Management of Alcoholic Hepatitis and Cirrhosis W Ray

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

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)

Total Adult Per Capita Alcohol Consumption (liters)

Per Capita Alcohol Consumption per Drinker (2005)

Per Capita Alcohol Consumption per Drinker (2005)

Problematic Drinking • Epidemiologic Definitions – Binge drinker: Five or more drinks on one

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: 1. Recurrent substance use resulting in a failure to fulfill major

DSM-IV Definitions Abuse: 1. Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, home 2. Recurrent substance use in situations in which it is physically hazardous 3. Recurrent substance-related legal problems 4. 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 Abuse/ Dependence Cirrhosis HCC ALD Heavy/Binge Drinkers All Drinkers

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

Alcoholic Liver Disease Steatosis /Steatohepatitis Alcoholic Hepatitis Cirrhosis

Alcoholic Liver Disease Steatosis /Steatohepatitis Alcoholic Hepatitis Cirrhosis

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

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

Pharmacotherapy of Alcoholism Drug Class Data for ALD Disulfiram Aldehyde Potentially toxic dehydrogenase Inhibitor

Pharmacotherapy of Alcoholism Drug Class Data for ALD Disulfiram Aldehyde Potentially toxic dehydrogenase Inhibitor Naltrexone Opioid antagonist Potentially toxic 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) Equivocal Colchicine Negative Silymarin

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

Alcoholic Hepatitis • Syndrome consisting of – Excessive alcohol consumption – Typical clinical presentation:

Alcoholic Hepatitis • Syndrome consisting of – Excessive alcohol consumption – Typical clinical presentation: jaundice, anorexia, fever, tender hepatomegaly – Moderately elevated aminotransferase (100 -300 U/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)

Corticosteroids Re-analysis of 3 previous RCTs • Selecting patients with MDF < 32 (n=205) • Prednisolone 40 mg qd x 28 days 90 80 Steroids 78. 4 Placebo 72. 2 70 60 50 49. 9 52. 8 40 30 20 10 0 Age>50 Cr>1 mg/dl Mathurin. J Hep 2002; 36: 480, Mendenhall. NEJM 1984; 311: 1464, Carithers. Ann Intern Med 1989; 110: 685, Ramond. NEJM 1992; 326: 507

Pentoxyfylline Single center RCT (n=101) • Severe AH (MDF > 32) Pentoxyfylline (400 mgs

Pentoxyfylline Single center RCT (n=101) • Severe AH (MDF > 32) Pentoxyfylline (400 mgs tid) Versus Placebo x 28 days Pentoxyfylline In-hospital Fatality (%) 50 45 40 35 30 25 Placebo 46. 1 24. 5 20 Predictors of survival • Pentoxyfylline • Age • Creatinine 15 10 5 0 Pentoxyfylline n=49 Akriviadis. Gastroenterology. 2000; 119: 1637 -48 Placebo n = 52

STOPAH Trial • Multicenter, double-blind, randomized trial in UK (n=1103) • 2 -by-2 factorial

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 (40 mg qd) Placebo Pentoxyfylline (400 mg tid) n=273 Placebo n=274 n=272 Thursz. NEJM 2015; 372: 1619

STOPAH Trial • Primary End Point: 28 day mortality Prednisolone (p=0. 06) • Multivariable

STOPAH Trial • Primary End Point: 28 day mortality Prednisolone (p=0. 06) • Multivariable odds ratios: – Prednisolone: 0. 61 (p=0. 02) – Pentoxyfylline: 1. 10 (p=0. 62) Pentoxyfylline (p=0. 69) No evidence of benefit for combination

Pentoxyfylline or Not? Akriviadis Trial • Main cause of death = HRS – PTX:

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

Treatment Algorithm O’Shea. Hepatology 2010; 307

Nutrition Randomized trial of total enteral nutrition (TEN) versus corticosteroids (n=71) TEN: • 2,

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, waterrestricted, 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%) •

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 100% <25 80% Survival BMI ≥ 25 69% 57% 60% 40%

ALD and Overnutrition 100% <25 80% Survival BMI ≥ 25 69% 57% 60% 40% 30% 20% 0% Asrani (unpublished data) 1 year 5 year

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

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