Population-based screening for hemochromatosis using phenotypic and DNA testing among employees of health maintenance...

Hemochromatosis reportedly affects 3 to 8 persons per 1,000 and is associated with an elevated risk of morbidity and mortality. We sought to ascertain its prevalence in a community and to assess the association between phenotype and genotype.

All health maintenance organization employees were invited to participate in hemochromatosis screening using a repeated elevation of the transferrin saturation test as the case definition (> or = 50% in women and > or = 60% in men with no other cause). Iron overload from hemochromatosis was defined as serum ferritin concentration > or = 95th percentile and mobilizable iron > or = 99th percentile for age and sex, or hepatic iron index > or = 1.9. The HFE gene was analyzed for mutations.

Participation among employees was 28% (1,653 of 6,000); 83% were women. The prevalence of hemochromatosis was 8 per 1,000 (13 of 1,653), and the prevalence of iron overload from hemochromatosis was 4 per 1,000 (5 of 1,653). Compared with those who had no HFE mutation, the relative risk (RR) for hemochromatosis was greatest for C282Y homozygotes (RR = 147), compound heterozygotes (RR = 19), and H63D homozygotes (RR = 9). Overall, 38% of participants had at least one HFE mutation. Screening based on an initial elevated transferrin saturation test had the best sensitivity, whereas DNA testing offered the best specificity and predictive value positive for iron overload disease.

In this population, we found a greater than expected prevalence of hemochromatosis and demonstrated a clear association with the HFE genotype. Promotion of screening is complicated by controversies in case definition and the large number of persons who will be detected before they have clinically significant iron loading, in whom the risk of clinical disease is unknown. Larger screening studies in more diverse populations are necessary to characterize the burden of disease and to follow those at risk (based on HFE or iron status measures) to establish the natural history of hemochromatosis.