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Hemochromatosis is a common inherited disorder of iron metabolism in which dysregulation of intestinal iron absorption results in deposition of excessive amounts of iron in parenchymal cells with eventual tissue damage and impaired function in a wide range of organs. The iron-storage pigment in tissues is called hemosiderin because it was believed to be derived from the blood. The term hemosiderosis is used to describe the presence of stainable iron in tissues, but tissue iron must be quantified to assess body-iron status accurately (see below and Chap. 126). Hemochromatosis 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.

Although there is debate about definitions, the following terminology is widely accepted.

  1. Hereditary hemochromatosis is most often caused by a mutant gene, termed HFE, which is tightly linked to the HLA-A locus on chromosome 6p (see “Genetic Basis,” below). 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 428-1). 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.

  2. 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.

TABLE 428-1Classification of Iron Overload States


HFE-associated hemochromatosis mutations are among the most common inherited disease alleles, although the prevalence varies in different ethnic groups. It is most common in populations of northern European extraction in whom approximately 1 in 10 persons are heterozygous carriers and ...

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