Unsaturated Iron-binding Capacity: A Screening Test for C282Y Hemochromatosis?

Transferrin saturation (TS) has been recommended for screening for hemochromatosis (1). It is widely available, and results may be increased even in young adults with hemochromatosis. The TS assay is a two-step assay with serum iron in the numerator and total iron-binding capacity, unsaturated iron-binding capacity (UIBC), or serum transferrin in the denominator. Serum iron/(serum iron + UIBC) equals the TS. In a previous study, we compared UIBC to TS as a screening test for C282Y hemochromatosis in a population of asymptomatic voluntary blood donors (2). Because blood donation could potentially affect iron status, we have reevaluated TS and UIBC in referred hemochromatosis patients and used first-time blood donors as control cases (n = 386, all wild type by C282Y genotyping). “Discovered” cases refers to C282Y homozygotes found through pedigree studies, and “screened” cases refers to cases discovered during a population screening project in 5211 voluntary blood donors (2). The sample consisted of 78 male probands, 58 discovered men, 5 screened men, 26 female probands, 37 discovered women, and 11 screened women. All hemochromatosis patients and control cases had C282Y genotyping by Rsa1 restriction enzyme digestion (3). Homozygotes with a normal TS and ferritin (n = 5) were confirmed by direct DNA sequencing to exclude false-positive genetic testing (4). Serum iron was determined by colorimetric analysis (Roche Diagnostics or Beckman Coulter). UIBC was determined on the Beckman Coulter LX-20 (Reagent 153-50; Diagnostic Chemicals Limited) or by adapting an existing assay to an automated microwell plate reader (Unimate 7 UIBC; Roche Diagnostics). TS by UIBC was directly compared with TS determined by immunochemical transferrin on the Beckman Coulter IMMAGE immunochemistry system (correlation coefficient = 0.986; n = 192). Between-run precision of UIBC was determined by measuring three levels of control daily for 31 days. CVs were 2.8–7.2%. The diagnostic accuracy of UIBC and TS for the diagnosis of C282Y homozygotes was examined by ROC curve analysis with a program developed at this medical center (5). UIBC data were transformed to 1/UIBC for direct comparison to TS. The thresholds were determined from the ROC curves on the basis of the likelihood ratios [sensitivity/(1 − specificity)]. The areas under the curves were 0.96 (95% confidence interval, 0.94–0.98) for 1/UIBC and 0.96 (95% confidence interval, 0.94–0.98) for TS. Thresholds were ≥44% (sensitivity, 88%; specificity, 99%) for TS and ≤27 μmol/L (sensitivity, 88%; specificity, 98%) for UIBC (Table 1 ). These thresholds are similar to those determined in the screening of 5211 blood donors in which the UIBC detected more C282Y homozygotes with fewer false positives and at a reduced cost (2). These results raise the question stated in the title of this Letter. The cost of the UIBC assay in this study was estimated to be $1. It is intuitive that, using any cost-analysis system, the cost of the single-step UIBC will be less than the cost of the two-step assay using serum iron plus UIBC, total iron-binding capacity, or transferrin. In the less-common cases of hemochromatosis that are not associated with HFE mutations, the disease is defined by iron overload, and thus both UIBC and TS would be expected to be abnormal. UIBC has been used successfully in other studies that screened for hemochromatosis without genotyping in all patients (6)(7). Therefore, UIBC, which has been used for large-scale population screening studies (8), appears to perform as well as TS as a screening test for hemochromatosis at a reduced cost. Effects of diagnostic thresholds for detecting 215 C282Y homozygotes. Proportion of C282Y homozygotes identified by a positive test result. Proportion of wild-type controls identiifed by a negative test result. Effects of diagnostic thresholds for detecting 215 C282Y homozygotes. Proportion of C282Y homozygotes identified by a positive test result. Proportion of wild-type controls identiifed by a negative test result.

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