Role of HFE gene mutations in liver diseases other than hereditary hemochromatosis.

Heavy iron overload, as occurs in primary and secondary hemochromatosis, may cause fibrosis of parenchymal organs, including the heart, liver, and pancreas, and it is a risk factor for the development of hepatocellular carcinoma. Recent evidence indicates that lesser degrees of hepatic iron deposition are also risk factors for nonhemochromatotic liver disease. For example, several recent studies showed extraordinarily high prevalences (about 60% to 75%) of HFE mutations in patients with porphyria cutanea tarda and significantly increased prevalences of these mutations in patients with nonalcoholic steatohepatitis from Australia and the United States. It is less well established that the prevalence of the HFE mutations is increased in alcoholic liver disease and in chronic viral hepatitis, but in both conditions, patients harboring one of these mutations, especially C282Y, are more likely to have advanced hepatic fibrosis or cirrhosis. Thus, these mutations both incite and exacerbate nonhemochromatotic liver disease. In this review, we summarize current knowledge of these associations and emphasize important unresolved questions that require further study.