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Hemoglobin A1c Testing 

  • Author: Gary L Horowitz, MD; Chief Editor: Thomas M Wheeler, MD  more...
 
Updated: Sep 15, 2015
 

Reference Interval

The reference range for healthy adults is 4.8–5.9%.

The decision limits for nonpregnant adults, according to the American Diabetes Association, are as follows:

  • For patients with diabetes mellitus, the goal of therapy is less than 7.0%.
  • The diagnostic criterion for diabetes is greater than or equal to 6.5% NGSP units.
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Interpretation

Hemoglobin A1c (glycated hemoglobin) reflects the average blood glucose concentration over the course of the RBC lifespan, roughly 120 days in normal individuals.

It provides different, and complementary, information to a single glucose concentration. Some patients may have near normal fasting glucose values but very high postprandial levels, and others may have elevated fasting levels with only moderately elevated postprandial levels. Hemoglobin A1c provides information comparable to what might be provided by having frequent glucose values throughout the day over the course of 3 months.[1, 2, 3]

Thus, elevated values give a sense of the degree of overall glucose control in patients with diabetes mellitus. Intensive glucose control in diabetic patients, reflected in lower hemoglobin A1c values, has been shown to "delay the onset and slow the progression of diabetic retinopathy, nephropathy, and neuropathy."[4] The goal of therapy is to attain a value of less than 7.0% (while minimizing hypoglycemic episodes).

Hemoglobin A1c should be monitored regularly in diabetic patients.

As of January, 2010, the American Diabetes Association began promoting the use of hemoglobin A1c as the preferred diagnostic test for diabetes mellitus. Among its advantages over fasting glucose values (or 2-hour glucose values during an oral glucose tolerance test) is that samples can be drawn at any time and need no special handling (whereas ongoing glycolysis can falsely lower glucose values).[5, 6]

Most laboratories report a calculated eAG (estimated average glucose) along with every measured hemoglobin A1c, which is designed to facilitate communication with patients as well as to help clinicians appreciate the degree of hyperglycemia the A1c represents.

Note that falsely low values can occur in patients whose RBC lifespan is shorter than normal (eg, hemolytic anemia, some hemoglobinopathies) as well as in patients who have received transfusions from nondiabetic patients.

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Background

Description

Hemoglobin A1c is a specific fraction of hemoglobin A found in healthy individuals as well as individuals with diabetes mellitus. It is formed when the N-terminal valine of the beta chain of hemoglobin A is modified by the addition of a sugar moiety. This process is nonenyzmatic, so the term glycation is preferred to the term glycosylation, although the latter is commonly used. Once formed, hemoglobin A1c is stable. As a result, the hemoglobin A1c level reflects the average blood glucose level over the course of the red blood cell’s lifespan, roughly 120 days.

A landmark paper showed convincingly that intensive control of diabetes (ie, maintaining near-normal concentrations of glucose throughout the day, reflected in lower A1c levels) "delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy."[4] Fingerstick glucose measurements by patients remain the mainstay of diabetes management for adjusting daily insulin doses, but this study established the importance of ongoing, periodic A1c measurements to monitor compliance and efficacy of therapy.

For example, in patients whose records of fingerstick glucose are incomplete, reflecting good control in the week prior to a physician’s visit, a hemoglobin A1c value of 6.8% is reassuring, whereas a value of 9.6% indicates that glucose levels were probably much higher in the preceding weeks.

A limitation of hemoglobin A1c is that it does not provide any indication of the changes in glucose concentrations throughout the day, for which frequent glucose measurements are needed. In the image below, both patients would have the same A1c level, but the patient in blue has far fewer highs and lows, and represents a much better degree of control.

Same average blood glucose. Same average blood glucose.

The extent of hemoglobin glycation is related not only to the glucose concentration in blood but also to the average RBC lifespan. In patients with shortened average lifespans, the hemoglobin A1c level can be misleading (falsely low).[7, 8] Similarly, in patients who have recently been transfused, the hemoglobin A1c level will reflect, to some extent, the donors’ glucose levels.

With the relatively recent introduction of a reference method for the measurement of hemoglobin A1c,[9] it became apparent that the methods used historically, though very highly correlated to the true hemoglobin A1c concentrations, included chemical species other than A1c; in fact, the values were roughly 2 units higher than the true value (ie, a value of 7% was closer to 5% in conventional units).[10] Different countries have approached this problem in different ways. Many countries have adopted totally new units (mmol/mol), but the United States has decided to continue to report conventional units (%).[10] The relationship between the 2 sets of units is as follows:

IFCC-A1c (mmol/mol) = [NGSP-A1c (%) – 2.15] x 10.929

However, in an effort to smooth the transition to the new units, as well as to help both physicians and patients appreciate the clinical context of various hemoglobin A1c levels, many laboratories are now reporting eAG (estimated average glucose) along with every hemoglobin A1c level.[11] Although the correlation is far from perfect and the use of this parameter has been somewhat controversial,[12] it has received support from many major organizations, including the American Diabetes Association, the American Association for Clinical Chemistry, and the College of American Pathologists. The equation to calculate eAG (in mg/dL) from hemoglobin A1c (in %) is as follows:

eAG (mg/dL) = 28.7 x NGSP-A1c (%) – 46.7

On balance, clearly, reporting an eAG of 226 mg/dL in addition to an A1c of 9.5% can enhance patient care.

