Beruflich Dokumente
Kultur Dokumente
doi: 10.1111/hepr.12270
Special Report
1. INTRODUCTION
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H. Ishibashi et al.
2. DIAGNOSIS OF PBC
2.1 Diagnosis of PBC: general principles
BC IS AN autoimmune-mediated, chronic
cholestatic liver disease that predominantly affects
middle-aged women. The initial symptom is most often
pruritus, though the disease generally progresses insidiously without symptoms for many years. Jaundice progresses without improvement once it becomes overt,
and portal hypertension occurs at a high rate.
Clinically, increased levels of serum biliary enzymes
[alkaline phosphatase (ALP) and -glutamyl transferase
(GGT)] and detection of antimitochondrial antibodies
(AMAs) are characteristic. AMAs are found in 95% of
patients with PBC when using the most sensitive detec-
Early PBC
AMA may be detectable in the serum of individuals
without symptoms of PBC and with normal liver tests.
Histopathological changes of PBC with no or mild progression are apparent and this condition is designated
early PBC. Follow-up without medication is appropriate.
Autoimmune cholangitis, autoimmune
cholangiopathy
Patients whose clinical features are compatible with
PBC may be negative for AMA but have a high titer of
antinuclear antibody (ANA) in their serum. In 1987,
Brunner and Klinge first described this condition as
immunocholangitis, while others have used different
terminology, such as autoimmune cholangiopathy,
primary autoimmune cholangitis, or autoimmune cholangitis. The current understanding is that this condition
is atypical PBC.
AMA-negative PBC
Approximately 10% of patients who have biochemical
evidence of cholestasis, accompanied by histological
features of PBC, are negative for AMA. Autoreactive T
Symptoms
1) None of the following
2) General fatigue
3) Cholestasis-associated
Pruritus (scratching)
Jaundice
4) Liver injury and cirrhosis-associated
Hematemesis and melena
Abdominal fullness
Consciousness disturbance
5) Comorbid autoimmune diseases -associated
Sicca syndrome, etc.
Complications
1) Cholestasis-associated
Osteoporosis
Hyperlipidemia
2) Liver injury and cirrhosis-associated
Portal hypertension
Hepatocellular carcinoma
Ascites
Hepatic encephalopathy
3) Comorbid autoimmune diseases -associated
Sjgrens syndrome
Rheumatoid arthritis
Hashimoto thyroiditis, etc.
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H. Ishibashi et al.
1
2
3
4
no progression
mild progression
moderate progression
advanced progression
Parenchymal change
In the early stage of PBC, non-specific necroinflammatory changes are found in the parenchyma.
Interface hepatitis and chronic cholestatic changes are
also found. During the progression of irreversible bile
duct damage and loss, there are several characteristic
findings that reflect cholestasis, including ductular reaction (proliferating bile ductules), copper deposition
(orcein-positive granules), bile plaques, hepatocellular
ballooning (cholate stasis), MalloryDenk bodies, and
feathery degeneration. These features are associated with
the progression of biliary fibrosis and biliary cirrhosis.
Changes similar to small cell dysplasia are also often
found in zone 1 (periportal area), which is useful for
the diagnosis of PBC. In addition to these cholestatic
changes reflecting bile duct loss, chronic hepatitic
changes resembling autoimmune hepatitis, such as
interface and lobular hepatitis, are also found in most
PBC cases, and are involved in the progression of
hepatic fibrosis and cirrhosis.
Histological staging
The characteristic histological findings of PBC are heterogeneously distributed throughout the liver. Thus, in
small specimens such as those taken from needle liver
biopsy, sampling errors are likely to be recognized when
using the classification systems of Scheuer and Ludwig,
because these two systems define each stage by a sole
histological feature (Supporting information Memo 2).
Therefore the novel staging system of Nakanuma (2009)
(Tables 68) is recommended for histological staging of
PBC, as this system could avoid the sampling errors
caused by the heterogeneous distribution of histological
features.
Recommendations:
1 The novel system for histological grading and staging
of PBC proposed by Nakanuma et al. is recommended (LE6, GRC1).
