameters of the admission CBC reflecting the pres-
ence of SIRS, including the MCV, RDW, and mean platelet
volume (MPV), were collected on each patient. Predictive mod-
els were generated using logistic regression. The best perform-
ing prognostic model was compared to the performance of
Kings’ College Criteria (KCC) and Model for End-Stage Liver
Disease (MELD) score. Results: Among the 205 patient cohort,
122 (59.5%) of patients recovered without LT (spontaneous
survivors), and 83 patients died (n=63) and/or required liver
transplantation (n=21). Spontaneous survivors were younger,
more likely to have had an acetaminophen (APAP) overdose as
the cause of their ALF, and lower ammonia, total bilirubin, INR,
lactate, phosphate, and RDW (all comparisons, P<0.001).
Spontaneous survivors also tended to have earlier stages of
hepatic encephalopathy (P<0.001), lower MELD scores (mean
MELD 25 vs 32, P<0.0001) and fewer SIRS criteria on presen-
tation (P=0.008). A predictive model inclusive of ALF etiology
hepatic encephalopathy, INR, MCV, and RDW had a c-statistic
of 0.91. The sensitivity, specificity and percent correct classi-
fication of the model were 87%, 82% and 84%, respectively
outperforming the KCC and the MELD score. Conclusion: In
patients with ALF, the inclusion of admission erythrocyte indi-
ces which are available on every automated CBC (RDW and
MCV) in prognostic models improve the diagnostic accuracy of
standard prognostic models.
Disclosures:
The following people have nothing to disclose: Kimberly A. Forde, Thure Caire,
Craig Newcomb, R. Todd Stravitz
562A AASLD ABSTRACTS
745
Pre-existing liver diseases lead acute HEV infection to
progressive liver failure
Jong-Hon Kang1, Takeshi Matsui1, Kazumasa Nagai1, Akiko
Tomonari1, Kazunari Tanaka1, Kunihiko Tsuji1, HIroyuki Maguchi1,
Yoshiyasu Karino2, Itaru Ozeki2, Shuhei Hige2, Tomoaki Naka-
jima2, Takumi Ohmura2, Kazuaki Takahashi3, Masahiro Arai3,
Shunji Mishiro3; 1Center for Gastroenterology, Teine Keijinkai
Hospital, Sapporo, Japan; 2Department of Hepatology, Sapporo
Kosei General Hospital, Sapporo, Japan; 3Department of Medical
Sciences, Toshiba General Hospital, Tokyo, Japan
Background / Aims: Acute sporadic infection of hepatitis E virus
(HEV) has been emerging in industrialized countries because of
scientific and medical impacts. In the endemic areas, clinical
courses of acute HEV depend upon the presence of pre-existing
liver disease such as chronic HBV. However, in the developed
countries, whether underlying liver diseases could affect natural
course in acute HEV or not is obscure. The aim of this study is
to clarify the clinical impact of pre-existing liver disease on pro-
gression of acute liver failure (ALF) in hepatitis E (HE). Methods:
A total of 94 patients with sporadic and autochthonous hepa-
titis E in Sapporo, Japan, were enrolled. Acute HEV infection
was diagnosed upon the detection of HEV RNA by PCR and/
or anti-HEV antibody (IgM or IgA) in sera by enzyme linked
immune-sorbent assay. HEV genotype (Gt) s were determined
by comparison of a 326-nt sequence within ORF1 of HEV
genome. ALF was defined to be a case with longer prothrom-
bin time (INR > 1.5). Alcoholic liver disease (ALD) was defined
to be a case with ingestion over 80g ethanol/day. Results: Out
of 94 patients with HE (75 males, median age 52 years), 23
had underlying liver diseases; ALD in 10, NAFLD in 8, inactive
HBV carrier in 4, liver injury with uncertain reason in 2. Among
these 94 patients, ALF developed in 30, in which 4 presented
hepatic encephalopathy and 2 deceased. HEV Gt 3 was deter-
mined in 34 patients, Gt 4 in 56, co-infection with Gt 3+4 in
1, but Gts was not determined in remaining 3. Compared with
self-limited HE, ALF were associated with presence of pre-exist-
ing liver disease (13/30 vs. 10/64, p=0.0036) and infection
of HEV Gt 4 (27/29 vs. 29/61, p<0.0001). No relationship
was found between ALF and other host factors including etha-
nol intake, body weight (BW) and body mass index (BMI). In
addition, presence of pre-existing liver diseases was correlated
with amount of ethanol intake/day (77.5 vs. 20g, p=0.0077)
and BMI (25.62 vs. 22.03, p=0.0110). Conclusion: Our study
demonstrates that the presence of underlying liver diseases
including NAFLD and ALD could be the predictive factor for
deterioration in acute HEV in Japan. Host factors, such as mild
obesity and/or moderate amount of alcohol intake, may play
a role as background of pre-existing liver disease.
Disclosures:
The following people have nothing to disclose: Jong-Hon Kang, Takeshi Matsui,
Kazumasa Nagai, Akiko Tomonari, Kazunari Tanaka, Kunihiko Tsuji, HIroyuki
Maguchi, Yoshiyasu Karino, Itaru Ozeki, Shuhei Hige, Tomoaki Nakajima,
Takumi Ohmura, Kazuaki Takahashi, Masahiro Arai, Shunji Mishiro
746
A pilot study to determine the efficacy and safety of rib-
avirin in patients of acute severe hepatitis E
Rahul Gupta, Sandeep S. Sidhu, Varun Mehta, Ajit Sood; Gastro-
enterology, Dayanand Medical College and hospital, Ludhiana,
India
Purpose: The role of ribavirin for treatment of severe acute or
chronic hepatitis E virus (HEV) infection is not well defined. A
single centre prospective pilot study was undertaken to inves-
tigate the applicability and efficacy of ribavirin therapy in
HEPATOLOGY, October, 2014
acute severe HEV infections. Methods: A total of ten patients
with severe acute or fulminant hepatitis E were enrolled in this
study. Specific antiviral drug ribavirin was prescribed 400
mg twice a day, per orally for 7 days, in addition to standard
of care treatment. Safety parameters were analysed during
therapy and at the end of treatment. Patients were followed
up at week 1, 2, 3, 4 and 8 from the commencement of the
ribavirin therapy. The primary end point was improvement in
survival and secondary end points were improvement in liver
function tests, HEV RNA kinetics and encephalopathy by 1 or
more grades. Results: The median age of the patients was 32.5
years (range, 22-53 years), with nine males and one female.
All patients had jaundice and two had encephalopathy. All
patients were positive for IgM anti HEV at week one. HEV RNA
was positive in nine patients and negative in one at week 0.
HEVRNA viral levels showed decline and became negative by
third week in all patients. Mean HEVRNA levels (in copies/
ml) at week 0, 1 and 2 were 6.3x105 (range 0-3.8x106),
9.4x103 (range 0-4.0x104) and 2.2x102 (range 0-2.1x103),
respectively. Four patients became negative for HEV RNA by
end of 1st week, other three at end of week 2 and rest three
at end of week 3, respectively. All patients except one showed
declining trends of bilirubin, serum alanine amintransferase
(ALT), serum aspartate aminotransferase (AST) and INR with
normalization by week 8. Ribavirin was well tolerated by all
patients. Nine of ten patients showed complete recovery in
terms of clinical, biochemical and virological parameters. One
patient despite completing therapy with ribavirin and achieving
negativity for HEV RNA, died after 10 weeks. Conclusions:
Ribavirin monotherapy in present study although given for short
duration showed clinical, biochemical and virological response
in all patients, except one. Ribavirin was well tolerated and
found safe in present study. This preliminary study indicates the
beneficial role of ribavirin in acute severe hepatitis E patients.
A randomized controlled trial for the role of ribavirin in severe
acute hepatitis E is required before making any specific recom-
mendations.
Disclosures:
The following people have nothing to disclose: Rahul Gupta, Sandeep S. Sidhu,
Varun Mehta, Ajit Sood
747
Granulocyte colony stimulating factor (G-CSF) to treat
acute (on chronic) liver failure: effect on immune and
stem cell mobilisation
Cornelius Engelmann1, Katrin Splith2, Thomas Berg1, Moritz
Schmelzle2,3; 1Gastroenterology/Hepatology, University Hospital
Leipzig, Leipzig, Germany; 2Translational Centre of Regenerative
Medicine (TRM), Leipzig, Germany; 3Visceral, Transplantation,
Thoracic and Vascular Surgery, University Hospital Leipzig,
Leipzig, Germany
Background and aims: Granulocyte stimulating factor (G-CSF)
is a potential new treatment option for patients with severe
acute (on-chronic) liver failure that mobilises hematopoetic stem
cells (CD34+) and improves patients outcome. But until now
its mechanism of action leading to an improvement of liver
regeneration could not have been clarified. In this investigation
the impact of immune- and stem-cell mobilisation into the blood
on patients outcome was evaluated. Methods: Filgrastim was
administered as an individualised treatment with 12 subcuta-
neous doses (5 mg/kg day 1-5 daily, day 6-26 every third day)
between 03/2013 and 01/2014 to eight patients with acute
(on chronic) liver failure refractory to standard therapy (alco-
holic hepatitis n=6, flupirtin induced liver failure n=2). Patients
were clarified about the off-label use and gave informed con-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
sent prior drug administration. Results: Two patients died and
one patient was successfully transplanted (non survivors) within
two weeks due to severe liver failure (28-day transplant-free
mortality 37,5 %). Five patients survived 28 days or longer
(survivors). Gender, age as well as renal and liver function
test did not differ between groups prior treatment initiation.
In all patients mobilisation of macrophages, neutrophils and
CD39+Immune-cells by G-CSF could be demonstrated. In con-
trast to survivors, non-survivors showed an up-regulation of
regulatory T cells (CD4+CD25+CD39+) already at baseline
that could not further be stimulated in the line of G-CSF admin-
istration. These patients did not respond to G-CSF regarding
stem cell mobilisation [CD133+ (CD39+)]. Several diagnostic
markers like γ glutamyl transferase, creatinine or bilirubin cor-
related significantly with blood levels of different cell-subsets.
Conclusions: With these preliminary observations we could
show that survivors and non-survivors had at least in parts dif-
ferent pattern of immune and stem cells in peripheral blood
during G-CSF stimulation. Tregs might be an immune-cell sub-
set indicating a worse prognosis of patients with severe liver
failure. Therefore monitoring stem and immune cell levels might
help to indicate subgroups of patients who really benefit from
G-CSF administration. A multi center randomized trial compar-
ing G-CSF and standard of care is in preparation.
Disclosures:
Thomas Berg - Advisory Committees or Review Panels: Gilead, BMS, Roche,
Tibotec, Vertex, Jannsen, Novartis, Abbott, Merck; Consulting: Gilead, BMS,
Roche, Tibotec; Vertex, Janssen; Grant/Research Support: Gilead, BMS, Roche,
Tibotec; Vertex, Jannssen, Merck/MSD, Boehringer Ingelheim, Novartis; Speak-
ing and Teaching: Gilead, BMS, Roche, Tibotec; Vertex, Janssen, Merck/MSD,
Novartis, Merck, Bayer
Moritz Schmelzle - Grant/Research Support: Novartis
The following people have nothing to disclose: Cornelius Engelmann, Katrin
Splith
748
C/EBP homologous protein (CHOP) promotes hepato-
cyte death by ERO1α signaling during acute liver failure
Ling Lu, Jianhua Rao, Haoming Zhou, Xuehao Wang; Liver Trans-
plantation Center, First Affiliated Hospital of Nanjing Medical Uni-
versity, Nanjing, China
Background: C/EBP Homologous Protein (CHOP) has been
shown to play a key role in endoplasmic reticulum (ER) stress-me-
diated apoptosis. ERO1α, a target of CHOP, is an important
oxidizing enzyme to regulate ROS, which play a prominent
role in hepatocellular death during acute liver failure (ALF),
but little is known regarding whether or how CHOP facilitates
ROS-induced hepatocellular injury. The aim of the study was
to investigate roles and mechanisms of CHOP in ALF. Results:
In the liver tissues from ALF patients, the expression of CHOP
was significantly increased compared with healthy controls
and was accompanied by increased expression of PERK, ATF4
and ERO1a. In the mouse model of GaIN/LPS-induced ALF, the
hepatocellular injury was accompanied by upregulated CHOP
and ERO1a. In contrast, CHOP deficiency decreased hepa-
tocellular apoptosis/necrosis and increased animal survival.
Furthermore, the disruption of CHOP decreased ERO1a expres-
sion, resulting in a reduction of ROS-induced cell death in vivo
and in vitro. Interestingly, ERO1a overexpression restored
GaIN/LPS induced hepatocellular injury in CHOP deletion
mice. Conclusion: Our studies for the first time demonstrate
CHOP contribute to liver damage during ALF via promoting
ERO1a, which is a key molecule to link ER stress and ROS.
Targeting CHOP or ERO1a may be a novel approach for the
management of ALF.
Disclosures:
563A
The following people have nothing to disclose: Ling Lu, Jianhua Rao, Haoming
Zhou, Xuehao Wang
749
The clinical and immunological chracteristics of acute
liver failure with autoimmune features – for early diag-
nosis and proper treatment–
Hirotoshi Ebinuma1, Hidetsugu Saito1,2, Yoshiyuki Yamagi-
shi1, Nobuhiro Nakamoto1, Po-sung Chu1, Yuko Wakayama1,
Nobuhito Taniki1, Akihiro Yamaguchi1, Shunsuke Shiba1, Shingo
Usui1, Kazuo Sugiyama1, Takanori Kanai2; 1Division of Gastroen-
terology & Hepatology, Department of Internal Medicine, School
of Medicine, Keio University, Tokyo, Japan; 2Faculty of Pharmacy,
Keio University, Tokyo, Japan
Background and Aim: Acute liver failure with autoimmune fea-
tures (ALF-AF) is sometimes a clinical entity presenting gradual
and progressive course to acute liver failure without early diag-
nosis and proper treatments. The criteria of histologic diagnosis
of liver tissue was proposed by Stavitz RT, et al (Hepatology
2011; 53: 516-523), but liver biopsy would be contraindica-
tion because the decrease of coagulating function in patients
with acute liver failure. ALF-AF would effectively recover with
immunosuppressive agents such as steroids if treatment could
be early initiated. Therefore the proper understanding of
pathophysiology is necessary for early diagnosis of ALF-AF.
To search for pathophysiological characteristics of ALF-AF,
we analyzed clinical and immunological findings of patients
with ALF-AF retrospectively. Materials and Methods: Clinical
records of 66 patients with ALF-AF treated in our hospital were
retrospectively analyzed and compared those of 34 patients
with viral acute liver failure (VALF). We measured the level of
24 cytokines and chemokines in their plasma by the Bio-PlexTM
suspension array system (Bio-Rad Laboratories; Tokyo) in cases
whose pretreatment plasma was available. Results: The aver-
age age of ALF-AF was 47.2, and female dominant. Ten cases
presented hepatic encephalopathy (HE) over 10 days after
disease onset (subacute-type in Japan) and 27 presented HE
within 10 days (acute-type), 3 were late-onset hepatic failure
(HE after 8 weeks of onset), and 26 were severe hepatitis (pro-
thrombin time INR at pretreatment ≥ 1.5 without HE). Patients
with VALF dominantly revealed HE within 10 days after onset.
As reported previously, atrophy and radiological heterogeneity
of the liver in CT-scan were significant in patients with severe
ALF-AF. The cytokine and chemokine examination showed sig-
nificant higher levels of IL-17 (ALF-AF: 30.7±32.8 vs VALF:
11.8±14.5, p=0.0396), basic FGF (8.0±13.0 vs 1.5±3.3,
p=0.0211), MIP-1α (7.5±12.7 vs 1.6±3.9 p=0.0362), and
TNF-α (44.4±47.7 vs 18.6±25.2, p=0.0351) in patients with
ALF-AF, although their AST and ALT levels were significantly
lower than those of VALF. The administrations of immuno-
suppressive agents before emergence of HE was contributed
to their rescue without liver transplantation. Conclusion: The
radiological findings by CT-scan, such as liver atrophy and het-
erogeneity, in addition of subacute clinical course and higher
proinflammatory status were useful for the diagnosis of ALF-AF.
Early diagnosis and proper immunosuppressive treatment are
necessary for rescue without liver transplantation.
Disclosures:
The following people have nothing to disclose: Hirotoshi Ebinuma, Hidet-
sugu Saito, Yoshiyuki Yamagishi, Nobuhiro Nakamoto, Po-sung Chu, Yuko
Wakayama, Nobuhito Taniki, Akihiro Yamaguchi, Shunsuke Shiba, Shingo Usui,
Kazuo Sugiyama, Takanori Kanai
564A AASLD ABSTRACTS
750
Increased CD11b+CD163+ macrophages caused liver
injury in acute liver Failure (ALF) non-survivors
Rashi Sehgal1, Arshi Khanam1, Ashish Vyas1, Shiv K. Sarin2, Nir-
upma Trehanpati1; 1Research, Institute Of Liver and Biliary Sci-
ences, New Delhi, India; 2Hepatology, Institute Of Liver and Biliary
Sciences, New Delhi, India
Purpose: Acute liver failure (ALF) is a serious life threatening ail-
ment. Viral, drug or toxic insults are likely to produce liver injury
mediated through CD8+ T-cells. Monocytes/macrophages are
the key effector cells of innate immune system. Their plasticity
could determine pro-inflammatory (M1 macrophages) /pro-res-
olutionary (M2 macrophages) state in ALF. A better under-
standing of macrophage plasticity during ALF could promote
immune-modulating therapies and thus may attenuate liver
injury and aid liver regenerative responses. Patients and meth-
ods: 24 ALF patients with different etiologies were recruited;
HEV-related ALF (HEV-ALF, n=16), ATT induced ALF n= 2, HBV
related ALF n= 3, cryptogenic n=3. Phenotypic and functional
profile of CD14+ monocytes and CD11b+ CD163+ macro-
phages (M2 type macrophages) and their phagocytic activity
was determined by the uptake of opsonized E.coli. Reactive
oxygen species (ROS) production by macrophages and mono-
cytes was determined, with and without stimulation of fMLP, E
Coli and PMA. Results: Out of 24, only 25% patients with HEV-
ALF survived. The frequency of monocyte derived M2 macro-
phages was significantly increased in non-survivors (p=0.009).
While the phagocytic activity was significantly higher in sur-
vivors (38 ± 3% vs. 15 ± 5, p=0.009), ROS production was
significantly higher in non-survivors (resting, p=0.04, E. coli,
p=0.04, fMLP, p=0.03 & PMA p=0.03) compared to survivors.
There was no significant difference in frequency of monocytes
and their phagocytic activity between survivors and non-survi-
vors. Conclusion: The frequency of Monocytes derived Macro-
phages was high in non-survivors. These cells were polarized
towards M2 type showing increased ROS production which
may possibly contribute to liver injury resulting in death of
patients.
Figure A-B: A. Median Fluorescence Intensity (MFI) of CD163 on
CD11b+ macrophages. B. Macrophage derived ROS production
between Survivors and Non- Survivors.
Disclosures:
The following people have nothing to disclose: Rashi Sehgal, Arshi Khanam,
Ashish Vyas, Shiv K. Sarin, Nirupma Trehanpati
HEPATOLOGY, October, 2014
751
Micro RNAs miR-106a, miR-122 and mir-197 are
increased in severe acute viral hepatitis with coagulop-
athy
Lukas Weseslindtner1, Iris F. Macheleidt2, Hannah Eischeid2, Rob-
ert Paul Strassl3, Theresia Popow-Kraupp3, Harald Hofer4, Marga-
rete Odenthal2, Heidemarie Holzmann1; 1Department of Virology,
Medical University of Vienna, Vienna, Austria; 2Institute for Pathol-
ogy, University Hospital of Cologne, Cologne, Germany; 3Division
of Clinical Virology, Department of Laboratory Medicine, Medical
University of Vienna, Vienna, Austria; 4Division of Gastroenterol-
ogy and Hepatology, Department of Internal Medicine III, Medical
University of Vienna, Vienna, Austria
Background: The severity of acute viral hepatitis, which may
be caused by several biologically distinct viruses, is mediated
by the grade of hepatic inflammation and necrosis and varies
greatly among individual patients. In a small part of infected
individuals acute viral hepatitis can lead to severe liver dam-
age, indicated by a strong increase of bilirubin and coagulopa-
thy. Aim: We comprehensively investigated extracellular micro
RNA (miRNA) profiles in sera from patients with acute viral
hepatitis to identify those miRNAs that indicate severe acute
hepatitis which is associated with coagulopathy. Methods: Our
analysis included serum samples which were acquired within
two weeks after the onset of symptoms from 54 patients who
suffered from acute viral hepatitis (defined as ALT elevation
10-times the normal value) caused by four different hepatotro-
pic viruses (Hepatitis A Virus: n=4, Hepatitis B Virus: n=27,
Hepatitis C Virus: n=19 and Hepatitis E Virus: n=4). Out of
these 54 patients, 6 individuals suffered from severe hepati-
tis, indicated by a strong increase of bilirubin levels and the
development of coagulopathy. The profile of 768 miRNAs was
analyzed using a microarray-based approach in samples from
these 6 patients, as well as in samples from 18 acutely infected
patients without coagulopathy. Selected miRNAs were then
quantified by PCR in all 54 patients from the cohort. Results:
Comprehensive RNA profiling identified miRNAs which signifi-
cantly differed between acutely infected patients with and with-
out coagulopathy. Levels of miR-106a, miR-122 and mir-197
were significantly higher in patients who suffered from severe
acute hepatitis, as compared to patients who did not develop
coagulopathy. Significantly elevated miR-106a, miR-122 and
mir-197 levels in sera from patients with severe acute viral hep-
atitis were confirmed by quantitative real-time PCR (p<0.01,
Mann Whitney U-test). Conclusion: The miRNAs miR-106a,
miR-122 and mir-197 could be potential biomarkers to identify
those patients who develop severe acute viral hepatitis which
is also associated with coagulopathy.
Disclosures:
Harald Hofer - Speaking and Teaching: Janssen, Roche, MSD, Gilead, Abbvie
The following people have nothing to disclose: Lukas Weseslindtner, Iris F.
Macheleidt, Hannah Eischeid, Robert Paul Strassl, Theresia Popow-Kraupp, Mar-
garete Odenthal, Heidemarie Holzmann
752
Raf kinase inhibitor 1 (Rkip1): a potential modifier of
fibrogenesis in liver and heart
Rabea A. Hall1, Andrey Kazakov2, Ulrich Laufs2, Michael Boehm2,
Frank Lammert1; 1Department of Medicine II, Saarland Univer-
sity Medical Center, Saarland University, Homburg, Germany;
2Department of Medicine III, Saarland University Medical Center,
Homburg, Germany
Background: Recently we observed that long-term administra-
tion of carbon tetrachloride (CCl4) induces fibrosis in both liver
and heart in the mouse. To dissect common and organ-spe-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
cific mechanisms of fibrosis, we challenged BXD recombinant
inbred lines with CCl4. BXD lines represent a genetic reference
population (GRP) that is genetically mosaic but homozygous
for all loci. Our aim was to identify potential candidate genes
with effects on hepatic and cardiac fibrogenesis. Methods and
results: Thirty BXD lines were used as a GRP for genome-wide
quantitative trait loci (QTL)-analyses. Fibrosis was induced by
CCl4 for six weeks (0.7 ml/kg BW, 12 i.p. injections). We
observed significant differences for hepatic and cardiac fibro-
sis among the BXD lines and using a genome-wide marker
panel, we mapped co-localizing loci linked to collagen accu-
mulation for liver and heart on chromosomes 5 and 18. These
QTL were further screened for candidate genes by expression
QTL (eQTL)-mapping. Hence, gene expression levels (Affy 1.0
ST whole genome arrays) were included into the mapping anal-
ysis as quantitative traits. Among all locally regulated quanti-
tative trait genes (cis-QTGs) within the QTL on chromosome 5,
Rkip1 was identified as major cis-QTG (LRS = 64.6) and further
in silico analyses affirmed it as a potential candidate gene.
Therefore, we compared fibrosis progression in CCl 4-chal-
lenged Rkip1-knockout (Rkip-/-) and C57Bl/6N wild-type mice
by quantification of collagen accumulation in liver and heart.
After six weeks of fibrosis induction, Rkip-/- mice showed sig-
nificantly less cardiac collagen accumulation (p < 0.05), as
assessed by Sirius red staining. However, in the liver hydroxy-
proline levels were enhanced (p < 0.001) in Rkip-/-mice, and
so were Col1a2 expression levels (p < 0.05). Conclusions: This
study reveals that CCl4-induced fibrosis is a systemic model that
allows comparative analysis of fibrosis mechanisms in liver and
heart in genetically identical individuals. Genome-wide analy-
sis of hepatic and cardiac fibrosis identified common and reg-
ulatory QTLs of fibrogenesis. Rkip1 deficiency appears to have
anti-fibrotic effects in heart but not liver, pointing to organ-spe-
cific mechanisms of fibrosis progression and resolution.
Disclosures:
Michael Boehm - Advisory Committees or Review Panels: Astra Zeneca, Bayer
AG, Boehringer Ingelheim, Daiichi-Sankyo, MSD, Novartis, Pfizer, Sanofi-Aven-
tis, Servier; Consulting: Astra Zeneca, AWD Dresden, Bayer, Boehringer Ingel-
heim, Berlin-Chemie, Daiichi-Sankyo, MSD, Novartis, Pfizer, Sanofi-Aventis,
Servier, Medtronic; Grant/Research Support: Astra Zeneca, Bayer AG, Boeh-
ringer Ingelheim, Novartis, Pfizer, Sanofi-Aventis, Servier, Medtronic
The following people have nothing to disclose: Rabea A. Hall, Andrey Kazakov,
Ulrich Laufs, Frank Lammert
753
The Role of Toll Like Receptor 4 signaling by Hepatic
Stellate Cells in Hepatocarcinogenesis
Jinsheng Guo1, Yangyang Ouyang1, Chengzhao Lin2, Yujing Wu1,
Yuanqing Zhang1, Yirong Cao1, Shiyao Chen1, Jiyao Wang1,
Scott L. Friedman1,3; 1Division of Digestive Diseases, Zhong Shan
Hospital, Fu Dan University, Shanghai, China; 2Institutes of Bio-
medical Sciences, Fu Dan University, Shanghai, China; 3Division
of Liver Diseases, Icahn School of Medicine at Mount Sinai, New
York, NY
Background & Aims: Hepatic stellate cells (HSCs) are the
major origin of scar-forming myofibroblasts in injured liver.
Toll like receptor 4 (TLR4) has been identified to be a key
signaling molecule on that regulates HSC expression network
and function. The aim of this study was to explore the effects
of TLR4 signaling on the cellular interaction between HSCs and
hepatocellular carcinoma (HCC) cells. Methods: Genome-wide
mRNA expression microarray was used to assess differential
expression between wild type (JS1) and TLR4 knockout (JS2)
murine HSC lines. RT-qPCR, Western Blot, ELISA, and cytokine
array analysis were used to verify the transcription, protein
translation and secretion of the differentially expressed genes.
565A
The effect of HSCs on the proliferation of HCC cells was inves-
tigated by incubating JS1 and JS2 cell supernatants with HCC
lines HepG2 and Hepa1-6, followed by CCK8 assay. In in
vivo studies JS1 or JS2 cells were mixed with Hepa1-6 cells in
a ratio of 1:2 (Hepa1-6 2×105/100μl/mice) to subcutaneous
transplanted into either nude mice or wild type or TLR4-/- C57
mice, respectively. Morphological studies were performed with
H&E, reticulin fiber and Masson trichrome staining. Immuno-
histochemical staining for the blood vessels and proliferating
cells were performed with anti-CD34 and c-kit antibodies.
Western Blots were performed for fibronectin (FN), MMP-2,
VEGF and HIF-1α within the tumors. Results: In line with the
mRNA expression profile, the protein levels of focal adhesion
molecule (FN), matrix metalloprotenase (MMP-2), secretory
growth factors (DLK1, IGF1, FIGF, FGF7, IL-6) and chemokine
(CXCL12) were upregulated in JS1 cells compared to JS2 cells.
By cytokine array analysis differential expression and secre-
tion GM-CSF, IL-1rα, sICAM-1, G-CSF, RANTES, and CCL1
were found between JS1 and JS2. Both JS1 and JS2 promote
the proliferation of HepG2 and Hepa1-6 cells, with a much
stronger effect observed from JS1 cells. In vivo, tumor growth
was enhanced in both nude mice and C57 wild type and TLR4-
/- mice when Hep1-6 cells were co-transplanted with JS1 or JS2
cells. The speed of tumor growth, distribution of blood vessels,
and number of proliferating cells were higher in JS1-Hep1-6
co-transplanted tumors that that in JS2-Hep1-6 tumors, which
was coincident with higher expression of FN, MMP-2, VEGF
and HIF-1α protein within the tumors. Conclusions: TLR4 signal-
ing mediates the expression of a number of tumor promoting
secretory factors from HSCs. Activated HSCs create an immu-
nosuppressive microenvironment to facilitate HCC cells growth.
These studies help delineate the TLR4-mediated role of HSC in
the development of HCC.
Disclosures:
Scott L. Friedman - Advisory Committees or Review Panels: Pfizer Pharmaceutical,
Sanofi-Aventis; Consulting: Conatus Pharm, Exalenz, Genenetch, Glaxo Smith
Kline, Hoffman-La Roche, Intercept Pharma, Isis Pharmaceuticals, Melior Dis-
covery, Nitto Denko Corp., Debio Pharm, Synageva, Gilead Pharm., Ironwood
Pharma, Alnylam Pharm, Tokai Pharmaceuticals, Bristol Myers Squibb, Takeda
Pharmaceuticals, Nimbus Discovery, Bristol Myers Squibb, Intermune, Astra Zen-
eca, Abbvie, Intermune; Grant/Research Support: Galectin Therapeutics, Tobira
Pharm, Vaccinex Therapeutics, Tobira; Stock Shareholder: Angion Biomedica
The following people have nothing to disclose: Jinsheng Guo, Yangyang Ouy-
ang, Chengzhao Lin, Yujing Wu, Yuanqing Zhang, Yirong Cao, Shiyao Chen,
Jiyao Wang
754
Highly Efficient Gene Targeting of a LncRNA in Human
LX-2 Hepatic Stellate Cells using TALENs
Daniel L. Motola1, Kaveh Daneshvar1, Samuel R. York1, Alan Mul-
len1,2, Raymond T. Chung1; 1Gastrointestinal Unit, Massachusetts
General Hospital, Harvard Medical School, Boston, MA; 2Harvard
Stem Cell Institute, Harvard University, Cambridge, MA
Background/Aims: Chronic liver disease is the12th leading
cause of mortality in the United States. However, there are
currently no effective therapies that can halt or reverse pro-
gressive hepatic fibrosis seen in many forms of chronic liver
disease. Hepatic stellate cells (HSCs) are the primary driver
of hepatic fibrosis; thus, HSC-specific drug targets are greatly
needed. Long non-coding (lnc) RNAs are a newly appreciated
class of RNAs that are transcribed and processed similarly to
canonical messenger (m) RNAs, but do not code for proteins
and instead exert their biological function as RNAs. LncRNAs
have been shown to play key roles in cell identity and devel-
opment through diverse mechanisms. The role of lncRNAs in
HSCs is unknown; therefore, efficient methods of gene target-
ing are needed in order to facilitate their study and define their
566A AASLD ABSTRACTS
roles in hepatic fibrosis. Here we present, for the first time, an
efficient strategy that targets lncRNAs using TALENs (Transcrip-
tion activator-like effector nucleases) within human LX2 cells, a
well studied activated HSC-line. Methods: A TALEN pair was
generated to target the 1st exon of a lncRNA divergently tran-
scribed from ID1 on chromosome 20. LX2 cells have been pre-
viously shown to contain 4 copies of Chromosome 20. Human
LX2 cells were transiently transfected with a TALEN pair and
two homology arm plasmids containing either a GFP reporter
or puromycin resistance gene driven by PGK promoters. The
homology constructs are designed to insert two BGH-polyA
signals about 50 bp downstream of the lncRNA transcription
start site to cause termination of transcription. Selection mark-
ers contain LOX-P sites for later removal by Cre recombinase.
Results: Four days after transfection, treatment with 0.5 mg/ml
puromycin was initiated. At confluence, cells were harvested
and plated at ~1 cell/well in 96 well plates. Single colonies
were isolated after a period of growth and DNA was har-
vested for analysis for targeted recombination at the lncRNA
locus by genomic PCR and sequencing. From 180 wells, 36
viable, puromycin-resistant clones were recovered. Twelve of
these clones expressed GFP. Of these twelve, 5 were targeted
at all four chromosomes based on PCR. In contrast, 10 of 24
non-GFP clones were targeted but all 10 retained at least one
un-targeted allele. Conclusion: These results demonstrate that
TALENs induced highly efficient (42%) homologous recombina-
tion at all targeted lncRNA alleles. The targeting strategy used
here will thus greatly facilitate the study of lncRNAs in hepatic
fibrosis and is broadly applicable to coding genes as well.
Disclosures:
Raymond T. Chung - Consulting: Abbvie; Grant/Research Support: Gilead, Mass
Biologics
The following people have nothing to disclose: Daniel L. Motola, Kaveh Danesh-
var, Samuel R. York, Alan Mullen
755
The role of Fyn in hepatic stellate cells activation and
liver fibrosis
Yin Ying Lu1, Guanghua Rong1, Dechun Feng2, Chunping Wang1,
Xiujuan Chang1, Xudong Gao1, Yan Chen1, Jianhui Qu1, Zhen
Zeng1, Hong Wang1, Bin Gao2, Yongping Yang1; 1Center forTh-
erapeutic Research of Hepatocarcinoma, Beijing 302 hospital,
Beijing, China; 2Laborator of Liver Diseases, National Institute
on Alcohol Abuse and Alcoholism, National Institutes of Health,
Bethesda, MD
The activation of hepatic stellate cells (HSCs) is the hallmark
of the initial liver fibrosis. Understanding the signaling path-
way involved in HSC’s activation is essential to delineate the
underlying mechanism of liver fibrosis and develop effective
therapeutic interventions to limit and reverse the development
of live fibrosis. The Src family kinases (SFKs) play important
roles in cell migration, invasion and proliferation. However, the
role of SFKs in HSC’s activation leading to liver fibrosis remains
poorly defined. In this study, we found that Fyn was the pre-
dominant SFK member expressed in freshly isolated mouse
HSCs detected by using RT-PCR and western blot. Fyn was also
highly expressed in human fibrotic liver tissues compared with
normal liver tissues. Further studies revealed that Fyn activation
(by phosphorylating its Y420) is enhanced in TGF-β1 treated
mouse HSCs. The similarly activated Fyn was also detected in
HSCs of human fibrotic liver tissues by immunohistochemical
staining. To further examine the function of Fyn in the activation
of HSCs, we knocked down the Fyn expression by Fyn spe-
cific shRNA in HSCs cell lines. Downregulation of Fyn reduced
basal and PDGF-BB stimulated HSC cell migration and focal
HEPATOLOGY, October, 2014
adhesion kinase (FAK) activation. Meanwhile, an overexpres-
sion of constitutively activated Fyn increased cell migration
and FAK activation. In addition, a reduced α-smooth muscle
actin (α-SMA) expression was observed when either knocking
down Fyn expression or overexpressing a dominant negative
FAK mutant in HSCs treated with TGF-β. Consistently, a small
molecule inhibitor of Src family kinase AZD0530 (Saracatinib)
inhibited TGF-β1-induced Fyn activation and α-SMA expres-
sion, inhibited PDGF-BB-stimulated cell migration in a dose-de-
pendent manner in HSCs. These results demonstrated that Fyn
promotes the activation and migration of HSCs through the
Fyn/FAK axis. Downregulation of Fyn (by shRNA or pharma-
cological inhibitor AZD0530) significantly inhibited the activa-
tion of HSCs. In conclusion, Fyn plays a critical role in HSC’s
activation and liver fibrosis, may serve as a novel intervention
target for liver fibrosis.
Disclosures:
The following people have nothing to disclose: Yin Ying Lu, Guanghua Rong,
Dechun Feng, Chunping Wang, Xiujuan Chang, Xudong Gao, Yan Chen, Jianhui
Qu, Zhen Zeng, Hong Wang, Bin Gao, Yongping Yang
756
A Hepatic Stellate Cell Expression Signature Identifies
Novel Cell Markers and Predicts Outcomes in Chronic
Liver Disease
David Zhang, Hsin I Chou, Yujin Hoshida, Scott L. Friedman; Icahn
School of Medicine at Mount Sinai, New York, NY
AIM: Targeting hepatic stellate cells (HSCs) will greatly
enhance the specificity and reduce the off-target effects of novel
treatments. Our aim was to construct an HSC gene expression
signature that is uniquely expressed by this cell type in healthy
and diseased liver. METHODS: We curated 98 microarray
datasets from >30 sources representing HSCs and each cell
population in the liver; all datasets were from the same array
platform and quantile-normalized. Stringent criteria were
applied to identify genes that were highly enriched in HSCs.
RESULTS: The signature was validated in two clinical data-
sets and examined for an association with adverse clinical
outcomes. The signature is strongly associated with cirrhosis
when comparing cirrhotic and normal samples (FDR q-value
< 0.001), and associated with both fibrotic (p = 0.009) and
inflammatory (p = 0.042) subsets of NAFLD patients. The
HSC signature was also correlated with adverse outcomes in
two published cohorts (Hoshida, et al. NEJM 2008, n = 82;
Hoshida, et al. Gastro 2013, n = 216). Although the signature
was not constructed from any outcomes data, its expression
nevertheless correlated with risk of death (p = 0.010) in the
one cohort, and risk of death (p = 0.002), decompensation
(p = 0.039), and Child-Pugh progression (p = 0.001) in the
other. Even after considering bilirubin level and platelet counts,
the HSC expression is independently associated with risk of
Child-Pugh progression (HR= 2.16, p=0.003) and death (HR
= 2.34, p=0.001). Interestingly, HSC signature expression did
not correlate with risk of HCC incidence or recurrence in either
cohort. A subset of genes in the signature were used to iden-
tify putative novel extracellular markers of HSCs; 20% of the
HSC signature is composed of genes that encode extracellular
or cell surface proteins by gene ontology. We compared the
expression of these cell surface factors in immortalized HSC
and hepatocyte cell lines by qRT-PCR. Significantly enriched
genes were validated by western blot of human HSC lines and
IHC in mouse livers treated with CCl4. CONCLUSIONS: We
have identified a group of genes that are highly enriched in
HSCs. These genes are useful for tracking and targeting these
cells, and independently predict adverse events in advanced
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
liver disease. Use of this signature will shorten the path to drug
development by identifying novel, clinically meaningful targets
for therapeutics and diagnostics.
Disclosures:
Scott L. Friedman - Advisory Committees or Review Panels: Pfizer Pharmaceutical,
Sanofi-Aventis; Consulting: Conatus Pharm, Exalenz, Genenetch, Glaxo Smith
Kline, Hoffman-La Roche, Intercept Pharma, Isis Pharmaceuticals, Melior Dis-
covery, Nitto Denko Corp., Debio Pharm, Synageva, Gilead Pharm., Ironwood
Pharma, Alnylam Pharm, Tokai Pharmaceuticals, Bristol Myers Squibb, Takeda
Pharmaceuticals, Nimbus Discovery, Bristol Myers Squibb, Intermune, Astra Zen-
eca, Abbvie, Intermune; Grant/Research Support: Galectin Therapeutics, Tobira
Pharm, Vaccinex Therapeutics, Tobira; Stock Shareholder: Angion Biomedica
The following people have nothing to disclose: David Zhang, Hsin I Chou, Yujin
Hoshida
757
Grb2-associated binder 1 protects against liver fibrosis
via suppression of CCL5 production from hepatocytes
Yuichi Yoshida, Takashi Kizu, Kunimaro Furuta, Satoshi Ogura,
Mayumi Egawa, Norihiro Chatani, Yoshihiro Kamada, Shinichi
Kiso, Tetsuo Takehara; Department of Gastroenterology and Hepa-
tology, Osaka University, Suita, Osaka, Japan
Background and Aims: During the progression of liver fibrosis,
various growth factors, including HGF or EGF family ligands,
are involved in liver fibrogenesis. However, the downstream
signaling in hepatocytes remains poorly understood. Grb2-as-
sociated binder 1 (Gab1) adaptor protein amplifies signals
downstream of a broad range of growth factors/receptor
tyrosine kinases. Although these signals are implicated in
liver fibrogenesis, the role of Gab1 remains unclear. Here,
we addressed the role of Gab1 in experimental liver fibrosis
using genetic ablation strategy. Methods: Hepatocyte-specific
Gab1 conditional knockout (Gab1CKO) mice were gener-
ated using Cre-loxP system. Liver fibrosis was investigated
in Gab1CKO 10 days after bile duct ligation (BDL). Results:
Gab1CKO mice developed more severe liver fibrosis with a
2-fold increase in the fibrosis area assessed by picrosirius red
staining (p<0.05) and a 1.5-fold increase in hepatic hydroxy-
proline content (p<0.05) compared with control mice. αSMA
staining also showed enhanced activation of hepatic stallate
cells in Gab1CKO mouse liver. Consistent with this, Gab1CKO
mice demonstrated an increased expression of fibrosis related
genes, such as Col1α, ACTA2 or TGFβ1 (p<0.05). We also
confirmed the similar enhanced liver fibrosis in Gab1CKO mice
in carbon tetrachloride-induced liver fibrosis model, suggesting
that Gab1 in hepatocytes might have anti-fibrotic role irrespec-
tive of etiology of liver diseases. To investigate the molecu-
lar mechanisms of Gab1-mediated signal in liver fibrosis, we
next performed the cDNA microarray analysis and identified
chemokine (C-C motif) ligand 5 (Ccl5), a fibrosis-promoting
factor, as up-regulated in the livers of Gab1CKO mice at the
fibrosis stage. The validation study also confirmed that KO
mouse livers displayed a 5-fold increase in gene expression of
CCL5 (p<0.05). Interestingly, immunohistochemical analysis of
CCL5 protein in the liver sections after BDL showed that pro-
tein expression of CCL5 was increased in the hepatocytes of
Gab1CKO mice but not in non-parenchymal cells (NPCs) after
BDL. Furthermore, in vitro studies using primary hepatocytes
or mouse hepatocyte cell lines revealed that the loss of Gab1
resulted in increased hepatocyte CCL5 synthesis upon LPS stim-
ulation via NF-κB pathways. Finally, pharmacological antago-
nism of CCL5 reduced BDL-induced liver fibrosis in Gab1CKO
mice, suggesting that hepatic over-expression of CCL5 in Gab-
1CKO mice functioned to exacerbate liver fibrosis. Conclusion:
Our study demonstrates that hepatocyte Gab1 is required for
liver fibrosis and that hepatocyte Gab1/CCL5 axis could be a
novel therapeutic target for liver cirrhosis.
567A
Disclosures:
Tetsuo Takehara - Grant/Research Support: Chugai Pharmaceutical Co., MSD
K.K.
The following people have nothing to disclose: Yuichi Yoshida, Takashi Kizu,
Kunimaro Furuta, Satoshi Ogura, Mayumi Egawa, Norihiro Chatani, Yoshihiro
Kamada, Shinichi Kiso
758
The peripherally-restricted CB1 antagonist AM6545
reduces liver fibrogenesis via growth inhibitory effects
for hepatic myofibroblasts and anti-inflammatory prop-
erties
Jinghong Wan1, Aida Habib1, Jasper Lodder1, Arthur Brouil-
let2, Fouad Lafdil2, Adrien Guillot2, Catherine Pavoine3, Richard
Moreau1, Ariane Mallat2, Sophie Lotersztajn1; 1Inserm UMR1149,
Center for Research on inflammation, Paris, France; 2Inserm UMR
955, Hopital Henri Modor, Creteil, France; 3Inserm UMR1166,
Faculté de Médecine Pierre et Marie Curie, Creteil, France
BACKGROUND AND AIMS .The Cannabinoid receptor1
(CB1) has been identified as a potentially potent antifibro-
genic target. Unfortunately, mood disorders associated with
brain permeant CB1 antagonists has precluded further clinical
development of these molecules. Recent research efforts have
allowed to design several non-brain penetrant CB1 antago-
nists. The aim of the present study was to validate the antifi-
brogenic efficacy of a peripherally-restricted CB1 antagonist,
AM6545, and to study its mechanism of action. METHODS:
Liver fibrosis was induced in male C57Bl6/J mice by bile duct
ligation for 12 days, and acute liver injury by a single intra-
peritoneal injection of CCl4. AM6545, rimonabant or vehicle
were administered daily in BDL mice (n= 10 mice/group) and
CCl4-exposed animals (n=10 mice/group) for 12 and 3 days,
respectively. Mechanistic studies were performed in human
hepatic myofibroblasts isolated from liver explants, and in peri-
toneal macrophages and Kupffer cells isolated from WT and
CB1 KO mice. RESULTS Compared to BDL control mice, BDL
animals exposed to the peripherally- restricted CB1 antagonist
AM6545 showed a strong reduction of liver fibrosis, character-
ized by a 44% decrease in collagen deposition, a 46% reduc-
tion in the density of α-SMA positive cells, and a 65% inhibition
of TGF-β mRNA induction. AM6545 affected all the fibrogenic
parameters to the same extent as rimonabant. AM6545 also
decreased collagen gene expression and the density of a-SMA
positive cells following acute liver injury elicited by CCl4. In
vitro, AM6545 inhibited hepatic myofibroblast proliferation,
with the same potency as the brain penetrant molecule. Inter-
estingly, AM6545 treatment also elicited anti-inflammatory
properties towards hepatic macrophages. Indeed, AM6545-ex-
posed BDL mice displayed a significant decrease in hepatic
expression of F4/80 and Ly6C, and a lower hepatic induction
of CCR1, CCR5 and CCl5. In keeping, cultured peritoneal
macrophages exposed to AM6545 or Kupffer cells isolated
from CB1 KO mice showed a strong reduction in inflamma-
tory M1 gene expression. CONCLUSIONThese data demon-
strate that the peripherally-restricted CB1 antagonist AM6545
retains potent antifibrogenic properties . Its antifibrogenic effect
may result from combined growth inhibition of hepatic myofi-
broblasts and antiinflammatory effects on Kupffer cells. These
data open interesting perspectives on the use of peripherally-re-
stricted CB1 antagonists as antifibrogenic molecules.
Disclosures:
The following people have nothing to disclose: Jinghong Wan, Aida Habib,
Jasper Lodder, Arthur Brouillet, Fouad Lafdil, Adrien Guillot, Catherine Pavoine,
Richard Moreau, Ariane Mallat, Sophie Lotersztajn
568A AASLD ABSTRACTS
759
MicroRNA-155 (miR-155) deficiency attenuates liver
fibrosis and not liver injury or inflammation in an ani-
mal model of steatohepatitis
Timea Csak, Shashi Bala, Dora Lippai, Karen Kodys, Donna Cat-
alano, Gyongyi Szabo; UMass Medical School, Worcester, MA
Background & Aim: MicroRNAs (miRs) regulate steatosis,
inflammation and fibrosis in the liver. Fibrosis is the conse-
quence of chronic tissue damage and inflammation. We
hypothesized that deficiency of miR-155, a master regulator of
inflammation, attenuates steatohepatitis and fibrosis. Methods:
Wild type (WT) and miR-155-deficient (KO) mice were fed
methionine-choline-deficient (MCD) or -supplemented (MCS)
control diet for 5 weeks. Liver injury, inflammation and fibro-
sis were assessed. Results: In WT mice MCD diet resulted in
steatohepatitis (histology, elevated ALT, triglyceride and cyto-
kine levels) and increased miR-155 expression in total liver,
hepatocytes and Kupffer cells compared to MCS controls. In
miR-155KO mice MCD diet resulted in significantly reduced
steatosis while MCS diet increased hepatic fat accumulation
compared to WT mice suggesting diet-specific regulation by
miR-155. Liver injury assessed by histology and serum ALT was
not prevented in the miR-155 KO mice. miR-155 deficiency also
failed to attenuate inflammatory cell infiltration, CD68 mac-
rophage recruitment and NFκB activation in MCD compared
to MCS diet-fed controls. Furthermore, liver TNFα and MCP1
protein levels were significantly higher in miR-155KO MCD
diet-fed animals compared to WT. Consistent with increased
inflammation, expression of SHIP1 mRNA, a negative regulator
of inflammatory pathways, was lower in the KO mice. Despite
comparable liver injury and enhanced inflammation between
WT and miR-155KO, miR-155KO mice exhibited reduced
liver fibrosis with significantly reduced collagen, αSMA, TIMP-1
mRNA/protein levels and reduced collagen deposition quan-
tified by Sirius Red staining compared to WT mice on MCD
diet. Consistent with the attenuated fibrosis, we found signifi-
cantly lower expression of vimentin, a mesenchymal marker
and indirect indicator of epithelial-to-mesenchymal transition
(EMT), in MCD diet-fed miR-155KO mice vs. WT. Searching for
a possible explanation for reduced fibrosis, we tested CEBPβ,
a miR-155 target that promotes TGFβ response towards EMT in
epithelial cells. We found that CEBPβ nuclear binding was sig-
nificantly increased in the miR-155KO compared to WT mice
suggesting a potential mechanism for hepatoprotection. Con-
clusions: Our novel data demonstrate that miR-155 deficiency
promotes inflammation in MCD-steatohepatitis underlining the
importance of the negative regulatory role of miR-155 in the
inflammation pathways. Our finding also revealed that despite
enhanced inflammation, miR-155 deficiency attenuates liver
steatosis and fibrosis in NASH suggesting that miR-155 regu-
lates fibrosis independent of inflammation.
Disclosures:
Gyongyi Szabo - Consulting: Idenix; Grant/Research Support: BMS, GSK, Cona-
tus, Idera, Johnson&Johnson, Novartis, Ocera, Roche, Shering - Plough, Wyeth,
Integrated Therapeutics, Idera
The following people have nothing to disclose: Timea Csak, Shashi Bala, Dora
Lippai, Karen Kodys, Donna Catalano
HEPATOLOGY, October, 2014
760
The adiponectin peptide agonist ADP355 attenuates
CCl4-mediated liver fibrosis: therapeutic implications by
multiple molecular mechanisms in vivo and in vitro
Pradeep Kumar, Tekla Smith, Khalidur Rahman, Natalie Thorn,
Frank A. Anania; Department of Medicine, Division of Digestive
Diseases, Emory University School of Medicine, Atlanta, GA
BACKGROUND: Adiponectin is known to possess anti-fibrogenic
properties; however clinical testing of such a large peptide that
circulates in high concentrations would be cost prohibitive.
Recently adiponectin-like small synthetic peptide agonists were
beneficial in the treatment of diabetes mellitus and breast can-
cer in mice. The AIM of the present work was to study ADP355
a synthetic decapeptide, employing both in vivo and in vitro
approaches to determine its efficacy as an anti-fibrotic agent;
and, identify whether AP-1 was responsible for adiponectin-me-
diated MMP-1 transcriptional activation. METHODS: In vivo
experiments—adult C57B6/j male mice were gavaged with
CCl4 thrice weekly for six weeks. A gold nanoparticle-ADP355
conjugate was administered to the experimental mice and their
respective controls for the two weeks of the study. Liver injury
was assessed by serum biochemistry and histology, as well as
immunoblot and immunohistochemical analysis for α-smooth
muscle actin (α-SMA), connective tissue growth factor (CTGF),
desmin, transforming growth factor beta one (TGFβ1), adenos-
ine monophosphate kinase (AMPK) as well as endothelial nitric
oxide (NO)-synthase (eNOS). In vitro experiments—rat hepatic
stellate cells (HSCs) or the human HSC cell line (LX2) were
transiently transfected with MMP-1 promoter deletion constructs
along with appropriate controls. RESULTS: Mice gavaged with
CCl4 and injected with ADP355 nanoparticle conjugates had
significantly lower transaminases levels than mice treated with
gold nanoparticles alone. We confirmed the presence of cir-
culating nanoparticles in vivo using mass spectroscopy, and
localized the particles with dark-field microscopy of the liver.
Quantitation of Sirius Red staining was significantly reduced in
CCl4-gavaged ADP355 treated mice. Key markers of fibrogen-
esis—α-SMA, TGFβ1, CTGF, TIMP-1—were markedly attenuated
at mRNA and protein levels. These studies were corroborated
by ex vivo immunohistochemical liver staining. Conversely liver
lysates from ADP355 treated mice increased phosphorylation
of both AMPK and eNOS (p<0.05) while Akt phosphorylation
was attenuated. Adiponectin/ADP355 treatment, of transiently
transfected HSCs did increase MMP-1 promoter activation four-
fold; however the deletion mutant at -275 bp upstream from
the start site abolished this effect. In silico analysis of the MMP
promoter revealed that AP-1 was the most likely transcription
factor mediating adiponectin/ADP355 activation. CONCLU-
SIONS: These findings suggest ADP355 is a potent anti-fibrotic
agent that along with other adiponectin-like peptides which
are emerging should be considered in phase I clinical studies
as therapy.
Disclosures:
The following people have nothing to disclose: Pradeep Kumar, Tekla Smith,
Khalidur Rahman, Natalie Thorn, Frank A. Anania
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
761
The interaction of beta-Arrestin-2 with AT1-receptor sig-
nalling in liver fibrosis
Robert Schierwagen1, Judith Heinzen1, Sabine Klein1, Frank E.
Uschner1, Kanishka Hiththetiya2, Christian P. Strassburg1, Tilman
Sauerbruch1, Jonel Trebicka1; 1Internal Medicine I, University of
Bonn, Bonn, Germany; 2Institute for Pathology, University of Bonn,
Bonn, Germany
Introduction: The G-protein-coupled AT1-receptor (AT1R) plays
a crucial role in fibrogenesis. Beta-Arrestin-2 (βArr2) is a neg-
ative regulator of AT1R by binding and uncoupling the recep-
tor from the G-protein coupled pathway and inhibits JAK2/
Rho-kinase. On the other hand βArr2 also activates ERK1/2
via Ras/Raf1. In this study the effect of βArr2 signalling was
investigated in liver fibrosis. Methods: βArr2-, AT1R-, dou-
ble-knockout (DKO) and wildtype (WT) mice were subjected to
CCl4-intoxication (28 days) or bile duct ligation for induction
of fibrosis (BDL; 14 days). Angiotensin II (AngII) was infused
via osmotic mini-pumps (14 days) for continuous stimulation
of the AT1R. Inhibition of JAK2 was induced by subcutaneous
injections of AG490 for 7 days. The hepatic hydroxyrproline
content, mRNA-levels (Taqman-PCR) and protein-expression
and phosphorylation of JAK2, ERK1/2, moesin (Western blot)
were determined in these mice. Hepatic fibrosis (αSMA and
Sirius Red) and inflammation (F4/80 and Ki67) were ana-
lyzed by immunohistochemistry. Besides mice specimen human
cirrhotic liver samples were compared to those of non-cirrhotic
patients. Results: Hepatic βArr2 and downstream signal-
ling proteins (JAK2, RhoA, Arhgef2, Rho-kinase, Ras, Raf1,
ERK1/2) were overexpressed in human and experimental fibro-
sis. Components of the renin-angiotensin-system (Renin, Angio-
tensinogen, ACE, ACE2, AT1-receptor) and profibrotic makers
were significantly downregulated in βArr2-knockout (βArr2-
/-) mice compared to WT, but showed higher increase after
AT1R stimulation due to JAK2-activation. AT1R stimulation led
to activation of JAK2 but failed to activate Ras/Erk-pathway.
However βArr2-/- showed less fibrosis upon liver injury (BDL,
CCl4), which suggests AT1R independent effects. Discussion:
βArr2 may play an important role in human and experimental
liver fibrogenesis. In absence of βArr2 fibrogenesis was signifi-
cantly decreased. The underlying mechanisms in absence of
βArr2 have still to be clarified, whether the observed effects on
fibrosis are related to decreased upstream signalling or to the
altered downstream signalling of the AT1R.
Disclosures:
Christian P. Strassburg - Advisory Committees or Review Panels: Novartis, Roche;
Speaking and Teaching: Novartis, Merz, MSD, Falk Pharma, BMS, Abbvie
The following people have nothing to disclose: Robert Schierwagen, Judith
Heinzen, Sabine Klein, Frank E. Uschner, Kanishka Hiththetiya, Tilman Sauer-
bruch, Jonel Trebicka
762
Identification of long noncoding RNAs induced in
hepatic stellate cell myofibroblasts
Samuel R. York1, Chan Zhou1, Jennifer Y. Chen1, Kaveh Danesh-
var1, Alan Mullen1,2; 1Gastrointestinal Unit, Massachusetts Gen-
eral Hospital, Harvard Medical School, Boston, MA; 2Harvard
Stem Cell Institute, Cambridge, MA
Background/Aims: Hepatic fibrosis is the underlying cause of
cirrhosis and liver failure in nearly every form of chronic liver
disease, and hepatic stellate cells (HSCs) are the cell type pri-
marily responsible for this fibrosis. HSCs are a key part of
normal wound repair in the liver, but with repeated activa-
tion that occurs in the setting of chronic liver disease, these
cells differentiate into activated HSC myofibroblasts that are
569A
unable to shut off collagen production. The recent discovery
of long noncoding (lnc) RNAs has revealed the presence of
previously unknown genes that encode biologically active
RNAs that are not translated into proteins. Many lncRNAs are
expressed only in specific cell types. Thus, there may be a set
of lncRNAs that are induced with differentiation of quiescent
HSCs into activated HSC myofibroblasts and regulate fibrosis.
Methods: We have used RNA sequencing (RNA-seq) to assem-
ble polyadenylated RNA transcripts in activated human HSC
myofibroblasts and in HSC myofibroblasts that were reverted
into quiescent HSCs by culture in Matrigel. This analysis was
coupled with chromatin immunoprecipitation and sequencing
(ChIP-Seq) to identify chromatin modifications that mark sites
of active transcription and provide further validation of the
assembled lncRNA transcripts. These transcripts were further
filtered to remove those with protein coding potential. Rapid
amplification of cDNA ends (RACE PCR) was performed to
confirm the 5’ and 3’ ends of individual lncRNAs, and PCR was
used to clone the full-length transcripts. Next, RNA fluorescent
in situ hybridization (FISH) was performed to determine the
subcellular localization the lncRNAs. Finally, the expression
of individual lncRNAs was analyzed across a panel of 20
human tissues to determine cell type specificity. Results: We
have identified approximately 5000 lncRNA transcripts present
in activated HSC myofibroblasts. The transcriptional start sites
for over 60% of these lncRNAs are located in close proximity
to the promoters of protein coding genes, and a subset of these
lncRNAs is induced in activated HSC myofibroblasts compared
to quiescent HSCs. The computational assembly of lncRNA
transcripts was validated by cloning the predicted lncRNAs.
We also find that these lncRNAs tend to show a restricted
pattern of expression across different cell types. Conclusion:
Cell type specific lncRNAs are induced upon differentiation of
quiescent HSCs into activated HSC myofibroblasts and provide
potential targets to inhibit fibrosis.
Disclosures:
The following people have nothing to disclose: Samuel R. York, Chan Zhou,
Jennifer Y. Chen, Kaveh Daneshvar, Alan Mullen
763
Genetic or pharmacologic inhibition of microRNA-21
does not prevent liver fibrosis or hepatocellular carci-
noma in mice
J Matias Caviglia, Myoung Kuk Jang, Geum-Youn Gwak, Ingmar
Mederacke, Xueru Mu, Dianne H. Dapito, Robert F. Schwabe;
Medicine - Digestive and Liver Diseases, Columbia University,
New York, NY
Background: Activation of hepatic stellate cells (HSC) during
liver fibrogenesis leads to changes in the microRNA expression
profile. Some microRNAs including miR-21 are upregulated
in fibrogenesis and carcinogenesis, and inhibition miR-21
reduces lung and kidney fibrosis. Moreover, miR-21 has been
suggested to be an oncomir that drives cancer development.
Aim: To profile microRNAs expression in hepatic stellate cells
and to determine whether targeting of specific candidates such
as miR-21 prevents the development of liver fibrosis and can-
cer. Methods: The microRNA expression profile of activated
HSC was determined by microarray and significant changes
were confirmed by qPCR. MiR-21 expression in liver tumors
was measured by qPCR. Genetic deletion of miR-21 or inhibi-
tion by locked nucleic acid antisense oligonucleotides (antag-
omirs) was used to prevent the induction of miR-21 during
fibrosis and hepatocarcinogenesis. Liver fibrosis was evalu-
ated using four models: (1) treatment with carbon tetrachloride
(CCl4), (2) 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)
570A AASLD ABSTRACTS
administration, (3) bile-duct ligation (BDL), (4) MDR2 deletion.
Hepatocarcinogenesis was evaluated in two models (1) treat-
ment with diethylnitrosamine at 21 days, followed by chronic
treatment with CCl4 and (2) spontaneous tumor development
in MDR2KO mice. Report: A signature of HSC activation was
identified consisting of 22 microRNAs which showed similar
changes in three models of HSC activation: CCl4-induced fibro-
sis, BDL, and HSC activation in culture. miR-21 showed the
greatest change with 8- to 24-fold upregulation (p<0.05). Mir-
21 null mice did not display reduced hepatotoxic or cholestatic
fibrosis. These data were confirmed with miR-21 antagomirs,
which also did not alter development of toxic and cholestatic
liver fibrosis despite efficient suppression of miR-21 expression.
Accordingly, inhibition of miR-21 with antisense oligonucle-
otides did not prevent HSC activation in culture or liver fibrosis.
miR-21 was also 2- to 4-fold upregulated in murine HCCs.
However miR-21 null mice and mice treated with miR-21 antag-
omirs did not display reduced development of liver tumors.
Conclusion: Our data in multiple murine models demonstrate
that miR-21 is dispensable for the development of liver fibrosis
and tumors despite profound uregulation. Hence, inhibition of
miR-21 does not represent a strategy for the treatment for liver
fibrosis or cancer.
Disclosures:
The following people have nothing to disclose: J Matias Caviglia, Myoung Kuk
Jang, Geum-Youn Gwak, Ingmar Mederacke, Xueru Mu, Dianne H. Dapito,
Robert F. Schwabe
764
Pharmacological inhibition of apoptosis signal-regulat-
ing kinase 1 (ASK1) in a murine model of NASH with
pre-existing disease blocks fibrosis, steatosis, and insu-
lin resistance
Satyajit Karnik1, Michael Charlton2, Yury Popov3, Zachary D.
