Grand Round

Syed Talha Shah
The Patient
 45 years old male, a known case of:
 Hepatitis B,
 Hepatitis D,
 CLD,
 With a history of:
 Alcohol Drinking
 Tobacco Smoking
Presentation to the ER
 Came to the ER on February 7th with a history of:
 Blood in vomitus
 Black Stools
 Yellow discoloration over the skin
 Generalized weakness with abdominal discomfort
HOPC
 According to the patient, he was in his usual state of
health 20 days back until when he did binge drinking
of alcohol.
 Not late afterwards, he had 2 episodes of vomiting that

contained blood (though , small in quantity – around
one table spoon).
 Alongside, he noticed blackness in his stools,

intermittently.
HOPC (Cont..)
 Over this period of 20 days, he developed yellowish
discoloration over his body (skin) in a gradual manner,
that started from his eyes (sclera).
 He also felt pain in his abdomen that was generalized

in nature and almost persistent.
HOPC (Cont..)
 For this, he went to Isra University Hospital in
Hyderabad where upon he was admitted. EGD was
done that identified non bandable grade II esophageal
varices. Moreover, 2 L of ascitic fluid was drained.
 However, his condition didn’t improve so he was

referred towards Karachi for tertiary care.
Medications
 Following medications were started at ISRA
 Cap Omeprazole (Losec) 40 mg

 Inj Octreotide
 Inj Albumin 100 ml OD
 Inj Tazo 4.5 g TDS
 No history of any long term medications

Past Medical and Personal History
 HBV (since ~ 5 years; HBsAg +ve)
 HDV (since ~ 4 years; Anti HDV + ve)
 Alcohol use (2-3 L/day since many years)
 Tobacco smoking (~5 cigarettes/day - 40 pack years)
 Chars addiction
 The presenting complains were not experienced

before.
Systemic Review
 Cardio-Respiratory: No c/o palpitations, Chest pain on
exertion, SOB, orthopnea, cough (except for dry cough
occasionally), sputum.
 Gastro interstinal: Constipation, Abdominal Pain,

Heartburn, Hematemesis.
No c/o diarrhea, pain during defecation, something
coming out during defecation or fresh blood P/R.
 Neurological: No c/o focal weakness, blackouts..

Examination
 Middle aged male, wearing a toxic look, lying on the
bed in a comfortable position. Awake but a little
drowsy.
 Jaundice: Markedly positive (On Scelra and Skin)

 Pallor: Positive
 Dehydration: Mild (dry mouth, skin turgor intact)
 Cyanosis, Edema, JVP, Clubbing, Lymph nodes: -ve

Vitals
 Blood Pressure 130/77 mmHg
 Pulse 90 bpm
 Temperature 98.6 F
 R/R 20 breaths/min
 O2 Sat (at room air) 98%
Abdominal Examination
 Inspection: Distended, Umbilicus everted – centrally
placed, No striae or scar marks could be noted.
 Palpation and Percussion: Soft, Non tender. No

visceromegaly could be felt. Shifting dullness and Fluid
Thrill were positive.
 Ausculation: Gut sounds audible at a rate of 3-4 per min.

No bruit could be heard over the right hypochondrium.
 Flapping tremors: positive

Rest of Systemic Examination
 Respiratory: Chest moving symmetrically with
respiration. B/L harsh vesicular breathing. B/L crepts
heard over the lower lung zones. Resonance and vocal
fermitus were normal up till mid lung zone but
dull/absent in the lower zones.
 Neruological: GCS 15/15.
 CVS: S1 + S2 + O
Case Summary
 45 years old male k/c Hep B, Hep D, CLD with a history of
Alcohol use, Tobacco Smoking.
 Came with c/o fever, hematemesis, melena, jaundice and

generalized weakness with abdominal discomfort.
 Upon examination, he was looking toxic, drowsy and

