HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity

Gurrin LCB, N. A.; Dalton, G. W.; Osborne, N. J.; Constantine, C. C.; McLaren, C. E.; English, D. R.; Gertig, D. M.; Delatycki, M. B.; Nicoll, A. J.; Southey, M. C.; Hopper, J. L.; Giles, G. G.; Anderson, G. J.; Olynyk, J. K.; Powell, L. W.; Allen, K. J. (2009) HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity. Hepatology 50:94-101

The risk of hemochromatosis-related morbidity is unknown among HFE compound heterozygotes (C282Y/H63D). We used a prospective population-based cohort study to estimate the prevalence of elevated iron indices and hemochromatosis-related morbidity for compound heterozygotes. In all, 31,192 subjects of northern European descent were genotyped for HFE C282Y and H63D. An HFE-genotype stratified random sample of 1,438 subjects, followed for an average of 12 years to a mean age of 65 years, completed questionnaires and gave blood. Clinical examinations were blinded to HFE genotype. A total of 180 (84 males) clinically examined C282Y/H63D participants were compared with 330 (149 males) controls with neither HFE mutation; 132 (65 males) and 270 (122 males), respectively, had serum iron measures at both timepoints. Mean serum ferritin (SF) and transferrin saturation (TS) were significantly greater for male and female compound heterozygotes than for wild-types at baseline and follow-up (all P < 0.02)="" except="" for="" females="" who="" were="" premenopausal="" at="" baseline,="" where="" sf="" was="" similar="" in="" both="" genotype="" groups.="" for="" subjects="" with="" serum="" measures="" from="" both="" baseline="" and="" follow-up,="" mean="" sf="" and="" ts="" levels="" did="" not="" change="" significantly="" for="" men="" or="" for="" postmenopausal="" women,="" but="" for="" premenopausal="" women="" sf="" levels="" increased="" from="" 43="" to="" 109="" microg/l="" for="" compound="" heterozygotes="" and="" from="" 35="" to="" 64="" microg/l="" for="" wild-types="" (both="" p="">< 0.001).="" male="" and="" female="" compound="" heterozygotes="" had="" a="" similar="" prevalence="" of="" hemochromatosis-related="" morbidity="" to="" wild-types.="" one="" of="" 82="" males="" and="" zero="" of="" 95="" females="" had="" documented="" iron="" overload-related="" disease.="" conclusion:="" for="" male="" compound="" heterozygotes,="" mean="" iron="" indices="" do="" not="" change="" during="" middle="" age="" but="" for="" female="" compound="" heterozygotes="" menopause="" results="" in="" increased="" mean="" sf.="" although="" compound="" heterozygotes="" might="" maintain="" elevated="" iron="" indices="" during="" middle="" age,="" documented="" iron="" overload-related="" disease="" is="">