The most common form of hemochromatosis was classically described as the triad of cirrhosis, diabetes and skin melanosis ('bronze diabetes'). It is a late-onset disorder, which is inherited in an autosomal recessive pattern and characterized by iron deposition in parenchymal cells of the liver, pancreas and heart. Macrophages of the reticuloendothelial system are relatively spared. This disorder results from a small but chronic increase in intestinal iron absorption, averaging about two-to three-fold above the normal level. Over time, the presence of iron causes damage by promoting the formation of toxic oxygen radicals, which attack cellular structures and thereby cause reactive fibrosis. The earliest manifestation of HFE-as-sociated hemochromatosis is increased transferrin saturation, often approaching 100% before tissue iron deposition is noted. The treatment for hemochromatosis is phlebotomy, and this has been used effectively for more than half a century. Initially, blood is removed frequently to rapidly decrease storage iron. Later, iron balance is maintained by periodic phlebotomy, titrated to meet the needs of the individual patient. This treatment apparently produces no significant morbidity, and it has been shown to normalize the life expectancy of affected patients.
Hemochromatosis has been recognized as an inborn error of iron metabolism since the 1930s. In 1976 a French physician, Marcel Simon, made the important observation that the genetic predisposition to hemochromatosis was linked to the human major histocompatibility complex on chromosome 6p, and was most frequently associated with an HLA-A3 hap-lotype. This insight laid the groundwork for the discovery of causative mutations in the HFE gene 20 years later. It is now known that most patients with classical hemochromatosis are homozygous for a unique mutation (cysteine 282 to tyrosine, or C282Y) in HFE.
HFE is an atypical HLA class I molecule, similar to its chromosomal neighbors. Although most members of this family are involved in immune regulation, HFE has no known function in the immune system. It interacts with the transferrin receptor on the cell surface, but there is controversy regarding the consequences of this interaction. It is still not clear how HFE functions in the regulation of intestinal iron absorption, but recent information suggests that it plays some role in regulating the expression of hepcidin.
The C282Y mutation is highly prevalent. In typical populations of individuals of European descent, the carrier frequency has been estimated to be between about 1 in 8 and 1 in 10. This means that about 1 in 200 individuals are homozygous, and at risk of iron loading. However, not all C282Y homozygotes will develop clinical hemochromatosis. There is a wide range in iron loading and its complications. Some individuals will have severe manifestations by the third decade of life, whereas others may never have signs or symptoms of hemochroma-tosis. This variability is probably explained by both genetic factors (modifying genes) and environmental factors (e.g. alcohol intake, dietary iron consumption, menstruation). The modifying genes have not yet been identified, but their characterization is the subject of active investigation in this field.
In addition to C282Y, other mutations and polymorphisms have been identified in the HFE gene. The most common of these is a histidine-to-aspartic acid substitution at amino acid 63 of the protein (H63D). This polymorphism is found in about one-fifth of the world's population. Although it may occasionally be associated with iron overload, particularly when it is found in individuals heterozygous for the C282Y mutation, its clinical significance remains poorly understood, though clinical laboratories test for it. Most other HFE mutations are quite rare and are not identified by routine screening tests.
In the past, the proportion of at-risk C282Y homozygous individuals who develop clinical hemochromatosis was estimated to be about 20-40%. Recently, Beutler and colleagues published the results of a large, questionnaire-based study of patients seen by a health maintenance organization, in which they concluded that fewer than 1% of C282Y homozygotes would have severe disease. However, their study design likely underestimated the number of affected individuals whom most clinicians would feel compelled to treat for hemochro-matosis. This controversy is the subject of ongoing debate in the literature and has not yet been resolved. Until more data are available, it is probably prudent to assume that earlier estimates of prevalence may be correct. The consensus in the field is that this must still be considered a very prevalent disorder.
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