EXPERIMENTAL LIVER-CIRRHOSIS INDUCED BY ALCOHOL AND IRON

To determine if alcoholic liver fibrogenesis is exacerbated by dietary iron supplementation, carbonyl iron (0.25% wt/vol) was intragastrical ly infused with or without ethanol to rats for 16 wk. Carbonyl iron ha d no effect on blood alcohol concentration, hepatic biochemical measur ements, or liver histology in control animals. In both ethanol-fed and control rats, the supplementation produced a two- to threefold increa se in the mean hepatic non-heme iron concentration but it remained wit hin or near the range found in normal human subjects, As previously sh own, the concentrations of liver malondialdehyde (MDA),(1) liver 4-hyd roxynonenal (4HNE), and serum aminotransferases (ALT, AST) were signif icantly elevated by ethanol infusion alone. The addition of iron suppl ementation to ethanol resulted in a further twofold increment in mean MDA, 4HNE, ALT, and AST. On histological examination, focal fibrosis w as found < 30% of the rats fed ethanol alone. In animals given both et hanol and iron, fibrosis was present in all, with a disuse central-cen tral bridging pattern in 60%, and two animals (17%) developed micronod ular cirrhosis. The iron-potentiated alcoholic liver fibrogenesis was closely associated with intense and diffuse immunostaining for MDA and 4HNE adduct epitopes in the livers. Furthermore, in these animal, acc entuated increases in procollagen alpha 1(I) and TGF beta 1 mRNA level s were found in both liver tissues and freshly isolated hepatic stella te cells, perisinusoidal cells believed to be a major source of extrac ellular matrices in liver fibrosis, The dietary iron supplementation t o intragastric ethanol infusion exacerbates hepatocyte damage, promote s liver fibrogenesis, and produces evident cirrhosis in some animals. These results provide evidence for a critical role of iron and iron-ca talyzed oxidant stress in progression of alcoholic liver disease.