jaundiced. The abdomen was distended with positive fluid
thrill. On chest, basal crackles were heard B/L. Flapping
tremors were present (Assessment of Grade II Hepatic
Encephalopathy was made).
Differential Diagnosis
 ACLF
 ESLD
 Hepatoma
 Obstructive Jaundice
 Non variceal bleed (e.g Peptic Ulcer)
Day 1 - Investigations
CBC UCE LFTs Other
Hb 10.5 Na 124 T Bil 28.49 PT 28.6
PCV 31 K 4.5 D Bil 18.81 INR 2.8
TLC 9.4 Cl 93 ALT 80 LDH 442
DLC 60 % N HCO3 21.5 Alk PO4 60 Uric acid 2.90
Plt 80 Urea 33 GGT 92 Amylase 232
Cr 0.68 Lipase 124

Total Protein 6.27
Albumin 2.46
Globulin 3.81
A/G Ration 0.65

ABGs (Day 1)
pH 7.396
PCO2 32.8 mmHg
PO2 77.4 mmHg
HCO3 21.0 mmol/L
SO2 95%
Assessment
 Diagnostic paracentesis was done. DR Report awaited
 PSE Grade II
Day 1 -Management (in ICU)
Generic Name Dosage Route Frequency
Inj. Poperacillin + Tazobactam 4.5gm I/V 1+1+1
Inj. Omeprazole 40mg I/V 1+0+1

Tab. Rifaximin 550mg P.O 1+0+1
Inj Octreotide 50ug/h I/V Infusion
Tab. Spironolactone 50mg + - P.O ½+0+0

Furosemide 40mg
Tab Lorazepam 2mg P.O 1+0+1

(Vitamin B 1,6 & 12 Supplemet) - I/V 1+0+1
Tab Levetiracetam 500mg P.O 1+0+1
Syp Lactulose 30ml P.O 1+0+1
Normal Saline 80ml/h I/V Infusion

Liver Severity Scores (D 1)
CTP C
MELD 22.3
MELD Na 25
SOFA 11
APACHEII 8
GAHS 8
CLIF C ACLF 58
Day 2-3
 The Patient remained afebrile.
 His conscious level improved (became alert and
oriented).
 Melena got settled (1-2 stool/day).
 Vomiting settled as well (though nausea persisted).
 Jaundice remained clinically the same.
 Vitally stable
 I/O 3310/3330
CBC UCE LFTs
Hb 10.2 (<- 10.5) Na 126 (<-124) T Bil 28.24
PCV 30 K 4.2 D Bil 18.44
TLC 7.2 (<- 9.4) Cl 97 ALT 77
Plt 102(<- 80) HCO3 21.5 Alk PO4 57
PT 35.4 Urea 24 (<- 33) GGT 56
INR 2.8 Cr 0.76

Ascitic Fluid DR
Color Yellow,
Appearance Turbid
RBC 71
WBC 300
Neutrophils 33%
SAAG 1.66
Ultrasound Whole Abdomen
 Liver: Slightly shrunken in size with altered
parenchyma.
 Gall Bladder: Multiple tiny calculi
 Spleen: Enlarged in size (16cm)
 Moderate ascitic fluid noted
 Rest of the scan was unremarkable (i.e. Pancreas,
Kidneys were normal in appearance)
Management
Octoetride infusion was stopped on Day2.
The rest of medications were continued.
He was shifted to the ward on day 4.

CBC UCE
Hb 10.5(<- 10.2) Na 135 (<-126)
PCV 32 K 3.8
TLC 8.3 (<- 7.2) Cl 99
Plt 108 (<- 102) HCO3 214.1
Urea 21 (<- 24)
PT 41.0 (<- 35.4) Cr 0.78
INR 3.4 (<- 2.8)

Day 5-9
 Patient remained in the ward.
 Tazo contined till the 9th day.
 Clinically, the patient’s improved and remained stable.
Labs Upon Discharge
CBC UCE LFTs
Hb 10.0 Na 133 T Bil 22.61 (<- 28.24)
PCV 29 K 3.1 D Bil 12.33 (<- 18.44)
TLC 13.1 Cl 101 ALT 76 (<- 77)
Plt 100 HCO3 27.2 Alk PO4 69 (<- 57)
Urea 19 GGT 56 (<-56)
PT 31.5 (<- 41) Cr 1.05
INR 2.5 (<- 3.1)