In addition to its use in monitoring therapy in patients with diabetes, hemoglobin A1c has recently been touted as having a role in screening for diabetes. Indeed, as of January, 2010, the American Diabetes Association has promoted the assay in its practice guidelines as the preferred test (using a criterion of ≥6.5% NGSP units).[13]

A short note is in order with respect to hemoglobin variants. As long as one normal beta chain exists (eg, sickle cell trait, or hemoglobin C trait), one can measure hemoglobin A1c. Even in some cases with no normal beta chains (eg, sickle cell disease, or SC disease), the abnormal beta chains are glycated and can be measured by some methods. In other cases (eg, hereditary persistence of fetal hemoglobin), no beta chains exist to glycate, so glycated hemoglobin is not present. In all of these cases, though, the RBC lifespan issue may take precedence over the ability (or the lack thereof) to measure glycated hemoglobin and must be kept in mind. As noted earlier, regular fingerstick glucose monitoring throughout the course of the day can provide reliable data in these situations.[7]

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Contributor Information and Disclosures
Author

Gary L Horowitz, MD Associate Professor of Pathology, Harvard Medical School; Director of Clinical Chemistry Laboratory, Department of Pathology, Division of Laboratory Medicine, Beth Israel Deaconess Medical Center

Gary L Horowitz, MD is a member of the following medical societies: College of American Pathologists, Massachusetts Medical Society, American Association for Clinical Chemistry, Massachusetts Society of Pathologists

Disclosure: Nothing to disclose.

Chief Editor

Thomas M Wheeler, MD Chairman, Department of Pathology and Immunology, WL Moody, Jr, Professor of Pathology, Professor of Urology, Baylor College of Medicine

Thomas M Wheeler, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American Medical Association, American Society for Clinical Pathology, American Society of Cytopathology, American Thyroid Association, American Urological Association, College of American Pathologists, United States and Canadian Academy of Pathology, International Society of Urological Pathology, Harris County Medical Society

Disclosure: Received stock from PathXL for medical advisory board. for: PathXL, Inc.

References
  1. Ensenauer R, Brandlhuber L, Burgmann M, Sobotzki C, Zwafink C, Anzill S, et al. Obese Nondiabetic Pregnancies and High Maternal Glycated Hemoglobin at Delivery as an Indicator of Offspring and Maternal Postpartum Risk: The Prospective PEACHES Mother-Child Cohort. Clin Chem. 2015 Aug 11. [Medline].

  2. Mastronardi CA, Whittle B, Tunningley R, Neeman T, Paz-Filho G. The use of dried blood spot sampling for the measurement of HbA1c: a cross-sectional study. BMC Clin Pathol. 2015. 15:13. [Medline].

  3. Pivovarov R, Albers DJ, Hripcsak G, Sepulveda JL, Elhadad N. Temporal trends of hemoglobin A1c testing. J Am Med Inform Assoc. 2014 Nov-Dec. 21 (6):1038-44. [Medline].

  4. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progressions of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993. 329:977-986.

  5. Greenwood DA, Blozis SA, Young HM, Nesbitt TS, Quinn CC. Overcoming Clinical Inertia: A Randomized Clinical Trial of a Telehealth Remote Monitoring Intervention Using Paired Glucose Testing in Adults With Type 2 Diabetes. J Med Internet Res. 2015 Jul 21. 17 (7):e178. [Medline].

  6. Chan CL, Pyle L, Newnes L, Nadeau KJ, Zeitler PS, Kelsey MM. Continuous glucose monitoring and its relationship to hemoglobin A1c and oral glucose tolerance testing in obese and prediabetic youth. J Clin Endocrinol Metab. 2015 Mar. 100 (3):902-10. [Medline].

  7. Sacks DB. Hemoglobin variants and hemoglobin A1c analysis: problem solved?. Clin Chem. 2003 Aug. 49(8):1245-7. [Medline].

  8. Wang Y, Beckwith B, Smith C, Horowitz G. Misleading glycated hemoglobin results in a patient with hemoglobin SC disease. Clin Chem. 2007 Jul. 53(7):1394-5. [Medline].

  9. Jeppsson JO, Kobold U, Barr J, Finke A, Hoelzel W, Hoshino T. Approved IFCC reference method for the measurement of HbA1c in human blood. Clin Chem Lab Med. 2002 Jan. 40(1):78-89. [Medline].

  10. Kahn R, Fonseca V. Translating the A1C Assay. Diabetes Care. 2008 Aug. 31(8):1704-7. [Medline].

  11. Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ. Translating the A1C assay into estimated average glucose values. Diabetes Care. 2008 Aug. 31(8):1473-8. [Medline].

  12. Hempe JM, Soros AA, Chalew SA. Estimated average glucose and self-monitored mean blood glucose are discordant estimates of glycemic control. Diabetes Care. 2010 Jul. 33(7):1449-51. [Medline]. [Full Text].

  13. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010 Jan. 33 Suppl 1:S62-9. [Medline].

  14. Jaisson S, Leroy N, Guillard E, Desmons A, Gillery P. Analytical performances of the D-100TM hemoglobin testing system (Bio-Rad) for HbA1c assay. Clin Chem Lab Med. 2015 May 23. [Medline].

 
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Same average blood glucose.
 
 
 
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