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Background Most persons who are homozygous for C282Y, the HFE allele most commonly asssociated with hereditary hemochromatosis, have elevated levels of serum ferritin and transferrin saturation. Diseases related to iron overload develop in some C282Y homozygotes, but the extent of the risk is controversial.
Methods We assessed HFE mutations in 31,192 persons of northern European descent between the ages of 40 and 69 years who participated in the Melbourne Collaborative Cohort Study and were followed for an average of 12 years. In a random sample of 1438 subjects stratified according to HFE genotype, including all 203 C282Y homozygotes (of whom 108 were women and 95 were men), we obtained clinical and biochemical data, including two sets of iron measurements performed 12 years apart. Disease related to iron overload was defined as documented iron overload and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels, physician-diagnosed symptomatic hemochromatosis, and arthropathy of the second and third metacarpophalangeal joints.
Results The proportion of C282Y homozygotes with documented iron-overload–related disease was 28.4% (95% confidence interval [CI], 18.8 to 40.2) for men and 1.2% (95% CI, 0.03 to 6.5) for women. Only one non-C282Y homozygote (a compound heterozygote) had documented iron-overload–related disease. Male C282Y homozygotes with a serum ferritin level of 1000 µg per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who had the wild-type gene.
Conclusions In persons who are homozygous for the C282Y mutation, iron-overload–related disease developed in a substantial proportion of men but in a small proportion of women.
Source Information
From the Murdoch Children's Research Institute (K.J.A., N.J.O., M.B.D., A.E.N.), the Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology (L.C.G., C.C.C., N.J.O., G.G.G., D.R.E., J.L.H., D.M.G.), and the Departments of Pediatrics (K.J.A., M.B.D., A.E.N.) and Pathology (M.C.S.), the University of Melbourne, Melbourne; the Royal Melbourne Hospital, Melbourne (A.J.N.); the Walter and Eliza Hall Institute, Melbourne (M.B.); the Queensland Institute of Medical Research and the University of Queensland, Brisbane (G.J.A., L.W.P.); the Cancer Council Victoria, Melbourne (G.G.G., D.R.E.); and the University of Western Australia and the Western Australian Institute of Medical Research, Perth (J.K.O.) — all in Australia; the University of California, Irvine, Irvine (C.E.M.); and the University of California, Berkeley, Berkeley (C.D.V.).
Address reprint requests to Dr. Allen at the Department of Gastroenterology, Royal Children's Hospital, Flemington Rd., Parkville 3052, Victoria, Australia, or at katie.allen{at}rch.org.au.
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