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Functional Blood Chemistry Manual

Hemoglobin A1c

Marker Name: Hemoglobin A1c


Laboratory reference range: 4.8–5.6%

Functional reference range: 4.6–5.3%


Hemoglobin A1c is a subtype of hemoglobin that is non-enzymatically glycosylated by circulating glucose. The action of hemoglobin A1c is indistinguishable from other subtypes of hemoglobin; however, measuring levels of hemoglobin A1c in the blood is useful for estimating average levels of blood glucose over a three-month period. Therefore, hemoglobin A1c can be used to inform diabetes mellitus diagnosis and monitor the efficacy of exercise, dietary management, and treatment of diabetes.1

Hemoglobin in newly formed red blood cells contains negligible amounts of covalently bound glucose, yet glucose can freely permeate the cell membranes of red blood cells.1 Thus, glucose can freely interact with hemoglobin molecules within red blood cells. The N-terminus of the beta chain of hemoglobin non-covalently interacts with glucose, then proceeds through a Schiff base and Amadori rearrangement to form a covalent bond between glucose and hemoglobin.2 Over the following weeks, these Amadori rearrangement products transition to intermediate and advanced glycosylation endproducts.3,4 These reactions are irreversible and persist for the life of the red blood cell.

This non-enzymatic covalent bonding of glucose and hemoglobin takes place in a dose-dependent fashion, such that greater amounts of circulating glucose correspond to higher levels of glycosylated hemoglobin, or hemoglobin A1c. The typical lifespan of a red blood cell is 120 days, with approximately 1 percent of the entire erythrocyte population degrading and replenishing itself daily.1,5 Taken together, this indicates that any spot assessment of hemoglobin A1c level in the blood provides an average circulating glucose level for the previous three months.2

Estimated average glucose (eAC) is calculated from the measured hemoglobin A1c level and is included in most laboratory reports with hemoglobin A1c.6 While hemoglobin A1c reflects mean blood glucose over the previous 120 days, commercially available assays of glycated hemoglobin actually correlate best with mean blood glucose over the previous eight to 12 weeks.2,6 In other words, blood glucose levels within the past 30 to 90 days have a greater effect on the hemoglobin A1c measurement than those in the preceding months.1,7

Importantly, modern hemoglobin A1c assay equipment can vary as much as 0.5 percent from the actual value in the blood.8 Moreover, there appears to be a high degree of inter- and intra-personal variability in hemoglobin A1c measurements over time.7 Finally, since the hemoglobin A1c assay specifically quantifies a fraction of hemoglobin A, people with a predominance of other forms of hemoglobin (e.g., HbF, HbS, HbE, HbD, Hb Fukuoka, Hb Philadelphia, and Hb Raleigh) may have reported hemoglobin A1c levels that are difficult to interpret clinically.9,10

Under normal circumstances, an elevated hemoglobin A1c reflects higher-than-normal circulating glucose levels for the preceding three months.5 This is consistent with a diagnosis of diabetes mellitus. Various nonwhite racial and ethnic groups may have higher hemoglobin A1c levels after adjusting for many factors that may affect glycemia. Therefore, the normal range of hemoglobin A1c may need to be interpreted in context of the patient’s ethnicity or race.1,11 Any circumstance that increases the lifespan of red blood cells such as polycythemia or splenectomy can artificially elevate hemoglobin A1c levels.

Other than chronic hypoglycemia, the clinical significance of an abnormally low hemoglobin A1c level is unclear. Any condition that shortens the lifespan of a red blood cell can result in a lower-than-expected level of hemoglobin A1c. For example, glucose-6-phosphate dehydrogenase deficiency, sickle cell disease, thalassemia, pernicious anemia, and hemolytic anemia can change the rate at which hemoglobin and red blood cells are produced and removed from circulation, i.e., the red blood cell turnover rate.12 Any condition that increases red blood cell turnover rate and, by extension, increases the production of new red blood cells, will make hemoglobin A1c underestimate the true level of circulating glucose. The same is true for blood donation, hemolysis, or hemorrhage within the three months prior to the hemoglobin A1c test. Some studies suggest that low A1c (< 5.0 percent) may be interpreted as a general marker of poor health and may occur in disease states such as cancer.13

If there is reason to believe that hemoglobin A1c may be an inaccurate measure of average circulating glucose levels, a fructosamine assay can be used to determine intermediate-term blood glucose averages (previous two to three weeks).7



High in:1,6,10,11

  • Diabetes mellitus
  • Polycythemia
  • Post-splenectomy
  • Certain variant forms of hemoglobin
  • Non-white ethnicity (may be normal)

Low in:6,10,13-16

  • Chronic hypoglycemia
  • Anemia
    • Iron deficiency
    • Vitamin B12 deficiency
    • Folate deficiency
    • Autoimmune hemolytic anemia
  • Blood transfusion
  • Blood donation
  • Chronic renal failure
  • Hemolysis
  • Hemorrhage
  • Certain variant forms of hemoglobin
  • Cancer


High in:

  • Impaired glucose tolerance and insulin resistance
  • Non-pathological (A1c may be high or high-normal in individuals with increased red blood cell survival time)

Low in:

  • General marker of ill health


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