Glycohemoglobin (HbA1c): Definition and Clinical Significance
Glycohemoglobin (HbA1c) is a form of hemoglobin that results from the non-enzymatic glycation of hemoglobin molecules, specifically when glucose attaches to the N-terminal valine of the hemoglobin β-chain, forming a stable adduct that reflects average blood glucose levels over the previous 2-3 months. 1
What is Glycohemoglobin?
- Glycohemoglobin (most commonly referred to as hemoglobin A1c or HbA1c) forms when glucose in the bloodstream attaches to hemoglobin in red blood cells through a non-enzymatic process called glycation 1
- The specific chemical structure is a hemoglobin molecule with a stable glucose adduct (N-1-deoxyfructosylhemoglobin) attached to the NH2-terminal valine of the hemoglobin β-chain 1
- This glycation process occurs continuously throughout the 120-day lifespan of red blood cells, with the rate of formation directly proportional to the ambient glucose concentration 1
Clinical Significance and Interpretation
- HbA1c serves as the gold standard for long-term glycemic monitoring in diabetes management, reflecting average blood glucose levels over approximately 2-3 months 1
- The most recent month's blood glucose levels contribute approximately 50% to the HbA1c value, with 25% from 30-60 days prior and 25% from 60-120 days prior 1
- An HbA1c of 6% corresponds to a mean plasma glucose level of approximately 135 mg/dL (7.5 mmol/L), with each 1% increase in HbA1c corresponding to an increase of about 35 mg/dL (2 mmol/L) in mean plasma glucose 1
- HbA1c has been strongly linked to diabetes complications and serves as a primary tool for assessing glycemic status in both clinical practice and research 1
Standardization and Measurement
- HbA1c measurement has been standardized internationally, with the National Glycohemoglobin Standardization Program (NGSP) in the U.S. ensuring that 99% of laboratories use certified assays traceable to the Diabetes Control and Complications Trial reference 1
- The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) established a reference measurement system for global standardization 1
- Common measurement methods include:
Clinical Applications and Monitoring Frequency
- For people with diabetes, HbA1c should be assessed at least twice a year, and more frequently (every 3 months) for those not meeting glycemic goals, experiencing treatment changes, or having frequent hypoglycemia/hyperglycemia 1
- HbA1c can be used as a supplementary criterion for diabetes diagnosis 1
- Point-of-care HbA1c testing can provide timely opportunities for treatment adjustments during healthcare appointments 1
Limitations and Confounding Factors
- HbA1c may be inaccurate in conditions affecting red blood cell turnover, such as:
- Hemolytic anemia and other anemias
- Glucose-6-phosphate dehydrogenase deficiency
- Recent blood transfusions
- Use of drugs stimulating erythropoiesis
- End-stage kidney disease
- Pregnancy 1
- Hemoglobin variants (particularly hemoglobin S or C) can interfere with HbA1c measurements, potentially causing spuriously high or low results 1
- HbA1c cannot be measured in individuals with homozygous hemoglobin variants like sickle cell disease (HbSS) or HbEE 1
- HbA1c does not provide information about glycemic variability or hypoglycemic events 1, 2
Alternative Glycemic Monitoring Methods
- When HbA1c cannot be reliably measured, alternative methods include:
- CGM provides additional metrics beyond average glucose, including time in range, time above range, and time below range, offering a more comprehensive view of glycemic control 1, 2
By understanding what glycohemoglobin represents and its clinical applications, healthcare providers can better monitor diabetes control and adjust treatment plans to improve patient outcomes and reduce the risk of diabetes-related complications.