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What Is the Penetrance of Hereditary Hemochromatosis?

About one quarter of older men who were homozygous for the HFE C282Y mutation had clinically evident disease.

Most clinical cases of hereditary hemochromatosis occur in people who are homozygous for the C282Y mutation in the HFE gene; people who are "compound heterozygotes" (i.e., heterozygous for each of 2 mutations, C282Y and H63D) also can develop clinical disease. Although these mutations are common in many white populations, the penetrance of hemochromatosis — the likelihood that genetically affected people will develop clinically evident disease — is unclear.

Using stored blood samples that were collected in the early 1990s, researchers screened 30,000 Australians of northern European ancestry for mutations associated with hemochromatosis. One in 146 screened subjects was a C282Y homozygote, and 1 in 42 was a compound heterozygote. Then, an average of 11 years later (2004–2006), when subjects’ mean age was 65, the researchers attempted to contact all 203 homozygotes and 242 randomly selected compound heterozygotes to evaluate them in more detail; these subjects underwent physical examinations, additional blood testing, and liver biopsies, if appropriate.

For C282Y homozygotes, the prevalence of documented iron-overload clinical disease was 28% in men and 1% in women; more than half these patients had biopsy-proven liver fibrosis or cirrhosis. Only one compound heterozygote had documented liver disease. Among homozygotes, 45% of men, but only 8% of women, had serum ferritin levels exceeding 1000 µ/L.

Comment: In this study, the penetrance of clinical hemochromatosis by age 65 was 28% for men who were homozygous for the C282Y mutation. As might be expected, follow-up and completeness of evaluations were imperfect in this long-term cohort study; thus, these figures for penetrance might be underestimates. Women are relatively protected from clinical disease because of physiologic iron loss during menstruation and possibly because of other sex-linked genetic factors.

— Allan S. Brett, MD

Published in Journal Watch General Medicine January 16, 2008

Citation(s):

Allen KJ et al. Iron-overload–related disease in HFE hereditary hemochromatosis. N Engl J Med 2008 Jan 17; 358:221.

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