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Department of Pathology, Brigham & Womens Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115.
a Address correspondence to this author at: Brigham & Womens Hospital, Thorn 530, 75 Francis St., Boston, MA 02115. E-mail
dsacks{at}rics.bwh.harvard.edu.
Background: Glycohemoglobin (gHb), measured as hemoglobin (Hb) A1c or as total gHb, provides a common means for assessing long-term glycemic control in individuals with diabetes mellitus. Genetic variants and chemically modified derivatives of Hb can profoundly affect the accuracy of these measurements, although effects vary considerably among commercially available methods. The prevalence of genetic variants such as HbS, HbC, and HbE, and chemically modified derivatives such as carbamyl-Hb among patient populations undergoing testing is not insignificant. Clinical laboratories and sites responsible for point-of-care testing of gHb need to be aware of the interferences produced in assays by these Hbs.
Approach: We conducted a review of the literature describing the effects of variant Hbs on gHb assay methods commonly used in clinical laboratories.
Content: This review summarizes the documented effects of both common and uncommon Hb variants and derivatives on the measurement of gHb. Where known, we discuss mechanisms of interference on specific assays and methodologies. We specifically address effects of commonly encountered Hbs, such as carbamyl-Hb, HbS, HbC, HbE, and HbF, on assays that use cation-exchange chromatography, immunoassays, or boronate affinity methods for measuring gHb.
Summary: A variety of patient- and laboratory-related factors can adversely affect the measurement of gHb in patients harboring Hb variants or derivatives. Identification of the variant or derivative Hb before or during testing may allow accurate measurement of gHb by the selection of a method unaffected by the given variant or derivative. However, laboratories should make available alternative, non-Hb-based methods for assessing long-term glycemic control in individuals with HbCC, HbSS, or HbSC disease, or with other underlying disorders where the concentration of gHb does not accurately reflect long-term glycemic control.
The following articles in journals at HighWire Press have cited this article:
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C. D. Saudek, W. H. Herman, D. B. Sacks, R. M. Bergenstal, D. Edelman, and M. B. Davidson A New Look at Screening and Diagnosing Diabetes Mellitus J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2447 - 2453. [Abstract] [Full Text] [PDF] |
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M. Fukui, M. Tanaka, G. Hasegawa, T. Yoshikawa, and N. Nakamura Association Between Serum Bioavailable Testosterone Concentration and the Ratio of Glycated Albumin to Glycated Hemoglobin in Men With Type 2 Diabetes Diabetes Care, March 1, 2008; 31(3): 397 - 401. [Abstract] [Full Text] [PDF] |
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J. M. Abadie and A. A. Koelsch Performance of the Roche Second Generation Hemoglobin A1c Immunoassay in the Presence of Hb-S or Hb-C Traits Ann. Clin. Lab. Sci., January 1, 2008; 38(1): 31 - 36. [Abstract] [Full Text] [PDF] |
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A. Smaldone Glycemic Control and Hemoglobinopathy: When A1C May Not Be Reliable Diabetes Spectr, January 1, 2008; 21(1): 46 - 49. [Full Text] [PDF] |
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S.-T. Lee, C. W. Weykamp, Y.-W. Lee, J.-W. Kim, and C.-S. Ki Effects of 7 Hemoglobin Variants on the Measurement of Glycohemoglobin by 14 Analytical Methods Clin. Chem., December 1, 2007; 53(12): 2202 - 2205. [Abstract] [Full Text] [PDF] |
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Y. Wang, B. Beckwith, C. Smith, and G. Horowitz Misleading Glycated Hemoglobin Results in a Patient with Hemoglobin SC Disease Clin. Chem., July 1, 2007; 53(7): 1394 - 1395. [Full Text] [PDF] |
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R. J. Schrot, K. T. Patel, and P. Foulis Evaluation of Inaccuracies in the Measurement of Glycemia in the Laboratory, by Glucose Meters, and Through Measurement of Hemoglobin A1c Clin. Diabetes, April 1, 2007; 25(2): 43 - 49. [Abstract] [Full Text] [PDF] |
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W. L. Roberts Hemoglobin Constant Spring Can Interfere with Glycated Hemoglobin Measurements by Boronate Affinity Chromatography Clin. Chem., January 1, 2007; 53(1): 142 - 143. [Full Text] [PDF] |
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J. K. Kirk, R. B. D'Agostino Jr., R. A. Bell, L. V. Passmore, D. E. Bonds, A. J. Karter, and K.M. V. Narayan Disparities in HbA1c Levels Between African-American and Non-Hispanic White Adults With Diabetes: A meta-analysis. Diabetes Care, September 1, 2006; 29(9): 2130 - 2136. [Abstract] [Full Text] [PDF] |
