Pitfalls in Hemoglobin A1c Measurement: When Results may be Misleading

A Capsule Commentary to this article was published on 25 September 2013

ABSTRACT

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.

This is a preview of subscription content, access via your institution.

REFERENCES

  1. 1.

    Sacks DB. Measurement of Hemoglobin A1c. Diabetes Care. 2012;35:2674–80.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33(Suppl. 1):S62–9.

    Article  Google 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.

    Article  Google 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.

  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.

    CAS  PubMed Central  PubMed  Article  Google 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.

    PubMed Central  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Homa K, Majkowska L. Difficulties in interpreting HbA1c results. Pol Arch Med Wewn. 2010;120:148–54.

    CAS  PubMed  Google 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.

    PubMed Central  PubMed  Article  Google 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.

    PubMed Central  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Brooks AP, Metcalfe J, Day JL, Edwards MS. Iron deficiency and glycosylated haemoglobin A. Lancet. 1980;2:141.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Article  Google 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.

    PubMed  Article  Google Scholar 

  21. 21.

    Larese J. When is hemoglobin A1c inaccurate in assessing glycemic control? NYU Langone Internal Medicine Blog, Faculty Peer Reviewed. http://www.clinicalcorrelations.org/?p=5190. 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    HbA1c assay interferences. National Glycohemoglobin Standardization Program Web site. Available at: http://www.ngsp.org/interf.asp. 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Google 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.

    Article  Google Scholar 

  29. 29.

    Davie SJ, Gould BJ, Yudkin JS. Effect of vitamin C on glycosylation of proteins. Diabetes. 1992;41(2):167–73.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    PubMed  Article  Google 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.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Lind T, Cheyne GA. Effect of normal pregnancy upon glycosylated haemoglobins. Br J Obstet Gynaecol. 1979;86:210–3.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Sacks DB. A1c versus glucose testing: a comparison. Diabetes Care. 2011;34(2):518–23.

    PubMed  Article  Google Scholar 

  42. 42.

    Smaldone A. Glycemic control and hemoglobinopathy: when A1c may not be reliable. Diabetes Spectrum. 2008;21:46–9.

    Article  Google 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.

    PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed Central  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    PubMed Central  PubMed  Article  Google 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.

    PubMed Central  PubMed  Article  Google 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.

    PubMed Central  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgments

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Michael S. Radin MD, FACE.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Radin, M.S. Pitfalls in Hemoglobin A1c Measurement: When Results may be Misleading. J GEN INTERN MED 29, 388–394 (2014). https://doi.org/10.1007/s11606-013-2595-x

Download citation

KEY WORDS

  • diabetes
  • evaluation
  • patient centered care
  • physician decision support