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Medline ® Abstract for Reference 70

of 'Pathogenesis of alcoholic liver disease'

Mechanisms of alcohol-induced hepatic fibrosis: a summary of the Ron Thurman Symposium.
Purohit V, Brenner DA
Hepatology. 2006;43(4):872.
This report is a summary of Ron Thurman Symposium on the Mechanisms of Alcohol-Induced Hepatic Fibrosis which was organized by The National Institutes of Health in Santa Barbara, California, June 25, 2005. The Symposium and this report highlight the unique aspects by which drinking alcoholic beverages may result in hepatic fibrosis. Acetaldehyde, the first metabolite of ethanol, can upregulate transcription of collagen I directly as well as indirectly by upregulating the synthesis of transforming growth factor-beta 1 (TGF-beta1). Reactive oxygen species (ROS) generated in hepatocytes by alcohol metabolism can activate collagen production in hepatic stellate cells (HSCs) in a paracrine manner. Alcohol-induced hepatocyte apoptotic bodies can be phagocytosed by HSCs and Kupffer cells and result in increased expression of TGF-beta1 and subsequent HSC activation. Kupffer cells may contribute to the activation of HSCs by releasing ROS and TGF- beta1. Innate immunity may suppress hepatic fibrosis by killing activated HSCs and blocking TGF-beta1 signaling. In patients infected with hepatitis C virus (HCV), alcohol may promote hepatic fibrosis by suppressing innate immunity. HCV core and non-structural proteins contribute to HCV-induced hepatic fibrosis. Alcohol and HCV together may promote hepatic fibrosis through increased oxidative stress and upregulation of fibrogenic cytokines. The inactive aldehyde dehydrogenase (ALDH2) and the super-active alcohol dehydrogenase (ADH2) alleles may promote hepatic fibrosis through increased accumulation of acetaldehyde in the liver. Hepatic fibrosis can be reversed by inducing selective apoptosis or necrosis of activated HSCs, or by reverse trans-differentiation of activated HSCs into the quiescent phenotype.
Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA. vpurohit@mail.nih.gov