title: Increased risk of death from iron overload among 422 treated probands with HFE hemochromatosis and serum levels of ferritin greater than 1000 μg/L at diagnosis.
abstract: OBJECTIVE
  We investigated the risk of death from iron overload among treated hemochromatosis probands who were homozygous for HFE C282Y and had serum levels of ferritin greater than 1000 μg/L at diagnosis.
  
  
  METHODS
  We compared serum levels of ferritin at diagnosis and other conditions with the rate of iron overload-associated death using data from 2 cohorts of probands with hemochromatosis who were homozygous for HFE C282Y (an Alabama cohort, n = 294, 63.9% men and an Ontario cohort, n = 128, 68.8% men). We defined iron overload-associated causes of death as cirrhosis (including hepatic failure and primary liver cancer) caused by iron deposition and cardiomyopathy caused by myocardial siderosis. All probands received phlebotomy and other appropriate therapy.
  
  
  RESULTS
  The mean survival times after diagnosis were 13.2 ± 7.3 y and 12.5 ± 8.3 y in Alabama and Ontario probands, respectively. Serum levels of ferritin greater than 1000 μg/L at diagnosis were observed in 30.1% and 47.7% of Alabama and Ontario probands, respectively. In logistic regressions of serum ferritin greater than 1000 μg/L, there were significant positive associations with male sex and cirrhosis in Alabama probands and with age, male sex, increased levels of alanine and aspartate aminotransferases, and cirrhosis in Ontario probands. Of probands with serum levels of ferritin greater than 1000 μg/L at diagnosis, 17.9% of those from Alabama and 14.8% of those from Ontario died of iron overload. Among probands with serum levels of ferritin greater than 1000 μg/L, the relative risk of iron overload-associated death was 5.4 for the Alabama group (95% confidence interval [CI], 2.2-13.1; P = .0002) and 4.9 for the Ontario group (95% CI, 1.1-22.0; P = .0359).
  
  
  CONCLUSIONS
  In hemochromatosis probands homozygous for HFE C282Y, serum levels of ferritin greater than 1000 μg/L at diagnosis were positively associated with male sex and cirrhosis. Even with treatment, the relative risk of death from iron overload was 5-fold greater in probands with serum levels of ferritin greater than 1000 μg/L.
authors.affiliation: Southern Iron Disorders Center, Birmingham, Alabama, USA. ironmd@isp.com
authors.forename: James C
authors.initials: JC
authors.lastname: Barton
authors.forename: J Clayborn
authors.initials: JC
authors.lastname: Barton
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Acton
authors.forename: Jeffrey
authors.initials: J
authors.lastname: So
authors.forename: Susanne
authors.initials: S
authors.lastname: Chan
authors.forename: Paul C
authors.initials: PC
authors.lastname: Adams
mesh_terms: D000328:Adult; D000368:Aged; D000407:Alabama; D019943:Amino Acid Substitution; D009202:Cardiomyopathies / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D005293:Ferritins / Q000097:blood*; D006432:Hemochromatosis / Q000175:diagnosis* / Q000473:pathology*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D019190:Iron Overload / Q000401:mortality*; D008103:Liver Cirrhosis / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009864:Ontario; D017354:Point Mutation; D044967:Serum / Q000737:chemistry; D012737:Sex Factors; D016019:Survival Analysis
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D005293:Ferritins