Discharge Medications
Cap. 40mg P.O 1+0+1

Omeprazole
Tab. Rifaximin 550mg P.O 1+0+1
Tab. P.O ½+0+0

Spironolactone
50mg +
Furosemide
40mg
Tab Lorazepam 2mg P.O 1+0+1
Syp. Lactulose P.)

Re admission – Day 30
 The patient got admitted due to hepatic
encephalopathy grade III with one episode of fit,
altered level of conciousness and variceal bleed
(hematemesis).
 He was kept in the ICU again.
 Terlipressin and Carvedilol were given, 6 FFPs were

transfused and EVBL was done.
Investigations (Day 30)
Hb 11.5 Na 134 T Bil 15.46
PCV 35 K 4.3 D Bil 12.40
TLC 14.8 Cl 100 ALT 111
Plt 110 HCO3 25.7 Alk PO4 119
Urea 15 GGT 71
PT 30.8 Cr 1.13 AST 95
INR 2.4 CRP 6.24 Albumin 2.89
LDH 475
CTP C
MELD 20
MELD Na 21
SOFA 9
APACHEII 7
GAHS 7
CLIF C ACLF 61
 Hepatitis B PCR: Negative
 Hepatitis D PCR: 543IU

Admission on Day 60
 The patient got admitted again on Day 60 due to
hepatic encephalopathy and variceal bleed (2-3
episodes of hematemesis).
 This time, he was treated conservatively (Rx included

Inj Octeotride) along with transfusion of 6 FFPs. Upon
this, he got stable.
Investigations (Day 60)
Hb 10.9 Na 132 T Bil 7.31

PCV 32 K 4.2 D Bil 5.84
TLC 15.5 Cl 103 ALT 64
Plt 80 HCO3 9.4 Alk PO4 177
Urea 21 GGT 86
PT 26.1 Cr 1.04 AST 123
INR 2.0 ESR 70 Albumin 3.39
LDH 998
Lactate 47.0
CTP C
MELD 22.09
MELD Na 25.67
SOFA 13
APACHEII 9
GAHS 8
CLIF C ACLF 61
Advice
 He was advised Liver Transplant
ACUTE ON CHRONIC
LIVER FAILURE (ACLF)
Chronic Liver Disease
 Chronic liver diseases (CLD) are defined by the

following triad: 1) prolonged course of a hepatic
disease >6 months; 2) inflammatory and/ or
degenerative morphological findings; and 3) uncertain
prognosis.
Hepatology Jan2015; EMJ “DEFINITIONS OF ACUTE-ON-CHRONIC LIVER FAILURE..”;

Roland A, Ali AK
Acute Liver Failure
 Acute liver failure may be:
 Fulminant - characterized by the development of hepatic

encephalopathy within 8 weeks after the onset of acute
liver disease. Coagulopathy (international normalized ratio
[INR] ≥ 1.5) is invariably present.
 Subfulminant - when these findings appear between 8

weeks and 6 months after the onset of acute liver disease
and carries an equally poor prognosis.
Current Medical Diagnosis and Treatment 2015 edition

Coining of the term ‘ACLF’
 Acute on Chronic Liver Failure (ACLF): This term
was first used in 1995 to describe a condition in which
two insults to liver are operating simultaneously, one
of them being ongoing and chronic, and the other
acute.
Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific

Association for the Study of the Liver (APASL) 2014
What is ACLF?
 Acute-on-chronic liver failure (ACLF) is an
increasingly recognized entity encompassing an acute
deterioration of liver function in patients with chronic
liver disease, which is usually associated with a
precipitating event and (usually*) results in the failure
of one or more organs and high short term mortality
EASL, Journal of Hepatology 2012 “Acute-on chronic liver failure” R Jalan P Gines
* According to APASL
ACLF
 ‘..patients with previously well compensated chronic
liver disease in whom an acute decompensation of liver
function occurs due to the effects of a precipitating
event..’
Sen et al Liver 2002;22(S2) 5-13.

