Paul Y. Kwo, MD, FACG

Alcoholic Hepatitis Paul Y. Kwo, MD P f Professor off Medicine M di i Medical Director, Liver Transplantation Gastroenterology/Hepatology Division Indiana University School of Medicine 975 W. Walnut, IB 327 Indianapolis, IN 46202-5121 phone 317-274-3090 317 274 3090 fax 317-274-3106 email [email protected]

Alcoholic Liver Disease • A major cause of morbidity and mortality in the United States • Encompasses a clinico-histological spectrum including - Fatty liver (hepatic steatosis) : present in 90% of heavy drinkers, rapidly reversible with abstinence - Alcoholic hepatitis occurs in 10-35% of heavy drinkers, precursor of cirrhosis - Alcoholic cirrhosis Hepatocellular cancer • Majority of people who abuse alcohol do not develop advanced lesions of alcoholic liver disease - 10-35% develop alcoholic hepatitis and/or cirrhosis

ACG Western Regional Postgraduate Course - Las Vegas, NV Copyright 2015 American College of Gastroenterology

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Paul Y. Kwo, MD, FACG

Alcohol • One standard drink •180 ml or 6 ounces of wine •360 ml or 12 ounces of beer •45 ml or 1.5 ounces of 90 proof –all contain ~12 grams of alcohol

•Threshold for Alcoholic Liver Disease –50-60 g alcohol/day for men, > 20 g/day for women –Low risk for alcoholic cirrhosis even at this level of consumption (4.2-5.9% in Italy, Denmark)

Liver Damage from Alcohol Excess Common, usually asymptomatic

Fatty Liver

Acute Alcoholic Hepatitis

Cirrhosis

ACG Western Regional Postgraduate Course - Las Vegas, NV Copyright 2015 American College of Gastroenterology

Variable severity. Typical hepatic inflammation Jaundice acute liver failure

Compensated or decompensated with portal hypertension/ encephalopathy/ ascites

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Paul Y. Kwo, MD, FACG

Alcoholic steatosis

Alcoholic Hepatitis with Mallory Hyaline and neutrophilic infiltrate

Mallory Body

Abnormal laboratory tests seen with excess alcohol consumption >

> >

>

ACG Western Regional Postgraduate Course - Las Vegas, NV Copyright 2015 American College of Gastroenterology

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Paul Y. Kwo, MD, FACG

Alcohol Metabolism Pathway: ADH and Alcohol Metabolism Microsomal (CYP 450) Pathways

Multiple pathogenic mechanisms lead to liver damage

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4

Paul Y. Kwo, MD, FACG

Assessing Illness Severity some rely on response to therapy to predict prognosis  Maddrey’s Discriminant Function  Lille model: • incorporates response to steroids

 MELD Score  Glasgow Alcoholic Hepatitis Score  ECBL (early change in bilirubin levels): • incorporates response to steroids

Maddrey’s Discriminant Function  Most commonly used predictive model; developed to facilitate assessment of response to steroids t id in i 1978; 1978 modified difi d in i 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.

ACG Western Regional Postgraduate Course - Las Vegas, NV Copyright 2015 American College of Gastroenterology

5

Paul Y. Kwo, MD, FACG

Lille Model  Six variables used to identify patients with severe AH (DF ≥ 32) not responding to steroids  Lille score calculated after 7 days of steroids: 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)  http://www.lillemodel.com/

 Score ≥ 0.45 associated with marked decrease in 6 month survival (25% ( % vs 85%) %)  Superior to 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

ACG Western Regional Postgraduate Course - Las Vegas, NV Copyright 2015 American College of Gastroenterology

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Paul Y. Kwo, MD, FACG

MELD Score  MELD derived to predict 3 month survival in cirrhosis patients  2 studies demonstrate prognostic benefit in alcoholic hepatitis  MELD score >11 comparable 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

Medical Therapies       

Abstinence Steroids Pentoxifylline Control craving Address Nutritional Needs Antinflammatory ? Antioxidant

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Paul Y. Kwo, MD, FACG

Therapy-Corticosteroids  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 2-3 weeks (guided by Lille score < 0.45)  CONTRAINDICATIONS:  -Infection/sepsis  

-GI bleed -Renal insufficiency

Prednisolone for Severe Alcoholic Hepatitis 100 Corticosteroids

Survival (%)

50 Placebo

0 90

180

Day Ramond, 1992

ACG Western Regional Postgraduate Course - Las Vegas, NV Copyright 2015 American College of Gastroenterology

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Paul Y. Kwo, MD, FACG

Corticosteroids Improve 28-Day Survival in Patients with Severe Alcoholic Hepatitis: Individual Data Analysis of the Last 5 Randomized Controlled Trials Entry: DF > 32 # Patients 28-day Survival

Survival

C

202

79.2 ± 2.9%

NC

185

64.1 ± 3.5%

Univariate Analysis of Predictive Factors: C Age Creatinine Encephalopathy

p=0.0005

p=0.0005 p