The importance of screening for hemochromatosis.

H EREDITARY HEMOCHROMATOSIS, commonly described as human leukocyte antigen–linked or HFE-associated hemochromatosis, is an inherited disorder of iron metabolism leading to excessive absorption of iron from the gastrointestinal tract. Patients with hemochromatosis may develop progressive iron loading in many parenchymal organs, resulting in cirrhosis complicated by liver failure or hepatocellular carcinoma, diabetes, arthropathy, and cardiac disease. Patients with cirrhosis associated with HH have a significantly increased risk of premature mortality. By contrast, patients diagnosed prior to the development of cirrhosis have a normal life expectancy when compared with ageand sexmatched controls. Therefore, population screening for HH has been advocated with the goal of identifying patients in the precirrhotic stage of the disease, particularly because noninvasive, sensitive, and specific screening tests are available and because iron depletion therapy is safe and can lead to improved outcomes. Furthermore, the identification of the HFE gene has made possible confirmation of the diagnosis of HH using DNA-based testing for the homozygous C282Y mutation. However, critics have maintained that population screening for HH is not warranted until the true penetrance of the C282Y mutation with regard to disease burden is known. According to these critics, population screening prior to clarification of case definition, natural history, and morbidity and mortality associated with HH would be costly, produce stress and discomfort to otherwise healthy individuals, and expose them to the risk of stigmatization and discrimination. Prior to discussing the pros and cons of screening for HH, we must define whether screening would use a phenotypic-based approach (ie, measuring serum TS and ferritin levels) or a genotypic-based approach (ie, HFE mutation analysis). Prior to the identification of the HFE gene, most population screening studies measuring TS found a prevalence of putative homozygosity of approximately 1:500, particularly among populations of northern European descent. Recent studies using HFE mutation analysis have found that the prevalence of the C282Y homozygosity is much higher and that many C282Y homozygotes do not express iron overload as measured by serum TS and ferritin level. In addition, many clinicians have noted that HH appears to be much less common in practice than would be expected based on such high prevalence estimates. These apparent discrepancies may be due to either low penetrance of the HH genotype or lack of recognition of patients with HH. Indeed, an analysis of death certificates showed a considerable temporal increase in the rate of HHassociated deaths over the last 20 years, perhaps owing to an improved recognition of the disease, which suggests that the condition is still underdiagnosed. It is likely that genetic and environmental factors and interactions modify disease expression and influence the penetrance of the HH genotype. Thus, heterogeneity in populations selected to be screened based, perhaps, on the presence of other disease-modifying genes, diet, and alcohol use have likely led to the widely variable estimates of the penetrance of the homozygous C282Y genotype, which has been reported to range from 1% to greater than 50%. Nevertheless, a number of studies have shown that a significant proportion of C282Y homozygotes have biochemical evidence of iron overload. In a study of 122 C282Y homozygotes, 90% had TS of 55% or higher, and the authors reported a serum ferritin level of greater than 300 μg/L in 96% of men and greater than 200 μg/L in 97% of women. Phatak et al found a TS of 45% or higher in 11 of 12 C282Y homozygotes; 100% of men and 50% of women homozygous for C282Y had ferritin levels above 200 μg/L. In contrast, only 7% of patients with genotypes C282Y/H63D or H63D/H63D had a serum ferritin level above 300 μg/L, suggesting a lower risk of iron overload in subjects with these genotypes compared with C282Y homozygotes. In population screening studies, 50% to 70% of C282Y homozygotes detected using TS also had elevated ferritin levels, suggesting that a significant proportion of these patients are at risk for comFrom the Division of Gastreonterology/ Hepatology, University of Washington School of Medicine, Seattle. The authors have no relevant financial interest in this article. Suja Dubois, MD