Abstract
Primary iron overload is one of the most common inherited diseases worldwide. Several genetic mutations underlie the various forms of the disease, which have similar pathophysiological profiles but distinct clinical presentations. Patients with hereditary hemochromatosis absorb too much iron from the diet, which accumulates over time within parenchymal cells. This accumulation leads to eventual organ failure as a consequence of iron-mediated formation of free radicals. The mechanism underlying this excessive absorption of iron is a sensing defect caused by the reduced formation of hepcidin, the master regulator of iron homeostasis, as a consequence of mutations in the genes encoding several membrane-bound signaling molecules present on hepatocytes. A considerable number of carriers of these specific genetic mutations, however, do not develop iron overload, indicating that additional genetic and environmental factors modify the severity and clinical penetrance of disease. In affected patients, early initiation of treatment by phlebotomy can prevent organ damage. Genetic screening of first-degree relatives can be also used to identify individuals at risk. Our expanding knowledge of the regulation of iron metabolism and the role of factors that modify the severity of the disease may lead to the design of new and improved treatments.
Key Points
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Hereditary hemochromatosis is a common genetic disorder that has various forms and is easy to diagnose
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Although the different forms of hereditary hemochromatosis have similar phenotypes, they are caused by different genetic defects
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Patients with hereditary hemochromatosis produce reduced amounts of the master regulator of iron homeostasis, hepcidin, resulting in increased dietary iron absorption and accumulation in tissues
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If untreated, hereditary hemochromatosis can result in progressive organ failure and death, whereas early initiation of treatment is associated with a normal life expectancy
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Genetic and environmental factors can modify the clinical penetrance and severity of hereditary hemochromatosis
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Weiss, G. Genetic mechanisms and modifying factors in hereditary hemochromatosis. Nat Rev Gastroenterol Hepatol 7, 50–58 (2010). https://doi.org/10.1038/nrgastro.2009.201
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DOI: https://doi.org/10.1038/nrgastro.2009.201
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