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Hemochromatosis is a relatively common inherited disorder of iron metabolism prevalent in European populations. Once thought to be a single disease entity, it is now known to be an iron-storage disorder with genetic heterogeneity but with a final common metabolic pathway resulting in the inappropriately high cellular release of iron. This leads to an increase in intestinal iron absorption and the deposition of excess iron in parenchymal cells with eventual tissue damage and organ failure. Thus, the term hemochromatosis now refers to a group of genetic diseases that predispose to iron overload, potentially leading to fibrosis and organ failure. Cirrhosis of the liver, diabetes mellitus, arthritis, cardiomyopathy, and hypogonadotropic hypogonadism are the major clinical manifestations.
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The following terminology is widely accepted.
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Hereditary hemochromatosis is most often caused by a mutation in the homeostatic iron regulator (HFE) gene, which is tightly linked to the HLA-A locus on chromosome 6p. Persons who are homozygous for the mutation are at increased risk of iron overload and account for 80–90% of clinical hereditary hemochromatosis in persons of northern European descent. In such subjects, the presence of hepatic fibrosis, cirrhosis, arthropathy, or hepatocellular carcinoma constitutes iron overload–related disease. Rarer forms of non-HFE hemochromatosis are caused by mutations in other genes involved in iron metabolism (Table 414-1). The disease can be recognized during its early stages when iron overload and organ damage are minimal. At this stage, the disease is best referred to as early hemochromatosis or precirrhotic hemochromatosis.
Secondary iron overload occurs as a result of an iron-loading anemia, such as thalassemia or sideroblastic anemia, in which erythropoiesis is increased but ineffective. In the acquired iron-loading disorders, massive iron deposits in parenchymal tissues can lead to the same clinical and pathologic features as in hemochromatosis.
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Although HFE-associated hemochromatosis mutations are common, the prevalence varies in different ethnic groups. It is most common in populations of northern European extraction in whom ~1 in 10 persons are heterozygous carriers and 0.3–0.5% are homozygotes, with even higher percentages in some Celtic populations such as those residing in Ireland and Brittany. However, expression of the disease is variable ...