Nonexpressing homozygotes for C282Y hemochromatosis: minority or majority of cases?

Genetic testing for the C282Y mutation of the HFE gene has been a major advance in the diagnosis of hereditary hemochromatosis. In most studies, more than 90% of typical hemochromatosis patients are homozygous for the C282Y mutation. Large-scale population screening studies in predominantly Caucasian populations have demonstrated a high prevalence of C282Y homozygotes of approximately 1 in 300. Despite this high prevalence by genetic testing, the clinical diagnosis of hemochromatosis and mortality from the disease are much less common. One possibility is the presence of many undiagnosed cases with nonspecific symptoms, and deaths occurring that are attributed to liver disease, diabetes, and heart disease without the recognition of iron overload secondary to hemochromatosis. Another possibility is a high prevalence of nonexpressing homozygotes. In this review, the available data on nonexpressing C282Y homozygotes is collected including information on pathogenesis, environmental interactions, and implications for population screening using genetic testing. Copyright 2000 Academic Press.