title: HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 microg/L are at low risk of hemochromatosis.
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 microg/L as the strongest predictor of cirrhosis. The optimal treatment regimen for those with SF concentrations above the normal range but <1000 microg/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 microg/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).
  
  
  CONCLUSIONS
  Previously undiagnosed C282Y homozygotes with SF concentrations that remain below 1000 microg/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.
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia. katie.allen@rch.org.au
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Allen
authors.forename: Nadine A
authors.initials: NA
authors.lastname: Bertalli
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Osborne
authors.forename: Clare C
authors.initials: CC
authors.lastname: Constantine
authors.forename: Martin B
authors.initials: MB
authors.lastname: Delatycki
authors.forename: Amy E
authors.initials: AE
authors.lastname: Nisselle
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Nicoll
authors.forename: Dorota M
authors.initials: DM
authors.lastname: Gertig
authors.forename: Christine E
authors.initials: CE
authors.lastname: McLaren
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Anderson
authors.forename: John K
authors.initials: JK
authors.lastname: Olynyk
authors.forename: Lawrie W
authors.initials: LW
authors.lastname: Powell
authors.forename: Lyle C
authors.initials: LC
authors.lastname: Gurrin
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005293:Ferritins / Q000097:blood*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006432:Hemochromatosis / Q000097:blood* / Q000235:genetics*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011446:Prospective Studies; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D005293:Ferritins