New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments.
Activation of methionine to S-adenosylmethionine is depressed in alcoholics. Its repletion opposes alcoholic liver cirrhosis in baboons, decreases mortality in cirrhotic patients, and opposes oxidative stress resulting from cytochrome P4502E1 (CYP2E1) induction by alcohol, ketones, and fatty acids. Their excess causes alcoholic and nonalcoholic steatohepatitis. CYP2E1 is also induced in Kupffer cells, promoting their activation and release of inflammatory cytokines, including tumor necrosis factor (TNF)-alpha. The TNF-alpha inhibitor pentoxifylline decreased mortality from alcoholic hepatitis. Polyenylphosphatidylcholine (PPC), an antioxidant phosphatidylcholine mixture extracted from soybeans, 50% of which consists of the highly bioavailable dilinoleoylphosphatidylcholine, restores phospholipids of the damaged membranes and reactivates their enzymes, including phosphatidylethanolamine methyltransferase, needed for phospholipid regeneration. In baboons, PPC prevented cirrhosis by stimulating collagenase and by opposing lipid peroxidation, which produces the fibrogenic hydroxynonenal. PPC was beneficial in patients with alcoholic hepatitis, and it opposed fibrosis in heavy drinkers and decreased aminotransferases in patients with hepatitis C. The antioxidant silymarin also successfully opposed alcoholic cirrhosis in baboons and in some but not all clinical trials; this effect also pertains to a-tocopherol. The anti-inflammatory corticosteroids and colchicine yielded mixed results. Finally, replacing long-chain with medium-chain triglycerides opposed the fatty liver experimentally and clinically.
Lieber
Charles S
CS
Section of Liver Disease and Nutrition, Bronx VA Medical Center and Mt. Sinai School of Medicine, (151-2), 130 West Kingsbridge Road, Bronx, NY 10468, USA. liebercs@aol.com
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000437:Alcoholism / Q000150:complications; D000975:Antioxidants / Q000627:therapeutic use*; D003078:Colchicine / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D015227:Lipid Peroxidation; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D008111:Liver Function Tests; D008297:Male; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012436:S-Adenosylmethionine / Q000627:therapeutic use; D012720:Severity of Illness Index; D016896:Treatment Outcome
D000305:Adrenal Cortex Hormones; D000975:Antioxidants; D016207:Cytokines; D012436:S-Adenosylmethionine; D003078:Colchicine