Alcoholic Liver Disease

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1 Alcoholic Hepatitis Paul Y. Kwo, MD Professor of Medicine i Medical Director, Liver Transplantation Gastroenterology/Hepatology Division Indiana University School of Medicine 975 W. Walnut, IB 327 Indianapolis, IN phone fax 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 % develop alcoholic hepatitis and/or cirrhosis 1

2 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 g alcohol/day for men, > 20 g/day for women Low risk for alcoholic cirrhosis even at this level of consumption ( % in Italy, Denmark) Liver Damage from Alcohol Excess Fatty Liver Common, usually asymptomatic Acute Alcoholic Hepatitis Variable severity. Typical hepatic inflammation Jaundice acute liver failure Cirrhosis Compensated or decompensated with portal hypertension/ encephalopathy/ ascites 2

3 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 > > > > 3

4 Alcohol Metabolism Pathway: ADH and Alcohol Metabolism Microsomal (CYP 450) Pathways Multiple pathogenic mechanisms lead to liver damage 4

5 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 in 1978; modified d in 1989 Discriminant function : (4.6 x [PT -control PT]) + (serum bilirubin) ADF 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:

6 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: Age (years) Albumin on day 0 (g/l) Evolution in bilirubin level (μmol/l) Renal insufficiency Bilirubin on day 0 (μmol/l) PT (seconds) 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: Lille Model Louvet A et al. Hepatology 2007;45:

7 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 7

8 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 100 Prednisolone for Severe Alcoholic Hepatitis Corticosteroids Survival (%) 50 Placebo Day Ramond,

9 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 ± 2.9% NC ± 3.5% Univariate Analysis of Predictive Factors: C Age Creatinine Encephalopathy p= p= p< p< p< Mathurin, 2008 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 Louvet A et al. Gastroenterology 2009;137:541-8 of infection 9

10 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: Pentoxifylline Probability of Survival PTX Control Time (Days) Akriviadis,

11 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: The STOPAH trial for alcoholic hepatitis 1103 patients were randomized to one of four treatment groups: prednisolone and pentoxifylline, prednisolone and placebo, pentoxifylline and placebo, or double placebo Treatment Group Prednisolone and pentoxifylline Prednisolone and placebo Pentoxifylline and placebo Patients Percent mortality (n = 1103) at 28 days Double placebo Beyond 28 days, however, neither drug was significantly associated with a survival benefit. Infections were about twice as frequent in the prednisolone group than in the no-prednisolone group (13.5% vs 7.9%; P =.0026). Thursz et al. American Association for the Study of Liver Diseases (AASLD). Abstract LB-1. 11

12 Nutrition Therapy Near Universal Malnutrition in Alcohol Hepatitis Mortality Correlates With Low Calorie Intake Approaches Enteral Parenteral Medium Chain Triglycerides Branched Chain Amino Acids A Worthy Adjunctive Approach Lucey M et al. N Engl J Med 2009;360:

13 Liver Transplantation AH is typically considered a contraindication to transplantation Historically, 6 months of abstinence is recommended as minimal listing criterion by tradition Recidivism rates range from 11-50% at 3-5 years post-transplantation French pilot study of OLT in severe alcoholic hepatitis without response to steroids Mathurin P. Liver Transplantation 2005;11:S21-24, Mathurin P et al. N Engl J Med 2011;365: Proposed algorithm for alcoholic hepatitis Am J Gastroenterol 2010;105:

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