Conflicts of Interest in the last 12 months

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1 STEATOHEPATITIS Richard K. Sterling, MD, MSc, FACP, FACG VCU Hepatology Professor of Medicine Chief, Section of Hepatology Virginia Commonwealth University Richmond, VA

2 Conflicts of Interest in the last 12 months Advisory Board Roche/Genentech, Merck, Vertex, Bayer, Salix, BMS, Abbott Research support Roche/Genentech, Merck, Bayer, Boehringer Ingelheim, Vertex, BMS, Abbott Speaker None Stock/Financial interest None

3 Definitions Histology Pathophysiology Presentation Therapy Objectives

4 Definitions Steatosis = fatty liver (>5%) Microvesicular Macrovesicular Mixed Steatohepatitis = fatty liver with inflammation and cytologic ballooning Grade Degree of inflammation Pattern Fibrosis Degree Pattern

5 Steatohepatitis Fatty change (>5%) Ballooning degeneration Lobular inflammation Mallory bodies Perisinusoidal fibrosis

6 Steatohepatitis Macrovesicular Cytologic ballooning Mallory bodies

7 Alcoholic Liver Disease Fermented beverages have been around since 10,000 B.C. In the US: 7.4% of adults abuse alcohol 44% of all liver related deaths are attributed to alcohol

8 Alcoholic Steatohepatitis Alcohol metabolism EtOH Acetate Stomach ADH- gender ethnicity ALDH Acetaldehyde Mitochondria Liver toxicity ADH NADH NAD Small bowel LIVER Microsomal ethanol Oxidizing system (MEOS) - CYP 2E1 - Inducible by chronic alcohol

9 Pathogenesis of ASH in the Liver Hepatic stellate cells Leaky gut PV endotoxemia LPS Kupffer Cell Other stimuli TGF- β matrix Fibrosis TNF-α KV Kowdley, MD Hepatocyte

10 Mechanisms of Alcoholic Liver Injury Acetaldehyde Inhibition of mitochondrial beta-oxidation of fatty acids Oxygen-free radicals Glutathione depletion Acetaldehyde Adducts Redox Status NAD depletion Fat accumulation LIVER Hepatitis C Oxidative Stress Oxygen-free radicals Decreased Anti-oxidants Cytokines TNFα TGFβ

11 Natural History of Alcoholic Hepatitis Normal liver Alcohol (90-100%) reverse 80% Steatosis 20% progress 50% reverse Steatohepatitis 50% progress, 38% with abstinence Fibrosis ~20% of alcoholics Cirrhosis

12 Factors Associated with Liver Injury Dose Duration Gender Ethnicity Other factors Obesity Iron Overload Viral hepatitis (HCV, HBV) Genetic (PNPLA3)

13 PNPLA3 Patatin-Like Phospholipase Domain-Containing Protein 3 Polymorphism of adiponutrin Present in 12-14% of NAFLD compared to 3% controls Acyl-CoA independent pathway of TG synthesis MG + MG -> DG + glycerol MG + DG -> TG + glycerol In NAFLD, it is independently associated with Steatosis Inflammation NASH and fibrosis Also a risk of developing alcoholic liver injury

14 Alcohol Threshold Men 80 grams (6-pack/day) Women grams (4 drinks/day) 12 oz beer 4 oz drink Glass of wine grams

15 Alcoholic Liver Disease: Natural History Alcoholic hepatitis: Women more likely to develop cirrhosis Those with clinically severe hepatitis more likely to progress to cirrhosis Perivenular lesions, degree of necrosis predictors of development of cirrhosis Acute mortality 10-20% (related to severity, complications and renal failure) 50-80% if DF > 32

16 Alcoholic Liver Disease Clinical Features Symptoms/signs of intoxication Symptoms/signs of withdrawal Hepatomegaly Jaundice Features of chronic liver disease Spiders, dypuytrens contractures Extrahepatic manifestations: pancreatitis, neurologic disease, etc Fevers Leukocytosis (leukemoid reaction) AST:ALT > 2 Hemolysis: Zieve s syndrome

17 Alcohol and AST:ALT ratio Both AST and ALT are elevated but rarely exceed 300 IU/L (never above 500) If > 300, think acetaminophen AST / ALT ratio > 2 : 1 Cytoplasmic isoenzymes for both cast and calt but mitochondrial isoenzyme only for mast. ALT requires pyridoxal phosphate (vit-b6), which is consumed for the metabolism of alcohol.

18 Alcoholic Liver Disease Management Management of intoxication Management of withdrawal Nutrition (key and often overlooked) Management of metabolic derangements: electrolytes: Mg, PO 4, K, thiamine, glucose, folate vitamin K

19 Alcoholic liver disease: Steroid treatment Discriminant function (DF) = 4.6 x (PT-control) + bilirubin (mg) Indications for steroids DF > 32 Encephalopathy Contraindications for steroids Sepsis GI bleeding If contraindications, treat and reassess

20 Comparison of Diagnostic Indices on Survival Author N MELD DF Sensitivity % Specificity % AUROC Sheth 34 > > Srikureja 202 > > Dunn 73 > > Soultati 34 > > Both MELD and DF have similar sensitivity (75-85%) while MELD has higher specificity Adapted from O Shea et al. Hepatology 2010;51:

21 Effects of steroids on survival in alcoholic steatohepatitis Author n Severity Carithers Ramond Mathurin assessmen t DF DF + Bx DF + Bx F/U % Survival 4 wks 8 wks 1 yr Pred vs placebo 94:65 88:45 70:41 Meta-analysis of 11 randomized studies (Imperiale and McCullough, AIM 1990) 37% reduction in mortality (95% CI 20-50%) In those with HE, 34% protective efficacy (95% CI 15-48%) Minimal protective effect in those without HE More effective in studies that excluded active GI bleeding

22 A few more things MELD may be better than DF in predicting survival No threshold for use of steroids (~18) Pentoxifylline (400 mg tid) Not compared to steroids Seems to be a safe alternative Not helpful if steroids fail If no improvement after 1 week, steroids unlikely to be of benefit (Lily criteria) Liver transplantation not an option

23 Used with Permission: O Shea et al. Hepatology 2010;51:

24 g/kg protein kcal/kg energy Consider transplant Used with Permission: O Shea et al. Hepatology 2010;51: