STEATOHEPATITIS Richard K. Sterling, MD, MSc, FACP, FACG VCU Hepatology Professor of Medicine Chief, Section of Hepatology Virginia Commonwealth University Richmond, VA
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
Definitions Histology Pathophysiology Presentation Therapy Objectives
Definitions Steatosis = fatty liver (>5%) Microvesicular Macrovesicular Mixed Steatohepatitis = fatty liver with inflammation and cytologic ballooning Grade Degree of inflammation Pattern Fibrosis Degree Pattern
Steatohepatitis Fatty change (>5%) Ballooning degeneration Lobular inflammation Mallory bodies Perisinusoidal fibrosis
Steatohepatitis Macrovesicular Cytologic ballooning Mallory bodies
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
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
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
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
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
Factors Associated with Liver Injury Dose Duration Gender Ethnicity Other factors Obesity Iron Overload Viral hepatitis (HCV, HBV) Genetic (PNPLA3)
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
Alcohol Threshold Men 80 grams (6-pack/day) Women 40-60 grams (4 drinks/day) 12 oz beer 4 oz drink Glass of wine 10-12 grams
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
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
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.
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
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
Comparison of Diagnostic Indices on Survival Author N MELD DF Sensitivity % Specificity % AUROC Sheth 34 >11 86 81 0.82 >32 86 48 0.86 Srikureja 202 >18 85 84 0.89 >32 83 60 0.81 Dunn 73 >21 75 75 0.83 >41 75 69 0.83 Soultati 34 >30 100 94 0.97 >108 100 97 0.98 Both MELD and DF have similar sensitivity (75-85%) while MELD has higher specificity Adapted from O Shea et al. Hepatology 2010;51:307-328
Effects of steroids on survival in alcoholic steatohepatitis Author n Severity Carithers Ramond Mathurin 66 61 122 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
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
Used with Permission: O Shea et al. Hepatology 2010;51:307-328
1.2-1.5 g/kg protein 35-40 kcal/kg energy Consider transplant Used with Permission: O Shea et al. Hepatology 2010;51:307-328