Clinical Case
Conference
Ranjeeta Bahirwani
July 28, 2010
Blame it on the Sauce….
Cc- “I feel like crap and am yellow”
50 M with no PMH admitted with 1 week h/o
jaundice, abdominal pain and distention; also
with increasing fatigue.
 + h/o chronic alcohol abuse, attempted AA without
success
 Recent alcohol binging over the past 2 months
especially on weekends-drinks a fifth of whiskey/day

Clinical Case
PMH/PSH:

None
Allergies:

NKDA
FH:

No FH of liver disease
Medications:

None
Social History:
Single businessman
 + ETOH-multiple attempts at
rehab
 No IVDU
 No tobacco
Physical Examination
Vitals: 98 F, 98, 90/45, 18, 98% RA
GEN: + jaundice, NAD
 HEENT: + scleral icterus
 CV: RRR, no murmurs/rubs
 Lungs: CTAB
 Abdomen: no caput medusae, distended with
shifting dullness, + mild TTP diffusely, no HSM
 Ext: 1+ LE edema bilaterally
 Skin: no spider angiomata
 Neuro: A + O x 3; no asterixis

Labs
133
110
43
11.1
100
3.8
10
2.3
20.2
N-87%
MCV 105
198
TB 25.3, DB 17.3; albumin 2.5
AST 185, ALT 50, Alk phos 90; amylase 150, lipase 230
INR 2.2, PT 22.1, PTT 49
Ascites: albumin <1, 150 WBC (10% segs)
RUQ U/S: large ascites, nodular liver, mild splenomegaly
Questions



What is your clinical assessment of this patient?
How would you manage him next?
What is his prognosis?
Clinical Case
Conference
Ranjeeta Bahirwani
July 28, 2010
Alcoholic Liver Disease




Affects 1% of the US Population
Ranges from simple steatosis, alcoholic hepatitis,
to cirrhosis
Accounts for >12000 deaths/yr
2nd most frequent indication for OLT
Alcoholic Liver Disease-Spectrum
Alcoholic Hepatitis






Clinical syndrome of jaundice and liver failure, generally
with chronic alcohol use (mean ~100 gm/day)
Common symptoms apart from jaundice include fever,
ascites, cachexia, RUQ pain and HE
Risk factors include amount of alcohol ingested (not a
linear relationship); increased risk with female sex
Genetic factors (increased risk in children of alcoholics)
Protein calorie malnutrition
Concomitant viral hepatitis (HCV)
Pathogenesis


Oxidative metabolism to acetaldehyde generates
reactive oxygen species, which induce lipid
peroxidation, causing hepatocellular death via
necrosis/apoptosis
Increased endotoxin levels due to intestinal
permeability leading to increased proinflammatory cytokines by activating Kupffer
cells (TNF α levels are higher in pts with AH
than in pts with inactive cirrhosis)
Lucey M et al. N Engl J Med 2009;360:2758-2769
Diagnosis








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Elevated AST and ALT ( rarely > 300 IU/ml)
AST/ALT > 2:1 (> 80% pts)
Increased GGT (70-90% pts) -independent of liver disease
Leukocytosis with neutrophilia
Increased MCV (80-100% pts) –due to ETOH induced
marrow toxicity, B12/folate deficiency
Elevated creatinine-ominous sign (HRS)
Carbohydrate deficient transferrin
Elevated IgA levels
Hyperbilirubinemia, coagulopathy, TCP
Histology
Assessing Illness Severity





Maddrey’s Discriminant Function
MELD
Glasgow Alcoholic Hepatitis Score
ECBL
Lille model
Maddrey’s Discriminant Function

Most commonly used predictive model; developed to
facilitate assessment of response to steroids in 1978;
modified in 1989
Discriminant function =
(4.6 x [PT -control PT]) + (serum bilirubin)

A DF ≥ 32 in the presence of HE predicts > 50%
mortality at 28 days (in the absence of therapy); one
month survival > 90% if DF < 32
Ramond MJ et al. N Engl J Med 1992; 326: 507–512.
MELD



