Iron-Overload-Related Disease in HFE Hereditary Hemochromatosis

doi:10.1056/NEJMoa073286

Volume 358:221-230		January 17, 2008		Number 3

Iron-Overload–Related Disease in HFE Hereditary Hemochromatosis

Katrina J. Allen, M.D., Ph.D., Lyle C. Gurrin, Ph.D., Clare C. Constantine, Ph.D., Nicholas J. Osborne, Ph.D., Martin B. Delatycki, M.D., Ph.D., Amanda J. Nicoll, M.D., Ph.D., Christine E. McLaren, Ph.D., Melanie Bahlo, Ph.D., Amy E. Nisselle, B.Sc., Chris D. Vulpe, M.D., Ph.D., Gregory J. Anderson, Ph.D., Melissa C. Southey, Ph.D., Graham G. Giles, Ph.D., Dallas R. English, Ph.D., John L. Hopper, Ph.D., John K. Olynyk, M.D., Lawrie W. Powell, M.D., Ph.D., and Dorota M. Gertig, M.D., D.Sc.

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ABSTRACT

Background Most persons who are homozygous for C282Y, the HFEallele 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 northernEuropean descent between the ages of 40 and 69 years who participatedin the Melbourne Collaborative Cohort Study and were followedfor an average of 12 years. In a random sample of 1438 subjectsstratified according to HFE genotype, including all 203 C282Yhomozygotes (of whom 108 were women and 95 were men), we obtainedclinical and biochemical data, including two sets of iron measurementsperformed 12 years apart. Disease related to iron overload wasdefined as documented iron overload and one or more of the followingconditions: cirrhosis, liver fibrosis, hepatocellular carcinoma,elevated aminotransferase levels, physician-diagnosed symptomatichemochromatosis, and arthropathy of the second and third metacarpophalangealjoints.

Results The proportion of C282Y homozygotes with documentediron-overload–related disease was 28.4% (95% confidenceinterval [CI], 18.8 to 40.2) for men and 1.2% (95% CI, 0.03to 6.5) for women. Only one non-C282Y homozygote (a compoundheterozygote) had documented iron-overload–related disease.Male C282Y homozygotes with a serum ferritin level of 1000 µgper liter or more were more likely to report fatigue, use ofarthritis medicine, and a history of liver disease than weremen who had the wild-type gene.

Conclusions In persons who are homozygous for the C282Y mutation,iron-overload–related disease developed in a substantialproportion 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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Iron-Overload–Related Disease in HFE Hereditary Hemochromatosis
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N Engl J Med 2008; 358:2293-2295, May 22, 2008. Correspondence

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