Goodman5, Michelle Nash1, Maisoun Sulfab1, Vivian Barry1,
Erik G. Huntzicker1, Dorothy French1, Kelvin Li4, Martin Deca-
ris4, Claire Emson4, Scott M. Turner4, David Breckenridge5, Dan-
iel Tumas5; 1Biology Research, Gilead Sciences, Foster City, CA;
2Department of Gastroenterology and Hepatology, Mayo Clinic,
Rochester, MN; 3Division of Gastroenterology and Hepatology,
Beth Israel Deaconess Medical Center, Harvard Medical School,
Boston, MA; 4Kinemed Inc, Emeryville, CA; 5Center for Liver Dis-
eases, Inova Fairfax Hospital, Falls Church, CA
BACKGROUND & SIGNIFICANCE: Oxidative stress pathways
are implicated in the pathogenesis of NASH. Reactive oxygen
species (ROS) activate hepatic stellate cells (HSCs) resulting in
increased collagen production and expression of α smooth mus-
cle actin (αSMA). Apoptosis signal-regulating kinase 1 (ASK1)
responds to ROS by activating the p38 and JNK pathways and
inducing a profibrogenic response in HSCs. We have demon-
strated that the ASK1 pathway is activated in human NASH
liver biopsies. GS-4997 is a selective small molecule inhibitor
of ASK1 that has completed phase 1 evaluation in healthy sub-
jects. We previously evaluated the activity of a selective small
molecule ASK1 inhibitor in a murine model of NASH with pro-
phylactic treatment. Here, we evaluate the therapeutic efficacy
by treating animals with established NASH (F1/2). METHODS:
A western-style diet was administered continuously to 12 week
old male C57BL/6 mice for 320 days. At day 240, NASH was
established and animals were divided into 3 cohorts (n=15/
group): start of treatment disease controls, end of treatment
vehicle controls, and treatment with a selective small molecule
ASK1 inhibitor for 75 days. Endpoint evaluations included his-
tological scoring, clinical pathology, liver hydroxyproline (HYP)
levels, collagen synthesis by D2O-labelling, fibrillar collagen
HEPATOLOGY, October, 2014
area determined by 2nd harmonic imaging, and metabolic
endpoints including food intake, body weight, fasting blood
glucose levels, and an oral glucose tolerance test, and phar-
macokinetics. RESULTS: ASK1 inhibitor treatment did not affect
food intake compared to controls but did result in significant
body weight reduction and decreased fasting blood glucose
and insulin levels by 17% and 13%, respectively. In an oral
glucose tolerance test, ASK1 inhibitor treated animals had
33% and 37% reductions in AUC glucose and insulin, respec-
tively. ASK1 inhibitor treatment led to a reduction in plasma
AST, ALT, and cholesterol levels. ASK1 inhibition resulted in a
68% reduction of hepatic steatosis, a 44% reduction in HYP,
reduction in αSMA and p-P38 expression, an 84% reduction
in fibrillar collagen area, and reduced the synthesis of both
soluble and insoluble collagen compared to controls. CON-
CLUSIONS: In animals with established NASH, treatment with
a selective ASK1 inhibitor significantly improved key metabolic
parameters associated with NASH and significantly reduced
hepatic steatosis and fibrosis. The data demonstrate that inhi-
bition of ROS induced signaling through ASK1 with a selective
small molecule inhibitor had therapeutic benefit in established
NASH. These data support testing of GS-4997 in human
NASH patients.
Disclosures:
Satyajit Karnik - Consulting: Monsoon Dx; Employment: Gilead Sciences
Yury Popov - Consulting: Gilead Sciences, Inc; Grant/Research Support: Gilead
Sciences, Inc, Takeda
Zachary D. Goodman - Consulting: Gilead Sciences, Abbvie; Grant/Research
Support: Gilead Sciences, Fibrogen, Galectin Therapeutics, Merck, Vertex, Syn-
ageva, Conatus
Michelle Nash - Employment: Gilead Sciences
Vivian Barry - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead
Sciences, Inc.
Erik G. Huntzicker - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Dorothy French - Employment: Gilead Sciences; Stock Shareholder: Genentech
- Roche
Kelvin Li - Employment: KineMed, Inc; Stock Shareholder: KineMed, Inc
Martin Decaris - Employment: KineMed Inc.
Claire Emson - Employment: KineMed
Scott M. Turner - Employment: KineMed, Inc.
David Breckenridge - Employment: Gilead Sciences
Daniel Tumas - Employment: Gilead Sciences, Inc
The following people have nothing to disclose: Michael Charlton, Maisoun Sulfab
765
Inhibition of MAP3K5, Apoptosis signal-regulating
kinase 1, with an oral small molecule inhibitor blocks
hepatic fibrosis and steatosis in murine models of NASH
and PSC
Satyajit Karnik1, Michael Charlton2, Michelle Nash1, Maisoun
Sulfab1, Vivian Barry1, Erik G. Huntzicker1, Dorothy French1,
David Breckenridge1, Britton Corkey3, Gregory Notte3, James E.
Nelson4, Kris V. Kowdley4, Daniel Tumas1; 1Biology Research,
Gilead Sciences, Foster City, CA; 2Gastroenterology and Hepatol-
ogy, Mayo Clinic, Rochester, MN; 3Medicinal Chemistry, Gilead
Sciences, Foster City, CA; 4Liver Center of Excellence, Digestive
Disease Institute and Benaroya Research Institute, Virginia Mason
Medical Center, Seattle, WA
BACKGROUND & SIGNIFICANCE: Oxidative stress pathways
are implicated in the pathogenesis of NASH. Reactive oxygen
species (ROS) drive hepatic stellate cell (HSCs) activation by
increasing collagen production and αSMA expression. Apop-
tosis signal-regulating kinase 1 (ASK1) responds to ROS by
regulating the p38 and JNK pathways. Here, we demonstrate
the activation of the ASK1 pathway in human NASH patients
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
and evaluate a selective small molecule ASK1 inhibitor in
murine models of NASH and PSC. METHODS: RNA transcripts
were evaluated in NASH (n=16) and healthy (n=8) human
liver biopsies by qRT-PCR. Murine NASH model: high fat, high
cholesterol, high sugar diet was administered continuously to
12-week old male C57BL/6 mice concomitantly with vehicle
or a selective small molecule ASK1 inhibitor, GS-444217. At
days 90, 180, 270, and 360, cohorts of animals (n=10/time/
treatment group) were evaluated for metabolic parameters and
fibrosis endpoints including liver hydroxyproline (HYP) levels
and liver histology. Murine Mdr2-/- PSC model: At 4 weeks of
age, animals (n=20/group) were treated with either vehicle or
GS-444217 for 4 and 8 weeks. Liver fibrosis was assessed by
HYP and liver histology. RESULTS: Human NASH liver biopsies
had increased ASK1 pathway activation based on decreased
expression of Trx, an ASK1 inhibitor, and increased expression
of TxNIP, an inducer of ASK1 signaling. Increased TxNIP lev-
els were associated with higher TGF-β1, αSMA, and Col1a1
expression. In a murine NASH model, treatment with the ASK1
inhibitor reduced hepatic steatosis, inhibited fibrosis progres-
sion by 71% based on HYP level, and reduced αSMA, p-P38,
and collagen expression. ASK1 inhibitor treated animals were
resistant to diet-induced body weight gain, had an improved
lipid profile, and reduced AST, ALT, and M30 (a marker of
hepatocyte apoptosis) levels. ASK1 inhibitor treated animals
had a 51% reduction in fasting insulin levels, and 17% and
13% improvement in glucose and insulin AUC during oral glu-
cose challenge. In a murine Mdr2-/- PSC model, treatment with
ASK1 inhibitor reduced fibrosis progression by 15% and 30%
after 4 and 8 weeks, respectively and markers of fibrosis (P-II-
INP, HA, TIMP-1) were significantly reduced. CONCLUSIONS:
The ASK1 signaling pathway in liver is active in human NASH.
Inhibition of ASK1 prevented progression of hepatic fibrosis
and steatosis and improved metabolic parameters in a NASH
model. ASK1 inhibition also reduced fibrosis in an Mdr2-/-
PSC model. These novel preclinical data suggest a critical role
for ASK1 in the pathogenesis and progression of NASH and
PSC and support evaluation of an ASK1 inhibitor in patients.
Disclosures:
Satyajit Karnik - Consulting: Monsoon Dx; Employment: Gilead Sciences
Michelle Nash - Employment: Gilead Sciences
Vivian Barry - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead
Sciences, Inc.
Erik G. Huntzicker - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Dorothy French - Employment: Gilead Sciences; Stock Shareholder: Genentech
- Roche
David Breckenridge - Employment: Gilead Sciences
Britton Corkey - Employment: Gilead Sciences
Gregory Notte - Employment: Gilead Sciences; Stock Shareholder: Gilead Sci-
ences
Kris V. Kowdley - Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research
Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria,
Janssen, Merck, Mochida, Vertex
Daniel Tumas - Employment: Gilead Sciences, Inc
The following people have nothing to disclose: Michael Charlton, Maisoun Sul-
fab, James E. Nelson
571A
766
Differential roles of C5a receptors C5aR and C5L2 in
liver and kidney fibrosis
Ina V. Martin2, Tammo Ostendorf2, Jürgen Floege2, Frank Lam-
mert1, Susanne N. Weber1; 1Department of Medicine II, Saarland
University, Homburg, Germany; 2Division of Nephrology, RWTH
University of Aachen, Aachen, Germany
Background: Complement factor C5a has two known receptors,
C5aR and C5L2. C5aR is involved in transduction of the proin-
flammatory effects of C5a, whereas C5L2 has been suggested
as a decoy receptor. We previously demonstrated a pro-fi-
brotic role of C5a and C5aR in kidney and liver, but nothing is
known concerning the potential involvement of C5L2 in organ
fibrosis. Methods: C5aR-/-, C5L2-/- and wild-type (WT) control
mice were challenged with CCl4 for 6 weeks to induce liver
fibrosis or subjected to 5 days of unilateral ureteral obstruction
(UUO), a model of renal fibrosis. Extracellular matrix (ECM)
deposition, the inflammatory status and injury markers were
analyzed by gene expression analyses and immunohistochem-
istry. Results: Following induction of liver fibrosis, collagen con-
tents were significantly lower in C5aR-/- but unchanged in
C5L2-/- mice. Transcript analyses of cytokines in the chronic
fibrosis model (TGFβ-1, TNFα, IL6, IL12, IL23, IL27) showed
a prominent reduction in both receptor-deficient lines vs. WT
mice. Twenty-four hours after an acute single CCl4 challenge,
these cytokines were highly induced specifically in C5L2-/-
mice as compared to WT and C5aR-/- mice. During progres-
sion of kidney fibrosis both C5a receptors were overexpressed.
Compared to WT mice, C5aR deficiency led to a significant
reduction of renal collagen I and IV, α-smooth muscle actin and
vimentin expression; C5L2 deficiency in renal fibrosis resulted
in only mild reduction of ECM, whereas MCP-1, RANTES,
TNFα and IL-6 expression increased. Transcripts of TGFβ-1 and
KIM-1, a tubular injury marker, were markedly reduced in both
C5aR-/- and C5L2-/- mice vs. WT controls. Conclusions: Our
findings taken together demonstrate that C5aR is involved in
chronic fibrogenesis in both liver and, although less potently,
also in the kidney. In the liver, C5L2 provides protection from
early inflammatory insults, and in kidney fibrosis C5L2 might
also play a weak anti-inflammatory role, indicating organ-spe-
cific regulatory effects of C5 during fibrogenesis.
Disclosures:
The following people have nothing to disclose: Ina V. Martin, Tammo Ostendorf,
Jürgen Floege, Frank Lammert, Susanne N. Weber
767
Coniferyl Ferulate Attenuated Liver Fibrosis Through
Inhibition Of Transforming Growth Factor-Β Receptor
Ya N. Zhou, Wen W. Fu, Ping Liu; Institute of Liver Diseases,
Shuguang Hospital, Shanghai University of Traditional Chinese
Medicine, Shanghai,, Shanghai, China
Object: Coniferyl ferulate (CF) is an activity component
extracted from Angelica sinensis. This study investigated the
effect of CF on liver fibrosis. Methods: Screening transform-
ing growth factor-β receptor (TGFβR) 1 inhibitor analogues
from 518 components with software for pharmacological cal-
culation. Evaluate the effect of one analogue CF on TGFβR1
through the kinase experiment in vitro. Liver fibrosis was
induced by intraperitoneal injection of carbon tetrachloride
(CCl4) in C57BL/6 mouse for 5 weeks. The CCl4-injected
mice were randomly divided into three groups followed by
oral administration of water, CF and Sorafenib (positive con-
trol) respectively from week 3 to week 5. The control group
was gave water. Phosphorylation protein chips were used
572A AASLD ABSTRACTS
to evaluate the effect of CF on transforming growth factor-β
(TGF-β) signaling pathway. Biochemical parameters and his-
tological changes of the liver were determined. The expres-
sions of significant differential proteins screened by protein
chips were detected with western blot. In addition, the effect
of CF was also evaluated in mouse HSC line JS-1. Results:
The result showed that CF was one of the components most
similar to TGFβR1 inhibitor. And the CF could inhibit the activ-
ity of TGFβR1 in kinase experiment. The data of protein chip
indicated that 87% proteins increased in model group were
down regulated by CF. In CCl4 mice, treatment with CF had
a beneficial effect on decreasing the serum alanine amino-
transferase (ALT), aspartate aminotransferase (AST) and total
bilirubin (TBIL) parameters increased in model group (P<0.05).
Changes in histopathology showed that CF attenuated inflam-
matory and decreased collagen deposition in the liver. The
expressions of collagen I, alpha smooth muscle actin (α-SMA),
TGF-β1, TGFβR1, psmad2/3, and pERK were decreased in
CF group compared with model group (P<0.05). In vitro, CF
could inhibit TGF-β1-induced the activity of JS-1, and IC50
was 55μM. Moreover, the TGF-β1-induced the expressions of
collagen I, α-SMA and TGFβR1 were decreased significantly
by CF in JS-1(P<0.05). Conclusion: We first demonstrated that
CF inhibited the activity of HSC and attenuated liver fibrosis
through the inhibition of TGFβR1. These results may shed light
on the therapeutic prospects of CF for liver fibrosis.
Disclosures:
The following people have nothing to disclose: Ya N. Zhou, Wen W. Fu, Ping Liu
768
Lysyl oxidase activity contributes to collagen stabiliza-
tion during liver fibrosis progression and limits hepatic
fibrosis reversal in mice
Susan B. Liu1, Naoki Ikenaga1, Deanna Sverdlov1, Zhen-Wei
Peng1, Detlef Schuppan2,1, Yury Popov1; 1Division of Gastroen-
terology and Hepatology, Beth Israel Deaconess Medical Cen-
ter, Boston, MA; 2Institute of Translational Immunology, University
Medical Center, Mainz, Germany
Background & Aims: Collagen stabilization through irreversible
cross-linking is thought to determine the progression of hepatic
fibrosis and to limit the reversal of advanced fibrosis, but the
molecular mechanism behind collagen stabilization remains
poorly defined. Here, we studied the functional role of the lysyl
oxidase (LOX) pathway in collagen stabilization, liver fibrosis
progression and regression in mice with chemical LOX inhibi-
tion. Methods: Advanced liver fibrosis was induced by chronic
oral gavage with carbon tetrachloride (CCl4) for 6 weeks,
and spontaneous reversal was studied after CCl4 withdrawal
for up to 8 weeks. Chronic LOX inhibition was achieved with
irreversible inhibitor β-aminopropionitrile (BAPN, 100mg/kg
daily) during the progression phase of liver fibrosis in vivo.
Fibrotic matrix stability and crosslinking was directly assessed
by a stepwise collagen extraction assay (Popov Y et al, Gastro-
enterology 2011). Pattern and extent of fibrosis were analyzed
using histological and biochemical methods. Results: During
progressive liver fibrosis, LOX inhibition did not impact total
hepatic collagen deposition. However, the composition of the
fibrotic matrix was altered in advanced stages, with a signif-
icant decrease in the highly cross-linked collagen fraction in
mice with LOX inhibition. Fibrogenic activity of hepatic stellate
cells, as determined by α-SMA expression and profibrogenic
gene expression, was notably attenuated in advanced, but
not early, fibrosis stages upon LOX inhibition. Mice treated
with LOX inhibitor, BAPN, during CCl4-induced fibrosis demon-
strated accelerated fibrosis reversal after CCL4 withdrawal,
HEPATOLOGY, October, 2014
as determined via quantitative reduction in hepatic collagen
content and histological signs of fibrosis regression already at
4 weeks of recovery. Conclusions: Lysyl oxidase activity con-
tributes significantly to collagen cross-linking and stabilization,
and fibrogenic activation of hepatic stellate cells in advanced
stages of hepatotoxin-induced liver fibrosis. While lysyl oxi-
dase inhibition does not reduce net collagen accumulation in
the progression phase, it renders liver fibrosis more readily
reversible after hepatotoxin withdrawal. This supports the con-
cept of LOX inhibition in the treatment of liver fibrosis, while
the LOX species that is most relevant for collagen crosslinking
needs to be defined.
Disclosures:
Detlef Schuppan - Consulting: Boehringer Ingelheim, Aegerion, Gilead, Gen-
zyme, GSK, Pfizer, Takeda, Sanofi Aventis, Silence
Yury Popov - Consulting: Gilead Sciences, Inc; Grant/Research Support: Gilead
Sciences, Inc, Takeda
The following people have nothing to disclose: Susan B. Liu, Naoki Ikenaga,
Deanna Sverdlov, Zhen-Wei Peng
769
Deficiency of stress induced heat shock transcription
factor 1 (HSF1) Exacerbates Liver Fibrosis: Regulation of
Inflammatory Cytokines and Fibrogenesis
Pranoti Mandrekar, Arlene Lim; Medicine, University of Massachu-
setts Medical School, Worcester, MA
Background and Aims: Hepatic fibrosis is a hallmark of chronic
liver injury and characterized by excessive deposition of extra-
cellular matrix components, especially type I collagen, disrupt-
ing normal liver architecture. Previous studies show that hsp47,
a collagen-specific ER molecular chaperone, is required for sta-
bilization and appropriate folding of pro-collagen mediated by
pro-fibrogenic cytokine, TGF-β via activation of stress induced
heat shock transcription factor1 (HSF1). We hypothesize that
HSF1 plays an important role in hepatic fibrosis via regula-
tion of hsp47 and collagen synthesis. Methods: HSF1 deficient
(HSF1KO) and WT littermates were treated with carbon tetra-
chloride (CCl4) twice weekly for 6 weeks. Liver fibrosis was
assessed by Sirius Red staining and α-SMA expression. Hepatic
stellate cell activation markers and pro-fibrogenic transcripts
as well as pro-inflammatory cytokines and HSF1 DNA bind-
ing activity and target genes, hsp47, hsp70 and hsp90 were
assessed by real-time PCR. Results: Our results show induction
of liver fibrosis after chronic CCl4 treatment was significantly
higher in HSF1KO mice compared to WT controls, reflected
in elevated serum alanine aminotransferase and accompa-
nied by elevation of pro-fibrogenic markers, α1-(I)-collagen
(p<0.05) and activated hepatic stellate cell marker, α-smooth
muscle actin (α-SMA) (p<0.02). Interestingly, HSF1 target
genes were differentially regulated in CCl4 treated HSF1KO
mice. Collagen chaperone, hsp47 expression was significantly
increased (p<0.04) whereas hsp70 was reduced (p<0.001)
without any changes in hsp90 in CCl4 treated HSF1KO mice.
Expression of tissue inhibitor of metalloproteinase-1 (TIMP-1)
was elevated, whereas extracellular matrix proteins MMP-8
and MMP-13 were significantly decreased in CCl4 treated
HSF1KO mice. Pro-inflammatory cytokine, MCP1 was upregu-
lated (p<0.04), whereas TGF-β was reduced (p<0.05) in CCl4
treated HSF1KO mice. While HSF1 DNA binding activity in the
liver was increased early at 72hrs after acute CCl4 treatment,
nuclear HSF1 and DNA binding was decreased in fibrotic
livers after 6 weeks during increased hsp47 expression, sug-
gesting HSF1 independent regulation of hsp47 expression.
Conclusion: Our results reveal that deficiency of HSF1 exac-
erbates murine liver fibrosis by increasing pro-inflammatory
cytokine MCP1 and profibrogenic genes. Further, induction of
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
collagen-specific chaperone, hsp47 is independent of HSF1
during hepatic fibrosis. Our studies propose an important pro-
tective role for HSF1 during liver fibrosis suggesting its thera-
peutic potential.
Disclosures:
The following people have nothing to disclose: Pranoti Mandrekar, Arlene Lim
770
Cthrc1 alleviates cholestatic liver fibrosis through a neg-
ative feedback loop with p-smad3 in mice
Zhaolian Bian, Qi Miao, Wei Zhong, Xiong Ma; Ren Ji Hospital,
School of Medicine, Shanghai Jiao Tong University, Shanghai,
China
Background and aims: Collagen triple helix repeat containing-1
(Cthrc1) was found as a novel gene expressed in the adventitia
and neointima on arterial injury. It is shown to increase cell
migration while reducing collagen type I and III deposition in
arterial injury. Herein, we investigate the roles of Cthrc1 in
cholestatic liver fibrosis in vivo and vitro. Methods: The hepatic
Cthrc1 expression in primary biliary cirrhosis (PBC) and pri-
mary sclerosing cholangitis (PSC) patients were investigated by
immunohistochemistry. We generate cholestatic liver fibrosis
animal model by feeding mice with 3, 5-diethoxycarbonyl-1,
4-dihydrocollidine (DDC) diet or undergoing bile duct ligation
(BDL). We enforce or knockdown Cthrc1 by injecting adenovi-
rus vector that express cthrc1 (Ad-Cthrc1) or short hairpin RNA
which interfere with the Cthrc1 mRNA (Ad-shCthrc1) in vivo.
Chromatin immunoprecipitation (ChIP) assays further confirmed
the association of p-smad3 proteins with the Cthrc1 promoter.
The direct protein interactions between p-smad3 and Cthrc1
were determined by co- immunoprecipitation. Results: This
study unraveled a negative feedback loop involving Cthrc1
and p-smad3 in cholestatic liver fibrosis. The Cthrc1 protein
was strongly upregulated in PBC and PSC patients. The Cthrc1
mRNA and protein were also highly induced by DDC feeding
and BDL in mice. Mice injected with ad-Cthrc1 significantly
attenuated DDC or BDL-induced cholestatic liver fibrosis. This
effect was associated with a decreased number of hepatic stel-
late cells and the expression of α-smooth muscle actin (α-SMA).
When we knockdown the Cthrc1 by injecting Ad-shCthrc1,
liver fibrosis induced by DDC diet or BDL were aggravated
in mice. ChIP assays confirmed that p-smad3 could binding
with the Cthrc1 promoter, and luciferase assays indicate that
p-smad3 activate the Cthrc1 promoter. From the co-immuno-
precipitation, we found that Cthrc1 could bind with p-smad3,
and promote its degration through the proteasome pathway in
hepatic stellate cell. Then, inhibited the proliferation of hepatic
stellate cells and synthesis of collagen type I, III and α-SMA.
Conclusions: Cthrc1 and p-smad3 is a negative feedback loop
in cholestatic liver fibrosis. Cthrc1 attenuates cholestatic liver
fibrosis through promoting degration of p-smad3. Cthrc1might
become a potential therapeutic option for cholestatic liver
fibrosis. Key words: Cthrc1, HSC, p-smad3, cholestatic liver
fibrosis.
Disclosures:
The following people have nothing to disclose: Zhaolian Bian, Qi Miao, Wei
Zhong, Xiong Ma
573A
771
‘Lucky grandchildren’: Inbred mice whose grandparents
developed liver fibrosis appear to be protected against
the same disease
Andrea Schmetz, Frank Lammert, Susanne N. Weber; Department
of Medicine II, Saarland University Medical Center, Homburg,
Germany
Background: Epigenetic mechanisms might modify the fibro-
genic response to liver injury. Recently a history of CCl4-in-
duced liver damage was shown to result in an epigenetic
suppressive adaptation of the wound healing response in male
F2 rats (Zeybel et al. Nat Med 2012). Our aim now was to
investigated whether ancestral liver injury leads to mutligen-
erational reprogramming of the fibrotic response in inbred
mouse strains. Methods: To address this question we designed
an experiment in which male mice from the BALB/cJ inbred
strain were treated with CCl4 intraperitoneally for six weeks
to induce liver fibrosis. The mice were subsequently bred for
two generations. Half of the resulting F2 generation (N = 50)
was challenged with CCl4 again for six weeks. The treated
group was compared to control mice (N = 12) without induc-
tion of fibrosis in previous generations. Liver histopathology
was assessed after collagen staining of collagen, and hepatic
collagen contents were quantified enzymatically. As markers
to determine the severity of fibrosis we measured the hepatic
expression levels of collagens I and III, transforming growth fac-
tor (TGF)-beta 1 and alpha-smooth muscle actin (SMA). Results:
Our findings provide evidence for a significant decrease in
fibrosis severity in animals with ancestors exposed to the hep-
atotoxin CCl4. Collagen I expression decreased significantly
as did collagen in histopathology (both P < 0.05). In line with
these findings, alpha-SMA mRNA levels showed a trend to
decrease in mice with a transgenerational background of fibro-
sis, and liver/body weight ratio showed similar alterations.
Peculiarly, TGF-beta 1 mRNA levels increased, and collagen III
expression did not differ significantly between pre-treated ped-
igrees and control progeny. Discussion: This is the first data set
to provide evidence for multigenerational epigenetic modula-
tion of fibrogenesis in inbred mouse strains. We speculate that
modifications of histones controlling the fibrogenic genes could
result in the attenuation of fibrosis through an advantageous
shift of the collagen I/III ratio. A myofibroblast-secreted soluble
factor might stimulate heritable epigenetic signatures that allow
the progeny to adapt to fibrogenic stimuli.
Disclosures:
The following people have nothing to disclose: Andrea Schmetz, Frank Lammert,
Susanne N. Weber
772
Signaling via the osteopontin and high-mobility group
box-1 axis drives the fibrogenic response to liver injury
Elena Arriazu1, Xiaodong Ge1, Tung Ming Leung1, Aritz Lopategi1,
Yongke Lu1, Raquel Urtasun1, Neil D. Theise2, Natalia Nieto1;
1Medicine/ Liver Diseases, Icahn School of Medicine at Mount
Sinai, New York, NY; 2Division of Digestive Diseases, Mount Sinai
Beth Israel Medical Center, New York, NY
Background: Liver fibrosis is highly associated with inflamma-
tion and extracellular matrix deposition, mainly collagen-I,
largely produced by activated hepatic stellate cells; yet, the
precise link between hepatocyte injury, inflammation and scar-
ring remains unknown. Work from our laboratory demonstrated
significant induction of osteopontin (OPN) - an extracellular
matrix protein- and of high-mobility group box-1 (HMGB1) -a
proinflammatory damage-associated molecular pattern- follow-
574A AASLD ABSTRACTS
ing liver injury. Hypothesis: Since OPN was found upstream of
HMGB1, we hypothesized that OPN by increasing HMGB1
could be involved in the pathogenesis of liver fibrosis regulating
scarring. Results: Long-term hepatitis C progressors displayed
enhanced hepatic OPN and HMGB1 immunostaining, which
correlated with fibrosis stage, while the expression remained
similar in non-progressors. The hepatocyte cytoplasmic OPN
and HMGB1 expression was remarkable whereas loss of
nuclear HMGB1 occurred in patients with hepatitis C-induced
fibrosis compared to healthy explants. Overt liver fibrosis along
with marked induction of HMGB1 occurred in CCl4-injected
OpnHEP transgenic mice yet it was less in wild-type mice and
almost absent in Opn-/- mice. Blockade of HMGB1 secretion
or Hmgb1 ablation in hepatocytes partially prevented liver
fibrosis in mice. Co-culture with hepatocytes, which secrete
OPN and HMGB1, and challenge with recombinant OPN or
HMGB1 enhanced collagen-I expression in hepatic stellate
cells, which was blocked by neutralizing antibodies. Recom-
binant OPN induced acetylation of HMGB1 in hepatic stellate
cells due to an increase in NADPH oxidase activity and the
consequent decrease in histone acetyl transferase activity lead-
ing to up-regulation of collagen-I expression. Last, recombinant
HMGB1 signaled via the receptor for advanced glycation-end
products activating the PI3K/pAkt1/2/3 signaling pathway
and up-regulating collagen-I expression in hepatic stellate cells.
Conclusion: During liver injury, OPN expression increases and
enhances HMGB1, which acts as a key upstream alarmin driv-
ing the profibrogenic response in hepatic stellate cells.
Disclosures:
The following people have nothing to disclose: Elena Arriazu, Xiaodong Ge,
Tung Ming Leung, Aritz Lopategi, Yongke Lu, Raquel Urtasun, Neil D. Theise,
Natalia Nieto
773
Sortilin deficiency affects fibrosis differently in hepato-
cellular versus cholangiocyte models of liver injury
Rafael Bruck1,3, Einav Hubel2, Tamar Thurm2, Isabel Zvibel2,3;
1Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv,
Israel; 2Research Center, Tel Aviv Medical Center, Tel Aviv, Israel;
3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Background/Aims: The p75 neurotrophin receptor (p75NTR)
was shown to be crucial for hepatic stellate cells (HSC) acti-
vation. This receptor can form heterodimers with sortilin, bind-
ing pro-nerve growth factor (proNGF) and inducing neuronal
apoptosis. We investigated the role of neurotrophins and their
receptors, in particular sortilin, in activation and apoptosis of
HSC and in the development and regression of hepatic fibro-
sis. Methods: Fibrosis was induced by three times weekly i.p.
administration of thioacetamide (TAA) for 4, 6, 10 weeks
(150mg/Kg body weight) and α-naphtylisothiocyanate (ANIT)
(50mg/Kg body weight) twice weekly for 4 weeks to sortilin-/-
mice and their wild type (WT) counterparts. Apoptosis was
assessed using a caspase 3 activity kit. Fibrosis was deter-
mined by Sirius red staining, hydroxyproline levels and by
qRT-PCR for fibrosis markers. Results: HSC derived from sorti-
lin-/- mice displayed increased in vitro activation and were less
susceptible to NGF-induced apoptosis compared to HSC from
wild type mice. Sortilin-/- showed increased hepatic fibrosis
after 4 and 6 weeks of TAA administration, as demonstrated
by increased Sirius Red staining, increased hydroxyproline lev-
els and higher expression of collagen I and α-smooth muscle
actin. Moreover, sortilin -/- mice had attenuated regression of
fibrosis after TAA, due to reduced HSC apoptosis. In contrast,
in a model of cholangiocyte injury induced by chronic ANIT
administration, sortilin-deficient mice exhibited dramatically
HEPATOLOGY, October, 2014
attenuated fibrosis, accompanied by reduced early expression
of pro-inflammatory cytokines TNFα and MCP-1 and attenu-
ated ductular reaction. Conclusions: Sortilin deficiency leads
to increased liver fibrosis and attenuated fibrosis regression in
a model of hepatocellular damage. However, in a model of
cholangiocyte injury, sortilin deficiency results in strongly atten-
uated fibrosis, due to reduced early inflammation.
Disclosures:
The following people have nothing to disclose: Rafael Bruck, Einav Hubel, Tamar
Thurm, Isabel Zvibel
774
Linagliptin mediated DPP-4 inhibition ameliorates
inflammation and fibrosis in models of NASH and bili-
ary fibrosis
Xiao-Yu Wang1, Shih-Yen Weng1, Yong Ook Kim1, Thomas Klein2,
Detlef Schuppan1,3; 1Institute of Translational Immunology,Univer-
sity Medical Center of the Johannes Gutenberg-University Mainz,
Mainz, Germany; 2Boehringer Ingelheim Pharma GmbH & Co.
KG, Biberach an der Riss, Germany; 3Division of Gastroenter-
ology, Beth Israel Deaconess Medical Center, Harvard Medical
School, Boston, MA
Background: Non-alcoholic steatohepatitis (NASH) is char-
acterized by steatosis, lobular inflammation and progres-
sive pericellular fibrosis. Glucagon like peptide 1 (GLP-1) is
an attractive molecule for the treatment of insulin resistance
and therefore NASH. GLP-1 is rapidly inactivated by cell sur-
face dipeptidyl peptidase-4 (DPP-4). Therefore we studied the
effect of the indirect GLP-1 agonist Linagliptin, a hepatotropic
DPP4-inhibitor, on liver inflammation and fibrosis in models of
biliary fibrosis and NASH. Methods: Linagliptin was adminis-
tered daily by gavage at 0.5, 5, 10 and 50 mg daily per kg
BW to Mdr2KO mice from week 7-11 of agefor 4 weeks, and
to 8 week old C57BL/6mice fed a methionine and choline defi-
cient diet (MCD) for 4 and 6 weeks. Liver tissue from mice was
examined histologically, immunohistochemically and biochem-
ically (Hyp), to estimate the effect of Linagliptin on the develop-
ment of fibrosis and NASH. Fibrosis and inflammation related
transcript levels were quantified by quantitative real-time poly-
merase chain reaction (qPCR). Results: Mice fed the MCD diet
showed a rapid induction of hepatic steatosis, inflammation
and a 2-fold increase in fibrosis (total liver collagen content)
compared to controls, with an up to 10-fold upregulation of
procollagen α1(I), TGFβ1, αSMA, MMP-3 and- 9, TIMP-1,
CCL3 and TNF α mRNA expression.The 4 week Linagliptin
treatment at10 and 50mg/kg/day lowered serum ALT, AST,
ALP and triglycerides. 50 mg/kg/day decreased expression
of αSMA, procollagen α1(I), TIMP-1 and MMP-3 compared to
vehicle-treated controls.5mg/kg/day of Linagliptin for 6 weeks
significantly attenuatedsteatosis, inflammation, macrophage
infiltration, and the number of activated hepatic stellate cells.
In line with levels of macrophages, circulating proinflammatory
cytokines like IL-6 were significantly reduced. In Mdr2KO mice,
10 and 50mg/kg/day of Linagliptin significantly decreased
procollagenα1(I) and TGFβ1, TIMP-1, MMP-8 transcript lev-
els, but increased putatively anti-fibrotic MMP-9 and -13.
However, despite a reduction in Sirius red stained collagen
area biochemical hepatic collagen accumulation (Hyp) was
not significantly reduced in both the Mdr2KO and the MCD
model. Conclusion: In experimental biliary fibrosis (Mdr2KO
mice) and in a surrogate NASH model oral Linagliptin was
well tolerated and significantly decreased hepatic steatosis,
inflammation and mildly attenuated the progression of fibrosis,
independently of the antifibrotic effect. In conclusion, these
studies suggrest that linagliptin is highly hepatotropic, and
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
apart from its antidiabetic action may qualify as an adjunctive
therapy for NASH and fibrosis.
Disclosures:
Thomas Klein - Employment: Boehringer Ingelheim
Detlef Schuppan - Consulting: Boehringer Ingelheim, Aegerion, Gilead, Gen-
zyme, GSK, Pfizer, Takeda, Sanofi Aventis, Silence
The following people have nothing to disclose: Xiao-Yu Wang, Shih-Yen Weng,
Yong Ook Kim
775
The Hippo pathway effector YAP is an early regulator of
hepatic stellate cell activation
Inge Mannaerts1, Sofia B. Leite1, Stefaan Verhulst1, Lien F. Thoen1,
Sofie Claerhout2, Georg Halder2, Leo A. van Grunsven1; 1Liver
Cell Biology Lab, Vrije Universiteit Brussel, Brussels, Belgium;
2VIB Center for the Biology of Disease, and KU Leuven Center for
Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium
Background and Aims: Hepatic stellate cell (HSC) activation
is a wound-healing response to liver injury. However, upon
chronic damage, continued HSC activation disrupts the bal-
ance in matrix remodeling, leading to pathological accu-
mulation of scar tissue or fibrosis and ultimately to cirrhosis.
Although the importance of HSC activation in this process is
well recognized, the mechanisms of HSC activation are poorly
understood. Activated HSCs are characterized by increased
proliferation and matrix production. YAP and TAZ, two homol-
ogous transcriptional co-activators that act as the downstream
effectors of the Hippo pathway, regulate cell proliferation in
response to mechanical stress and changes in matrix composi-
tion. We therefore hypothesized that Hippo signaling, and in
particular YAP and TAZ, mediate the changes in HSC behav-
ior following liver injury. Methods and Results: Activation of
primary HSCs after plating primary HSCs on plastic and in
cells isolated from mice treated with carbon tetrachloride or
after bile duct ligation, induced nuclear translocation of YAP
and early and strong up-regulation of its down-stream target
genes Ankrd1 and Ctgf. Culturing HSCs on substrates with a
stiffness of 1.5 kPa or in 3D-spheroids prevented the nuclear
translocation of YAP and the up-regulation of Ankrd1 and Ctgf.
Abrogation of YAP/TAZ signaling using siRNAs, verteporfin or
Latrunculin treatment reduced Ankrd1 and Ctgf expression and
the degree of HSC activation. Conclusion: Our results indicate
that YAP activation is a critical driver of HSC stimulation in
response to liver injury.
Disclosures:
The following people have nothing to disclose: Inge Mannaerts, Sofia B. Leite,
Stefaan Verhulst, Lien F. Thoen, Sofie Claerhout, Georg Halder, Leo A. van
Grunsven
776
Toll-like Receptor 3 Accelerates Liver Fibrosis by Enhanc-
ing IL-17 Production in Mice
Wonhyo Seo, Hyuk-Soo Eun, Young-Sun Lee, Hyon-Seung Yi, Jong-
Min Jeong, So Yeon Kim, Yoo Kyung Kang, Jin Yong Kim, Byung
Jun Choi, Won-Il Jeong; Korea Advanced Institute of Science and
Technology, Daejeon, Republic of Korea
Study`s purpose: Toll-like receptor 3 (TLR3) is a receptor which
recognizes double-stranded RNA associated with viral infec-
tion, subsequently leading to the production of type I interferon
and other cytokines. In addition, IL-17 is highly involved in the
progression of liver fibrosis but the exact mechanism of IL-17
production in liver fibrosis has not been fully understood yet.
Therefore, we have investigated the effects of TLR3 activation
on IL-17 production during liver fibrosis. Methods: To induce
575A
liver fibrosis, wild type (WT) and TLR3-depleted mice were
injected with carbon tetrachloride (CCl4) or bile duct ligation
was performed for 2 weeks. For investigating the source of
IL-17 production at early time periods, mice were sacrificed at
0, 12, 24 and 36 hours after CCl4 treatment. Hepatic stellate
cells (HSCs) and Kupffer cells were isolated using liver perfusion
methods. CD4 T cells and γδ T cells, known as major source of
IL-17 production in liver, were also freshly isolated from liver,
spleen and lymph nodes with magnetic beads. To investigate
IL-17 production, co-culturing CD4 T or γδ T cells with HSCs
or Kupffer cells were performed in the presence or absence of
poly I:C, a synthetic TLR3 agonist. Results: TLR3-depleted mice
showed significantly attenuated liver fibrosis compared to WT
mice in CCl4 challenge but not in bile duct ligation. In addi-
tion, serum IL-17 levels were remarkably decreased in TLR3-de-
pleted mice compared with WT. More interesting was that γδ
T cells were identified as a major source of IL-17 production at
early time point (12 hour) after CCl4 challenge in WT mice.
In vitro co-culturing γδ T cells with HSCs or Kupffer cells, poly
I:C-mediated TLR3 activation in quiescent HSCs enormously
increased IL-17 expression of γδ T cells but quiescent HSCs
without TLR3 activation did not enhance IL-17 expression in γδ T
cell. However, Kupffer cells with or without TLR3 activation did
not increase IL-17 expression of γδ T cells during co-culturing.
Conclusion: In CCl4-induced liver fibrosis, TLR3 accelerates
liver fibrosis via enhanced IL-17 production of γδ T cells, which
might be associated with TLR3 activation of HSCs by unknown
self-TLR3 ligands released from damaged hepatocytes. There-
fore, TLR3 could be a novel therapeutic target for liver fibrosis
induced by drug-mediated hepatocyte damage.
Disclosures:
The following people have nothing to disclose: Wonhyo Seo, Hyuk-Soo Eun,
Young-Sun Lee, Hyon-Seung Yi, Jong-Min Jeong, So Yeon Kim, Yoo Kyung Kang,
Jin Yong Kim, Byung Jun Choi, Won-Il Jeong
777
Deletion of the cytoplasmic domain of Tissue Factor
ameliorates liver fibrosis and decreases TGFβ expres-
sion in a murine model of cirrhosis
Virginia Knight, Jorge Tchongue, Dinushka Lourensz, Alison X. Liu,
Peter Tipping, William Sievert; Centre for inflammatory diseases,
Monash University, Clayton, VIC, Australia
Tissue Factor (TF) has a well-known function in haemostasis
but also plays an important role in angiogenesis, sepsis and
inflammation. TF has 3 domains, the cytoplasmic domain acts
as a signalling receptor to promote a proinflammatory phe-
notype in macrophages (Cunningham 1999). Deletion of the
TF cytoplasmic domain reduces the severity of inflammatory
arthritis in an experimental murine model (Yang 2004). The
aim of this study was to investigate whether deletion of the TF
cytoplasmic domain protected against fibrogenesis in a model
of hepatic inflammation and fibrosis. Methods: 9 week old
wildtype (WT) and C57/BL6 mice with deletion of the TF cyto-
plasmic domain (TF §CT/ §CT) received twice weekly intraper-
itoneal injections of carbon tetrachloride for 8 weeks. Fibrosis
was quantified by computer assisted morphometry of Sirius red
stained liver sections. Hydroxyproline assay quantified hepatic
collagen content. Hepatic TGFβ protein content was measured
by ELISA and αSMA and TGFβ gene expression was assessed
by RT PCR using whole liver mRNA Liver sections were stained
with F4/80 and CD68 to identify macrophages. Results: Mor-
phometric analysis of Sirius red stained sections after 8 weeks
of CCL4 revealed significantly less collagen deposition per
total area in TF §CT/ §CT mice compared to WT (1.76% vs
3.39%, p<0.05). In addition, hepatic hydroxyproline content
576A AASLD ABSTRACTS
was significantly lower in TF §CT/ §CT vs WT (0.37 vs 0.61
mg/mg, p<0.05). There was a significant decrease in αSMA
gene expression in TF §CT/ §CT compared to WT (0.35 vs
3.93 fold change compared to vehicle control respectively,
p<0.01) which was accompanied by significantly fewer αSMA
+ve cells in liver sections (p<0.0001). TF §CT/ §CT mice pro-
duced significantly less TGF β mRNA than wildtype (0.22 vs
3.57 fold greater than control respectively, p<0.0001) and
TGF β protein (45% reduction, p< 0.001). Significantly fewer
F4/80+ macrophages and CD68+ activated macrophages
were observed in the TF §CT/ §CT compared to wildtype. Con-
clusion: We have shown for the first time that mice with dele-
tion of the cytoplasmic domain of TF exhibit significantly less
hepatic fibrosis than wild type mice. The TF §CT/ §CT animals
show reduced αSMA gene expression with fewer αSMA+ cells
histologically and reduced TGF β gene and protein expression
compared to WT animals. These outcomes are consistent with
decreased HSC activation, which may be due to a reduction in
activated macrophages in TF §CT/ §CT animals.
Disclosures:
William Sievert - Speaking and Teaching: Gilead Sciences, Bristol Myers Squibb,
Merck, Gilead Sciences, Bristol Myers Squibb, Merck, Gilead Sciences, Bristol
Myers Squibb, Merck, Gilead Sciences, Bristol Myers Squibb, Merck
The following people have nothing to disclose: Virginia Knight, Jorge Tchongue,
Dinushka Lourensz, Alison X. Liu, Peter Tipping
778
Platelets as a novel target in liver fibrosis: extrahepatic
supply of PDGF-B by platelets drives hepatic stellate cell
activation and biliary liver fibrosis progression
Shuhei Yoshida1,2, Naoki Ikenaga1, Susan B. Liu1, Deanna Sverd-
lov1, Masahiko Shimada2, Maki Tobari2, Tetsuya Hamano3,
Takayoshi Nishino2, Atsushi Mitsunaga3, Detlef Schuppan1,4, Yury
Popov1; 1Gastroenterology and Hepatology, Beth Israel Deaconess
Medcal Center, Harvard Medical School, Boston, MA; 2Division
of Gastroenterology and Hepatology, Yachiyo Medical Center,
Tokyo Women’s Medical University, Yachiyo, Japan; 3Division of
Endoscopy, Yachiyo Medical Center, Tokyo Women’s Medical
University, Yachiyo, Japan; 4Institute of Translational Immunology,
University Medical Center, Mainz, Germany
Background & Aims: Platelet-derived growth factor beta
(PDGF-B) is the major mitogen for hepatic stellate cells (HSC).
We studied the cellular sources of PDGF-B and tested the antifi-
brotic efficacy efficacy of anti-platelet therapy and a novel high
affinity anti-PDGF-B monoclonal antibody (mAB), MOR8457,
in mouse models of biliary fibrosis. Methods: Cellular sources
of PDGF-B were studied using QRT-PCR, ELISA and immuno-
histological methods. Platelet depletion was achieved with
anti-CD41 mAb. MOR8457 was administered i.p. weekly in
Mdr2-/- and in mice fed 3,5-diethoxycarbonyl-1,4-dihydro-
collidine (DDC). Liver fibrosis was evaluated by histology,
biochemical determination of collagen content and QRT-PCR.
Results: While protein levels of PDGF-B in liver and serum
were elevated in fibrotic Mdr2-/- mice, PDGF-B mRNA was
not increased. Platelet clusters were detected in sinusoids and
identified as extrahepatic source of PDGF-B protein in Mdr2-/-
mice. Platelet depletion with anti-CD41 antibody normalized
hepatic PDGF-B protein within 48h, reduced the HSC activation
marker αSMA and shifted gene expression towards a fibrolytic
profile. Anti-platelet therapy with low-dose dietary aspirin sig-
nificantly improved long-term, but not short-term, fibrosis out-
comes in the Mdr2-/- model. Treatment of Mdr2-/- mice with
MOR8457 for 6 weeks resulted in a dose-dependent decrease
in fibrosis, with up to 45% reduction of collagen deposition
and >50% inhibition of profibrogenic transcripts. Antifibrotic
activity of MOR8457 was confirmed in the mechanistically
HEPATOLOGY, October, 2014
different model of DDC-induced biliary fibrosis. In human dis-
ease, serum PDGF-BB levels were elevated in patients with liver
fibrosis of various etiologies in early histological fibrosis stages
(F1-2, n=16, p<0.05), as compared with patients with no sig-
nificant fibrosis (F0, n=12). There was a correlation between
serum PDGF-BB level, histological stages (F0-2, r=0.5762) and
serum levels of liver fibrosis-specific 7S domain of type IV col-
lagen (r=0.8947). Conclusions: Platelet activation and homing
to the liver is the major source of PDGF-B dependent fibrogenic
activation of HSC in biliary fibrosis. Pharmacological targeting
of platelets with anti-platelet therapy or selective antibody inhi-
bition of PDGF-B potently attenuate biliary fibrosis progression.
Disclosures:
Detlef Schuppan - Consulting: Boehringer Ingelheim, Aegerion, Gilead, Gen-
zyme, GSK, Pfizer, Takeda, Sanofi Aventis, Silence
Yury Popov - Consulting: Gilead Sciences, Inc; Grant/Research Support: Gilead
Sciences, Inc, Takeda
The following people have nothing to disclose: Shuhei Yoshida, Naoki Ikenaga,
Susan B. Liu, Deanna Sverdlov, Masahiko Shimada, Maki Tobari, Tetsuya
Hamano, Takayoshi Nishino, Atsushi Mitsunaga
779
Anti-fibrotic and anti-inflammatory activity of the ade-
nosine receptor 2b antagonist, GS-6201, in a murine
model of PSC
Satyajit Karnik1, Yong Ook Kim2, Michelle Nash1, Maisoun Sul-
fab1, Dewan Zeng3, Hongyan Zhong1, Simon C. Robson4, Detlef
Schuppan2,4, Daniel Tumas1; 1Biology, Gilead Sciences, Foster
City, CA; 2Institute of Translational Immunology, Johannes Guten-
berg University Mainz, Mainz, Germany; 3Clinical Research,
Gilead Sciences, Foster City, CA; 4Division of Gastroenterology,
Beth Israel Deaconess Medical Center, Harvard Medical School,
Boston, MA
BACKGROUND& SIGNIFICANCE: Tissue adenosine levels are
increased in response to inflammation. Previous studies have
demonstrated a role for adenosine signaling in hepatic fibrosis,
but it remains controversial which of the 4 adenosine receptor
(ADOR) family members are involved in disease pathogenesis.
Here, we identify ADOR 2b (A2bR) as the key pro-fibrotic sig-
naling receptor, determine the activity of the ADOR 2b signal-
ing pathway in human disease, and test the efficacy of 2 potent
and selective A2bR antagonist in murine models of PSC. METH-
ODS: In vitro experiments were conducted on primary human
cells (3 donors). Human liver biopsies were analyzed for A2bR
expression by a board certified pathologist. GS-6201, a small
molecule antagonist of A2bR was tested in Mdr2-/-, a murine
model of PSC. GS-6201 was administered as admixture in
diet (0.01%, 0.03%, 0.1%) to 8 week old Mdr2-/- FVB mice
(n=20/dose group) for 28 or 56 days. MRS-1754, another
A2bR antagonist, was injected intraperitoneally daily for 4
weeks at 2 doses (0.5mg/kg or 2mg/kg). Endpoint evaluation
included quantification of liver hydroxyproline (HYP) levels,
serum biochemistry, and qPCR analysis. RESULTS: QPCR analy-
sis confirmed expression of the ADOR family in hepatic (human
hepatocytes, hepatic stellate cells (HSCs), hepatic sinusoidal
endothelial cells) and immune cells (macrophages, monocytes,
B cells, and T cells) with ~10 fold higher expression of A2bR in
HSCs and macrophages. NECA, an ADOR agonist, increased
collagen production by 3-fold in HSCs, while agonists selective
for other ADOR family members had no activity. GS-6201
inhibited the response of primary HSCs and macrophages to
NECA, resulting in reductions of collagen, IL-6, and TGF-β pro-
tein level. In human PSC liver biopsies, increased expression
of A2bR protein correlated with fibrosis stage. RT-PCR analysis
revealed a good correlation between the expression of A2bR,
IL-6 and TGF-β1. GS-6201 reduced liver HYP levels by 35%
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
in Mdr2-/- mouse, accompanied by reductions in IL-6, TGF-β,
and αSMA expression. Mdr2-/- mice treated with 2mg/kg
MRS1754 displayed a 32% and 37% reduction of relative and
total hepatic collagen respectively. Q-PCR.analysis revealed a
downregulation of fibrosis (αSMA, COL1a, TGF-β) transcripts.
CONCLUSIONS: 1) A2bR is selectively upregulated in rodent
and human HSCs and macrophages, two key effectors in liver
fibrogenesis; 2) The A2bR signaling pathway results in pro-
fibrogenic cellular responses; 3) In human PSC and NASH,
A2bR expression correlated with enhanced expression of profi-
brogenic genes including TGF-β1 and IL-6; 4).The A2bR antag-
onist, GS-6201, suppresses fibrosis in a murine model of PSC.
Disclosures:
Satyajit Karnik - Consulting: Monsoon Dx; Employment: Gilead Sciences
Michelle Nash - Employment: Gilead Sciences
Dewan Zeng - Employment: Gilead
Hongyan Zhong - Employment: Gilead Sciences, Inc
Simon C. Robson - Grant/Research Support: Pfizer, NIH; Independent Contrac-
tor: eBioscience, Biolegend, EMD Millipore, Mersana; Speaking and Teaching:
ACP, Elsevier, ATC; Stock Shareholder: Nanopharma, Puretech
Detlef Schuppan - Consulting: Boehringer Ingelheim, Aegerion, Gilead, Gen-
zyme, GSK, Pfizer, Takeda, Sanofi Aventis, Silence
Daniel Tumas - Employment: Gilead Sciences, Inc
The following people have nothing to disclose: Yong Ook Kim, Maisoun Sulfab
780
Role of LARP6 and nonmuscle myosin in partitioning of
collagen mRNAs to the ER membrane
Hao Wang, Yujie Zhang, Lela Stefanovic, Branko Stefanovic; Bio-
medical Sciences Department, College of Medicine, Florida State
University, Tallahassee, FL
Purpose: Liver fibrosis is characterized by excessive produc-
tion of type I collagen. To find a cure for the liver fibrosis, it’s
important to elucidate the mechanisms of type I collagen bio-
synthesis. Type I collagen is a heterotrimer protein composed
of two α1(I) and one α2(I) polypeptides. The collagen mRNAs
have to be targeted to ER membrane for collagen peptides
to be synthesized. The goal of this study is to characterize
the molecular mechanisms involved in subcellular localization
of collagen mRNAs. Methods: LARP6 was knocked down by
transfection the human lung fibroblast cells with siRNA, and
nonmuscle myosin was depolymerized by ML-7 treatment. The
cells were fractioned into cytosol and membrane fractions by
digitonin extraction and distribution of Collagen mRNAs in the
fractions was analyzed by RT-PCR and real-time PCR. Collagen
polypeptides in each fraction were analyzed by Western blot.
Two dimensions (2-D) SDS PAGE was used to determine the
degree of posttranslational modifications. Results: In untreated
lung fibroblast cells, Collagen α1(I) and α2(I) mRNAs were
found entirely associated with the membrane fraction, simi-
larly to other secretory proteins like Fibronectin and MMP12
mRNAs. Inhibition of the translation by Pateamine A and Puro-
mycin dramatically released FIB and MMP12 mRNAs from
the membrane. However, Collagen mRNAs were maintained
in the membrane fraction. This result indicates that Collagen
mRNAs associate with ER independently of translation. LARP6
is a RNA binding protein that binds 5’ stem-loop of Collagen
mRNAs with high affinity and specificity. Knock down of LARP6
released Collagen mRNAs from the membrane into the cytosol,
which reveals its important role in Collagen mRNAs target-
ing. Depolymerization of nonmuscle myosin by ML-7 releases
Collagen mRNAs from membrane as well. In the absence of
LARP6 or nonmuscle myosin filaments, collagen polypeptides
become hypermodified and are poorly secreted, indicating
lack of coordination of their synthesis and folding. The hyper-
577A
modified collagen polypeptides then accumulated intracellu-
larly, suggesting that targeting of collagen mRNAs to the ER
membrane by LARP6 and nonmuscle myosin is a critical step in
collagen biosynthesis. Conclusion: Collagen mRNAs associate
with the ER membrane in translation independent manner and
LARP6 and nonmuscle myosin mediate Collagen mRNAs target-
ing. Direct targeting of Collagen mRNAs to the ER membrane
coordinates translation of Collagen mRNAs, resulting in proper
modifications of the polypeptides and effective secretion of
heterotrimeric type I collagen. This unique mechanism may be
a target for future development of antifibrotic drugs.
Disclosures:
The following people have nothing to disclose: Hao Wang, Yujie Zhang, Lela
Stefanovic, Branko Stefanovic
781
Differential roles of non-receptor tyrosine kinase Fak
family members in TGF-β-mediated fibrogenic signaling
in hepatic stellate cells
Jonghwa Kim1, SoHee Kang1, Soohyun Park1, Ju-Yeon Cho1, Won
Sohn1, Geum Youn Gwak1, Byung Chul Yoo1, David A. Brenner2,
Yong-Han Paik1; 1Sungkyunkwan University School of Medicine,
Samsung Medical Center, Seoul, Republic of Korea; 2UC San
Diego, La Jolla, CA
Backbground: In response to various liver injuries, hepatic
stellate cells (HSC), a major player in fibrogenesis, are acti-
vated by the major profibrogenic cytokine TGF-β. The fibro-
genic signaling of TGF-β is either dependent or independent of
Smad pathway. In addition, TGF-β also induces cell migration,
through activation of non-receptor tyrosine kinase Fak family
members. In this study, we investigated the roles that Fak family
members play in TGF-β-mediated fibrogenic signaling in HSC.
Methods: TGF-β-induced fibrogenic signaling in HSC cell line
LX-2 was assessed by RT-PCR and Western blot of α-SMA, col-
lagen, NADPH oxidase(NOX)4, and CTGF. Activation of Smad
pathway was assessed by detecting Smad2/3 phosphorylation
in Western blot and by measuring the nuclear translocation in
immunofluorescence(IF) staining. Pharmacological inhibitors of
Fak family kinases (PF-228 and PF-271) and siRNA transfection
were performed to suppress activation of Fak family members.
Inhibitors of Src family kinases or Rho-associate protein kinase
(ROCK) were also used to suppress phosphorylation of Fak
family members or inhibit FAK downstream signaling, respec-
tively. Results: TGF-β treatment of LX-2 up-regulated expression
of α-SMA, type I collagen, NOX4, and CTGF, as evidenced
in RT-PCR and Western blot. In addition, phosphorylation of
focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2
(PYK2), two members in Fak family, were increased in less
than 1hr treatment. Two inhibitors of FAK and PYK2 (PF-228
and PF-271) block phosphorylation of both FAK and PYK2,
and also inhibit TGF-β mediated upregulation of α-SMA, type
I collagen, NOX4, and CTGF, in a dose-dependent manner
(0-5μM). Saracatinib, a broad inhibitor of Src family kinases,
also decreased expression of fibrogenic genes, as well as acti-
vation of Fak family kinases. Pre-treatment of ROCK inhibi-
tor, Y-27632, decreased TGF-β mediated upregulation, too.
These data suggest that Src/FAK/PYK2/ROCK axis play an
essential role in TGF-β-mediated fibrogenic signaling in HSC.
Knockdown of FAK using siRNA transfection decreased phos-
phorylation and nuclear localization of Smad2 and expression
of NOX4 on TGF-β stimulation, suggesting that FAK mediate
TGF-β/Smad-dependent pathway. Whereas, siRNA of PYK2
decreased CTGF expression but had no effect on both Smad2
activation and NOX4 expression, suggesting that PYK2 medi-
ate Smad-independent pathway. Conclusions: TGF-β mediated
578A AASLD ABSTRACTS
fibrogenic signaling in HSC diverges to Smad-dependent path-
way by focal adhesion kinase (FAK) and to Smad-independent
pathway by proline-rich tyrosine kinase-2 (PYK2).
Disclosures:
The following people have nothing to disclose: Jonghwa Kim, SoHee Kang,
Soohyun Park, Ju-Yeon Cho, Won Sohn, Geum Youn Gwak, Byung Chul Yoo,
David A. Brenner, Yong-Han Paik
782
Liver injury and pro-fibrotic markers, but not frank
fibrosis, are enhanced in Has3-/- mice after carbon tet-
rachloride exposure: potential role for enhanced matrix
metabolism
Jennifer M. McCracken, Krutika T. Deshpande, Michele Pritchard;
University of Kansas Medical Center, Kansas City, KS
During liver injury and repair extracellular matrix (ECM) is
synthesized and degraded as part of the normal remodeling
process. When this process is dysregulated, an imbalance
results and fibrosis occurs. Has3 is one of three transmembrane
proteins that synthesize the glycosaminoglycan hyaluronan
(HA), a ubiquitous ECM component that is increased during
tissue injury and fibrosis. Native HA is a high molecular mass
polymer and helps to maintain or reestablish tissue homeosta-
sis. During tissue injury, HA is degraded to lower molecular
mass fragments and contributes to inflammation downstream of
receptor ligation on various immune and non-immune cells; this
HA-mediated augmentation of inflammation can exacerbate tis-
sue injury. Here we hypothesized that in the absence of Has3,
there would be less high molecular mass HA present and there-
fore enhanced injury and subsequent fibrosis mediated by low
molecular mass HA after exposure to a model, fibrosis-induc-
ing, hepatotoxicant. Wild-type or Has3-/- mice were exposed
to a single (acute) or ten (chronic) carbon tetrachloride (CCl4)
injections and euthanized 24, 48, 72 or 96H later. Control
mice were given olive oil injections. In the acute study Has3-/-
animals had increased peak plasma alanine aminotransferase
activities, as well as increased peak hepatic triglyceride levels
and hepatic macrophage inflammatory protein 2 (MIP2) and
tumor necrosis factor α (TNFα) mRNAs; these changes were
independent of differences in protein levels or enzymatic activ-
ity of CYP2E1, the enzyme responsible for bioactivating CCl4.
Consistently, Has3-/- animals also had increased hepatic tran-
scripts for intermediate biomarkers of fibrogenesis, including
α-smooth muscle actin (α-SMA) and type 1 collagen (Col1a1
and Col1a2). Following the chronic study, Has3-/- animals
again had increased hepatic mRNAs for α-SMA, Col1a1, and
Col1a2 but did not have increased fibrosis as shown by Sir-
ius red staining. However, Has3-/- mice did exhibit increased
hepatic accumulation of transcripts for matrix metalloproteinase
13 (MMP13), a collagenase, while hepatic accumulation of
MMP2, MMP9, two gelatinases, and tissue inhibitor of matrix
metalloproteinase 1 mRNAs were not different between geno-
types. Taken together, these data suggest that Has3-deficiency
promotes liver injury following acute CCl4 exposure, but does
not affect frank fibrosis following chronic CCl4 exposure pos-
sibly due to increased ECM metabolism, mediated by the col-
lagenase activity of MMP13. These studies were supported
by grants to J.M.M. (T32 ES007079-26A2) and M.T.P. (P20
GM103549, R00 AA017918),
Disclosures:
The following people have nothing to disclose: Jennifer M. McCracken, Krutika
T. Deshpande, Michele Pritchard
HEPATOLOGY, October, 2014
783
Hepatic Stellate Cells Express the Hepatocyte-enriched
Transcription Factor, Hepatocyte Nuclear Factor 4α
Marzena Swiderska-Syn1, Guanhua Xie1, Jason D. Coombes2,
Gregory A. Michelotti1, Anna Mae Diehl1; 1Division of Gastroen-
terology, Duke University Medical Center, Durham, NC; 2Regener-
ation and Repair, Institute of Hepatology, London, United Kingdom
Background: Hepatic stellate cells (HSC) resemble mesenchy-
mal stem cells, but whether HSC can differentiate into mature
liver epithelial cells is controversial. If HSC are capable of
becoming hepatocytes, they should be able to express hepato-
cyte-enriched transcription factors. Hepatocyte nuclear factor
4-α (HNF4-α) is essential for maintaining functional differentia-
tion of hepatocytes. Thus, HNF4α has been widely used as an
hepatocyte marker. Our Aim was to determine if HSC express
HNF4α. Methods: HNF4α expression was localized in rodent
and human liver sections using 3 distinct, highly-specific anti-
bodies that detect either the P1 or P2 isoform of HNF4α (from
F. Sladek, U.C.Riverside) or both P1+P2 HNF4α isoforms (from
R. Schwabe, Columbia U, NY), coupled with co-staining for
desmin (a HSC marker). The percent of hepatocytes and HSC
that were HNFα(+) were quantified in healthy and injured liv-
ers and correlated with changes in whole liver HNF4α mRNA
levels. In addition, whole cell mRNA and protein expressions
of HNF4α were assessed in primary mouse HSC and 2 clonal
HSC lines (human LX2, mouse GRX) using qRT PCR and FACS.
The relative nuclear and cytosolic expression of HNF4α protein
was also assessed in primary mouse HSC on culture day 0 or
7 by probing Western blots with the same antibodies used for
immunostaining. Results: In healthy mouse livers, HNF4α was
expressed by hepatocytes and HSC. 82% of hepatocytes and
48% of HSC expressed HNF4α. Similar findings were noted
in humans: 63% hepatocytes and 37% HSC were HNF4α(+).
Numbers of HNF4α(+) hepatocytes and HSC fell by ~50%
and ~30% after bile duct ligation (n=5), CCL4 (n=5),or par-
tial hepatectomy (n=5); human NASH livers had ~50% fewer
HNF4α(+) hepatocytes and 30% fewer HNF4a(+) HSC than
healthy livers (each p < 0.05 vs. control). Whole liver HNF4α
mRNA levels confirmed that HNF4α expression decreased sig-
nificantly after liver injury (p < 0.05 vs. control). qRT PCR and
FACS demonstrated HNF4α mRNA and protein in the clonal
HSC lines, and in primary HSC on culture day 0 and day 7.
HNF4α mRNA expression fell by ~70% during culture-induced
activation. Nuclear and cytosolic expression of HNF4α pro-
tein was confirmed by immunoblot of primary HSC extracts.
Conclusion: Hepatic stellate cells express HNF4-α transcrip-
tion factor that is typically enriched in hepatocytes, and which
is required for hepatocyte differentiation. During liver injury,
both hepatocytes and HSC down-regulate HNF4α expression.
These findings are consistent with lineage tracing evidence
showing that HSC can become hepatocytes, and demonstrate
that hepatocytic differentiation is impaired during liver injury.
