Review Article

Limitations of A1c Interpretation

Authors: Jessica G. Shepard, PharmD, Anita Airee, PharmD, BCPS, Andrew W. Dake, MD, M. Shawn McFarland, PharmD, Amit Vora, MD

Abstract

Hemoglobin A1c is the measurement of glycated hemoglobin and can aid in both the diagnosis and continued management of diabetes mellitus. Accurate glycosylated hemoglobin A1c (A1c) measurements are an essential part of decision making in the diagnosis and treatment of type 2 diabetes mellitus. Although national standards exist to eliminate technical error with A1c testing, multiple patient conditions can falsely decrease or elevate the A1c. In this review, we discuss the methods to measure A1c and the corresponding conditions that can affect the clinical utility of the test. Conditions that affect the A1c can be either those that impair erythrocyte production or alter the normal process of glycation. Some variation also has been associated with patient ethnicity and even with normal aging. We describe alternatives to A1c testing for the above clinical scenarios in an effort to make the practicing clinician aware of alternatives for glucose evaluation.

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References

1. American Diabetes Association. Standards of medical care in diabetes–2010. Diabetes Care 2010;33 (Suppl 1):S11-S61.
 
2. Centers for Disease Control and Prevention. 2014 National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. http://www.cdc.gov/diabetes/pdfs/data/2014-report-estimates-of-diabetes-and-its-burden-in-the-united-states.pdf. Accessed September 23, 2015.
 
3. International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32:1327-1334.
 
4. US Preventive Services Task Force. Update summary: abnormal glucose and type 2 diabetes mellitus in adults: screening. http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryDraft/screening-for-abnormal-glucose-and-type-2-diabetes-mellitus. Published April 2015. Accessed May 18, 2015.
 
5. American Diabetes Association. Standards of medical care in diabetes-2015. Diabetes Care 2015;38(Suppl 1):S1-S90.
 
6. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 2011;17(Suppl 2):1-53.
 
7. Patel P, Macerollo A. Diabetes mellitus: diagnosis and screening. Am Fam Physician 2010;81: 863-870.
 
8. Centers for Medicare & Medicaid Services. Quality measures and performance standards. http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/sharedsavingsprogram/Quality_Measures_Standards.html. Accessed May 18, 2015.
 
9. National Glycohemoglobin Standardization Program. http://www.ngsp.org. Accessed May 18, 2015.
 
10. Saudek CD, Derr RL, Kalyani RR. Assessing glycemia in diabetes using self-monitoring blood glucose and hemoglobin A1c. JAMA 2006;295:1688-1697.
 
11. Tahara Y, Shima K. The response of GHb to stepwise plasma glucose change over time in diabetic patients. Diabetes Care 1993;16:1313-1314.
 
12. Sacks DB, Arnold M, Bakris GL, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin Chem 2011;57:e1-e47.
 
13. Little RR, Rohlfing CL, Sacks DB, et al. Status of hemoglobin A1c measurement and goals for improvement: from chaos to order for improving diabetes care. Clin Chem 2011;57:205-214.
 
14. Little RR. Analysis of point-of-care and over-the-counter testing methods for hemoglobin A1c: how good do they need to be? J Diabetes Sci Technol 2010;4:1504-1506.
 
15. Chang A, Frank J, Knaebel J, et al. Evaluation of an over-the-counter glycated hemoglobin (A1C) test kit. J Diabetes Sci Technol 2010;4:1495-1503.
 
16. Ansari A, Thomas S, Goldsmith D. Assessing glycemic control in patients with diabetes and end-stage renal disease. Am J Kidney Dis 2003;41:523-531.
 
17. Little RR, Rohlfing CL, Tennill AL, et al. Measurement of Hba(1C) in patients with chronic renal failure. Clin Chim Acta 2013;418:73-76.
 
18. 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.
 
19. Ng JM, Cooke M, Bhandari S, et al. The effect of iron and erythropoietin treatment on the A1C of patients with diabetes and chronic kidney disease. Diabetes Care 2010;33: 2310-2313.
 
20. Nielsen LR, Ekbom P, Damm P, et al. HbA1c levels are significantly lower in early and late pregnancy. Diabetes Care 2004;27: 1200-1201.
 
