HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 μg/L are at low risk of hemochromatosis

Authors

  • Katrina J. Allen,

    Corresponding author
    1. Murdoch Childrens Research Institute, Melbourne, Australia
    2. Department of Pediatrics
    3. Department of Gastroenterology, Royal Children's Hospital, Melbourne, Australia
    • Murdoch Childrens Research Institute, The University of Melbourne Department of Paediatrics, Department of Gastroenterology, Royal Children's Hospital, Flemington Road, Parkville 3052, VIC, Australia
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    • fax: +61 3 9345 6240

  • Nadine A. Bertalli,

    1. Murdoch Childrens Research Institute, Melbourne, Australia
    2. Centre for MEGA Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Australia
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  • Nicholas J. Osborne,

    1. Murdoch Childrens Research Institute, Melbourne, Australia
    2. Department of Pediatrics
    3. Centre for MEGA Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Australia
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  • Clare C. Constantine,

    1. Centre for MEGA Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Australia
    2. Department of Epidemiology, University of California Irvine, Irvine, CA
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  • Martin B. Delatycki,

    1. Murdoch Childrens Research Institute, Melbourne, Australia
    2. Department of Pediatrics
    3. Austin Health, Melbourne, Australia
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  • Amy E. Nisselle,

    1. Murdoch Childrens Research Institute, Melbourne, Australia
    2. Department of Pediatrics
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  • Amanda J. Nicoll,

    1. Royal Melbourne Hospital, Melbourne, Australia
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  • Dorota M. Gertig,

    1. Victorian Cytology Service, Inc., Melbourne, Australia
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  • Christine E. McLaren,

    1. Department of Epidemiology, University of California Irvine, Irvine, CA
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  • Graham G. Giles,

    1. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
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  • John L. Hopper,

    1. Centre for MEGA Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Australia
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  • Gregory J. Anderson,

    1. Queensland Institute of Medical Research and University of Queensland, Brisbane, Australia
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  • John K. Olynyk,

    1. Department of Gastroenterology, Fremantle Hospital, Fremantle, Australia; School of Medicine and Pharmacology, University of Western Australia, Perth, Australia; and Western Australian Institute of Medical Research, Perth, Australia
    2. Curtin Health Innovation Research Institute, Perth, Australia
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  • Lawrie W. Powell,

    1. Queensland Institute of Medical Research and University of Queensland, Brisbane, Australia
    2. University of Queensland, Brisbane, Australia; Royal Brisbane and Women's Hospital, Brisbane, Australia
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  • Lyle C. Gurrin,

    1. Centre for MEGA Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Australia
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  • for the HealthIron Study Investigators

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    • The HealthIron Study Investigators also include: M. Bahlo (The Walter and Eliza Hall Institute for Medical Research, Melbourne, Australia), C. D. Vulpe (University of California Berkeley, Berkeley, CA), S. M. Forrest (Australian Genome Research Facility, Melbourne, Australia), M. Southey (Department of Pathology, The University of Melbourne, Melbourne, Australia), and A. Fletcher (Department of Human Services, Melbourne, Australia).


  • This study was funded by National Institute of Diabetes, Digestive and Kidney Diseases (USA) (1 RO1 DK061885-01 A2) and the National Health and Medical Research Council (Australia) (grants no. 251668, 209057). Cohort recruitment was funded by VicHealth and The Cancer Council Victoria. The National Health and Medical Research Council also provided funding for the following authors: L.C.G. and K.J.A. (Career Development Awards), M.B.D. and J.K.O. (Practitioner Fellowships), G.J.A. (Senior Research Fellowship) and J.L.H. (Australia Fellowship).

  • Potential conflict of interest: Nothing to report.

Abstract

Hemochromatosis gene (HFE)-associated hereditary hemochromatosis (HH) is a genetic predisposition to iron overload and subsequent signs and symptoms of disease that potentially affects approximately 80,000 persons in Australia and almost 1 million persons in the United States. Most clinical cases are homozygous for the Cys282Tyr (C282Y) mutation in the HFE gene, with serum ferritin (SF) concentration >1000 μg/L as the strongest predictor of cirrhosis. The optimal treatment regimen for those with SF concentrations above the normal range but <1000 μg/L is unknown. We assessed HFE mutations in a prospective cohort of 31,192 participants of northern European descent, aged 40-69 years. An HFE-stratified random sample of 1438 participants including all C282Y homozygotes with iron studies 12 years apart were examined by physicians blinded to participants' HFE genotype. All previously undiagnosed C282Y homozygotes (35 male, 67 female) and all HFE wild-types (131 male, 160 female) with baseline and follow-up SF concentrations <1000 μg/L were assessed for HH-associated signs and symptoms including abnormal second/third metacarpophalangeal joints (MCP2/3), raised liver enzymes, hepatomegaly, and self-reported liver disease, fatigue, diabetes mellitus, and use of arthritis medication. The prevalence of HH-associated signs and symptoms was similar for C282Y homozygotes and HFE wild-types for both normal and moderately elevated SF concentrations. The maximum prevalence difference between HFE genotype groups with moderately elevated SF was 11% (MCP2/3, 95% confidence interval = −6%, 29%; P = 0.22) and for normal SF was 6% (arthritis medicine use, 95% confidence interval = −3%, 16%; P = 0.11). Conclusion: Previously undiagnosed C282Y homozygotes with SF concentrations that remain below 1000 μg/L are at low risk of developing HH-associated signs and symptoms at an age when disease would be expected to have developed. These observations have implications for the management of C282Y homozygotes. HEPATOLOGY 2010

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