ACLF – A Distinct Entity
 Prospective data to define this is lacking but there is a
large body of circumstantial evidence suggesting that
this condition is a distinct clinical entity
Hepatology Jan2015; EMJ “DEFINITIONS OF ACUTE-ON-CHRONIC LIVER
FAILURE..”; Roland A, Ali AK
How do we define it?
 Being a new entity, so far, there’s not a single,
universally accepted definition.
 At least 13 definitions have been proposed.

Hepatology Jan2015; EMJ “DEFINITIONS OF ACUTE-ON-CHRONIC LIVER FAILURE..”;
Roland A, Ali AK
Two Consensus Definitions
 ‘Acute hepatic insult manifesting as jaundice and
coagulopathy, complicated within 4 weeks by ascites
and/or encephalopathy in a patient with previously
diagnosed or undiagnosed chronic liver disease’;
(APASL)
 ‘Acute deterioration of pre-existing, chronic liver

disease, usually related to a precipitating event and
associated with increased mortality at 3 months due to
multi-system organ failure’. (EASL-AASLD)
A reason for the contention
 Studies based on APASL criteria have reported renal
dysfunction in 22.8–34 % of patients with ACLF and as
high as 51 % using the more sensitive AKIN criteria.
This highlights the fact that a significant number of
patients of ACLF based on APASL criteria who do not
have renal dysfunction (using even the most sensitive
criteria to detect renal involvement) would definitely
be missed if renal dysfunction is considered in the
definition.
ACLF – As defined by APASL
 The ACLF is an acute hepatic insult manifesting as
jaundice (serum bilirubin 5 mg/dl (85micromol/l)
and coagulopathy (INR 1.5 or prothrombin activity
\40 %) complicated within 4 weeks by clinical
ascites and/or encephalopathy in a patient with
previously diagnosed or undiagnosed chronic liver
disease/ cirrhosis, and is associated with a high 28-
day mortality.
What sort of CLD?
 Data from AARC, that was based on liver biopsy studies,
revealed that a good number of patients with ACLF didn’t
have underlying cirrhosis. However, they still had a poor
prognosis (>33 % mortality at 28 days).
 Therefore chronic liver disease with or without cirrhosis

can present with ACLF
 Patients with known previous decompensation with

jaundice, hepatic encephalopathy, and ascites should be
excluded (1b, C).
Common causes of CLD
 The common underlying chronic liver diseases include
alcoholic liver disease, Hepatitis B, Hepatitis C,
NAFLD related chronic liver disease, or cirrhosis of the
liver

What qualifies as an ‘Acute Insult’?
 Major etiologic agents responsible for precipitating ACLF are as
follows:
 Hepatotropic viral infections (1a, A): Reactivation of HBV

and super-infection with HEV are the major causes of acute
insult in ACLF (1a, A).
 Non-infectious causes: Active alcohol consumption (within

the last 28 days) - commonest cause (1a, A). Drug-induced liver
injury, severe autoimmune hepatitis, and flare of Wilson’s
disease are other causes of acute insult in ACLF (1a, A).
Acute-on-chronic liver failure: consensus recommendations of APASL 2014

What qualifies as an ‘Acute Insult’?
(Cont.)
 Non-hepatotropic insults like surgery, trauma, and viral
infections if producing direct hepatic insult could lead to
ACLF (2b, C).
 Variceal bleed per se may not qualify as an acute insult for

ACLF, and we need more data to ascertain this (5,D).
 In a proportion of patients, the acute hepatic insult may

not be identifiable by the current routine assessment (5,D).

