Management of Alcoholic Hepatitis and Cirrhosis W. Ray Kim, MD Gastroenterology and Hepatology Stanford University School of Medicine

Total Adult Per Capita Alcohol Consumption (liters)

Per Capita Alcohol Consumption per Drinker (2005)

Problematic Drinking Epidemiologic Definitions Binge drinker: Five or more drinks on one occasion Heavy drinker: Adult men having more than two drinks per day Adult women having more than one drink per day

DSM-IV Definitions Abuse: Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, home Recurrent substance use in situations in which it is physically hazardous Recurrent substance-related legal problems Continued substance use despite having persistent or recurrent social or interpersonal problems Dependence: Abuse accompanied by 1. Compulsive drinking behavior 2. Tolerance 3. Withdrawal

Alcoholic Liver Disease Cirrhosis HCC Abuse/ Dependence ALD All Drinkers Heavy/Binge Drinkers

Alcoholic Liver Disease Steatosis Alcoholic Hepatitis Cirrhosis /Steatohepatitis

Importance of Abstinence Survival after Dx of Cirrhosis Survival after Decompensation n=278 n=233 Powell and Klatskin, 1968

Pharmacotherapy of Alcoholism Drug Class Data for ALD Disulfiram Aldehyde dehydrogenase Inhibitor Potentially toxic Naltrexone Opioid antagonist Acamprosate Modulator of glutamate and GABA Not studied in cirrhosis, may be useful Topiramate Na channel blocker Not studied in cirrhosis Baclofen Centrally acting muscle relaxant Showed efficacy in 1 RCT in cirrhosis

Pharmacotherapy of Alcoholic Fibrosis/Cirrhosis Drug Results Propylthiouracil Equivocal S-adenosylmethionine (SAME) Colchicine Negative Silymarin (Milk thistle) Phosphatidylcholine

Alcoholic Hepatitis Syndrome consisting of Excessive alcohol consumption Typical clinical presentation: jaundice, anorexia, fever, tender hepatomegaly Moderately elevated aminotransferase (100-300U/L) with higher AST than ALT (AST/ALT>2) Exclusion of other causes of acute and chronic liver disease. Spectrum: Mild injury to severe, life-threatening injury Acute on chronic damage: 10%-35% of hospitalized alcoholic patients Concomitant cirrhosis in more than 50%

Corticosteroids Re-analysis of 3 previous RCTs Selecting patients with MDF < 32 (n=205) Prednisolone 40mg qd x 28 days Mathurin. J Hep 2002;36:480, Mendenhall. NEJM 1984;311:1464, Carithers. Ann Intern Med 1989;110:685, Ramond. NEJM 1992;326:507

In-hospital Fatality (%) Pentoxyfylline Single center RCT (n=101) Severe AH (MDF > 32) Pentoxyfylline (400 mgs tid) Versus Placebo x 28 days n=49 n = 52 In-hospital Fatality (%) Pentoxyfylline Placebo Predictors of survival Pentoxyfylline Age Creatinine Akriviadis. Gastroenterology. 2000;119:1637-48

STOPAH Trial Multicenter, double-blind, randomized trial in UK (n=1103) 2-by-2 factorial design: Prednisolone and/or Pentoxyfylline Patient selection Average alcohol consumption > 80 g/d (M) and > 60 g/d (W) Bilirubin > 4.7 mg/dl, Discriminant function > 32 Endpoints Primary: Mortality at 28 days Secondary: death or LTx at 90 days and at 1 year Prednisolone (40mg qd) Placebo Pentoxyfylline (400mg tid) n=273 n=274 n=272 Thursz. NEJM 2015;372:1619

STOPAH Trial Primary End Point: 28 day mortality Multivariable odds ratios: Prednisolone: 0.61 (p=0.02) Pentoxyfylline: 1.10 (p=0.62) Prednisolone (p=0.06) Pentoxyfylline (p=0.69) No evidence of benefit for combination

Pentoxyfylline or Not? Akriviadis Trial Main cause of death = HRS PTX: 6/12 deaths Placebo: 22/24 death Serum creatinine trend STOPAH HRS: No major concern Acute kidney injury reported in 2% overall Terlipressin was allowed according to the site PI discretion. Serum creatinine at baseline: 0.88 ± 0.53 cf. creatinine in Akriviadis Trial PTX = 1.2 ± 0.9 Placebo = 1.3 ± 0.8

Treatment Algorithm O’Shea. Hepatology 2010;307

Nutrition Randomized trial of total enteral nutrition (TEN) versus corticosteroids (n=71) TEN: 2,000 kcal/d polymeric enteral diet as the sole nutritional supply Low-sodium, low-fat, water-restricted, enriched in branched-chain amino acids Continuously infused into the stomach via feeding tube with a peristaltic pump 8 TEN patients withdrawn from the trial (intolerance in 5) Cabre. Hepatology 2000;32:36-42

Total Enteral Nutrition No difference in short term mortality (25% versus 31%) Earlier death with enteral feeding (7 versus 23 days, p=0.03) TEN Prednisolone Mortality during follow-up was higher with steroids: 10/27 vs. 2/24, p=0.04 Cabre. Hepatology 2000;32:36-42

ALD and Overnutrition BMI Survival Asrani (unpublished data)

Medical Management of AH/ALD Abstinence Nutrition Drug Therapy Liver Transplant Evaluation Social Support