Alcoholic Hepatitis: Management Options

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2 Alcoholic Hepatitis: Management Options Paul J. Thuluvath, MD. FRCP Institute of Digestive Health & Liver Diseases, Mercy Medical Center, Baltimore Professor of Surgery & Medicine, Georgetown University, Washington DC

3 Disclosure I do not have any financial relationships relevant to this topic I will discuss off-label use of medications

4 Case History 34 yr old man with new onset of jaundice No previous history. Worked as a stockbroker, no drug use, admitted drinking wine regularly Total bilirubin 15 mg/dl, DB 12 mg/dl, AST 212, ALT 70, alkphosp 125; INR 3.2, Hb14.5, MCV 102, WBC 12000, Plat 120,000 U/S of liver steatosis JAMA 2004;291:1238

5 Alcohol related morbidity and mortality 3 rd leading preventable cause of death 2.3 million years lost in 2001 in the USA JAMA 2004;291:1238

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7 Beer is living proof that God loves us and wants us to be happy Benjamin Franklin Always remember that I have taken more out of alcohol than alcohol has taken out of me Winston Churchill Alcohol may be the man s worst enemy, but the bible says love your enemy Frank Sinatra

8 For every 1-liter alcohol consumption, there is 14% increase of cirrhosis in man and 8% in women

9 One death every 2 minutes (9.2% of all deaths in the region) in Columbia The alcohol pattern in Columbia is similar to that of USA (7.8 L of pure alcohol/person) 60% of all traffic deaths in Columbia are related to alcohol Regulation and taxation have the highest impact on alcohol use

10 Alcoholic Liver Disease 20% Alcoholic Hepatitis Alcoholism Fatty Liver 90% Normal Liver 10% 30% 15% Alcoholic Cirrhosis

11 Alcoholic Hepatitis A clinical syndrome characterized by rapid onset of jaundice and liver failure after decades of alcohol use may also present with fever, ascites, myopathy, hepatomegaly and HE Age: yrs, M>F (but women are more prone) AST/ALT >2.0 (presumed mechanisms include decreased hepatic ALT or pyridoxal 5- phosphate, or increased hepatic mitochondrial aspartate)

12 Alcoholic Hepatitis Symptomatic alcoholic hepatitis 50% will have concomitant cirrhosis 50% of mild alcoholic hepatitis will progress to cirrhosis About a quarter will have normal histology if they abstain from alcohol Recidivism is common (67-81%) Naltrexone or acamprosate may reduce recidivism Baclofen may be helpful

13 Predictors of Outcome Maddrey s score: 4.6 x PT {patient PT-control PT} + serum total bilirubin (in mg/dl) DF>32 associated with high mortality 30-day mortality ~30% Higher in the presence of encephalopathy Glasgow alcoholic hepatitis score (age, WBC, BUN, bilirubin, PT/INR) MELD score (bilirubin, creatinine, INR) >21 associated with 20% 90-day mortality Lille score

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15 Alcoholic Hepatitis - Treatment Nutritional supplementation (enteral + supplements) Discordant results Current SOC is steroid therapy (prednisone 40 mg daily for 28 days) in those with Maddrey s score (DF) > 32 1-month survival higher in treated group (85% vs. 65%) J Hepatol 2002:36:480 (analysis of 3 trials) non-responders (~40% do not respond) have a 6-month mortality of 70% Other treatment options include pentoxifylline, N- acetyl cysteine (NAC), liver transplantation

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18 Pentoxifylline improves survival N=49 N=52 Hepatorenal syndrome is lower in treated group compared to placebo (12% vs. 42%, p <0.001)

19 Pentoxifylline Cochrane database analysis 5 trials including 336 patients Mortality: RR 0.64 (CI ) Evidence was not firm Whitfield K et al Cochrane Databse Syst Rev 2009 Oct 7 Could be used when corticosteroid is contraindicated

20 **Infection was more common in Infliximab group Infliximab 10 mg/kg at week 0,2,4

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22 Lille Score The model uses 6 variables age, creatinine, albumin, PT baseline bilirubin (Day 0) bilirubin at day 7 (on treatment)

