Symptoms Variable Vague (fatigue, malaise, right upper quadrant discomfort) Mostly absent Signs Hepatomegaly common Splenomegaly in some Portal HTN unusual Laboratory values Increased AST, ALT typical +/2 increased alk. phos., GGT Increased cholesterol, triglycerides common Increased glucose common Viral markers (2) Autoantibodies (2) Iron studies abnormal sometimes Imaging Fatty liver

Steatosis Steatohepatitis Cirrhosis

Steatosis Almost invariable Steatohepatitis Incidence/prevalence unknown  About 50% hospitalized patients progress to cirrhosis 10% hospitalized patients revert to normal histology Cirrhosis Develops in 15-20% patients after a decade or so Ultimate consequence of antecedent steatohepatitis

Clinically compensated at diagnosis Abstinent: > 80% Drinking: about 60% Clinically decompensated at diagnosis Abstinent: about 60% Drinking: about 30%

Condition	%
Severe fibrosis	15-50
Cirrhosis	7-16

Metals Antimony Barium salts Borates Carbon disulfide Chromates Phosphorus Rare earths of low atomic numbers Thallium compounds Uranium compounds Cytotoxic/cytostatic drugs l-Asparaginase Azacytidine Azauridine Methotrexate Antibiotics Azaserine Bleomycin Puromycin Tetracycline Other drugs Amiodarone Coumadin Dichloroethylene Ethionine Ethyl bromide Estrogens Flectol H Glucocorticoids Hydrazine Hypoglycin Orotate Perhexilene maleate Safrole

Abetalipoproteinemia Familial hepatosteatosis Galactosemia Glycogen storage disease Hereditary fructose intolerance Homocystinuria Systemic carnitine deficiency Tyrosinemia Resfum's disease Schwachman's syndrome Weber-Christian syndrome Wilson's disease

Diabetes mellitus Inflammatory bowel disease Jejuno-ileal bypss Kwashiorkor and marasmus Obesity Serum lipid abnormalities Starvation and cachexia Severe anemia Total parenteral nutrition

Contribution Factor	Alcoholic Liver Disease	NASH
Increased Cyp2E1	+	+
Endotoxin	+	+
Macrophage activation	+	+
Decreased hepatocyte ATP	+	+

Current Management	Potential Future Therapy
Weight loss Treatment of diabetes, lipid disorders Avoid EtOH, hepatotoxic drugs	Constrain macrophage activation Antioxidants (vitamin E, glutathione pro-drugs) Antibiotics (gut decontamination) Anti-cytokines (anti-TNFa antibodies, soluble receptors) Protect hepatocyte ATP stores PARP inhibitors Minimize Cyp2E1 activity Dietary modification (avoid fats)