Journal of General Internal Medicine

, Volume 29, Issue 2, pp 388–394 | Cite as

Pitfalls in Hemoglobin A1c Measurement: When Results may be Misleading

  • Michael S. RadinEmail author
Review Article


Since the beginning of clinical use in the 1970s, hemoglobin A1c (A1c) has become the standard tool for monitoring glycemic control in patients with diabetes. The role of the A1c test was broadened in 2010, when the American Diabetes Association added A1c as a diagnostic criterion for diabetes. Because of hemoglobin A1c’s integral role in diagnosis and treatment, it is important to recognize clinical scenarios and interfering factors that yield false results. The purpose of this review is to describe the A1c measurement, outline clinical scenarios or factors that may yield false results, and describe alternative laboratory biomarkers.


diabetes evaluation patient centered care physician decision support 



The author would like to acknowledge Virginia Peragallo-Dittko, RN, BC-ADM, CDE, FAADE for her guidance with this manuscript.

Conflict of Interest

The author declares that he does not have a conflict of interest.


  1. 1.
    Sacks DB. Measurement of Hemoglobin A1c. Diabetes Care. 2012;35:2674–80.PubMedCrossRefGoogle Scholar
  2. 2.
    Little RR, Rohlfing CL, Sacks DB. Status of hemoglobin A1c measurement and goals for improvement: from chaos to order for improving diabetes care. Clin Chem. 2011;57(2):205–14.PubMedCrossRefGoogle Scholar
  3. 3.
    American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33(Suppl. 1):S62–9.CrossRefGoogle Scholar
  4. 4.
    International Expert Committee. International Expert Committee report on the role of A1C assay in the diagnosis of diabetes. Diabetes Care. 2009;32:1327–34.CrossRefGoogle Scholar
  5. 5.
    Steinberg MH, Benz EJ Jr, Adewoye AH, Ebert BL. Hemoglobin synthesis, structure, and function. In: Hematology: Basic Principles and Practice. 5th ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2009. Chap 33.Google Scholar
  6. 6.
    Bunn HF, Haney DN, Kamin S, Gabbay KH, Gallop PM. The biosynthesis of hemoglobin A1c: slow glycosylation of hemoglobin in vitro. J Clin Invest. 1976;57:1652–9.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Saudek CD, Brick JC. Clinical advances in hemoglobin A1c measurement: the clinical use of hemoglobin A1c. J Diabetes Sci Technol. 2009;3(4):629–34.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Tahara Y, Shima K. Kinetics of HbA1c, glycated albumin, and fructosamine and analysis of their weight functions against preceding plasma glucose level. Diabetes Care. 1995;18:440–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Nathan DM, Kuenen J, Borg R, et al. Translating the A1c assay into estimated average glucose values. Diabetes Care. 2008;31(8):1473–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Homa K, Majkowska L. Difficulties in interpreting HbA1c results. Pol Arch Med Wewn. 2010;120:148–54.PubMedGoogle Scholar
  11. 11.
    Little RR, Roberts WL. Laboratory advances in hemoglobin A1c measurement: a review of variant hemoglobins interfering with hemoglobin A1c measurement. J Diabetes Sci Technol. 2009;3(3):446–51.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Chang A, Frank J, Knaebel J, Fullam J, Pardo S, Simmons DA. Evaluation of an over-the-counter glycated hemoglobin (A1c) test kit. J Diabetes Sci Technol. 2010;4(6):1495–503.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Al-Ansary L, Farmer A, Hirst J, et al. Point-of-care testing for HbA1c in the management of diabetes: a systematic review and metaanalysis. Clin Chem. 2011;57(4):568–76.PubMedCrossRefGoogle Scholar
  14. 14.
    Lenters-Westra E, Slingerland RJ. Six of eight hemoglobin A1c point-of-care instruments do not meet the general accepted analytical performance criteria. Clin Chem. 2010;56:44–52.PubMedCrossRefGoogle Scholar
  15. 15.
    Herman WH, Cohen RM. Racial and ethnic differences in the relationship between HbA1c and blood glucose: Implications for the diagnosis of diabetes. J Clin Endocrinol Metab. 2012;97(4):1067–72.PubMedCrossRefGoogle Scholar
