Gastroenterology

Gastroenterology

Volume 135, Issue 6, December 2008, Pages 1945-1952
Gastroenterology

Clinical Advances in Liver, Pancreas, and Biliary Tract
The Natural History of Serum Iron Indices for HFE C282Y Homozygosity Associated With Hereditary Hemochromatosis

https://doi.org/10.1053/j.gastro.2008.08.056Get rights and content

Background & Aims

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 μg/L. For males with SF 300–1000 μg/L at baseline, the predicted probability of progressing to SF >1000 μg/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 μg/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.

Section snippets

Patients and Methods

The present study, known as HealthIron, is a substudy of the Melbourne Collaborative Cohort Study (MCCS17). Between 1990 and 1994, 41,528 people (24,479 females) in the target age range of 40–69 years were enrolled in the MCCS. Participants were recruited via the electoral roll (voting is compulsory in Australia), advertisements, and community announcements in local media. All participants gave a blood sample at baseline. For most participants, blood spots were aliquotted onto Guthrie cards;

Features of C282Y Homozygotes

A total of 203 C282Y homozygotes (95 males, 108 females) were identified in this cohort of 31,192 people of northern European extraction. Of these, 146 (72%) participated in the follow-up, and 143 provided blood samples that yielded at least one SF or TS measurement at baseline or follow-up (Table 1). The average time between the baseline and follow-up visits was 12.0 years (range, 9.8–14.3 years).

The average age of C282Y homozygotes at baseline was 53.5 years (SD, 8.9) for males and 54.9 years

Discussion

We have studied the natural history of SF and TS measurements over a mean period of 12 years for a sample of C282Y homozygotes who are participating in a large prospective cohort study. The majority of male C282Y homozygotes (84%) had elevated SF values at baseline (mean age, 55 years) and more than one third had SF >1000 μg/L, suggesting that a substantial proportion of male C282Y homozygotes had developed significant iron loading by this age. A similar high prevalence was observed at

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    The HealthIron Study Investigators also include Melanie Bahlo (The Walter & Eliza Hall Institute for Medical Research, Melbourne, Australia), Amanda Nicoll (Royal Melbourne Hospital, Melbourne, Australia), Amy Nisselle (Murdoch Childrens Research Institute, Melbourne, Australia), and Chris Vulpe (University of California, Berkeley, California).

    The authors disclose the following: Supported by the National Institute of Diabetes, Digestive and Kidney Diseases (US) (1 RO1 DK061885-01 A2); National Health and Medical Research Council (NHMRC) (Australia) (project grant number 251668); by VicHealth and The Cancer Council Victoria for cohort recruitment; The Cancer Council Victoria and the NHMRC (program grant 209057, enabling grant 396414) for continuing follow-up; and by NHMRC Career Development Award (to L.C.G. and K.J.A), NHMRC Practitioner Fellowship (to M.B.D. and J.K.O), NHMRC Senior Research Fellowship (to M.C.S and G.J.A.), and NHMRC Australia Fellowship (to J.L.H.).

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