MELD score has been shown in multiple studies to
predict short term mortality in pts with AH
MELD >11 is roughly equivalent to DF >32; although
studies have suggested MELD cutoffs of 18, 19 and 21 for
predicting prognosis
MELD score on admission ≥ 18, MELD at 1 week  20
or rise in MELD  2 have been shown in a retrospective
study to be more sensitive (91%) and specific (85%) than
DF or CTP score in predicting mortality
Dunn W et al. Hepatology 2005; 41: 353-8
Srikureja W et al. J Hepatol 2005; 42:700-6
Glasgow Alcoholic Hepatitis Score
Score
Age
WCC(109/l)
Urea (mmol/l)
PT ratio
Bili (mol/l)



1
<50
<15
<5
<1.5
<125
2
3
≥ 50
≥15
≥5
1.5-2.0
125-250
>2.0
>250
Derived in 2005 to identify variables related to 28 and 84
day survival after admission in pts with AH
In patients with DF ≥ 32 and GAHS < 9, no difference in
survival noted with steroids
With DF ≥ 32 and GAHS ≥ 9, 24 day (78 vs 52%) and 84
day (59 vs 38%) survival better with steroids
Forrest EH et al. Gut 2005; 54: 1174-9
Forrest EH et al. Gut 2007; 56: 1743-6
ECBL

Derived to determine which patients with severe (DF ≥
32) and biopsy-proven AH do not respond to
corticosteroids

An early change in bilirubin levels (ECBL), defined as
bilirubin level at 7 days lower than bilirubin level on the
first day of treatment identified 95% of pts with
continued improvement in liver function on steroids

At 6 months, patients with ECBL had 83% survival
compared to 23% without drop in bilirubin at day 7
Mathurin P et al. Hepatology 2003;38:1363-1369
Lille Model
Model generated using 6 variables to identify patients with
severe AH (DF ≥ 32) not responding to steroids
Lille score:

3.19–0.101×Age (years) +0.147×Albumin on day 0 (g/L) +0.0165×Evolution in
bilirubin level (μmol/L) −0.206× Renal insufficiency −0.0065× Bilirubin on day 0
(μmol/L) −0.0096×PT (seconds)


Pts with score ≥ 0.45 had marked decrease in 6 month
survival (25% vs 85%), predicted 75% of observed deaths
Better than CTP, DF, GAHS, and MELD at predicting
prognosis
Louvet A et al. Hepatology 2007; 45: 1348-54
Lille Model
Louvet A et al. Hepatology 2007; 45: 1348-54
Lucey M et al. N Engl J Med 2009;360:2758-2769
Lucey M et al. N Engl J Med 2009; 360: 2758-2769
Therapy-Corticosteroids
Most intensely studied yet most hotly debated
 Block cytotoxic as well as inflammatory pathways (inhibit NFKB, decrease TNF α levels)
 Decrease intracellular adhesion molecule 1 in sinusoidal cellsinhibit leukocyte activation
Prednisolone 40mg daily recommended in pts with DF ≥ 32 or
HE for 28 day course +/- taper (provided ECBL or Lille score
< 0.45)
CONTRAINDICATIONS:
-Infection/sepsis
-GI bleed
-Renal insufficiency

Steroids for AH



Data from the 3 largest trials of Prednisolone vs placebo
analyzed patients with DF ≥ 32
28 day survival was 85% vs 65%; NNT 5
The 5 largest trials were re-analyzed in Cochrane review
which confirmed the survival benefit in patients with DF ≥
32 or HE
*** ~40% pts with AH are UNRESPONSIVE to steroids
Mathurin P, Hepatology 2008; 48: 635A
Rambaldi A APT 2008; 27:1167-78
Steroids-Role of Infection