No deposition of granules
Deposition of granules in a few periportal hepatocytes in < 1/3 of portal tracts
Deposition of granules in several periportal hepatocytes in 1/3 to 2/3 of portal tracts
Deposition of granules in many hepatocytes in > 2/3 of portal tracts
II. Staging by sum total of two (A and B) or three (A, B, and C) criteria
Stage
Stage
Stage
Stage
Stage
Sum of scores
1
2
3
4
(no progression)
(mild progression)
(moderate progression)
(advanced progression)
Two criteria
Three criteria
0
12
34
56
0
13
46
79
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H. Ishibashi et al.
Disease severity
PBC progresses insidiously on a chronic course without
acute exacerbation, and a good hepatic reserve is maintained for a long period. Therefore, severity is evaluated
at the advanced stage (sPBC) and the modified Child
Pugh grading system with a modified total bilirubin
level is applied (Table 10).
Death
T.Bilirubin (mg/dL)
Albumin (g/dL)
PT (%)
INR
Ascites
Encephalopathy
14
3.5<
70%<
<1.7
None
None
410
2.83.5
4070%
1.72.3
Mild
Grade12
>10
<2.8
<40%
>2.3
Moderate
Grade 34
Hepatic failure
Jaundice
Non-jaundice
Symptomatic
Clinical jaundice/
stage non-jaundice
Asymptoatic
Score
Prognosis
Clinical type
HCC
Varices
Itching
Anti-gp210
Anti-centromere
Age
LTHOUGH THERE IS no completely curative treatment for PBC, ursodeoxycholic acid (UDCA) is currently considered the first-line treatment for the disease.
UDCA delays the progression of PBC, although it does
not have a significant benefit for PBC at the advanced
stage.
The clinical usefulness of UDCA is evaluated according to the following factors: (i) improvement of serum
biochemical markers, such as ALP, GGT, AST, ALT and
total bilirubin; (ii) histological improvement of cholan-
3.2 Prescription
Ursodeoxycholic acid (UDCA)
Extensive clinical trials including randomized clinical
trials (RCT) and meta-analyses were carried out for
UDCA after the first report by Poupon et al. After lively
debates, it was concluded that UDCA not only improves
the serum biochemical values of PBC patients but also
prolongs the period to death or liver transplantation.
The clinical guidelines for PBC by the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASD)
recommend that UDCA be given at a dose of 1315 mg/
kg/day, whereas in Japan, it is usually given at 600 mg/
day. In clinical trials performed with Japanese PBC
patients, 600 mg/day UDCA was given to PBC patients
for 48132 weeks and then the results of liver tests were
analyzed. Improvement was demonstrated in 81.8%
(27/33) of cases. Therefore, 600 mg/day is considered
as a standard dose, irrespective of body weight. The
dose can be increased up to 900 mg/day or decreased
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depending on weight and adverse events. Coadministration with bezafibrate is then considered if
900 mg/day UDCA has little effect. UDCA results in
biochemical improvement, but is not likely to act
against the core pathogenesis of PBC; administration
is usually maintained throughout life.
Recommendations:
1 Administration of bezafibrate (Bezatol, 400 mg/
day) may be considered in patients who exhibit a
suboptimal response to UDCA. (LE 2a, GR B)
Recommendations:
UDCA should be used to improve liver biochemical
tests and histological findings, and to prolong the
time until death or liver transplantation, though it
does not provide significant benefit for those at the
advanced stage. (LE 1a, GR A)
In general, UDCA should be administered at 600 mg/
day, and increased to 900 mg/day if the response is
suboptimal. (LE 2a, GR B)
UDCA is usually given TID, but the effects have been
shown to be similar even if it is given as a single daily
dose or BID. (LE 2a, GR B)
The following definitions are proposed by the Intractable Hepatobiliary Disease Study Group of Japan for
evaluation of the effects of UDCA after starting
therapy. Good response: serum ALP, ALT and IgM
become normal within 2 years; Fair response: serum
ALP, ALT and IgM become <1.5 UNL at 2 years;
Poor response: serum ALP, ALT and IgM remain
>1.5 UNL at 2 years. (LE 6, GR C1)
UCDA is the only drug shown to have long-term
efficacy. (LE 2a, 2b, C, GR C1)
Bezafibrate
Bezafibrate, a peroxisome proliferator-activated receptor
(PPAR ) agonist, has been reported to show biochemical improvements and effectiveness in patients
with PBC, mainly by Japanese researchers. However, the
long-term effects of bezafibrate have not yet been evaluated, and the use of the drug for PBC is not recommended in the clinical guidelines by EASL and AASLD.