Disclosures:
Anna Mae Diehl - Consulting: Roche; Grant/Research Support: Gilead, Genfit
The following people have nothing to disclose: Marzena Swiderska-Syn, Guan-
hua Xie, Jason D. Coombes, Gregory A. Michelotti
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
784
Activation of JNK modulates the profibrogenic actions
of myostatin in hepatic stellate cells (HSC)
Alessandra Caligiuri1, Wanda Delogu1, Angela Provenzano1, Chi-
ara Rosso2, Elisabetta Bugianesi2, Fabio Marra1; 1University of
Florence, Florence, Italy; 2University of Turin, Turin, Italy
Background/Aims: Myostatin, a member of the transforming
growth factor-β superfamily, is expressed in several organs and
in the skeletal muscle. The biological functions of myostatin are
mediated by different receptors, including activin receptor IIB
(ActRIIB). Myostatin has been implicated in pathogenesis of
metabolic syndrome. Recently, myostatin levels have been asso-
ciated with fibrosis during NASH. However, no information is
available on the possible direct role of myostatin in the biology
of HSC. Aim of the study was to evaluate the effect of myostatin
on biological actions and intracellular signaling in human HSC.
Methods: We employed both an immortalized human HSC line
(LX-2) and primary HSC isolated from human livers. Cell pro-
liferation was evaluated by MTT. Cell migration was assessed
with modified Boyden chambers. Gene expression and secre-
tion of cytokines or ECM proteins were measured by qRT-PCR
and ELISA, respectively. Intracellular signaling pathways were
evaluated using phosphorylation-specific antibodies. Results:
Transcripts for ActRIIB were expressed by human HSC and in
the liver of patients with NASH. Induction of steatohepatitis
by administration of a methionine and choline-deficient diet
significantly increased the expression of ActRIIB. Exposure of
HSC to myostatin (50 ng/ml) induced a significant increase
in cell migration in both LX-2 and primary HSC, and time-de-
pendently reduced cell proliferation. In addition, myostatin
increased mRNA expression of TGF-beta, procollagen type1,
and TIMP-1, and induced collagen I secretion. We tested the
ability of myostatin to activate intracellular signaling pathways
in HSC. Myostatin rapidly and markedly induced phosphory-
lation of Smad3 and JNK. In contrast, p38MAPK and ERK1/2
were only modestly activated. Pretreatment of both LX-2 or pri-
mary HSC with the selective JNK inhibitor, SP600125 (20
mM), caused a marked inhibition of myostatin-induced cell
migration. SP600125 also significantly inhibited the ability
of myostatin to stimulate collagen secretion. Conclusions: HSC
express ActRIIB and respond to myostatin with increased che-
motaxis, reduced proliferation, and increased expression of
profibrogenic factors. JNK activation is required for stimulation
of migration and secretion of procollgen I. These data identify
a muscle-to-liver pathway whereby a myokine may contribute
to fibrogenesis in metabolic liver diseases.
Disclosures:
Fabio Marra - Advisory Committees or Review Panels: Abbott; Consulting: Bayer
Healthcare; Grant/Research Support: ViiV
The following people have nothing to disclose: Alessandra Caligiuri, Wanda
Delogu, Angela Provenzano, Chiara Rosso, Elisabetta Bugianesi
785
Role of gamma-ketoaldehydes as novel mediators of
experimental fibrogenesis and stellate cells activation
Lisa Longato1, Dipok K. Dhar1, Sean S. Davies2, Jackson L. Rob-
erts2, Tu Vinh Luong1, Brian Davidson1, Giuseppe Fusai1, Jude
A. Oben1, Kevin Moore1, Massimo Pinzani1, Krista Rombouts1;
1Medicine (Institute for Liver and Digestive Health), University Col-
lege London, London, United Kingdom; 2Pharmacology, Vanderbilt
University, Nashville, TN
Background and aims. Reactive lipid aldehydes formed during
lipid oxidation such as 4-hydroxynonenal (4-HNE), are key
activators of hepatic stellate cells (HSCs) to a pro-fibrogenic
phenotype. γ-Ketoaldehydes (γ-KAs), are a family of structurally
579A
related reactive aldehydes, comprising of levuglandins and
their stereo and structural isomers (isolevuglandins),which are
formed during oxidation of arachidonic acid or as a by-product
of the cyclo-oxygenase pathway. γ-KAs are characterized by an
extremely high reactivity to form protein adducts and cross-links,
estimated 100-folds greater than the one of 4-HNE. Increased
circulating concentrations of proteins cross-linked to γ-KAs are
present in patients with alcoholic liver disease. In this study we
have investigated whether one specific γ-KAs, namely levug-
landin E2 (LGE2), can induce activation of HSCs. Methods.
Culture-activated, serum-starved primary mouse and human
HSCs were exposed to various concentrations (0.5 pM-5 mM)
of levuglandin E2 (LGE2) for up to 48 hours. Endpoints mea-
sured included proliferation (BrdU incorporation), cytotoxicity
(lactate dehydrogenase (LDH) release and MTS assay), RNA
and protein expression, and collagen secretion in conditioned
medium. In parallel experiments, sham or bile-duct ligated BAL-
B/c mice were treated for 2 weeks either with normal water or
water supplemented with salicylamine, a specific scavenger for
γ-KAs formation. Liver injury was assessed via morphometric
and serum biochemical analyses. Results. HSCs exposed to
LGE2 exhibited profound cytotoxicity at 5 μM concentration,
as indicated by LDH leakage and reduced MTS. This was likely
mediated by apoptosis, as indicated by an increase in PARP
cleavage, occurring as early as 8 hours after LGE2 exposure.
Notably, induction of apoptosis was preceded by a significant
increase in markers of the unfolded protein response (UPR),
such as the pro-apoptotic factor CHOP, and the chaperone
GRP78/Bip. In contrast at lower, non-cytotoxic doses (ranging
from 50 pM-500 nM, with a maximum effect observed at 0.5
nM), LGE2 promoted HSC activation as indicated by increased
expression of α-smooth muscle actin and vimentin, sustained
activation of signalling pathways, as shown by the increased
phosphorylation of the kinases p42/44 ERK1/2 and JNK/
SAPK, together with increased IL-8 and MCP-1 mRNA levels. In
vivo, salicylamine administration partially improved cholestatic
liver injury in mice by reducing some serum parameters of liver
injury. Conclusions. γ-Ketoaldehydes represent a newly identi-
fied class of activators of HSCs in vitro, which are biologically
active at concentrations as low as 50 pM.
Disclosures:
Kevin Moore - Advisory Committees or Review Panels: Servier
Massimo Pinzani - Advisory Committees or Review Panels: Intercept Pharmaceu-
tical, Silence Therapeutic, Abbot; Consulting: UCB; Speaking and Teaching:
Gilead, BMS
The following people have nothing to disclose: Lisa Longato, Dipok K. Dhar, Sean
S. Davies, Jackson L. Roberts, Tu Vinh Luong, Brian Davidson, Giuseppe Fusai,
Jude A. Oben, Krista Rombouts
786
Keratinocyte growth factor inhibits hepatic inflammation
and fibrosis in murine models of hepatic injury
Barbara Czech, Claus Hellerbrand; University Hospital Regens-
burg, Regensburg, Germany
Keratinocyte growth factor (KGF) plays a pivotal role in regulat-
ing cell proliferation, migration, differentiation and survival, in
response to injury and tissue repair. The activation of hepatic
stellate cells (HSCs) is the key event of hepatic fibrosis, and
we have previously shown that KGF expression is upregulated
during the activation of HSCs. However, no data exist on the
expression and function of KGF in chronic liver disease. This
aim of this study was characterize the role of KGF in liver fibro-
sis Methods and Results: KGF-deficient (KGF-ko) and wildtype
(wt) control mice were subjected to two models of hepatic fibro-
sis (i) application of thioacetamide (TAA) in the drinking water
and (ii) feeding a methionine-choline deficient diet (MCD)
580A AASLD ABSTRACTS
inducing non-alcoholic steatohepatitis. In both models KGF-ko
mice exhibited significantly elevated serum transaminases, his-
tological inflammation and hepatic TNF and IL-1 expression
compared to wt-mice. Further, KGF-ko showed advanced HSC
activation, profibrogenic gene expression (Collagen I and TGF-
beta) and fibrosis as assessed by measurement of hydroxy-
proline and histological analysis. Application of recombinant
KGF to KGF-ko mice ameliorated the enhanced inflammation
and fibrosis compared to wt-mice in the MCD-model. Sum-
mary and conclusion: Recombinant KGF therapy is already
approved in the US and Europe for decreasing the incidence
and duration of oral mucositis, and has been shown to be safe.
Furthermore, we have previously shown that FGFR2IIIb, which
is the exclusive receptor for KGF, acts as a tumor-suppressor
in hepatocellular carcinoma. Thus, KGF appears as promising
novel anti-fibrogenic drug for the treatment of hepatic fibrosis
in patients with chronic liver disease.
Disclosures:
The following people have nothing to disclose: Barbara Czech, Claus Heller-
brand
787
The Role of Receptor-Mediated Endocytosis of H-ferritin
in Induction of NFkappaB-dependent Proinflammatory
Signalling in Hepatic Stellate Cells
Manuel A. Fernandez-Rojo, Anita Burgess, Amber Glanfield, Diem
Hoang-Le, Grant A. Ramm; Hepatic Fibrosis, The Queensland Insti-
tute of Medical Research, Brisbane, QLD, Australia
Introduction: Hepatic stellate cells (HSCs) are responsible for
collagen deposition leading to fibrosis following liver injury/
inflammation. Serum levels of the acute phase protein ferritin
are elevated in inflammation and act as an indicator of disease
severity in chronic liver disease. We have previously demon-
strated that H-subunit ferritin actually contributes to this process
as a pro-inflammatory mediator in HSC biology via an iron-in-
dependent, NFkappaB-regulated signalling pathway, inducing
the expression of cytokines e.g., IL-1beta, IL-6, RANTES. Aims:
To determine the role and mechanism of endocytosis vs cell
surface binding in mediating the pro-inflammatory response
of Ferritin in HSC. Methods: Primary rat HSCs were treated
with 10nM H-ferritin for 0-24hrs. HSC were pre-treated with
inhibitors of microtubule formation (colchicines, nocodazole),
lysosomal acidification (chloroquine) and intracellular protein
transport (monensin), dynamin-2-dependent internalization
(Dyngo-4), clathrin-coated pit (CCP) internalization (PitStop2),
lipid raft formation (β-methyl cyclodextrin) prior to ferritin stim-
ulation. qPCR was used to determine relative expression of
NFkappaB-regulated transcripts. Results: Microtubule inhibition
(colchicines, nocodazole) had no significant effect on ferri-
tin-induced expression of NFkappaB-derived IL-1beta suggest-
ing that microtubule-dependent endocytosis was not necessary
for signalling and that cell surface binding of ferritin may be
required. Indeed, inhibition of CCP endocytosis and inhibition
of Dynamin-dependent endocytosis abolished Ferritin-induced
pro-inflammatory response in HSC. Conversely, disruption of
lipid rafts exacerbates response to Ferritin. Moreover, monensin
treatment resulted in a 75% reduction in ferritin-induced IL-1β
expression while chloroquine completely abolished IL-1beta
expression. Finally, experiments in 2-deoxyglucose-treated
HSC supported the concept that Ferritin-mediated signalling
depends on glycolysis. Conclusion: These results suggest that
HSC ferritin uptake and ferritin-induced signalling is mediated
by CCP but not via microtubule-dependent pathways. More-
over, intracellular trafficking of either ferritin and/or ferri-
tin-induced signalling intermediates via endosomes might be
HEPATOLOGY, October, 2014
important for the induction of proinflammatory mediators of
fibrogenesis. Further studies assessing the role of alternative
microtubule-independent (i.e., caveolin-mediated) endocytotic
pathways, and the localisation of H-ferritin on or within HSCs,
will yield insight into the precise mechanisms of ferritin bind-
ing in HSC and proinflammatory signalling elicited in hepatic
fibrogenesis.
Disclosures:
The following people have nothing to disclose: Manuel A. Fernandez-Rojo, Anita
Burgess, Amber Glanfield, Diem Hoang-Le, Grant A. Ramm
788
Alternative regulation of macrophages activation by
IL-4 receptor alpha in fibrosis progression and reversal
Shih-Yen Weng1, Santosh Vijayan1, Xiao-Yu Wang1, Kornelius
Padberg1, Yong Ook Kim1, Brombacher Frank2, Detlef Schup-
pan1,3; 1Institute of Translational Immunology, University Medical
Center, Johannes Gutenberg University, Mainz, Germany, Mainz,
Germany; 2University of Cape Town, Cape Town, South Africa,
Cape Town, South Africa; 3Division of Gastroenterology, Beth
Israel Deaconess Medical Center, Harvard Medical School, Bos-
ton, USA, Boston, MA
Liver fibrosis progression and regression are modulated by
cells of the innate immune system, especially macrophages.
Macrophages can be divided roughly into classically and alter-
natively activated (CAM and AAM, respectively). We aimed to
investigate the functional role of these subtypes in progression
and reversal of liver fibrosis. While AAM have been impli-
cated in fibrogenesis, the functional roles of CAM and AAM
in liver fibrosis remain largely unknown. AAM polarization
is controlled by signaling transmitted through IL-4 and IL-13
ligation to corresponsive receptors IL-4Ra and IL-13Ra1. The
downstream signature gene as Arg1, Mrc1 and STAT6 are
thus upregulated. We aimed to investigate the functional role
of these subtypes in progression and reversal of liver fibrosis.
IL-4Ra expression was determined in the CCL4 oral gavage
model in C57BL6 mice and in spontaneously fibrotic Mdr2
KO mice. After CCL4 for 6 wk and in 2 wk of reversal IL-4Ra
was strongly induced. In Mdr2 KO mice, IL-4Ra expression
increased until age 6 wk, and decreased thereafter. Accord-
ingly, Arg1 and M2 chemokines like CCL17 were up-regulated
after 6wk in both models. To address the function of IL-4Ra in
vivo, a systemic IL-4Ra and a macrophage-specific IL-4RaKO
(IL-4RanLysM) were used in the CCL4 model. The AAM marker
YM1 was significantly decreased along with attenuated fibro-
sis in IL-4Ra KO mice. In IL-4RanLysM mice fibrosis related
genes such as COL1A1 and aSMA were reduced during fibro-
genesis but increased during fibrolysis, suggesting divergent
roles of IL-4Ra+ macrophages during fibrogenesis&fibrolysis.
Concomitant with the increased fibrosis resolution in the IL-4Ra
KO mice there was an increase of resident macrophages
(CD11b+ F4/80+). This phenotype was replicated in IL-4/
IL-13 double KO mice. Our studies demonstrate that IL-4Ra
and its ligands (IL-4/IL-13) in general and in macrophages in
particular modulate fibrosis progression and reversal in discor-
dant ways. IL-4Ra- CD11b+ F4/80+ cells appear to contrib-
ute to fibrogenesis but to speed up fibrolysis. However, other
IL-4Ra responsive cells (mainly Th2 cells) also appear to have a
role in modulating inflammation and fibrogenesis. Modulation
of IL-4Ralpha1 by specific pharmacological intervention is a
promising antifibrotic approach to inhibit fibrosis progression
and induce its reversal.
Disclosures:
Detlef Schuppan - Consulting: Boehringer Ingelheim, Aegerion, Gilead, Gen-
zyme, GSK, Pfizer, Takeda, Sanofi Aventis, Silence
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
The following people have nothing to disclose: Shih-Yen Weng, Santosh Vijayan,
Xiao-Yu Wang, Kornelius Padberg, Yong Ook Kim, Brombacher Frank
789
Hepatic stellate cell activation is regulated by neuropi-
lin-synectin mediated autophagic degradation of PDG-
FR-α
Mary Drinane, Usman Yaqoob, Debabrata Mukhopadhyay,
Shengbing Huang, Frank A. Sinicrope, Sheng Cao, Vijay Shah;
Mayo Clinic, Rochester, MN
Introduction: The platelet derived growth factor (PDGF) recep-
tor alpha (PDGFR-α) signaling pathway is critical for hepatic
stellate cell (HSC) activation and developmental of fibrosis.
Previous data has implicated neuropilin-1 (NRP) in HSC acti-
vation although mechanisms remain incomplete. Synectin is
a scaffold protein that mediates receptor signaling and is a
binding partner of NRP-1. Our aim was to investigate the tan-
dem role of NRP-1 and synectin in regulation of PDGFR-α sig-
naling and HSC activation. Methods/Results: Knockdown of
either synectin or NRP in HSC reduced PDGFR-α protein levels
by 70% with no effect on mRNA levels. Knockdown of either
synectin or NRP led to reduced pools of plasma membrane
PDGFR-α and increased pools of internalized PDGFR-α based on
confocal microscopy colocalization analysis and biotinylation
assays. Inhibition of lysosomal degradation by Bafilomycin A1
and siRNA mediated knockdown of the autophagy protein
ATG5 rescued PDGFR-α protein levels in both synectin and NRP
knockdown cells while inhibition of proteasome mediated deg-
radation with MG132 did not. Furthermore, knockdown of
either synectin or NRP increased LC3B-II protein levels and
increased immunofluorescence intensity of ATG5 suggestive of
autophagic flux. Finally, shRNA mediated synectin knock down
in LX2 cells blocked HSC activation as assessed by attenuated
PDGF induced cell proliferation and migration. Conclusion:
NRP and its binding partner synectin act in tandem to promote
HSC activation by protecting cells from autophagy mediated
degradation of PDGFR-α.
Disclosures:
The following people have nothing to disclose: Mary Drinane, Usman Yaqoob,
Debabrata Mukhopadhyay, Shengbing Huang, Frank A. Sinicrope, Sheng Cao,
Vijay Shah
790
microRNA-194 regulates the expression of TNF-α, IL-1α
and IL-6 via modulating akt/NF-κB pathway in hepatic
stellate cells
Pushpendra K. Sahu, Satendra Kumar, Parul Gupta, Senthil K.
Venugopal; Faculty of Life Sciences and Biotechnology, South
Asian University, New Delhi, India
Background: Hepatic stellate cells are the key cells involved in
the progression of liver fibrosis. Under normal physiological
conditions, these cells are quiescent and store vitamin A gran-
ules. In response to injury, these cells proliferate, secrete extra-
cellular matrix proteins and transdifferentiate into myofibroblast
like cells. Previously we had shown that miRNA-194 was inhib-
ited in fibrosis and its overexpression led to decreased rac1
protein levels. In this study, we hypothesized that miRNA-194
could inhibit fibrosis via akt/NF-κB-induced profibrogenic
cytokines secretion pathway. Methods: microRNA-194 was
over-expressed in LX-2 cells using siPORT NeoFX transfection
reagent. After 72 hours, the cells were collected either for total
RNA enriched with microRNAs or protein isolation. Total RNA
enriched with miRNAs was isolated, cDNA was synthesized
and real time PCR for miRNA-194 or the pro-inflammatory
581A
cytokines (IL-1α, IL-6 and TNF-α) was performed. Total cellular
protein was isolated and Western blots were performed for
Akt, phospho-akt, NF-kB p65 subunit and fibrosin. Both cell
proliferation and apoptotic assays, using titer-glo and TUNEL
assay, were performed in microRNA-194 transfected cells. In
all the experiments non-specific control miRNA (NS-miRNA)
was used as internal control. Effect of the IL-1α (1 μg/ml), IL-6
(2 μg/ml) and TNF-α (10 ng/ml) on intracellular miRNA-194
levels was studied by challenging the cells with these cytokines
for 24 hours in serum-free conditions. The cells were isolated
and intracellular expression of miRNA-194 was estimated.
Results: Over-expression of miRNA-194 led to 20-fold increase
of intracellular levels of miRNA-194 as determined by real
time RT-PCR. Transfection of miRNA-194 in LX-2 cells resulted
in a significant decrease in the expression of IL-1α (55%
inhibition), IL-6 (30% inhibition) and TNF-α (35% inhibition)
compared to NS-miRNA transfected cells. Western blot results
showed decreased akt activation (8-fold decrease), NF-kB p65
levels (6-fold decrease) and fibrosin levels (2-fold decrease)
compared to NS-miRNA transfected cells. Over-expression
of miRNA-194 resulted in a significant decrease in prolifera-
tion while no effect was observed on apoptosis in LX-2 cells.
Intracellular expression of miRNA-194 was inhibited (2-4 fold
decreased compared to the control cells) in response to these
pro-fibrogenic cytokines. Conclusion: These data demonstrate
that over-expression of miRNA-194 could inhibit fibrogenesis,
at least in part, by inhibiting profibrogenic cytokines via p-akt/
akt/NF-kB pathway in hepatic stellate cells.
Disclosures:
The following people have nothing to disclose: Pushpendra K. Sahu, Satendra
Kumar, Parul Gupta, Senthil K. Venugopal
791
Pharmacological modulation of IL-4Ralpha regulates
liver fibrosis progression and regression by tuning M2
macrophage polarization
Shih-Yen Weng1, Xiao-Yu Wang1, Santosh Vijayan1, Kornelius
Padberg1, Yong Ook Kim1, Jeff R. Crosby2, Michael L. McCaleb2,
Detlef Schuppan1,3; 1Institute of Molecular and Translational Medi-
cine, University Medicine, Johannes Gutenberg University, Mainz,
Germany, Mainz, Germany; 2Isis Pharmaceuticals, Carlsbad, CA,
Carlsbad, CA; 3Division of Gastroenterology, Beth Israel Deacon-
ess Medical Center, Harvard Medical School, Boston, USA, Bos-
ton, MA
Progression and regression of liver fibrosis have been linked
with the innate immune system, especially macrophages.
Depending on the pattern of cytokines stimulation, macro-
phages can be divided roughly into M1 (classical) and M2
(alternative) macrophages. While M2 have been implicated in
fibrogenesis, the roles of M1 and M2 in liver fibrosis progres-
sion and regression are largely unexplored. We used the CCL4-
model of liver fibrosis progression (6 weeks) and spontaneous
regression after omission of the toxin (2 weeks) in C57BL6
mice, and the spontaneous biliary fibrosis model of Mdr2 KO
mice (progression), to functionally explore the role of M2 in
regulating fibrogenesis and fibrolysis. IL-4Ralpha was induced
during fibrogenesis and the in first 2 wk of spontaneous fibrosis
reversal. A specific antisense oligonucleotide (ASO) suppressed
IL-4Ralpha expression in murine macrophages by 90% at 2μg/
ml compared to a scrambled ASO control. When applied to
CCL4-treated mice twice weekly at 40 mg/kg i.p. from wk 2
to wk 4 of the reversal phase, the ASO suppressed IL-4Ralpha
expression by ~50%, which was accompanied by decreased
M2 markers (Arg1, Mrc1) and increased M1 markers (CCL3,
MMP-8, MMP-9), and a decrease of collagen deposition (Sirius
582A AASLD ABSTRACTS
Red morphometry). Serum ALT was increased 4.1 fold in ASO-
treated mice vs untreated mice. A similar antifibrotic but only a
mildly proinflammatory effect was observed in Mdr2 KO mice
with spontaneous fibrosis progression when treated with the
ASO from 6-10 weeks of age. In this study, somewhat unex-
pectedly, suppression of IL-4Ralpha using a specific ASO atten-
uated fibrogenesis during progression, but promoted fibrolysis
during regression. This may be due to (partial) inhibition of
IL-4Ralpha expressed on putatively fibrogenic Th2 T cells apart
from M2 macrophages.
Disclosures:
Jeff R. Crosby - Employment: ISIS Pharmaceuticals
Michael L. McCaleb - Employment: Isis Pharmaceuticals; Stock Shareholder: Isis
Pharmaceuticals
Detlef Schuppan - Consulting: Boehringer Ingelheim, Aegerion, Gilead, Gen-
zyme, GSK, Pfizer, Takeda, Sanofi Aventis, Silence
The following people have nothing to disclose: Shih-Yen Weng, Xiao-Yu Wang,
Santosh Vijayan, Kornelius Padberg, Yong Ook Kim
792
Development of Sonic hedgehog transgenic mouse mod-
els using hydrodynamics-based transfection
Sook In Chung1, Hye Lim Ju1, Kwang-Hyub Han2, Weonsang S.
Ro2; 1Brain Korea 21 PLUS project for Medical Science College
of medicine, Seoul, Republic of Korea; 2Internal medicine, Yonsei
University College of Medicine, Seoul, Republic of Korea
Background/Aims: Liver fibrosis is a major health problem
worldwide. Nevertheless, pathogenesis and underlying mech-
anisms of liver fibrosis are not fully understood. Sonic hedge-
hog(SHH) signaling regulates critical cell fate decisions and
modulates wound healing responses in adult tissue, including
the liver. In this study, we developed a SHH transgenic mouse
models for liver fibrosis using a hydrodynamic injection method
and the Sleeping Beauty Transposon System. Using the trans-
genic model, we investigated the role of SHH signaling in
the development of liver fibrosis. Methods: Transposon vector
encoding SHH was constructed. To induce liver fibrosis, plas-
mids encoding the Sleeping Beauty transposase and the SHH
transposons were mixed in 2.5 ml of 0.9% saline and injected
into the lateral tail veins of 6-week-old C57BL/6 mice. The
mice were observed at 6 months post hydrodynamic injection.
The development of liver fibrosis was observed histologically.
Results: Liver fibrosis was induced by stably expressing SHH.
Development of liver fibrosis was determined via Masson’s
trichrome and picro-sirius red staining. The histological exam-
ination showed that the fibrotic area in the control group was
less than 3% of the total hepatic area examined, whereas the
degree of hepatic fibrosis in the SHH group increased more
than 6-folds (18.6%). Immunohistochemical analysis revealed
nuclear localization of Gli1 and Gli2, the SHH signaling down-
stream transcription factors. Expression levels of fibrosis-related
genes significantly increased compared to the control group
such as type I collagen α1, α-smooth muscle actin, desmin,
and platelet-derived growth factor (PDGF). The levels of serum
AST, ALP, and ALT in SHH group were significantly higher than
those in control. Conclusion: Over-expression of SHH in the
mouse liver promoted liver fibrogenesis, suggesting its role in
the development of liver fibrosis and genetic interaction with
other pro-fibrogenic signaling such as TGF-beta and PDGF sig-
naling.
Disclosures:
The following people have nothing to disclose: Sook In Chung, Hye Lim Ju,
Kwang-Hyub Han, Weonsang S. Ro
HEPATOLOGY, October, 2014
793
Human neutrophil peptide-1 exacerbates hepatic fibro-
sis associated with Kuppfer cell activation and hepato-
cyte apoptosis in a murine model of alcoholic liver
disease
Rie Ibusuki1,2, Hirofumi Uto1, Kozono Masaya1, Kohei Oda1,
Akihiko Oshige1, Kotaro Kumagai1, Seiichi Mawatari1, Tsutomu
Tamai1, Akihiro Moriuchi3, Hirohito Tsubouchi3,4, Akio Ido1,3;
1Kagoshima University Graduate School of Medical and Dental
Science, Kagoshima, Japan; 2Department of International Island
and Community Medicine, Kagoshima University Graduate School
of Medical and Dental Sciences,., kagoshima, Japan; 3Department
of HGF Tissue Repair and Regenerative Medicine, Kagoshima
University Graduate School of Medical and Dental Sciences,
kagoshima, Japan; 4kagoshima city hospital, kagoshima, Japan
Background: Hepatocellular injury with neutrophil infiltration is
one of the histologic features of alcoholic liver disease, which
includes alcoholic steatohepatitis, and nonalcoholic steatohep-
atitis (NASH). Human neutrophil peptide (HNP)-1 is an antimi-
crobial peptide secreted by neutrophils. We have previously
reported that transgenic (TG) expression of HNP-1 enhances
hepatic fibrosis in a murine steatohepatitis model established
by ethanol administration or a choline-deficient, L-amino acid–
defined diet. However, the mechanism by which HNP-1 exac-
erbate hepatic fibrosis is not fully understood. Materials and
Methods A strain of TG mice expressing HNP-1 cDNA under
the control of a β-actin–based CAG promoter was established.
Ethanol was orally administered in freely available drinking
water to induce liver injury, and histological findings were
compared. Gene and protein expression in liver tissue were
evaluated by RT-PCR and Western blot analysis, respectively.
Kupffer cells were assessed using F4/80 and CD68 staining,
and apoptosis was assessed using a TUNEL assay. SK-Hep1
hepatocellular carcinoma cells were used to study the effect
of HNP-1 on hepatocytes in vitro. Results After 24 weeks of
ethanol administration, hepatic fibrosis, as assessed by Sirius
red staining, Azan staining, and serum hyaluronic acid lev-
els, was more severe in TG mice than in WT mice. TG mice
had signifcantly more Kupffer cells and higher CD14 protein
expression in the liver compared to WT mice. Higher expres-
sion of NFκB was also observed in TG mice. In addition, there
were significantly more TUNEL-positive hepatocytes in TG mice
compared to WT mice, which was accompanied by higher
protein expression of caspase-3, cleaved PARP, and Bax in
liver tissue. In contrast, TG mice had significantly lower hepatic
expression of anti-apoptotic Bcl2 protein. Furthermore, HNP-1
induced apoptosis in SK-Hep1 cells in vitro in a concentra-
tion-dependent manner, and caspase 3/7 was activated by the
addition of HNP-1. This pro-apoptotic effect of HNP-1 in vitro
was more pronounced in the presence of ethanol. Conclusion
HNP-1 secreted by neutrophils may exacerbate hepatic fibrosis
in alcoholic liver disease via increased Kupffer cell activation
and hepatocyte apoptosis.
Disclosures:
Hirohito Tsubouchi - Grant/Research Support: MSD, Chugai Pharmaceutical, Kan
Research Institute, Daiichi-Sankyo, Eisai, Tanabe Mitsubishi
The following people have nothing to disclose: Rie Ibusuki, Hirofumi Uto, Kozono
Masaya, Kohei Oda, Akihiko Oshige, Kotaro Kumagai, Seiichi Mawatari, Tsu-
tomu Tamai, Akihiro Moriuchi, Akio Ido
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
794
Epigallocatechin gallate treatment decreases osteopon-
tin expression and attenuates N-Nitrosodimethylamine
induced hepatic fibrosis in rats
Joseph George, Mikihiro Tsutsumi; Hepatology, Kanazawa Medi-
cal University, Uchinada, Japan
Background and Aims: Osteopontin (OPN) is a matricellular
cytokine and a stress-induced pro-fibrogenic molecule that pro-
motes activation of stellate cells during pathogenesis of hepatic
fibrosis. The current investigation was aimed to study the effect
of epigallocatechin gallate (EGCG) to decrease osteopontin
expression and subsequent arrest of experimentally induced
hepatic fibrosis. Methods: The liver injury was induced with
intraperitoneal injections of N-nitrosodimethylamine (NDMA)
in a dose of 1 mg/100 g body weight on 3 consecutive days
of every week for 4 weeks. Another group of animals received
0.2 mg EGCG/100 g body weight orally 2 h prior to NDMA
administration. The animals were sacrificed at the end of 2nd
week and 4th week from the beginning of exposure. Serum
OPN, type IV collagen, and hyaluronic acid (HA) levels were
measured. Glutathione and malondialdehyde levels were
determined in the fresh liver tissue. The paraffin liver sections
were stained for collagen, α-SMA, 4-HNE and OPN. Western
blotting and qPCR were performed for OPN. Results: Serum
OPN levels were increased in both early and advanced fibro-
sis and the data were significantly correlated with collagen,
α-SMA, 4-HNE, and OPN staining in the liver. EGCG treated
animals depicted a significant decrease of OPN, type IV col-
lagen, and HA in the serum as well as staining for collagen,
α-SMA, 4-HNE, and OPN in the liver. Western blotting and
qPCR for OPN demonstrated marked reduction in OPN expres-
sion. Furthermore, animals treated with EGCG maintained
antioxidant status and exhibited marked decrease of hepatic
fibrosis. Conclusions: The data demonstrated that serum OPN
correlates with the degree of hepatic fibrosis. Treatment with
EGCG resulted in decrease of oxidative stress and reactive
oxygen species and prevented upregulation of OPN with a
subsequent decrease of hepatic fibrosis. EGCG could protect
against chronic liver injury and fibrogenesis and could pave
the way for therapeutic intervention of hepatic fibrosis.
Disclosures:
The following people have nothing to disclose: Joseph George, Mikihiro Tsutsumi
795
Iron excess exacerbates proinflammatory and fibro-
genic gene expression in genetically obese mice and in
primary human hepatic stellate cells in response to TNF-
α or TGF-β
Priya Handa1,2, Vicki Morgan-Stevenson1,2, Bryan D. Maliken1,2,
James E. Nelson1,2, Matthew M. Yeh3, Kris V. Kowdley1,2; 1Liver
Center of Excellence, Digestive Disease Institute, Seattle, WA;
2Benaroya Research Institute, Virginia Mason Medical Center,
Seattle, WA; 3University of Washington Medical Center, Seattle,
WA
Aim: We have previously shown that reticuloendothelial system
(RES) iron is associated with increased severity of nonalcoholic
steatohepatitis (NASH) and advanced fibrosis in nonalcoholic
fatty liver diseases. We hypothesized that an acute iron over-
load in obese (Leprdb/db) mice or iron loading of primary
human hepatic stellate cells would cause inflammatory NF-KB
and profibrogenic activation. Further, we asked if iron over-
load could exacerbate the inflammatory/fibrogenic effect of
cytokines such as TNF-α or TGF-β in the primary human stellate
cells. Methods: Obese leptin receptor deficient (Leprdb/db)
583A
were maintained on normal chow for 8 weeks before receiving
a single dose of 1.25 mg/g wt Fe-dextran by IP injection. They
were fed a normal chow or a high fat (HF) diet for 8 weeks
after IP injection. After 16 weeks, the chow - fed (C), the PI
(parenteral iron) mice, PI+ HF mice, and the HF-fed mice were
sacrificed, and their livers were assessed for hydroxyproline (a
measure of collagen content) and changes in gene expression
related to fibrogenesis. To determine if iron overload had an
effect on primary human stellate cells, a time course study was
performed with ferric ammonium citrate (FAC) between 0-6
hours and gene expression changes related to fibrogenesis and
NF-KB activation were measured. Results: PI+HF mice livers had
significantly higher levels of hydroxyproline relative to chow-
fed controls. PI mice showed high levels of ASMA gene expres-
sion relative to controls. Parenteral iron administration also led
to elevated levels of NF-KB-dependent proinflammatory genes
such as TLR4, MCP-1 and iNOS. In the primary human stellate
cells, we found that increasing exposure time to iron showed
an elevation in gene expression of NF-KB, and NF-KB-depen-
dent genes such as MCP-1, TNF-α, IL-6, IL-1β and HO-1, with
4-6 hours yielding the highest expression. We also found that
collagen1α1, MMP-2, TIMP-1 and TGF-β were upregulated in
response to iron. We asked if iron in the presence of cytokines
such as TNF-α or TGF-β would potentiate proinflammatory and
profibrogenic gene expression and found that coadministration
of iron/TNF-α led to synergistic upregulation of TNF-α, IL-6
and collagen1α1 levels; and cotreatment with iron/TGF-β led
to heightened expression of TIMP-1, TGF-β and collagen1α1.
Conclusions: In a mouse model of genetic obesity, acute iron
excess coupled with a HF diet promotes fibrogenesis. In pri-
mary human stellate cells, iron overload, either alone or in
conjunction with cytokines, elevates proinflammatory and fibro-
genic gene activation. These findings highlight a key role for
iron as a profibrotic agent in accelerating NASH progression.
Disclosures:
Kris V. Kowdley - Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research
Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria,
Janssen, Merck, Mochida, Vertex
The following people have nothing to disclose: Priya Handa, Vicki Morgan-Ste-
venson, Bryan D. Maliken, James E. Nelson, Matthew M. Yeh
796
Modulating Tumor-Stromal Interactions by Targeting
Adenosine Monophosphate-Activated Kinase (AMPK) in
Human Hepatic Stellate Cells and Hepatocellular Carci-
noma
Katrin Schölzel, Lisa Longato, Tu Vinh Luong, Brian Davidson,
Giuseppe Fusai, Massimo Pinzani, Krista Rombouts; Division of
Medicine, University College London, Institute for Liver and Diges-
tive Helath, London, United Kingdom
AIM: End stage liver disease is characterized by liver fibro-
sis and cirrhosis, a major risk factor for the development of
hepatocellular carcinoma (HCC). Human hepatic stellate cells
(hHSC) are the key players in liver fibrosis associated with
HCC. Hence, tumor-stromal interactions are considered a
potential target for anticancer and antifibrogenic therapies.
A key regulator of both hHSC and HCC is adenosine mono-
phosphate-activated kinase (AMPK), a fuel-sensing enzyme.
AMPK has been implicated in carcinogenesis as liver kinase
B1 (LKB1), a tumor suppressor, is an upstream activating kinase
for AMPK. The LKB1-AMPK axis has been shown to suppress
cell proliferation via the mTOR signalling pathway in solid
tumors. However, recent data demonstrate an LKB1-indepen-
dent tumor suppressing effect of AMPK, indicating a distinct
role for AMPK in cancer development. In this study, the bi-di-
584A AASLD ABSTRACTS
rectional tumor stromal crosstalk between hHSC and HCC was
investigated by pharmacological modulation of AMPK activity
in hHSC. METHODS: Serum-starved hHSC were exposed to
various concentrations of AICAR (250uM-4mM) or Compound
C (2.5uM-40uM) for 24 hours. Endpoints included prolifera-
tion (BrdU incorporation) and tetrazolium metabolic activity.
HepG2 and PLC/PRF/5 cells were cultured and conditioned
medium was obtained after 48 hours of incubation in serum-
free medium. Proliferation and metabolic activity of hHSC was
measured in the presence of the conditioned medium of PLC/
PRF/5 or HepG2 cells in combination with AICAR or Com-
pound C by BrdU and MTS test. Next, the expression levels
and activation of kinases up- and downstream of AMPK were
investigated by western blot analysis. RESULTS: The AMPK-ac-
tivator AICAR significantly inhibited proliferation in hHSC in
a dose dependent manner which coincided with a reduction
in metabolic activity. In contrast, Compound C showed an
inverse correlation between inhibition of cell proliferation and
metabolic activity in a dose dependent manner. HepG2 con-
ditioned medium significantly induced proliferation of hHSC
which was abolished by the application of AICAR. Interest-
ingly, conditioned medium of PLC/PRF/5 cells did not induce
hHSC proliferation significantly. These findings are in line with
the observation that both AMPK and LKB1 are activated/phos-
phorylated in hHSC treated with conditioned medium of PLC/
PFR/5 but not HepG2. CONCLUSIONS: These data indicate
that HCC secreted proteins can have a strong impact on the
LKB1-AMPK axis and cell proliferation in hHSC. Understanding
the imbalance in energy homeostasis in hHSC and HCC may
lead to finding new targets to modulate the tumor-stromal cross-
talk in hepatocellular carcinoma progression.
Disclosures:
Massimo Pinzani - Advisory Committees or Review Panels: Intercept Pharmaceu-
tical, Silence Therapeutic, Abbot; Consulting: UCB; Speaking and Teaching:
Gilead, BMS
The following people have nothing to disclose: Katrin Schölzel, Lisa Longato, Tu
Vinh Luong, Brian Davidson, Giuseppe Fusai, Krista Rombouts
797
A new communication system regulating extracellular
matrix in liver fibrosis: RANK/RANKL/OPG
Leonie Beljaars, Carian E. Boorsma, Burak Guney, Klaas Poelstra,
Barbro N. Melgert; Pharmacokinetics, Toxicology and Targeting,
University of Groningen, Groningen, Netherlands
Fibrosis is characterized by increased extracellular matrix
(ECM) deposition by activated hepatic stellate cells and
decreased ECM degradation by macrophages. Communica-
tion mechanisms between these cell types to control ECM turn-
over are poorly understood. We investigated whether these
cells can communicate using a system well-known in bone
ECM turnover, namely receptor activator of nuclear factor κB
(RANK), its ligand (RANKL), and the decoy receptor of RANKL,
osteoprotegerin (OPG). Methods. We examined cell-specific
expressions of RANK/RANKL/OPG in vitro in several cell
lines and in vivo in liver tissue of mice exposed to CCL4 by
immunohistochemistry, ELISA and flow cytometry and related
the expression to parameters of fibrogenesis and fibrolysis.
In addition, we included effects of the profibrotic factor trans-
forming growth factor-beta (TGFβ) and the antifibrotic com-
pound interferon gamma (IFNγ). Results. In vitro, we found that
RANK was only expressed by macrophages (RAW264.7 and
THP-1) and was induced by IFNγ. RANKL was only expressed
by HEPG2 cells; TGFβ did not alter, while IFNγ significantly
enhanced RANKL expression. OPG was expressed by 3T3
and LX-2 fibroblasts; TGFβ significantly increased OPG expres-
sion, while IFNγ inhibited this increased expression. In vitro
HEPATOLOGY, October, 2014
treatment of RAW264.7 macrophages with RANKL increased
MMP9 expression and cathepsin K activity. Co-incubation of
RANKL and OPG reduced these effects, while OPG alone
did not alter these proteolytic enzymes. In vitro treatment of
fibroblasts with OPG did not induce a pro-fibrotic response
(α-sma and col1a1 expression) in control or TGFβ-activated
cells. In vivo, OPG expression was increased in fibrotic mouse
livers (8-weeks CCL4) compared to normal livers. Staining
was seen particularly in fibrotic collagen bands, correspond-
ing with localization of OPG in myofibroblasts. This increased
expression was also detectable in serum of these mice (35±4
vs 3±0.2 ng/ml OPG; p<0.05; n=6-8). Treatment of fibrotic
mice with IFNγ or with HSC-targeted IFNγ (week 6-8) yielded
significantly lower OPG levels both in liver tissue and serum.
Conclusions. RANK/RANKL/OPG are present in fibrotic livers
and may constitute an important new communication system
in fibrogenesis and fibrolysis. (Myo)fibroblasts produce OPG
in fibrotic conditions under the influence of TGFβ and can
thereby scavenge RANKL. RANKL, produced by hepatocytes,
can activate proteolytic macrophages but their function may
be impaired in fibrotic conditions due to high OPG levels.
IFNγ exerts antifibrotic effects by decreasing OPG and increas-
ing RANKL levels. The impact of this regulatory system in vivo
needs further investigation.
Disclosures:
Klaas Poelstra - Consulting: BiOrion Technologies BV; Grant/Research Support:
BiOrion Technologies BV; Stock Shareholder: BiOrion Technologies BV
The following people have nothing to disclose: Leonie Beljaars, Carian E.
Boorsma, Burak Guney, Barbro N. Melgert
798
Markers of extracellular matrix remodeling can eluci-
date the matrix turnover profile of the fibrotic liver
Niels Ulrik B. Hansen1,2, Federica Genovese1, Diana J. Leem-
ing1, Morten A. Karsdal1,2; 1Nordic Bioscience, Herlev, Denmark;
2The Faculty of Health Science, University of Southern Denmark,
Odense, Denmark
Background: Liver fibrosis develops as a consequence to
chronic liver injury and is characterized by excessive extracel-
lular matrix (ECM) remodeling, reflected by an increase in the
turnover of matrix proteins and protease activity. ECM protein
fragments are released into circulation or into the supernatant
when culturing precision-cut tissue slices. These proteins frag-
ments can be measured by specific assays based on monoclo-
nal antibodies recognizing the neo-epitope generated by the
protease cleavage, so-called protein fingerprint. Aim: The aim
of this study was to setup up an ex-vivo model for liver fibrosis
in order to investigate the ECM turnover profile of fibrotic liver.
Methods: 10 male 12 weeks old Wistar rats were injected i.p.
with carbon tetrachloride (CCl4) twice a week over a period
of 8 weeks to induce liver fibrosis. Serum was collected at
baseline and at termination. The liver was excised and pre-
cision-cut tissue slices were cultured. The slices were cultured
for 2 days in either medium alone, IBMX (phosphodiesterase
inhibitor) or GM6001 (multiple matrix metalloproteinase inhib-
itor) added to the medium. Markers of formation of collagen
type I (P1NP) along with formation and degradation markers
of collagen type III (Pro-C3 and C3M) were measured in rat
serum and in the supernatants of the precision-cut tissue slices.
Results: Pro-C3 and C3M were significantly elevated in serum
from CCl4-treated animals at termination compared to base-
line (p<0.01). C3M was significantly increased in superna-
tants from CCl4-treated animal tissue slices (p<0.0001) when
compared to slices from control animals, while C3M levels
were significantly decreased by IBMX or GM6001 presence
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
in the medium (p<0.0001 and p<0.05 respectively). Pro-C3
levels in supernatant were significantly decreased by IBMX or
GM6001 (p<0.0001 and p<0.05). P1NP was significantly
elevated in supernatants from CCl4-treated animal slices
(p<0.05), and IBMX was able to significantly decrease these
levels (P<0.0001). However these results were not reflected in
serum. Conclusion: The CCl4 precision-cut tissue slice ex vivo
model provides a valuable translational tool for investigating
the extracellular matrix remodeling associated with liver fibro-
sis. Since the same ECM remodeling markers can be measured
in circulation and in the supernatants of cultured precision-cut
tissue slices by means of the protein fingerprint technology, we
could demonstrate that the serum fragments originate from the
liver. This tool will help elucidate the matrix turnover profile of
the fibrotic liver.
Disclosures:
Federica Genovese - Employment: Nordic Bioscience
Diana J. Leeming - Employment: Nordic Bioscience
Morten A. Karsdal - Stock Shareholder: Nordic Bioscience
The following people have nothing to disclose: Niels Ulrik B. Hansen
799
Role of Genetic Polymorphisms in the Development of
Nonalcoholic Fatty Liver Disease (NAFLD) and Steato-
hepatitis (NASH)
Fernando Bril1,2, Marina Kawaguchi-Suzuki3, Reginald Frye3,
Paola Portillo Sanchez1,2, Maryann Maximos6, Song Lai4, Jean
Hardies5, Fermin Tio7, Kenneth Cusi1,2; 1Endocrinology, Diabetes
and Metabolism, University of Florida, Gainesville, FL; 2Endocrinol-
ogy, Diabetes and Metabolism, Malcom Randall VA Medical Cen-
ter, Gainesville, FL; 3Pharmacotherapy and Translational Research,
University of Florida, Gainesville, FL; 4CTSI Human Imaging Core
- McKnight Brain Institute, University of Florida, Gainesville, FL;
5Radiology, Univeristy of Texas Health Science Center at San Anto-
nio, San Antonio, TX; 6Pediatric Gastroenterology, Hepatology,
and Nutrition, University of Florida, Gainesville, FL; 7Pathology,
University of Texas Health Science Center at San Antonio, San
Antonio, TX
Genetic factors are believed to play a role on the develop-
ment of NAFLD, as even in individuals closely matched for
all clinical variables, some do not develop hepatic steatosis,
many develop only simple steatosis, while others steatohep-
atitis and eventually, cirrhosis. In order to assess the role of
genetic factors that may be associated with NAFLD and NASH,
PNPLA3 (patatin-like phospholipase domain-containing protein
3), APOC3 (apolipoprotein C3), and PPARG (peroxisome pro-
liferator-activated receptor-gamma) single nucleotide polymor-
phisms (SNPs) were analyzed. A total of 176 patients were
included in the study. Liver magnetic resonance imaging and
spectroscopy (1H-MRS) and a liver biopsy (n=131) were per-
formed to characterize liver disease. An oral glucose tolerance
test was performed to determine diabetes status and insulin
resistance was calculated during the fasting state (HOMA-IR
and AdipoIR [fasting plasma free fatty acids x insulin]). Poly-
morphisms associated with increased liver fat by 1H-MRS
after adjusting for age, gender, and ethnicity included:
rs738409 (PNPLA3: +3.4% liver fat per G allele, p=0.03) and
rs2281135 (PNPLA3: +3.1% liver fat per T allele, p=0.05).
Moreover, both of these SNPs were also associated with higher
plasma alanine aminotransferase levels (an increase of 7±3
IU/L per risk allele for both SNPs after adjustments for age,
gender and ethnicity, p=0.04). Neither PPARG nor APOC3
had any association with liver fat content by 1H-MRS. To fur-
ther characterize the mechanisms by which these SNPs may
affect liver fat, their relationship with different measurements of
585A
insulin resistance was assessed. None of the examined SNPs
were associated with liver (HOMA-IR), or adipose tissue (Adi-
poIR) insulin resistance. Regarding severity of liver disease,
PNPLA3 and APOC3 SNPs were not associated with the pres-
ence of NASH, worse necroinflammation, or fibrosis. How-
ever, PPARG rs17817276 was associated with the presence
of NASH: patients with the GG genotype had a lower preva-
lence of NASH versus other variants: 50% vs. 86%, p=0.004
(OR=0.39, p=0.03) after adjusting for age, and ethnicity.
Conclusions: genetic variants may hold the answer to individ-
ual variations in the severity of NAFLD and NASH. Although
PNPLA3 SNPs were associated with liver fat content, no signif-
icant association was observed with insulin resistance or with
severity of NASH. PPARG rs17817276 was associated with a
higher prevalence of NASH, which emphasizes the important
role that thiazolidinediones (i.e. pioglitazone) may have in the
treatment of this disease.
Disclosures:
Kenneth Cusi - Consulting: Merck, Daichi-Sankyo, Roche, Janssen; Grant/
Research Support: Takeda, Novartis, Mannkind
The following people have nothing to disclose: Fernando Bril, Marina Kawagu-
chi-Suzuki, Reginald Frye, Paola Portillo Sanchez, Maryann Maximos, Song Lai,
Jean Hardies, Fermin Tio
800
Low serum vitamin D concentration in patients with
nonalcoholic fatty liver disease is not associated with
increased mortality: Results from the National Health
and Nutrition Examination Survey 18-year mortality
follow-up data
Ivo C. Ditah1, Albert Ndzengue1, Zeenat Y. Bhat2, Chijioke
Enweluzo3, Chobufo M. Ditah4, Callistus Ditah6, Michael Charl-
ton5, Patrick S. Kamath1; 1Gastroenterology, Mayo Clinic, Roches-
ter, MN; 2Medicine, Wayne State University School of medicine,
Detroit, MI; 3medicine, Wake Forest School of Medicine, Winston
Salem, NC; 4Medicine, University of Yaounde, Yaounde, Cam-
eroon; 5Hepatology and Transplantation, Intermountain Medical
Center, Salt Lake City, UT; 6Medicine, University of Michigan Med-
ical School, Ann Arbor, MI
Background Nonalcoholic fatty liver disease (NAFLD) is becom-
ing the leading cause of chronic liver disease. Predicting
mortality risk in individuals with NAFLD remains a major chal-
lenge. Vitamin D deficiency (VDD) has been associated with
NAFLD and liver fibrosis. It is unknown whether the association
between VDD and NAFLD is of any clinical significance. This
study examines whether VDD in patients with NAFLD is associ-
ated with increased mortality in a nationwide population-based
survey of US adults. Methods Data from the Third National
Health and Nutrition Examination (NHANES III) and the
NHANES III Mortality-linked files were used. To determine the
cause of death, the National Center for Health Statistics linked
NHANES III participants to the National Death Index registry
through December 31, 2006. Analyses were restricted to 4145
adults aged 20-74 years who had serum vitamin D levels avail-
able. Cox proportional regression models were used to exam-
ine mortality across quartiles of 25(OH)D concentration among
NAFLD patients. Results The prevalence of NAFLD was 33.0%.
The prevalence of VDD in patients with NAFLD was 53.7%.
In multivariate analyses, female sex, low HDL cholesterol,
smoking, non-Hispanic blacks and Mexican Americans were
associated with increased risk of having 25(OH)D <17.6ng/
dl. Having a GFR of >60ml/min, higher albumin, high inten-
sity physical activity and non-winter seasons were associated
with a decrease risk of being VDD. The median follow-up time
was 14.3(range 1.5-18.1) years. The overall 18-year Kaplan-
586A AASLD ABSTRACTS
Meier survival was 79.2%. Survival differed by serum 25(OH)
D quartiles; 76.6% for <17.6ng/mL, 72.8% for 17.7-24.2ng/
dL, 80.0% for 24.3-32.1ng/mL and 84.7% for >=32.2ng/ml
The majority of 235(28.3%) deaths occurred in patients within
the 17.7-24.2 ng/mL quartile of 25(OH)D concentration. Car-
diovascular diseases accounted for 40.2%(333) of the deaths
while 24.0%(199) were cancer related. Only 22(2.7%) deaths
were liver related. Overall, there was no association between
all-cause mortality and being in the lower quartiles of 25(OH)D
levels(>32.2ng/mL being reference). A trend towards increase
mortality was noted with lower quartiles of vitamin D for all-
cause and cardiovascular related deaths, but this is not statisti-
cally significant. No significant increase in the number of liver
related deaths were observed with lower quartiles of vitamin
D concentration. Conclusion This study shows that VDD seen
in NAFLD is not associated with increased mortality. In the
absence of further evidence, clinicians should avoid costly mea-
surements of 25(OH)D in asymptomatic patients with NAFLD
unless they are at risk for bone disease.
Disclosures:
Patrick S. Kamath - Advisory Committees or Review Panels: Sequana Medical
The following people have nothing to disclose: Ivo C. Ditah, Albert Ndzengue,
Zeenat Y. Bhat, Chijioke Enweluzo, Chobufo M. Ditah, Callistus Ditah, Michael
Charlton
801
Prevalence of nonalcoholic fatty liver disease and its
association with aging
Ainara Cano2, Cristina Alonso2, Itziar Mincholé2, David Bal-
goma2, Pablo Ortiz2, Maria L. Martinez-Chantar1,4, Shelly C. Lu3,
Jose M. Mato1,4; 1Metabolomics, CIC bioGUNE, Derio, Spain;
2OWL METABOLOMICS, DERIO, Spain; 3KECK SCHOOL OF
MEDICINE, UNIVERSITY OF SOUTHERN CALIFORNIA, LOS
ANGELES, CA; 4CIBERehd, DERIO, Spain
Aging entails dramatic alterations in the liver capacity, which
tends to accumulate lipids. In the last ten years, the prevalence
of nonalcoholic fatty liver disease (NAFLD) has increased con-
siderably and now is thought to affect 30% of the general pop-
ulation with even higher rates in aged people. Metabolomics,
the study of compounds smaller than 1,500 Da is applied to
unravel the metabolic condition of an organism in a specific
situation(1). Recently, we described an aging-associated lipi-
domic signature in mice(2). In addition, patients with diverse
body mass index (BMI) present serum distinctive metabolomic
signatures of steatosis and NASH(3). This finding has made it
possible to obtain a set of BMI-dependent lipid biomarkers that
differentiate between NASH and steatosis with areas under the
receiver operating characteristic curve (ROC) of 0.94, reach-
ing values of 0.99 for the cohort with BMI<30 kg/m2(4). Here,
we have used this diagnostic test to determine the incidence
of steatosis and NASH in non-obese men and women during
normal aging. Healthy male and female volunteers (n=262),
with BMI<30 kg/m2 were classified according to their age into
four cohorts: 20-30 (n=44), 30-40 (n=76), 40-50 (n=78), and
50-60 (n=64) years of age. Inclusion criteria involved normal
blood pressure and serum biochemistry (ALT, AST, glucose,
triglycerides, cholesterol), moderate alcohol intake, and not
to be medicated for diabetes, hypertension or hyperlipidemia.
Chloroform/methanol serum extracts were analyzed by reverse
ultra-per¬formance liquid chromatography coupled to mass
spectrometry (UPLC-MS). Then, volunteers were diagnosed as
normal liver, steatosis or NASH using the metabolomic diag-
nostic test. Sixteen percent of volunteers between 20-30 years
of age where diagnosed of steatosis, whereas 5% had NASH.
These percentages remained similar between 30-40 years
HEPATOLOGY, October, 2014
of age. However, in the following decade the percentage of
individuals with steatosis doubled (33%) whereas the preva-
lence of NASH remained constant (7%). This raise in NAFLD
was mainly due to an increased incidence of steatosis in men.
Between 50-60 years of age the total prevalence of steatosis
increased to 45% whereas that of NASH remained constant
(5%) and the differences between women and men leveled off.
Conclusion: In 262 individuals from 20-60 years of age with
BMI<30 kg/m2, non-diabetic, with normal blood pressure and
biochemistry, the prevalence of steatosis, defined by serum
metabolomic profiling, increased with age from 16% to 45%
whereas the incidence of NASH remained around 5%. In men,
the incidence of NAFLD started to increase between 40-50
years of age whereas in women it started a decade later.
Disclosures:
Jose M. Mato - Advisory Committees or Review Panels: ABBOTT; Stock Share-
holder: OWL METABOLOMICS
The following people have nothing to disclose: Ainara Cano, Cristina Alonso,
Itziar Mincholé, David Balgoma, Pablo Ortiz, Maria L. Martinez-Chantar, Shelly
C. Lu
802
Hepatic Steatosis as a Component of Spinal and Bulbar
Muscular Atrophy (SBMA, Kennedy’s Disease)
Hawwa Alao1, Derrick Fox3, Angela Kokkinis3, Colleen Had-
igan2, Christopher Grunseich3, Kenneth Fischbeck3, Yaron Rot-
man1; 1Liver Disease Branch, National Institutes of Health/
National Institute of Diabetes and Digestive and Kidney Diseases,
Bethesda, MD; 2Laboratory of Immunoregulation, National Insti-
tutes of Health/National Institutes of Allergy and Infectious Dis-
eases, Bethesda, MD; 3Neurogenetics Branch, National Institutes
of Health/National Institute of Neurological Disorders and Stroke,
Bethesda, MD
Background: Spinal and bulbar muscular atrophy (SBMA,
Kennedy’s Disease) is an X-linked neurodegenerative disorder
caused by CAG-repeat expansion mutation in the androgen
receptor (AR), leading to progressive muscle weakness with
signs of androgen insensitivity. Transaminases are typically
elevated in these patients and attributed to muscle injury. How-
ever, since androgens have been implicated in regulation of
hepatic fat accumulation, we sought to determine whether there
is liver involvement in the disorder. Methods: 26 male patients
with SBMA, enrolled in a study at the National Institute of Neu-
rological Disorders and Stroke, underwent prospective evalua-
tion including laboratory testing, liver ultrasound, measurement
of liver fat content by 3T magnetic resonance spectroscopy
(MRS) and evaluation by a hepatologist. Results: Patients were
55 years old (30-71), 85% Caucasian and with an average
BMI of 27 kg/m2 (20-42.7). Diabetes was present in 3 patients
(12%) and obesity in 4 (15%). ALT was elevated in all but
one patient (average 66 U/L, range 26-127) and was greater
than AST in 26/28 (92%). Average CPK was 1084 U/L and
was abnormal in 92% of subjects. As expected, ALT and CPK
were highly correlated (r2=0.48, p<0.001). Triglyceride levels
(average 161 mg/dL, range 85-450) were normal (<200 mg/
dL) in 79% of subjects. Liver fat content by MRS was available
for 22 subjects, and was abnormal (>5.5%) in 21 (96%) of
them (average fat content 22.3%, range 3.3-52.6%). Of the
four patients without MRS data, ultrasound suggested signifi-
cant fatty infiltration in 3, as well as in the only patient with
normal MRS. Fat content by MRS did not correlate with BMI;
liver fat was abnormal even in the 7 subjects with a BMI < 25
kg/m2 (average 13%, range 5.8-28.3%). Liver fat was not
correlated with serum triglycerides or cholesterol levels. ALT
activity was not correlated with degree of hepatic fat accu-
mulation, even after correction for the association with muscle
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
enzymes. Neither ALT nor liver fat were associated with the
number of CAG repeats. Conclusion: Evidence for hepatic ste-
atosis is highly prevalent in patients with SBMA and appears
independent of the typical metabolic risk factors, suggesting a
direct mechanistic association with the AR mutation. Elevated
ALT (and AST) activities seem to reflect both muscle and liver
sources and do not correlate well with the degree of steatosis,
similar to “classic” NAFLD. In the absence of liver histology, it
is unclear whether the SBMA-associated steatosis also contains
a component of steatohepatitis.
Disclosures:
The following people have nothing to disclose: Hawwa Alao, Derrick Fox,
Angela Kokkinis, Colleen Hadigan, Christopher Grunseich, Kenneth Fischbeck,
Yaron Rotman
803
Protease-Activated Receptor-2 (PAR2)–A Novel Thera-
peutic Target in Nonalcoholic Steatohepatitis (NASH)
Andrew M. Shearer1,2, Karyn Austin2, Srijoy Guha2, Nga
Nguyen2, Richard Looby3, Allyson Clappin3, James Baleja1, Lidija
Covic1,2, Athan Kuliopulos1,3; 1Department of Developmental,
Molecular and Chemical Biology, Tufts University School of Med-
icine, Boston, MA; 2MORI, Tufts Medical Center, Boston, MA;
3Oasis Pharmaceuticals, Lexington, MA
Purpose: PAR2 is a signaling receptor that is highly abundant
in hepatocytes, stellate, and inflammatory cells which is pro-
posed to contribute to inflammatory and fibrotic processes that
lead towards NASH and liver cirrhosis. The aim is to investi-
gate the therapeutic potential of a PAR2-based liver-homing
pepducin PZ-235 in fatty liver models and evaluate efficacy
against liver fibrosis in severe NASH models using histologic,
systemic and liver specific reporters as markers of disease
progression. Given its lipidic nature, we hypothesized that
PZ-235 may efficiently partition to liver and thereby suppress
liver fibrosis in animals. Methods: We used mouse models
of NASH including an acute 2-week methionine/choline-defi-
cient (MCD) diet and chronic 16-week high fat diet (HFD), and
chronic liver injury model with carbon tetrachloride (CCl4) for
8-weeks to evaluate the efficacy of PZ-235. Mechanistic stud-
ies to interrogate the role of PAR2 in liver stellate cell activa-
tion and hepatocellular cell death using LX2 and HepG2 cells
were performed. Results: Biodistribution and pharmacokinetic
analysis showed that PZ-235 preferentially homed to liver with
27-48% of PZ-235 present in liver at 4-48 h after injection. In
NASH models in mice, there was a striking reduction in vesic-
ular fat and triglycerides in PZ-235 treatment groups that was
confirmed by liver histology. Significantly decreased plasma
ALT was observed in the PZ-235 cohorts. NAS scores were
lower in the PZ-235 treated animals with the largest reduc-
tions in both steatosis and lobular inflammation. These data
suggest that PAR2 antagonism with PZ-235 protects against
liver steatosis, inflammatory infiltrates, and hepatocyte injury
in diet-induced models of NASH. Concurrent treatment of mice
with PZ-235 undergoing CCl4-induced liver fibrosis/necrosis
gave 66% suppression of hepatocellular necrosis compared
to vehicle treatment (P=0.006) and 36% protection against
fibrosis as assessed by Sirius-red staining (P=0.031) at the 8
week endpoint. Importantly, delayed PZ-235 treatment at 4
weeks after initiation of CCl4-induced liver fibrosis retained
the ability to suppress the further development of liver fibrosis
by 70% (P=0.0006). PZ-235 conferred resistance to oxidative
stress-damage in hepatocytes and suppressed PAR2-induced
stellate cell calcium mobilization, ERK1/2 phosphorylation and
inflammatory cytokine secretion. Conclusion: These findings
reveal that inhibiting PAR2 with PZ-235 affords significant pro-
587A
tection against liver fibrosis, necrosis, inflammation and steato-
sis, pointing to PAR2 pepducins as an effective broad-based
strategy of therapeutic intervention in NASH.
Disclosures:
Lidija Covic - Grant/Research Support: Oasis Pharmaceuticals
Athan Kuliopulos - Management Position: Oasis Pharmaceuticals
The following people have nothing to disclose: Andrew M. Shearer, Karyn Aus-
tin, Srijoy Guha, Nga Nguyen, Richard Looby, Allyson Clappin, James Baleja
804
Cardiovascular Death in Recipients of Liver Transplants
with Nonalcoholic Steatohepatitis: An Analysis of the
UNOS Database
Emily H. Wong1, Jason Vanatta1, Donna Hathaway2, Elizabeth A.