Period for the ‘Acute Insult’
 A period of 28 days (4 weeks) has been mostly
agreed for defining the impact of an acute event.
 “ A period of 28 days was considered adequate for

inclusion as the last drink ”

APASL 2014
Assessing CLD
 Diagnosis of chronic liver disease in a case of ACLF is
made by history, physical examination, and previous
laboratory/radiological investigations.
 Ultrasound and CT abdomen can pick up CLD.
 However, it may be difficult to clearly assess CLD in

the presence of inflammation and liver failure using
non invasive tests.
Role of Liver Biopsy
 Hence, Liver biopsy through the transjugular route can
be implied when the presence of underlying chronic
liver disease and/or the cause of chronic liver disease
and/or the acute insult are not clear.
 Liver biopsy may point out the stage of fibrosis and

prognosis, and outcome in patients with ACLF

Histopatholgy – Prognostic Value
 Liver regeneration is considered to play an important
role in ACLF as prognosis can be improved if the
critical threshold of functional liver cell mass is
regained. Decompensated cirrhosis is considered
irreversible owing to the loss of regeneration potential.
Liver histology can provide morphologic evidence
supporting these concepts and for assessing
regenerative potential and prognosis

Caution !
 There’s a bleeding risk in the setting of a deranged
clotting profile. Thus, the need for biopsy should be
individualized.
Acute-on-chronic liver failure: consensus recommendations of

the Asian Pacific Association for the Study of the Liver (APASL)
2014
Assessing Liver Failure
 Jaundice – Serum Bilirubin >5 mg/dl (85um/L)
 Coagulopathy - INR >1.5 (or Prothrombin activity < 40%)
 Development of clinical ascites and/or encephalopathy

Bleeding Risk
 Coagulation profile in ACLF: prothrombin time (INR)
is a useful prognostic marker in patients with ACLF.
However, it is not helpful in predicting the risk of
bleeding (2a, B).
Acute-on-chronic liver failure: consensus

recommendations of the Asian Pacific Association
for the Study of the Liver (APASL) 2014
Septicemia in ACLF
 Bacterial infections are much more common in patients
with cirrhosis than in the general population
 In a recent study, in critically ill non-transplanted patients

with ACLF, bacteremia was an independent predictor of
poor prognosis.
 Sepsis developing in a patient with ACLF has high

mortality due to multi-organ dysfunction (1a, A).

Preventing Septicemia in Cirrhosis
 Identifying infections at the earliest and prompt
initiating of (empirical) antibiotic therapy is helpful in
preventing progression to sepsis, organ failure, and
mortality. The same analogy could be applied for ACLF
(3a, C).
Acute-on-chronic liver failure: consensus

recommendations of the Asian Pacific Association for
the Study of the Liver (APASL) 2014
The “Golden Window”
 “Golden window’’ is a short period of about 1 week
before the onset of sepsis and development of extra-
hepatic organ failure in a patient with ACLF.
Therapeutic interventions during this period are likely
to prevent organ failure and provide a potential
opportunity for ameliorating or reversing the hepatic
injury and failure (2b, A).
Acute-on-chronic liver failure: consensus recommendations

of the Asian Pacific Association for the Study of the Liver
(APASL) 2014
APASL 2014
www.hepatitisc.uw.edu
Toronto Notes 2014
Medscape.com
In interpreting the MELD Score in hospitalized patients,
the 3 month mortality is:
 40 or more — 71.3% mortality

 30–39 — 52.6% mortality
 20–29 — 19.6% mortality
 10–19 — 6.0% mortality
 <9 — 1.9% mortality
Case Recap
Hepatitis
B
Hepatitis Alcohol
D Drinking
Chronic
Liver
Disease
Case Recap
Acute Insult
(Binge Drinking
of Alcohol)
CLD ACLF
Case Recap (3)
Hematemesis Jaundice
ACLF
Hepatic
Melena
Encaphalopathy
Inclusion Criteria for ACLF
 Period of liver failure: within 28 days
 Jaundice (Bilirubin > 5mg/dl)
 Coagulopathy (INR>1.5)
 Clinical Ascites and/or Encephalopathy
Exclusion Criteria
Already decompensated cirrhosis prior to insult
Hepatocellular Carcinoma
Case Recap - Liver Severity Scores
Day 1 Day 30 Day 60
CTP C C C
MELD 24.3 20 22.09
MELD Na 25 24 25.67
SOFA 11 9 13
APACHEII 8 8 9
GAHS 8 7 8
ACLF Grade 3 3 3
CLIF C ACLF 58 61 61
CLIF-C ACLF Score at Day 1
CLIF-C ACLF Score at Day 60
Questions?