23 Louvet A et al Hepatology 2007;45:

24 M O R T A L I T Y Louvet A et al Hepatology 2007;45:

25 Lille Score Lille Score is an excellent predictor of survival at day-7 on treatment with steroids Non-response (Lille score > 0.45 or worsening liver disease on day-7) to steroid at day-7 is associated with a high mortality

26 Louvet A et al Hepatology 2007;45:

27 Pentoxifylline in non-responders Louvet A et al. J Hepatol 2008:48:465

28 2-step strategy Early (day-7) withdrawal in some nonresponders followed by pentoxifylline for another 28 days (n=29) Comparison to 58 matched nonresponders to corticosteroid No survival advantage at 2 months Louvet A et al. J Hepatol 2008:48:465

29 Pentoxifylline is ineffective in non-responders to corticosteroids Louvet A et al. J Hepatol 2008:48:465

30 Enteral Nutrition +/- NAC Randomized, controlled trial in 52 patients (28 NAC, 24 placebo) in biopsy proven alcoholic hepatitis N-acytyl cysteine (IV) for 14 days or placebo; all have enteral nutrition support Survival 1 month: 70.2% (NAC), 83.8% (control) 6 month: 62.4% (NAC), 67.1% (control) Moreno C et al J Hepatol 2010 August1

31 Other Treatments Corticosteroids + Pentoxifylline No advantage (Sidhu SS et al DDS 2012) Antoxidant therapy No advantage (Stewart S et al 2007 J Hepatol)

32 Steroid + N-acetyl cysteine (NAC) vs. Steroids alone 174 patients with DF >32 + histology consistent with alcoholic hepatitis were randomized from 11 centers in France Group 1: Prednisone 40 mg daily for 4 weeks Group II: Prednisone 40 mg daily for 4 weeks + NAC for 5 days Nguyen-Khac E et al N Engl J Med 2011;365:1871-9

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34 Prednisone group Day1-5: 1000 ml of D5 in 24 hours N-Acetyl Cysteine + Prednisone Day1: 150 mg/kg (in 250 ml of 5% dextrose) in 30 minutes followed by 50 mg/kg in 4 hrs (500 ml D5), 100 mg/kg in 16 hrs (1000 ml D5) Day mg/kg in 1000 ml D5 over 24 hrs Nguyen-Khac E et al N Engl J Med 2011;365:1871-9

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36 Mortality Month 1 Month 2 Month 3 Month 6 Prednisone+ NAC 8.2% 15.3% 22.4% 27.1% Prednisone 23.6%* 32.6%* 33.7% 38.2% * P <0.005 Nguyen-Khac E et al N Engl J Med 2011;365:1871-9

37 Nguyen-Khac E et al N Engl J Med 2011;365:1871-9

38 Liver Transplantation?

39 Liver Transplantation for Alcoholic Hepatitis Case control study of LT in patients with non-response to steroids (NRS) at day-7 (Lille score 0.88) 26 listed within 13 days of NRS Selected by consensus (social, co-morbidities..) Less than 2% of patients admitted with alcohlolic hepatitis were selected. 6 month survival (77% vs. 23%) Three patients resumed drinking at 720, 740 and 1140 days Mathurin P et al N Engl J Med 2011;365:1790

40 Kaplan Meier Estimates of Survival among the 26 Study Patients and Randomly Selected Matched Controls. Mathurin P et al. N Engl J Med 2011;365:

41 Long term survival in severe alcoholic hepatitis 272 with severe alcoholic hepatitis treated with steroids 6 month survival responders (Lille <0.45) 82.7% non-responders (Lille >0.45) 27.6% Louvet A et al Hepatology 2010;52:381a

42 Long term survival in severe alcoholic hepatitis treated with steroids Overall 5-year survival: 32.6% responders and abstinent 80.4% responders and not abstinent 39% Non-responders who drank 0% Recidivism heavy drinking 53.6% after median time of 180 days ( days) If patients survived 6 months and they abstained, 5-year survival was 75.9% vs. 32.6% if they drank Louvet A et al Hepatology 2010;52:381a

43 Conclusions Severe alcoholic hepatitis (DF>32) should be given a trial of corticosteroids combination of prednisone and NAC is an option Pentoxifylline 400 mg TID for 28 days if steroid is contraindicated Those who do not respond at day-7 should be considered for alternate treatment strategies In selected cases, liver transplantation may be considered (?)