Changes in hemoglobin can affect Hemoglobin A1C (HbA1C) results, as can other factors.
HbA1C has been used clinically since the 1970s and is currently a standard tool for diagnosing and monitoring diabetes mellitus. It is a minor component of hemoglobin, the iron-containing compound in red blood cells that binds oxygen and facilitates oxygenation throughout the body. Both hemoglobin and glucose are found in relatively high amounts in RBCs and over time, some glucose will bind nonenzymatically with hemoglobin, producing hemoglobin A1C. The more glucose that binds to hemoglobin, the higher the HbA1C. In fact, the rate of HbA1C production parallels the average glucose levels within the RBC (Radin 2014).
Hemoglobin levels themselves can affect HbA1C levels as HbA1C is calculated as the ratio of glycated hemoglobin to total hemoglobin. One cross-sectional analysis of 87,284 individuals without anemia or diabetes found that a lower hemoglobin level was significantly associated with a higher HbA1C, even when fasting glucose was not within the diabetic range (Bae 2014)
Additional factors that falsely elevate or reduce HbA1C (Eyth 2023, Radin 2014):
Falsely elevated HbA1C:
- Anemia due to a deficiency of iron, B12, or folate
- Anemia associated with infection or tumors
- Chronic ingestion of alcohol, salicylate, and opioids
- Extended RBC lifespan
- Hemoglobinopathies, e.g., thalassemia
- Hyperbilirubinemia
- Lead poisoning
- Medication, including immunosuppressants, protease inhibitors
- Severe hypertriglyceridemia
- Slower RBC turnover
- Uremia
Falsely decreased A1C:
- Blood loss
- Chronic kidney failure
- Erythropoietin
- Hemoglobin variants
- Hemolytic anemia due to an increase in younger, less exposed RBCs (Bae 2014)
- High altitude
- Iron supplementation
- Pregnancy
- RBC transfusion
- Shortened RBC lifespan
- Sickle cell anemia, though effects may vary (Klonoff 2020)
- Spherocytosis
- Splenomegaly
- Vitamin E ingestion
- NOTE: Ascorbic acid may falsely decrease or elevate HbA1C, depending on the laboratory method used for evaluation.
Alternative biomarkers for assessing glycemic control can be evaluated if the use of HbA1C is limited (Radin 2014):
- 1,5 Anhydroglucitol (1.5-AG), which negatively correlates with glycemic control, where higher levels mean less glycemic control. 1,5-AG may be confounded by renal failure, pregnancy, or chronic liver disease.
- Continuous glucose monitoring, which measures interstitial glucose levels and can identify glycemic fluctuations but may be confounded by wide variations in glucose levels. Results may also be confounded by acetaminophen and ascorbic acid ingestion.
- Fructosamine, which reflects short-term glycemic control by measuring glycated proteins, primarily albumin, in the blood. Changes in serum albumin, uremia, lipemia, ascorbic acid, liver disease, and nephrotic syndrome may confound fructosamine results.
- Glycated albumin can also be measured and, like fructosamine, reflects glycemic control over the past 14-21 days. It can also be confounded by changes in serum albumin.
Read more at the ODX Research Blog
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References
Bae, Ji Cheol et al. “Hemoglobin A1c values are affected by hemoglobin level and gender in non-anemic Koreans.” Journal of diabetes investigation vol. 5,1 (2014): 60-5. doi:10.1111/jdi.12123
Eyth, Emily. and Roopa Naik. “Hemoglobin A1C.” StatPearls, StatPearls Publishing, 13 March 2023.
Klonoff, David C. “Hemoglobinopathies and Hemoglobin A1c in Diabetes Mellitus.” Journal of diabetes science and technology vol. 14,1 (2020): 3-7. doi:10.1177/1932296819841698
Radin, Michael S. “Pitfalls in hemoglobin A1c measurement: when results may be misleading.” Journal of general internal medicine vol. 29,2 (2014): 388-94. doi:10.1007/s11606-013-2595-x
Sakamoto, Nobuaki et al. “Associations of anemia and hemoglobin with hemoglobin A1c among non-diabetic workers in Japan.” Journal of diabetes investigation vol. 11,3 (2020): 719-725. doi:10.1111/jdi.13159