Hepatic iron overload and hepatocellular carcinoma.
The liver is the main storage site for iron in the body. Excess accumulation of iron in the liver has been well-documented in two human diseases, hereditary hemochromatosis and dietary iron overload in the African. Hepatic iron overload in these conditions often results in fibrosis and cirrhosis and may be complicated by the development of hepatocellular carcinoma. Malignant transformation usually occurs in the presence of cirrhosis, suggesting that free iron-induced chronic necroinflammatory hepatic disease plays a role in the hepatocarcinogenesis. However, the supervention of hepatocellular carcinoma in the absence of cirrhosis raises the possibility that ionic iron may also be directly hepatocarcinogenic. Support for this possibility is provided by a recently described animal model of dietary iron overload in which iron-free preneoplastic nodules and hepatocellular carcinoma developed in the absence of fibrosis or cirrhosis. The mechanisms by which iron induces malignant transformation have yet to be fully characterized but the most important appears to be the generation of oxidative stress. Free iron generates reactive oxygen intermediates that disrupt the redox balance of the cells and cause chronic oxidative stress. Oxidative stress leads to lipid peroxidation of unsaturated fatty acids in membranes of cells and organelles. Cytotoxic by-products of lipid peroxidation, such as malondialdehyde and 4-hydroxy-2'-nonenal, are produced and these impair cellular function and protein synthesis and damage DNA. Deoxyguanosine residues in DNA are also hydroxylated by reactive oxygen intermediates to form 8-hydroxy-2'-deoxyguanosine, a major promutagenic adduct that causes G:C to T:A transversions and DNA unwinding and strand breaks. Free iron also induces immunologic abnormalities that may decrease immune surveillance for malignant transformation.
Kew
Michael C
MC
Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town 7925, South Africa. Michael.kew@uct.ac.za
D006528:Carcinoma, Hepatocellular / Q000150:complications*; D004032:Diet; D006432:Hemochromatosis / Q000150:complications; D006801:Humans; D019190:Iron Overload / Q000150:complications*; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000150:complications*