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S.-T. Lee, M. S. Kim, D. Y. Choi, S. K. Kim, and C.-S. Ki Incidence of variant hemoglobin (hb) and increased fetal hb concentrations and their effect on hb a1c measurement in a korean population. Clin. Chem., July 1, 2006; 52(7): 1445 - 1446. [Full Text] [PDF] |
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C. B. Hart Race Differences in Long-Term Diabetes Management in an HMO: Response to Adams et al. Diabetes Care, June 1, 2006; 29(6): 1461 - 1462. [Full Text] [PDF] |
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C. D. Saudek, R. L. Derr, and R. R. Kalyani Assessing Glycemia in Diabetes Using Self-monitoring Blood Glucose and Hemoglobin A1c JAMA, April 12, 2006; 295(14): 1688 - 1697. [Abstract] [Full Text] [PDF] |
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N. Ostendorf, T. Glosemeyer-Allhoff, K. Schauerte, and R. Yamamoto Hemoglobin (Hb) Stanleyville II Causes Gross Overestimation of the Hb A1c Proportion in Routine HPLC Clin. Chem., September 1, 2005; 51(9): 1752 - 1754. [Full Text] [PDF] |
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K. Zurbriggen, M. Schmugge, M. Schmid, S. Durka, P. Kleinert, T. Kuster, C. W. Heizmann, and H. Troxler Analysis of Minor Hemoglobins by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry Clin. Chem., June 1, 2005; 51(6): 989 - 996. [Abstract] [Full Text] [PDF] |
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W. L. Roberts, S. Safar-Pour, B. K. De, C. L. Rohlfing, C. W. Weykamp, and R. R. Little Effects of Hemoglobin C and S Traits on Glycohemoglobin Measurements by Eleven Methods Clin. Chem., April 1, 2005; 51(4): 776 - 778. [Full Text] [PDF] |
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R. R. Little, H. Vesper, C. L. Rohlfing, M. Ospina, S. Safar-Pour, and W. L. Roberts Validation by a Mass Spectrometric Reference Method of Use of Boronate Affinity Chromatography to Measure Glycohemoglobin in the Presence of Hemoglobin S and C Traits Clin. Chem., January 1, 2005; 51(1): 264 - 265. [Full Text] [PDF] |
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A. Chico, A. Padros, and A. Novials The Korle-Bu Hb Variant in Caucasian Women With Type 1 Diabetes: A pitfall in the assessment of diabetes control Diabetes Care, September 1, 2004; 27(9): 2280 - 2281. [Full Text] [PDF] |
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D. E. Goldstein, R. R. Little, R. A. Lorenz, J. I. Malone, D. Nathan, C. M. Peterson, and D. B. Sacks Tests of Glycemia in Diabetes Diabetes Care, July 1, 2004; 27(7): 1761 - 1773. [Full Text] [PDF] |
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B. L Armor and M. L Britton Diabetes Mellitus Non-Glucose Monitoring: Point-of-Care Testing Ann. Pharmacother., June 1, 2004; 38(6): 1039 - 1047. [Abstract] [Full Text] [PDF] |
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J L Camargo and J L Gross Conditions associated with very low values of glycohaemoglobin measured by an HPLC method J. Clin. Pathol., April 1, 2004; 57(4): 346 - 349. [Abstract] [Full Text] [PDF] |
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D. B. Sacks Hemoglobin Variants and Hemoglobin A1c Analysis: Problem Solved? Clin. Chem., August 1, 2003; 49(8): 1245 - 1247. [Full Text] [PDF] |
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C M Florkowski, T A Walmsley, S O Brennan, and P M George Haemoglobin Marseille-Long Island and interpretation of HbA1c: which HbA1c result is the "right answer"? Postgrad. Med. J., March 1, 2003; 79(929): 174 - 175. [Abstract] [Full Text] [PDF] |
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R. M. Cohen, Y. R. Holmes, T. C. Chenier, and C. H. Joiner Discordance Between HbA1c and Fructosamine: Evidence for a glycosylation gap and its relation to diabetic nephropathy Diabetes Care, January 1, 2003; 26(1): 163 - 167. [Abstract] [Full Text] [PDF] |
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E. Bisse, C. Schauber, N. Zorn, T. Epting, A. Eigel, A. Van Dorsselaer, H. Wieland, J. Kister, and L. Kiger Hemoglobin Gorwihl [{alpha}2{beta}25(A2)Pro->Ala], an Electrophoretically Silent Variant with Impaired Glycation Clin. Chem., January 1, 2003; 49(1): 137 - 143. [Abstract] [Full Text] [PDF] |
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T Lahousen, R E Roller, R W Lipp, and W J Schnedl Silent haemoglobin variants and determination of HbA1c with the HPLC Bio-Rad Variant II J. Clin. Pathol., September 1, 2002; 55(9): 699 - 703. [Abstract] [Full Text] [PDF] |
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D. B. Sacks, D. E. Bruns, D. E. Goldstein, N. K. Maclaren, J. M. McDonald, and M. Parrott Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus Clin. Chem., March 1, 2002; 48(3): 436 - 472. [Abstract] [Full Text] [PDF] |
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W. L. Roberts, B. K. De, D. Brown, C. M. Hanbury, J. D. Hoyer, W. G. John, T. L. Lambert, R. B. Lundell, C. Rohlfing, and R. R. Little Effects of Hemoglobin C and S Traits on Eight Glycohemoglobin Methods Clin. Chem., February 1, 2002; 48(2): 383 - 385. [Full Text] [PDF] |
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