21. Spencer DH, Grossman BJ, Scott MG. Red cell transfusion decreases hemoglobin A1c in patients with diabetes. Clin Chem 2011;57:344-346.
 
22. Sugimoto T, Hashimoto M, Hayakawa I, et al. Alterations in HbA1c resulting from the donation of autologous blood for elective surgery in patients with diabetes mellitus. Blood Transfus 2014;12(Suppl 1):s209-s213.
 
23. Tarim O, Kucukerdo?an A, Gunay U, et al. Effects of iron deficiency anemia on hemoglobin A1c in type 1 diabetes mellitus. Pediatric Int 1999;41:357-362.
 
24. Son JI, Rhee SY, Woo JT, et al. Hemoglobin A1c may be an inadequate diagnostic tool for diabetes mellitus in anemic subjects. Diabetes Metab J 2013;37:343-348.
 
25. McCready F, Cundy T. Effects of splenectomy for hereditary spherocytosis on glycated haemoglobin in a woman with type 2 diabetes. Diabet Med 2009;26:570-571.
 
26. Bry L, Chen PC, Sacks DB. Effects of hemoglobin variants and chemically modified derivatives on assays for glycohemoglobin. Clin Chem 2001;47:153-163.
 
27. Beutler E. Disorders of hemoglobin. In: Harrison T, Fauci A, eds. Harrison’s Principles of Internal Medicine, 14th ed. New York: McGraw Hill;1996:645-652.
 
28. Cox T, Hess PP, Thompson GD, et al. Interference with glycated hemoglobin by hemoglobin F may be greater than is generally assumed. Am J Clin Pathol 1993;99:137-141.
 
29. Torres Lde S, Okumura JV, Silva DG, et al. Hemoglobin D-Punjab: origin, distribution and laboratory diagnosis. Rev Bras Hematol Hemoter 2015;37:120-126.
 
30. Office of Disease Prevention and Health Promotion. Healthy People 2020. www.healthypeople.gov/2020. Accessed May 20, 2015.
 
31. Smaldone A. Glycemic control and hemoglobinopathy: when A1c may not be reliable. Diabetes Spectrum 2008;21:46-49.
 
32. Little RR, Roberts WL. A review of variant hemoglobins interfering with hemoglobin A1c measurement. J Diabetes Sci Technol 2009;3:446-451.
 
33. Sacks DB. Hemoglobin A1c in diabetes: panacea or pointless? Diabetes 2013;62:41-43.
 
34. Herman WH, Ma Y, Uwaifo G, et al. Differences in A1C by race and ethnicity among patients with impaired glucose tolerance in the Diabetes Prevention Program. Diabetes Care 2007;30:2453-2457.
 
35. Ziemer DC, Kolm P, Weintraub WS, et al. Glucose-independent, blackwhite differences in hemoglobin A1c levels: a cross-sectional analysis of 2 studies. Ann Intern Med 2010;152:770-777.
 
36. Selvin E, Steffes MW, Ballantyne CM, et al. Racial differences in glycemic markers: a cross-sectional analysis of community-based data. Ann Intern Med 2011;154:303-309.
 
37. Tsugawa Y, Mukamal KJ, Davis RB, et al. Should the hemoglobin A1c diagnostic cutoff differ between blacks and whites? A cross-sectional study. Ann Intern Med 2012;157:153-159.
 
38. Nathan DM, Francis TB, Palmer JL. Effect of aspirin on determinations of glycosylated hemoglobin. Clin Chem 1983;29:466-469.
 
39. Davie SJ, Gould BJ, Yudkin JS. Effect of vitamin C on glycosylation of proteins. Diabetes 1992;41: 167-173.
 
40. Ceriello A, Giugliano D, Quatraro A, et al. Vitamin E reduction of protein glycosylation in diabetes. New prospect for prevention of diabetic complications? Diabetes Care 1991;14:68-72.
 
41. Weykamp CW, Penders TJ, Baadenhuijsen H, et al. Vitamin C and glycohemoglobin. Clin Chem 1995;41:713-716.
 
42. Park MH, Kim DH, Lee EK, et al. Age-related inflammation and insulin resistance: a review of their intricate interdependency. Arch Pharm Res 2014;37:1507-1514.
 