Study of 246 pts with severe AH revealed no
difference in infection rates before or after
initiation of steroids (25.6 versus 23.7%)
Infection occurred more frequently in steroid nonresponders (42.5%) versus responders (11.1%)
Lille model and MELD were associated with
survival, not presence of infection
Louvet A et al. Gastroenterology 2009; 137: 541-8
Infection in Patients With Severe Alcoholic Hepatitis Treated
With Steroids: Early Response to Therapy Is the Key Factor
Louvet A et al. Gastroenterology 2009; 137: 541-8
Pentoxifylline


Non-selective phosphodiesterase inhibitor and TNF α
suppressor
RCT of 101 patients with severe AH (DF ≥ 32)
receiving 4 weeks of PTX 400mg TID versus placebo
revealed lower hospital mortality in PTX group (24.5%)
versus placebo group (46.1%)-HRS was the cause of
death in 50% PTX pts and 92% of placebo pts
***TNF α levels were not predictive of survival but
increased markedly in non-survivors vs survivors
Akriviadis E et al. Gastroenterology 2000; 119:1637-48
Pentoxifylline vs Prednisolone
RCT of 68 pts with severe AH (DF ≥ 32) receiving
Prednisolone vs PTX
3 month mortality was 35% in steroid group vs 14.7% in
PTX; more pts in steroid group developed HRS
Krishna De et al. World J Gastroenterol 2009; 15:1613-19
PTX in Steroid Non-Responders


121 pts with severe AH were treated with steroids; of 87
non-responders (using ECBL), 29 were switched to PTX
and 58 kept on steroids
There was no survival benefit at 2 months in pts switched
to PTX (35.5 versus 31%)
Louvet A et al. J Hepatol 2008; 48: 465-70
PTX in Advanced Cirrhosis



335 patients with cirrhosis (CTP C) were given PTX or
placebo for 6 months-mortality was no different at 2 or 6
months in either group (6 month mortality 30% in PTX
group and 31.5% in placebo group)
The proportions of patients without complications
(infection, renal insufficiency, HE, or GI bleed) were higher
in the PTX group than in the placebo group at 2 months
(78.6% vs 63.4%) and 6 months (66.8% vs 49.7%).
133 pts had AH, 55 had DF  32 and got steroids along with
PTX vs placebo-there was no difference in 2 and 6 month
mortality between these groups
Lebrec D et al. Gastroenterology 2010; 138: 1755-62
PTX in Advanced Cirrhosis
Lebrec D et al. Gastroenterology 2010; 138: 1755-62
TNF α antagonists



Infliximab and Etanercept have been studied for severe
AH
Infliximab showed a positive effect in small studies; RCT
comparing Infliximab and Prednisolone was stopped early
due to increase rates of infections and death
Etanercept was studied in 48 patients with MELD  15
versus placebo x 3 weeks; 6 month mortality was higher in
Etanercept group (58 versus 23%); infection rates were
also higher (35 versus 9%)
Naveau S et al. Hepatology 2004; 39: 1390-7
Boetticher NC et al. Gastroenterology 2008; 135: 1953-60
Other agents




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PTU- (? mitigates hepatic ischemia from ETOH
induced hypermetabolic state)-no benefit
Anabolic androgenic steroids-increase muscle
mass but do not improve survival
Vitamin E
Silymarin
Colchicine
S-Adenosylmethionine
Nutrition


Risk of death in AH is closely correlated with
degree of malnutrition
RCT comparing enteral tube feeding (2000
kcal/day) vs Prednisolone in 71 pts with severe
AH revealed similar 1 month and 1 yr survival in
both groups highlighting the effects of
nutritional support
Cabre E et al. Hepatology 2000; 32: 36-42
Lucey M et al. N Engl J Med 2009; 360: 2758-2769
AASLD Algorithm
Liver Transplantation


AH is considered a contraindication to
transplantation and 6 months of abstinence is
recommended as minimal listing criterion
although small studies have shown no worse
outcomes in pts with AH
Recidivism rates range from 11-50% at 3-5 years
post-transplantation
Mathurin P. Liver Transplantation 2005; 11: S21-24