The natural history of serum iron indices for HFE C282Y homozygosity associated with hereditary hemochromatosis.
OBJECTIVE
There are few longitudinal studies of serum ferritin (SF) and transferrin saturation (TS) levels in individuals homozygous for the C282Y mutation. We characterized the development of elevated iron measures in C282Y homozygotes followed for 12 years.


METHODS
From 31,192 people aged 40-69 years at baseline, we identified 203 C282Y homozygotes (95 males), of whom 116 had SF and fasting TS levels measured at baseline (mean age, 55 years) and 86 were untreated and had iron measures at follow-up (mean, 12 years later). The probabilities of SF at follow-up exceeding clinical thresholds were predicted from baseline SF and TS under a multivariate normal model.


RESULTS
For C282Y homozygotes, at baseline, 84% of males and 65% of females had elevated SF and 37% of males and 3% of females had SF >1000 microg/L. For males with SF 300-1000 microg/L at baseline, the predicted probability of progressing to SF >1000 microg/L at follow-up was between 13% and 35% and, for females, between 16% and 22%. For C282Y homozygotes with normal baseline SF, <15% were predicted to develop SF >1000 microg/L if left untreated.


CONCLUSIONS
The majority of C282Y homozygotes who are likely to develop SF levels sufficient to place them at risk of iron overload-related disease will have done so by mean age 55 years. TS >95% at mean age 55 years in males increases the likelihood that SF levels will be elevated at mean age 65 years, but this effect is absent in females, most likely because of physiologic blood loss associated with menstruation.
Centre for MEGA Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Australia.
Lyle C
LC
Gurrin
Nicholas J
NJ
Osborne
Clare C
CC
Constantine
Christine E
CE
McLaren
Dallas R
DR
English
Dorota M
DM
Gertig
Martin B
MB
Delatycki
Melissa C
MC
Southey
John L
JL
Hopper
Graham G
GG
Giles
Gregory J
GJ
Anderson
John K
JK
Olynyk
Laurie W
LW
Powell
Katrina J
KJ
Allen
D000328:Adult; D000368:Aged; D004909:Erythrocyte Indices; D005260:Female; D005293:Ferritins / Q000097:blood*; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006432:Hemochromatosis / Q000097:blood / Q000235:genetics*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000097:blood*; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D012189:Retrospective Studies; D013997:Time Factors
C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D005293:Ferritins; D007501:Iron