  16. 16.
    Brooks AP, Metcalfe J, Day JL, Edwards MS. Iron deficiency and glycosylated haemoglobin A. Lancet. 1980;2:141.PubMedCrossRefGoogle Scholar
  17. 17.
    Tarim O, Küçükerdoğan A, Günay U, Eralp O, Ercan I. Effects of iron deficiency anemia on hemoglobin A1c in type 1 diabetes mellitus. Pediatr Int. 1999;41:357–62.PubMedGoogle Scholar
  18. 18.
    Coban E, Ozdogan M, Timuragaoglu A. Effect of iron deficiency anemia on the levels of hemoglobin A1c in nondiabetic patients. Acta Haematol. 2004;112:126–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Nitin S. HbA1c and factors other than diabetes mellitus affecting it. Singap Med J. 2010;51:616–22.Google Scholar
  20. 20.
    Arnold JG, McGowan HJ. Delay in diagnosis of diabetes mellitus due to inaccurate use of hemoglobin A1c levels. J Am Board Fam Med. 2007;20:93–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Larese J. When is hemoglobin A1c inaccurate in assessing glycemic control? NYU Langone Internal Medicine Blog, Faculty Peer Reviewed. Updated February, 2012. Accessed August 2013.
  22. 22.
    Spencer DH, Grossman BJ, Scott MG. Red cell transfusion decreases hemoglobin A1c in patients with diabetes. Clin Chem. 2011;57(2):344–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Falko JM, O’Dorisio TM, Cataland S. Spurious elevations in glycosylated hemoglobin (HbA1) secondary to hypertriglyceridemia. Arch Intern Med. 1982;142(7):1370–1.PubMedCrossRefGoogle Scholar
  24. 24.
    HbA1c assay interferences. National Glycohemoglobin Standardization Program Web site. Available at: Updated August, 2012. Accessed August 2013.
  25. 25.
    Hoberman HD, Chiodo SM. Elevation of the hemoglobin A1 fraction in alcoholism. Alcohol Clin Exp Res. 1982;6(2):260–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Hazelette SE, Liebelt RA, Brown WJ, Androulakakis V, Jarjoura D, Truitt EB Jr. Evaluation of acetaldehyde-modified hemoglobin and other markers of chronic heavy alcohol use: effects of gender and hemoglobin concentration. Alcohol Clin Exp Res. 1998;22(8):1813–9.Google Scholar
  27. 27.
    Rastelli G, Gerra G, Mineo F, et al. Homeostasis of blood glucose and abuse of exogenous opiates: evaluation of fructosamine and glycosylated hemoglobin. Minerva Med. 1987;78(17):1291–6.PubMedGoogle Scholar
  28. 28.
    Tran HA, Silva D, Petrovsky N. Case study: potential pitfalls of using hemoglobin A1c as the sole measure of glycemic control. Clin Diabetes. 2004;22(3):141–3.CrossRefGoogle Scholar
  29. 29.
    Davie SJ, Gould BJ, Yudkin JS. Effect of vitamin C on glycosylation of proteins. Diabetes. 1992;41(2):167–73.PubMedCrossRefGoogle Scholar
  30. 30.
    Freedman BI, Shenoy RN, Planer JA, et al. Comparison of glycated albumin and hemoglobin A1c concentrations in diabetic subjects on peritoneal and hemodialysis. Perit Dial Int. 2010;30:72–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Joy MS, Cefalu WT, Hogan SL, Nachman PH. Long-term glycemic control measurements in diabetic patients receiving hemodialysis. Am J Kidney Dis. 2002;39(2):297–307.PubMedCrossRefGoogle Scholar
  32. 32.
    Lurie S, Mamet Y. Red blood cell survival and kinetics during pregnancy. Eur J Obstet Gynecol Reprod Biol. 2000;93(2):185–92.PubMedCrossRefGoogle Scholar
  33. 33.
    Lind T, Cheyne GA. Effect of normal pregnancy upon glycosylated haemoglobins. Br J Obstet Gynaecol. 1979;86:210–3.PubMedCrossRefGoogle Scholar
  34. 34.
    Hanson U, Hagenfeldt L, Hagenfeldt K. Glycosylated hemoglobins in normal pregnancy: sequential changes and relation to birth weight. Obstet Gynecol. 1983;62:741–4.PubMedGoogle Scholar
  35. 35.
    Phelps RL, Honig GR, Green D, Metzger BE, Frederiksen MC, Freinkel N. Biphasic changes in hemoglobin A1c concentrations during normal human pregnancy. Am J Obstet Gynecol. 1983;147:651–3.PubMedGoogle Scholar
  36. 36.
    Ceriello A, Giugliano D, Quatraro A, Donzella C, Dipalo G, Lefebvre PJ. Vitamin E reduction of protein glycosylation in diabetes. New prospect for prevention of diabetes complications? Diabetes Care. 1991;14(1):68–72.PubMedCrossRefGoogle Scholar
