OVERVIEW OF ALD ALCOHOLIC LIVER DISEASE DISCLOSURE

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1 ALCOHOLIC LIVER DISEASE KEVIN D MULLEN MD West Virginia University Morgantown WV DISCLOSURE I have nothing to disclose. AMOUNT OF ALCOHOL PER STANDARD DRINK > (30 ) GRAM OF ALCOHOL PER DAY USA Canada UK Europe Australia and New Zealand Japan Syria/Lebanon 12 g 13.6 g 9.5 g 9.8 g 9.2 g 23.5 g 45 g OVERVIEW OF ALD Alcohol abuse costs U.S. $235 billion annually > 2 million in U.S. with some form of ALD Likely underestimated due to social stigma Turner C, et al. Br J Addict Sep;85(9): Harwood, et al., NIAAA, 05 1

2 OVERVIEW OF AH,000 admissions with average cost of $,000 > twice the cost of Myocardial Infarction Cost 2.5 fold higher in those who died LACK OF ADVANCEMENT IN THE TREATMENT OF ALCOHOL HEPATITIS 1 month 6 month 4 year Mortality (%) USA 1991 Denmark (65) 24 Harwood, et al., NIAAA, 07 SPECTRUM OF ALCOHOLIC LIVER DISEASE DIAGNOSIS OF AH Rapid onset of jaundice in a patient with heavy alcohol use, usually precipitated by binge drinking Transaminse levels AST<500/ALT<0 AST/ALT ratio >2 Exclude other causes of acute hepatitis Gastroenterology. 11;141: Clinical Pathologic Syndrome Heterogeneous Patient Population - Hospital Mortality Varies (0-100%) Patient Selection for Treatment is Important - Dependent on Accurate Markers ISSUES AT HAND Which Patients Should be Treated? What Should the Treatment be? - Corticosteroids - Anti-cytokines - Anti-oxidants Future Considerations 2

3 DIAGNOSIS OF AH Clinical diagnosis is accurate in 75 85% Liver biopsy remains the gold standard for the diagnosis N Engl J Med. 09: 3;26 J Hepatol. 12; vol. 57/399 4 PREDICTORS OF PROGNOSIS Maddrey Discriminant Function Hepatic Encephalopathy MELD O Shea, et al. Hepatology January 10 MADDREY DISCRIMINANT FUNCTION Modified Equation 4.6 x (Patient s Prothrombin time - control time )+ Serum Bilirubin Discriminant Score > % Mortality in Group PREDICTORS OF PROGNOSIS Maddrey Discriminant Function Hepatic Encephalopathy MELD 3

4 HEPATIC ENCEPHALOPATHY IN Mortality in Group Hepatic Encephalopathy Hepatic Encephalopathy Present Absent PREDICTORS OF PROGNOSIS Maddrey Discriminant Function Hepatic Encephalopathy MELD % 10% Admission MELD Score Score <18 Score >=18 p-value< Hospital days Srikureja, 05 ISSUES WITH MELD No Prospective Confirmation What MELD Score Should be Used? Study Proposed Score Sheth (02) 9 Dunn (05) Srikureja (05) 18 or SUMMARY Best Current Prognostic Measures - Maddrey Discriminant Function - Hepatic Encephalopathy MELD may be Better - Additional Studies Necessary Future Scoring Systems - Glasgow Score - Lille Model ISSUES AT HAND Which Patients Should be Treated? What Should the Treatment be? - Corticosteroids - Anti-cytokines - Anti-oxidants Future Considerations 4

5 IMMUNOSUPPRESSION AND CYTOKINE THERAPY Cytokines Hyper Immune System Alcoholic Hepatitis Oxidative Stress STEROIDS IN R A T I O N A L E Decrease Collagen Formation Increase Albumin Production Enhance Appetite Suppress Hepatic Inflammation - Cytokine mediated Suppress an Overactive Immune System IMMUNOSUPPRESSION AND CYTOKINE CORTICOSTEROID THERAPY CORTICOSTEROIDS IN ALCOHOL HEPATITIS (NO CONSENSUS) Cytokines Hyper Immune System Alcoholic Hepatitis Oxidative Stress Beneficial Effect Helman 1971 Lesesne 1978 Maddrey 1978 Carithers 1989 Ramond 1992 Mathurin 1996 No Beneficial Effect Porter 1971 Campra 1973 Blitzer 1977 Shumaker 1978 Depew 19 Theodossi 1982 Mendenhall 1984 CALCULATIONS FOR PROTECTIVE EFFICACY WITH HEPATIC ENCEPHALOPATHY STEROIDS IN ETOH HEPATITIS (SHORT TERM SURVIVAL) MORTALITY RATE Steroids = 45% = % 1. Risk Difference % - 45% = 15% 2. Reciprocal of Risk Difference 1/.15 = 6.67 The number of patients needed to treat to avoid one death=6-7. % Mortality 0 Steroids Carithers (N=66) Ramond (N=61) 5

6 DISCRIMINANT FUNCTION Hepatic Encephalopathy STEROIDS IN ETOH HEPATITIS (LONG TERM SURVIVAL) Percent Surviving Methylprednisolone Methylprednisolone Days Days % Mortality 0 1 Year 2 Years Steroids Mathurin, 1996 CORTICOSTEROIDS IN Treat Only Patients with Severe Disease - Discriminant Function/HE/MELD Survival Improved up to 6-12 months 5-7 Pts Must be Treated to Avoid one Death - Patient Selection Required - Biopsy if Diagnosis in Doubt Use Prednisolone Rather than Prednisone AND STEROIDS Why Do Hepatologists Disagree Steroids Ineffective in the Largest Study Personal Experience - Number Needed to Treat is Some Patients Just too Sick - Incorrect Diagnosis Side Effects - 4 Week Treatment May be to Long Contraindications - GI Bleeding, Infection, Pancreatitis Steroids in AH (6 months) 1. Patients in renal failure / GI bleeding 2. Should every patient have a trial of corticosteroids (?) 3. Some patients are too sick 4. Treat Sepsis 100 Prednisolone THINGS TO CONSIDER BEFORE USING CORTICOSTEROIDS 0 < >54 Discriminant Function 6

7 Steroids and Nutrition in ETOH Hepatitis Mortality (1 month) Day of Death (Median) Mortality (After 1 month) Enteral Nutrition (n=35) 31% 7 8% Steroids (n=36) 25% 23 37% Cabre, 00 A Difference is Only a Difference If it Makes a Difference 7