Screening for hemochromatosis by measuring ferritin levels: a more effective approach

Abstract

Because the penetrance of HFE hemochromatosis is low, traditional population screening measuring the transferrin saturation is unlikely to be cost-effective because the majority of subjects detected neither have clinical disease nor are likely to develop it. Three independent studies show that only patients with serum ferritin concentrations more than 1000 g/L are at risk for cirrhosis, one of the main morbidities of hemochromatosis. Among 29 699 white subjects participating in the Scripps/Kaiser hemochromatosis study, only 59 had serum ferritin levels more than 1000 g/L; 24 had homozygous mutant or compound heterozygous mutant HFE genotypes. In all but 5 of the other subjects, the causes of elevated ferritin were excessive alcohol intake, cancer, or liver disease. Screening for hemochromatosis with serum ferritin levels will detect the majority of patients who will be clinically affected and may detect other clinically significant disease in patients who IntroductionAt one time, hereditary hemochromatosis was regarded as the "poster child" for genetic screening for a common, treatable disease. However, enthusiasm for screening for hemochromatosis waned after several large controlled studies showed that the penetrance of the homozygous state for the HFE C282Y mutation is much lower than had previously been thought. These studies showed that the nonspecific symptoms attributed to iron overload in C282Y homozygotes were equally prevalent in controls, leading to a more specific definition of penetrance based on the presence of liver disease. Although there may be disagreement of whether the penetrance in males is of the order of 2% as shown by our studies 1 and those of others, 2,3 or whether it approaches 5% as suggested by the prevalence of cirrhosis found by others, 4,5 it is clear that earlier penetrance estimates of 95% 6 or 43% 7 on which calculation of the cost-effectiveness of screening strategies were based are no longer tenable.Because such cost estimates are based on the number of patients who may be helped by therapy, the low penetrance of hemochromatosis makes screening much more expensive than had originally been estimated. Accordingly, strategies aimed at lowering the expense of screening, such as performing less costly unsaturated iron binding capacity measurements rather than transferrin saturation determinations, 8 or focusing on "at-risk" groups 9-12 have been proposed to bring population screening closer to cost-effectiveness. Although such approaches may decrease somewhat the cost per case found, the majority of detected subjects will not have a clinical phenotype, nor will they be fated to develop one in the future. As a result, many essentially normal patients will be subjected to further extensive and often expensive examinations from which they will not benefit.What is needed is a means of limiting screening to subjects who are not only at high risk of being homozygous for the C282Y mutation (which occurs almost exclusively in persons of European ancestry) but who also are at increased ris...

Total and Cause-Specific Mortality by Elevated Transferrin Saturation and Hemochromatosis Genotype in Individuals With Diabetes: Two General Population Studies

“…Exp, exposed. be for TS, ferritin, or both needs to be resolved (33). The dose-response relationship with increased risk of total mortality for stepwise increasing TS has also been shown in two previous population-based studies (12); however, risk in the population cohorts increased from TS $40%, whereas in this study, based on individuals with diabetes, risk increased from TS $30%.…”

Hepcidin knockout mice as a model of iron-overload associated liver disease

“…Serum ferritin levels observed in hepcidin knockout mice are comparable with data seen in untreated HH patients [137]. Measurement of serum ferritin in HFE patients is of clinical importance since HH patients with serum ferritin < 1000µg/L are unlikely to display advanced liver fibrosis while ferritin values > 1000µg/L confer more than threefold higher risk for development of advanced fibrosis [137,138,139,140,141,142].…”

HFEMutations in Caucasian Participants of the Hemochromatosis and Iron Overload Screening Study with Serum Ferritin Level <1000 μg/L

“…Genetic testing is less invasive than previous diagnostic tools, such as liver biopsy, and may be reassuring to patients and their families. Previous studies have suggested that only patients with a ferritin level ≥1000 µg/L should undergo further investigation for hemochromatosis and treatment (11). Previously undiagnosed C282Y homozygotes with serum ferritin values that remain <1000 µg/L are at low risk for developing hemochromatosis-related signs and symptoms at an age when the clinical manifestations would be expected to have developed (12).…”