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  • Hemochromatosis classically refers to HFE-mediated genetic iron overload, but several alternatively mediated genetic iron overload syndromes have been described.
  • C282Y is the major mutation and H63D the minor mutation of the HFE gene; individuals with two copies of C282Y or one copy of both mutations (compound heterozygote) are at risk for iron overload.
  • Excess iron deposition in tissues leads to end-organ damage; advanced hemochromatosis typically involves the liver first and may also involve the pancreas, heart, pituitary gland and other organs.
  • Most patients are identified by laboratory screening or family history and are asymptomatic at diagnosis.
  • Symptomatic patients usually present with nonspecific complaints of fatigue, arthralgias, and abdominal pain.
  • Screening studies include serum iron/total iron-binding capacity (abnormal if >45% in women, >50% in men) and serum ferritin (abnormal if >200 mcg/dL in women, >300 mcg/dL in men); if either test is positive, genetic testing should be pursued.
  • Liver biopsy to assess iron concentration and hepatic iron index is indicated if serum ferritin is >1000 mcg/dL, liver tests are abnormal, or hepatomegaly is noted on physical examination.

Eighty percent of clinically established cases of hemochromatosis worldwide and over 90% of cases in the United States result from the autosomal-recessive inheritance of two copies of the major mutation (C282Y) of the HFE gene. Individuals with this genotype are described as C282Y homozygotes. Ten to 15% of Caucasian populations are heterozygotes, possessing one copy of the major mutation. This mutation is believed to have originated more than 6000 years ago amid Celtic or Viking ancestry. It has been postulated that the mutation may have had a potential selective advantage, preventing iron deficiency in the setting of scarce resources such as red meat.

Prevalence estimates of homozygosity for the C282Y mutation in populations of Northern European descent are 1 in 260 persons. Prevalence rates vary by gender and ethnicity. The disease is more common in men, which is attributed to increased dietary iron consumption as well as iron losses in women during menstruation. The disease is rarely seen in African Americans, Mexican Americans, and Asians. Approximately 90–95% of HFE-related hemochromatosis cases in the United States are related to homozygosity for C282Y and 80% in European populations (EASL p. 4).

One copy of the H63D mutation, the minor mutation of the HFE gene, may be found in 15–40% of Caucasian populations. About 4% of cases of hemochromatosis result from the inheritance of one copy of the major mutation, C282Y, and one copy of the minor mutation, H63D. These individuals are described as compound heterozygotes. However, the great majority of compound heterozygotes will not develop clinically significant iron overload. The risk has been estimated to be 200 times less than in C282Y homozygotes. H63D homozygotes typically do not develop clinically significant iron overload. Individuals with this genotype may have an elevated transferrin saturation, but an elevated ferritin should prompt a search for secondary causes of iron overload.

Phenotypic expression ...

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