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Syed Talha Shah

 With a history of:

 Not late afterwards, he had 2 episodes of vomiting that

 Alongside, he noticed blackness in his stools,

 He also felt pain in his abdomen that was generalized

 However, his condition didn’t improve so he was

 Cap Omeprazole (Losec) 40 mg

 No history of any long term medications

 The presenting complains were not experienced

 Gastro interstinal: Constipation, Abdominal Pain,

 Neurological: No c/o focal weakness, blackouts..

 Jaundice: Markedly positive (On Scelra and Skin)

 Cyanosis, Edema, JVP, Clubbing, Lymph nodes: -ve

 Palpation and Percussion: Soft, Non tender. No

 Ausculation: Gut sounds audible at a rate of 3-4 per min.

 Flapping tremors: positive

 Neruological: GCS 15/15.

 Came with c/o fever, hematemesis, melena, jaundice and

 Upon examination, he was looking toxic, drowsy and

Hb 10.5 Na 124 T Bil 28.49 PT 28.6

PCV 31 K 4.5 D Bil 18.81 INR 2.8

TLC 9.4 Cl 93 ALT 80 LDH 442

DLC 60 % N HCO3 21.5 Alk PO4 60 Uric acid 2.90

Plt 80 Urea 33 GGT 92 Amylase 232

Cr 0.68 Lipase 124

Total Protein 6.27

A/G Ration 0.65

PCO2 32.8 mmHg

PO2 77.4 mmHg

HCO3 21.0 mmol/L

Inj. Poperacillin + Tazobactam 4.5gm I/V 1+1+1

Inj. Omeprazole 40mg I/V 1+0+1

Inj Octreotide 50ug/h I/V Infusion

Tab. Spironolactone 50mg + - P.O ½+0+0

Tab Lorazepam 2mg P.O 1+0+1

(Vitamin B 1,6 & 12 Supplemet) - I/V 1+0+1

Tab Levetiracetam 500mg P.O 1+0+1

Syp Lactulose 30ml P.O 1+0+1

Normal Saline 80ml/h I/V Infusion

Hb 10.2 (<- 10.5) Na 126 (<-124) T Bil 28.24

PCV 30 K 4.2 D Bil 18.44

TLC 7.2 (<- 9.4) Cl 97 ALT 77

Plt 102(<- 80) HCO3 21.5 Alk PO4 57

PT 35.4 Urea 24 (<- 33) GGT 56

INR 2.8 Cr 0.76

The rest of medications were continued.

He was shifted to the ward on day 4.

Hb 10.5(<- 10.2) Na 135 (<-126)

TLC 8.3 (<- 7.2) Cl 99

Plt 108 (<- 102) HCO3 214.1

Urea 21 (<- 24)

PT 41.0 (<- 35.4) Cr 0.78

INR 3.4 (<- 2.8)

Hb 10.0 Na 133 T Bil 22.61 (<- 28.24)

PCV 29 K 3.1 D Bil 12.33 (<- 18.44)

TLC 13.1 Cl 101 ALT 76 (<- 77)

Plt 100 HCO3 27.2 Alk PO4 69 (<- 57)

Urea 19 GGT 56 (<-56)

PT 31.5 (<- 41) Cr 1.05

INR 2.5 (<- 3.1)

Cap. 40mg P.O 1+0+1

Tab. P.O ½+0+0

Syp. Lactulose P.)

 He was kept in the ICU again.