Genotypic/phenotypic correlations in genetic hemochromatosis: Evolution of diagnostic criteria

Background & Aims: The identification of a candidate gene for hereditary hemochromatosis in 69%-100% of patients with hemochromatosis has resulted in a diagnostic genotypic test (C282Y), The aim of this study was to reassess the phenotypic diagnostic criteria for hemochromatosis in patients homozygous for the C282Y mutation of the HFE gene. Methods: Transferrin saturation, ferritin, hepatic iron index, and iron removed by venesection were studied in C282Y++ homozygotes and C282Y-- putative homozygotes. Results: Patients were homozygous for the C282Y mutation in 122 of 128 cases (95%), In C282Y homozygotes, the results were as follows: hepatic iron index, >1.9 in 91.3%; transferrin saturation, >55% in 90%; serum ferritin, >300 mu g/L in 96% of men and >200 mu g/L in 97% of women; and iron removed, >5 g in 70% of men and 73% of women. There were four homozygotes for C282Y with no biochemical evidence of iron overload, Conclusions: The sensitivity of the phenotypic tests in decreasing order was as follows: serum ferritin, hepatic iron index, transferrin saturation, and iron removed by venesection. Although the genetic test is useful in the diagnostic algorithm, this study has shown both iron-loaded patients without the mutation and homozygous patients without iron overload.