Tolley3, Satheesh Nair1, James Eason1, Sanjaya K. Satapathy1;
1Department of Surgery, Methodist Transplant Institute, University
of Tennessee Health Sciences Center, Memphis, TN; 2Department
of Advanced Practice and Doctoral Studies, University of Ten-
nessee Health Sciences Center, Memphis, TN; 3Biostatistics and
epidemeology, University of Tennessee Health Sciences Center,
Memphis, TN
Background: A recent meta-analysis with short term follow up
has implicated cardiovascular complications as an important
cause of non-graft related deaths in NASH recipients. The
purpose of this study was to further evaluate this problem in
a large, multi-institutional cohort with long follow-up. Meth-
ods: Using the UNOS STAR dataset, we reviewed 63,287
adult transplants from January 2002 through June 2013. Inclu-
sion criteria were primary whole organ deceased donor liver
transplants in recipients 18 years or older from 2002-June
2013 (MELD era). Exclusion criteria were recipient less than
18 years old; concomitant diagnosis of hepatocellular carci-
noma; multi-organ, living donor, and split liver recipients; and
recipients of organs donated after cardiac death. Additional
exclusions were made based on missing data and implausible
values for donor age, CIT, BMI, serum albumin, total biliru-
bin, and creatinine. Cardiovascular related deaths included
all deaths listed as “cardiac arrest”, “myocardial infarction”,
“arrhythmia”, “congestive failure”, “arterial embolism” and
“other cardiac”. Using the primary, secondary or tertiary diag-
nosis variable in the STAR dataset, recipients were grouped as
NASH if they had diagnosis of non-alcoholic steatohepatitis or
cryptogenic cirrhosis; and grouped as non-NASH if they had
hepatitis C, alcoholic cirrhosis, primary biliary cirrhosis (PBC),
primary sclerosing cholangitis (PSC), or auto immune hepati-
tis (AIH). There were 5,289 NASH recipients identified and
matched 1:2 with 10,080 non-NASH controls by gender, age
at transplant (+/- 3 years) and MELD score (+/-3). Conditional
logistic regression was used to estimate the odds ratio and 95%
confidence intervals. All data was analyzed using SAS 9.3
(Cary, NC). Chi square tests were used to compare categorical
variables between NASH and non-NASH groups. T-tests were
used for continuous variables. Results: The NASH group had a
higher proportion of cardiovascular related deaths compared
to the non-NASH group (19% v 14%, p= .0015); however,
conditional logistic regression failed to confirm an increased
odds of cardiovascular related death for NASH recipients [OR
1.046 95% CI: 0.628-1.742; p=0.8623]. Additionally, when
all causes of death were included, conditional logistic regres-
sion indicated that the odds of death was lower for NASH
vs non-NASH recipients [OR 0.774 95%CI: 0.708, 0.864;
p<.0001]. Conclusion: This analysis suggests that NASH
patients do not have an increased odds of cardiovascular
related death compared to their non-NASH counterparts.
Disclosures:
588A AASLD ABSTRACTS
Satheesh Nair - Advisory Committees or Review Panels: Jansen; Grant/Research
Support: Gilead; Speaking and Teaching: Bayer, Salix, Gilead
Sanjaya K. Satapathy - Advisory Committees or Review Panels: Gilead
The following people have nothing to disclose: Emily H. Wong, Jason Vanatta,
Donna Hathaway, Elizabeth A. Tolley, James Eason
805
Progression to hepatic steatosis and fibrosis by serum
biomarkers is frequent in HIV mono-infection and is
associated with black ethnicity, poor HIV control and
hyperglycemia: a 7-year study of 1,291 cases
Giada Sebastiani, Kathleen C. Rollet-Kurhajec, Norbert Gilmore,
Costas Pexos, Richard Lalonde, Marina B. Klein; Medicine, McGill
University Health Centre, Montreal, QC, Canada
Background/aims: Data on liver disease progression in HIV
mono-infection without viral hepatitis are scarce. We employed
serum biomarkers to study incidence and predictors of hepatic
steatosis and fibrosis. Methods: We included consecutive HIV
mono-infected patients. Hepatic steatosis was diagnosed by
hepatic steatosis index (HSI)>36. Significant liver fibrosis was
diagnosed by AST-to-platelet ratio index (APRI)>1.5 and/or
Fib-4>3.25. Advanced fibrosis was diagnosed by nonalcoholic
fatty liver disease (NAFLD) fibrosis score>0.676. We used Cox
proportional hazards models adjusted for age, sex, ethnicity,
hypertension, HIV infection duration, CD4 count, albumin and
glycemia. Results: 1,291 HIV mono-infected patients (median
age 43 years, 70% male) were included in 2007-2013.
During a median follow-up of 4.4 (IQR, 1.6-6.3) years, 24%
developed hepatic steatosis, 4% significant liver fibrosis and
2% advanced fibrosis. Variables associated with progression
to hepatic steatosis were black ethnicity (HR=2.14; 95% CI
1.55-2.95) and low albumin (HR=0.94; 0.91-0.96). Variables
associated with progression to significant liver fibrosis were
low CD4 count (HR=0.83; 0.70-0.98), low albumin (HR=0.89;
0.85-0.94) and high glucose (HR=1.16; 1.09-1.24). Variables
associated with progression to advanced fibrosis were low
CD4 count (HR=0.65; 0.47-0.89) and longer HIV duration
(HR=1.64; 1.05-2.56). Figure 1 depicts survival curve of pro-
gression to steatosis by ethnicity category. Conclusions: Pro-
gression to hepatic steatosis is frequent in HIV mono-infected
patients, particularly in those of black ethnicity. This population
can also progress to significant and advanced liver fibrosis.
Identification of patients at risk for progression can help early
initiation of interventions, such as optimization of HIV infection
control and targeting euglycemia.
Survival curves of progression to hepatic steatosis by ethnicity
category
Disclosures:
Giada Sebastiani - Advisory Committees or Review Panels: Boheringer Ingelheim,
Roche, Novartis; Grant/Research Support: ViiV, Vertex; Speaking and Teaching:
Merck, Gilead, Echosens
Richard Lalonde - Grant/Research Support: BMS, BI
HEPATOLOGY, October, 2014
Marina B. Klein - Advisory Committees or Review Panels: viiv, Merck, Gilead,
NIH, CIHR, FRQS; Consulting: Merck, viiv; Grant/Research Support: viiv, Merck;
Speaking and Teaching: Merck
The following people have nothing to disclose: Kathleen C. Rollet-Kurhajec, Nor-
bert Gilmore, Costas Pexos
806
Histological Severity And Glycemic Stage Drive The Evo-
lution Of Atherogenic Risk Profile In Nonalcoholic Fatty
Liver Disease
Mohammad S. Siddiqui, Kavish Patidar, Ankit V. Patel, Velimir A.
Luketic, Sherry L. Boyett, Michael O. Idowu, R. Todd Stravitz, Scott
Matherly, Puneet Puri, Richard K. Sterling, Arun J. Sanyal; Internal
Medicine, VCU, Richmond, VA
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD)
is associated with varying degrees of fasting glycemia rang-
ing from normal nondiabetic, pre-diabetes mellitus (pre-DM)
to diabetes mellitus (DM). NAFLD also increases atherogenic
risk profile with increased triglycerides and small density
LDL (sdLDL). It is not known if all subjects with NAFLD have a
monomorphic atherogenic risk profile and what factors drive
inter-subject variability. Specifically, the interactions between
glycemic status and liver histology in driving the atherogenic
risk profile are unknown. AIM: To define the impact of glycemic
status and liver histology as a determinant of the atherogenic
risk profile in affected subjects. METHODS: 162 consecutive
biopsy proven subjects with NAFLD were studied. All biop-
sies were graded according to NASH-CRN criteria. Regression
analysis was used to show association between histological
features and clinical parameters versus atherogenic risk pro-
file. RESULTS: The non-DM (N=69), pre-DM (N=32), and
DM (N=62) were similar in terms of demographic and liver
enzymes. (1) Histologic findings: Subjects with DM were more
likely to have NASH compared to non-DM and pre-DM (84%
vs 62% vs 54%, p< 0.01). The prevalence of cirrhosis was
6% and 7% respectively in non-DM and pre-DM compared to
26% in those with DM (p< 0.01). (2) Relationship of glycemic
status and histology vs laboratory markers: Non-DM: steatosis
grade was directly related to serum AST (R=0.311, p<.01),
alkaline phosphatase (R=0.271, p=.02) and indirectly to INR
(p< 0.04). It was also inversely related to HDL-C (r=-0.35, p<
0.01) and homocysteine (r=-0.37, p< 0.01). Lobular inflam-
mation was not related to laboratory and atherogenic markers.
Cytologic ballooning was directly associated with serum apoB
(R=0.25, p=.05, LDL-P (R=0.277, p=.04), small dense LDL-cho-
lesterol (sdLDL-C, R=0.241, p=.06) and %sdLDL-C (R=0.273,
p=.03). Pre-DM: Steatosis was inversely related to serum HDL-C
(R=-0.351, p=.04) and INR (R=-0.4, p<.01) in pre-DM. In
addition, lobular inflammation was inversely associated with
serum HDL subclass-2 (R=-0.47, p=.02) and free fatty acids
(R=-0.41, p=.05). DM: Steatosis was directly related to serum
apolipoprotein B (R=0.30, p=.02) and LDL particle concentra-
tion (LDL-P; R=0.34, p<.01). An inverse relationship between
fibrosis and sdLDL-C, %sdLDL, apolipoprotein A1, HDL-parti-
cle concentration and lipoprotein(a) cholesterol was observed.
CONCLUSION: The IR-glycemic stage and specific histological
features interact to drive the evolution of the atherogenic profile
in subjects with varying severity of NAFLD.
Disclosures:
Velimir A. Luketic - Grant/Research Support: Intercept, Merck, Idenix, Vertex,
Gilead, BMS, Novartis, abbvie, Genfit, Takeda
Puneet Puri - Advisory Committees or Review Panels: Health Diagnostic Labora-
tory Inc.; Consulting: NPS Pharmaceuticals Inc.
Richard K. Sterling - Advisory Committees or Review Panels: Merck, Vertex, Salix,
Bayer, BMS, Abbott, Gilead; Grant/Research Support: Merck, Roche/Genen-
tech, Pfizer, Gilead, Boehringer Ingelheim, Bayer, BMS, Abbott
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Arun J. Sanyal - Advisory Committees or Review Panels: Bristol Myers, Gilead,
Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Nimbus, Genentech, Echo-
sens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept,
Ikaria, Takeda, GalMed, Novartis, Gilead; Independent Contractor: UpToDate,
Elsevier
The following people have nothing to disclose: Mohammad S. Siddiqui, Kavish
Patidar, Ankit V. Patel, Sherry L. Boyett, Michael O. Idowu, R. Todd Stravitz,
Scott Matherly
807
Validation of surrogate indexes of peripheral and
hepatic insulin resistance and evaluation of their utility
as non-invasive predictors of histological features in
patients with Non-Alcoholic Fatty Liver Disease
Chiara Rosso1, Ester Vanni1, Lavinia Mezzabotta1, Roberto Gam-
bino1, Francesca Saba1, Federico Salomone3, Ramy Ibrahim
Kamal Jouness1, Melania Gaggini2, Emma Buzzigoli2, Chiara
Saponaro2, Fabrizia Carli2, Gian Paolo Caviglia1, Maria Lorena
Abate1, Antonina Smedile1, Mario Rizzetto1, Maurizio Cassader1,
Amalia Gastaldelli2, Elisabetta Bugianesi1; 1Medicale Science,
University of Turin, Turin, Italy; 2Cardiometabolic Risk Unit, Insti-
tute of Clinical Physiology, CNR, Pisa, Italy; 3Gastroenterology,
Azienda Sanitaria Provinciale di Catania, Catania, Italy
Background and Aims. Non-alcoholic fatty liver disease
(NAFLD) is characterized by insulin resistance (IR) in target
organs/tissues, which is implicated in the progression of liver
damage. In clinical practice, IR is evaluated by the homeostasis
model of assessment (HOMA), a rather crude index of IR that
does not discriminate the hepatic and peripheral components.
Recently other surrogate indices of IR sites have been proposed.
We aimed to 1. validate the available IR indexes vs hepatic and
peripheral IR assessed by stable isotope tracers in a group of
NAFLD subjects and 2. examine the relation of the best perform-
ing indexes with histological features in an independent cohort
of 126 patients with histological-proven NAFLD. Methods. The
validation cohort consisted of 24 NAFLD patients in which
hepatic IR was derived from Endogenous Glucose Production
(EGP) and peripheral IR from glucose clearance measured by
[6-62-H2] glucose in the basal state and after a 4h-oral glucose
tolerance test. Surrogate indexes of hepatic IR (as described
by Laakso and De Fronzo) and peripheral IR (oral glucose
insulin sensitivity (OGIS) and Matsuda insulin sensitivity index-
(ISI)) were computed according to published formulas. Results.
Hepatic IR indexes described by Laakso and De Fronzo signifi-
cantly correlated with hepatic IR calculated as EGPxINS, but
the first one had a better performance (r=0.52, P=0.009 and
r=0.415, P=0.044, respectively). Glucose clearance by tracer
was poorly correlated with ISI (r=0.298, P=0,166) and almost
significantly related to OGIS (r=0.374, P=0.078). In the larger
NAFLD cohort, the prevalence of basal IR according to HOMA
(values >75th percentile of normal) was 57.8%, peripheral IR
according to OGIS (<25th percentile) was 67.8% and hepatic
IR according to Laakso (>75th percentile) was 87.2%. In a
multivariate model, peripheral IR (OGIS) was the best predictor
of severe fibrosis (p=0.0023) and of NASH (p=0.0019), inde-
pendent of age, BMI, steatosis, HOMA-R and Laakso index.
Conversely, hepatic IR (Laakso) was the best predictor of ste-
atosis (p=0.0055), independently of age, BMI, HOMA-R and
OGIS. Logistic regression analysis confirmed the strong associ-
ation of hepatic IR with steatosis (p=0.0002) and of peripheral
IR with fibrosis (p=0.001). Conclusion. Laakso and OGIS are
the most appropriate surrogate indexes to measure respectively
hepatic and peripheral IR. They can be used as non-invasive
predictors of the severity of steatosis (Laakso) and of fibrosis
(OGIS) in NAFLD patients. Funded by FP7/2007-2013 under
589A
grant agreement n° HEALTH-F2-2009-241762 for the project
FLIP and by PRIN 2009ARYX4T.
Disclosures:
Mario Rizzetto - Advisory Committees or Review Panels: Merck, Janssen, BMS
The following people have nothing to disclose: Chiara Rosso, Ester Vanni, Lavinia
Mezzabotta, Roberto Gambino, Francesca Saba, Federico Salomone, Ramy
Ibrahim Kamal Jouness, Melania Gaggini, Emma Buzzigoli, Chiara Saponaro,
Fabrizia Carli, Gian Paolo Caviglia, Maria Lorena Abate, Antonina Smedile,
Maurizio Cassader, Amalia Gastaldelli, Elisabetta Bugianesi
808
Progression of early atherosclerotic vascular damage in
patients with NAFLD and in controls of general popula-
tion during 10 years of follow up
Anna Ludovica Fracanzani1, Giuseppina Pisano1, Silvia Tirabos-
chi1, Marianna Porzio1, Rosa Lombardi1, Cristina Bertelli1, Luca
Valenti1, Andrea Baragetti2, Liliana Grigore2, Alberico Catapano2,
Silvia Fargion1; 1Department of Pathophysiology and Transplanta-
tion, Maggiore Policlinico Hospital Foundation IRCCS, University
of Milan, Milan, Italy; 2Centro Studi Aterosclerosi Department of
Pharmacological and Biomolecular Sciences, Multimedica IRCCS,
University of Milano, Milan, Italy
NAFLD, the hepatic manifestation of metabolic syndrome, rep-
resents a risk factor for vascular damage. Carotid intima-media
thickness (cIMT) is a known precursor of cardiovascular dis-
ease. Aim: to evaluate 1) risk factors affecting the progression
of cIMT and early carotid plaques (CP) in patients with NAFLD
and in a control group from general population, 2) incidence
of major cardiovascular events in ten years of follow up 3)
correlation between vascular damage and severity of steatosis.
Material and methods: 125 patients with NAFLD diagnosed
by ultrasonography matched 1:2 for sex and age with sub-
jects from general population underwent vascular evaluation
in 2003 and were prospectively followed for a period of 10
years. In all subjects cIMT by ecocolordoppler, clinical and
biochemical data were evaluated at enrollment (time 0). After
10 years follow-up (time 1), 90/125 patients with NAFLD and
194/250 controls underwent abdominal ultrasonography to
evaluate the presence of liver steatosis and a second cIMT
measurements and CP evaluation, the remaining patients were
lost at follow up. All clinical, biochemical and pharmacolog-
ical data were recorded at time 0 and 1. Results: At enroll-
ment cIMT was significantly more elevated in NAFLD than in
controls (0.87±0.23,vs 0.64±0.14, p=0.001) and the preva-
lence of CP significantly higher (21% v.s 6%, p=0.001). After
10 years 58/194 (30%) controls developed steatosis, while
in 5 NAFLD patients steatosis disappeared. cIMT remained
significantly more elevated in NAFLD than in controls who
developed steatosis (0.95 ± 0.21 and 0.77 ± 0.13 mm, p=
0.004), the average cIMT progression was milder in patients
with NAFLD than in controls who developed steatosis (0.05 ±
0.3 and 0,12± 0.9 mm, p= 0.04), the progression of plaque
resulted greater in NAFLD (37% vs 12%, p= 0.001). At time
1, at logistic regression analysis variables significantly associ-
ated with cIMT progression were age unit (O.R. 1,10, 95%C.I.
1.06-1.15, p=0,001) and diabetes (O.R. 5.5, 95%C.I. 1.10-
43, p=0.03). Seventeen subjects (6%) developed major car-
diovascular events, all occurred in patients with progression
of cIMT and steatosis at enrolment. In conclusion our results
demonstrate that subjects of general population are at high risk
of developing steatosis throughout their life, confirm that cIMT
is useful in predicting future vascular events and point out the
need for evaluation not only of subjects with NAFLD but also of
healthy subjects for the early diagnosis of NAFLD and cardio-
vascular damage.
Disclosures:
590A AASLD ABSTRACTS
The following people have nothing to disclose: Anna Ludovica Fracanzani,
Giuseppina Pisano, Silvia Tiraboschi, Marianna Porzio, Rosa Lombardi, Cristina
Bertelli, Luca Valenti, Andrea Baragetti, Liliana Grigore, Alberico Catapano,
Silvia Fargion
809
5-aminolevulinic acid combined with ferrous iron pro-
tects from ischemia-reperfusion injury in mouse steatotic
liver model by inducing carbon monoxide generation
Shao-Wei Li1,3, Terumi Takahara2, Toshiro Sugiyama2, Kazuhiro
Tsukada3, Tohru Tanaka4, Xiao-Kang Li1; 1Division of Transplan-
tation Immunology, National Research Institute for Child Health
and Development, Tokyo, Japan; 2Third Department of Internal
Medicine, University of Toyama, Toyama City, Japan; 3Second
Department of Surgery,, University of Toyama, Toyama, Japan;
4SBI Pharmaceuticals Co., Ltd, Tokyo, Japan
Background and Aim: Steatotic liver grafts are challenging
because they are more susceptible to oxidative stress by isch-
emia-reperfusion (I/R) injury. An intermediate in heme synthe-
sis, 5-aminolevulinic acid (5-ALA) is fundamental in aerobic
energy metabolism. Heme oxygenase-1 (HO-1) cleaves heme
to form biliverdin, carbon monoxide (CO) and iron (Fe2+),
which is used with 5-ALA. We have recently reported that
5-ALA with Fe2+ (5-ALA/Fe2+) can protect the kidney against
I/R renal injury. In the present study we tried to investigate
the hypothesis that 5-ALA/Fe2+ has a beneficial effect on
acute I/R injury in mouse steatotic liver model. Methods: Male
C57BL/6 mice were all fed with methionine and choline-defi-
cient high fat (MCDHF) diet for 3 weeks to establish steatotic
liver model, then randomized into 5 groups as follows: MCDHF
diet (MCDHFD); MCDHF diet and saline treated before I/R
(MCDHF I/R); MCDHF diet and 5-ALA/Fe2+ treated before IR
(MCDHF+5-ALA/Fe2+ I/R). 5-ALA /Fe2+ was orally adminis-
trated 3 times at 48, 24 and 0.5 hr before ischemia. I/R liver
injury was induced warm ischemia for 15min, followed by 1hr
or 3hrs reperfusion in (1h) and (3h) group, respectively. Then,
the liver and serum were examined. For in vitro study, inflam-
matory cytokines were measured by treated with or without
5-ALA/Fe2+ in LPS-stimulated RAW 264.7 cells. Results: Serum
AST and ALT levels, thiobarbituric acid-reactive substances
(TBARS) content in the liver, the area of necrosis in the liver,
the number of TUNEL-positive cells and F4/80 positive macro-
phages were significantly higher in both MCDHF I/R the (1h)
and (3h) groups than the MCDHFD group, and were dramat-
ically attenuated in MCDHF+5-ALA/Fe2+ both (1h) and (3h).
Compared to MCDHF I/R (1h) and (3h) groups, inflammatory
cytokine genes such as TNF-α, IL-6, osteopontin, INF-γ, iNOS
were all markedly reduced by 5-ALA/Fe2+ treatment (p<0.05
respectively). Endogenous CO concentration in the steatotic
liver was up-regulated at 30 and 60 minutes after oral admin-
istration of 5-ALA/Fe2+. Moreover, HO-1 expression was sig-
nificantly increased by treatment with 5-ALA/Fe2+e. In vitro
study in RAW264.7 cells, 5-ALA/Fe2+ significantly diminished
the expression of inflammatory cytokines, but induced HO-1
expression. Conclusion: These results suggest that 5-ALA/Fe2+
noticeably protected I/R injury in mouse fatty liver model. We
identify the protective effects of 5-ALA/Fe2+ by its anti-oxi-
dant, anti-inflammatory and anti-apoptotic mechanisms through
the generation of endogenous CO and up-regulation of HO-1
expression. Thus, 5-ALA/Fe2+ may be a promising candidate
for a liver transplantation pretreatment.
Disclosures:
The following people have nothing to disclose: Shao-Wei Li, Terumi Takahara,
Toshiro Sugiyama, Kazuhiro Tsukada, Tohru Tanaka, Xiao-Kang Li
HEPATOLOGY, October, 2014
810
Oral glucose tolerance test predicts hepatic fibrosis in
nonalcoholic fatty liver disease patients without overt
diabetes mellitus
Sohji Nishina1, Hideyuki Hyogo2, Miwa Kawanaka3, Teruki
Miyake4, Masanori Abe4, Satoyoshi Yamashita5, Hiroshi Tobita6,
Shuichi Sato6, Yoichi Hiasa4, Kazuaki Chayama2, Keisuke Hino1;
1Hepatology and Pancreatology, Kawasaki Medical School,
Kurashiki city, Okayama, Japan; 2Medicine and Molecular Sci-
ences, Graduate School of Biomedical Sciences, Hiroshima Uni-
versity, Hiroshima city, Hiroshima, Japan; 3Internal Medicine 2,
Kawasaki Hospital, Kawasaki Medical School, Okayama city,
Okayama, Japan; 4Gastroenterology and Metabology, Ehime Uni-
versity Graduate School of Medicine, Matsuyama, Ehime, Japan;
5Gastroenterology and Hepatology, Shimonoseki Medical Cen-
ter, Shimonoseki city, Yamaguchi, Japan; 6Gastroenterology and
Hepatology, Shimane University, School of Medicine, Matsue city,
Shimane, Japan
Background & Aim: Earlier therapeutic intervention in abnor-
mal glucose metabolism may prevent the progression of nonal-
coholic fatty liver disease (NAFLD), since insulin resistance is a
risk factor for disease progression in NAFLD. Therefore, earlier
diagnosis of abnormal glucose metabolism is important in the
management of NAFLD patients. The aim of this study was to
assess whether oral glucose tolerance test (OGTT) is useful for
identifying NAFLD patients without overt diabetes mellitus (DM)
who are at high risk for disease progression. Methods: We
performed 75 g OGTT in 321 biopsy-proven NAFLD patients
without overt DM (fasting plasma glucose<126 mg/dl and
hemoglobin A1c (HbA1c)%7.0%). Plasma glucose and immu-
noreactive insulin (IRI) were measured at 0, 30, 60 and 120
min after glucose loading. The results of OGTT were divided
into normal, impaired fasting glucose (IFG), impaired glucose
tolerance (IGT) or DM based on the classification of the Expert
Committee on the Diagnosis and Classification of DM. Staging
of liver fibrosis was classified according to the classification
of Brunt et al. Results: The proportion of IFG/IGT and DM
in all patients was 43% and 17%, respectively. Of note the
proportion of IFG/IGT and DM significantly increased as liver
fibrosis progressed (38% in F0, 55% in F1, 63% in F2, 62%
in F3 and 100% in F4), which was consistent with increase in
homeostasis model assessment for insulin resistance (HOMA-R)
according to progression of liver fibrosis. Among the glucose
metabolism-related parameters, IRI, HOMA-IR, HbA1c, glucose
and insulin levels at 30, 60, 120 minutes, plasma glucose area
under the curve (AUC glucose), IRI area under the curve (AUC
IRI) were significantly higher in patients with advanced liver
fibrosis (F3-4) than those with none to moderate liver fibrosis
(F0-2). Multivariate logistic regression analysis identified AUC
glucose^ 320 mg/ml (OR: 1.88, P=0.043) and AST^43 IU/l
as independent associated factors with advanced liver fibrosis
in NAFLD patients without overt DM. In addition, AUC glucose
was significantly correlated with fibrosis indices such as type
IV collagen 7S, FIB-4 index and AST to platelet ratio index
(APRI) (P<0.0001), even though correlation coefficient was
small (r=0.20-0.25). Conclusions: As liver fibrosis progressed,
OGTT detected abnormal glucose metabolism more frequently
in NAFLD patients without overt DM. Therefore, OGTT may be
recommended for NAFLD patients without overt DM in terms of
early detection and therapeutic intervention for abnormal glu-
cose metabolism in individuals who are at high risk for disease
progression.
Disclosures:
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS 591A

Kazuaki Chayama - Consulting: Abbvie; Grant/Research Support: Dainippon Quentin M. Anstee - Advisory Committees or Review Panels: GENFIT; Speaking
Sumitomo, Chugai, Mitsubishi Tanabe, DAIICHI SANKYO, Toray, BMS, MSD; and Teaching: Abbott Laboratories
Speaking and Teaching: Chugai, Mitsubishi Tanabe, DAIICHI SANKYO, KYO- The following people have nothing to disclose: Stuart McPherson, Elsbeth Hender-
RIN, Nihon Medi-Physics, BMS, Dainippon Sumitomo, MSD, ASKA, Astellas, son, Timothy Hardy, Alastair D. Burt
AstraZeneca, Eisai, Olympus, GlaxoSmithKline, ZERIA, Bayer, Minophagen,
JANSSEN, JIMRO, TSUMURA, Otsuka, Taiho, Nippon Kayaku, Nippon Shin-
yaku, Takeda, AJINOMOTO, Meiji Seika, Toray
The following people have nothing to disclose: Sohji Nishina, Hideyuki Hyogo, 812
Miwa Kawanaka, Teruki Miyake, Masanori Abe, Satoyoshi Yamashita, Hiroshi
Tobita, Shuichi Sato, Yoichi Hiasa, Keisuke Hino Role of Genetic Polymorphisms on the Improvement of
Liver Histology after Pioglitazone Treatment in Patients
with Nonalcoholic Fatty Liver Disease (NAFLD)
811 Marina Kawaguchi-Suzuki, Fernando Bril, Kenneth Cusi, Taimour
Natural history of NAFLD: A study of 108 patients with Langaee, Yan Gong, Reginald Frye; University of Florida, Gaines-
paired liver biopsies ville, FL
Stuart McPherson1,2, Elsbeth Henderson1, Timothy Hardy2, Alastair Background: Pioglitazone has been shown to be an effective
D. Burt3, Chris Day1,2, Quentin M. Anstee1,2; 1Liver Unit, Free- long-term treatment for nonalcoholic steatohepatitis (NASH).
man Hospital, Newcastle upon Tyne, United Kingdom; 2Institute However, response in patients with NASH is variable, and
of Cellular Medicine, Newcastle University, Newcastle upon Tyne, improvement in liver histology is not always observed. The
United Kingdom; 3The School of Medicine, University of Adelaide, aim of this study was to identify genetic polymorphisms that
Adelaide, SA, Australia contribute to variability in treatment response. Methods: A total
of 55 patients with NASH and prediabetes/ type 2 diabetes
Introduction: Non-alcoholic fatty liver disease (NAFLD) is the
mellitus (T2DM) (age: 53 ± 9 years; gender: 41 males and
most common cause of liver disease in many countries. There
14 females; weight: 99 ± 17 kg; prevalence of T2DM: 60%)
remains considerable uncertainty about natural history and
were treated for 18 months with pioglitazone 45 mg/day;
prognosis. Few studies, totalling <400 patients, have exam-
32 patients from the initial randomized placebo-controlled
ined the evolution of steatosis/steatohepatitis and fibrosis of
trial and 23 patients, originally randomized to placebo, that
NAFLD in patients with paired biopsies. In general it is thought
were treated as part of the open-label phase from 18 to 36
that fibrosis progression in patients with “NAFL” (steatosis +/-
months (NCT00994682). Patients were genotyped for 63 sin-
mild inflammation) is uncommon, whereas non-alcoholic ste-
gle nucleotide polymorphisms, which were selected based on
atohepatitis (NASH; steatosis + hepatocyte ballooning and
previous association with the pathophysiology of NAFLD or
inflammation) more frequently progresses. Our aim was to
with pioglitazone response in patients with T2DM. Selected
assess the histological severity of NAFLD in a cohort with serial
genes include: RETN (resistin, a hormone believed to link obe-
liver biopsy data and to determine clinical factors that predict
sity with T2DM), PLIN1 (perilipin, a key protein that coats and
fibrosis progression. Methods: Patients with 2 liver biopsies
protects lipid storage droplets in adipocytes), ADORA1 (ade-
>1 year apart were identified from the Newcastle Hospitals
nosine receptor present in adipose tissue that inhibits lipoly-
NAFLD clinic. Clinical and laboratory data were collected
sis), and PPARG (PPAR-γ, pioglitazone target) among others.
from the time of liver biopsy. Results: 108 patients (mean age
Results: After 18 months of pioglitazone treatment, resolution
48±12 years; 66% male; 48% diabetic) were identified with
of NASH was more likely in patients with ADORA1 rs903361
≥2 liver biopsies (median interval 6.6 years, range 1.3-22.6).
G allele (OR=3.60, p=0.02). Specifically, improvement
81 (75%) patients had NASH and 27 patients with NAFL.
in steatosis was associated with the presence of the PPARG
Overall 45 (42%) patients had progression of fibrosis, 43
rs4135247 G allele (OR=9.74, p=0.04) while improvement in
(40%) had no change in fibrosis, while 20 (18%) had fibrosis
necroinflammation was more frequent with RETN rs4804765
regression. The mean rate of fibrosis was 0.08±0.25 stages/
T allele (OR=3.76, p=0.03) and ADORA1 rs903361 G allele
year overall, increasing to 0.29±0.24 stages/year in progres-
(OR=7.96, p=0.03). Improvement was defined as reduction
sors. Importantly, no significant difference in the proportion
of at least 2 grades in the histology. Overall, polymorphisms
exhibiting fibrosis progression was found between those with
associated with change in the NAFLD activity score were:
NAFL or NASH at index biopsy (10/27 (37%) vs. 36/83
RETN rs4804765 (better reduction by 0.85 points for each
(43%) p=0.65). 12/27 (44%) with NAFL at baseline pro-
T allele, p=0.003), ADORA1 rs903361 (better reduction by
gressed to NASH at follow-up biopsy, whereas 6/75 (8%) with
0.85 points for each G allele, p=0.006), and PLIN1 rs894160
NASH regressed to NAFL. Weight change was a significant
(worse reduction by 0.76 points for each T allele, p=0.01).
factor associated with inter-biopsy change in disease activity
Of note, this last variant was associated with worse response
measured by NAFLD activity score (rs=0.23 p=0.026). Of 10
in inflammation (β=0.38, p=0.0004) and fibrosis (β=0.34,
patients with NAFL who had fibrosis progression, 3 progressed
p=0.003). PNPLA3 rs738409 and rs2281135 polymorphisms
by 1 stage, 5 by 2 stages and 2 by 3 stages; all had NASH
were not associated with response to pioglitazone therapy.
on the follow-up biopsy. Of concern, 6 of 27 (22%) patients
Conclusions: Genetic polymorphisms likely have significant
with baseline NAFL had reached stage 3 fibrosis at the follow
impact on response to pioglitazone treatment in patients
up biopsy, but none were cirrhotic. Among the patients with
with NASH and may potentially help to identify responders
NAFL, 80% of those who had fibrosis progression were dia-
and individualize therapy (i.e., RETN rs4804765, ADORA1
betic at the time of follow-up liver biopsy compared with 25%
rs903361, PLIN1 rs894160, and PPARG rs4135247). Future
of non-progressors (p=0.005). The FIB-4 score was the only sig-
studies in larger populations are warranted.
nificant baseline factor that predicted fibrosis progression (OR
Disclosures:
2.1 [95%CI 1.1-3.9], p=0.02). However, the AUROC was
Kenneth Cusi - Consulting: Merck, Daichi-Sankyo, Roche, Janssen; Grant/
only 0.63 (p=0.04). Conclusion: Contrary to current dogma, Research Support: Takeda, Novartis, Mannkind
this study suggests that NAFL is not entirely benign and has the The following people have nothing to disclose: Marina Kawaguchi-Suzuki, Fer-
potential to progress to NASH and clinically significant fibrosis, nando Bril, Taimour Langaee, Yan Gong, Reginald Frye
particularly if patients develop diabetes.
Disclosures:
Chris Day - Advisory Committees or Review Panels: GSK
592A AASLD ABSTRACTS
813
The Protease Fibroblast Activation Protein (FAP) in Liver
Disease
Mark D. Gorrell1, Kathryn H. Williams2, Ana Julia Vieira de
Ribeiro1, Sumaiya Chowdhury1, Elizabeth J. Hamson1, Oli-
ver Schilling3, Emilia Prakoso1, Nicholas A. Shackel1, Susan V.
McLennan2, William W. Bachovchin4, Fiona M. Keane1, Geoffrey
W. McCaughan1, Amany Zekry5, Stephen Twigg2; 1Centenary
Institute, University of Sydney, Newtown, NSW, Australia; 2Endo-
crinology, University of Sydney, Sydney, NSW, Australia; 3Insti-
tute for Molecular Medicine and Cell Research, Albert-Ludwigs
University of Freiburg, Freiburg, Germany; 4Biochemistry, Tufts
University, Boston, MA; 5The Inflammation and Infection Research
Centre, University of New South Wales, Sydney, NSW, Australia
More than 400 human genes encode proteases. The main
advantages of exploiting proteases are that both therapeu-
tics and assays can use specific chemical compounds that
are far less expensive than antibodies. FAP is predominantly
expressed in disease states, including liver and lung fibrosis,
solid tumours, arthritis and atherosclerosis. Substrates of this
protease include α-2-antiplasmin, collagen I and Neuropeptide
Y. In a diet-induced obesity model, we have found that FAP
gene knockout (gko) mice have improved glucose tolerance and
liver histopathology, and less insulin resistance and fatty liver,
compared to wild type mice. FAPgko mice resist liver fibrosis.
Using our recently published novel FAP activity assay1, we
observed that serum levels of FAP enzyme activity co-segregate
with liver stiffness as a measure of fibrosis in two adult cohorts
with NAFLD. Cohort 1 contained 108 patients with type 2 dia-
betes who had transient elastography and Cohort 2 contained
148 patients with morbid obesity with liver biopsies. In Cohort
1, serum FAP was an independent risk factor for median liver
stiffness ≥ 10.3 kPa. There was an 8-fold increased odds ratio
of having a median liver stiffness of ≥ 10.3 kPa for those in the
highest FAP tertile, compared with subjects in the lowest tertile
(p=0.01). A serum FAP level below 730 pmol AMC/min/mL
had a negative predictive value for significant fibrosis of 95%.
In Cohort 2, the FAP level was added to the NAFLD fibrosis
score (NFS) to correctly reclassify 49% of patients as low risk of
severe fibrosis who by NFS had been classified as intermediate
risk. Measuring FAP in serum is rapid and should thus become
an inexpensive supplement to the NFS to avoid patients being
sent for unnecessary further tests. Cell lines derived from FAP
gko mice were engineered to express functional FAP enzyme
(FAPe+) vs inactive FAP (FAPe-). Proteomic analyses of these
cells showed FAP-specific cleavage of many bioactive pep-
tides. In vitro ‘wound healing’ found that cells with FAP activity
exhibited greater cell migration but comparable proliferation
and apoptosis. Conclusions: (1) FAP has an important role in
glucose and lipid metabolism and in fibrosis progression. (2)
Adding a FAP serum measurement to the existing clinical NFS
algorithm may correctly diagnose as non-fibrotic about half of
the patients who would otherwise receive an uncertain diagno-
sis and require further testing. (3) FAP enzyme activity causes
increased cell migration. 1. Keane FM, et al. Quantitation of
fibroblast activation protein (FAP)-specific protease activity in
mouse, baboon and human fluids and organs. FEBS open bio
2014;4:43-54.
Disclosures:
William W. Bachovchin - Board Membership: AP; Consulting: arisaph phar-
maceuticals; Grant/Research Support: AP; Patent Held/Filed: AP; Stock Share-
holder: AP
Geoffrey W. McCaughan - Advisory Committees or Review Panels: Novartis,
Novartis, Novartis, Novartis; Speaking and Teaching: Astellas, Gilead, Roche,
MSD, Astellas, Gilead, Roche, MSD, Astellas, Gilead, Roche, MSD, Astellas,
Gilead, Roche, MSD
HEPATOLOGY, October, 2014
The following people have nothing to disclose: Mark D. Gorrell, Kathryn H. Wil-
liams, Ana Julia Vieira de Ribeiro, Sumaiya Chowdhury, Elizabeth J. Hamson,
Oliver Schilling, Emilia Prakoso, Nicholas A. Shackel, Susan V. McLennan, Fiona
M. Keane, Amany Zekry, Stephen Twigg
814
Association of Hepatic Nuclear Hormone Receptor
Expression Profiles with Features of Hepatic Histology in
Children with Nonalcoholic Fatty Liver Disease
Joel E. Lavine1, Michael Downes2, Kevin P. May3, Ruth Yu2, Jeffrey
B. Schwimmer4, Cynthia A. Behling4, Elizabeth M. Brunt5, Mark
L. van Natta3, James Tonascia3, Ronald M. Evans2; 1Pediatric
Gastroenterology, Hepatology and Nutrition, Columbia Univer-
sity, New York, NY; 2Gene Expression Laboratory, Salk Institute,
La Jolla, CA; 3Bloomberg School of Public Health, Johns Hop-
kins, Baltimore, MD; 4Pediatric Gastroenterology and Hepatology,
University of California, San Diego, San Diego, CA; 5Pathology,
Washington University, St. Louis, MO
Significance: Nonalcoholic fatty liver disease (NAFLD) is the
most common cause of chronic liver disease in American
children and adolescents. Existent targets for NAFLD therapy
include agonists of specific nuclear hormone receptors such as
the farnesoid-X receptor-α (FXRα) and peroxisome-proliferator
activated receptor γ (PPARγ). Whether nuclear hormone recep-
tor (NHR) differences play a role in disease susceptibility or
treatment response is unknown. Objective: To assess whether
differential expression of hepatic NHR in children relates to
diagnosis or severity of nonalcoholic steatohepatitis (NASH)
or NAFLD histology. Methods: Total liver mRNA was obtained
from a single-center subset of children 10-19y undergoing per-
cutaneous biopsy at end-of-treatment in the NASH Research
Network TONIC trial (Lavine et al. JAMA,2011). Comparisons
of NHR expression determined by high throughput quantitative
PCR were made between categories of steatosis, lobular inflam-
mation, ballooning, and NASH diagnosis. Statistical analyses
used Student’s t-test to assess differential NHR expression by
features of hepatic histology. A hierarchical cluster analysis
of the 35 NHRs was performed, with the Calinski-Harabasz
index used to determine the # of clusters and a dendrogram
used to display a graphical summary of the cluster analysis.
Results: Forty children (85% Hispanic, 17% girls) with a history
of biopsy-proven NAFLD underwent analyses. At end-of-treat-
ment biopsy, 19 subjects had NASH. Detectable mRNA was
expressed for 35 distinct NHR. PPAR-δ demonstrated higher
expression for diagnosis of NASH v “not NASH” (p=0.02),
for stage of fibrosis (2-4 v 0-1, p=0.04), lobular inflammation
(2-3 v 1-2, p=0.01) and ballooning (1-2 v 0, p=0.08). Reti-
noic acid receptor-β (RARβ) demonstrated significantly higher
expression for diagnosis of NASH v “not NASH” (p=0.02)
and for steatosis (2-3 v 1-2, p=0.01). Expression of PPARγ and
PPARγ2 demonstrated significant differences in lobular inflam-
mation (0-1 v. 2-3, p=0.01 and p<0.001, respectively). Higher
FXRα expression levels associated with higher steatosis score
(p=0.01). Conclusions: Expression differences in specific NHR
known to be pleiotropic transactivators regulating lipid metabo-
lism and energy homeostasis, bile acid metabolism, and basal
metabolic functions are associated with the histologic severity
of NAFLD including the diagnosis of NASH. If protein levels for
these effectors are found to relate to these expression profiles,
these receptors identify novel therapeutic targets.
Disclosures:
Joel E. Lavine - Consulting: Merck, Crosscare, Gilead, Takeda Millenium; Grant/
Research Support: Janssen
Jeffrey B. Schwimmer - Speaking and Teaching: Daiichi Sankyo, Inc.
Cynthia A. Behling - Grant/Research Support: NASH CRN
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Elizabeth M. Brunt - Consulting: Synageva; Independent Contractor: Rottapharm,
Kadmon; Speaking and Teaching: Geneva Foundation
The following people have nothing to disclose: Michael Downes, Kevin P. May,
Ruth Yu, Mark L. van Natta, James Tonascia, Ronald M. Evans
815
There is substantial phenotypic variability in lean versus
obese subjects with NAFLD across the world: The Global
NASH Study
Angelo H. Paredes1, Lawrence Serfaty2, Claudia P. Oliveira3,
Abhijit Chowdhury4, Sherry L. Boyett1, Mohammad S. Siddiqui1,
Arun J. Sanyal1; 1Internal Medicine/Division of Gastroenterology,
Hepatology and Nutrition, Virginia Commonwealth University,
Richmond, VA; 2Service d’Hépatologie, Saint-Antoine Hospital,
Paris, France; 3Gastroenterology, University of São Paulo, São
Paulo, Brazil; 4Digestive and Liver Diseases, Institute of Post Grad-
uate Medical Education & Research, Kolkata, India
BACKGROUND: It is not known if the pathophysiology and
clinical-histological phenotype of nonalcoholic fatty liver dis-
ease (NAFLD) in lean vs obese subjects is similar in different
parts of the world. AIMS: (1) to compare the phenotype of lean
versus overweight (OW) and obese (OB) subjects with NAFLD
across multiple continents, (2) to determine if the phenotype of
lean subjects with NAFLD is similar in these regions, and (3)
to evaluate the interactions between BMI, insulin resistance (IR)
and histology across regions. METHODS: A cross-sectional
study of histologically defined subjects from a single center
each in France (Fr), Brasil (Br), India (In) and United States (US)
was performed. Liver histology was scored locally using NASH
CRN criteria. RESULTS: A total 70 lean (BMI < 25 kg/m2) sub-
jects (Fr:Br:In:US: 16:19:22:13) with NAFLD were compared
to 136 OW (BMI >25<29 kg/m2) (n= 28:33:52:23) and 224
OB subjects (BMI > 29 kg/2) (n=81:11:22:103). Clinical Pro-
file: Subjects in India and France were younger (mean 40-44
yrs) compared to US and Brasil (mean age: 56-58 yrs). French
lean subjects had the lowest prevalence of T2DM (p< 0.03
vs OB subjects) while Brasil had the highest rates (66%, p<
0.01 vs Fr). Lean subjects with NAFLD had similarly elevated
LDL-cholesterol as OW and OB subjects in all regions but had
higher HDL-cholesterol. Triglycerides were significantly lower
in lean subjects with NAFLD in France compared to obese
subjects and lean subjects elsewhere. Physiological profile: US:
there was a mixture of insulin sensitive and resistant subjects
in all BMI categories with 20% of obese subjects being insulin
sensitive (low blood glucose and insulin). France: IR worsened
progressively from lean-OW-OB subjects. Brasil: Lean subjects
were split between insulin sensitive (40%) and severe IR (60%).
India: lean and obese subjects had similar IR; a greater propor-
tion of subjects in each weight category were insulin sensitive
compared to other regions. Histology: US: Lean subjects have
similar histologic severity as OW and OB subjects. France: the
severity of all histological parameters progressed from lean to
OW to OB subjects (p< 0.03 for all). Brasil: Lean subjects have
similarly aggressive disease as other weight groups. India:
The histology was similar in lean versus OW and OB subjects.
Insulin sensitive subjects had similar severity of NAFLD as those
with advanced IR within all weight groups in all regions. CON-
CLUSIONS: The phenotype of NAFLD in lean subjects varies by
region. Some obese subjects with NAFLD are insulin sensitive.
We hypothesize that genetics and region-specific disease mod-
ifiers account for these differences.
Disclosures:
Lawrence Serfaty - Advisory Committees or Review Panels: MSD, Janssen, Roche,
Gilead, BMS, Abbvie; Speaking and Teaching: Aptalis
593A
Arun J. Sanyal - Advisory Committees or Review Panels: Bristol Myers, Gilead,
Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Nimbus, Genentech, Echo-
sens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept,
Ikaria, Takeda, GalMed, Novartis, Gilead; Independent Contractor: UpToDate,
Elsevier
The following people have nothing to disclose: Angelo H. Paredes, Claudia P.
Oliveira, Abhijit Chowdhury, Sherry L. Boyett, Mohammad S. Siddiqui
816
Prevalence and Risk Factors for Advanced Liver Fibrosis
in Adults Undergoing Intestinal Transplantation
Genevieve Huard1, M. Isabel Fiel2, Jang Moon3, Lauren Schwartz4,
Kishore Iyer3, Thomas D. Schiano1,3; 1Medicine, Division of Liver
Diseases, Icahn School of Medicine at Mount Sinai, New York,
NY; 2Pathology, Division of Liver Pathology, Icahn School of Med-
icine at Mount Sinai, New York, NY; 3Recanati-Miller Transplan-
tation Institute, Icahn School of Medicine at Mount Sinai, New
York, NY; 4Medicine, Division of Gastroenterology, Icahn School
of Medicine at Mount Sinai, New York, NY
Introduction: Parenteral nutrition-associated liver disease
(PNALD) occurs commonly in intestinal transplant (ITx) candi-
dates on total parenteral nutrition (TPN). Currently, no predic-
tive factor exists to help identify patients (pts) with advanced
liver fibrosis on TPN. Aims: Establish the prevalence and risk
factors for advanced liver fibrosis in adults at ITx. Methods: Ret-
rospective chart review of all ITx performed between 01/2006
and 05/2014. Children, pts not on TPN and those without a
protocol liver biopsy at the time of ITx were excluded. Advanced
liver fibrosis was defined as stage 3 or 4 fibrosis (Brunt classi-
fication). Baseline characteristics, laboratory values and liver
pathology findings were analyzed. Results: Sixty-one ITx were
performed and 34 (56%) met the inclusion criteria. The median
age was 51.4 years, 18 were females (53%) and 24 (71%)
were Caucasians. The most frequent cause of IF was mesenteric
ischemia in 12 pts (35%). The most frequent indications for
ITx were: line sepsis, PNALD and ultra-short gut (n=10 (29%)
each). Thirty-two (94%) pts received an isolated ITx, of which
2 also received a kidney and 2 received a pancreas. Two pts
(6%) received a liver-containing allograft, one for PNALD and
the other for primary sclerosing cholangitis associated with
PNALD. The median BMI was 22.6 kg/m2 (IQR: 5.6) and the
median duration of TPN prior to ITx was 421.5 days (IQR:
487). The median number of calories/kg/day was 24.7 (IQR:
6.6) and the median number of grams of dextrose, amino acids
and lipids per kg per day were 4.6 (IQR: 1.9), 1.2 (IQR 0.5)
and 0.4 (IQR: 0.2), respectively. At the time of ITx, the median
total bilirubin was 0.65 (IQR: 1.5). Advanced liver fibrosis at
the time of ITx was found on the liver biopsy of 10 pts (29%).
In univariate analysis, there was a statistically significant dif-
ference in the mean BMI (20.2 vs 22.9 kg/m2, p=0.03), the
mean platelet count (137 vs 242 x 103/uL, p=0.01), the mean
AST level (102 vs 63 U/L, p=0.05) and the mean duration of
total bilirubin over 3.0 (25.5 vs 3.8 days p=0.04) in pts with vs
without advanced fibrosis. There was no statistically significant
difference in TPN composition or duration, SB length and total
bilirubin 1 and 3 months after ITx between the 2 groups. In the
multivariable model, a total bilirubin over 3.0 for more than
a month prior to ITx was associated with an OR of advanced
fibrosis of 1.74 (p=0.04). Conclusion: This study shows that
one third of the ITx recipients had advanced liver fibrosis at
the time of ITx. Having a total bilirubin over 3.0 for more than
a month prior to ITx was a significant risk factor for advanced
liver fibrosis at the time of ITx.
Disclosures:
Thomas D. Schiano - Advisory Committees or Review Panels: vertex, salix, merck,
gilead, pfizer; Grant/Research Support: massbiologics, itherx
594A AASLD ABSTRACTS
The following people have nothing to disclose: Genevieve Huard, M. Isabel Fiel,
Jang Moon, Lauren Schwartz, Kishore Iyer
817
Racial disparities in nonalcoholic fatty liver disease
related mortality among US Adults: Results of the
National Health and Nutrition Examination Survey
18-year mortality follow-up data
Ivo C. Ditah1, Taiwo N. Ngwa1, Albert Ndzengue3, Zeenat Y.
Bhat6, Chijioke Enweluzo2, Callistus Ditah4, Michael Charlton5,
Patrick S. Kamath1; 1Gastroenterology, Mayo Clinic, Roches-
ter, MN; 2Medicine, Wake Forest School of Medicine, Winston
Salem, NC; 3Medicine, University of Yaounde, Yaounde, Cam-
eroon; 4Medicine, University of Michigan Medical School, Ann
Arbor, MI; 5Hepatology and Liver Transplantation, Intermountain
Medical Center, Salt lake City, UT; 6Medicine, Wayne State Uni-
versity School of Medicine, Detroit, MI
Background The distribution of NAFLD in the general popula-
tion varies significantly even among individuals with similar
metabolic profiles. Genetic studies suggest that variations in
the patatin-like phospholipase domain containing 3 (PNPLA3)
follow a racial pattern consistent with the racial distribution of
NAFLD in the population. PNPLA3 is most prevalent in Hispan-
ics and is associated with progression of hepatic steatosis. Yet,
it is unknown whether the long-term outcomes of NAFLD differ
by race. This study evaluated racial disparities in mortality
among individuals with NAFLD in the United States. Methods
Data from the Third National Health and Nutrition Examination
(NHANES III) and the NHANES III Mortality-linked files were
analyzed for this study. To determine the cause of death, the
National Center for Health Statistics linked NHANES III partic-
ipants to the National Death Index registry through December
31, 2006. Analyses were restricted to 11,863 adults aged
20-74 years who had liver ultrasound available. Racial differ-
ences in all-cause and cause-specific mortality were compared
using chi2 tests. Cox regression was used to compare survival
between NAFLD groups and by race. Results The median age
of all participants was 41 years. Patients with NAFLD were
older than those without NAFLD. By race, 82.7%, 11.4%,
and 5.9% were non-Hispanic whites(NHW), non-Hispanic
Blacks(NHB) and Mexican American(MA) respectively. The
prevalence of NAFLD varied significantly by race (P<0.001):
NHWs 32.6% NHBs 28.8% and MA 41.6 %. The median
followup time was 14.7 years (IQR 13.1-16.3) with a range of
0.08 to 18.2 years. In all, there were 1,909 (16.1%) deaths
among the study cohort. The 18-year Kaplan-Meier survival dif-
fered by NAFLD status; 86.5% in participants without NAFLD
and 79.6% in those with NAFLD; this corresponded to a 50%
unadjusted higher risk of all-cause mortality in the NAFLD
group (HR 1.50; 95% CI 1.32, 1.7, P<0.001). However, in
multivariate analyses, there was no significant difference in
all-cause mortality among all subjects (HR 1.0, 95% CI 0.81,
1.23) and by race: NHWs, 1.03 (0.81, 1.30); NHBs, 1.30
(0.78, 1.88); MA, 0.87 (0.47, 1.63). The most common cause
of death was cardiovascular disease (34.3%). Liver-related
mortality accounted only for 2% of deaths. By race, NAFLD
was not predictive of cardiovascular, liver, cancer and diabe-
tes related mortality once potential confounders were adjusted
for. Conclusion Although the determinants and distribution of
hepatic steatosis differ by race, there are no racial differences
in NAFLD related all-cause and cause-specific mortality in the
general population.
Disclosures:
Patrick S. Kamath - Advisory Committees or Review Panels: Sequana Medical
HEPATOLOGY, October, 2014
The following people have nothing to disclose: Ivo C. Ditah, Taiwo N. Ngwa,
Albert Ndzengue, Zeenat Y. Bhat, Chijioke Enweluzo, Callistus Ditah, Michael
Charlton
818
Steatosis Assessment By Cap™ Using Xl Probe
Victor de Ledinghen1, Christophe Corpechot2, Julien Vergniol1,
Pierre Bedossa3, Andrew R. Hall4, Olivier Chazouillères2, Yves
Menu5, Amar P. Dhillon4, Valerie Paradis3; 1Hepato-gastroenterol-
ogy, Haut Leveque Hospital, Pessac, France; 2Hepato-gastroenter-
ology, Saint Antoine Hospital, Paris, France; 3Pathology, Beaujon
Hospital, Clichy, France; 4Pathology, Royal Free Hospital, London,
United Kingdom; 5Radiology, Saint Antoine Hospital, Paris, France
There is currently no routine non-invasive method validated to
assess steatosis in obese patients. The aim of this study was to
validate CAP measured on FibroScan (FS) using the XL probe
for steatosis evaluation taking both MRI and liver biopsy as
gold standard. Two cohorts were enrolled, one for reproduc-
ibility evaluation & validation versus MRI, one for validation
versus liver biopsy. Cohort 1: 59 consecutive patients with
mean BMI = 26+/-4 kg/m2 who underwent FS and liver MRI
on the same day at Saint Antoine hospital. FS examination
was performed consecutively 3 times with both M probe and
XL probes. Steatosis was quantified using liver MRI and the
3-points Dixon method. Cohort 2: 237 consecutive patients
with mean BMI = 25+/-6 kg/m2 who underwent FS (both
probes) and liver biopsy within 7 days at Haut Leveque hos-
pital. Biopsy reading was performed by double-blind read-
ing with consensus by 2 independent pathologists. Steatosis
was graded as follows: S0: steatosis≤10%, S1: 11~33%, S2:
34~66%, S3: ≥67%. Morphometric evaluation of steatosis
(measured fat proportionate area, mFPA) was assessed using
the method described in (Hall et al., Liver Int, 2013). Correla-
tion was assessed using spearman coefficient. Reproducibility
was assessed using intra-class correlation coefficient (ICC).
Diagnostic performance was assessed using area under ROC
curve (AUROC) and Delong test for comparison. Using both
M and XL probes, reproducibility in term of ICC was: 0.81
[0.73; 0.88] and 0.84 [0.76; 0.89], respectively. Diagnostic
performance of CAP on XL probe to diagnose liver fat on MRI
was : 0.84 [0.74;0.94], 0.92 [0.84;0.99], 0.88 [0.78;0.97],
0.85 [0.75;0.95] to detect liver fat content ≥ 1%, ≥ 5%, ≥
10% and ≥ 30%, respectively. In the cohort with liver biopsy,
performance of CAP on XL probe for the diagnosis of steatosis
was: grade ≥S1: AUC=0.85 [0.80-0.90], ≥S2: AUC=0.89
[0.83; 0.94], =S3: AUC=0.94 [0.90; 0.97]. Using liver mor-
phometry as a reference, CAP performance was: AUC=0.83
[0.78; 0.89], 0.93 [0.90; 0.97], 0.95 [0.91; 0.98], for the
detection of 1%, 5% and 10% of mFPA, respectively. Bland
and Altman analysis showed no significant mean difference
between M and XL probes for CAP assessment. Performances
of CAP assessed on M probe were statistically similar to those
assessed using XL probe. In conclusion, CAP algorithm has
been developed for the XL probe of the FibroScan. Results have
shown an equivalent reproducibility using both probes and
good to excellent diagnostic accuracy for steatosis evaluation
on either MRI or liver biopsy. Overweight patients in whom
steatosis is more prevalent can now benefit for non-invasive
steatosis evaluation using CAP.
Disclosures:
Victor de Ledinghen - Advisory Committees or Review Panels: Merck, Janssen,
Gilead, BMS, Abbvie; Grant/Research Support: Gilead, Janssen; Speaking and
Teaching: AbbVie, BMS
Olivier Chazouillères - Consulting: APTALIS, MAYOLY-SPINDLER
Amar P. Dhillon - Independent Contractor: Echosens
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
The following people have nothing to disclose: Christophe Corpechot, Julien
Vergniol, Pierre Bedossa, Andrew R. Hall, Yves Menu, Valerie Paradis
819
Distinction between non-alcoholic steatohepatitis and
simple steatosis according to the controlled attenua-
tion parameter and liver stiffness value using transient
elastography in patients with non-alcoholic fatty liver
disease: a Korean multicenter study
Young Eun Chon1, Soo Young Park2, Hana Park3, Ja Kyung Kim4,
Jae Young Jang5, Chun Kyon Lee6, Kwang-Hyub Han6, Seung Up
Kim6; 1Shinchon Severance Hospital, Yonsei university college of
medicine, Seoul, Republic of Korea; 2Kyungpook National Uni-
versity School of Medicine, Seoul, Republic of Korea; 3CHA Bun-
dang Medical Center, CHA university College of Medicine, Seoul,
Republic of Korea; 4Gangnam Severance Hospital, Yonsei univer-
sity college of medicine, Seoul, Republic of Korea; 5Soon Chun
Hyang University College of Medicine, Seoul, Republic of Korea;
6National Health Insurance Cooperation, Seoul, Republic of Korea
Background: Although the performance of noninvasive markers
to assess the degree of necroinflammatory activity and fibrosis
in patients with non-alcoholic fatty liver disease (NAFLD) has
been investigated, the diagnostic accuracy of these markers has
been unsatisfactory. We investigated whether the controlled
attenuation parameter (CAP) and liver stiffness value (LSV) as
measured by transient elastography (TE) can be used to distin-
guish between non-alcoholic steatohepatitis (NASH) and simple
steatosis. Methods: In total, 183 patients (35 healthy donors,
155 patients with simple steatosis, and 50 patients with NASH)
who underwent liver biopsy and TE were recruited from five
tertiary centers in South Korea from November 2011 to Decem-
ber 2013. Results: The study population exhibited a mean age
of 41 years and male predominance (n=111, 60.7%). The
baseline characteristics of the patients were similar among the
five tertiary centers. The CAP and LS were significantly cor-
related with the degree of steatosis (r=0.656, P<0.001) and
fibrosis (r=0.714, P<0.001), respectively. The optimal cutoff
values for steatosis were 250 dB/m for S1, 280 dB/m for S2,
and 300 dB/m for S3; those for fibrosis were 6.0 kPa for F1,
7.0 kPa for F2, 9.0 kPa for F3, and 11.0 kPa for F4. Based on
the independent predictors derived from multivariate analysis
(P<0.001, hazard ratio [HR] 7.56, 95% confidence interval
[CI] 2.70–21.15 for CAP>250 dB/m; P<0.001, HR 8.07,
95% CI 3.14–20.72 for LS>7.0 kPa; and P=0.001, HR 4.87,
95% CI 1.98–11.98 for alanine aminotransferase>40 IU/L),
we developed a novel CLA model for discriminating patients
with NASH. This model showed diagnostic accuracy with an
AUROC of 0.885 (95% CI, 0.802–0.935), ranging from 0 to
3. NASH developed in 2.8% of patients with a CLA score of 0,
37.9% with a score of 1, 81.5% with a score of 2, and 92.1%
with a score of 3 (P<0.001). Conclusion: The CAP and LS can
be used as reliable noninvasive markers for grading steato-
sis and fibrosis in Korean patients with NAFLD. A novel CLA
model showed acceptable accuracy in distinguishing NASH
from simple steatosis. Further studies are required for external
validation.
Disclosures:
The following people have nothing to disclose: Young Eun Chon, Soo Young
Park, Hana Park, Ja Kyung Kim, Jae Young Jang, Chun Kyon Lee, Kwang-Hyub
Han, Seung Up Kim
595A
820
Non- Viral Liver Disease Burden In HIV Positive Individ-
uals: An Observational Retrospective Cohort Study
Natalie Shur1,2, Martin Fisher3,2, Yvonne Gilleece3, Sumita
Verma1,2; 1Department of Gastroenterology and Hepatology,
Brighton and Sussex University Hospital, Brighton, United King-
dom; 2Department of Medicine, Brighton and Sussex Medical
School, Brighton, United Kingdom; 3Department of HIV and Geni-
tourinary Medicine, Brighton and Sussex University Hospital, Brigh-
ton, United Kingdom
Introduction Recent advances in antiviral therapy have dramati-
cally improved outcomes in HIV-positive individuals co-infected
with hepatitis B and C. However, there remains limited data
on non-viral liver disease burden in such individuals. Our aim
therefore was to assess prevalence and predictors of chronic
liver disease (CLD) due to non-alcoholic fatty liver disease
(NAFLD), and alcohol or antiretroviral (ARV) use in HIV-posi-
tive individuals. Patients & Methods Retrospective cohort study
between 2005 and 2012. HIV-positive patients with negative
hepatitis B and C serology, at least two aminoalanine trans-
ferase (ALT) level >1ULN over a six month period, and further
investigations (one or more of abdominal imaging, Transient
Elastography (TE) and liver biopsy) were included. CLD was
defined as: abnormal imaging and/or histological or TE evi-
dence of >F1 (Metavir) fibrosis. Binary logistic regression was
performed. Data are presented as mean ±SD. Results Of the
total HIV cohort (n=3872), 27% (n=1047) had persistently
abnormal ALT over a six month period despite a negative hepa-
titis B and C serology. Of them 244 (23.3%) were investigated
further and after excluding those with opportunistic infections
and unavailable medical records, 222 fulfilled study criteria of
whom 147 (66.2%) had evidence of CLD. This included abnor-
mal imaging in 169 (76.1%) and >F1 fibrosis on TE and or
liver biopsy in 53 (23.9%).Underlying aetiology for CLD was
alcohol (45.5%), NAFLD (67.8%) and ARV use (74%), with
69% having more than one risk factor. Overall 83 (37.4%)
were drinking alcohol above the weekly recommended amount.
On multivariate logistic regression fasting serum cholesterol
(p=0.31, OR=1.134, 95%CI 1012-1.271) and triglyceride
(p=0.15, OR=1.570, 95%CI 1.093-2.255) were independent
predictors of CLD. There were 36 patients (16.2%) who had
clinically significant liver disease (≥F2 fibrosis, moderate to
severe hepatic steatosis or non-cirrhotic portal hypertension).
Conclusions Despite a negative viral serology, approximately
30% of HIV positive individuals have persistently abnormal
ALT although only about 1:5 undergo further liver related work
up. Of those investigated, CLD due to NAFLD, and alcohol or
ARV use is diagnosed in about two thirds with almost 70% hav-
ing more than one risk factor. Independent predictors for CLD
appear to be similar to metabolic syndrome risk factors. Our
data suggests a need for increasing awareness and institution
of screening strategies for non-viral liver disease in HIV-positive
individuals.
