Iron, hemochromatosis, and hepatocellular carcinoma
Section snippets
HCC in other iron-overload disorders
A pathophysiologic role for iron in the promotion of hepatic carcinogenesis would be more obvious if iron overload independent of cause was associated with HH. In fact, the available data suggest that hepatic iron overload owing to other causes, such as homozygous β thalassemia and the dietary form observed in South African blacks, also are associated with an increased risk for HCC.
A recent retrospective questionnaire study surveyed 52 thalassemia centers in Italy to identify cases of HCC
Iron, HFE mutations, and HCC in other forms of chronic liver disease
The epidemiologic data suggesting that marked hepatic iron loading is associated with an increased risk for HCC are convincing. Whether more modest degrees of iron overload that may be present in patients with other types of chronic liver disease or those who carry mutations in HFE predispose to HCC remains unclear. Several studies have examined whether carriage of HFE mutations is associated with HCC among patients with chronic hepatitis C or alcohol-induced liver disease. Most
Iron overload and HCC in the absence of cirrhosis
The development of HCC in the absence of cirrhosis also provides indirect evidence that iron accumulation in the liver independently causes carcinogenesis. In fact, HCC has been well documented in the absence of cirrhosis among patients with HH.36, 37, 38 In addition, there is evidence that the hepatic iron content is increased among non-HH patients with HCC arising in a noncirrhotic liver. Turlin et al.36 reviewed 24 patients with HCC in the absence of cirrhosis. The hepatic iron status was
Possible mechanisms of iron-induced HCC
Several human, animal, and in vitro studies point to a causative role for excess iron stores as a possible mechanism for hepatic carcinogenesis.39 These can be classified as direct effects and indirect effects of iron overload. Direct effects include effects of iron on cellular proliferation, direct damage by non—transferrin-bound iron to DNA, with resultant inactivation of tumor suppressor genes such as p53 or their products via posttranscriptional or posttranslational changes. Indirect
Summary
Iron overload in the setting of HH is associated with an increased risk for HCC. There also is evidence that iron overload in the setting of end-stage liver disease is associated with HCC. The current data are inconclusive as to whether mild to moderate iron overload associated with hepatitis C or alcohol-induced liver disease or carriage of HFE mutations increase the risk for HCC among patients with cirrhosis. Iron overload in the liver may promote hepatic carcinogenesis via DNA damage and
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Supported in part by National Institutes of Health grants DK 38215, DK 02957, and DK 54698.