1. Clinical Case Conference
Ranjeeta Bahirwani
July 28, 2010

2. 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

3. Clinical Case Medications: PMH/PSH: Allergies: Social History: FH:
None
Social History:
Single businessman
+ ETOH-multiple attempts at rehab
No IVDU
No tobacco
PMH/PSH:
None
Allergies:
NKDA
FH:
No FH of liver disease 3

4. 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 4

5. Labs
133
110 43
11.1
MCV 105
100
20.2
N-87%
198
3.8 10
2.3
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 5

6. Questions What is your clinical assessment of this patient?
How would you manage him next?
What is his prognosis?

7. Clinical Case Conference
Ranjeeta Bahirwani
July 28, 2010

8. 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

9. Alcoholic Liver Disease-Spectrum

10. 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)

11. 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 pro-inflammatory cytokines by activating Kupffer cells (TNF α levels are higher in pts with AH than in pts with inactive cirrhosis)

12. Lucey M et al. N Engl J Med 2009;360:2758-2769

13. Diagnosis 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

14. Histology

15. Assessing Illness Severity
Maddrey’s Discriminant Function
MELD
Glasgow Alcoholic Hepatitis Score
ECBL
Lille model

16. Maddrey’s Discriminant Function
Most commonly used predictive model; developed to facilitate assessment of response to steroids in 1978; modified in 1989
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.
 Discriminant function =
(4.6 x [PT -control PT]) + (serum bilirubin)

17. 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

18. Glasgow Alcoholic Hepatitis Score
Age < ≥ 50
WCC(109/l) < ≥15
Urea (mmol/l) < ≥5
PT ratio < >2.0
Bili (mol/l) < >250
Score
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:
Forrest EH et al. Gut 2007; 56:

19. 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:

20. 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) ×Albumin on day 0 (g/L) ×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:

21. Lille Model
Louvet A et al. Hepatology 2007; 45:

22. Lucey M et al. N Engl J Med 2009; 360: 2758-2769

23. Therapy-Corticosteroids
Most intensely studied yet most hotly debated
Block cytotoxic as well as inflammatory pathways (inhibit NF-KB, decrease TNF α levels)
Decrease intracellular adhesion molecule 1 in sinusoidal cells-inhibit 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

24. 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:

25. 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 non-responders (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

26. 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

27. 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:

28. 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:

29. 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:

30. 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:

31. PTX in Advanced Cirrhosis
Lebrec D et al. Gastroenterology 2010; 138:

32. 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:
Boetticher NC et al. Gastroenterology 2008; 135:

33. Other agents
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

34. 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

35. Lucey M et al. N Engl J Med 2009; 360: 2758-2769

36. AASLD Algorithm

37. 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