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HFE Mutations and Hereditary Hemochromatosis

Iron overload–related disease developed in a substantial proportion of men who were homozygous for the C282Y mutation.

Hereditary hemochromatosis is a common genetic disorder, but we know little about its natural history. Patients with mutations in the hemochromatosis (HFE) gene display various disease phenotypes: genetic predisposition without iron overload, iron overload with or without symptoms, or iron overload with end-organ damage.

Researchers assessed the prevalence of iron overload–related disease, as well as morbidity and long-term mortality, for 31,192 people (age range, 40–69) of northern European descent who participated in the Melbourne Collaborative Cohort Study. Researchers identified 203 HFE C282Y homozygotes, 3295 C282Y heterozygotes, and 719 people who were heterozygous for two HFE mutations (C282Y and H63D; compound heterozygotes). Iron overload–related disease was defined as documented iron overload plus one or more of the following conditions: physician-diagnosed symptomatic hemochromatosis, arthropathy consistent with iron overload, or liver disease (cirrhosis, fibrosis, liver cancer, or elevated liver-enzyme levels).

During approximately 12 years of follow-up, 8.0% of the total cohort died, including 9.4% of the C282Y homozygotes, 9.0% of the C282Y heterozygotes, and 8.2% of the compound heterozygotes. In a subanalysis, all 203 people who were homozygous for the C282Y HFE mutation were compared with a stratified random sample of 1235 people from the other genotype groups. Among C282Y homozygotes, documented iron overload–related liver disease was identified in 28.4% of men and in only 1.2% of women. The only other instance of documented iron overload–related disease occurred in a compound heterozygote.

Comment: This prospective cohort study is the largest to date to evaluate long-term outcomes in people with hemochromatosis. Although the overall mortality rate was similar among all people with HFE mutations, C282Y homozygotes showed a higher prevalence of iron overload–related disease. With longer follow-up, relative mortality rates could rise among C282Y homozygotes as people with iron overload–related liver disease develop complications. This study highlights the importance of identifying C282Y homozygotes to prevent long-term morbidity and mortality. It also demonstrates the very low incidence of iron overload–related disease in the other mutations, including compound heterozygotes.

— Atif Zaman, MD MPH

Published in Journal Watch Gastroenterology January 17, 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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