Disclosures:
Martin Fisher - Advisory Committees or Review Panels: AbbVie, Bristol Myers
Squibb, Gilead, Janssen, Merck
Yvonne Gilleece - Speaking and Teaching: Janssen, Bristol-Myer Squibb, Gilead,
Viiv, Merck, Pfizer
Sumita Verma - Advisory Committees or Review Panels: Janssen; Grant/Research
Support: Gilead, Roche, Janssen
The following people have nothing to disclose: Natalie Shur
596A AASLD ABSTRACTS
821
Patients with Non-Alcoholic Steatohepatitis are at High
Risk of Developing Post-Transplant Diabetes
Zobair Younossi1,3, Maria Stepanova1,3, Sammy Saab2, Kelly E.
Hoyle1, Rebecca Cable1, Alita Mishra1,3, Stephen C. Clement1,
Sharon L. Hunt1,3; 1Center for Liver Disease, Department of Med-
icine, Inova Fairfax Hospital, Falls Church, VA; 2Departments of
Medicine and Surgery, David Geffen School of Medicine at Uni-
versity of California at Los Angeles, Los Angeles, CA; 3Betty and
Guy Beatty Center for Integrated Research, Inova Health System,
Falls Church, VA
BACKGROUND AND AIM: Non-alcoholic steatohepatitis
(NASH), the progressive subtype of non-alcoholic fatty liver
disease (NAFLD), is rapidly becoming an important indication
for liver transplantation. NASH is often seen together with the
components of metabolic syndrome including type II diabetes
(DM). The causal relationship between NASH and DM is cur-
rently believed to be bidirectional. The aim of this study was to
assess the risk of post-transplant DM in subjects who underwent
liver transplantation for NASH. METHODS: All adult (18+)
subjects who underwent liver transplantation for NASH or cryp-
togenic cirrhosis (the NASH cohort) from the Scientific Registry
of Transplant Recipients with annually recorded post-transplant
DM were included (2002-2012). Patients with alcoholic cirrho-
sis (ALD) were used as controls. RESULTS: A total 5,890 NASH
subjects and 6,114 ALD controls were included. Patients with
NASH were older (57.9±9.5 vs. 54.3±8.7 years), less likely
male (56.1% vs. 77.9%), more likely obese (BMI ≥30: 50.5%
vs. 31.2%) and had higher rate of pre-transplant diabetes
(35.3% vs. 13.7%) (all p<0.0001). They also had slightly
lower MELD score: 22.4±8.5 vs. 23.6±8.8 (p<0.0001).
Post-transplant, 36.6% of NASH and 29.1% of ALD patients
developed DM (p<0.0001). In fact, higher rates of post-trans-
plant diabetes were observed starting 6 months post-trans-
plant: 25.0% in NASH and 19.0% in ALD (p<0.0001). The
risk of developing post-transplant DM in the NASH cohort was
also significantly higher in later follow up. In particular, by 3
years post-transplant, the relative risk of having DM in NASH
patients as compared to ALD was RR (95% CI) = 1.27 (1.21-
1.35), p<0.0001. By follow-up year 5, RR = 1.26 (1.19-1.33),
p<0.0001, and the hazard ratio for the time to development
of DM was 1.35 (1.27-1.44), p<0.0001. Even after exclusion
of those who developed DM potentially due to intense early
post-transplant immunosuppression (DM that resolved after the
first year), long-term DM remained higher in the NASH cohort:
12.1% vs. 8.2%, RR = 1.47 (1.30-1.66), p<0.0001. In multi-
variate analysis, after adjustment for confounders including the
use of immunosuppressants, having NASH was independently
associated with development of post-transplant DM: aHR =
1.17 (1.07-1.27), p=0.0003. CONCLUSIONS: Subjects
receiving liver transplantation due to NASH are at higher risk
of developing post-transplant DM. This suggest the presence of
an underlying metabolic disorder beyond fatty liver that may
be causative for developing of both NASH and DM.
Disclosures:
Sammy Saab - Advisory Committees or Review Panels: BMS, Gilead, Merck,
Genentech; Grant/Research Support: Merck, Gilead; Speaking and Teaching:
BMS, Gilead, Merck, Genentech, Salix, Onyx, Bayer, Janssen; Stock Share-
holder: Salix, Johnson and Johnson, BMS, Gilead
The following people have nothing to disclose: Zobair Younossi, Maria Ste-
panova, Kelly E. Hoyle, Rebecca Cable, Alita Mishra, Stephen C. Clement,
Sharon L. Hunt
HEPATOLOGY, October, 2014
822
Population incidence of nonalcoholic fatty liver disease:
A prospective study using serial proton-magnetic reso-
nance spectroscopy and transient elastography
Vincent W. Wong1, Grace LH Wong1, David K. Yeung2, Winnie
C. Chu2, Henry Lik-Yuen Chan1; 1Department of Medicine and
Therapeutics, The Chinese University of Hong Kong, Hong Kong,
China; 2Department of Imaging and Interventional Radiology, The
Chinese University of Hong Kong, Hong Kong, China
Background: Because abdominal ultrasonography cannot reli-
ably quantify hepatic steatosis, the incidence of nonalcoholic
fatty liver disease (NAFLD) is currently unknown. By using state-
of-the-art non-invasive tests of hepatic steatosis and fibrosis, we
aimed to study the incidence of NAFLD in the general popula-
tion and risk factors of incident NAFLD. Methods: Community
subjects were recruited via the government census database
by random sampling and underwent serial assessments.
Proton-magnetic resonance spectroscopy was performed
to measure intrahepatic triglyceride content, with a cutoff of
5.0% being used to define fatty liver. Transient elastography
by Fibroscan was performed to measure liver stiffness, with
a cutoff of 9.6 kPa being used to define advanced fibrosis.
Results: 565 subjects with normal intrahepatic triglyceride con-
tent (<5.0%) at baseline underwent follow-up assessment after
a median interval of 47 months (range 34-60 months). The
mean age at baseline was 48 years, 62.7% were women, and
the body mass index was 21.9 (SD 2.9) kg/m2. 78 (13.8%)
subjects developed incident fatty liver with a mean intrahe-
patic triglyceride content of 8.9% (SD 5.3%) at follow-up. After
excluding 2 men with significant alcohol consumption, the pop-
ulation incidence of NAFLD at 3-5 years was 13.5% (95% CI
10.6-16.3%; 3.4% per year). Only 1 subject with incident
NAFLD had high liver stiffness by transient elastography (11.1
kPa) suggestive of advanced fibrosis. After adjusting for age,
gender, smoking and insulin resistance, metabolic syndrome
at baseline increased the risk of incident fatty liver by 4.56
fold (95% CI 2.34-8.90). The rs738409 GG variant in pata-
tin-like phospholipase 3 (PNPLA3) gene was present in 16.7%
of subjects with incident fatty liver and 9.9% of those without
(P=0.14) Among 394 subjects with body mass index (BMI)
<23.0 kg/m2 at follow-up, 33 (8.4%) developed fatty liver.
Lean subjects with incident fatty liver had higher BMI, waist cir-
cumference and hemoglobin A1c at follow-up than those with-
out. The alanine aminotransferase (ALT) level at follow-up was
abnormal (>30 IU/L in men and 19 IU/L in women) in 51.3%
of subjects with incident fatty liver and 30.6% of those without
(P<0.001). Conclusions: 13.5% of Hong Kong Chinese adults
develop NAFLD in 3-5 years. Metabolic syndrome is the most
important risk factor of NAFLD. Incident NAFLD is uncommon
in lean subjects and is usually due to central obesity. Alanine
aminotransferase is an unreliable test for incident NAFLD. [Sup-
ported by the General Research Fund from the Hong Kong SAR
Government (476512).]
Disclosures:
Vincent W. Wong - Advisory Committees or Review Panels: Abbvie, Gilead;
Consulting: Merck, NovaMedica; Speaking and Teaching: Gilead, Echosens
Grace LH Wong - Advisory Committees or Review Panels: Otsuka, Gilead;
Speaking and Teaching: Echosens, Furui, Gilead, Janssen, Bristol-Myers Squibb,
Otsuka
Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, MSD,
Bristol-Myers Squibb, Roche, Novartis Pharmaceutical; Speaking and Teaching:
Echosens, Abbvie
The following people have nothing to disclose: David K. Yeung, Winnie C. Chu
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
823
Prediction of 10-year clinical outcomes in NASH by
non-invasive fibrosis and steatosis tools, hepatic venous
pressure gradient (HVPG) and liver histology
Giada Sebastiani1, Marc Deschenes1, Rasha Alshaalan1, Maria
Rubino1, Philip Wong1, Peter Metrakos2, Maged Peter Ghali1;
1Medicine, McGill University Health Centre, Montreal, QC, Can-
ada; 2Section of Hepatobiliary and Transplant Surgery, McGill
University Health Centre, Montreal, QC, Canada
Background/aims: Non-invasive methods for liver fibrosis
diagnosis predict clinical outcomes in viral hepatitis and fatty
liver. No study has specifically targeted NASH. Methods: We
included patients who met the following criteria: transjugular
liver biopsy with measurement of HVPG; biopsy-proven diag-
nosis of NASH; absence of severe complications at entry;
non-invasive methods for hepatic fibrosis and steatosis (HVPG,
APRI, FIB-4, NAFLD fibrosis score, ultrasound, hepatic steatosis
index and Xenon-133 scan) available within 6 months from
liver biopsy; a minimum follow-up of 1 year. Clinical outcomes
were defined by death, liver transplantation, cirrhosis compli-
cations. Kaplan–Meier survival analysis and Cox regression
model were conducted. Performance for prediction of out-
comes was expressed as area under the curve (AUC). Results:
148 patients (69% male; mean age 50 years) were included
in 2003-2013. During a median follow-up of 5.3 (IQR, 3.2-
7.3) years, 16% developed cirrhosis complications, 4% died
or underwent liver transplantation. After adjustment for age,
sex, BMI, fibrosis stage, the following variables were associ-
ated with clinical outcomes: fibrosis stage (HR=2.27, 95% CI
1.21-4.25), HVPG (HR=1.31, 1.12-1.55), Fib-4 (HR=1.57,
1.05-2.34). Liver histology had the best performance to predict
outcomes (AUC=0.783), followed by HVPG (AUC=0.762).
Among non-invasive methods, Fib-4 had the best performance
(AUC=0.738), followed by NAFLD fibrosis score (AUC=0.706)
and APRI (AUC=0.706). Survival curves of progression to
outcomes by HVPG, Fib-4, NAFLD fibrosis score and APRI
category are shown in Figure 1A, 1B, 1C, 1D, respectively.
Neither histologic steatosis nor non-invasive steatosis methods
predicted outcomes. Conclusions: Non-invasive methods for
liver fibrosis predict 10-years outcomes of patients with NASH.
They may help early determination of prognosis and prompt
initiation of interventions.
Disclosures:
Giada Sebastiani - Advisory Committees or Review Panels: Boheringer Ingelheim,
Roche, Novartis; Grant/Research Support: ViiV, Vertex; Speaking and Teaching:
Merck, Gilead, Echosens
Marc Deschenes - Advisory Committees or Review Panels: Merk, gilead, vertex,
janssen, roche
Philip Wong - Advisory Committees or Review Panels: merck, roche, gilead;
Grant/Research Support: merck, roche, gilead, vertex
597A
Maged Peter Ghali - Consulting: Roche, Gilead
The following people have nothing to disclose: Rasha Alshaalan, Maria Rubino,
Peter Metrakos
824
Liver Fat and Insulin Resistance as Major Determinants
of Plasma Alanine Aminotransferase Levels in Nonalco-
holic Fatty Liver Disease
Maryann Maximos1,3, Fernando Bril2,3, Paola Portillo Sanchez2,3,
Romina Lomonaco2,3, Diane Biernacki2,3, Amitabh Suman6,
Michelle Weber7, Beverly Orsak4,5, Kenneth Cusi2,3; 1Pediatric
Gastroenterology, Hepatology, and Nutrition, University of Flor-
ida, Gainesville, FL; 2Endocrinology, Diabetes and Metabolism,
University of Florida, Gainesville, FL; 3Endocrinology, Diabetes,
and Metabolism, Malcom Randall VA Medical Center, Gainesville,
FL; 4Diabetes, University of Texas Health Science Center at San
Antonio, San Antonio, TX; 5Diabetes, Audie L. Murphy VA Medi-
cal Center, San Antonio, TX; 6Gastroenterology, Hepatology, and
Nutrition, Malcom Randall VA Medical Center, Gainesville, FL;
7Pathology, Malcom Randall VA Medical Center, Gainesville, FL
Plasma alanine aminotransferase (ALT) levels are usually used
to guide further evaluation in patients with nonalcoholic fatty
liver disease (NAFLD). However, the mechanisms behind these
elevations are not well understood. The aim of this study was
to assess the role of insulin resistance, liver fat, and liver his-
tology in elevations of ALT in overweight and obese patients
with NAFLD using state-of-the-art techniques. We enrolled 440
patients that were divided into three groups: no NAFLD (n=60),
NAFLD with normal ALT (n=165), and NAFLD with elevated
ALT (n=215). We measured: 1) liver fat by magnetic reso-
nance imaging and spectroscopy (1H-MRS); 2) severity of liver
disease by biopsy (n=293); 3) insulin sensitivity at the level of
the liver (suppression of hepatic glucose production [HGP]) by
a euglycemic hyperinsulinemic clamp with 3-3H-glucose; and
4) insulin sensitivity in the adipose tissue during the fasting state
(ATIRi: free fatty acids [FFA] x fasting plasma insulin). Regard-
less of plasma ALT levels, patients with NAFLD had a worse
metabolic profile than those without NAFLD. When patients
with NAFLD and normal vs. elevated ALT were compared, even
when well matched for BMI, those with elevated ALT showed
worse insulin resistance in the adipose tissue (ATIRi: 9.3±0.6
vs. 5.6±0.5 μU/ml • mmol/L, p<0.0001), lower adiponectin
levels (7.8±0.4 vs. 9.2±0.6 μg/mL, p<0.05), and more liver
fat (26.8±1.0% vs. 17.9±0.8%, p<0.0001). However, no dif-
ference was observed in hepatic insulin resistance measured as
suppression of HGP by low-dose insulin (-44±3% vs. -40±2%,
p=0.23). Similar results were found when only patients with
NASH and normal vs. elevated ALT were compared. Both insu-
lin resistance in the adipose tissue (5.3±0.4 vs. 10.8±0.7 μU/
ml • mmol/L, p<0.0001) and liver fat by 1H-MRS (29.0±1.1%
vs. 20.5±1.7%, p<0.0001) were worse in the group with ele-
vated ALT. Furthermore, liver biopsy demonstrated that those
with elevated ALT had a significant increase in steatosis grade
compared to those with normal ALT (2.2±0.1 vs. 1.6±0.1,
p<0.0001), which supports our findings with 1H-MRS. How-
ever, and most importantly, no differences were seen between
the two groups in the rest of the histological parameters (inflam-
mation [p=0.62], ballooning [p=0.13], and fibrosis [p=0.12]).
Conclusion: Insulin resistance and liver fat as measured by
1H-MRS are major driving mechanisms in the elevation of ALT
levels. Contrary to common belief, severity of liver histology in
patients with NASH showed no differences in inflammation,
ballooning, or fibrosis between patients with normal and ele-
vated ALT.
Disclosures:
598A AASLD ABSTRACTS
Beverly Orsak - Employment: UTHSCSA
Kenneth Cusi - Consulting: Merck, Daichi-Sankyo, Roche, Janssen; Grant/
Research Support: Takeda, Novartis, Mannkind
The following people have nothing to disclose: Maryann Maximos, Fernando
Bril, Paola Portillo Sanchez, Romina Lomonaco, Diane Biernacki, Amitabh
Suman, Michelle Weber
825
Plasma cytokeratin-18 in a healthy population: how
does it correlate with metabolic risk factors, alcohol
consumption, steatosis and elastography
Sofia Carvalhana1,2, Jorge Leitão3, Ana C. Alves4, Mafalda
Bourbon4, Helena Cortez-Pinto1,2; 1Gastroenterology, Hospital
de Santa Maria, CHLN, Lisboa, Portugal; 2Instituto de Medicina
Molecular, FML, Lisboa, Portugal; 3Internal medicine, CHUC,
Coimbra, Portugal; 4INSA, Lisboa, Portugal
Background: Serum cytokeratin-18 (CK-18) has been proposed
as a non-invasive alternative for the diagnosis of nonalcoholic
fatty liver disease (NAFLD), particularly non-alcoholic steato-
hepatitis (NASH). Little is known about the distribution and
correlation with metabolic factors, alcohol consumption and
elastography of CK-18 in a healthy population, unselected for
liver disease. Aims: evaluate the distribution of, and how met-
abolic risk factors, alcohol consumption, steatosis and elas-
tography correlates with serum levels of CK-18, in the general
population. Methods: Recruitment from a prospective epide-
miological study of the general Portuguese adult population.
CK-18 fragments were measured (M30 apoptosense, Peviva),
steatosis assessed by ultrasound and CAP (controlled attenua-
tion parameter) and elastography by fibroscan®. Results: 195
individuals studied (57.4% male), mean age and BMIs (body
mass index) were 51.3+/-17.3 years and 27.4+/-4.9 kg/m2,
respectively; 30% had a normal BMI, 45% were overweight
and 25% were obese. Prevalence of steatosis on ultrasound
was 42.1%. Mean (SD), median (minimum-maximum), and
5th and 95th percentile of CK-18 values were 81 (70.6), 63
(5-508), 15 and 230 U/L, respectively. Median CK-18 were
elevated in patients with steatosis vs. without steatosis and
in those with metabolic syndrome (MS) vs. without MS: 81
[IQR: 48–95] vs. 46 [IQR: 34–47] U/L (p <0.0001) and 76
[IQR: 60–118] vs. 56 [IQR: 45–58] U/L (p=0.004), respec-
tively. CK-18 significantly correlated with ALT (ρ=0.44), ste-
atosis (ρ=0.37), waist circumference (ρ=0.35), MS (ρ=0.31)
AST (ρ=0.30), CAP (ρ=0.28), LDL (ρ=0.25), BMI (ρ=0.25), tri-
glyceride (ρ=0.22), HDL (ρ=-0.21) and elastography (ρ=0.19),
but not with alcohol consumption. Conclusion: CK-18 levels in
the general population have a large variation, significantly
correlating with the presence of steatosis and metabolic risk
factors, although not influenced by alcohol consumption.
Disclosures:
Helena Cortez-Pinto - Advisory Committees or Review Panels: Norgine, Lund-
beck; Speaking and Teaching: Janssen, Gilead Janssen
The following people have nothing to disclose: Sofia Carvalhana, Jorge Leitão,
Ana C. Alves, Mafalda Bourbon
HEPATOLOGY, October, 2014
826
Serum autotaxin levels are independently associated
with hepatic steatosis in morbidly obese women
Vikrant Rachakonda1, Valerie L. Reeves2, Jules Aljammal2, James
P. DeLany2, Petra Kienesberger3, Erin E. Kershaw2; 1Division of
Gastroenterology, Hepatology, and Nutrition, University of Pitts-
burgh School of Medicine, Pittsburgh, PA; 2Division of Endocrinol-
ogy and Metabolism, University of Pittsburgh School of Medicine,
Pittsburgh, PA; 3Department of Biochemistry and Molecular Biol-
ogy, Dalhousie University, Halifax, NS, Canada
Background: Obesity and insulin resistance are strongly asso-
ciated with nonalcoholic fatty liver disease (NAFLD). Autotaxin
is an adipocyte-derived lysophospholipase D that generates
the signaling molecule lysophosphatidic acid (LPA). Although
adipose tissue expression of autotaxin has been linked to insu-
lin resistance in human and animal studies of obesity, the role
of autotaxin in NAFLD remains unclear. Aim: To determine
the relationship between serum autotaxin levels and NAFLD in
women with WHO Class II or Class III obesity. Methods: 102
nondiabetic women with median BMI of 42.9 (IQR 40.1 –
46.1) were included in the study. Demographic and anthropo-
metric features were recorded. Body composition was assessed
using either dual-energy X-ray absorptiometry or bioelectrical
impedance analysis. Serum aminotransferases and fasting lip-
ids were measured. Homeostatic model assessment of insulin
resistance (HOMA-IR) was determined from fasting glucose and
insulin levels. Hepatic fat was assessed by liver-spleen attenu-
ation ratio (L/S ratio) from unenhanced abdominal CT scans.
NAFLD was defined by L/S ratio < 1.1. Fasting serum levels of
CRP, adiponectin, leptin, IL-6 and autotaxin were determined
with ELISA. Linear regression was used to determine indepen-
dent predictors of NAFLD. Results: In this cohort of 102 obese
women, 37 (36.2%) had NAFLD; these subjects had higher
BMI, fat mass index (FMI), fat-free mass index (FFMI) and waist
circumference than those without NAFLD. Patients with NAFLD
had higher median HOMA-IR, VLDL, triglycerides and ALT
levels. Among measured adipokines, median levels of leptin
[63.00 (50.55-76.80) ng/ml vs. 53.60 (37.95-63.58) ng/
ml, p=0.019] and autotaxin [298.04 (266.72-379.46) ng/ml
vs. 279.04 (223.70-317.96) ng/ml, p=0.022] were higher
in subjects with NAFLD. Serum autotaxin was significantly cor-
related with systolic and diastolic blood pressure, fasting blood
glucose, serum insulin, HOMA-IR and alkaline phosphatase.
Multivariable linear regression analysis demonstrated that
race [β=-0.089 (95% C.I. -0.172−-0.005), p=0.038], FFMI
[β=-0.024 (-0.045−-0.002),p=0.033], serum triglycerides [β=-
0.001 (-0.001−-0.0001), p=0.026)], and log-transformed
autotaxin [β=-0.145 (-0.288−-0.002), p=0.048)] were inde-
pendently associated with L/S ratio. Conclusion: Serum auto-
taxin levels are significantly higher in obese women with
NAFLD compared to those without NAFLD, and autotaxin is
independently associated with hepatic steatosis in obese non-
diabetic females. These findings suggest a mechanistic link
between autotaxin and NAFLD. Future studies are planned to
elucidate interactions between autotaxin, LPA signaling, and
hepatic steatosis.
Disclosures:
The following people have nothing to disclose: Vikrant Rachakonda, Valerie L.
Reeves, Jules Aljammal, James P. DeLany, Petra Kienesberger, Erin E. Kershaw
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
827
Circulating Cholesteryl Ester Transfer Protein is Associ-
ated with Percentage of Collagen Deposition in Patients
with Nonalcoholic Fatty Liver Disease
Elzafir Elsheikh1,2, Zahra Younoszai2, Munkhzul Otgonsuren2,
Fanny Monge1, Lakshmi Alaparthi1, Brian P. Lam1, Sharon L.
Hunt1,2, Zachary D. Goodman1, Zobair Younossi1,2; 1Center for
Liver Diseases, Inova Fairfax Hospital, Falls Church, VA; 2Betty and
Guy Beatty Center for Integrated Research, Inova Health System,
Falls Church, VA
Background: Nonalcoholic Fatty Liver Disease (NAFLD) is a
potentially progressive liver disease associated with meta-
bolic syndrome and dyslipidemia. A comprehensive under-
standing of the mechanisms on how lipids and lipoprotein
metabolism may play a role in the pathogeness of NAFLD
remains unknown. Aim: To assess the relationship between
collagen depositions quantified by morphometry and lipopro-
tein homeostasis in well-characterized group of patients with
biopsy-proven NAFLD. Methods: The study cohort consisted of
consecutive patients with biopsy-proven NAFLD (n=104) and
controls (n=40). Sections of each biopsy were stained with
Sirius Red and used for measurement of the percentages of
collagen with morphometry. Concentrations of Lipoprotein (a),
Apolipoprotein (ApoE and ApoJ) and cholesteryl ester transfer
protein (CETP) (ng/ml) were determined in the serum collected
at the time of liver biopsy using ELISA technique. Results: Of
the NAFLD group, 56% had histologic NASH. There were no
statistically significant difference in the proportion of race/eth-
nicity, age and gender between subgroups, and also average
BMI (kg/m2) were similar for all groups (47 kg/m2). Lipopro-
tein (a) was higher in NAFLD group as compared to controls
when 75% percentile was used as cutoff point (29% vs. 12%,
P=0.05). Circulating serum CETP level was significantly asso-
ciated with the percentage of collagen deposition (r=0.29;
P=0.02). Histologically and clinically, CTEP also significantly
correlated with Mallory-Denk bodies (r=0.17; P=0.04), por-
tal fibrosis (r=0.17; P=0.05), and bridging fibrosis (r=0.20;
P=0.02), as well as the liver enzyme aspartate aminotransfer-
ase (AST) (r=0.23; P=0.01). Conclusions: CETP may be associ-
ated with development of fibrosis in NAFLD. It will be of interest
to measure the CETP activity, as a mechanistic generator of
collagen deposition in NAFLD.
Disclosures:
Brian P. Lam - Advisory Committees or Review Panels: BMS; Speaking and Teach-
ing: Gilead; Stock Shareholder: Gilead
Zachary D. Goodman - Consulting: Gilead Sciences, Abbvie; Grant/Research
Support: Gilead Sciences, Fibrogen, Galectin Therapeutics, Merck, Vertex, Syn-
ageva, Conatus
The following people have nothing to disclose: Elzafir Elsheikh, Zahra Younoszai,
Munkhzul Otgonsuren, Fanny Monge, Lakshmi Alaparthi, Sharon L. Hunt, Zobair
Younossi
599A
828
Body Fat Distribution and the Risk of Incident and
Remittent Nonalcoholic Fatty Liver Disease: Prospective
Cohort Study
Donghee Kim1, Goh Eun Chung1, Min-Sun Kwak1, Won Kim2,
Yoon Jun Kim3, Jung-Hwan Yoon3; 1Internal Medicine, Healthcare
Research Institute, Seoul national university hospital Gangnam
Healthcare center, Seoul, Republic of Korea; 2Internal Medicine,
Seoul Metropolitan Government Seoul National University Bora-
mae Medical Center, Seoul, Republic of Korea; 3Internal Medicine,
Liver Research Institute, eoul National University College of Medi-
cine, Seoul, Republic of Korea
Backgrounds: Body fat deposition (visceral adipose tissue
[VAT] vs. subcutaneous adipose tissue [SAT]) has been shown
to be associated with the nonalcoholic fatty liver disease
(NAFLD) in cross-sectional studies. The aim of this study was to
investigate the prospective association of body fat distribution
with incident and remittent NAFLD in a 5 year longitudinal
study in apparently healthy general population. Methods: We
performed a cohort study in 5,100 participants in 2007-2008.
Study participants were followed in health checkups between
2012 and 2013. NAFLD was diagnosed on the basis of typical
ultrasonographic findings. The VAT and SAT were evaluated
by computed tomography taken at the umbilicus level. Clinical
and laboratory metabolic parameters were reviewed. Results:
Out of 5,100 subjects who enrolled between 2007 and 2008,
we enrolled 3,718 subjects without known liver disease. The
final analysis involved 2,017 (54.2% of 3,718) participants
from the initial cohort who participate in a 5 year follow-up
health screening performed in 2011 and 2013. We observed
288 incident cases of NAFLD (20.9%, out of 1375) and 159
remittent cases of NAFLD (24.8%, out of 642) during 5 years
follow-up. In univariate analyses, the incident NAFLD was
significantly associated with male gender, body mass index,
high-density lipoprotein cholesterol, triglycerides, VAT, SAT,
HOMA-IR, and increased prevalence of hypertension, smok-
ing. Increasing VAT were associated with higher incidence of
NAFLD (highest quintile vs. lowest quintile of VAT were hazard
ratio (HR) 2.04 95% confidence interval (CI) (1.23-3.38, p for
trend = 0.001, P<0.001) in multivariable analysis. In the con-
trary, multivariable analysis adjusted for traditional risk factors
in a subgroup of NAFLD at baseline showed that the increased
SAT were significantly associated with the remittent NAFLD
(HR 1.28 per 1-SD, 95% CI 1.03-1.60, P=0.026), although
this association was no longer significant after adjusting for
change of waist circumference. CONCLUSIONS: In this pro-
spective study, higher VAT area was prospectively associated
with a higher risk of incident NAFLD in dose dependent man-
ner over the 5-year follow-up period. In the contrary, higher
SAT area was beneficially associated with remittent NAFLD in
prospective nature even adjusting known metabolic risk factors.
These data suggest that body fat deposition per se might be an
independent risk and preventive factor for NAFLD.
Disclosures:
The following people have nothing to disclose: Donghee Kim, Goh Eun Chung,
Min-Sun Kwak, Won Kim, Yoon Jun Kim, Jung-Hwan Yoon
600A AASLD ABSTRACTS
829
Dynamicity of Adiposity determine evolution of non-al-
coholic fatty liver even in lean subjects: a prospective
cohort study
Pankaj Singh, Kausik Das, Debashis Misra, Gautam Ray, Amal
Santra, Abhijit Chowdhury; Gastroenterology, School of Digestive
and Liver Disease, Institute of Post Graduate Medical Education &
Research, Kolkata, India
Objective: To evaluate the evolution of non-alcoholic fatty liver
(NAFL) in a cohort of lean subjects with and without NAFL.
METHODS: 5 year follow up (FU) data of a prospective com-
munity-based cohort (Baseline 2008; reassessment 2013-14)
is being presented. The cohort consisted of 267 lean subjects
(112 with sonographically defined NAFL and 155 subjects
without NAFL at baseline) defined as having BMI <23 Kg/
m2 and waist circumference (WC) <90 or <80 cm in men and
women, respectively. FU data was available in 137 (male 71;
NAFL 54, No NAFL 83 at baseline). Outcomes in terms of new
development and regression of NAFL were evaluated. RESULTS:
Baseline/FU profile is provided in Table. New-onset NAFL was
detected in 26 out of 83 subjects amounting to the incidence
of 31% in 5-year or 62.65 per 1000 person-years of FU. Dis-
appearance of NAFL was seen in 29 i.e. 53.7% over 5-year
period. New-onset NAFL (n=26): Significantly higher measures
at baseline and higher degree of increment of adiposity (BMI,
WC and skinfold thickness) was recorded in new-onset NAFL in
comparison to those with no NAFL at baseline. Appearance of
obesity (73% vs 19% in new-onset NAFL and no NAFL respec-
tively; p=0.001) along with new onset dyslipidemia (46% vs
19% in new-onset NAFL and no NAFL respectively; p=0.015)
were more frequent in them. 7 subjects acquired NAFL without
significant gain in adiposity. NAFLD regression (n=29): These
subjects had higher subcutaneous fat rather than BMI or WC
at baseline which became comparable to the subjects with-
out NAFL with significantly higher degree of decrease over 5
years. Conclusion: New-onset NAFL was detected in 31% lean
subjects over a 5 year period. Higher degree of adiposity at
baseline and higher degree of increase over time characterised
the subjects with new-onset NAFL. Decrease in subcutaneous
fat corroborated with regression of NAFL.
Baseline and follow up characteristics of study cohort
All values are in median (range). BMI Body Mass Index; WC
Waist circumference; SST Subscapular Skinfold Thickness.
Disclosures:
HEPATOLOGY, October, 2014
The following people have nothing to disclose: Pankaj Singh, Kausik Das,
Debashis Misra, Gautam Ray, Amal Santra, Abhijit Chowdhury
830
Lesser risk of advanced liver fibrosis in morbidly obese
patients
Fabio Nascimbeni1,2, Judith Aron-Wisnewsky3,5, Pierre Bedossa6,
Joan Tordjman3,4, Raluca Pais2,4, Thierry Poynard2,4, Karine Clé-
ment3,4, Vlad Ratziu2,4; 1Department of Biomedical, Metabolic
and Neural Sciences, University of Modena and Reggio Emilia,
Modena, Italy; 2Hepatogastroenterology, Hospital Pitie salpetri-
ere, Paris, France; 3Sorbonne Universités, UMR_S 1166-ICAN,
Nutriomics, 75006 Paris, Université Pierre et Marie-Curie,, Paris,
France; 4INSERM UMR_S 1166-ICAN, Nutriomics, Institute of Car-
diometabolism and Nutrition, ICAN, Paris, France; 5Heart and
Metabolism Division, Assistance Publique-Hôpitaux de Paris, Pitié-
Salpêtrière Hospital,, Paris, France; 6Pathology Department, Hos-
pital Pitie salpetriere, Clichy, France
Despite being morbidly obese with severe insulin resistance,
patients (pts) undergoing bariatric surgery seem to have milder
forms of NASH compared to modestly overweight/obese pts
seen in liver clinics where advanced fibrosis and cirrhosis are
not uncommon. Aim. To explore this discrepancy after adjust-
ment for steatosis grade, insulin resistance and glycemic sta-
tus. Methods. 625 morbidly obese pts undergoing bariatric
surgery (Bariatric-cohort:BC) and 369 non-morbidly obese pts
referred for NAFLD to a liver center (Hepato-cohort:HC), from
the same urban area were studied during the same period.
Other liver diseases were excluded. Liver biopsies were read
using the FLIP algorithm and the SAF score. Advanced fibrosis
(AF) was defined as bridging fibrosis or cirrhosis. BC and HC
were compared according to steatosis grade, glycemic status
and insulin resistance (IR). A case-control study with a 1:1 ran-
dom selection of age and sex-matched patients from the two
cohorts was performed. Results. Both AF and NASH were more
prevalent in the HC than in the BC (22%vs.7%,p<0.001 and
42%vs.35%,p=0.019, respectively). BC pts had more pre-dia-
betes/diabetes (58%vs.48%,p=0.002) and higher HOMA-IR
(7.3±22.9vs.4.2±3.9,p<0.001) than HC pts while the latter
were older (53±12vs.43±12 yrs,p<0.001), more frequently
male (64%vs.20%,p<0.001), with dyslipidemia and higher
ALT (67±40 vs. 35±27, p<0.001). 14% of HC and 21% of
BC had grade 0 steatosis (p<0.01) but grades 1 to 3 steatosis
were distributed similarly. The higher prevalence of AF in the
HC persisted after adjustment for steatosis grade, glycemic
status and HOMA-IR. After matching 230 HC and 230 BC
pts for age and sex, the difference in AF persisted (22% vs.
12%, respectively, p=0.003), even in the subgroup of patients
with pre-diabetes/diabetes (33% vs. 14%, p<0.001). The
association between HC (vs. BC) and AF was independent
of age, sex, BMI, metabolic factors, HOMA-IR and ALT with
an odds ratio of 3.36 (1.31-8.60) in the whole cohorts and
4.91 (1.50-16.39) in the age and sex-matched cohorts. In
contrast, the prevalence of NASH was similar in the matched
cohorts (45%) and HC was not independently associated with
the presence of NASH. Conclusion. Despite having a similar
age and sex-adjusted prevalence of NASH, morbidly obese
pts undergoing bariatric surgery have less severe fibrotic liver
disease than non-morbidly obese pts seen in hepatology units.
Differences in age, sex and metabolic profile do not account
for this higher fibrotic risk in hepatology pts. Future studies are
needed to understand the more severe liver damage in pts with
overweight/moderate obesity or the protective effect seen in
morbidly obese pts.
Disclosures:
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Thierry Poynard - Advisory Committees or Review Panels: MSD; Grant/Research
Support: BMS; Stock Shareholder: Biopredictive
Vlad Ratziu - Advisory Committees or Review Panels: GalMed, Abbott, Genfit,
Enterome, Gilead; Consulting: Astellas, Axcan, Pfizer, Sanofi-Synthelabo, Genen-
tech, Nycomed
The following people have nothing to disclose: Fabio Nascimbeni, Judith
Aron-Wisnewsky, Pierre Bedossa, Joan Tordjman, Raluca Pais, Karine Clément
831
Altered Fasting and Postprandial Serum Bile Acids in
Patients with Non-Alcoholic Steatohepatitis (NASH)
Brian C. Ferslew1,2, Curtis K. Johnston2, Eleftheria Tsakalozou2,
Mingming Su3, Guoxiang Xie3, Wei Jia3, Kim L. Brouwer2, Alfred
S. Barritt4; 1Drug Metabolism and Pharmacokinetics, Theravance
Biopharma, South San Francisco, CA; 2Pharmaceutical Sciences,
University of North Carolina at Chapel Hill, Chapel Hill, NC;
3Metabolomics Shared Resource, University of Hawaii Cancer
Center, Honolulu, HI; 4Medicine, University of North Carolina at
Chapel Hill, Chapel Hill, NC
Purpose: The incidence of NASH is rising and is highly asso-
ciated with metabolic syndrome and increased mortality. Tar-
geting of farnesoid X receptor (FXR) with bile acids (BA) or
FXR-selective derivatives is under investigation as treatment for
NASH, yet the baseline BA profile in NASH has not been
described. This study examined the baseline fasting and post-
prandial BA profile in NASH patients and healthy controls.
Methods: Patients with biopsy-confirmed NASH (n=7) and
age- and sex-matched healthy subjects (n=14) were admin-
istered a high fat breakfast after an overnight fast. Baseline
and serial postprandial serum samples were collected over
120min; 30 serum BA were quantified by UPLC-MS/MS. Data
are presented as mean ± SEM (* p<0.05 NASH vs. healthy).
Results: The fasting serum concentration of total un-, glycine-,
and taurine-conjugated BA was elevated in patients with NASH
compared to healthy controls (1108±371 vs 706±140nM,
1844±552 vs 679±102nM* and 584±315 vs 104±25nM,
respectively). Postprandial BA concentrations were increased
for all conjugation groups and timepoints resulting in signifi-
cantly higher area under the concentration-time (0-120 min)
curves in NASH patients vs healthy subjects (135±35 vs
74±16mM×min, 374±70 vs 187±16mM×min*, and 100±47
vs 30±6mM×min*, respectively; Fig. 1). Conclusion: This is
the first description of the BA profile in patients with NASH.
NASH patients had increased circulating concentrations of
endogenous glycine- and taurine-conjugated BA. These clini-
cal findings correspond with known changes in expression of
hepatic BA transporters and conjugation enzymes in NASH.
Further research should investigate the influence of the altered
BA profile on NASH therapy and disease progression.
601A
Fig. 1: Concentration-time profile of fasting and postprandial total
serum un-, glycine-, and taurine-conjugated bile acids in NASH
patients (triangles; n=7) and healthy subjects (circles; n=14);
mean ± SEM.
Disclosures:
Kim L. Brouwer - Board Membership: Qualyst Transporter Solutions, ASCPT;
Consulting: Takeda, Johnson & Johnson, Otsuka, AbbVie
Alfred S. Barritt - Grant/Research Support: Salix Pharmaceuticals; Speaking and
Teaching: Abbott Molecular
The following people have nothing to disclose: Brian C. Ferslew, Curtis K. John-
ston, Eleftheria Tsakalozou, Mingming Su, Guoxiang Xie, Wei Jia
832
HLA Class II Alleles Are Strongly Associated with
Non-alcoholic Fatty Liver Disease (NAFLD), Non-alco-
holic Steatohepatitis (NASH) and Fibrosis
Azza Karrar1, Zheng Li1, Ali M. Moosvi1, Siddharth Hariharan1,
Yun Fang1, Maria Stepanova1, Zachary D. Goodman2, Zobair
Younossi1,2; 1Betty and Guy Beatty Center for Integrated Research,
Inova Health System, Falls Church, VA; 2Center for Liver Disease,
Department of Medicine, Inova Fairfax Hospital, Falls Church, VA
Background and Aims: The potential association of human leu-
kocyte antigen (HLA) class II genes with NASH has not been
fully described. Our aim was to assess the association between
HLA class II Antigens polymorphism and NAFLD and NASH.
Methods: DNA from biopsy-proven NAFLD patients were gen-
otyped using (PCR-SSO) for HLA class II Antigens (HLA-DR1,
-DR3, -DP &-DQ). Liver biopsies were assessed for NASH
and Fibrosis. Multivariate analysis was performed to draw
correlations between HLA antigen frequencies and the differ-
ent variables; p-values ≤ 0.05 were considered to be signifi-
cant. Results: The study cohort included 140 subjects; 85 had
biopsy-proven NAFLD [NASH=35(41.2%); Pericellular Fibro-
sis=33(38.8%), Portal Fibrosis=53(62.4%); Bridging Fibrosis
and Cirrhosis= 13(15.3%)] and 55 controls without liver dis-
ease. DPB1*05[(n=6 (7.1%) vs. 0(0.0%), p=0.04] & DRB1*07
[(n=27(31.8%) vs. 10(18.2%), p=0.07] were found more fre-
quently in NAFLD than controls. On the other hand, DRB1*01
[(n=10(11.7 %) vs. 15(27.3%), p=0.01] and DPA1*01
[(n=67(78.8%) vs. 51(92.7%), p=0.02] were less frequently
found in NAFLD. Furthermore, DQA1*05[(n=16(45.7%) vs.
10(20.0%), p=0.01] & DRB3*01[(n=10(28.6%) vs. 6(12.0%),
p=0.05] were more frequently seen in NASH; while DQA1*01
was seen less frequently in NASH [(n= 10(28.6%) vs. Non
NASH 28(56.0%), p=0.01]. Finally, DPB1*03 [n=4(36.4%)
vs. 9(12.2%), p=0.03] and DRB1*04 [n=6(54.6%) vs.
17(22.9%), p=0.02] were seen more frequently in bridg-
ing fibrosis and cirrhosis, while DQA1*01 [n=10(30.3%)
602A AASLD ABSTRACTS
vs. 28(53.9%), p=0.03] and DPA1*01 [n=38(71.7%) vs.
29(90.6%), p=0.03] were seen less frequently in NAFLD
with fibrosis. In multivariate analysis, DRB1*07 was inde-
pendently associated with higher risk for NAFLD [Odds Ratio
(OR):3.2(1.1-9.8), p=0.04]. DPB1*03 was independently
associated with higher risk of bridging fibrosis and cirrhosis in
NAFLD [OR:6.5(1-43.7), p=0.056] and DQA1*01 was asso-
ciated with lower risk of hepatic fibrosis in NAFLD [OR:0.3(0.1-
0.9), p=0.02]. DQA1*05 [OR:4.6(1.4-15.4), p=0.01] was
independently associated with higher risk for NASH devel-
opment while DQA1*01 was independently associated with
lower risk for NASH development [OR:0.3(0.1-0.9), p=0.02].
Males were also at a higher risk than females for development
of NASH [OR:7.6(1.9-30.7), p=0.004]. Conclusion: In this
first study of HLA class II genetic susceptibility to NAFLD and
NASH in the US, HLA- DQA*05 was more common in NASH
patients while DQA*01 was more common among controls
and protective against fibrosis suggesting a disease suscepti-
bility association. HLA-class II DQ alleles play important role
in predisposing to NASH development among patients with
NALFD.
Disclosures:
Zachary D. Goodman - Consulting: Gilead Sciences, Abbvie; Grant/Research
Support: Gilead Sciences, Fibrogen, Galectin Therapeutics, Merck, Vertex, Syn-
ageva, Conatus
The following people have nothing to disclose: Azza Karrar, Zheng Li, Ali M.
Moosvi, Siddharth Hariharan, Yun Fang, Maria Stepanova, Zobair Younossi
833
Serum soluble CD163 is associated with steatohepatitis
and advanced fibrosis in non-alcoholic fatty liver dis-
ease
Eoin R. Feeney1,3, Jessica L. Mueller1, Kyle Malecki1, Lindsay Y.
King1,3, Joseph Misdraji2,3, Kathleen E. Corey1,3, Raymond T.
Chung1,3; 1Division of Hepatology, Massachusetts General Hos-
pital, Boston, MA; 2Division of Pathology, Massachusetts General
Hospital, Boston, MA; 3Harvard Medical School, Boston, MA
Purpose: Soluble CD163 (sCD163) is a marker of macrophage
and Kupffer cell activation and has been shown to correlate
with hepatic inflammation and fibrosis in hepatitis B virus
(HBV) and hepatitis C virus (HCV) infection. The relationship
between sCD163 and non-alcoholic fatty liver disease (NAFLD)
is unknown. Methods: Liver biopsies and serum samples were
obtained from subjects undergoing gastric bypass surgery.
All were HBV/HCV negative, and without a history of signifi-
cant alcohol use. Biopsies were scored for presence of fibro-
sis (modified Brunt stage, F0-F4), and NAFLD activity score
(NAS, 0-6). Non-alcoholic steatohepatitis (NASH) was defined
as NAS≥5. We selected subjects with a) no fibrosis/steato-
sis (F0, NAS=0), b) steatosis and no fibrosis (F=0, NAS<5),
c) NASH without advanced fibrosis, (NAS ≥ 5, F<3) or d)
advanced fibrosis (F ≥ 3, any NAS). Serum sCD163 was mea-
sured by ELISA. Between group differences were compared
with unpaired t-tests. Fibrosis score and NAS were correlated
with sCD163 using linear regression. Results: A total of 70
subjects were included (Table). Subjects were predominantly
female (84%) and white (64%). Mean (SD) BMI was 47(7) kg/
m2. Compared to controls, those with advanced fibrosis had
higher ALT and AST, and were more likely to be older, male,
white, and diabetic. There was no difference in BMI across
groups. sCD163 correlated with ALT(r=0.443), AST(r=0.556),
fibrosis score (r=0.410) and NAS(r=0.406) (P<0.001 for all
comparisons). The association between sCD163, fibrosis and
NAS scores remained significant after correction for age, gen-
der, race and diabetes. sCD163 was significantly higher in
subjects with advanced fibrosis compared to those with F<3
HEPATOLOGY, October, 2014
[1031(529) vs 683(324) ng/mL, P=0.006] and in those with
NAS≥5 compared with NAS<5 [878(416) vs 653(330) ng/
mL, P=0.015]. Conclusions In obese patients serum sCD163
strongly correlated with histologic scoring of both fibrosis and
NAFLD activity. These data underline the role of Kupffer cells
in steatohepatitis and fibrosis, and suggest sCD163 could be
useful as a biomarker in NAFLD.
Data mean (SD) unless stated.
Disclosures:
Jessica L. Mueller - Employment: NIDDK
Kathleen E. Corey - Advisory Committees or Review Panels: Gilead; Speaking
and Teaching: Synageva
Raymond T. Chung - Consulting: Abbvie; Grant/Research Support: Gilead, Mass
Biologics
The following people have nothing to disclose: Eoin R. Feeney, Kyle Malecki,
Lindsay Y. King, Joseph Misdraji
834
Serum levels of apoptosis inhibitor of macrophage (AIM)
are associated with hepatic fibrosis and insulin resis-
tance in patients with nonalcoholic fatty liver disease
Kohei Oda1, Hirofumi Uto1, Yoshio Sumida2,3, Takeshi Okanoue4,
Seiichi Mawatari1, Rie Ibusuki1, Hiroka Onishi1, Haruka Sakae1,
Kaori Ono1, Eriko Toyokura1, Akihiko Oshige1, Dai Imanaka1,
Tsutomu Tamai1, Akihiro Moriuchi5, Hirohito Tsubouchi5,6, Akio
Ido1,5; 1Digestive and Lifestyle Diseases, Department of Human and
Environmental Sciences, Kagoshima University Graduate School of
Medical and Dental Sciences, Kagoshima, Japan; 2Department of
Gastroenterology and Hepatology, Kyoto Prefectual University of
Medicine, Kyoto, Japan; 3Center for Digestive and Liver Diseases,
Nara City Hospital, Nara, Japan; 4Department of Gastroenter-
ology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan;
5Department of HGF Tissue Repair and Regenerative Medicine,
Kagoshima University Graduate School of Medical and Dental Sci-
ences, Kagoshima, Japan; 6Kagoshima City Hospital, Kagoshima,
Japan
Background and aims: Nonalcoholic fatty liver disease
(NAFLD) is a condition associated with metabolic syndrome
and insulin resistance. Since the prognosis of NAFLD depends
on the severity of hepatic fibrosis, prediction and prevention of
hepatic fibrosis is of critical importance. Apoptosis inhibitor of
macrophage (AIM) is a protein specifically produced by mac-
rophages that is reported to be involved in metabolic syndrome
and insulin resistance. The aim of this study was to elucidate
the role of AIM in NAFLD, including nonalcoholic steatohep-
atitis (NASH) and nonalcoholic fatty liver (NAFL). Methods:
Two hundred fifty seven patients with biopsy-proven NAFLD,
including 205 with NASH and 52 with NAFL, were analyzed
in this study. The association between serum AIM (sAIM) lev-
els and liver histology or blood biochemical test results was
investigated. sAIM levels were determined using the ELISA kit
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
manufactured by TransGenicInc. Insulin resistance was deter-
mined by homeostasis model assessment–insulin resistance
(HOMA-IR). Results: sAIM levels were significantly higher in
the NASH group compared to the NAFL group (NASH vs.
NAFL, 2623 vs. 1166 ng/mL; P<0.001). sAIM levels were
significantly correlated with markers of hepatic fibrosis such
as platelet count, hyaluronic acid, and type IV collagen 7S,
as well as hepatic fibrosis scores such as the FIB4 index and
NAFIC score which is composed of ferritin, fasting insulin and
type IV collagen 7S. sAIM levels were also significantly asso-
ciated with histopathological findings in the liver, including
the degree of hepatic fibrosis and Matteoni classification. Fur-
thermore, there were significant positive correlations between
sAIM levels and serum levels of cytokeratin (CK)-18 fragment
and HOMA-IR, respectively. In the multivariate analysis, high
sAIM was an independent factor associated with NASH and
insulin resistance (HOM-IR≥2.5), respectively, in patients with
NAFLD (odds ratio [OR], 14.31; 95% confidential interval [CI],
2.50–81.90; P<0.01 and OR, 2.56; 95% CI, 1.14–5.79;
P=0.02). In the receiver operating characteristic (ROC) anal-
ysis, the sAIM cut-off value of 2378 ng/mL was able to dis-
criminate between NASH and NAFL (area under ROC curve,
0.784) better than other serum markers such as CK-18 frag-
ment (0.563), hyaluronic acid (0.765), and type IV collagen
7S (0.777). Conclusions: sAIM is a potential biomarker for
hepatic fibrosis and insulin resistance in NAFLD. AIM produced
by macrophages may be involved in the pathophysiology of
NAFLD, and control of AIM levels may represent a novel thera-
peutic approach for NAFLD.
Disclosures:
Hirohito Tsubouchi - Grant/Research Support: MSD, Chugai Pharmaceutical, Kan
Research Institute, Daiichi-Sankyo, Eisai, Tanabe Mitsubishi
The following people have nothing to disclose: Kohei Oda, Hirofumi Uto, Yoshio
Sumida, Takeshi Okanoue, Seiichi Mawatari, Rie Ibusuki, Hiroka Onishi, Haruka
Sakae, Kaori Ono, Eriko Toyokura, Akihiko Oshige, Dai Imanaka, Tsutomu
Tamai, Akihiro Moriuchi, Akio Ido
835
Moderate-Vigorous Physical Activity (MVPA) Volume is
an Important Factor for Management of Non-Alcoholic
Fatty Liver Disease: A Retrospective Study
Sechang Oh1, Takashi Shida2, Rina So3, Takehiko Tsujimoto3,
Kiyoji Tanaka3, Junichi Shoda1; 1Faculty of Medicine, University
of Tsukuba, Tsukuba, Japan; 2Graduate School of Comprehensive
Human Sciences, University of Tsukuba, Tsukuba, Japan; 3Faculty
of Health and Sports Science, University of Tsukuba, Tsukuba,
Japan
Background: Recently, the beneficial effect of increased phys-
ical activity (PA) for obese subjects with non-alcoholic fatty
liver disease (NAFLD) has been reported. However, there is
an overall paucity of evidence about the benefits of PA for
NAFLD management. The optimal strength and volume of PA in
lifestyle modification that is required to improve NAFLD patho-
physiology and that should be recommended as appropriate
management of this condition are unclear. Objective: A retro-
spective analysis of a large sample of obese, middle-aged men
was conducted to determine the benefits of different varying PA
dose (intensity and volume) in lifestyle modification on improv-
ing the pathophysiology of NAFLD. Design: A total of 169
obese men with NAFLD were enrolled in a 3-month weight loss
program via lifestyle modification consisting of dietary restric-
tion plus aerobic exercise. Among the obese subjects, 82 per-
formed moderate to vigorous intensity physical activity (MVPA)
for <250 min/wk (mean: 160.3 ± 7.2) and 87 performed
MVPA for >250 min/wk (mean: 409.7 ± 14.5). The daily PA
volume was measured by a uniaxial accelerometer. Moreover,
603A
analyses of anthropometry, blood biochemistry, ultrasonogra-
phy, and leukocyte gene expression levels were done, and the
results were compared in terms of the MVPA volume. Results:
In the 3-month program, the increase in MVPA volume was
strongly associated with the improvement in pathological fac-
tors associated with NAFLD. The obese subjects in the MVPA
≥250 min/wk group showed significantly attenuated levels of
hepatic fat content (-31.0% vs. -21.7%), in comparison with
those in the MVPA <250 min/wk group. This attenuation was
likely independent of the detectable weight reduction. MVPA
for ≥250 min/wk led to a significant decrease in the abdom-
inal visceral fat area severity (-38.6% vs. -23.4%), levels of
ferritin (-11.8% vs. +0.1%), and lipid peroxidation (-15.6% vs.
-2.8%), and a significant increase in the adiponectin (+17.9%
vs. +4.6%) and HDL-C (4.0% vs. 9.6%) levels. In association
with these changes, the gene expression levels of sterol regu-
latory element-binding protein 1c and carnitine palmitoyltrans-
ferase I in leukocytes also significantly decreased (-5.6% vs.
+2.4%) and increased (+4.3% vs. -2.7%), respectively. How-
ever, the parameters in liver function test (AST; -19.1% vs.
-14.2%, ALT -34.4 vs. -30.9% and γGT-44.2% vs.-45.5%) did
not differ significantly between the groups. Conclusions: MVPA
for ≥250 min/wk induces a potent improvement in NAFLD
pathophysiology in obese men. It is likely that the benefits are
acquired through reducing inflammation and oxidative stress
levels and altering fatty acid metabolism.
Disclosures:
The following people have nothing to disclose: Sechang Oh, Takashi Shida, Rina
So, Takehiko Tsujimoto, Kiyoji Tanaka, Junichi Shoda
836
Performance of FibroMax (SteatoTest, ActiTest, Fibro-
Test) in patients with NAFLD for predicting liver lesions
(Steatosis, Activity and Fibrosis) assessed by SAF scor-
ing system and FLIP algorithm
Mona Munteanu1, Fabio Nascimbeni2, Pierre Bedossa3, Marion
Houot1, Frederic Charlotte2, Yen Ngo1, Raluca Pais2, Olivier Deck-
myn2, Vlad Ratziu2, Thierry Poynard2; 1Research, BioPredictive,
Paris, France; 2Groupe Hospitalier Pitié-Salpêtrière, APHP, Paris,
France; 3Hopital Beaujon, APHP, Paris, France
Background. FibroMax is a panel of blood tests assessing
the severity of fibrosis (FibroTest), steatosis (SteatoTest), and
necro-inflammatory activity (ActiTest and NashTest). In con-
trast with viral hepatitis (specific scoring system METAVIR,
extensive validations), blood tests have been less validated in
NAFLD patients (pts). Recently (Hepatology 2014), SAF score
(S=Steatosis; A=Activity; F=Fibrosis) and FLIP algorithm have
permitted to categorize liver lesions in NAFLD and to identify
histologically severe forms (HSF, as A≥3 and/or F≥3). The
aim was to validate FibroMax using SAF/FLIP in NAFLD pts.
Methods. Pts from 2 NAFLD cohorts (consecutive metabolic risk
factors’ pts, tertiary center, cohort 1) and multicenter NASH
therapeutic trial (cohort 2), were included if interpretable biop-
sies have been centrally and blindly reassessed with SAF/
FLIP algorithm, and contemporaneous FibroMax prospectively
assessed according to analytical recommendations, applicabil-
ity algorithms and previously validated cutoffs. For categorical
scores area under the AUC (AUROCs) were assessed with
Obuchowski measures (weighted AUROCs between all com-
binations of SAF scores preventing spectrum effect), were per-
formed per protocol (PP) and in intention to diagnose (ITD).
Results. 207 pts were included; 60% male, median age 54yr,
BMI 29, biopsy length 25mm; according to SAF/FLIP: 16(8%)
were classified as not-NAFLD (steatosis<5%), 64 (31%) as Ste-
atosis without NASH and 127 (61%) as NASH. Performances
604A AASLD ABSTRACTS
of blood tests were highly significant (Table; all P<0.001) for
predicting SAF scores and FLIP categories. Sensitivity analyses
performed in ITD, according to cohorts, gender and biopsy
specimens length gave similar results. Conclusion: Non inva-
sive blood tests such as SteatoTest, ActiTest and Fibrotest were
accurate for predicting steatosis, activity and fibrosis (histo-
logical SAF scores) in patients with NAFLD, with and without
NASH.
FibroMax blood tests performance for the diagnosis of SAF/FLIP
algorithm
Disclosures:
Mona Munteanu - Employment: Biopredictive
Marion Houot - Employment: BioPredictive
Yen Ngo - Employment: BioPredictive
Olivier Deckmyn - Management Position: BioPredictive; Stock Shareholder: Bio-
Predictive
Vlad Ratziu - Advisory Committees or Review Panels: GalMed, Abbott, Genfit,
Enterome, Gilead; Consulting: Astellas, Axcan, Pfizer, Sanofi-Synthelabo, Genen-
tech, Nycomed
Thierry Poynard - Advisory Committees or Review Panels: Merck; Grant/Research
Support: BMS, Gilead; Stock Shareholder: Biopredictive
The following people have nothing to disclose: Fabio Nascimbeni, Pierre
Bedossa, Frederic Charlotte, Raluca Pais
837
Adverse outcomes of pregnancy in mothers with NAFLD
and their offspring
Hannes Hagström1, Jonas F. Ludvigsson2,4, Anders Ekbom2, Rolf
W. Hultcrantz1, Olof Stephansson2, Knut Stokkeland3; 1Depart-
ment of Gastroenterology and Hepatology, Institution of Medicine,
Huddinge, Karolinska Institutet, Stockholm, Sweden; 2Department
of Medical Epidemiology and Biostatistics, Institution of Medicine,
Solna, Karolinska Institutet, Stockholm, Sweden; 3Department of
Medicine, Visby Hospital, Institution of Medicine, Solna, Karo-
linska Institutet, Visby, Sweden; 4Department of Pediatrics, Örebro
University Hospital, Örebro, Sweden
Introduction: Non-alcoholic fatty liver disease (NAFLD) is a fre-
quent clinical problem affecting the entire world, but little is
know about its potential association with pregnancy outcome.
We investigated pregnancy outcomes in mothers with NAFLD.
Methods: The Swedish national Medical Birth Register (MBR),
covering 97-99% of all births, was used to identify all births
between 1992 and 2011 (N=1 960 416). By linkage with the
National Patient Register we identified women with a diagnosis
of NAFLD prior to delivery. The MBR was then used to identify
gestational diabetes, preeclampsia, gestational hypertension,
Caesarean section, Apgar score <7 at five minutes, preterm
birth (<37 weeks), low birth weight (<2500 grams), children
born small for gestational age and congenital malformations.
Mothers without NAFLD were used as a control group. Logistic
regression was used to estimate relative risks (RR) adjusted
for maternal age, smoking status and body mass index (BMI)
at early pregnancy, parity and diabetes mellitus. Missing
data were uncommon and handled using multiple imputa-
tion. Results: We identified 110 mothers with NAFLD. 45%
of NAFLD mothers were obese (BMI >30), compared to 9%
of controls. The adjusted relative risks for mothers with NAFLD
were increased for gestational diabetes (aRR 2.72, 95%CI
1.23-6.02), preeclampsia (aRR 2.7, 95%CI 1.46-5.01), Cae-
HEPATOLOGY, October, 2014
sarean section (aRR 1.83, 95%CI 2.15-3.42), preterm birth
(aRR 3.33, 95%CI 1.87-5.92), low birth weight (aRR 2.61,
95%CI 1.32-5.17) and for congenital malformations (aRR
2.13, 95%CI 1.04-4.34). There were no increased risks for
Apgar score <7 at five minutes, small for gestational age birth
or gestational hypertension. Conclusions: Mothers with NAFLD
diagnosed prior to giving birth have increased risks for adverse
outcomes of pregnancy, and should be monitored with extra
care during pregnancy and labor.
Disclosures:
Anders Ekbom - Advisory Committees or Review Panels: Centocor, Scher-
ing-Plough, Centocor, Schering-Plough, Centocor, Schering-Plough, Centocor,
Schering-Plough; Speaking and Teaching: Astra Zeneca, Astra Zeneca, Astra
Zeneca, Astra Zeneca
The following people have nothing to disclose: Hannes Hagström, Jonas F. Lud-
vigsson, Rolf W. Hultcrantz, Olof Stephansson, Knut Stokkeland
838
Survey of Diagnostic and Treatment Patterns of NAFLD
and NASH in the United States: Real Life Practices Differ
From Published Guidelines
Zurabi Lominadze1, Stephen A. Harrison2, Michael Charlton3,
Rohit Loomba4, Brent A. Neuschwander-Tetri5, Stephen H. Cald-
well6, Kris V. Kowdley7, Mary E. Rinella8,1; 1Medicine, Northwest-
ern University, Chicago, IL; 2Gastroenterology and Hepatology,
Brooke Army Medical Center, San Antonio, TX; 3Liver disease and
liver transplant, Intermountain Medical Center, Murray, UT; 4Gas-
troenterology and Hepatology, University of California, San Diego,
CA; 5Gastroenterology and Hepatology, Saint Louis University,
Saint Louis, MO; 6Gastroenterology and Hepatology, University of
Virginia, Charlottesville, VA; 7Gastroenterology and Hepatology,
Virginia Mason Medical Center, Seattle, WA; 8Division of Gastro-
enterology and Hepatology, Northwestern University, Chicago, IL
Introduction: Management guidelines from the AASLD/ACG/
AGA published in 2012 for non-alcoholic fatty liver disease
(NAFLD) and steatohepatitis (NASH) recommend weight loss,
vitamin E, and pioglitazone as effective therapies for the treat-
ment of biopsy-confirmed NASH. However, little is known
about how physicians in the United States diagnose NASH or
whether published guidelines are being followed. Aim: The aim
of this study was to assess the current diagnostic and treatment
patterns for the management of NAFLD and NASH among aca-
demic Gastroenterologists and Hepatologists in the US. Using a
23-question survey, we compared providers with general Gas-
troenterology practices to those who specialize in Hepatology.
Finally, we compared diagnostic and treatment practices to
the published guidelines. Methods:This survey was developed
to collect information regarding respondents’ practice environ-
ments, diagnostic techniques, and medication usage. The Fish-
er’s exact test was used for comparisons between groups, with
a two-tailed p-value ≤0.05 considered significant. Results: 482
mostly academic Gastroenterologists and Hepatologists were
polled and 163 responded. Approximately half of providers
rely on elevated aminotransferases to perform liver biopsy.
98% recommend diet and exercise. Vitamin E and pioglita-
zone are prescribed for NASH by 70% and 14% of providers,
respectively. Hepatologists are more likely to prescribe vitamin
E than Gastroenterologists (76% vs 61%, p=0.04) but both
groups are equally unlikely to prescribe pioglitazone (14%).
Despite recommendations to the contrary, ≈25% prescribe
pioglitazone and vitamin E without biopsy confirmation. Met-
formin is used as frequently as pioglitazone despite its proven
lack of efficacy. In those (30% of all respondents) who did not
use Vitamin E, 70% felt the risk outweighed the benefit. We
found an adherence rate of 40-73% to published guidelines
for those questions with a clear recommendation. There was no
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
significant difference seen in adherence to guidelines between
gastroenterologists and hepatologists. Conclusion: Adherence
to practice guidelines could be improved. Although liver biopsy
remains the gold standard to diagnose NASH it is performed
routinely by less than 25% of respondents. This survey suggests
that NASH is under-diagnosed even in academic practices and
highlights the need to refine non-invasive tools. Therapeutically,
diet and exercise are almost universally recommended. Vitamin
E is the most commonly utilized drug for suspected NASH,
while insulin sensitizing therapy is relatively infrequently pre-
scribed to patients with NASH, possibly due to perceived com-
plexity or risks.
