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Unsaturated iron-binding capacity: a screening test for C282Y hemochromatosis?

To the Editor:

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 [greater than or equal to] 44% (sensitivity, 88%; specificity, 99%) for TS and [less than or equal to] 27 [micro]mol/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.

References

(1.) Witte DL, Crosby WH, Edwards CQ, Fairbanks VF, Mitros FA. Hereditary hemochromatosis. Clin Chim Acta 1996;245:139-200.

(2.) Adams PC, Kertesz AE, McLaren C, Barr R, Bamford A, Chakrabarti S. Population screening for hemochromatosis: a comparison of unbound iron binding capacity, transferrin saturation and C282Y genotyping in 5,211 voluntary blood donors. Hepatology 2000;31:1160-4.

(3.) Adams PC, Chakrabarti S. Genotypic/phenotypic correlations in genetic hemochromatosis: evolution of diagnostic criteria. Gastroenterology 1998;114:319-23.

(4.) Jeffrey G, Chakrabarti S, Hegele R, Adams PC. Polymorphism in intron 4 of HFE may cause overestimation of C282Y homozygote prevalence in haemochromatosis. Nat Genet 1999; 22:325-6.

(5.) Pellar TG, Leung FY, Henderson AR. A computer program for rapid generation of receiver operating characteristic curves and likelihood ratios in the evaluation of diagnostic tests. Ann Clin Biochem 1988;25:411-6.

(6.) Hickman P, Hourigan L, Powell LW, Cordingley F, Dimenski G, Ormiston B, et al. Automated measurement of unsaturated iron binding capacity is an effective screening strategy for C282Y homozygous hemochromatosis. Gut 2000;46:405-9.

(7.) Witte D. Mild liver enzyme abnormalities: eliminating hemochromatosis as cause. Clin Chem 1997;43:1535-8.

(8.) Adams PC. Population screening for haemochromatosis. Gut 2000;46:301-3.

Paul C. Adams *

Vipin Bhayana

London Health Sciences Centre

University of Western Ontario

London, Ontario N6A 5A5, Canada

* Address correspondence to this author at: Department of Medicine, London Health Sciences Centre-University Campus, 339 Windermere Rd., London, Ontario, N6A 5A5 Canada. Fax 519-663-3232; e-mail padams@julian.uwo.ca.
Table 1. Effects of diagnostic thresholds for detecting 215 C282Y
homozygotes.

 C282Y
Threshold homozygotes Wild Type

UIBC
 [less than or equal 185 2
 to] 25 [micro]mol/L
 [less than or equal 188 6
 to] 27 [micro]mol/L
 [less than or equal 196 16
 to] 30 [micro]mol/L
 [less than or equal 198 45
 to] 32 [micro]mol/L

TS
 [greater than or equal 165 1
 to] 55%
 [greater than or equal 179 1
 to] 50%
 [greater than or equal 189 5
 to] 44%
 [greater than or equal 197 32
 to] 40%

 Sensitivity, Specificity,
Threshold (a) % (b) %

UIBC
 [less than or equal 86 99
 to] 25 [micro]mol/L
 [less than or equal 87 98
 to] 27 [micro]mol/L
 [less than or equal 91 96
 to] 30 [micro]mol/L
 [less than or equal 92 88
 to] 32 [micro]mol/L

TS
 [greater than or equal 77 100
 to] 55%
 [greater than or equal 83 100
 to] 50%
 [greater than or equal 87 99
 to] 44%
 [greater than or equal 92 92
 to] 40%

(a) Proportion of C282Y homozygotes identified by a positive
test result.

(b) Proportion of wild-type controls identified by a negative
test result.
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Title Annotation:Letters
Author:Adams, Paul C.; Bhayana, Vipin
Publication:Clinical Chemistry
Article Type:Letter to the editor
Date:Nov 1, 2000
Words:1036
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