  37. 37.
    Gross BN, Cross LB, Foard JC, Wood YA. Falsely low hemoglobin A1c levels in a patient receiving ribavirin and peginterferon alpha-2b for hepatitis C. Pharmacotherapy. 2009;29(1):121–3.PubMedCrossRefGoogle Scholar
  38. 38.
    Greenberg PD, Rosman AS, Eldeiry LS, Naqvi Z, Bräu N. Decline in haemoglobin A1c values in diabetic patients receiving interferon-alpha and ribavirin for chronic hepatitis C. J Viral Hepat. 2006;13(9):613–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Bry L, Chen PC, Sacks DB. Effects of hemoglobin variants and chemically modified derivatives on assays for glycohemoglobin. Clin Chem. 2001;47(2):153–63.PubMedGoogle Scholar
  40. 40.
    Schnedl WJ, Krause R, Halwachs-Baumann G, Trinker M, Lipp RW, Krejs GJ. Evaluation of HbA1c determination methods in patients with hemoglobinopathies. Diabetes Care. 2000;23:339–44.PubMedCrossRefGoogle Scholar
  41. 41.
    Sacks DB. A1c versus glucose testing: a comparison. Diabetes Care. 2011;34(2):518–23.PubMedCrossRefGoogle Scholar
  42. 42.
    Smaldone A. Glycemic control and hemoglobinopathy: when A1c may not be reliable. Diabetes Spectrum. 2008;21:46–9.CrossRefGoogle Scholar
  43. 43.
    Ambruster DA. Fructosamine: structure, analysis, and clinical usefulness. Clin Chem. 1987;33(12):2153–63.Google Scholar
  44. 44.
    Goldstein DE, Little RR, Lorenz RA, Malone JI, Nathan D, Peterson CM, Sacks DB. Tests of glycemia in diabetes. Diabetes Care. 2004;27(7):1761–73.PubMedCrossRefGoogle Scholar
  45. 45.
    Chen HS, Wu TE, Lin HD, et al. Hemoglobin A1c and fructosamine for assessing glycemic control in diabetic patients with CKD stages 3 and 4. Am J Kidney Dis. 2010;55:867–74.PubMedCrossRefGoogle Scholar
  46. 46.
    Peacock TP, Shihabi ZK, Bleyer AJ, et al. Comparison of glycated albumin and hemoglobin A1c levels in diabetic subjects on hemodialysis. Kidney Int. 2008;73:1062–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Inaba M, Okuno S, Kumeda Y, et al. Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J Am Soc Nephrol. 2007;18:896–903.PubMedCrossRefGoogle Scholar
  48. 48.
    Beck R, Steffes M, Xing D, et al. The interrelationships of glycemic control measures: HbA1c, glycated albumin, fructosamine, 1,5-anhydroglucitrol, and continuous glucose monitoring. Pediatr Diabetes. 2011;12(8):690–5.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Dungan KM. 1,5-anhydroglucitol (GlycoMarkTM) as a marker of short-term glycemic control and glycemic excursions. Expert Rev Mol Diagn. 2008;8(1):9–19.PubMedCrossRefGoogle Scholar
  50. 50.
    McGill JB, Cole TJ, Nowatzke W, et al. Circulating 1,5-anhydroglucitol levels in adult patients with diabetes reflect longitudinal changes of glycemia. Diabetes Care. 2004;27:1859–65.PubMedCrossRefGoogle Scholar
  51. 51.
    Nielsen JK. Continuous subcutaneous glucose monitoring shows a close correlation between mean glucose and time spent in hyperglycemia and hemoglobin A1c. J Diabetes Sci Technol. 2007;1(6):857–63.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Vaddiraju S, Burgess DJ, Tomazos I, Jain FC, Papadimitrakopoulos F. Technologies for continuous glucose monitoring: current problems and future promises. J Diabetes Sci Technol. 2010;4(6):1540–62.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Lucarelli F, Ricci F, Caprio F, et al. GlucoMen Day continuous glucose monitoring system: a screening for enzymatic and electrochemical interferents. J Diabetes Sci Technol. 2012;6(5):1172–81.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Klonoff DC, Buckingham B, Christiansen JS, Montori VM, Tamborlane WV, Vigersky RA, Wolpert H, Endocrine Society. Continuous glucose monitoring: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96(10):2968–79.PubMedCrossRefGoogle Scholar

Copyright information

© Society of General Internal Medicine 2013

Authors and Affiliations

  1. 1.Division of Endocrinology, Diabetes, and MetabolismWinthrop-University HospitalMineolaUSA

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