Disclosures:
Stephen A. Harrison - Advisory Committees or Review Panels: Merck, Nimbus
Discovery; Grant/Research Support: Merck, Genentech; Speaking and Teach-
ing: Merck, Vertex
Rohit Loomba - Consulting: Gilead Inc, Corgenix Inc, Janssen and Janssen Inc;
Grant/Research Support: Daiichi Sankyo Inc, AGA, Merck Inc
Brent A. Neuschwander-Tetri - Advisory Committees or Review Panels: Boehring-
er-Ingelheim
Stephen H. Caldwell - Advisory Committees or Review Panels: Vital Therapy;
Consulting: Wellstat diagnostics; Grant/Research Support: Genfit, Gilead Sci-
ences
Kris V. Kowdley - Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research
Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria,
Janssen, Merck, Mochida, Vertex
Mary E. Rinella - Advisory Committees or Review Panels: Gilead
The following people have nothing to disclose: Zurabi Lominadze, Michael Charl-
ton
839
The features and differences of GLP-1 analogues and
DPP-4 inhibitors as treatments for non-alcoholic fatty
liver disease patients with type 2 diabetes mellitus
Takamasa Ohki1, Isogawa Akihiro2, Koki Sato1, Nobuo Toda1;
1Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan; 2Dia-
betes and Metabolism, Mitsui Memorial Hospital, Tokyo, Japan
Background: We already reported that incretin based medi-
cine, such as GLP-1 analogues or DPP-4 inhibitors, leading to
improve not only glycaemic control but also liver inflammation
in non-alcoholic fatty liver disease (NAFLD) patients with type
2 diabetes mellitus (T2DM). However, the features and differ-
ences between GLP-1 analogues and DPP-4 inhibitors are not
well known. Aims: The aim of this study is to elucidate the fea-
tures and differences of each incretin based medicine in NAFLD
patients with T2DM compared to conventional treatments such
as diet therapy, exercise therapy, and other pharmacological
treatments including pioglitazone. Methods: We retrospec-
tively enrolled consecutive 209 Japanese NAFLD patients with
T2DM and divided these patients into three groups (GLP-1
group, DPP-4 group, and controls). We compared the base
line characteristics and the changes of laboratory data and
body weight among the three groups at the end of follow-up.
We also assessed the significant factors which contributed to
rapid normalization of serum ALT level using multivariate Cox
proportional hazard models. Results: There were 41 patients
treated with incretin based medicine (GLP-1 group), 88 patients
treated with DPP-4 inhibitors (DPP-4 group), and 80 patients
treated with conventional therapies (controls). At the end of fol-
low-up, serum ALT level, fast blood glucose level, and HbA1c
level significantly improved among the three groups. Although
the body weight significantly decreased in incretin based med-
icine group (83.3 kg to 78.9 kg, P < 0.01), the body weight
did not change in other two groups. The cumulative normaliza-
tion rates of serum ALT level significantly differed among the
three groups (P < 0.01); 20.9%, and 64.5% at 1 year, and 2
605A
years in GLP-1 group, 31.7%, and 46.8% in DPP-4 group, and
23.4%, and 30.5% in the controls, respectively. Multivariate
analysis indicated that administration of GLP-1 analogues (OR
0.61, P = 0.04), and age (per 1 year, OR 1.03, P = 0.01)
as independent factors which contributed to normalization of
serum ALT level. Conclusions: Use of incretin based medicines
led not only good control of T2DM but also reduction of body
weight, and rapid improvement of liver inflammation. Espe-
cially, GLP-1 analogues have synergic effect of T2DM control
and weight reduction which may lead to better outcome at the
time of 2 years after administration.
Disclosures:
The following people have nothing to disclose: Takamasa Ohki, Isogawa Akihiro,
Koki Sato, Nobuo Toda
840
Metabolic Stressors Associated with Progressive Non-
alcoholic Fatty liver Disease and Liver Transcriptional
Activity of Alanine and Aspartate Aminotransferases
Silvia Sookoian1, Gustavo O. Castaño3, Tomas Fernández
Gianotti2, Romina Scian2, Carlos J. Pirola2; 1Clinical and Molec-
ular Hepatology, IDIM-CONICET, Ciudad Autonoma de Buenos
Aires, Argentina; 2Molecular Genetics and Biology of Complex
Diseases, IDIM-CONICET, Ciudad Autonoma de Buenos Aires,
Argentina; 3Medicine and Surgery, Hospital Abel Zubizarreta,
Ciudad Autonoma de Buenos Aires, Argentina
Ballooning degeneration is not only a key feature required
for the diagnosis of NASH but is associated with progressive
NAFLD. We sought to characterize clinical and metabolic
predictors associated with hepatocellular ballooning in 256
NAFLD patients at different stages of disease severity. Explora-
tion of liver gene expression of glutamic-pyruvate (GPT1) and
glutamic-oxaloacetic (cytoplasmic GOT1 and mitochondrial
GOT2) aminotransferases was included to understand their cor-
relation with liver injury. Among explored metabolic stressors,
plasma glucose level was significantly associated not only with
ballooning but disease progression. Patients without ballooning
(101.8±23), absence of lobular inflammation (95±17) and
fibrosis scores 0-1 (103±31) had significantly lower glucose
levels (mg/dl) than patients with ballooning score 1-2 (122±43,
p<0.00002), lobular inflammation 1-3 (116±37, p<0.0001)
and fibrosis 2-3 (152±184, p<0.000001). Ballooning was
associated with high levels of cholesterol (p<0.02), plasma
triglycerides (p<0.01) and female sex (p<0.01) but still glu-
cose was an independent predictor (p<0.006). Patients with
lobular inflammation and fibrosis showed distinctive predictive
metabolic features such as HOMA and insulin levels; lobu-
lar inflammation was associated with systolic blood pressure
(p<0.05) and advance fibrosis was associated with abdomi-
nal obesity (p<0.02), sICAM-1 (p<0.04) and platelet TGFβ1-
mRNA levels (p<0.05). We further explored whether serum
ALT and AST activities were associated with liver changes in
the transcription of their corresponding coding genes. Notably,
serum levels of ALT and AST did not correlate with liver GPT1,
GOT1 and GOT2-mRNAs. Fatty liver was positively associated
with liver expression of GPT1-mRNA (R: 0.4, p<0.04) and
GOT1-mRNA (R: 0.46, p<0.01); the comparisons included
40 NAFLD patients and 10 patients with near normal liver
histology and elevated ALT/AST in serum. Liver GPT1, GOT1
and GOT2 mRNA levels were not associated with ballooning
or lobular inflammation. Conversely, liver GPT1-mRNA was
associated with advanced fibrosis (0.53±0.39) in comparison
with fibrosis 0-1 (0.22±0.30), p<0.02. Of note, there was a
4-fold higher liver expression of GOT2-mRNA in hypertensive
(0.08±0.05) vs. normotensive patients (0.02±0.02) p<0.03.
606A AASLD ABSTRACTS
Conclusions: Abnormal glycemic control is the major metabolic
determinant of progressive NAFLD. The severity of histologic
features is associated with serum enzymatic activity but not
liver transcriptional levels of GTP or GOT, except for fibrosis.
Liver expression of transaminases might be associated with
features of metabolic syndrome without necessarily involving
liver injury.
Disclosures:
Carlos J. Pirola - Grant/Research Support: Merck Sharp and Dohme
The following people have nothing to disclose: Silvia Sookoian, Gustavo O.
Castaño, Tomas Fernández Gianotti, Romina Scian
841
Irisin is associated with physical activity level and
hepatic steatosis grade in non-alcoholic fatty liver dis-
ease subjects
Rina So1,2, Sechang Oh3, Takashi Shida3, Kiyoji Tanaka1, Juni-
chi Shoda3; 1Health and Sport Sciences, University of Tsukuba,
Tsukuba, Japan; 2Research Fellow of the Japan Society for the
Promotion of Science, Tsukuba, Japan; 3Faculty of Medicine, Uni-
versity of Tsukuba, Tsukuba, Japan
Background: Non-alcoholic fatty liver disease (NAFLD) is the
most common chronic liver disease in people; it is strongly
associated with obesity. Recently, irisin, a myokine secreted
from exercised skeletal muscles, has been suggested as a prom-
ising target for managing NAFLD. Irisin activates thermogenic
programs, and it is associated with glucose homeostasis and
liver fat content. However, less evidence is available on its
associations with physical activity level and pathophysiological
parameters in NAFLD subjects. Objective: We measured irisin
levels to understand its secretory status in NAFLD subjects. We
then correlated these levels with data on anthropometry, blood
biochemistry, and ultrasonography to understand the associa-
tion with pathophysiological parameters. Moreover, the effects
of exercise training on the irisin secretory status and its asso-
ciated changes were studied in obese subjects with NAFLD.
Methods Irisin levels were measured by ELISA in 37 healthy
volunteers (age: 28 ± 10 years) and 274 NAFLD subjects (age:
52 ± 12 years). Anthropometric parameters, body composition
and blood biochemical indices, which included adipocytokine,
glucose, and lipid and hepatic profiles, were determined. We
divided the 274 NAFLD subjects into 4 groups according to
physical activity levels and body adiposity (divided by BMI
30) for cross-sectional study: inactive & non obese (IN, n =
99); inactive & obese (IO, n = 51); active & non obese (AN,
n = 85); and active & obese group (AO, n = 39). The 124
active subjects also completed an intervention study with a
12-week weight-loss program. Results Irisin levels were sig-
nificantly lower in NAFLD subjects than in healthy volunteers
(130 ± 41 vs. 335 ± 97; P<0.01). Also, irisin levels were
significantly higher in the active groups (AN; 197 ± 39 ng/ml,
AO; 204 ± 34 ng/ml) than in the inactive groups (IN; 62 ± 34
ng/ml, IO; 55 ± 29 ng/ml). The hepatic steatosis levels (AN
< IN < IO, AO) correlated with the irisin levels. In the weight-
loss program, subjects with increased irisin levels (n = 72) had
a greater reduction in fat mass, subcutaneous adipose area,
γ-GTP, leptin, and TNFα levels compared to subjects without
increased irisin levels (n = 42). Conclusion Irisin levels were
significantly lower in NAFLD subjects, especially for the inac-
tive group, and inversely correlated with the hepatic steatosis
grade. The increased irisin levels seen after the weight-loss
program were also associated with the attenuation of NAFLD
pathological factors. Collectively, irisin may be a novel mole-
cule important for NAFLD management.
Disclosures:
HEPATOLOGY, October, 2014
The following people have nothing to disclose: Rina So, Sechang Oh, Takashi
Shida, Kiyoji Tanaka, Junichi Shoda
842
Is liver stiffness measurement (LSM) by Fibroscan better
than FIB4 score for prediction of clinically significant
fibrosis in patients with NAFLD?
Raj Vuppalanchi, Samer Gawrieh, Regina Weber, Naga P. Cha-
lasani; Gastroenterology and Hepatology, Indiana University, Indi-
anapolis, IN
Introduction: Non-invasive assessment of liver fibrosis in
patients with non-alcoholic fatty liver disease (NAFLD) is very
desirable. Fibrosis 4 (FIB4) scoring system based on routine
laboratory tests is widely used to estimate the amount of liver
fibrosis in NAFLD and help identify patients that would require
further evaluation with a liver biopsy. Liver stiffness measure-
ment (LSM) using vibration controlled transient elastography by
Fibroscan is a novel non-invasive tool and currently available
in the United States for assessment of liver fibrosis in patients
with chronic liver disease. Aim: The aim of the current study is
to determine the diagnostic accuracy of FIB4 and LSM for pre-
diction of clinically significant fibrosis in patients with NAFLD
and also examine the relationship between FIB4 score and
LSM. Methods: Patients with biopsy proven NAFLD (duration
between liver biopsy and Fibroscan <1 year) or NASH related
cirrhosis were identified from an IRB approved prospective
database of patients undergoing Fibroscan. Clinically signifi-
cant fibrosis was defined as presence of clinically obvious cir-
rhosis or METAVIR Fibrosis stage of ≥ 2. Results: A total of 94
patients met study inclusion criteria from a total of 217 NAFLD
patients that underwent Fibroscan. The mean age of the study
cohort was 54 ± 10 years (60% woman; 94% Caucasian) with
a BMI of 31 ± 12 kg/m2. The mean ALT was 49 ± 36 U/L.
Clinically significant fibrosis was present in 70% (n=66) of the
study cohort. The diagnostic accuracy of LSM for clinically sig-
nificant fibrosis was good (AUROC=0.81) while the diagnostic
accuracy of FIB4 score was poor (AUROC=0.63) (Figure 1).
The optimal LSM cut-off value for a diagnosis of clinically signif-
icant fibrosis was 10.3 kPa with a sensitivity of 80% and spec-
ificity of 75%. The correlation between LSM and FIB score was
weak but significant (r=0.35, p-val=0.001). Conclusion: LSM
as measured by Fibroscan could be a useful tool for prediction
of clinically significant fibrosis and appears to be superior to
currently used FIB4 score.
AUROC curves for LSM and FIB4 for clinically significant fibrosis
in NAFLD
Disclosures:
Naga P. Chalasani - Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-
rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin
The following people have nothing to disclose: Raj Vuppalanchi, Samer Gaw-
rieh, Regina Weber
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
843
Endoscopic Duodenal–Jejunal Bypass Liner (Endobar-
rier) Improves Hepatic Parameters of Nonalcoholic Fatty
Liver Disease in Obese Uncontrolled type 2 Diabetes
Mellitus Patients
Oranit Cohen-Ezra1,5, Gabriella Segal-Lieberman2,5, Alon Lang3,5,
Maor Lahav3,5, Yeroham Kleinbaum4,5, Sima Katsherginsky4,
Keren Tsaraf1, Ziv Ben Ari1,5; 1Liver Disease Center, Sheba Med-
ical Center, Ramat Gan, Israel; 2Endocrine Institute, Sheba Medi-
cal Center, Ramat Gan, Israel; 3Gastroenterology Institute, Sheba
Medical Center, Ramat Gan, Israel; 4Radiology Department,
Sheba Medical Center, Ramat Gan, Israel; 5Sackler School of
Medicine, Tel Aviv University, Tel Aviv, Israel
Nonalcoholic fatty liver disease (NAFLD), the most common
cause of chronic liver disease in Western countries, may prog-
ress to cirrhosis, liver failure, and complicated hepatocellular
carcinoma. Recently, a nonsurgical bariatric technique, the
Endobarrier (GI Dynamics), an endoscopically-delivered device
that mimics gastric bypass surgery by shielding the duodenum
and upper jejunum from contact with chyme was reported to
lead to significant weight loss and to rapid improvement of
type 2 diabetes, both conditions are important risk factors for
NAFLD. We therefore investigated the effect of Endobarrier
treatment on hepatic parameters in obese uncontrolled type 2
diabetes mellitus patients with NAFLD. The Endobarrier device
was implanted for 12 months in the duodenum via an endo-
scopic procedure in 44 uncontrolled diabetic, obese, NAFLD
subjects (age 52.3±9.3y, 52.2% male, BMI 37.5±4.6 m2/kg).
BMI, waist circumference, serum liver enzyme levels, glucose,
HBA1c and lipid profile were performed as well as shear wave
elastography (SWE) (Aixplorer SuperSonic Imagine, France)
and Fibromax (FibroTest, ActiTest, SteatoTest, and NashT-
est) (BioPredictive, France) for the noninvasive evaluation of
hepatic injury before, 3 and 6 months during the implantation
of the Endobarrier device and when removing the device (12
months). At 3 and 6 months after implantation of the Endo-
barrier (interim results, n=29), the BMI, waist circumference,
serum liver enzyme levels, glucose, HBA1c and lipid profile
decreased significantly (from baseline and from 3 to 6 months).
The fibrosis stage (evaluated by SWE) and the: SteatoTest (fat
liver content), and NashTest (steatohepatitis score) (evaluated
by Fibromax) also improved significantly from baseline and
from 3 to 6 months. In 9 subjects (20.4%) the Endobarrier
was endoscopically explanted early. Conclusion: Endobarrier,
a minimally invasive bariatric technique, achieved significant
improvement in hepatic injury, fat liver content, steatohepatitis
score and fibrosis stage in advanced uncontrolled obese, dia-
betic, NAFLD patients. This device may be suitable for the treat-
ment of morbid obesity and its related comorbidities including
NAFLD.
Disclosures:
The following people have nothing to disclose: Oranit Cohen-Ezra, Gabriella
Segal-Lieberman, Alon Lang, Maor Lahav, Yeroham Kleinbaum, Sima Katshergin-
sky, Keren Tsaraf, Ziv Ben Ari
607A
844
Fetuin-A negatively correlates with liver and vascular
fibrosis in NAFLD subjects
Yoshihiro Kamada1,2, Motoya Sato1, Yuri Takeda1, Sachiho KIda1,
Yuka Ohara1, Hironobu Fujii1, Maaya Akita1, Kayo Mizutani1,
Yuichi Yoshida2, Makoto Yamada3, Hidetaka Hougaku4, Tetsuo
Takehara2, Eiji Miyoshi1; 1Department of Molecular Biochemistry
& Clinical Investigation, Osaka University, Graduate School of
Medicine, Suita, Japan; 2Department of Gastroenterology & Hepa-
tology, Osaka University, Graduate School of Medicine, Suita,
Japan; 3aMs New Otani Clinic, Osaka, Japan; 4Nara Institute of
Science and Technology, Ikoma, Japan
Background & Aims: Recent investigations demonstrated that
circulating secreted factors, such as adiponectin, leptin, tumor
necrosis factor-α (TNF-α), and fetuin-A significantly affect
pathophysiological progression in NAFLD. Fetuin-A (a2HS-gly-
coprotein) is a liver glycoprotein secreted into the circulation
at high concentrations. Fetuin-A is known as a transforming
growth factor (TGF)-β1 signaling inhibitor. Serum fetuin-A con-
centration is associated with nonalcoholic fatty liver disease
(NAFLD) and cardiovascular disease. However, the usefulness
of the serum fetuin-A level as a predictive fibrosis biomarker
in NAFLD patients is unclear. In this study, we investigated
the relationship between circulating fetuin-A levels and fibro-
sis related markers [platelet count, NAFLD fibrosis score, and
carotid intima media thickness (IMT)] in subjects with NAFLD.
We also investigated the effects of fetuin-A on hepatic stellate
cells (HSCs), which play a pivotal role in the progression of
hepatic fibrosis. Methods: A total of 294 subjects (male, 165;
female, 129) who received medical health check-ups, were
enrolled in this study. Written informed consent was obtained
from all subjects at the time of health check-up, and the study
was conducted in accordance with the Helsinki Declaration.
NAFLD was diagnosed using abdominal ultrasonography.
Serum fetuin-A was measured by ELISA. IMT was assessed
using a high-resolution ultrasound scanner. Using recombi-
nant human fetuin-A, we investigated the effects of fetuin-A on
HSCs. Results: Serum fetuin-A concentration was significantly
correlated with platelet count (R=0.19, P<0.01), NAFLD fibro-
sis score (R=-0.25, P<0.01), and mean IMT (R=-0.22, P<0.01).
Next, we analyzed the correlation between the serum fetuin-A
level and mean IMT in four groups segmented by mean IMT
value quartile (range of mean IMT; group 1: <0.7, group 2:
0.7–0.8, group 3: 0.8–1.0, group 4: ≥1 mm). Interestingly,
the serum fetuin-A level did not change in the three normal
groups, but significantly decreased only in the abnormal group
(mean IMT ≥1 mm). Multivariate analysis revealed that fetuin-A
concentration was a significant and independent determinant
of platelet count, NAFLD fibrosis score, and mean IMT. Recom-
binant fetuin-A suppressed TGF-β1 signaling and fibrosis-re-
lated gene expression and increased the expression of TGF-β1
pseudoreceptor bone morphogenic protein and activin mem-
brane-bound inhibitor (BAMBI). Conclusions: Serum fetuin-A
level is associated with liver/vessel fibrosis-related markers in
NAFLD patients. Circulating fetuin-A could be a useful serum
biomarker for predicting liver and vascular fibrosis progression
in NAFLD patients.
Disclosures:
Tetsuo Takehara - Grant/Research Support: Chugai Pharmaceutical Co., MSD
K.K.
The following people have nothing to disclose: Yoshihiro Kamada, Motoya Sato,
Yuri Takeda, Sachiho KIda, Yuka Ohara, Hironobu Fujii, Maaya Akita, Kayo
Mizutani, Yuichi Yoshida, Makoto Yamada, Hidetaka Hougaku, Eiji Miyoshi
608A AASLD ABSTRACTS
845
Clinical validation of the FLIP algorithm and the SAF
score in Non-Alcoholic Fatty Liver Disease
Fabio Nascimbeni1,2, Bedossa3,
Pierre Larysa Fedchuk2, Raluca
Pais2, Sven M. Francque4, Dominique G. Larrey5, Guruprasad P.
Aithal6, Lawrence Serfaty7, Mihai Voiculescu8, Pascal Lebray2,
Thierry Poynard2, Klaudia M. Traudtner9, Vlad Ratziu2; 1Depart-
ment of Biomedical, Metabolic and Neural Sciences, University
of Modena and Reggio Emilia, Modena, Italy; 2Department of
Hepatology and Gastroenterology, Pitié Salpêtrière Hospital, Uni-
versity Pierre et Marie Curie, INSERM UMR_S 938, Paris, France;
3Pathology Department, Beaujon Hospital, University Paris Diderot,
INSERM U773, Paris, France; 4Department of Gastroenterology
and Hepatology, Antwerp University Hospital, Faculty of Medi-
cine and Health Sciences, Antwerp University, Antwerp, Belgium;
5Department of Hepatogastroenterology and Transplantation,
Saint Eloi Hospital, INSERM1040-IRB, Montpellier, France; 6NIHR
Nottingham Digestive Diseases Biomedical Research Unit, Not-
tingham University Hospitals and University of Nottingham, Not-
tingham, United Kingdom; 7Saint Antoine Hospital, Paris, France;
8Institutul Fundeni, Bucharest, Romania; 9Astellas Pharma Europe
BV, Leiden, Netherlands
Background. The diagnosis and staging of NASH still relies on
liver histology. However, histological classifications of NAFLD
are based on morphology, thus empirical, with undetermined
clinical relevance and correlates. Aim. To investigate whether
different histological categories according to the FLIP algorithm
and the SAF score reflect distinct patient profiles and are pre-
dicted by relevant clinical/biological features. Methods. 140
liver biopsies of patients (pts) with suspected NAFLD based on
metabolic risk factors (cohort 1) and 78 liver biopsies from a
multicentric therapeutic trial of ASP9831 in NASH (cohort 2)
were reassessed with the FLIP algorithm (identifying NASH and
non-NASH, NAFL) and the SAF score (S=Steatosis; A=Activity;
F=Fibrosis; Hepatology 2012;56:1751, identifying histolog-
ically severe forms, HSF, as A≥3 and/or F≥3) by a single
liver pathologist, blinded to clinical data. Results. In cohort
1, 60 pts (43%) were diagnosed with NASH according to
the FLIP algorithm. They had more frequently central obesity,
diabetes and metabolic syndrome, higher BMI, waist circum-
ference, HOMA-IR and HbA1c than those diagnosed with
NAFL. They also had higher AST, ALT and GGT and lower
albumin and platelet count. NASH pts had more often bridging
fibrosis (48% vs. 1% in NAFL, p<0.001). Central obesity (OR
5.36;95%CI,1.09-26.43), HOMA-IR≥2 (6.24;1.66-23.38)
and ALT≥2ULN (3.46;1.50-7.94) independently predicted
the diagnosis of NASH by the FLIP algorithm. An HSF was
diagnosed by the SAF score in 47 pts (34%). Independent
predictors of HSF were: female sex (4.25;1.24-14.54), waist
circumference (1.05;1.01-1.09), HOMA-IR≥2 (6.22;1.17-
32.90), ALT≥2ULN (10.09;3.22-31.63) and platelet count
(0.98;0.97-0.99). Pooling cohort 1 and cohort 2 patients
(96% with NASH and 58% with HSF in cohort 2) confirmed
these results. Independent predictors of NASH by the FLIP algo-
rithm, in the pooled cohorts, were central obesity (3.94;1.34-
11.60), insulin resistance (HOMA-IR≥4 3.01;1.43-6.35) and
ALT≥2ULN (10.02; 4.48-22.43); independent predictors
of HSF by the SAF score were central obesity (5.51;1.10-
27.69), HOMA-IR≥4 (2.73;1.39-5.34), hypertriglyceridemia
(2.04;1.06-3.95), ALT≥2ULN (p<0.001; OR, 8.73; 95%CI,
3.50-21.80) and platelet count (p=0.003; OR, 0.99; 95%CI,
0.98-0.99). Conclusion. Pts diagnosed with NASH or HSF by
the FLIP algorithm and the SAF score have a distinct clinical
profile compatible with more advanced obesity-related insu-
lin resistance and biochemical liver injury than those with-
out NASH or with mild histological changes. These findings
HEPATOLOGY, October, 2014
demonstrate the clinical relevance of this new histological clas-
sification of NAFLD.
Disclosures:
Dominique G. Larrey - Board Membership: ROCHE GENE, MSD, TIBOTEC/
JANSSEN, ABBOTT, BOEHRINGER, BMS, GILEAD; Consulting: BAYER, SANOFI,
PFIZER, SERVIER-BIG, AEGERION, MMV, BIAL-QUINTILES, TEVA, ORION, NEG-
MA-LERADS, ASTELLAS; Grant/Research Support: Roche, Boehringer, BMS, GIL-
EAD; Independent Contractor: ABBOTT
Lawrence Serfaty - Board Membership: BMS, Gilead; Consulting: Merck; Speak-
ing and Teaching: Roche, Janssen, Merck, Janssen, BMS, Gilead
Pascal Lebray - Grant/Research Support: Merck, astellas; Speaking and Teach-
ing: Janssen, MSD, Gilead
Thierry Poynard - Advisory Committees or Review Panels: Merck; Speaking and
Teaching: BMS; Stock Shareholder: Biopredictive
Klaudia M. Traudtner - Employment: Astellas
Vlad Ratziu - Advisory Committees or Review Panels: GalMed, Abbott, Genfit,
Enterome, Gilead; Consulting: Astellas, Axcan, Pfizer, Sanofi-Synthelabo, Genen-
tech, Nycomed
The following people have nothing to disclose: Fabio Nascimbeni, Pierre
Bedossa, Larysa Fedchuk, Raluca Pais, Sven M. Francque, Guruprasad P. Aithal,
Mihai Voiculescu
846
Serum Vitamin D Deficiency is Associated with Nonalco-
holic Steatohepatitis in Adults
James E. Nelson1,4, Laura Wilson2, Christian Roth3, Matthew M.
Yeh5, Kris V. Kowdley4,1; 1Benaroya Research Institute, Seattle,
WA; 2Johns Hopkins Bloomberg School of Public Health, Balti-
more, MD; 3Seattle Childrens Research Institute, Seattle, WA;
4Liver Center of Excellence, Digestive Disease Institute Virginia
Mason Medical Center, Seattle, WA; 5Pathology, University of
Washington, Seattle, WA
Background: Recent studies have shown that vitamin D defi-
ciency (VDD) is associated with obesity and insulin resistance
and contributes to increased oxidative stress, systemic inflam-
mation and decreased adiponectin levels. Several studies
suggest VDD is prevalent among cases of suspected and biop-
sy-proven NAFLD in both children and adults. Aim: To deter-
mine the relationship of serum vitamin D levels to histologic
features of NAFLD, and associated demographic, clinical, and
laboratory data in the well characterized NASH CRN cohort.
Methods: Vitamin D 25(OH)D was quantified in serum by liquid
chromatography-tandem mass spectrometry in 193 adults (>18
yrs) with well characterized, biopsy-proven NAFLD. Vitamin D
Deficiency (VDD) was defined as <20ng/mL. Demographics,
socioeconomic, and comorbidities (Type 2 DM and metabolic
syndrome) were compared between the VDD and non-VDD
groups. Multivariable logistic regression analysis was used to
investigate the association of VDD and the presence of definite
nonalcoholic steatohepatitis (NASH) and individual features of
NAFLD including steatosis, lobular inflammation, portal inflam-
mation, ballooning degeneration and fibrosis, adjusting for
age, sex, race, BMI, ALT, and diabetes status. Results: VDD
was present in 55% of subjects and did not vary significantly
among different demographic or socioeconomic groups or with
the presence of comorbidities including diabetes type 2 and
metabolic syndrome. VDD subjects were more likely to have
definitive NASH compared to non-VDD subjects (65% vs 35%,
respectively, p=0.02). VDD was independently associated with
definitive NASH (OR= 3.64, 95%CI=1.80-7.33, p<0.001),
increased ballooning (OR= 2.49, CI=1.36-4.57, p=0.003)
and a higher lobular inflammation grade (OR= 1.90, CI=1.02-
3.51, p=0.042) after controlling for age, sex, diabetes, race,
BMI and ALT. VDD subjects were more likely to have fibro-
sis, but this failed to reach statistical significance (OR= 1.97,
CI=0.94-4.11, p=0.072). Conclusions: VDD is highly prev-
alent among U.S. patients with NAFLD and is independently
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
associated with a definitive diagnosis of NASH and increased
histological ballooning and inflammation scores. These data
support further study of the mechanism for VDD in the patho-
genesis of NASH and in dietary and/or lifestyle modifications
to increase vitamin D levels in patients with NAFLD.
Disclosures:
Kris V. Kowdley - Advisory Committees or Review Panels: AbbVie, Gilead, Merck,
Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research
Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria,
Janssen, Merck, Mochida, Vertex
The following people have nothing to disclose: James E. Nelson, Laura Wilson,
Christian Roth, Matthew M. Yeh
847
Hepatic copper and PNPLA3 in patients with non-alco-
holic fatty liver disease
Albert Stättermayer1, Stefan Traussnigg1, Elmar Aigner2, Chris-
tian Kienbacher1, Petra E. Steindl-Munda1, Christian Datz3, Fritz
Wrba4, Michael Trauner1, Peter Ferenci1; 1Gastroenterology &
Hepatology, Medical University of Vienna, Vienna, Austria; 2Inter-
nal Medicine I, Paracelsus Private Medical University, Salzburg,
Austria; 3Internal Medicine, Krankenhaus Oberndorf, Oberndorf,
Austria; 4Clinical Pathology, Medical University of Vienna, Vienna,
Austria
Background/aim: Non-alcoholic fatty liver disease (NAFLD) is
an increasing health burden in western countries. The pathoge-
netic mechanisms remain widely unclear. Besides insulin resis-
tance and dietary factors mutations of PNPLA3 (patatin-like
phospholipase domain-containing 3 gene) were identified.
Since preliminary data suggest that copper deficiency may
contribute to the development of NAFLD, the aim of this study
was to evaluate the association of hepatic copper content and
PNPLA3 with histological features in patients with NAFLD. Meth-
ods: One-hundred and eight NAFLD patients (m/f: 75/33,
mean age: 49.6±13.4y, mean BMI: 29.2±4.4kg/m^2), who
underwent liver biopsy for diagnostic work-up were included
(F0-2: 95 F3: 8 F4: 5). Steatosis was semiquantified as percent-
age of lipid droplets containing hepatocytes and was graded
as mild (5-33%), moderate (34-66%) or severe (>66%) accord-
ing to Brunt. NASH was defined by an activity score (NAS) ≥5.
Fibrosis was staged according to the METAVIR scoring system.
Hepatic copper content (in mg/g dry weight) was measured
by flame atomic absorption spectroscopy. SNP rs738409 in
PNPLA3 was investigated by real-time PCR. Results: Overall,
54.6% (n=59) of the patients had moderate/severe steatosis,
27.8% (n=30) had NASH and 12.0% (n=13) had advanced
fibrosis (F3/4). Hepatic copper content in NAFLD was 21±15
μg/g dry weight and was negatively correlated with steatosis
(ρ=-0.390, p<0.001). By multivariable logistic regression anal-
ysis moderate/severe steatosis was independently associated
with low hepatic copper content (OR: 0.292, CI95%: 0.889-
0.970, P=0.001), age (OR: 0.943, CI95%: 0.908-0.980,
P=0.002), BMI (OR: 1.139 CI95%: 1.017-1.276, P=0.024),
and PNPLA3 (OR: 2.165, CI95%: 1.156-4.055, P=0.016).
Advanced fibrosis was associated with age (OR: 1.116,
CI95%: 1.033-1.205, P=0.005) and NASH (OR: 20.099,
CI95%: 4.093-98.703, p<0.001). Conclusion: Moderate/
severe steatosis is independently associated with lower hepatic
copper content in NAFLD patients and copper deficiency might
contribute to the development of steatosis. Thus, copper substi-
tution might be a new therapeutic approach in NAFLD.
Disclosures:
Michael Trauner - Advisory Committees or Review Panels: MSD, Janssen, Gilead,
Abbvie; Consulting: Phenex; Grant/Research Support: Intercept, Falk Pharma,
Albireo; Patent Held/Filed: Med Uni Graz (norUDCA); Speaking and Teaching:
Falk Foundation, Roche, Gilead
609A
Peter Ferenci - Advisory Committees or Review Panels: Roche, Idenix, MSD, Jans-
sen, AbbVie, BMS, Tibotec, Böhringer Ingelheim; Patent Held/Filed: Madaus
Rottapharm; Speaking and Teaching: Roche, Gilead, Roche, Gilead, Salix
The following people have nothing to disclose: Albert Stättermayer, Stefan Trauss-
nigg, Elmar Aigner, Christian Kienbacher, Petra E. Steindl-Munda, Christian
Datz, Fritz Wrba
848
Impact of Liver Histology on Hepatic Elastography in
Non-alcoholic Fatty Liver Disease
Ranesh Palan1, William W. Kemp2, Bastiaan DeBoer3, Jeffrey M.
Hamdorf4, Michael J. House5, Gerry C. MacQuillan1,6, George
Garas6, Helena Ching1,6, Ross Mac Nicholas6, Stuart K. Roberts2,
Matthew T. Kitson2, Gary P. Jeffrey1,6, Leon Adams1,6; 1School
of Medicine and Pharmacology, The University of Western Aus-
tralia, Perth, WA, Australia; 2Department of Gastroenterology,
The Alfred, Melbourne, VIC, Australia; 3Department of Anatomical
Pathology, PathWest, Perth, WA, Australia; 4School of Surgery,
The University of Western Australia, Perth, WA, Australia; 5School
of Physics, The University of Western Australia, Perth, WA, Austra-
lia; 6Department of Gastroenterology and Hepatology, Sir Charles
Gairdner Hospital, Perth, WA, Australia
Liver fibrosis is the main determinant of prognosis and need for
targeted therapy in patients with non-alcoholic fatty liver dis-
ease (NAFLD). Assessment of liver fibrosis by transient elastog-
raphy (Fibroscan®) has advantages over liver biopsy, however
it is unclear whether the degree of hepatic steatosis, inflamma-
tion or other factors also influence liver stiffness measurements.
Methods: We performed a retrospective analysis of subjects
with NAFLD who underwent liver biopsy and a valid Fibros-
can assessment at two tertiary hospitals. Biopsies were scored
according to the NAFLD Clinical Research Network staging sys-
tem by one histopathologist. Hepatic steatosis was quantified
using computer generated image morphometry. The impact of
histological, clinical and biochemical variables on liver stiffness
were assessed using linear regression and receiver operator
characteristic (ROC) curve analysis. Results: 102 adults, [41%
male, 47% with diabetes, mean (SD) age of 51 (12) years]
were reviewed. The prevalence of significant fibrosis (F2-4),
advanced fibrosis (F3,4) and cirrhosis was 28%, 18% and 5%
respectively. The median (inter-quartile range) stiffness measure-
ment for the cohort was 10.7 (7.1-14.1) kPa. The area under
the ROC curve for predicting significant fibrosis, advanced
fibrosis and cirrhosis using Fibroscan was 0.801, 0.855 and
0.977 respectively. Hepatic steatosis quantified by image mor-
phometry was highly correlated with steatosis grade scored by
the histopathologist (Spearman r=0.74, p<0.001). Similarly,
liver stiffness was highly correlated with histopathologist scored
fibrosis stage (Spearman r=0.55, p<0.001). Hepatic steatosis
determined by liver pathologist grade or image morphome-
try, was not significantly associated with liver stiffness (beta=
-0.09, p=0.4 and beta=-0.68, p=0.5, respectively). Liver stiff-
ness was positively associated with serum ALT (p=0.057), lobu-
lar inflammation (p=0.002), hepatocyte ballooning (p=0.003)
and the NAFLD Activity Score (p=0.02), but these all became
non-significant after adjusting for fibrosis. Notably, among the
74 individuals with no/minimal fibrosis (F0/1), liver stiffness
was higher in the presence of NASH (n=23) versus those with-
out NASH (n=51) [10.2 (8.6-14.8) kPa vs. 8.6 (5.8-11.7) kPa,
p=0.04]. Furthermore, in subjects with no/minimal fibrosis on
histology, “cirrhosis” defined by Fibroscan (cut-off 16.0 kPa)
was present in 9/74 individuals and tended to be more com-
mon in subjects with NASH (22% vs. 8%, p=0.1). Conclusion:
NASH but not steatosis or ALT may confound liver stiffness
interpretation in subjects with NAFLD and cause a false positive
diagnosis of cirrhosis.
610A AASLD ABSTRACTS
Disclosures:
Michael J. House - Consulting: Resonance Health; Patent Held/Filed: Resonance
Health
Stuart K. Roberts - Board Membership: Jannsen, Roche, Gilead, BMS
Matthew T. Kitson - Consulting: MSD, Roche; Grant/Research Support: MSD;
Speaking and Teaching: Janssen-Cilag
Gary P. Jeffrey - Advisory Committees or Review Panels: MSD, Novartis
The following people have nothing to disclose: Ranesh Palan, William W. Kemp,
Bastiaan DeBoer, Jeffrey M. Hamdorf, Gerry C. MacQuillan, George Garas,
Helena Ching, Ross Mac Nicholas, Leon Adams
849
The association of soluble lectin-like oxidized LDL recep-
tor 1 (sLOX-1) level with histological severity in NAFLD
patients
Hiroshi Ishiba1, Yoshio Sumida1, Saiyu Tanaka2, Kazuyuki Kane-
masa2, Yuya Seko1, Akira Okajima1, Tasuku Hara1, Hiroyoshi
Taketani1, Kanji Yamaguchi1, Michihisa Moriguchi1, Hironori
Mitsuyoshi1, Kohichiroh Yasui1, Yoshito Itoh1, Masahito Minami1;
1Gastroenterology and Hepatology, Kyoto prefectural university of
medicine, Kyoto, Japan; 2Center for Digestive and Liver Diseases,
Nara City Hospital, Nara, Japan
Background: Nonalcoholic fatty liver disease (NAFLD) is a
broad spectrum of disease entity ranging from nonalcoholic
fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH)
and NASH-related cirrhosis. Patients with NAFLD, especially
NASH, are at risk for cardiovascular disease (CVD). Lectin-like
oxidized LDL receptor-1 (LOX-1), which was identified as an
endothelial cell surface major receptor for oxidative modifica-
tion of LDL cholesterol, has been shown to relate with CVD dis-
ease, diabetes and metabolic syndrome. The aim of this study
is to determine whether soluble LOX-1 (sLOX-1) level, a novel
marker for atherosclerosis, related to the severity of NAFLD
histology. Method: The level of plasma sLOX-1 was determined
in 93 Japanese patients with biopsy-proven NAFLD. We eval-
uated relationships of plasma sLOX-1 to physical and clinical
laboratory data, and liver histological evaluations, such as
NAFLD activity sore (NAS) (steatosis, inflammation, and bal-
looning), and fibrosis. The diagnosis of NASH was based on
Matteoni’s classification. Results: Seventeen patients were his-
tologically classified into NASH (53 had stage 0-2 fibrosis
and 17 had stage 3-4), and 23 patients were classified into
NAFL. There were not any statistical differences in sLOX-1 lev-
els between the two groups. The plasma level of sLOX-1 was
positively correlated with hyaluronic acid (r=0.248, p=0.021),
typeIV collagen 7s (r=0.255, p=0.014), and histological fibro-
sis stage (r=0.225, p=0.03), but not with NAS. The area
under the receiver operating characteristic curve for sLOX-1
in separating patients with (stage 3-4) and without severe
fibrosis (stage 0-2) was 0.625 with an optimal cutoff point of
140ng/l. The prevalence of patients with sLOX-1 more than
140ng/l were significantly higher in those with severe fibrosis
(82.4%) than those without severe fibrosis (47.4%, p=0.003).
In multiple regressions, the association between higher sLOX-1
(>140ng/l) and NASH severe fibrosis persisted after adjusting
for age, gender, body mass index, and insulin resistance. Con-
clusion: Circulating plasma sLOX-1 level was an independent
factor for predicting severe fibrosis in NAFLD patients. The
association of sLOX-1 and severe fibrosis suggests a possible
link between atherosclerosis and hepatic fibrosis in NAFLD.
LOX-1 may be a novel, exciting target for drug therapies in
NAFLD patients.
Disclosures:
HEPATOLOGY, October, 2014
Kohichiroh Yasui - Grant/Research Support: AstraZeneca K.K., CHUGAI Phar-
maceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Eisai Co., Ltd.,
FUJIFILM Medical Co., Ltd., Merck Serono, MSD K.K., Otsuka Pharmaceutical
Co., Ltd.
Yoshito Itoh - Grant/Research Support: MSD KK, Bristol-Meyers Squibb, Dain-
ippon Sumitomo Pharm. Co., Ltd., Otsuka Pharmaceutical Co., Chugai Pharm
Co., Ltd, Mitsubish iTanabe Pharm. Co.,Ltd., Daiichi Sankyo Pharm. Co.,Ltd.,
Takeda Pharm. Co.,Ltd., AstraZeneca K.K.:, Eisai Co.,Pharm.Ltd, FUJIFILM Med-
ical Co.,Ltd.
The following people have nothing to disclose: Hiroshi Ishiba, Yoshio Sumida,
Saiyu Tanaka, Kazuyuki Kanemasa, Yuya Seko, Akira Okajima, Tasuku Hara,
Hiroyoshi Taketani, Kanji Yamaguchi, Michihisa Moriguchi, Hironori Mitsuyoshi,
Masahito Minami
850
Combination of Geniposide and Chlorogenic Acid May
Reverse NASH Pathogenesis by Improving Gut Barrier
Function
Qin Feng2,1, Susan S. Baker1, Wensheng Liu1, Ricardo A. Arbizu1,
Ghanim Aljomah1, Maan Khatib1, Colleen A. Nugent1, Robert
D. Baker1, Yiyang Hu2, Lixin Zhu1; 1Pediatrics, University of Buf-
falo, Buffalo, NY; 2Institute of Liver Diseases, Shuguang Hospital
Affiliated to Shanghai University of Traditional Chinese Medicine,
Shanghai, China
Background & Aims: Nonalcoholic steatohepatitis (NASH), the
potentially progressive form of nonalcoholic fatty liver disease
(NAFLD) can lead to fibrosis and cirrhosis. Current treatment
is limited to weight loss, exercise and the control of metabolic
risk factors. More effective pharmacotherapies are necessary.
NASH is associated with increased gut permeability, which
leads to enhanced hepatic exposure to gut microbial products
including endotoxin. Geniposide and chlorogenic acid (GC)
are effective ingredients of Gardenia jasminoides and Herba
Artemisiae capillaris, respectively. Previous studies indicated
that the GC treatment could alleviate experimental NASH in
rats induced by high fat diet. Recently, we established a rat
NASH model of high fat diet in addition to dextran sulfate
sodium (DSS) treatment, which features increased gut per-
meability. With this NASH model, we aimed to evaluate the
effects of GC treatment and the underlying mechanisms. Meth-
ods: Sixteen male SD rats were given high fat diet and DSS
(1% in drinking water) for 26 weeks. The rats were randomly
divided into GC treatment group (n=8) and control (water
treatment) group (n=8). The medicine or distilled water was
administered by gavage from the 23rd week to the end of
the 26th week, when portal blood, peripheral blood, liver,
and intestines were collected. Liver triglyceride (TG) content,
serum fasting glucose and insulin, serum alanine aminotrans-
ferase (ALT), and serum LPS were determined. Liver and colon
pathologies were evaluated by hematoxylin-eosin (H&E) and
Oil red O staining of the cryosections. The mRNA expres-
sion of liver tumor necrosis factor-α (TNF-α) was examined
by quantitative real-time PCR. Results: Liver TG content (GC/
Control =166.7±6.1 /222.7±21.0mg/dl, p =0.0361), serum
ALT (GC/Control 36.4±2.8/52.1±5.7U, p =0.0226), portal
serum LPS level (GC/Control =0.11±0.01/0.17±0.02 EU/ml,
p =0.0135) and liver TNF-α mRNA expression (GC/Control
=1.62±0.39/2.48±0.38, p =0.046) were lower in the GC
treatment group compared with those of the control group. GC
treated animals exhibited improved liver pathologies for both
steatosis (Oil red O staining) and inflammation (H&E stain-
ing). Importantly, H&E staining indicated that GC treatment
suppressed colon inflammation. Conclusion: Suppressed colon
inflammation and decreased serum LPS in the GC treatment
group suggested that the GC therapy has a beneficial effect on
gut barrier function. This may contributeto the therapeutic effect
GC has on liver steatosis and inflammation. A time course study
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
is needed to confirm a causal relationship between improved
gut barrier and the improved liver health.
Disclosures:
The following people have nothing to disclose: Qin Feng, Susan S. Baker,
Wensheng Liu, Ricardo A. Arbizu, Ghanim Aljomah, Maan Khatib, Colleen A.
Nugent, Robert D. Baker, Yiyang Hu, Lixin Zhu
851
The serum levels of SDF-1α correlated with the fibrosis
and suggested the appearance of hepatic progenitor
cells in the advanced stage of NASH
Wataru Ando1, Hiroaki Yokomori2, Yutaka Inagaki3, Isao Oka-
zaki4,5, Yutaka Suzuki6, Tsutsui Nobuhiro6, Eigoro Yamanouchi7,
Hiroki Tanabe5, Hajime Kuroda7,8, Soichi Kojima9, Mitsuko Hara9,
Masaya Oda10, Takako Komiyama1; 1Clinical Pharmacy, Kitasato
University, Tokyo, Japan; 2General Internal Medicine, Kitasato
University Medical Center, Saitama, Japan; 3Regenerative Medi-
cine, Tokai University, Isehara, Japan; 4Internal Medicine, Sanno
Hospital, International University of Health and Welfare (IUHW),
Tokyo, Japan; 5Internal Medicine, IUHW Hospital, Tochigi, Japan;
6Surgery, IUHW Hospital, Tochigi, Japan; 7Radiology, IUHW
Hospital, Tochigi, Japan; 8Pathology, IUHW Hospital, Tochigi,
Japan; 9Micro-Signaling Regulation Technology Unit, RIKEN CLST,
Saitama, Japan; 10Internal Medicine, Sanno Medical Center,
IUHW, Tokyo, Japan
Background and Aim: Non-alcoholic steatohepatitis (NASH) is
emerging worldwide and progresses to cirrhosis with/without
hepatocellular carcinoma. Any useful marker to differentiate
NASH from non-alcoholic fatty liver disease is not available,
and the diagnosis of NASH needs liver biopsy besides radio-
logical findings. Our hypothesis is that the NASH patients
may have the higher serum levels of cytokines affecting the
advanced fibrosis and/or the appearance of hepatic progeni-
tor cells (HPC) which has been known as one of characteristics
in the advanced stage of NASH. Methods: Twenty-five NASH
patients confirmed histologically, and 14 healthy controls were
enrolled in this study with patients’ consent approved by ethi-
cal committees. The serum levels of stem cell factor 1 (SCF-1),
stem cell growth factor β (SCGF-β), stromal cell-derived factor
1α (SDF-1α), MCP-1, G-CSF, IL-6, IL-10, leptin, and ghrelin
measured by fluorescent beads-based immunoassay, were
compared with NASH activity (NAS), the grade of fibrosis by
Brunt’s classification and the appearance of HPC. Besides con-
ventional histological observation, immunohistochemistry (IHC)
and electron microscopy (EM) were conducted. The following
cell markers were used; CD68 for Kupffer cell, CD34 for endo-
thelial cells, vimentine and α-SMA for stellate cells, and CK19
/OV-6 for HPC. Results: Any laboratory data (AST, ALT, γGT,
total cholesterol (TC), HDL-C, LDL-C, triglyceride, and HbA1c)
were not correlated with NAS activity, and the grading of fibro-
sis. Among the serum levels of 9 cytokines, SDF-1α, SCGF-β,
MCP-1, G-CSF and leptin was significantly higher than that
in controls. Especially SDF-1α was 256.8 ± 190.1 pg/ml vs.
95.3 ± 73.2 (p = 0.001); SCGF-β 18,600 ± 12,764 pg/ml
vs. 11,987 ± 6,967 (p = 0.001). The correlation between
the SDF-1α, SCGF-β and MCP-1, and NAS activity were sig-
nificantly observed r = 0.340 (p = 0.034), r = 0.345 (p =
0.032), r = 0.484 (p = 0.002), respectively. The correlation
between SDF-1α and the grade of fibrosis was r = 0.575 (p
< 0.001), but SCGF-β and MCP-1 were not significant. Next,
as to SDF-1α, the raw data in each patient were compared
with the appearance of HPC. The serum level of SDF-1a over
350 pg/ml was seen in most patients in stage III-IV NASH liver
showing appearance of HPC characterized by small size, oval
shape, and high nucleo/cytoplasm ratio by EM. Conclusions:
611A
The serum level of SDF-1α is correlated with the grade of fibro-
sis and suggested the appearance of HPC. SDF-1α may be a
useful marker to detect NASH patients with the advanced stage
of fibrosis with the appearance of HPC, and to apply for the
evaluation of pharmacological effect.
Disclosures:
The following people have nothing to disclose: Wataru Ando, Hiroaki Yokomori,
Yutaka Inagaki, Isao Okazaki, Yutaka Suzuki, Tsutsui Nobuhiro, Eigoro Yama-
nouchi, Hiroki Tanabe, Hajime Kuroda, Soichi Kojima, Mitsuko Hara, Masaya
Oda, Takako Komiyama
852
Should we screen diabetic patients for fatty liver and
advanced fibrosis? A prospective study with 2080 con-
trolled attenuation parameter and liver stiffness mea-
surements
Raymond Kwok, Grace LH Wong, Henry Lik-Yuen Chan, Juliana C.
Chan, Alice P. Kong, Vincent W. Wong; Department of Medicine
and Therapeutics, The Chinese University of Hong Kong, Hong
Kong, China
Background: Type 2 diabetes is strongly associated with
nonalcoholic fatty liver disease and its severity. The current
American guidelines do not support fatty liver screening in
diabetic patients because of uncertainties surrounding screen-
ing tools. With new development in non-invasive tests, it is
now possible to accurately assess hepatic steatosis and fibrosis
in a large number of patients. Methods: Controlled attenua-
tion parameter (CAP) and liver stiffness (LS) were measured
by Fibroscan (Echosens, France) in consecutive patients who
attended a hospital clinic for diabetic complications screening.
We excluded patients with viral hepatitis and other concomi-
tant liver diseases. The XL probe was used in case M probe
measurements failed because of obesity. Hepatic steatosis
was graded by CAP using the M probe according to pub-
lished cutoffs (S1=222-232; S2=233-289; S3=290 dB/m or
above). Probe-specific cutoffs were used to define F3-4 and
F4. We followed the manufacturer’s reliability criteria based
on the number of valid acquisitions and the interquartile range
(IQR)-to-median ratio. Results: 2080 patients (45.4% women)
completed the examination. M probe measurements were
successful in 1927 (92.6%) patients, and the mean CAP was
262±65 dB/m (IQR 216-313). 1402 patients had fatty liver
(72.8%; 95% CI 70.8-74.7). The number of patients with S1,
S2 and S3 was 96 (5.0%), 574 (29.8%) and 732 (38.0%),
respectively. LS by M probe were reliable in 1908 of 2080
(91.7%) patients, and the mean LS was 7.5±5.3 kPa (IQR 4.8-
8.2). A further 123 patients underwent XL probe examination
and had reliable LS which was 9.2±10.0 kPa (IQR 4.4-9.5).
Combining the reliable results by either probe in 2031 (97.6%)
patients, 348 (17.1%, 95% CI 15.5-18.8%) had F3-4 and 233
(11.5%, 95% CI 10.1-12.9%) had F4. F4 was found in 4.8%,
6.3%, 7.0% and 18.9% of patients with S0, S1, S2 and S3,
respectively (P<0.001). Conclusions: Patients with type 2 dia-
betes have a high prevalence of fatty liver and cirrhosis. Our
data support fatty liver and fibrosis screening in this high-risk
group. [This work was substantially supported by a grant from
the Research Grants Council of Hong Kong (Project no. CUHK
477813).]
Disclosures:
Grace LH Wong - Advisory Committees or Review Panels: Otsuka, Gilead;
Speaking and Teaching: Echosens, Furui, Gilead, Janssen, Bristol-Myers Squibb,
Otsuka
Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, MSD,
Bristol-Myers Squibb, Roche, Novartis Pharmaceutical; Speaking and Teaching:
Echosens, Abbvie
Vincent W. Wong - Advisory Committees or Review Panels: Abbvie, Gilead;
Consulting: Merck, NovaMedica; Speaking and Teaching: Gilead, Echosens
612A AASLD ABSTRACTS
The following people have nothing to disclose: Raymond Kwok, Juliana C. Chan,
Alice P. Kong
853
Four simple risk factors predict post-transplant cardiac
mortality in patients with nonalcoholic steatohepatitis
Lisa B. VanWagner1,2, Brittany Lapin3, Donald M. Lloyd-Jones2,4,
Anton I. Skaro3, Mary E. Rinella1; 1Medicine, Division of Gastroen-
terology & Hepatology, Northwestern University Feinberg School
of Medicine, Chicago, IL; 2Preventive Medicine, Northwestern
University Feinberg School of Medicine, Chicago, IL; 3Surgery,
Division of Organ Transplantation, Northwestern University Fein-
berg School of Medicine, Chicago, IL; 4Medicine, Division of Car-
diology, Northwestern University Feinberg School of Medicine,
Chicago, IL
Background: Nonalcoholic steatohepatitis (NASH) is associ-
ated with an increased risk of cardiovascular disease (CVD)
mortality following liver transplant (LT); however, predictors of
these events are unknown. Aim: To assess predictors of post-LT
CVD mortality in patients with NASH. Methods: A cohort of
5,469 adults with NASH who underwent first LT (excluding
status 1) from 2/2002-12/2011 was identified in the Organ
Procurement and Transplantation Network database. An inde-
pendent physician panel reviewed recipient cause of death.
Cox proportional hazard model and Kaplan-Meier method
assessed CVD mortality, defined as primary cause of death
from thromboembolism, arrhythmia, heart failure, myocardial
infarction, cardiac arrest and/or stroke. Renal impairment was
defined as estimated glomerular filtration rate < 60. Results:
NASH recipients were mostly male (57.2%) and white (81.0%)
with a mean age of 55.2 years. Over a mean of 3.6 years of
follow-up, 252 CVD deaths occurred. Pre-transplant risk fac-
tors for CVD mortality included age ≥ 55 (OR=1.39, 95%
CI 1.03-1.88), male sex (OR=1.30, 95% CI 1.01-1.69), dia-
betes (OR=1.33, 95% CI 1.03-1.71), and renal impairment
(OR=2.02, 95% CI 1.47-2.77). A score of 1 was assigned
to sex, age, and diabetes, and a score of 2 to renal failure
based on model coefficients. The cohort was divided into 4
risk groups: low (score=0-1), intermediate (score=2), high
(score=3-4) and very high (score=5) risk. Very high risk recip-
ients were twice as likely as low risk recipients to die from a
CVD-related cause (incidence rate: 13.54 vs. 6.77 per 10
person-years; Figure 1, p<0.001). Conclusion: A simple score
of age ≥ 55, male sex, diabetes and renal impairment may be
a useful tool for predicting CVD mortality after LT for NASH
cirrhosis. Further validation, in a prospectively collected cohort,
is needed to confirm the prognostic value of the model.
Kaplan-Meier survival curve stratified by risk group (log-rank
p<0.001)
HEPATOLOGY, October, 2014
Disclosures:
Mary E. Rinella - Advisory Committees or Review Panels: Gilead
The following people have nothing to disclose: Lisa B. VanWagner, Brittany
Lapin, Donald M. Lloyd-Jones, Anton I. Skaro
854
Patients with non-alcoholic fat liver disease (NAFLD)
with lower levels of free serum copper and ceruloplas-
min have different clinical and biochemical characteris-
tics
Vinicius Nunes, Adriana R. Andrade, Ana Luiza V. Guedes, Clau-
dia P. Oliveira, Marcio A. Diniz, Jose Estefano, Daniel F. Mazo,
Eduardo Luiz R. Cancado; Hepatology, Universidade de São
Paulo - USP, São Paulo, Brazil
BACKGROUND AND AIM: Oxidative stress plays a role in
the pathogenesis of NAFLD. One of the enzymes that neu-
tralize oxidative stress is Cu/Zn superoxide dismutase,
which depends on the availability of adequate amounts of
copper. Copper deficiency has been linked to alterations on
lipid metabolism and also to hepatic steatosis. We aimed to
correlate ceruloplasmin levels and serum copper concentra-
tion with clinical, biochemical and histological parameters in
patients with NAFLD. METHODS: We retrieved data from a
database organized from 2011 to 2013, of 95 consecutively
admitted NAFLD patients that underwent liver biopsy, and
had measured the levels of ceruloplasmin and serum cooper
within 06 months from the biopsy date. These patients were
divided in groups based on ceruloplasmin (cut off: 25 mg/
dL) and free cooper levels (cut off: 0 mcg/dL and 15 mcg/
dL), calculated through the formula “total seric copper – (ceru-
loplasmin x 3.15)”. The risk factors for NAFLD in each group
were compared. RESULTS: Body Mass Index (BMI) was lower
in patients with ceruloplasmin levels <25 mg/dL (29.1±3.47
vs 32.8±6.24 Kg/m2; p=0.005) as were the levels of LDL,
HDL and total cholesterol, when compared with their counter-
part with ceruloplasmin >25 mg/dL (101±38 vs 116±35 mg/
dL, p= 0.05; 43±9 vs 51±16 mg/dL, p= 0.01; 174±43 vs
197±39mg/dL, p= 0.01, respectively). Otherwise, patients
with negative free copper had higher total cholesterol, HDL
and LDL levels (194±41 vs 187±42 mg/dL, p=0.39; 50±17 vs
47±12 mg/dL, p=0.89; 113±38 vs 109±35 mg/dL, p= 0.64,
respectively) and more steatohepatitis, however without statis-
tical significance, and lower HOMA-IR (cut off 3.5; p=0.03).
Patients with free copper lower than 15 mcg/dL had higher
HDL and lower LDL and total cholesterol levels, with statistical
significance only on LDL (50±15 vs 43±11 mg/dL, p=0.1;
106±35 vs 131±36 mg/dL, p=0.01; 186±40 vs 208±44
mg/dL, p=0.08, respectively). This group also showed lower
AST levels (37.7±27 vs 45.9±24 IU/L; p=0.04). Age, gender,
hypertension and diabetes were also evaluated but had no
statistical difference. CONCLUSIONS: Patients with NAFLD
had different clinical and biochemical markers according to
the levels of free copper and ceruloplasmin suggesting that
alterations in the metabolism of copper could have some role
in NAFLD development.
Disclosures:
The following people have nothing to disclose: Vinicius Nunes, Adriana R.
Andrade, Ana Luiza V. Guedes, Claudia P. Oliveira, Marcio A. Diniz, Jose
Estefano, Daniel F. Mazo, Eduardo Luiz R. Cancado
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
855
Tai chi ameliorates patient centered outcomes and
markers of systemic inflammation and liver injury in
subjects with nonalcoholic fatty liver disease
Angelo H. Paredes1, Jo L. Robins2, Jamie L. Sturgill2, Mohammad
S. Siddiqui1, Arun J. Sanyal1; 1Internal Medicine/Division of Gas-
troenterology, Hepatology and Nutrition, Virginia Commonwealth
University, Richmond, VA; 2School of Nursing, Virginia Common-
wealth University, Richmond, VA
BACKGROUND: Fatigue is the most common symptom in sub-
jects with nonalcoholic fatty liver disease (NAFLD). Chronic
fatigue has been associated with elevated systemic levels of
pro-inflammatory cytokines. While several drugs improve liver
histology in those with NAFLD, they have not been shown to
impact patient symptoms. Tai chi is a complementary and alter-
native medicine approach to improving perceived daily stress
and has been shown to improve chronic fatigue; its utility in
NAFLD is unknown. AIMS: To evaluate the effects of tai chi on
fatigue, depression and overall sense of wellness as well as
markers of systemic inflammation and liver injury in a “proof
of concept” study in subjects with NAFLD (NCT# 01467544).
METHODS:A randomized controlled trial of tai chi was per-
formed in obese non-diabetic women who met non-invasive
criteria for NAFLD (AST or ALT > 30 IU/L and high liver fat
scores) and no known chronic liver disease. Subjects were
randomized to either tai chi or no intervention for 8 weeks.
Subjects maintained their usual diet. Fatigue was assessed by
brief fatigue inventory and multi-dimensional fatigue symptoms
inventory. Overall patient centered outcomes were assessed
from patient-reported outcome surveys. The levels of IL-1, IL-8,
IFN-γ, TNF-α were also measured along with liver enzymes as
markers of liver injury. RESULTS: A total of 56 subjects were
randomized to tai chi or no interventions. The two groups were
well-matched with respect to age, body mass index, race,
ALT, severity of insulin resistance, cytokine levels and baseline
symptom scores. At the end of study, subjects in the tai chi
group had improvement in all symptom scales from baseline:
multidimensional fatigue inventory (16.9 to 1.6, p< 0.001),
Patient-Reported Outcomes Measurement System (19.3 to
15.6, p=.01), brief fatigue inventory (4.3 to 2.9, p=.09) and
Depression scores (0.6 to 0.3, p=.01). ALT also improved (24
IU/L to 21 IU/L, p=.05). Compared to the tai chi group, control
subjects had increased inflammatory cytokine levels at the end
of the study period: IL-1 (1.1 to 2.1 pg/ml, p=.04), IL-8 (14.2
to 19 pg/ml, p=.05), GSF (46.8 to 62.7 pg/ml, p=.06), IFN-γ
(147 to 222 pg/ml, p=.06), and TNF-α (25.2 to 36.7 pg/ml,
p=.02). ALT improvement positively correlated with a decrease
in IL-1, IFN-γ, and TNF-α, though it did not reach statistical sig-
nificance. There was no significant change in weight or mark-
ers of insulin resistance in either group. CONCLUSIONS: Tai
chi improves symptoms and patient-reported outcomes along
with ALT in subjects with NAFLD by preventing further deterio-
ration in markers of systemic inflammation.
Disclosures:
Arun J. Sanyal - Advisory Committees or Review Panels: Bristol Myers, Gilead,
Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Nimbus, Genentech, Echo-
sens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept,
Ikaria, Takeda, GalMed, Novartis, Gilead; Independent Contractor: UpToDate,
Elsevier
The following people have nothing to disclose: Angelo H. Paredes, Jo L. Robins,
Jamie L. Sturgill, Mohammad S. Siddiqui
613A
856
Atherogenic Dyslipidemia in the Setting of Insulin Resis-
tance Contributes to Cardiovascular Risk in Patients with
Nonalcoholic Fatty Liver Disease
Fernando Bril1,5, John Sninsky2, Arthur M. Baca2, Robert H.