43. Petersen KF, Befroy D, Dufour S, et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003;300:1140-1142.
 
44. Palmer JP, Ensinck JW. Acute-phase insulin secretion and glucose tolerance in young and aged normal men and diabetic patients. J Clin Endocrinol Metab 1975;41:498-503.
 
45. Pani LN, Korenda L, Meigs JB, et al. Effect of aging on A1C levels in individuals without diabetes: evidence from the Framingham Offspring Study and the National Health and Nutrition Examination Survey 2001-2004. Diabetes Care 2008;31:1991-1996.
 
46. Wiener K, Roberts NB. Age does not influence levels of HbA1c in normal subjects. QJM 1999;92:169-173.
 
47. Nowicka P, Santoro N, Liu H, et al. Utility of hemoglobin A(1c) for diagnosing prediabetes and diabetes in obese children and adolescents. Diabetes Care 2011;34:1306-1311.
 
48. Austin GE, Wheaton R, Nanes MS, et al. Usefulness of fructosamine for monitoring outpatients with diabetes. Am J Med Sci 1999;318:316-323.
 
49. Baker JR, Metcalf PA, Holdaway IM, et al. Serum fructosamine concentration as measure of blood glucose control in type I (insulin dependent) diabetes mellitus. Br Med J (Clin Res Ed) 1985;290:352-355.
 
50. Furusyo N, Hayashi J. Glycated albumin and diabetes mellitus. Biochim Biophys Acta 2013;1830:5509-5514.
 
51. Buse JB, Freeman JL, Edelman SV, et al. Serum 1,5-anhydroglucitol (GlycoMark): a short-term glycemic marker. Diabetes Technol Ther 2003;5:355-363.
 
52. Gebhart SS, Wheaton RN, Mullins RE, et al. A comparison of home glucose monitoring determinations of hemoglobin A1c, total glycated hemoglobin, fructosamine, and random serum glucose in diabetic patients. Arch Intern Med 1991;151:1133-1137.
 
53. Negoro H, Morley JE, Rosenthal MJ. Utility of serum fructosamine as a measure of glycemia in young and old diabetic and non-diabetic subjects. Am J Med 1988;85:360-364.
 
54. Selvin E, Rawlings AM, Grams M, et al. Fructosamine and glycated albumin for risk stratification and prediction of incident diabetes and microvascular complications: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study. Lancet Diabetes Endocrinol 2014;2:279.
 
55. Wright L, Hirsch IB. The challenge of the use of glycemic biomarkers in diabetes: reflecting on hemoglobin A1c, 1,5- anhydroglucitol, and the glycated proteins fructosamine and glycated albumin. Diabetes Spectrum 2012;25:141-148.
 
56. Chen HS, Wu TE, Lin HD, et al. Hemoglobin A(1c) and fructosamine for assessing glycemic control in diabetic patients with CKD stages 3 and 4. Am J Kidney Dis 2010;55:867-874.
 
56a. Ohkawara E, Nohara Y, Yoshihiko K, et al. Fructosamine assay using albumin extracted from serum. Biol Pharm Bull 2002;25:1121-1124.
 
56b. Walker SW, Howie AF, Smith AF. The measurement of glycosolated albumin by reduction of alkaline nitro-blue tetrazolium. Clin Chem Acta 1986;156:197-206.
 
57. Armbruster DA. Fructosamine: structure, anaylsis, and clinical usefulness. Clin Chem 1987;33:2153-2163.
 
58. Pandya HC, Livingstone S, Colgan ME, et al. Serum fructosamine as an index of glycemia: comparison with glycated hemoglobin in diabetic and non-diabetic individuals. Pract Diabetes 1987;4:126-128.
 
59. Kohnert KD, Heinke P, Vogt L, et al. Utility of different glycemic control metrics for optimizing management of diabetes. World J Diabetes 2015;6:17-29.
 
60. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986.
 
61. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853.
 
62. Rohlfing CL, Wiedmeyer HM, Little RR, et al. Defining the relationship between plasma glucose and HbA(1c): analysis of glucose profiles and HbA(1c) in the Diabetes Control and Complications Trial. Diabetes Care 2002;25:275-278.