When possible, bezafibrate should be administered in
combination with UDCA, because the drugs have different pharmacological mechanisms of action and demonstrate additive effects. Bezafibrate is given at 400 mg/day
in patients who exhibit a suboptimal response to
UDCA. However, in Japan, prescription of bezafibrate is
only approved for patients with hypertriglyceridemia;
PBC patients are still subject to off-label use.
Some reports indicate that fenofibrate, the other
PPARagonist, is also effective against PBC. Both
bezafibrate and fenofibrate are known to increase the
risk of rhabdomyolysis, and elevation of ALT is occasionally observed as an adverse effect of fenofibrate.
Prednisolone (PSL)
Table 11 Diagnostic criteria for corticosteroid use in PBCAIH overlap syndrome (Intractable Hepatobiliary Disease Study Group
in Japan, 2011)
PSL is recommended in addition to UDCA for cases that are considered to be PBCAIH overlap syndrome and meet the two
following criteria simultaneously:
(1) diagnosed with PBC using the criteria of the Intractable Hepatobiliary Disease Study Group in Japan (2010)
(2) diagnosed as probable/definite AIH using International Autoimmune Hepatitis Group (IAIHG) simplified criteria (2008).
(Supporting information Memo 7)
As for liver histology, HA scores in the PBC grading/staging systems in Table 8 should be used as follows: 0 for HA score 0 or 1,
1 point for HA score 2, and 2 points for HA score 3.
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H. Ishibashi et al.
Every 1 year
Every 24 years
Every 12 years
Every 1 year
(every 36 months in liver cirrhosis)
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H. Ishibashi et al.
3.6 Follow-up
Prognosis of asymptomatic PBC is excellent with little
progression, but 25% of patients with aPBC develop
some symptoms within 10 years. Serum total bilirubin
and cholestatic enzymes (ALP, GGT) are important for
assessing the activity and progression of PBC. Liver
biochemical tests should be done every 36 months.
In addition, thyroid hormone (every year) and bone
mineral density (every 24 years) tests are recommended because PBC is likely to be complicated with
other autoimmune diseases, such as Sjgrens syndrome, chronic thyroiditis, and rheumatoid arthritis.
Regular upper gastrointestinal endoscopy, depending
on stage (1 or 2 times per year), is required because
esophageal/gastric varices may develop even in patients
without jaundice. Abdominal ultrasound (US) and
serum AFP testing every 612 months are necessary in
patients with definite or suspected liver cirrhosis. Liver
cirrhosis, older age, and male sex are high risk factors for
developing hepatocellular carcinoma (HCC). Therefore,
testing for tumor markers and imaging studies [US and
computed tomography (CT)] are required for early
detection of HCC in patients with advanced PBC. Management for other complicating autoimmune diseases
should be done depending on each symptom.
Finally, special attention should be paid to pregnancy
in PBC and patients who have a desire to bear children.
The chance for pregnancy could be the same in the early
stage of aPBC as in the normal population; there is
no evidence to recommend avoidance of pregnancy in
patients with aPBC. In sPBC, however, if worsening of
icterus or varices is reported, then avoidance of pregnancy could be justified.
The impact of pregnancy on PBC is unclear because
both exacerbation and improvement of cholestasis
have been reported. Estrogen could potentially worsen
cholestasis; pruritus may become severe in pregnancy
and could be prolonged even after delivery. Conversely,
it should be noted that cholestasis could be symptomatic after pregnancy. After a patient has become pregnant, monitoring for varices is necessary as in other
cirrhotic patients, especially after the second trimester,
due to increase in circulating blood volume. The use of
blockers is considered to be safe. It is also advisable
ACKNOWLEDGMENTS
CONFLICTS OF INTEREST
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SUPPORTING INFORMATION