Superko2, Paola Portillo Sanchez1,5, Margaret C. Lo3, Beverly
Orsak4,6, Kenneth Cusi1,5; 1Endocrinology, Diabetes and Metabo-
lism, University of Florida, Gainesville, FL; 2Quest Diagnostics, San
Juan Capristano, CA; 3Internal Medicine, University of Florida,
Gainesville, FL; 4Diabetes, University of Texas Health Science Cen-
ter at San Antonio, San Antonio, TX; 5Endocrinology, Diabetes and
Metabolism, Malcom Randall VA Medical Center, Gainesville, FL;
6Diabetes, Audie L. Murphy VA Medical Center, San Antonio, TX
Patients with nonalcoholic fatty liver disease (NAFLD) and
nonalcoholic steatohepatitis (NASH) are at increased risk
of cardiovascular disease. Although many mechanisms may
account for this, the role of atherogenic lipoproteins has not
been fully assessed in this population. To this end, we recruited
118 patients and performed the following tests: (1) liver mag-
netic resonance imaging and spectroscopy (1H-MRS); (2) liver
biopsy; and (3) lipoprotein analysis that included, standard
lipids, and lipoprotein subfraction analysis (apolipoprotein
B and A1 levels, LDL particle size/phenotype, and LDL/HDL
subfractions [gradient gel electrophoresis and ion mobility]).
Patients were divided into 3 groups: no NAFLD (no-N; n=24),
non-obese with NAFLD (N+Ob-; n=33), and obese with NAFLD
(N+Ob+; n=91). No-N and N+Ob- groups were well matched
for BMI (29.0±1.2 vs. 28.3±0.3 kg/m2, p=0.47), T2DM
(63% vs. 79%, p=0.18), lipid profile, and statin use (56% vs.
55%, p=0.92). However, N+Ob- patients had more severe
insulin resistance at the level of the liver (HOMA: 3.0 [1.4-5.1]
vs. 1.7 [0.8-2.7], p=0.02) and adipose tissue (FFA-suppres-
sion during OGTT: 69±2% vs. 81±2%, p=0.001). Even when
standard lipids were no different between the groups, N+Ob-
patients had smaller LDL particle size (218±2 vs. 223±2 Å,
p=0.01) and a trend towards a higher proportion of LDL parti-
cles with a B phenotype (42% vs. 17%, p=0.06). Other proath-
erogenic changes in N+Ob- patients were increased LDL3a
and 2b subparticles, reduced large LDL1 particles, increased
HDL3b and 3c particles, and decreased HDL2a (all p<0.05).
Regardless of different BMI (28.3±0.3 vs. 35.8±0.4 kg/m2,
p<0.001), N+Ob- and N+Ob+ patients did not differ in the
prevalence of T2DM, liver fat content, or insulin resistance.
Accordingly, advanced lipid tests did not have significant dif-
ferences between groups. To assess the role of the severity of
liver disease in lipoprotein metabolism, NAFLD patients were
further divided into NASH vs. no NASH. Both groups were
well matched for clinical parameters (e.g. BMI, liver fat, and
insulin resistance). Again, no differences were observed in LDL
particle size or phenotype or in any lipoprotein subfraction.
Conclusion: Patients with NAFLD have a more atherogenic lipo-
protein profile (smaller LDL particles and more atherogenic HDL
subparticles) than patients without NAFLD, even when well-
matched for BMI and other clinical parameters. We speculate
that this lipoprotein profile is driven mostly by liver fat content
and insulin resistance, and appears not to be affected by the
severity of liver disease (NASH) or other metabolic features that
coexist with NAFLD, such as obesity or hyperglycemia.
Disclosures:
John Sninsky - Employment: Quest Diagnostics
Robert H. Superko - Employment: Celera-Quest Diagnostics
Beverly Orsak - Employment: UTHSCSA
Kenneth Cusi - Consulting: Merck, Daichi-Sankyo, Roche, Janssen; Grant/
Research Support: Takeda, Novartis, Mannkind
The following people have nothing to disclose: Fernando Bril, Arthur M. Baca,
Paola Portillo Sanchez, Margaret C. Lo
614A AASLD ABSTRACTS
857
High Density Lipoprotein Dysfunction in Patients with
Nonalcohol Steatohepatitis
Arthur J. McCullough1, Jaividhya Dasarathy2, Ling Li3, Gregory
Brubaker4, Belinda Willard3, Srinivasan Dasarathy1, Jonathan D.
Smith4, Takhar Kasumov1; 1Gastroenterology, Cleveland Clinic,
Cleveland, OH; 2Family Medicine, Metrohealth Medical Center,
Cleveland, OH; 3Core Service, Cleveland Clinic, Cleveland, OH;
4Molecular and Cellular Medicine, Cleveland Clinic, Clinic, OH
Background and Aim: Although nonalcoholic steatohepati-
tis (NASH) is a common liver disease with a risk of progres-
sion to cirrhosis, the major cause of morbidity and mortality
in NASH is cardiovascular disease (CVD). Oxidative stress
and inflammation play a central role in disease progression
within the liver but are also independent predictors of CVD
in NASH. Patients with NASH have reduced levels of high
density lipoprotein (HDL), which has cardioprotective effects
that include HDL dependent reverse cholesterol transport (RCT),
anti-oxidant and, anti-inflammatory functions. Since insulin
resistance, inflammation and oxidative stress cause HDL dys-
function through alterations of HDL composition, in addition
to being key components of NASH pathogenesis, we hypoth-
esized that dyslipidemia-induced hepatic oxidative stress and
inflammation in NASH causes loss of RCT and the anti-oxida-
tive functions. Methods. HDL functionality was measured using
the macrophage cholesterol efflux assay (%) and paraoxonase
(PON1) activity (arbitrary units of anti-oxidative function) by a
fluorometric assay in apoB-depleted serum from NASH (n=10)
and control (n=11) subjects. ATP binding casette subfamily
A1 (ABCA1, a protein that transports cholesterol to apoAI
forming nascent HDL)-dependent cholesterol efflux was mea-
sured in response to induction using 8-Br-cAMP to distinguish
ABCA1-dependent and total cholesterol efflux. The ABCA1-de-
pendent cholesterol efflux was calculated by substraction of
ABCA1-independent from total efflux. Results. NASH patients
had higher BMI, HOMA-IR scores, plasma AST, ALT and tri-
glycerides while plasma HDLc was non-significanlty lower
than controls. However, HDL function quantified by both total
and ABCA1-dependent cholesterol efflux capacity of apoB-de-
pleted serum from patients with NASH were significantly lower
than controls (Total: 15.0±2.4 vs. 19.2.0±2.8, p<0.001 and
ABCA1-dependent: 7.9±1.9 vs. 12.0±2.0, p<0.0005). Sim-
ilarly, NASH patients had significantly lower PON1 activity
(0.89±0.06 vs. 1.02±0.07, p<0.005). Serum triglyceride
and glucose levels were negatively correlated with cholesterol
efflux and PON1 activity. Insulin resistance (HOMA) negatively
correlated with cholesterol efflux but not with PON1 activity.
Hepatic oxidation in patients with NASH correlated with both
cholesterol efflux and PON1 activity. Conclusions. HDL func-
tion measured using cholesterol efflux and PON1 activity are
inversely correlated with CVD risk. HDL dysfunction may con-
tribute to CVD related mortality in NASH.
Disclosures:
The following people have nothing to disclose: Arthur J. McCullough, Jaividhya
Dasarathy, Ling Li, Gregory Brubaker, Belinda Willard, Srinivasan Dasarathy,
Jonathan D. Smith, Takhar Kasumov
HEPATOLOGY, October, 2014
858
Meta-Analysis Of Randomized Controlled Trials Com-
paring Current Pharmacologic Agents Vs. Placebo In
Non-Alcoholic Fatty Liver Disease
Ahmed Akhter2, Adnan Said1; 1Medicine, Gastroenterology and
Hepatology, University of Wisconsin, School of Medicine and
Public Health, Madison, WI; 2Medicine, University of Wisconsin,
School of Medicine and Public Health, Madison, WI
Background: Non-alcoholic fatty liver disease (NAFLD) con-
tinues to increase in incidence. Currently, there is no stan-
dardized regimen for treatment of NAFLD. Purpose: We
performed a meta-analysis of randomized placebo controlled
trials (RCTs) that evaluated thiazolidinediones (TZDs) such as
pioglitazone and rosiglitazone, as well as metformin and vita-
min E in adult patients with NAFLD in order to quantify the
treatment response. Outcome measures were improvement in
liver histology and biochemical and anthropometric measures.
Methods: For discrete variables, Odds ratio and 95% confi-
dence intervals were calculated using a random-effects model.
For continuous variables weighted averages were calculated.
Study heterogeneity and publication bias were assessed. Four
trials of TZDs, four of metformin and three with Vitamin E met
inclusion criteria. Results: The liver histology score including
steatosis (OR 3.40, 95% CI 2.21 to 5.25), ballooning (OR
1.67, 95% CI 1.04 to 2.68) and lobular inflammation (OR
2.58, 95% CI 1.68 to 3.97) all showed a greater proportion
of improvement with TZD use as compared to placebo. The
hepatic fibrosis score (OR 1.57, 95% CI 0.98 to 2.50) did
not demonstrate significant improvement with TZDs. Weighted
mean difference in ALT (-19.43, P=0.0007) and Hemoglo-
bin A1c (HbA1C) (-0.43, P=0.0006) demonstrated signifi-
cant improvement with TZD use. Weighted mean difference
in body weight with TZD (P=0.20) and BMI (P=0.55) showed
a non-significant increase compared to placebo. With met-
formin, weighted liver histologic scores for steatosis (mean dif-
ference 0.15, P=0.27), ballooning (-0.05, P=0.43), lobular
inflammation (0.07, P=0.12) and fibrosis (-0.198, P=0.15)
did not demonstrate significant change compared to placebo.
Weighted mean difference in fasting blood sugar (-8.45 mg/
dl, P<0.0001) demonstrated significant improvement with met-
formin use. Weighted mean difference in ALT (P=0.25), body
weight (P=0.56), and BMI (P=0.74) did not show significant
change compared to placebo. With Vitamin E, weighted liver
histologic scores for steatosis (-0.71, 95% CI -0.97 to -0.47,
P<0.0001) and ballooning (-0.38, 95% CI -0.14 to -0.62),
P=0.0016) demonstrated significant improvement compared to
placebo. Lobular inflammation (P=0.08) and fibrosis (P=0.62)
did not demonstrate significant change with vitamin E. ALT
(P=0.20) and weight (P=0.46) did not show significant change
with vitamin E compared to placebo. Conclusion: In patients
with NAFLD, TZDs and Vitamin E improve liver histologic
scores but metformin does not. Insulin resistance also improves
with both TZD and metformin. Fibrosis does not improve with
any of the agents.
Disclosures:
The following people have nothing to disclose: Ahmed Akhter, Adnan Said
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
859
Bile acid serum levels in adolescents with NAFLD: a bio-
marker for progression?
Jörg Jahnel1, Zoehrer Evelyn1, Günter Fauler1, Hubert Scharnagl1,
Tatjana Stojakovic1, Valerio Nobili2; 1Medical University Graz,
Graz, Austria; 2Hepato-Metabolic Disease Unit, Bambino Gesù
Children’s Hospital, Graz, Italy
Introduction: Nonalcoholic fatty liver disease (NAFLD) is fre-
quent in obese children. A reliable non-invasive biomarker
for monitoring of progression to liver fibrosis would be useful.
Serum bile acid (BA) levels are elevated in cirrhosis, probably
for mechanical reasons. Interestingly, BA can influence glu-
cose and lipid metabolism by stimulating insulin release via
the TGR5/GLP1 pathway; and, reciprocally, insulin can down-
regulate BA synthesis from cholesterol via the FXR/SHP and/or
the PI3K/AKT pathways. We hypothesized that changes in BA
levels in NAFLD vary depending on grade of fibrosis. Methods:
In this multicenter study adolescents with NAFLD (n=92) were
classified between stages of fibrosis (non-fibrosis n=27; fibro-
sis ≥1 n=65) based on liver-biopsy findings. Metabolic and
cholestatic status was assessed by blood tests (glucose, insulin,
cholesterol, LDL, HDL, AST, bilirubin, ALT, GGT). The full BA
pool, including 15 BA species, was measured by HPLC-MS/
MS and compared to healthy controls (n=105). Results: Both
groups showed hyperglycemia (non-fibrosis 126±44; fibrosis
119±18 mg/dl), hyperinsulinism (83±33 vs 88±41 μE/ml),
and elevated ALT levels (63±20 vs 87±58 U/l). Non-fibrotic
adolescents had significantly (p<0.001) decreased median BA
levels (1.28; range 1.18 – 2.34 mmol/l) compared to con-
trols (3.36; range 2.16 – 4.69 mmol/l). In fibrosis BA values
increased (1.86; 1.05 – 3.22 mmol/l; p<0.001). Non-fibrotic
patients lacked glycine-conjugated BA with a significant
(p<0.05) predominance of unconjugated BA. In fibrosis, gly-
cine-conjugated BA values rose and the BA pool resembled
that in healthy controls. Other values did not differ significantly
between the groups. Conclusion: BA levels decrease in early
NAFLD and seem to increase continuously during progression
to fibrosis and cirrhosis. BA may serve as a non-invasive bio-
marker for progression of disease.
Disclosures:
Jörg Jahnel - Grant/Research Support: Fresenius-Kabi, CRTS labaratories
The following people have nothing to disclose: Zoehrer Evelyn, Günter Fauler,
Hubert Scharnagl, Tatjana Stojakovic, Valerio Nobili
860
Oxidative stress-inducible factors promote liver fibrosis
in patients with Non-Alcoholic Fatty Liver Disease
Lavinia Mezzabotta1, Chiara Rosso1, Ester Vanni1, Roberto Gam-
bino1, Ramy Ibrahim Kamal Jouness1, Francesca Saba1, Federico
Salomone3, Melania Gaggini2, Emma Buzzigoli2, Chiara Sapon-
aro2, Fabrizia Carli2, Gian Paolo Caviglia1, Maria Lorena Abate1,
Antonina Smedile1, Mario Rizzetto1, Maurizio Cassader1, Amalia
Gastaldelli2, Elisabetta Bugianesi1; 1Medicale Science, University
of Turin, Turin, Italy; 2Cardiometabolic Risk Unit, Institute of Clini-
cal Physiology, CNR, Pisa, Italy; 3Gastroenterology, Azienda San-
itaria Provinciale di Catania, Catania, Italy
Background and Aims. Non-alcoholic fatty liver disease
(NAFLD) is characterized by the excessive accumulation of
triglycerides (TG) in the liver due to the increased inflow of free
fatty acids (FFAs). Accumulation of FFAs in the hepatocytes
promotes inflammation and oxidative stress (ox-stress) leading
to the release of hypoxia-inducible cytokines, such as angiopoi-
etin-like proteins (angptl), and to the increase of oxidized-low
density lipoproteins (oxLDLs) levels. We investigated the pat-
615A
tern and change of ox-stress parameters as well as glucose
and lipid profile in NAFLD patients after a glucose versus lipid
load and its impact on liver damage. Methods. We studied 44
patients with biopsy proven NAFLD during fasting and during
a 4h oral glucose tolerance test (OGTT 75g, n=24 patients) or
fat meal (200ml dairy cream plus an egg yolk, n=20 patients).
We measured lipid profile, hormones and ox-stress parameters
(oxLDLs, total anti-oxidative status (TAS), angptl4 and angptl6).
Insulin resistance (IR) indices were derived from 4h double trac-
ers infusion: hepatic-IR (hep-IR=EGP x fasting insulin), adipose
tissue-IR (adipo-IR=fasting lipolysis x fasting insulin). Results.
During fasting, oxLDLs positively correlate with TG (r=0.398;
P<0.01) and FFAs (r=0.313; P=0.04) while TAS positively
correlate with angptl6 levels (r=0.404; P<0.01). Angptl4 con-
centration positively correlate with FFAs (r=0.454; P<0.01)
and adipo-IR (r=0.318; P<0.035). Among histological fea-
tures, oxLDLs, angptl4 and angptl6 levels significantly correlate
with steatosis (r=0.313, P=0.046; r=0.411, P=0.006 and
r=0.422, P=0.004). TAS was significantly associated with
NAS score (P=0.05). Of note, angptl4 increased according
to the NAS score (P<0.01) and was significantly associated
with severe fibrosis (F≥3). During meals, glucose and insu-
lin curves were significantly higher in patients with F≥3 (all
P<0.01) in both groups, and during OGTT showed a step-
wise increase according to the degree of fibrosis. During lipid
meal the large increase in plasma TG had no association with
fibrosis while FFAs and oxLDLs levels were significantly higher
in patients with F≥3 (P<0,01). Conclusion. Ox-stress-inducible
factors are important mediators of necro-inflammation and
fibrosis in patients with NAFLD. Metabolic changes occurring
in the postprandial phase, particularly related to the increase
of glucose, insulin and FFAs, further contribute to liver dam-
age. Funded by FP7/2007-2013 under grant agreement n°
HEALTH-F2-2009-241762 for the project FLIP and by PRIN
2009ARYX4T.
Disclosures:
The following people have nothing to disclose: Lavinia Mezzabotta, Chiara
Rosso, Ester Vanni, Roberto Gambino, Ramy Ibrahim Kamal Jouness, Francesca
Saba, Federico Salomone, Melania Gaggini, Emma Buzzigoli, Chiara Sap-
onaro, Fabrizia Carli, Gian Paolo Caviglia, Maria Lorena Abate, Antonina
Smedile, Mario Rizzetto, Maurizio Cassader, Amalia Gastaldelli, Elisabetta
Bugianesi
861
Comparison of NAFLD Fibrosis Score (NFS) and transient
elastography (Fibroscan®), alone and in combination,
as non-invasive methods for the evaluation of fibrosis in
non-alcoholic fatty liver disease (NAFLD)
Edric Hee1, William W. Kemp2, Bastiaan de Boer3, Jeffrey M. Ham-
dorf4, Gerry C. MacQuillan5, George Garas5, Helena Ching1,5,
Ross Mac Nicholas5, Stuart K. Roberts2, Matthew T. Kitson2, Gary
P. Jeffrey1,5, Leon Adams1,5; 1School of Medicine and Pharmacol-
ogy, The University of Western Australia, Perth, WA, Australia;
2Department of Gastroenterology, The Alfred, Melbourne, VIC,
Australia; 3Department of Anatomical Pathology, PathWest, Perth,
WA, Australia; 4School of Surgery, The University of Western Aus-
tralia, Perth, WA, Australia; 5Department of Gastroenterology and
Hepatology, Sir Charles Gairdner Hospital, Perth, WA, Australia
Sequential use of noninvasive methods of predicting fibrosis
has been proposed to evaluate fibrosis in subjects with nonal-
coholic fatty liver disease (NAFLD) however, the accuracy of
this approach has not been validated. We aimed to evaluate
and compare the diagnostic accuracy of the NAFLD Fibro-
sis Score (NFS) and Liver Stiffness Measurement (LSM) indi-
vidually and in sequential combination to predict advanced
fibrosis in patients with NAFLD. Methods Subjects with NAFLD
616A AASLD ABSTRACTS HEPATOLOGY, October, 2014

who underwent liver biopsy and a valid Fibroscan assessment
within 6 months of each other at two tertiary hospitals were
retrospectively evaluated. Biopsies were scored according to
the NAFLD Clinical Research Network staging system with
F3-4 considered as advanced fibrosis. The diagnostic utility
of NFS and LSM were studied seperately, then in combina-
tion according to the algorithm suggested by Castera et al.
using previously published cut-offs. Results The cohort con-
sisted of 98 adults, (43% male) with a mean (SD) age of 52
(11) years and mean body mass index of 37 (6.5) kg/m2.
The prevalence of advanced fibrosis (F3,4) was 17%. NFS
and LSM were significantly correlated (Spearman rho=0.35,
p<0.001). For predicting advanced fibrosis, the area under
the receiver operator characteristic curve (AUROC) of LSM
alone was 0.841 (95% CI, 0.762-0.920) and NFS alone was
0.779 (95% CI, 0.663-0.895). Using recommended cut-offs,
NFS alone, LSM alone and the sequential combination all had
sensitivities and negative predictive values (NPV’s) greater than
90% for excluding advanced fibrosis (see Table). A greater
proportion of individuals had advanced fibrosis excluded with
the combination algorithm (43%) compared to LSM (31%) or
NFS (22%) alone (p<0.001). The specificity of each algorithm
for predicting advanced fibrosis was modest (51-79%) and the
positive predictive values poor (33-35%). The percentage of
subjects correctly classified (true positives plus true negatives)
was significantly higher with the combination of NFS plus LSM
(65%) compared to LSM (47%) and NFS (27%) (p<0.001).
Conclusions The combination of NFS and LSM can reliably and
effectively exclude advanced fibrosis in a greater proportion of
patients with NAFLD than either method alone.
Table 1: Diagnostic Utility of NFS, LSM and Combination of NFS
+ LSM.
ter in South Korea were enrolled. Diastolic dysfunction was
diagnosed and graded using echocardiographical parameters
including E/A ratio, e’/a’, deceleration time, and peak e’.
RESULTS: Mean age was 54.1 ± 10.4 years and 62.9% were
male. A total of 2,277 subjects (68.9%) had diastolic cardiac
dysfunction; 1,843 were grade 1 and 434 were grade 2.
More advanced diastolic dysfunction (normal, grade 1, grade
2) was associated with higher prevalence of NAFLD (OR,
2.15; 95% CI, 1.87-2.47; P<0.001). On multivariate analy-
sis, the presence NAFLD was significantly associated with both
the presence of diastolic dysfunction (odds ratio [OR], 2.02;
95% confidence interval [CI], 1.65-2.49; P<0.001) and the
increased diastolic dysfunction grades (normal, grade 1, grade
2) (OR, 1.63; 95% CI, 1.39-1.91; P<0.001) after adjustment
for age, sex, hypertension, body mass index, and serum lev-
els of cholesterol and triglycerides. More advanced diastolic
dysfunction (normal, grade 1, grade 2) was associated with
higher prevalence of NAFLD (OR, 2.15; 95% CI, 1.87-2.47;
P<0.001). CONCLUSIONS: Patients with NAFLD have an
increased risk for diastolic cardiac dysfunction independent of
classical risk factors.

Disclosures:
Stuart K. Roberts - Board Membership: Jannsen, Roche, Gilead, BMS
Matthew T. Kitson - Consulting: MSD, Roche; Grant/Research Support: MSD;
Speaking and Teaching: Janssen-Cilag
Gary P. Jeffrey - Advisory Committees or Review Panels: MSD, Novartis
The following people have nothing to disclose: Edric Hee, William W. Kemp,
Bastiaan de Boer, Jeffrey M. Hamdorf, Gerry C. MacQuillan, George Garas,
Helena Ching, Ross Mac Nicholas, Leon Adams

862
Nonalcoholic Fatty Liver Disease Is Associated with Left
Ventricular Diastolic Dysfunction
Jeong-Hoon Lee1, Donghee Kim2, Goh Eun Chung2, Min-Sun
Kwak2, Yoon Jun Kim1, Jung-Hwan Yoon1, Hyo-Suk Lee1; 1Depart-
ment of Internal Medicine and Liver Research Institute, Seoul
National University Hospital, Seoul, Republic of Korea; 2Depart- Disclosures:
ment of Internal Medicine, Healthcare System Gangnam Center, The following people have nothing to disclose: Jeong-Hoon Lee, Donghee Kim,
Seoul National University Hospital, Seoul, Republic of Korea Goh Eun Chung, Min-Sun Kwak, Yoon Jun Kim, Jung-Hwan Yoon, Hyo-Suk Lee
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) may
result in variable spectrum of cardiac abnormalities. The aim
of this study was to evaluate whether NAFLD is associated with
left ventricular diastolic dysfunction independently of other risk
factors. METHODS: A total of 3,306 subjects who underwent
health check-up including echocardiography between January
1 and December 31, 2010 at a single health screening cen-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
863
The relationship between ALT and liver histology
changes with age in NAFLD
Boon Bee George Goh1, Mangesh Pagadala1, Jaividhya Dasara-
thy2, Aynur Unalp3, Ruth Sargent1, Carol A. Hawkins4, Achuthan
Sourianarayanane1, Amer Khiyami5, Lisa M. Yerian6, Rish Pai6,
Srinivasan Dasarathy1, Arthur J. McCullough1; 1Gastroenterology
& Hepatology, Cleveland Clinic, Cleveland, OH; 2Family Medi-
cine, MetroHealth Medical Center, Cleveland, OH; 3Epidemiol-
ogy, Johns Hopkins University, Baltimore, MD; 4Gastroenterology,
MetroHealth Medical Center, Cleveland, OH; 5Pathology, Metro-
Health Medical Center, Cleveland, OH; 6Pathology, Cleveland
Clinic, Cleveland, OH
Background and Aims: The prevalence of non-alcoholic fatty
liver Disease (NAFLD) is increasing in parallel to the epidemics
of obesity and diabetes. Although histological differences have
been reported between pediatric and adult NAFLD, potential
age related changes in serum transaminases and liver histology
remain largely unexplored. Therefore, the aim of our study
was to investigate the clinical and histological characteristics
of NAFLD across different age groups of adults. Methods:
This was a cross sectional study of 502 biopsy proven NAFLD
patients recruited from two hepatology outpatient clinics in
Cleveland. Clinical data including demographics, anthropom-
etry, medical history, biochemical and liver biopsy findings
were evaluated. Comparisons of clinical characteristics and
histologic changes were made among different age groups;
group A(aged 18 to 44), B(aged 45 to 64) and C(aged 65
and over). Results: In this cohort of NAFLD patients, 34.9%,
56.0% and 9.1% of the cohort were distributed among group
A, B, and C respectively. While the prevalence of non-alco-
holic steatohepatitis (NASH) was comparable across age
groups, the prevalence of advanced fibrosis increased with
age; 17.7%, 31.1% and 50.0% of groups A, B and C respec-
tively (p=0.000). Mean ALT progressively decreased with age;
87, 64, 56 U/L in group A, B, and C respectively (p=0.000)
with a corresponding increase in the proportion of patients
with normal ALT with age (p=0.003). In contrast, there was no
difference in mean AST or proportion of patients with normal
AST (p=0.939) across age. The AST: ALT ratio (AAR) progres-
sively increased from 0.7 to 0.9 to 1.1 in group A, B and C
respectively (p=0.000). Similarly, with respect to increasing
age, ALT levels decreased, AST levels did not change while
AAR increased when subgroups of patients with NASH or
advanced fibrosis were considered specifically. Conclusion:
With advancing age, ALT levels progressively declined while
AST levels remained stable. Consequently, this lead to an
increasing AAR, which is often used as a surrogate measure
of advanced fibrosis. However, advancing age by association
with decreasing ALT also contributes to the increase in AAR.
Cautious interpretation of ALT and AAR are warranted in the
elderly as clinically significant disease may be present even
in the context of normal ALT levels. In addition, AAR may not
be increased due to progressive fibrosis, but as a function of
decreasing ALT with age. It is important for clinicians to rec-
ognize these associations when faced with middle aged and
elderly patients.
Disclosures:
Rish Pai - Consulting: Robarts Clinical Trials
The following people have nothing to disclose: Boon Bee George Goh, Mangesh
Pagadala, Jaividhya Dasarathy, Aynur Unalp, Ruth Sargent, Carol A. Hawkins,
Achuthan Sourianarayanane, Amer Khiyami, Lisa M. Yerian, Srinivasan Dasara-
thy, Arthur J. McCullough
617A
864
Non-alcoholic fatty liver disease (NAFLD) recurrence
after liver transplant (OLT) for non-alcoholic steatohepa-
titis(NASH)
Norio Kawamura1, Mustafa Nazzal1, Galal El-Gazzaz1, Mario
Spaggiari1, Masato Fujiki1, Teresa Diago1, Federico N. Aucejo1,
Koji Hashimoto1, Cristiano Quintini1, Charles Winans1, Bijan Eght-
esad1, Charles M. Miller1, John J. Fung1, Naim Alkhouri2, Dympna
Kelly1; 1transplantation center, Cleveland Clinic, Cleveland, OH;
2Gastroenterology and Hepatology, Cleveland Clinic, Cleveland,
OH
Introduction:Reported recurrence rates following OLT for NASH
are as high as 24%. The aim of this study was to investigate
recurrence rates and prognostic factors of NAFLD and NASH
post OLT. Methods: A retrospective review of all OLT from
4/2004 to 12/2011 was performed(n=1018). Patients with
a diagnosis of NASH cirrhosis were identified and studied for
pre and post OLT risk factors for NAFLD and NASH recurrence,
including BMI, hypertension, IDDM, triglyceride, cholesterol,H-
bA1c, metabolic syndrome, liver function tests, immunosup-
pression, graft and patient survival and donor factors. Fisher’s
exact test or chi-square test, and Wilcoxon rank sum test
were used for statistical analysis. Results:118/1018 (11.6%)
patients had NASH cirrhosis. Age ranged from 35-76 yrs,
59.3+/-7.8(mean+/-SD). 52(44.1%) were female. Mean fol-
low up time was 41.4+/-1.9months. MELD scores were 21.9+/-
5.4. BMI pre OLT was 32.4+/-6.6. 16 of 118(13.6%) patients
were morbidy obese(BMI>=40). 69/118(63.3%) patients had
IDDM before OLT. 92 patients(80%) received simulect induc-
tion. All patients received prograf. 108/118 patients received
steroids for 21days post OLT, and 10/118 patients received
steroids for 90days post OLT. 25/118(21%) patients devel-
oped NAFLD after OLT diagnosed by either liver biopsy(n=13)
or ultrasound(n=12). Median time to NAFLD recurrence was 15
months(2-91months). Only high HbA1c before OLT was asso-
ciated with higher recurrence rate of NAFLD(p<0.008) 9/118
(7.6%) patients developed NASH recurrence(biopsy proven).
Median time to recurrence was 26.5months(3-71months). High
cholesterol pre-OLT and split graft were associated with higher
NASH recurrence rates (P=0.030, 0.025). Predictors of graft
survival are recipient age>=65, female sex, BMI <30(pre or
post OLT), BMI decrease post OLT(decrease by more than 1),
female donor, and recipient without metabolic syndrome. Pre-
dictors of patient survival are recipient age (>=65), pre-OLT
hemodialysis, post-OLT BMI<30, BMI decrease post-OLT, and
recipient without metabolic syndrome. HDL level (>=40 male
and >=50 female) and HbA1c level (<5.5) before OLT were
significantly associated with better patient survival(P=0.031
and 0.022). Conclusion: NAFLD recurrence rates after OLT
are high(21.2%) and occur early at median of 15mos, but
NASH recurrence rates are low(7.6%). Increased BMI post
OLT, morbid obesity, and metabolic syndrome are not related
to NAFLD or NASH recurrence. Better diabetes control before
OLT may contribute to lower NAFLD recurrence and better
patient survival.
Disclosures:
Norio Kawamura - Consulting: Novartis, Vital therapies; Grant/Research Sup-
port: Genzyme, Sanofi; Speaking and Teaching: Astellas
John J. Fung - Advisory Committees or Review Panels: Astellas, Novartis; Consult-
ing: Vital Therapies; Grant/Research Support: Sanofi
Naim Alkhouri - Advisory Committees or Review Panels: Gilead Sciences
The following people have nothing to disclose: Mustafa Nazzal, Galal El-Gaz-
zaz, Mario Spaggiari, Masato Fujiki, Teresa Diago, Federico N. Aucejo, Koji
Hashimoto, Cristiano Quintini, Charles Winans, Bijan Eghtesad, Charles M.
Miller, Dympna Kelly
618A AASLD ABSTRACTS
865
Degree of hepatic fibrosis assessed using transient elas-
tography is independently related with coronary artery
calcification in nonalcoholic liver disease
Seng Chan You, Seung Up Kim, Beom Kyung Kim, Jun Yong Park,
Do Young Kim, Sang Hoon Ahn, Kwang-Hyub Han; Department of
Internal medicine, Institute of Gastroenterology, Yonsei university,
college of medicine, Seoul, Republic of Korea
Background: The prevalence of nonalcoholic fatty liver disease
(NAFLD) which is closely related to coronary atherosclerosis
is continuously increasing worldwide. Controlled attenuation
parameter (CAP) of transient elastography (TE) can assess the
degree of hepatic steatosis accurately. This study aimed to
investigate the prevalence of TE-defined NAFLD and to identify
factors which are associated with coronary artery calcifica-
tion (CAC) in patients with NAFLD. Methods: Between January
2012 and March 2014, a total of 385 asymptomatic subjects
without chronic liver diseases, heavy alcohol consumption, or
known heart diseases who underwent comprehensive medi-
cal health check-up including echocardiography, TE, carotid
ultrasound, fat computed tomography (CT), and coronary CT
were recruited. Of these, 144 (37.4%) subjects had TE-defined
NAFLD (CAP ≥ 250 dB/m). Results: The median age of the
whole study population (216 men and 169 women) was 56
(interquartile [IQR], 51-64) years. On multivariate analysis,
subjects with NALFD were significantly older (mean 57 vs. 55
years) and had higher body mass index (BMI) (mean 25.7 vs.
23.0 kg/m2), higher alanine aminotransferase level (mean
26.2 vs. 20.0 IU/L), higher triglyceride (140 vs. 99 mg/dL),
higher HOMA-IR (2.19 vs. 1.50), lower HDL-cholesterol (12.6
vs. 50.1 mg/dL), and higher amount of visceral fat area on
CT (127.1 vs. 92.9 cm2) (all P<0.05). On multivariate analy-
sis, higher BMI (odds ratio [OR] 3.76; 95% confidence inter-
val [CI] 1.03-6.98; P<0.001), triglyceride (OR 2.25; 95% CI
1.28-3.95; P=0.005), higher amount of visceral fat area (OR
1.96; 95% CI 1.06-3.62; P=0.032) independently predicted
the presence of NAFLD. In the sub-population with NAFLD (men
94 and women 50), the median age was 57 (IQR 51-64)
years. For these subjects with NAFLD, CAC score which is
significantly correlated the risk of coronary event showed an
independent positive correlation with higher liver stiffness (LS)
values of TE (β=0.274; P<0.001), together with older age
(β=0.187; P=0.020), male gender (β=0.230; P=0.005),
elevated erythrocyte sedimentation rate (ESR) (β=0.220;
P=0.007), and estimated glomerular filtration rate (eGFR) (β=-
0.220; P=0.004). Conclusions: The prevalence of TE-defined
NAFLD was relatively high (37.4%) in asymptomatic Asian sub-
jects who underwent medical health check-up. Among subjects
with NAFLD, fibrosis progression by nonalcoholic steatohepa-
titis (NASH), reflected by higher LS values, was independently
related to higher CAC score. Further studies are required to
investigate whether TE can be incorporated into a screening
strategy to identify the increased risk of coronary heart disease
in patients with NAFLD.
Disclosures:
The following people have nothing to disclose: Seng Chan You, Seung Up Kim,
Beom Kyung Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Kwang-Hyub
Han
HEPATOLOGY, October, 2014
866
Associations Between Helicobacter pylori, Leptin, and
Nonalcoholic Fatty Liver Disease (NAFLD)
Joseph Roberts, William LeBlanc, Kiran Bambha; University of Col-
orado Denver, Aurora, CO
Helicobacter pylori (H pylori) colonization may be more prev-
alent in NAFLD patients than in controls. H pylori also has
complex associations with the metabolic hormone leptin. Aim:
To analyze interactions between H pylori and leptin on the
risk for NAFLD. Methods: Using NHANES III, we identified
adults with data on H pylori serologies and leptin who also had
ultrasound (US) assessment of hepatic steatosis (HS), and who
did not have a history of alcohol excess or other chronic liver
diseases. NAFLD (defined by US HS) was coded as: yes vs no.
We modeled associations between H pylori and NAFLD using
multiple logistic regression, including assessment of interactions
between H pylori and leptin. Results: 2539 adults (≥20 yrs)
were included. Mean age was 43 yrs, 45% (1196) were male,
77% (1019) Non Latino White, mean BMI=26 kg/m2. NAFLD
was present in 29% (808). Mean leptin tertile values were:
3.2; 8.8; 23.6. H pylori positivity and leptin were each signifi-
cantly associated with NAFLD (p<0.0001 for both). There was
a significant interaction between H pylori and leptin (tertiles) on
NAFLD risk. Specifically, the OR [95% CI] for H pylori positivity
varied by leptin tertile (lowest to highest): 0.82 [0.67-0.99];
0.71 [0.63-0.81]; 1.26 [1.14-1.40], (all models adjusted for:
age, sex, race/ethnicity, BMI, HOMA-IR, hypertriglyceridemia,
hypercholesterolemia, hypertension, education).(Figure) Con-
clusion: H pylori positivity is significantly associated with risk
for NAFLD and demonstrates an interaction with leptin level.
Among individuals with lower leptin levels, H pylori positivity is
inversely associated with the risk for NAFLD; however, among
individuals in the highest leptin tertile, H pylori is associated
with increased risk for NAFLD. Our findings warrant further
physiologic investigations in patients with NAFLD to better
delineate complex associations between H pylori and meta-
bolic regulatory processes.
Disclosures:
The following people have nothing to disclose: Joseph Roberts, William LeBlanc,
Kiran Bambha
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
867
Nonalcoholic Fatty Liver Disease Is Associated With
Arterial Stiffness Measured by Cardio-Ankle Vascular
Index
Donghee Kim1,
Goh Eun Chung1,
Su-Yeon Choi1,
Min-Sun Kwak1,
Won Kim2, Yoon Jun Kim3, Jung-Hwan Yoon3; 1Seoul national
university hospital Gangnam Healthcare center, Seoul, Republic
of Korea; 2Seoul Metropolitan Government Seoul National Uni-
versity Boramae Medical Center, Seoul, Republic of Korea; 3Seoul
National University College of Medicine, Seoul, Republic of Korea
Introduction: Nonalcoholic Fatty Liver Disease (NAFLD) is
known to be related to risk factors of cardiovascular disease
such as dyslipidemia, diabetes, and metabolic syndrome.
Arterial stiffness is a strong predictor of future cardiovascu-
lar events and all-cause mortality, and it is one of the earliest
detectable manifestations of adverse structural and functional
change of vessel walls. Cardio-ankle vascular index (CAVI),
a new index of arterial stiffness, is recently developed and is
independent of blood pressure. In recent studies, CAVI was the
best reliable index of arterial stiffness in many cardiovascular
diseases. We investigated whether NAFLD is associated with
arterial stiffness as measured CAVI in the apparently healthy
general population. Methods: A total of 2,954 subjects (mean
age 55.8 ± 9.8, male 64.7%) who visited health screening
center were enrolled without known liver disease (Hepatitis
B, Hepatitis C, alcoholic, other hepatitis history) from 2010
to 2013. NAFLD was diagnosed by typical ultrasonographic
findings. Clinical characteristics included sex, age, body mass
index (BMI), waist circumference (WC), aspartate aminotrans-
ferase (AST), alanine aminotransferase (ALT), total cholesterol,
high-density lipoprotein (HDL) cholesterol, triglycerides (TG),
and glucose. Arterial stiffness was defined as age, sex-spe-
cific cutoff of upper quartile of CAVI. Results: CAVI was sta-
tistically significantly associated with age, BMI, WC, ALT,
TG, HDL cholesterol, and with increased odds of diabetes,
hypertension, dyslipidemia, and severity of NAFLD. Arterial
stiffness (Increased CAVI) showed positive relationship with
NAFLD (age, sex, BMI- adjusted odds ratio [OR] 1.41, 95%
confidence interval [CI] 1.16-1.70, p<0.001) and dose-de-
pendent association with moderate-severe NAFLD (OR 1.78,
95% CI 1.37-2.31, p<0.001). Multivariate regression analy-
sis adjusted for age, sex, BMI, WC, diabetes, hypertension,
smoking, total cholesterol, TG and HDL cholesterol showed that
arterial stiffness was significantly associated with presence of
NAFLD (OR 1.26, 95% CI 1.02-1.56) and moderate-severe
NAFLD (OR 1.48, 95% CI 1.11-1.98). Conclusions: Patients
with NAFLD are at high risk of arterial stiffness regardless of
classical risk factors. Detection of NAFLD should alert to the
existence of an increased cardiovascular risk. NAFLD per se
might be the independent risk factor for arterial stiffness.
Disclosures:
The following people have nothing to disclose: Donghee Kim, Goh Eun Chung,
Su-Yeon Choi, Min-Sun Kwak, Won Kim, Yoon Jun Kim, Jung-Hwan Yoon
619A
868
Extremely low awareness and under-diagnosis of
NAFLD in a population-based sample
Lisa B. VanWagner1,2, Mary E. Rinella1, Hongyan Ning2, Donald
M. Lloyd-Jones2,3, Cora E. Lewis4, Miriam B. Vos5; 1Medicine, Divi-
sion of Gastroenterology & Hepatology, Northwestern University
Feinberg School of Medicine, Chicago, IL; 2Preventive Medicine,
Northwestern University Feinberg School of Medicine, Chicago, IL;
3Medicine, Division of Cardiology, Northwestern University Fein-
berg School of Medicine, Chicago, IL; 4Department of Medicine,
Division of Preventive Medicine, University of Alabama at Birming-
ham, Birmingham, AL; 5Pediatrics, Division of GI, Hepatology and
Nutrition & Nutrition Health Sciences, Emory University, Atlanta,
GA
Background: NAFLD is the most common chronic liver disease
in the United States affecting 30% of the adult population and
70% of individuals with the metabolic syndrome, who are at
highest risk of developing severe disease. Yet, little is known
about NAFLD awareness in individuals with fatty liver. In a
large population-based cross-sectional sample of black and
white adults we aimed to assess the prevalence of undiag-
nosed fatty liver among individuals with and without meta-
bolic risk factors. Methods: Participants from the Coronary
Artery Risk Development in Young Adults study (Y25 exam;
age 43-55 years) with concurrent CT quantification of liver
fat and self report of previous diagnosis of fatty liver were
included (n=2,712). NAFLD was defined as liver attenuation ≤
51 Hounsfield units after exclusion of other causes of liver fat
(medication/alcohol use and HIV/Hepatitis C). Chi-squared
and logistic regression analyses were used to assess associ-
ations. Results: Mean participant age was 50.6 (4.0) years
with 293 (57.7%) female and 299 black (49.7%) participants.
Mean BMI was 30.6 (7.1) kg/m2. NAFLD prevalence was
23.8%, however only 15/646 (2.3%) participants with CT-de-
fined NAFLD were aware of a NAFLD diagnosis. Even when
the definition was broadened to include any self-reported liver
disease, only 34 (5.3%), reported knowing that they had fatty
liver despite CT findings. NAFLD aware participants were
more likely to be white (80.0% vs. 53.1%, p=0.04) and have
the metabolic syndrome (93.3% vs. 59.1%) and hyperten-
sion (80.0% vs. 50.6%) than NAFLD unaware participants
(p<0.05 for both). There were no significant differences in
age, sex, alcohol intake, physical activity, medication use,
diabetes status, waist circumference, education or income
level between NAFLD aware and unaware groups. In multi-
variable analyses adjusted for demographics, presence of the
metabolic syndrome was associated with NAFLD awareness
(OR=10.7, 95% CI: 1.38-82.8). However, the overall preva-
lence of NAFLD awareness even among metabolic syndrome
participants remained low (3.6%). In sensitivity analyses using
self-report of any liver disease (n=34) this association did not
change. Conclusion: There is a low awareness of fatty liver in
individuals with fat on imaging, which persists even among
those with metabolic risk factors who are at the highest risk of
severe liver disease. These findings highlight an opportunity to
raise public and practitioner awareness of NAFLD, particularly
among those at high metabolic risk, and to provide education
to patients and practitioners with the goal of increasing diag-
nosis, implementing early treatment strategies and optimizing
care.
Disclosures:
Mary E. Rinella - Advisory Committees or Review Panels: Gilead
The following people have nothing to disclose: Lisa B. VanWagner, Hongyan
Ning, Donald M. Lloyd-Jones, Cora E. Lewis, Miriam B. Vos
620A AASLD ABSTRACTS
869
Assessment of glycemic variability by continuous glu-
cose monitoring system in patients with nonalcoholic
fatty liver disease
Makiko Taniai, Etsuko Hashimoto, Kazuhisa Kodama, Tomomi
Kogiso, Katsutoshi Tokushige, Keiko Shiratori; Internal Medicine,
Institute of Gastroenterology, Tokyo Women’s Medical University,
Tokyo, Japan
<Background and Aims> Patients with nonalcoholic fatty liver
disease (NAFLD) often have metabolic disorders including
insulin resistance (IR) and type 2 diabetes mellitus (DM). DM
is known to be an independent risk factor for the develop-
ment and progression in NAFLD. Furthermore, postprandial
hyperglycemia and glycemic variability were reported to
involve hepatic fibrosis progression. A continuous glucose
monitoring system (CGMS) was recently introduced to detect
detailed daily glycemic variability including episodic hypo-
glycemia while sleeping. In this study, we investigated daily
blood sugar (BS) changes in NAFLD patients using CGMS.
<Patients and Methods> Sixty-five patients; 35 female, median
age 61 years, median body mass index (BMI) 27.1 with biop-
sy-proven NAFLD according to Brunt’s fibrosis stage; 9 patients
of F1, 23 of F2, 18 of F3, and 15 of F4, were enrolled. We
performed 75g oral glucose tolerance tests (OGTT) in 28
patients with <140mg/dl fasting BS without a diagnosis of DM
before enrollment, and the changes in BS during 24 hours by
Medtronic iPro2® CGMS were evaluated in all 65 patients.
Of 37 patients with DM including 3 diagnosed by OGTT, 7
received insulin injections, 3 sulfonylurea (SU), 3 metformin
(Met), 8 DPP4 antagonist (DPP4), 5 Met +DPP4, 3 SU+DPP4,
3 SU+Met+DPP4, and 12 dietary therapy alone. Informed
consent in writing was obtained from each patient and the
study protocol conformed to the ethical guidelines of the 1975
Declaration of Helsinki and our institutional review committee.
<Results> The prevalence of DM was significantly higher with
the progression of hepatic fibrosis, at 80% in patients with
cirrhosis vs. 50% without cirrhosis. CGMS revealed variability
of median BS, standard deviation of median BS, maximum
(max) BS, and differences in max and minimum (min) BS to
be significantly higher in cirrhotic patients (0.01, 0.01, 0.02,
and 0.003, respectively). Postprandial hyperglycemia exceed-
ing 300 mg/dl and a difference between max and min BS
over 200 mg/dl were seen only in 5 cirrhotic patients with
DM. Interestingly, nocturnal hypoglycemia with BS<60mg/dl
was seen in 7 males with remarkably high serum insulin levels
(median serum fasting immunoreactive insulin level 27.6 μU/
mL); median age 31 years, 6 patients with super-obesity; BMI
>35, 4 diagnosed with impaired glucose tolerance, 6 in F1 or
F2, and none being treated with anti-diabetic drugs. <Conclu-
sion> CGMS analysis revealed postprandial hyperglycemia
in cirrhotic patients and nocturnal hypoglycemia in relatively
young and highly overweight males with severe IR and mild
fibrosis revealed to be characteristic of NAFLD patients. The
latter might predict both the progression of hepatic fibrosis and
a poor outcome.
Disclosures:
The following people have nothing to disclose: Makiko Taniai, Etsuko Hashimoto,
Kazuhisa Kodama, Tomomi Kogiso, Katsutoshi Tokushige, Keiko Shiratori
HEPATOLOGY, October, 2014
870
Is fatty liver in diabetes a risk factor for HCC and car-
diovascular disease? Prospective 10-year cohort study
Masataka Seike, Koichi Honda, Junya Oribe, Mizuki Endo, Mie
Yoshihara, Masanori Tokoro, Masao Iwao, Hiroki Syo, Kazunari
Murakami; Gastroenterology, Oita University, Yufu-city, Japan
Objectives: Diabetes and fatty liver (FL) disease are risk fac-
tors for hepatocellular carcinoma and cardiovascular disease.
However, the effect of fatty liver in diabetes remains unclear.
We tried to elucidate the roles of fatty liver in diabetes related
to prognosis, including HCC, extrahepatic tumor, and cardio-
vascular events. Methods: Study design: Prospective cohort
study. A total of 670 diabetic patients (aged 40–79 years)
who underwent abdominal ultrasonography (US) between
April 2003 and March 2004 were enrolled. Of these patients,
233 were excluded from analysis because they were positive
for hepatitis B surface antigen, hepatitis C antibody, or alcohol
abuse or because they dropped out of our study in the subse-
quent 10 years. The remaining 458 patients were allocated to
two groups, a FL group (n =202; 109 males and 93 females,
mean age was 64 years.) and a non-FL (NFL) group (n = 235;
155 males and 80 females,mean age was 62 years), based
on US findings, and followed by a diabetologist and/or hepa-
tologist for 10 years. The primary endpoint was occurrence of
HCC and extrahepatic tumors. Cardiovascular events were a
secondary endpoint. Results: During the observation period,
24 patients were diagnosed with 24 gastrointestinal tumors,
including 9 patients with gastric cancer (1.9%) and 4 patients
with HCC (0.9%). Two HCC patients had past history of heavy
drinking of alcohol. The etiology of HCC in the remaining two
patients is unclear. No significant differences were observed
between the FL group and NFL group in the occurrence rates
of HCC, extrahepatic tumors, and cardiovascular events.
However, in the FL group, the ALT serum level (>30 IU/L) was
significantly associated with the incidence of macrovascular
events in univariate (odds ratio [OR], 5.296 (1.440-19.476)
p=0.0084) and multivariate (OR, 6.005 (1.555-23.182);
p=0.0093) analyses.The γ-GTP serum level (>50IU/L) was a
significant risk factor for extrahepatic tumors in all patients.
Conclusion: A serum ALT level of 30 IU/L is an independent
risk indicator of macrovascular disease in diabetic patients
with FL, whereas the presence of FL itself in diabetes patients
is not associated with an increased incidence of macrovas-
cular events and malignancy. However, serum ALT level is a
biomarker for cardiovascular events in patients with fatty liver.
Disclosures:
The following people have nothing to disclose: Masataka Seike, Koichi Honda,
Junya Oribe, Mizuki Endo, Mie Yoshihara, Masanori Tokoro, Masao Iwao,
Hiroki Syo, Kazunari Murakami
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS 621A

871 Joel E. Lavine - Consulting: Merck, Crosscare, Gilead, Takeda Millenium; Grant/
Research Support: Janssen
Risk of severe fibrosis is associated with age at meno-
Anna Mae Diehl - Consulting: Roche; Grant/Research Support: Gilead, Genfit
pause in nonalcoholic fatty liver disease (NAFLD)
The following people have nothing to disclose: Jagpal S. Klair, Ju Dong Yang,
Jagpal S. Klair1, Ju Dong Yang1, Manal F. Abdelmalek2, Cynthia Cynthia D. Guy, Ryan M. Gill, Katherine P. Yates, Aynur Unalp-Arida, Jeanne
D. Guy3, Ryan M. Gill4, Katherine P. Yates5, Aynur Unalp-Arida5, M. Clark, Ayako Suzuki
Joel E. Lavine6, Jeanne M. Clark7, Anna Mae Diehl2, Ayako
Suzuki8,9; 1Internal Medicine, University of Arkansas for Medical
Sciences, Little Rock, AR; 2Division of Gastroenterology and Hepa- 872
tology, Duke University, Durham, NC; 3Dept. of Pathology, Duke Autoimmunity to Human Heat Shock Protein-70 is Asso-
University, Durham, NC; 4Dept. of Pathology, University of Califor- ciated with the Presence of Coronary Artery Disease in
nia San Francisco, San Francisco, CA; 5NASH CRN Data Coordi- Patients with Nonalcoholic Fatty Liver Disease
nating Center, Johns Hopkins Bloomberg School of Public Health,
Elzafir Elsheikh1,2, Zahra Younoszai2, Munkhzul Otgonsuren2,
Baltimore, MD; 6Dept. of Pediatrics, Columbia University, New
Maria C. Albano3, Ingrid Schneider3, Hussain Allawi2, Brian P.
York, NY; 7Division of General Internal Medicine, Johns Hopkins
Lam1, Yousef Fazel2, Michael L. Campbell2, Thomas Jeffers2, Spen-
Bloomberg School of Public Health, Baltimore, MD; 8Division of
cer Frost2, Bryan Raybuck3, Zobair Younossi1,2; 1Center for Liver
Gastroenterology, Central Arkansas Veterans Healthcare System,
Diseases, Inova Fairfax Hospital, Falls Church, VA; 2Betty and Guy
Little Rock, AR; 9Division of Gastroenterology and Hepatology,
Beatty Center for Integrated Research, Inova Health System, Falls
University of Arkansas for Medical Sciences, Little Rock, AR
Church, VA; 3Department of Medicine, Inova Fairfax Hospital,
[Background & aim] We recently reported that pre-menopausal Falls Church, VA
women have less severe fibrosis than men and post-meno-
Background: Experimental evidence suggests a cardiopro-
pausal women among patients with nonalcoholic steatohep-
tective role of heat shock proteins (HSP) in several models of
atitis (NASH), suggesting a protective effect of estrogens. We
acute myocardial stress. Patients with both non-alcoholic fatty
hypothesized that among postmenopausal women, those who
liver disease (NAFLD) and coronary artery disease (CAD) have
had menopause at an earlier age are at an increased risk
lower levels of serum HSP. HSP may stimulate autoimmune
of hepatic fibrosis and that time after menopause positively
responses resulting in the production of antibodies. Aim The
correlates with fibrosis severity. In this analysis we aimed to
aim of this study is to investigate the possible role of anti-HSP
investigate the associations of premature menopause (age at
auto-antibodies in reduction of HSP in patients with NAFLD,
menopause of <40years) and the time from menopause with
leading to increased prevalence of coronary artery disease
fibrosis severity among women with NAFLD. [Methods] We
(CAD). Methods: We prospectively enrolled 119 patients
analyzed data from 491 post-menopausal women enrolled in
undergoing elective coronary angiography. Each patient had
the NASH CRN with 1) a histologic diagnosis of NAFLD and
fasting serum, clinical data and abdominal ultrasound (US).
2) self-reported information on age at menopause. Premature
All US were read centrally by a standard protocol. NAFLD
menopause was defined as age at menopause of <40 years
was defined as radiologic fatty liver in the absence of other
(yrs). Time difference between age at menopause and age at
causes of liver disease and excessive alcohol use. Patients
study enrollment was calculated as yrs. Liver biopsies were
were divided into NAFLD with CAD (n=54), NAFLD without
read and scored according to NASH CRN scoring system. The
CAD (n=15), only CAD (n=34) and Non-NAFLD and Non-
associations of premature menopause and the time from meno-
CAD (n=16). Each angiogram was reviewed centrally for the
pause with fibrosis severity (stage 0-4) were assessed using
presence and severity of CAD (number of proximal arterial seg-
ordinal logistic regression models with and without adjusting
ments with>70% stenosis). Concentrations of anti-HSP antibod-
for age at enrollment, race/ethnicity, waist circumference, cur-
ies (anti-HSP27, anti-HSP60 and anti-HSP70) were determined
rent smoking/alcohol use, hypertension, diabetes, HOMA-IR,
in the serum collected at the time of angiography using ELISA
and hormone replacement therapy (HRT). [Results] Mean age ±
technique. Results: The levels of the serum anti-HSP70 antibod-
SD at menopause was 44 ± 9 yrs. 29.5% women had prema-
ies were higher in NAFLD patients with CAD (median, 30.6
ture menopause. This group was younger at enrollment (55 ± 9
mg/ml) than NAFLD patients without CAD (median, 26.0 mg/
vs. 59 ± 7 yrs, p<0.001, t-test) and used HRT more often (32%
ml, P=0.04). We also found that the levels of the serum anti-
vs. 19%, p<0.003, Chi-square test). Premature menopause
HSP60 antibodies were higher in NAFLD patients with CAD
was associated with a higher stage of fibrosis (p<0.05, Wil-
(median, 23.8 mg/ml) than patients with only CAD (median,
coxon rank-sum test). No significant differences were noted in
16.6 mg/ml, P=0.04). Furthermore, severity of CAD positively
other histologic features or above-listed clinical variables. After
correlated with anti-HSP70 antibodies (r=0.33; P=0.01). In
adjusting for age at enrollment, premature menopause was
this cohort, levels of serum anti-HSP70 antibodies [OR: 1.08
associated with an increased likelihood of having more severe
(95% CI: 1.01-1.16)] and age [OR: 1.11 (95%: 1.03-1.21)]
fibrosis; cumulative odds ratio and 95% confidence interval
were independently associated with the risk of having CAD in
(COR[95%CI]) was 1.7[1.2, 2.4] (p< 0.004), which remained
patients with NAFLD. Levels of anti-HSP27 antibodies were not
similar after adjusting for the other variables. Time from meno-
significantly associated with CAD in NAFLD. Conclusions: In
pause was also directly associated with an increased likeli-
patients with NAFLD, anti-HSP70 auto-antibodies may play a
hood of having more severe fibrosis (COR[95%CI] for 5-year
role in the development of CAD by attenuating the cardiopro-
unit=1.2[1.1, 1.3], p<0.0001), which also remained the same
tective effect of the HSP70. The ratio of the anti-HSP antibodies
after adjusting for the other variables. [Conclusion] Age at
to HSP may also have diagnostic value.
menopause was significantly associated with a risk of fibro-
Disclosures:
sis among post-menopausal women with NAFLD. This finding,
Brian P. Lam - Advisory Committees or Review Panels: BMS; Speaking and Teach-
together with our previous reports, underscores the significance ing: Gilead; Stock Shareholder: Gilead
of reproductive information for risk stratification among female The following people have nothing to disclose: Elzafir Elsheikh, Zahra Younoszai,
patients with NAFLD. Munkhzul Otgonsuren, Maria C. Albano, Ingrid Schneider, Hussain Allawi,
Disclosures: Yousef Fazel, Michael L. Campbell, Thomas Jeffers, Spencer Frost, Bryan Ray-
buck, Zobair Younossi
Manal F. Abdelmalek - Consulting: Islet Sciences; Grant/Research Support:
Mochida Pharmaceuticals, Gilead Sciences, NIH/NIDDK, Synageva, Genfit
Pharmaceuticals
622A AASLD ABSTRACTS
873
Performance and limitations of five steatosis biomarkers
in patients with Non-alcoholic Fatty Liver Disease
Fabio Nascimbeni1,2, Larysa Fedchuk2, Raluca Pais2, Frederic
Charlotte3, Chantal Housset2, Paola Loria1, Vlad Ratziu2; 1Depart-
ment of Biomedical, Metabolic and Neural Sciences, University of
Modena and Reggio Emilia, Modena, Italy; 2Department of Hepa-
tology and Gastroenterology, Pitié Salpêtrière Hospital, University
Pierre et Marie Curie, Paris, France; 3Department of Pathology,
Pitié Salpêtrière Hospital, University Pierre et Marie Curie, Paris,
France
Background. Several steatosis biomarkers (SbM) are available
with limited independent validation. Aim. To determine the
diagnostic value and the limitations of several SbM using liver
biopsy as a reference standard in a large cohort of patients
with suspected NAFLD. Their performance for the diagnosis
and the quantification of steatosis, the confounding effect of
fibrosis and inflammation and their relationship to insulin resis-
tance were studied. Methods. 324 consecutive liver biopsies
performed for suspected NAFLD were included. Histological
steatosis was categorized as none(<5%), mild(5-33%), mod-
erate(33-66%) and severe(>66%). Five SbM were measured:
fatty liver index (FLI), NAFLD liver fat score (LFS), hepatic
steatosis index (HSI), visceral adiposity index (VAI) and tri-
glyceride x glucose (TyG) index. Results. The prevalence of
steatosis grades was: none 5%, mild 39%, moderate 30% and
severe 27%. Except for VAI, the SbM showed a linear trend
across the steatosis grades. However, their correlation with the
histological amount of steatosis was only weak to moderate
(Spearman’s rho: FLI, 0.28; LFS, 0.42; HSI, 0.30; VAI, 0.21;
TyG, 0.19). All SbM had an adequate diagnostic accuracy
for the presence of steatosis: AUROCs for FLI, LFS, HSI, VAI,
and TyG were 0.83, 0.80, 0.81, 0.92, and 0.90. However,
their ability to quantify steatosis was poor: none of them dis-
tinguished between moderate and severe steatosis (FLI 80±20
vs. 77±22; LFS 1.9±2.6 vs. 2.2±2.8; HSI 44±6 vs. 45±7; VAI
3.7±8.3 vs. 3.3±3.2; TyG 9.0±0.7 vs. 8.9±0.7, respectively,
all p=1.00), even after restricting the analysis to patients with
ultrasonographically defined fatty liver. AUROCs for predicting
steatosis>33% were 0.65, 0.72, 0.65, 0.59, and 0.59 for FLI,
LFS, HSI, VAI, and TyG, respectively. Both fibrosis and inflam-
mation significantly confounded the association between SbM
and steatosis: after adjustment for the amount of steatosis, the
mean values of all SbM were significantly higher in patients
with bridging fibrosis/cirrhosis or necroinflammation than in
those without. The SbM were all correlated with HOMA-IR,
independent from histological steatosis (Pearson’s coefficient:
0.29 for FLI, 0.86 for LFS, 0.35 for HSI, 0.16 for VAI, 0.33 for
TyG). Conclusion. All five SbM can diagnose steatosis and are
correlated with insulin resistance but are confounded by fibro-
sis and inflammation and do not accurately quantify steatosis.
This may limit their clinical utility, in particular for the serial
monitoring of patients undergoing therapeutic interventions.
More research is needed to identify truly independent and
quantitative markers of steatosis.
Disclosures:
Vlad Ratziu - Advisory Committees or Review Panels: GalMed, Abbott, Genfit,
Enterome, Gilead; Consulting: Astellas, Axcan, Pfizer, Sanofi-Synthelabo, Genen-
tech, Nycomed
The following people have nothing to disclose: Fabio Nascimbeni, Larysa Fed-
chuk, Raluca Pais, Frederic Charlotte, Chantal Housset, Paola Loria
HEPATOLOGY, October, 2014
874
A deficiency in 25-OH vitamin D is associated with
increased steatohepatitis in alcoholic patients
Clémence M. Canivet1, Rodolphe Anty1,2, Stephanie Patouraux1,2,
Antonio Iannelli1,2, Patricia Panaia-Ferrari1, Imed Ben Amor1,
Anne-Sophie Schneck1,2, Marie-Christine M. Saint-Paul1, Jean
Gugenheim1,2, Philippe Gual2, Albert Tran1,2; 1Centre Hospitalier
universitaire de Nice, Nice, France; 2Team 8 “hepatic complica-
tions in obesity”, Institut National de la Santé et de la Recherche
Médicale, Nice, France
Introduction: Among its pleiotropic effects, vitamin D could be
protective for the liver. A deficiency in 25-OH vitamin D is
generally associated with a higher level of fibrosis and/or
inflammation during chronic hepatitis whatever the cause of
the aggression. However some studies in hepatitis C and in
Non-alcoholic fatty liver diseases (NAFLD) are contradictory
and very few studies have been done in alcoholic patients.
We compared the blood level of 25-OH vitamin D with the
severity of liver lesions in alcoholic patients or obese patients
exposed to steatohepatitis and liver fibrosis. Patients and
method: Cohorts of 101 alcoholic patients (81.2 % of men,
48 [40.5-54] years old, median BMI 24 [22-27] kg/m2) and
398 morbidly obese patients (16.1% of men, 40 [31-50] years
old, median BMI 42.2 [39.5-45.4] kg/m2) were studied. All
the patients had a liver biopsy. 25-OH vitamin D was evalu-
ated with a Diasorin®Elisa Kit. Logistic regression analyses
were performed to obtain predictive factors of the severity of
liver histology. Results: The global level of 25-OH vitamin D
was already lower in alcoholic patients 8.0 [5.7-15.1] ng/
ml compared with obese patients 18.8 [12.9-24.2] ng/ml
(p<0.0000001) independently of liver complications. In alco-
holic patients 40.2% had a steatohepatitis and 20.6% a bridg-
ing fibrosis. The levels of 25-OH vitamin D were decreased in
patients with steatohepatitis or with bridging fibrosis but its low
level was independently associated only with steatohepatitis
(6.5 [4.5-8.0] vs 12.0 [6.6-18.4] ng/ml, p=0.000003). In
morbidly obese patients, 20.6% had a steatohepatitis, 28.9%
a “moderate” fibrosis (F≥2 according to the NASH CRNSS)
and 4.3% a bridging fibrosis. The 25-OH vitamin D level
decreased with “moderate” fibrosis (15.9 [11.1-23.5] vs 19.6
[13.7-24.7] ng/ml, P=0.02) but not with bridging fibrosis and
not with NASH. Stages of fibrosis were independently asso-
ciated with steatohepatitis in alcoholic and obese patients,
respectively, but not with a vitamin D deficiency. Conclusion:
Alcoholic patients were frequently deficient in 25-OH vitamin
D. This was highly more frequent compared to morbidly obese
patients. In alcoholic patients, low levels of 25-OH vitamin D
were associated with the bridging fibrosis and independently
associated with the presence of alcoholic steatohepatitis. The
role of vitamin D in the evolution of fibrosis could be indirect
through the severity of the inflammation. In morbidly obese
patients, these associations were not found. Vitamin D supple-
mentation in alcoholic patients should be tested in clinical trials
to determine if it is possible to prevent or reduce the severity of
liver histology and mortality.
Disclosures:
The following people have nothing to disclose: Clémence M. Canivet, Rodolphe
Anty, Stephanie Patouraux, Antonio Iannelli, Patricia Panaia-Ferrari, Imed Ben
Amor, Anne-Sophie Schneck, Marie-Christine M. Saint-Paul, Jean Gugenheim,
Philippe Gual, Albert Tran
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
875
Association between Type 2 Diabetes Genetic Suscepti-
bility Loci and Hepatocellular Carcinoma in Patients with
Type 2 Diabetes as Determined by Fibroscan
Masaaki Korenaga1, Misuzu Ueyama1, Nao Nishida1, Keiko
Korenaga1, Takumi Kawaguchi2, Hideyuki Hyogo 3, Hiroshi
Aikata3, Erina Kumagai1, Yoshihiko Aoki1, Masaya Sugiyama1,
Masatoshi Imamura1, Kazumoto Murata1, Tatsuya Kanto1, Nao-
hiko Masaki1, Masashi Mizokami1; 1Reserach center for hepstitis
and Immunology, National Center of Global Health and Medicine
(NCGM) at Kohnodai, Ichikawa, Japan; 2Department of Diges-
tive Disease Information & Research, Kurume University School of
Medicine, Kurume, Japan; 3Department of Gastroenterology and
Metabolism, Hiroshima University, Hiroshima, Japan
Background and Aims: Several metabolic disorders, such as
type 2 diabetes (T2DM), obesity, and hepatic steatosis, are
associated with liver cirrhosis (LC) and development of hepato-
cellular carcinoma (HCC). New genetic loci that contribute to
the development of T2DM have been identified by genome-wide
association studies. The aim of this study was to examine the
association between T2DM susceptibility loci and liver disease
progression in Japanese patients with T2DM. Methods: We
genotyped 642 Japanese patients with T2DM, who underwent
Fibroscan for liver stiffness measurements and were assessed
for the following T2DM-related single-nucleotide polymorphisms
(SNPs) in Japan: EIF2AK4 rs2250402, KRT4 rs2307027,
FAM60A rs3741872, ANGPT4rs574628, SPDEF rs2233647,
A2BP1 rs3785233, Intergenic rs2075931, SLC30A8
rs13266634 rs3802177, HHEX rs1111875 rs7923837,
CDKN2B rs10811661 rs564398, GCKR rs780094, IGF2BP2
rs4402960 rs1470579, CDKAL1 rs7754840 rs7756992,
TCF7L2 rs7903146, KCNJ11 rs5219, PPARG rs1801282,
KCNQ1 rs2237892, HNF1B rs7501939 rs4430796,
KCNJ15 rs743296 rs3746876, ACACB rs2268388, SRR
rs391300 rs4523957, PTPRD rs17584499, and KCNQ1
rs231359 rs223895. Three hundred thirty patients were
positive for hepatitis C virus (HCV), and 312 patients were
negative for HCV and hepatitis B virus (HBV). Fibroscan mea-
surements (M probe for patients with body mass index (BMI)
< 25 kg/m2, and XL probe for patients with BMI ≥ 25 kg/
m2) were used to distinguish between chronic hepatitis (CH;
≤7 kPa, n = 60) and LC/HCC (≥12.5 kPa, n = 118) in HCV
patients and for patients without HCV/HBV between controls
(normal: ≤6 kPa, n = 122) and cases (advanced fibrosis/HCC:
≥10 kPa, n = 72). All patients (n = 196) without HCV/HBV
had more than 10 years’ history of T2DM and were genotyped
as PNPLA3 rs738409. Results: There were no differences in
the distributions of these SNPs between the CH and LC/HCC
groups in HCV patients. In T2DM patients without HCV/HBV,
the ACACB rs2268388 risk alleles exhibited significant associ-
ations with case group (p = 0.0016, odds ratio [OR] 2.1785).
No other SNPs were significantly associated with advanced
fibrosis/HCC. The distribution of the PNPLA3 rs738409 risk
allele was significantly increased in the case group compared
to the control; however, the ACACB and PNPLA3 risk alleles
were independently associated with advanced fibrosis/HCC
(p = 0.0059, OR = 0.5027 and p = 0.0032, OR= 0.3076,
respectively). Conclusions: The rs2268388 in the ACACB gene
is associated with liver disease progression in Japanese T2DM
patients who are not infected with HCV/HBV.
Disclosures:
The following people have nothing to disclose: Masaaki Korenaga, Misuzu
Ueyama, Nao Nishida, Keiko Korenaga, Takumi Kawaguchi, Hideyuki Hyogo,
Hiroshi Aikata, Erina Kumagai, Yoshihiko Aoki, Masaya Sugiyama, Masa-
toshi Imamura, Kazumoto Murata, Tatsuya Kanto, Naohiko Masaki, Masashi
Mizokami
623A
876
NAFLD: A marker of severe Acute Pancreatitis
Sarfaraz A. Jasdanwala1, Shivank Madan2, Rajagopalan Siv-
aprasad1, Capecomorin Pitchumoni2; 1Monmouth Medical Center,
Long Branch, NJ; 2St peters university hospital, New Brunswick, NJ
Introduction: Obesity has been a well-recognized marker of
severity of acute pancreatitis (AP) [1]. However, many studies
have clearly made a distinction between obesity measured by
BMI as compared to metabolic (central) obesity which is part of
metabolic syndrome(MS) that includes diabetes mellitus, hyper-
tension and hyperlipidemia. Non-alcoholic fatty liver disease
(NAFLD) is a well-recognized complication of MS that is easily
diagnosed by ultrasound(US) abdomen, a routine procedure
on admission in all patients with AP to evaluate the presence of
gall stones. Aim: To correlate the severity of AP as determined
by Modified Atlanta Classification system(MAS), Determinant
Based Classification system (DBS), Mean BISAP score, pres-
ence or absence of pleural effusion(PlE), intensive care unit
(ICU) admission and mean length of stay (LOS) with presence
of NAFLD diagnosed by admission abdominal US and/or CT
scan. Methods: In this retrospective study, 325 cases that satis-
fied the American College of Gastroenterology (ACG) criteria
for the diagnosis of AP [2] were included. Approval from the
Institutional Review Board was obtained. Diagnosis of NAFLD
or exclusion of it was based on abdominal US and/or CT
which were available in all patients. Patients with non-alco-
holic AP were divided into two groups – with and without
NAFLD. We analyzed the frequency of PlE, BISAP score, MAS,
DBS, frequency of ICU admission and mean LOS. The results
were compared in the two groups using the student’s t- test and
CHI square test. Conclusions: NAFLD 1. as a single marker,
correlates well with all other indicators of severity; single as
well as well established scoring systems. 2. is associated with
increased severity of AP. 3. diagnosed by initial abdominal
US or CT performed in the ER should serve as a single, early,
easily available, radiological marker of severity in AP. Refer-
ences:1. Sawalhi S et al. Does the Presence of Obesity and/
or Metabolic Syndrome Affect the Course of Acute Pancreati-
tis?:A Prospective Study. Pancreas 2014; 43(4):565-70. 2.
Tenner S et al. American College of Gastroenterology Guide-
line: Management of Acute Pancreatitis. Am J Gastroenterol
2013;108:1400–15.
Disclosures:
The following people have nothing to disclose: Sarfaraz A. Jasdanwala, Shivank
Madan, Rajagopalan Sivaprasad, Capecomorin Pitchumoni
624A AASLD ABSTRACTS
877
Berberine with Alfa Lipoic Acid (ALA) in Non Alcoholic
Steato-hepatitis (NASH). A randomized double blinded
placebo control trial. A Clinical pilot – The BANISH Trial
Patrick Basu1,2, Niraj J. Shah3, M. Aloysius2; 1Columbia Univer-
sity School of Physicians and Surgeons, New York, NY; 2King’s
County Hospital Medical Center, NY, New York, NY; 3James J.
Peters VA Medical Center, Icahn School of Medicine at Mount
Sinai, NY, New York, NY
Objective: NASH is a globally challenging clinical morbidly;
causing cirrhosis and liver cancer in due time with formidable
cost burden. Therapeutic modalities have not yet been fully
established. Anti-oxidants and insulin sensitizers altering insulin
resistance, inhibiting intra hepatic oxidative stress with inhibi-
tion of formation of free radicals and blocking inflammatory
cytokines to prevent fibrosis. Berberine is a natural substance
extracted from plants like Berberis which is found to up-reg-
ulate intra hepatic pathways as insulin sensitizer, via GLP-1
up regulation and Acyl palmotyl mechanism on fatty acid oxi-
dation, induction of PPAR gama; all that blocks the terminal
inflammatory Cytokine release TNF Alfa to prevent fibrosis
that will prevent the End stage liver disease (ESLD) and liver
cancer. Methods: Hundred and twenty patients (n=120) with
NASH were recruited. Mean BMI 29.9% (29% to 32%) with
69 males and 51 females. Hispanic 46, Caucasians 34, Asian
Pacific15, Black 11, Asian 14. Mean HbA1C 6.2 (5.9- 6.8),
Mean HOMA 2.7 (2.1-3.6), ALT 54 (38-79), Triglyceride 287
(233-344), LDL c 163 (129-176), Leptin 63 (43-98), Adiponec-
tin 0.9 (0.1-1.1), RBP 4 of 5.8 (4.0-6.8), TNF Alfa 3.8 (2.1-
4.8), IL 12 of 5.3 (3.9-7.8), Serum Fibrotic and Steatotic scores
were measured at 0 and then at 6 months. Daily allowed
caloric content was 2,000 cal/ day, no documented exercise
except daily activities at baseline for 6 months. All patients
were divided into: Primary endpoints: ALT normalization, near
normalization of HOMA Index and lipid panel Secondary
endpoints: Normalization of Inflammatory markers eg. Leptin,
TNF Alfa, IL 10, and reversal of fibrosis and steatosis score.
Exclusion Criteria: Chronic hepatitis B and C, HIV, Other liver
diseases, Alcohol consumption more than 30 grams a week,
Diabetes, Drugs (Steroids, Tamoxifen) causing fatty liver or
any lipodystrophic syndromes. Results:table Conclusion: All the
study arms showed statistically significant (p<0.05) post inter-
ventional change except for Adiponectin in group A (p=0.09)
Results
Disclosures:
The following people have nothing to disclose: Patrick Basu, Niraj J. Shah, M.
Aloysius
HEPATOLOGY, October, 2014
878
Elevated biomarker-indicated liver disease and pro-in-
flammatory cytokines are associated with environmen-
tal PCB exposure in Anniston, Alabama
Heather B. Clair1, Keith C. Falkner1, Banrida Wahlang1, Russell
A. Prough1, Matthew C. Cave1,2; 1Department of Medicine/GI,
University of Louisville, Louisville, KY; 2Robley Rex VA Medical
Center, Louisville, KY
Purpose: Residents of Anniston, AL are exposed to high envi-
ronmental levels of polychlorinated biphenyls. A residential
adult cohort (Anniston Community Health Survey – ACHS) was
previously assembled in order to study the health effects of
PCBs in this population. Nonalcoholic steatohepatitis (NASH)
has previously been associated with PCB exposures in the
National Health and Nutrition Examination Survey (NHANES).
The current study investigates the effects of PCB exposure on
serum biomarkers of liver injury, inflammatory cytokines and
adipokines within ACHS. Methods: PCB-exposed subjects were
recruited from residences within the city limits of Anniston, Ala-
bama. Serum samples were obtained from the 774 individuals
consenting to a clinic visit. Whole (Ck 18 M65) and caspase-
cleaved cytokeratin 18 (CK18 M30) were measured using the
PEVIVA ELISAs. Serum cytokine/adipokines were measured
using Luminex cytokine bead array. Results: Means for each
biomarker were compared between ACHS and healthy con-
trols (HC) residing in Louisville, KY. ACHS had increased CK18
M65 and decreased CK18 M30. Serum concentrations of
pro-inflammatory cytokines IL-8 and IL-6 were increased. Serum
adiponectin was decreased, while leptin levels were increased,
however, insulin was not significantly different from HC. The
ACHS cohort was then stratified into three groups based on
serum biomarker-indicated liver injury: no liver disease (NLD,
M30<200 and M65<300, n=289), toxicant-associated ste-
atohepatitis (TASH, M30<200 and M65>300, n=353), and
other liver disease (OLD, M30>200, n=83). Biomarkers were
analyzed by multivariable linear regression to assess the rela-
tionship between PCB level and outcome. For the cohort and
each subgroup, insulin and leptin decreased with increasing
PCB level. The TASH group had higher insulin, IL-6, and PAI-1
levels than the NLD group. In the OLD group, IL-6 was also
elevated, but leptin was lower than that of the NLD group.
Conclusions: The prevalence of biomarker-indicated liver dis-
ease in the ACHS cohort was 60%, compared to 46% reported
for the general US population, and the CK18 profile indicates
that the majority of these cases are TASH. Compared to sub-
jects without liver disease, the TASH subgroup within ACHS is
associated with increased insulin, IL-6, and PAI-1. These data
were consistent with animal studies performed in our labora-
tory which demonstrated steatohepatitis with increased IL-6 and
PAI-1 in mice coexposed to high fat diet and PCBs.
Disclosures:
The following people have nothing to disclose: Heather B. Clair, Keith C. Falkner,
Banrida Wahlang, Russell A. Prough, Matthew C. Cave
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
879
Patients with type 2 diabetes mellitus (T2DM) and nor-
mal plasma aminotransferases are at high risk of non-
alcoholic fatty liver disease (NAFLD)
Paola Portillo Sanchez1,2, Fernando Bril1,2, Maryann Maximos5,2,
Romina Lomonaco1,2, Diane Biernacki1,2, Beverly Orsak3, Joan
Hecht4, Kenneth Cusi1,2; 1Endocrinology, Diabetes and Metab-
olism, University of Florida, Gainesville, FL; 2Endocrinology,
Diabetes and Metabolism, Malcom Randall VA Medical Center,
Gainesville, FL; 3Diabetes, University of Texas Health Science Cen-
ter at San Antonio, San Antonio, TX; 4Diabetes, Audie L. Murphy
VA Medical Center, San Antonio, TX; 5Pediatric Gastroenterology,
Hepatology, and Nutrition, University of Florida, Gainesville, FL
Nonalcoholic fatty liver disease (NAFLD), and its more severe
form with steatohepatitis (NASH), are common in patients with
type 2 diabetes (T2DM). However, it is believed that NAFLD
and NASH mainly affect those with elevated plasma alanine
aminotransferase (ALT) levels. The aim of this study was to
establish the prevalence of NAFLD in patients with T2DM and
normal ALT levels using liver magnetic resonance imaging and
spectroscopy (1H- MRS) and to assess their metabolic profile.
To this aim, we recruited 103 patients with T2DM and normal
plasma ALT levels (age: 60±1 years, male: 81%, BMI: 33±1
kg/m2, A1c: 7.6±0.1%) and measured: 1) liver triglyceride
content by 1H-MRS; 2) insulin sensitivity during the fasting state
at the levels of the liver (HOMA-IR) and the adipose tissue (adi-
pose tissue insulin resistance index [Adipo-IR]: fasting plasma
free fatty acids [FFA] x insulin); 3) insulin sensitivity in the adi-
pose tissue as suppression of FFA by low-dose insulin, during
the euglycemic clamp with 3-[3H]-glucose; and 4) severity of
liver disease by biopsy. The prevalence of NAFLD by 1H-MRS
in this predominantly overweight and obese population with
T2DM and normal plasma ALT levels was 76%. When patients
were divided according to BMI into four groups (<30, 30-34.9,
35-39.9, and ≥40 kg/m2) we observed an increasing preva-
lence of NAFLD (65%, 74%, 86%, and 89%, p=0.03). A sim-
ilar trend (62%, 71%, 82%, and 91%, p<0.01) was observed
when patients were divided into four groups according to
plasma A1c levels (<6.5%, 6.5-6.9%, 7.0-7.4%, and ≥7.5%).
These observations were further supported by the fact that both
BMI (r=0.31, p=0.002) and A1c (r=0.27, p=0.004) were
independently correlated with liver fat. However, when the
previous correlations were adjusted for adipose tissue insulin
resistance, both lost statistical significance, suggesting that the
association of liver fat content with obesity and glycemic con-
trol was mainly driven by insulin resistance. Of note, adipose
tissue insulin resistance showed the strongest correlation with
liver fat content when measured as the Adipo-IR or suppres-
sion of FFA by insulin (r=0.35, p=0.001 and r=0.51, p<0.01;
respectively). Among the subset of patients that underwent a
liver biopsy (n=37), NASH was more common than expected
(56%), regardless of their normal ALT levels. Conclusions: The
prevalence of NAFLD in overweight/obese patients with T2DM
is higher than previously believed, even in patients with normal
ALT levels. Adipose tissue insulin resistance appears to play an
important role in liver fat accumulation in these patients. Most
importantly, they are still at increased risk of developing severe
liver disease (NASH).
Disclosures:
Beverly Orsak - Employment: UTHSCSA
Kenneth Cusi - Consulting: Merck, Daichi-Sankyo, Roche, Janssen; Grant/
Research Support: Takeda, Novartis, Mannkind
The following people have nothing to disclose: Paola Portillo Sanchez, Fernando
Bril, Maryann Maximos, Romina Lomonaco, Diane Biernacki, Joan Hecht
625A
880
Effects of Liraglutide on Carotid Intima-Media Thickness
in Patients with Type-2 Diabetes and Non-Alcoholic
Fatty Liver Disease: An 8-Month Prospective Pilot Study
Angelo M. Patti, Manfredi Rizzo, Rosaria V. Giglio, Dragana
Nikolic, Antonino Terranova, Melchiorre Cervello, Alessandra Fer-
lita, Valeria A. Giannone, Giovanna Aurilio, Valentina Mistretta,
Lydia Giannitrapani, Maurizio Soresi, Giuseppe Montalto; Bio-
medical Department of Internal Medicine and Medical Specialties,
University of Palermo, Palermo, Italy
Recent studies suggest that GLP-1 analogues, such as liraglu-
tide, may decrease cardiovascular (CV) risk in subjects with
type 2 diabetes (T2DM), independently of their benefits on
glucose metabolism. These effects include impact on subclini-
cal atherosclerosis. However, its effectiveness in subjects with
non-alcoholic fatty liver disease (NAFLD), in the presence of
T2DM are scarce. In this 8-month prospective study, 29 sub-
jects with T2DM and NAFLD (16 men and 13 women, mean
age: 61±10 years) were enrolled, who were matched for age
and gender with another group of 29 subjects with T2DM but
without NAFLD (16 men and 13 women, mean age: 61±8
years). The NAFLD was ultrasonographically- and biochemis-
try-diagnosed. Liraglutide was added to metformin, at a dos-
age of 0.6 mg/day for two weeks, followed by a dose of
1.2 mg/day for the rest of the study. At baseline and after 8
months fasting plasma samples were analyzed and carotid-in-
tima media thickness (cIMT) was assessed by B-mode real-time
ultrasound. Statistical analysis was performed by ANOVA and
the Spearman correlation method. From baseline to 8 months
of liraglutide therapy HbA1c decreased significantly in both
groups (from 8.9±1.5 to 6.5±1.1% in subjects with T2DM
and NAFLD, and from 8.7±0.6 to 6.9±0.9% in subjects with
T2DM only, p<0.0001 for all). Anthropometric parameters and
plasma lipids did not change significantly in any group, even
some of differences approached the statistical significance.
Significantly reduced cIMT was seen only in group of sub-
jects with T2DM and NAFLD (from 0.96±0.27 to 0.85±0.12
mm, p=0.0325). However, correlation analysis revealed that
these changes were not related to changes in any other mea-
sured parameter. Liraglutide significantly decreased HbA1c
and cIMT in subjects with T2DM and NAFLD independently of
glycemic control. These data indicate the use of liraglutide not
only as an anti-diabetic therapy, but also in preventing CV risk
and probably hepatic steatosis. Further studies are needed to
support these encouraging findings.
Disclosures:
The following people have nothing to disclose: Angelo M. Patti, Manfredi Rizzo,
Rosaria V. Giglio, Dragana Nikolic, Antonino Terranova, Melchiorre Cervello,
Alessandra Ferlita, Valeria A. Giannone, Giovanna Aurilio, Valentina Mistretta,
Lydia Giannitrapani, Maurizio Soresi, Giuseppe Montalto
881
Oleuropein counteracts systemic inflammation and
hepatic immune cells infiltration in a mouse model of
NAFLD
Alessia Longo1, Mario Arciello1, Barbara Barbaro1, Gabriele
Toietta2, Roberta Maggio1, Carmela Viscomi1, Clara Balsano1,3;
1Francesco Balsano Foundation, Rome, Italy; 2Regina Elena Can-
cer Institute, Rome, Italy; 3Institute of Molecular Biology and Pathol-
ogy (IBPM) - CNR, Rome, Italy
The metabolic syndrome (MeS) is a cluster of metabolic abnor-
malities such as obesity, insulin-resistance and cardiovascu-
lar disease. MeS prevalence is growing worldwide with an
estimated prevalence of 40% in population over 50 years of
age. Nonalcoholic fatty liver disease (NAFLD) is considered a
626A AASLD ABSTRACTS
pathogenic factor of MeS as well as its hepatic manifestation.
NAFLD may potentially progress from asymptomatic hepatic
steatosis to nonalcoholic steatohepatitis, cirrhosis, end-stage
liver disease, and eventually to hepatocellular carcinoma. The
precise mechanisms causing NAFLD onset and progression
are poorly defined. Olive oil, an important component of the
Mediterranean diet, is known to produce beneficial effects on
liver, and heart and to reduce inflammation in metabolic syn-
drome patients, probably due to the content of polyphenols
such as oleuropein. The aim of our study was to assess whether
oleuropein supplementation to a high fat diet may counter-
act metabolic derangements and systemic inflammation pro-
duced by an excessive fat intake. As model for NAFLD we used
C57BL/6 mice fed with a high fat diet (HFD). After 8 weeks
of HFD feeding, mice received a HFD supplemented with 3%
oleuropein (OLE) for further 8 weeks [HFD+OLE]. After 16
weeks, HFD-fed mice show dismetabolism, elevated fat deposi-
tion, increased body (BW), liver (LW) and heart (HW) weights
and an increase of several circulating cytokines. At the end
of treatment HFD+OLE mice show reduced weight gain (BW
- 25%, LW – 50%, HW – 70%) compared to HFD-fed mice.
In accordance with literature, our histological investigations
highlighted reduced liver damage and inflammatory infiltra-
tion. Moreover, through cytokinome analysis performed using
the Bio-Plex multiplex biometric ELISA-based immunoassay, we
appreciated a significant reduction of a panel of cytokines,
including monocyte chemoattractant protein 1 (MCP1) and the
chemokine (C-X-C motif) ligand 1 (CXCL1) in the HFD+OLE
group compared to controls. Interestingly, MCP1 and CXCL1,
are renowned players in the recruitment of immune cells and
their increase is correlated to metabolic syndrome. These
results suggest that oleuropein, in addition to its already known
antioxidant properties, may prevent progression of NAFLD and
MeS occurrence acting on the activation of systemic inflamma-
tion. In particular, oleuropein may counteract immune cells infil-
tration in the liver, an event deeply implied in the progression
of hepatic damage.
Disclosures:
The following people have nothing to disclose: Alessia Longo, Mario Arciello,
Barbara Barbaro, Gabriele Toietta, Roberta Maggio, Carmela Viscomi, Clara
Balsano
882
Serum concentration of CDCA and TCDCA are inde-
pendently associated with Insulin sensitivity in a large
blood donor population
Alberto Porro1, Francesco Azzaroli1, Simoni Patrizia1, Domenico
Fiorillo1, Cecilia Camborata2, Paolo Cecinato1, Federica Buonfigli-
oli1, Davide Festi1, Silvia Spinozzi2, Paolo Parini3, Rosario Arena1,
Marco Montagnani1, Rocco Maurizio Zagari1, Franco Bazzoli1,
Aldo Roda3, Giuseppe Mazzella1; 1di Scienze Mediche e Chiru-
rgiche, University of Bologna, Bologna, Italy; 2Dipartimento di
Chimica “Ciamician, University of Bologna, Bologna, Italy; 3Karo-
linska Institutet, Stockholm, Sweden
Bile acids (BAs) seem to play an important role in glucose
homoeostasis. BAs are endogenous ligands to several recep-
tors, FXR, PXR, and TGR5. By binding to these receptors BAs
activate signalling pathways, and regulate cholesterol, glucose,
and metabolism/energy homoeostasis as well as their own
synthesis. We evaluate the association between total and sin-
gle BA fractions with insulin sensitivity in a large blood donor
population. Material: SOLENNE study was approved by EC.
Fasting blood liver tests, insulin, glucose, cholesterol, HDL-C,
LDL-C, triglycerides, FGF19,Lathosterol, C4, Bas by HPLC-MS
and Liver ultrasonography (bright liver, gallstones) were per-
HEPATOLOGY, October, 2014
formed in 284 consecutive blood donors. Subjects with overt
gastrointestinal disease or assuming drugs were excluded.
Statistical Analysis by MedCalc: Student t test (mean±SD),
Mann-Whitney when appropriate, χ2 test, uni & multivariate
analysis. Results: 284 (157 M and 127 F, 18 – 67 yrs) were
stratified according to sex (MvsF) and the presence (MIR #76,
FIR #42)/absence (HM #81, HF #85) of insulin resistance
(IR) by HOMA-r, liver steatosis and gallstone. BMI, ALT, GGT,
bood glucose were significantly higher in HM, while HDL-C
was significantly higher in HF. MIR had significantly high BMI,
HOMA-r, ALT, GGT, LDL-C, insulin, while FIR BMI, HOMA-R,
total cholesterol, triglycerides, glucose and insulin. Total(t)
serum BAs levels are significantly (P = 0,0154) lower in HF
vs HM(3.12±2.12 vs 4.14±3.12 mmol/L), primarily due to a
decreased concentration of total Cholic Acid (CA) (0.52±0.57
vs 0.75±0.82, mmol/L, P=0,048) and Chenodeoxycholic Acid
(CDCA) (1.38±1.19 vs 1.94±1.66, mmol/L, P=0.0132). No
sex related differences in tBA, tCA and tCDCA were observed
in IR subjects. Free CDCA and LCA concentrations were higher
in HM vs HF (0.63±088 vs0,37±0.46 mmol/L, P=0.017) and
(0.046±0.048 vs 0.030±0.018 mmol/L, P=0.0053). CA and
CDCA were significantly higher in MIR vs FIR. Total Glyco
(G) conjugated BA, G-CA, G-CDCA and G-DCA were signifi-
cantly higher in HM vs HF. Total Tauro (T) conjugated, T-CA
and T-DCA were significantly higher in FIR compared to HF.
CDCA (OR1,4; CI 95%1,0018 to 1,983, P=0,0488), and
TCDCA (OR15,89; CI95% 1,68 to 150,20; P=0,0158) were
variables independently associated with insulin sensitivity. Con-
clusion: Serum BA levels are higher in HM than in HF, while
these differences are lost in IR subjects; total T-BA, T-CA and
T-CDCA however are higher FIR in comparison with HF. CDCA
and TCDCA concentrations are independently associated with
insulin sensitivity.
Disclosures:
The following people have nothing to disclose: Alberto Porro, Francesco Azza-
roli, Simoni Patrizia, Domenico Fiorillo, Cecilia Camborata, Paolo Cecinato,
Federica Buonfiglioli, Davide Festi, Silvia Spinozzi, Paolo Parini, Rosario Arena,
Marco Montagnani, Rocco Maurizio Zagari, Franco Bazzoli, Aldo Roda,
Giuseppe Mazzella
883
The Development of a Non-invasive Model to Predict the
Presence of Nonalcoholic Steatohepatitis in Patients with
Nonalcoholic Fatty Liver Disease
Danny Issa1,2, George Boon-Bee Goh2, Rocio Lopez3, Mangesh R.
Pagadala2, Jaividhya Dasarathy4, Achuthan Sourianarayanane2,
Ruth Sargent2, Carol A. Hawkins5, Amer Khiyami5, Lisa M.
Yerian6, Rish Pai6, Srinivasan Dasarathy2, Naim Alkhouri2, Arthur
J. McCullough2; 1Department of Internal Medicine Fairview Hos-
pital, Cleveland Clinic, Cleveland, OH; 2Department of Gastro-
enterology and Hepatology, Cleveland Clinic, Cleveland, OH;
3Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH;
4Department of Family Medicine, MetroHealth Medical Center,
Cleveland, OH; 5MetroHealth Medical Center, Cleveland, OH;
6Department of Anatomic Pathology, Cleveland Clinic, Cleveland,
OH
BACKGROUND Nonalcoholic steatohepatitis (NASH) is an
advanced and aggressive form of nonalcoholic fatty liver dis-
ease (NAFLD), which remains difficult to diagnose without a
liver biopsy. A number of non-invasive biomarkers such as
CK-18 have shown promise but are not readily available in
clinical practice. Hyperferritinemia has increasingly been asso-
ciated with presence of NASH. Hence, we sought to explore
the relationship between ferritin and NASH and to develop a
composite model based on ferritin and other easily-obtainable
variables to predict the presence of NASH METHODS 405
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
adult patients with biopsy proven NAFLD were enrolled in the
study. Clinical data including demographics, anthropometry,
medical history, biochemical and liver biopsy findings were
evaluated. Comparisons were explored to assess differences
between patients with and without NASH, upon which a scor-
ing model was established using variables found to be inde-
pendent predictors of NASH RESULTS Among all patients with
NAFLD, 291 (72%) had biopsy-proven NASH and 114 (28%)
had non-NASH. The mean age was 48 ± 12 and 56% were
female. NASH patients were older, with a higher prevalence
of diabetes, hypertension, higher BMI, AST, ALT and a lower
platelet count (all P < 0.05). Ferritin levels were significantly
higher in NASH compared to non-NASH patients (184 vs 126,
respectively; P < 0.001) but lacked diagnostic accuracy for
predicting NASH alone [area under the curve (AUC 0.62)].
The addition of other significant variables such as AST, BMI,
platelet count, diabetes and hypertension to ferritin improved
the prediction of NASH with an AUC; 0.81 (95% CI: 0.76 -
0.86), (cutoff value=0.35, sensitivity=98%, negative predictive
values=85%), (cutoff value=0.79, specificity=85%, positive
predictive values=91%). Internal validation of the model using
imputed datasets demonstrated that the AUC did not change
materially CONCLUSIONS While higher ferritin was signifi-
cantly associated with NASH, ferritin alone lacked diagnostic
accuracy to predict NASH. However, incorporating several
easily obtainable variables with ferritin allowed the construc-
tion of a novel scoring system that can be easily applied in
the clinical setting to guide management of NAFLD. This score
compares favorably with previous scores which may only be
applicable to severely obese patients or require advanced lab-
oratory/proprietary variables. Based on our score, liver biopsy
would be obviated in 54% of the patients
Disclosures:
Rish Pai - Consulting: Robarts Clinical Trials
Naim Alkhouri - Advisory Committees or Review Panels: Gilead Sciences
The following people have nothing to disclose: Danny Issa, George Boon-Bee
Goh, Rocio Lopez, Mangesh R. Pagadala, Jaividhya Dasarathy, Achuthan Souri-
anarayanane, Ruth Sargent, Carol A. Hawkins, Amer Khiyami, Lisa M. Yerian,
Srinivasan Dasarathy, Arthur J. McCullough
884
Normal ALT and advanced liver fibrosis in morbidly
obese patients undergoing bariatric surgery
Fabio Nascimbeni1, Judith Aron-Wisnewsky4,6, Pierre Bedossa2,
Joan Tordjman4,5, Raluca Pais3,5, Thierry Poynard3,5, Vlad Rat-
ziu3,5; 1Department of Biomedical, Metabolic and Neural Sci-
ences, University of Modena and Reggio Emilia, Modena, Italy;
2Pathology Department, Hospital Beaujon, Clichy, France; 3Hepa-
togastroenterology, Hospital Pitie Salpetriere, Paris, France; 4Sor-
bonne Universités, UMR_S 1166-ICAN, Nutriomics, Institute of
Cardiometabolism and Nutrition, ICAN, Paris, France; 5INSERM
UMR_S 1166-ICAN, Nutriomics, Institute of Cardiometabolism
and Nutrition, ICAN, Paris, France; 6Heart and Metabolism Divi-
sion, Hospital Pitie Salpetriere, Paris, France
Most patients (pts) with morbid obesity (MO) referred for bariat-
ric surgery have normal ALT (NALT) and milder liver injury than
non-MO pts seen in liver clinics. However, in non-MO NAFLD
NALT is not associated with milder liver injury, and especially
not with less advanced fibrosis (AF). Aim. To determine if MO
pts undergoing bariatric surgery with NALT have a distinct
clinical and histological profile in comparison to non-MO pts
seen in liver clinics. Methods. 619 MO pts undergoing bariat-
ric surgery (Bariatric-cohort, BC) and 369 non-MO pts referred
for NAFLD to a liver clinic (Hepato-cohort, HC), from the same
urban area, were studied during the same period. Other liver
diseases were excluded. Liver biopsies were read using the
627A
FLIP algorithm and the SAF score. AF was defined as bridging
fibrosis or cirrhosis. ALT was measured at the time of liver
biopsy. The upper limit of normal (ULN) was set at 35U/L. A
sensitivity analysis with 3 ALT groups (normal low, NlwALT:
≤20; normal high, NhALT: 20-35; high, HALT: >35) was per-
formed in the BC. AUROCs were analyzed for NASH and AF.
Results. NALT was seen in 409 (66%) BC pts (29% NlwALT,
37% NhALT) and in only 68 (18%) HC pts (p<0.001). NALT
BC pts were less frequently male and had a less advanced
metabolic profile (lesser prevalence of diabetes and metabolic
syndrome; lower HDL, HOMA-IR, HbA1c and triglyceride lev-
els) than HALT BC pts. Compared with HALT BC pts, NALT BC
had AF (4% vs. 13%, respectively, p<0.001) and NASH less
often (26% vs. 51%, p<0.001). In contrast, in HC pts NALT
was not associated with the severity of the metabolic profile;
AF was equally prevalent in NALT and HALT (22% vs. 24%);
only NASH was less frequent in NALT (28% vs. 45%, p<0.01).
The OR of HALT for AF was 3.40 (1.81-6.40) in the BC but
not significantly increased in the HC [0.91 (0.49-1.70)]. The
AF prevalence had a positive linear trend across the 3 ALT
groups both in women (1% vs. 7% vs. 8%, p=0.006) and
in men (0% vs. 3% vs. 21%, p=0.006). The AUROC of ALT
for AF in the BC was 0.73 (0.66-0.81) but only 0.51 (0.44-
0.59) in the HC (p<0.001). HALT also predicted NASH in the
BC cohort [OR 3.07 (2.6-4.35)] with a trend across ALT sub-
groups that was only significant for women (17% vs. 29% vs.
47%, p<0.001) and a AUROC of 0.69 (0.65-0.73). Yet, the
association of HALT with NASH was weaker in the HC cohort
[AUROC 0.62 (0.57-0.68), p=0.08]. Conclusion. In MO pts
undergoing bariatric surgery, NALT is significantly associated
with milder histological injury, in particular fibrosis, and less
marked IR-related metabolic abnormalities. This contrasts with
non-MO NAFLD and suggests different pathogenic mechanisms
in the two populations.
Disclosures:
Thierry Poynard - Advisory Committees or Review Panels: Merck; Grant/Research
Support: BMS, Gilead; Stock Shareholder: Biopredictive
Vlad Ratziu - Advisory Committees or Review Panels: GalMed, Abbott, Genfit,
Enterome, Gilead; Consulting: Astellas, Axcan, Pfizer, Sanofi-Synthelabo, Genen-
tech, Nycomed
The following people have nothing to disclose: Fabio Nascimbeni, Judith
Aron-Wisnewsky, Pierre Bedossa, Joan Tordjman, Raluca Pais
885
Central obesity is associated with portal vein thrombosis
Julie Laurent, Camille Christol, Jean Bernard Ruidavets, Jean Fer-
rieres, Marie Angele Robic, Jean-Marie Peron, Jean-Pierre Vinel,
Christophe Bureau; Service d’Hépatogastroenterologie, CHU Tou-
louse, Toulouse, France
Introduction. Thirty percent of portal vein thrombosis (PVT)
remains of unknown origin. An association between metabolic
syndrome (MS) and peripheral vein thrombosis has already
been reported but not with PVT, to date. The aim of this study
was to compare the prevalence of MS’s criteria between
patients with PVT and a recognized cause (A), patients with
PVT of unknown origin, (B), and healthy controls (C). Patients
and methods. Between July/2003 and January/2014, all con-
secutive in- or outpatients with acute or chronic PVT without
cirrhosis nor cancer admitted in our unit were prospectively
enrolled in the national cohort. Patient’s characteristics and
risks factors for PVT were recorded at the time of inclusion.
Healthy controls were selected by random using electoral list
(1) and were matched 1/1 with patients according to age and
sex. The definition used for metabolic syndrome was NCEP
ATP III. Results. Seventy nine patients with PVT were included.
Among them, 40 (51 % = group A) presented one or several
628A AASLD ABSTRACTS
risk factors for PVT and 39 PVT (49 % = group B) were found
to be idiopathic. Age (on average 50 years) and sex (32% of
women) were similar between all 3 groups. The prevalence of
MS was 27.5% in group A vs 46.2% in group B (p < 0.05).
The later was also found to be significantly different compared
with group C (12.8% - p<0.001). The waist circumference and
body mass index were higher in group B than in group A (105
vs 93 cm, p<0.001 and 29.4 vs 25.1 kg/m2, p<0.001) and
higher than group C (105 vs 90 cm, p<0.001 and 29.4 vs
26.0 kg/m2, p<0.004). Overweight was observed in 79.5%
of patients in group B versus 45% in group A (p<0.002) and
59% in group C (p<0.05). The average visceral fat area
measured by CT-scan was higher in group B than in group A
(18223 mm2 vs 12690 mm2, p < 0.003). Among all criteria
of MS, waist circumference was the most powerful factor asso-
ciated with PVT between group B and A (OR: 6.68 [1.86-24.3]
- p<0.001), and between group B and C (OR: 17.3 [3.90-
76.7] – p<0.001). Conclusion: Central obesity is associated
with PVT and could become one of the first risk factors of diges-
tive thromboses. 1. Ahluwalia N, Drouet L, Ruidavets J-B, Perret
B, Amar J, Boccalon H, et al. Metabolic syndrome is associated
with markers of subclinical atherosclerosis in a French popula-
tion-based sample. Atherosclerosis 2006;186:345–53.
Disclosures:
Jean-Marie Peron - Board Membership: BAYER; Consulting: BMS, GILEAD, BOS-
TON SCIENTIFIC
Jean-Pierre Vinel - Grant/Research Support: Roche, Gore, LFB
The following people have nothing to disclose: Julie Laurent, Camille Christol,
Jean Bernard Ruidavets, Jean Ferrieres, Marie Angele Robic, Christophe Bureau
886
The quantitative amount of hepatic steatosis in NAFLD
patients predicts the risk of developing diabetes: a pro-
spective study with up to 25 years of follow-up
Patrik S. Nasr1, Mattias Ekstedt2, Ulrik L. Mathiesen3, Stergios
Kechagias1; 1Gastroenterology and Hepatology, Department of
Medical and Health Sciences, Linköping, Sweden; 2Gastroenter-
ology and Hepatology, Department of Clinical and Experimental
Medicine, Linköping, Sweden; 3Department of Internal Medicine,
Oskarshamn, Sweden
Purpose. Non-alcoholic fatty liver disease (NAFLD) is the most
common cause of elevated liver enzymes and chronic liver
disease in developed countries. Previous studies have shown
that NAFLD is closely associated with features of the metabolic
syndrome. In the present study we determined future risk of dia-
betes and liver-related morbidity in NAFLD patients. Moreover
we assessed if clinical and histopathological parameters at
baseline predict future morbidity. Methods. In a cohort study,
129 patients referred between 1988 and 1993 because of
chronically elevated aminotransferases and diagnosed with
biopsy-proven NAFLD were consecutively enrolled and pro-
spectively followed. Subjects still alive were re-evaluated at
two consultant meetings. Clinical and biochemical data were
recorded and compared with the corresponding parameters
and histopathological data at baseline. Hepatic fatty infiltration
was quantified with stereological point counting in biopsies
collected at baseline. Fibrosis stage was assessed semi-quan-
titatively. Results. Eighty-eight (85 %) of 104 patients still alive
were re-evaluated at first follow-up. Fifty-five (70 %) of 79
patients still alive were re-evaluated at second follow-up. Mean
follow-up time for first and second re-evaluation was 13.7 ±
1.3 years and 22.5 ± 2.4 years, respectively. At first follow-up
51 subjects (58 %) had diabetes. The corresponding figure at
second follow-up was 59 (67 %). During follow-up, 10 of the
129 patients (8 %) had developed end-stage liver disease.
HEPATOLOGY, October, 2014
Patients with diabetes at second follow-up did not have sig-
nificantly different BMI, waist or hip circumference at baseline
compared to those without diabetes. However patients with
diabetes at second follow up exhibited a more pronounced
hepatic fatty infiltration at baseline compared to those without
diabetes (14.3 ± 9.7 % vs. 8.0 ± 9.5 %, P = 0.01). BMI,
waist or hip circumference and presence of dyslipidemia at first
and second follow-up were not significantly different between
patients with and without subsequent development of diabetes.
Fibrosis stage at baseline was not significant for the outcome
of diabetes at second follow-up. However, severity of fibrosis
at baseline predicted the development of end-stage liver dis-
ease during follow-up (P = 0.021). Conclusion. The amount
of hepatic steatosis in NAFLD is associated with future risk of
developing type 2 diabetes. Severe fibrosis is associated with
future development of end-stage liver disease.
Disclosures:
The following people have nothing to disclose: Patrik S. Nasr, Mattias Ekstedt,
Ulrik L. Mathiesen, Stergios Kechagias
887
Cryptogenic cirrhosis category masks three quarters of
NASH patients getting liver transplant
Angela Dolganiuc1,2, Vikas Khullar2, Virginia C. Clark1, Roberto J.
Firpi1; 1Internal Medicine/Division of Gastroenterology, Hepatol-
ogy and Nutrition, University of Florida, Gainesville, FL; 2Internal
Medicine Residency program, University of Florida, Gainesville, FL
Non-Alcoholic Fatty Liver Disease (NAFLD) is an emerging
forerunning cause of liver transplant (LT) in USA and world-
wide. With the obesity epidemics on the rise, the incidence of
NAFLD/Non-Alcoholic Steato-Hepatitis (NASH) and its compli-
cations, such as cirrhosis and hepatocellular carcinoma (HCC),
have also increased over the last decades. To date, LT is the
last-resort treatment of NASH, yet lack of reliable clinical and
biochemical biomarkers limit pre-LT diagnosis of NASH largely
on the basis of liver histology. We aimed to identify clinical
and routine biochemical signature features of patients who
had undergone LT and had histological findings suggestive of
NASH in the explant livers, in order to define predictive param-
eters of NASH prior to LT. Our cohort includes patients from
the University of Florida Liver Transplant database from 1990-
2013, for a total 1,646 patients; of those 174 were listed
for cryptogenic cirrhosis (CC) or NASH cirrhosis as cause of
LT. Eighteen patients listed with NASH and 116 with CC had
electronic records and were included in the analysis. Of 116
patients who have undergone LT for CC, 18 were excluded
because they carried dual diagnosis. Of remaining 98 patients
listed with sole CC diagnosis as a cause for LT, 3 individuals
exhibited histologic evidence of alpha1-antitrypsin deficiency,
7 has strong stains for iron, and 3 have HCC along with cir-
rhosis in native liver explant, thus were excluded. Based on
biopsies of the explant liver, the group was further distributed
in a cohort of 24 patients which did not have inflammation or
steatosis (True CC), 24 patients which had steatosis and inflam-
mation (NASH) and 28 patients with inflammation but no ste-
atosis (Late-stage NASH). There were no differences between
the NASH cohort, CC group-derived NASH and true-CC cohort
in terms of age, gender, ethnicity or the frequency and char-
acteristics of metabolic syndrome. However, there were sig-
nificantly more obese patients in the NASH cohort (98%) and
CC group-derived NASH with (86%) or without (83%) steatosis
compared to true-CC (69%) cohort. In conclusion, only 24.5%
of patients who had histological features of NASH in native
liver explant were classified as NASH pre-LT; the other 75.5%
originated from CC category. Components of metabolic syn-
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS 629A

drome, including diabetes, dyslipidemia and hypertension, did Disclosures:

not provide discriminatory power for correct categorization of Renger Tiessen - Employment: PRA health sciences; Grant/Research Support:
Lumena
NASH pre-LT. Our study underlines the need for quality clini-
cal and biochemical markers of NASH aside from histological Ciara Kennedy - Employment: Lumena Pharmaceuticals
parameters, to aid accurate NASH diagnosis pre-LT. Bradley T. Keller - Consulting: Shire Human Genetic Therapies Inc; Employment:
Lumena Pharmaceuticals, Rivervest Venture Partners
Disclosures:
Nancy Levin - Consulting: Lumena Pharmaceuticals
Roberto J. Firpi - Advisory Committees or Review Panels: Gilead; Grant/Research
Support: Bayer, Genentech, Vertex, BMS, Janssen, Gilead, Merck Dee Wynne - Employment: lumenapharmaceuticals
The following people have nothing to disclose: Angela Dolganiuc, Vikas Khullar, Bronislava Gedulin - Employment: Lumena Pharmaceuticals
Virginia C. Clark Elizabeth Olek - Consulting: Lumena Pharmaceuticals, Inc
Alejandro Dorenbaum - Employment: Lumena Pharmaceutical, Stanford Univer-
sity; Stock Shareholder: BioMarin Pharmaceutical
The following people have nothing to disclose: Lisette Acevedo, Andre A. van
888 Vliet
LUM002 Positive Metabolic Profile Shown after Admin-
istration of 10mg For 28 Days in Type 2 Diabetes Mel-
litus Patients Leading to Potential Treatment for Patients
889
with Nonalcoholic Steatohepatitis (NASH)
Apolipoprotein A-V Gene Expression in Non-Alcoholic
Renger Tiessen2, Ciara Kennedy1, Bradley T. Keller1, Nancy Steatohepatitis
Levin1, Lisette Acevedo1, Dee Wynne1, Bronislava Gedulin1, Andre
Qin Feng1,2, Susan S. Baker1, Wensheng Liu1, Robert D. Baker1,
A. van Vliet2, Elizabeth Olek1, Alejandro Dorenbaum1; 1Lumena
Yiyang Hu2, Lixin Zhu1; 1Pediatrics, University of Buffalo, Buffalo,
Pharmaceuticals, Inc, San Diego, CA; 2Pharmaceutical Research
NY; 2Institute of Liver Diseases, Shuguang Hospital Affiliated to
Associates Group BV, Zuidlaren, Netherlands
Shanghai University of Traditional Chinese Medicine, Shanghai,
BACKGROUND: LUM002 is a potent inhibitor of the apical China
sodium-dependent bile acid transporter (ASBT) primarily local-
Background & Aims: Apolipoprotein (apo) A-V, a minor
ized on the luminal surface of the ileum. In previous clinical
plasma apolipoprotein, has been implicated in liver fat storage
studies LUM002 inhibited bile acid (BA) absorption, increased
and mobilization, and therefore may be involved in the patho-
fecal BA excretion, lowered serum BA and increased 7a-hy-
genesis of the metabolic syndrome. Non-alcoholic fatty liver
droxy-4-cholesten-3-one (C4) reflecting intrahepatic bile acid
disease (NAFLD) is the hepatic manifestation of the metabolic
biosynthesis resulting in decreased serum LDL-C. Fecal BA can
syndrome, with non-alcoholic steatohepatitis (NASH) being its
also bind to intestinal receptors and induce GLP-1 secretion.
severe form exhibiting liver inflammation. ApoA-V is expressed
Treatment with LUM002 offers a promising incretin-based strat-
only in the liver. The current study is designed to test our hypoth-
egy for the treatment of NASH, a disease characterized by fatty
esis that apoA-V plays a role in the pathogenesis of NASH.
liver, hyperlipidemia, insulin resistance, type 2 diabetes melli-
Methods: The study was approved by the Institutional Review
tus (T2DM), and obesity. METHODS: We conducted a 28-day,
Board of SUNY Buffalo. Patients were diagnosed with NASH
phase 1b, randomized, double-blind, placebo-controlled, dose
on liver biopsy according to Kleiner’s criteria. Hepatic gene
escalation study in healthy volunteers and in T2DM patients.
expression for apoA-V and other related genes was accessed
Only T2DM results are included here. All T2DM patients were
by microarray analysis and quantitative real-time PCR. Spear-
taking oral hypoglycemic agents (except thiazolidinediones)
man’s coefficient analyses were performed to examine possible
for at least 3 months and had a wash-out for 14 days prior to
correlations of apoA-V expression to the grade of steatosis,
dosing. Subjects received 10mg LUM002 (n=8) or placebo
and to the expression levels of other NASH related liver genes.
(n=3) once daily for 28 days. RESULTS: The T2DM group
Results: Our NASH microarray data showed increased gene
was all males with mean age 65.5+/- 3.4 (LUM002) and
expression of apoA-V in NASH livers compared to normal con-
67.7+/-2.1 (placebo) years. Mean BMI was 29.5+/-3.5 kg/
trols (NC) (NASH/NC=3.8, p =0.004). Similar results were
m2 (LUM002) and 29.8+/-1.9 (placebo). Pre-treatment fasting
observed with a different patient cohort by qRT-PCR (NASH/
serum glucose was within 7.0-12.5 mmol/L and HbA1c was
NC=5.9, p=0.000). The expression levels of apoB and MTP
>6.0% and <10% at screening. Mean total BA concentrations
were also elevated in NASH livers and positively correlated
in feces (days 27-28) were ~8-fold higher in LUM002 treated
with that of apoA-V. Among NASH patients, liver ApoA-V
subjects (1786.0 mmol/24hr) vs placebo (220.0 mmol/24hr).
expression was negatively correlated to grade of steastosis
Mean serum levels of C4 were ~2-fold higher on Day 14 (59.7
(r= -0.80, P<0.01). ApoA-V expression was also negative
ng/mL) and Day 28 (61.8 ng/mL), compared to Day 1 in
correlated to blood TG (r= -0.63, P<0.05), VLDL (r= -0.63,
LUM002 treated subjects, while no change was observed in
P<0.05); and positively correlated to serum ALT (r=0.73,
placebo. Lipid profiles in healthy subjects (n=49) and in normo-
P<0.01), AST (r=0.67, P<0.01) and HDL (r=0.7, P<0.01).
lipidemic T2DM subjects revealed a trend towards increased
No correlation was found for apoA-V with BMI, blood fast-
HDL-C and decreased triglycerides in the LUM002 group.
ing glucose, fasting insulin, TC, or LDL. Conclusions: Elevated
Fasting glucose levels in the T2DM group were unchanged
apoA-V expression in NASH livers indicates that apoA-V plays
in the placebo group and were reduced from Day 1 in the
a role in NASH pathogenesis. The fact that apoA-V expression
LUM002 group by 17.5% on Day 14 and by 14.1% on Day
positively correlated with those of apoB and MTP (proteins
28 (both p<0.05 vs Day 1). The most frequently reported treat-
essential for VLDL secretion), suggests that apoA-V is part of the
ment emergent adverse events were mild gastrointestinal AEs
mechanism for elevated VLDL secretion. The observation that
that were most likely related to the mechanism of action of
apoA-V expression in NASH livers was negatively correlated
LUM002. No clinically significant changes in liver enzymes or
with grade of steastosis suggests apoA-V is not required in
fat absorption parameters were observed. CONCLUSIONS:
lipid storage. More importantly, this observation suggests that
LUM002 dosed at 10 mg/day in T2DM patients was safe and
insufficient apoA-V activity may contribute to increased lipid
tolerable for 28 days of treatment and had a positive effect on
accumulation in liver. Further investigations along this route
lipid and glucose metabolism, supporting the possible utility of
may identify a novel target for the management of fatty liver
LUM002 for the treatment of patients with NASH.
diseases.
630A AASLD ABSTRACTS
Disclosures:
The following people have nothing to disclose: Qin Feng, Susan S. Baker, Wen-
sheng Liu, Robert D. Baker, Yiyang Hu, Lixin Zhu
890
U.S. Physician Survey of Current Practices in the Diag-
nosis and Treatment of Nonalcoholic Steatohepatitis
(NASH)
Stephen A. Harrison1, Sheldon Y. Okada2, Cathy A. Su2, Matthew
Paulson2, Jeffrey D. Bornstein2, Arun J. Sanyal3; 1Medicine, Brooke
Army Medical Center, Fort Sam Houston, TX; 2Gilead Sciences,
Foster City, CA; 3Medicine, Virginia Commonwealth University
School of Medicine, Richmond, VA
Background: NASH, a leading cause of cirrhosis, is the 3rd
leading cause of liver transplantation in the US. Guidelines
exist for its management, but it is unclear how well they are fol-
lowed. Methods: A survey invitation regarding NASH was sent
to 9,514 physicians from specialties typically involved in the
management of NASH: gastroenterologists (GI), hepatologists
(H), endocrinologists (EN), internists/primary care providers
(PCP). The aim was to understand the level of awareness of
clinical guidelines and the current practices in the diagnosis
and treatment of NASH. Results: The response rate was 4.8%.
Interested physicians were required to meet additional criteria
including currently managing NASH patients. 289 physicians
(75 GI, 75 H, 64 EN, and 75 PCP) met inclusion criteria and
completed a 35-item questionnaire. 92% of total physicians
were “very familiar” or “somewhat familiar” with the AASLD/
ACG/AGA NAFLD practice guidelines (PG). A significant pro-
portion of diagnosed NASH patients (39%) have not had a
liver biopsy to confirm the diagnosis. H performed the greatest
percentage of biopsies (53%) vs. GI (41% p=0.027), EN (29%
p< 0.001), and PCP (31% p<0.001) (figure 1). A greater pro-
portion of diagnosed NASH patients have metabolic syndrome
parameters than what is reported in the literature (T2DM 54%,
Obesity 71%, MS 59%). 82% of physicians use a lower thresh-
old value to define significant alcohol consumption compared
with PG recommendations. 88% of physicians prescribe some
form of pharmacologic treatment for NASH (Vit E: prescribed
to 53% of NASH patients, statins: 57%, metformin: 50%).
Conclusions: A significant majority of physicians report a high
awareness of the NAFLD PG. Only a minority of patients actu-
ally have a liver biopsy to confirm NASH, contrary to PG. The
vast majority of patients are prescribed medications despite a
lack of a confirmed diagnosis or significant data to support the
intervention. Alcohol thresholds to exclude NASH are lower
than expected. These data suggest a possible knowledge gap
with implementation of the NAFLD PG, and a need to develop
a non-invasive diagnostic for NASH.
Disclosures:
Stephen A. Harrison - Advisory Committees or Review Panels: Merck, Nimbus
Discovery; Grant/Research Support: Merck, Genentech; Speaking and Teach-
ing: Merck, Vertex
HEPATOLOGY, October, 2014
Sheldon Y. Okada - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Cathy A. Su - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead
Sciences, Inc.
Matthew Paulson - Employment: Gilead Sciences
Jeffrey D. Bornstein - Employment: Gilead Sciences
Arun J. Sanyal - Advisory Committees or Review Panels: Bristol Myers, Gilead,
Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Nimbus, Genentech, Echo-
sens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept,
Ikaria, Takeda, GalMed, Novartis, Gilead; Independent Contractor: UpToDate,
Elsevier
891
Wfa-M2bp Levels Are Usefull Indicators Of Progres-
sion And Inprovement For Monitoring Liver Fibrosis In
Patients With Nonalcoholic Steatohepatitis
Miwa Kawanaka, Ken Nishino, Jun Nakamura, Takahito Oka,
Noriyo Urata, Daisuke Goto, Mitsuhiko Suehiro, Hirofumi Kawa-
moto, Gotaro Yamada; General Internal Medicine2, Kawasaki
Hospital, Kawasaki Medical School, Okayama, Japan
[Objective] We reported the usefulness of cytokeratin18
(CK18) as an index of progress of the hepatic tissue in the
example of a repetition liver biopsy of NASH.(Hepatol-
ogy 474A,2013) .Recently, the novel sugar chain marker
WFA+M2BP has attracted attention as a potentially useful
non-invasive liver fibrosis marker, and reported high levels
of WFA+M2BP is high risk of hepatocellur carcinoma(HCC)
with hepatitis C, but its utility in NASH/NAFLD is unknown.
Therefore, we have assessed WFA-M2BP in NAFLD cases and
examied its utility as a marker of fibrotic change in the diag-
nosis of progression of fibrosis and repeat liver biopsies and
whether it could useful as prediction of HCC.[Subjects and
Methods] We assessed WFA-M2BP in 294 NAFLD patients at
who had undergone liver biopsies (mean age: 54.2±14; M/F:
149/145; F0/1/2/3/4: 24/87/65/87/31). In addition to
its utility in diagnosing fibrosis in NASH, we examined the
associations of WFA-M2BP to fibrosis stage. Moreover, M2BP
of a HCC cases and non HCC cases was measured. We also
assessed WFA-M2BP in 96 NAFLD patients (5.3±2.9y) who
underwent repeat liver biopsies We examined the associations
of WFA-M2BP to liver fibrosis changes. This kit measures gly-
cosylation isomer of Mac-2 binding protein based on the che-
miluminescence enzyme immunoassay method with CDP-StarR
chemiluminescent substrate. This kit is exclusively designed for
Automated Immunoassay System HISCL- series. [Results] WFA-
M2BP increased as fibrosis progressed (P<0.0001). Specifi-
cally, WFA-M2BP was significantly higher in F3 and F4 than in
F0-2 (0.8 vs 1.23; P<0.0001), the cutoff value was 1.01, the
AUC was 0.70, sensitivity was 68.4%, specificity was 70%,
PPV was 60%, and NPV was 77.5%; thus, WFA-M2BP was
useful in diagnosing NASH with progression of fibrosis. Among
cirrhotic liver, WFA-M2BP was higher with Burn out NASH
in which advanced fibrosis than non-burn out NASH(6.5 vs
1.8,p=o.0031). Furthermore the HCC cases(n=13)had signifi-
cantly high levels of M2BP compared with the non HCC cas-
es(n=281)(6.5 vs 1.8,p<0.0001).Fibrosis progressed in 29 of
the 96 patients who had undergone repeat liver biopsies; in
these cases, WFA-M2BP increased from 1.0±0.5 to 1.21±0.5.
In the 31 cases with no change in fibrosis, WFA-M2BP was
also unchanged (0.98±0.5Ç0.92±0.4). In the 36 cases in
which fibrosis improved, WFA-M2BP was significantly reduced
(1.1±0.5Ç0.8±0.3; p<0.05). [Conclusion] Assessment of
WFA-M2BP in NAFLD was considered useful in predicting pro-
gression of fibrosis and histological changes in NASH, as well
as therapeutic effects. Specially, WFA-M2BP is useful predict-
ing a Burn out NASH and future of HCC with NASH.
HEPATOLOGY, VOLUME 60, NUMBER 4 (SUPPL) AASLD ABSTRACTS
Disclosures:
The following people have nothing to disclose: Miwa Kawanaka, Ken Nishino,
Jun Nakamura, Takahito Oka, Noriyo Urata, Daisuke Goto, Mitsuhiko Suehiro,
Hirofumi Kawamoto, Gotaro Yamada
892
Vitamin D level is not associated with liver histology in
non-alcoholic steatohepatitis
Matthew T. Kitson1,2, Stephen Casey3, Alan Pham4, Adam Gor-
don1,2, William W. Kemp1,2, Peter Button5, Stuart K. Roberts1,2;
1Gastroenterology, Alfred Hospital, Melbourne, VIC, Australia;
2Gastroenterology, Monash University, Melbourne, VIC, Australia;
3Medicine, University of Melbourne, Melbourne, VIC, Australia;
4Anatomical Pathology, Alfred Hospital, Melbourne, VIC, Austra-
lia; 5Infopeople Pty Ltd, Sydney, NSW, Australia
Introduction: Non-alcoholic steatohepatitis (NASH) is a pro-
gressive form of non-alcoholic fatty liver disease (NAFLD) and
an increasingly common cause of end-stage liver disease.
While the pathogenesis of NASH is yet to be fully elucidated,
recently 25-hydroxyvitamin D [25(OH)D] level has been pur-
ported to be independently associated with the severity of
liver histology in NASH. We therefore assessed any associ-
ation between 25(OH)D level and liver histology in patients
with biopsy-proven NASH. Methods: 35 patients with biop-
sy-proven NASH and recent 25(OH)D level within 4 months
of liver biopsy were studied. Liver histology was assessed by
a single pathologist using the NAFLD Activity Score (NAS)
and Brunt fibrosis stage. Season of 25(OH)D level and use of
vitamin D supplementation was noted. Recent anthropometric
data, blood tests and liver stiffness measurement (L
631A
Matthew T. Kitson - Consulting: MSD, Roche; Grant/Research Support: MSD;
Speaking and Teaching: Janssen-Cilag
Stuart K. Roberts - Board Membership: Jannsen, Roche, Gilead, BMS
The following people have nothing to disclose: Stephen Casey, Alan Pham,
Adam Gordon, William W. Kemp, Peter Button
893
Clinical and Histologic Differences Between HIV-associ-
ated NAFLD and Primary NAFLD: A Case-control Study
Irine Vodkin1, Mark A. Valasek3, Ricki Bettencourt2, Edward R.
Cachay4, Rohit Loomba1,2; 1Division of Gastroenterology, Depart-
ment of Medicine, University of California, San Diego, San Diego,
CA; 2Division of Epidemiology, Department of Family and Preven-
tative Medicine, University of California, San Diego, San Diego,
CA; 3Department of Pathology, University of California, San
Diego, San Diego, CA; 4Division of Infectious Disease, Department
of Medicine, Univeristy of California, San Diego, San Diego, CA
Background and Aims: Prevalence of nonalcoholic fatty liver
disease (NAFLD) is higher in individuals with HIV infection
than in the general population. The prevalence of metabolic
syndrome in this population is rising. Limited data exists about
the clinical and pathologic characteristics of patients with HIV
and NAFLD, and whether NAFLD in this population differs in
clinical presentation and severity of liver histology from pri-
mary NAFLD. Therefore, we aimed to examine the differences
between HIV associated NAFLD and primary NAFLD. Meth-
ods: This is a cross-sectional analysis of a nested case-control
study. All HIV infected patients without viral hepatitis, heavy
alcohol use or other identifiable causes of liver disease were