By Charbel C. Khoury, MD
March 16, 2017
Hemoglobin A1c (HbA1c) testing is mainstay in screening, diagnosis, and management of diabetes mellitus.1 Since it measures the glycation of hemoglobin occurring over the entire lifespan of a red blood cell, the HbA1c is a very practical measure for clinicians and can be used to surmise the mean blood glucose over the previous 8 to 12 weeks.2 Nonetheless, several patient-specific factors such as iron/vitamin B12/folate deficiency anemias, chronic kidney disease, cirrhosis, and erythropoietin treatment have been known to affect the reliability of this assay, due to variations in red cell turnover.2 Moreover, HbA1c levels may vary with race. In fact, numerous studies have suggested that African Americans may have higher HbA1c levels than non-Hispanic whites with the same fasting and post-glucose load glucose levels.3
Sickle cell trait (SCT) alters red cell turnover, and affects around 8% to 10% of African Americans in the United States. A recent publication in JAMA examined the association between SCT and HbA1c.4 The authors retrospectively analyzed concurrent measures of fasting glucose and HbA1c as well as concurrent measures of two-hour postprandial glucose and HbA1c in 4620 African Americans enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study. At the same fasting, or two-hour plasma glucose concentration, the HbA1c concentration was 5.72% in the 367 individuals with SCT, vs. 6.01% in those without SCT. The lower HbA1c in SCT participants remained statistically significant in adjusted statistical models. Moreover, the HbA1c difference between SCT and non-SCT individuals was greater at higher levels of serum glucose.
When the authors used HbA1c to retrospectively screen a subset of nondiabetic participants for prediabetes or diabetes, defined using HbA1c values, they found that the prevalence of both conditions was significantly lower among participants with SCT vs those without SCT (3.8% vs 7.3% for diabetes and 29.2% vs 48.6% for prediabetes).4 When pre-diabetes or diabetes were diagnosed based on fasting or two-hour blood glucose levels, no difference in prevalence was seen between SCT and non-SCT, identifying the HbA1c result as the source of difference.
The assays used in this study, had been previously studied by the NGSP (formerly, the National Glycohemoglobin Standardization Program) which found no clinically significant interference of the sickled hemoglobin with the HbA1c measurements. Another explanation of these findings, is assuming the RBCs with SCT had a shorter lifespan than normal hemoglobin, this could result in less time available for glycation. However, studies on the lifespan of red cells with SCT have, so far, not been conclusive.4
All in all, these findings suggest that HbA1c may underestimate glycemia in black patients with SCT.4 While further studies are needed to confirm these findings, clinicians caring for African American patients should consider confirming their diagnosis with fasting and post-glucose load glucose levels, especially when their HbA1c is very close to the diagnostic threshold of 6.5%.3
- Standards of Medical Care in Diabetes-2017: Summary of Revisions. Diabetes Care 2017;40:S4-S5.
- Sandler CN, McDonnell ME. The role of hemoglobin A1c in the assessment of diabetes and cardiovascular risk. Cleve Clin J Med 2016;83:S4-S10.
- Bleyer AJ, Aloi JA. Sickle Cell Trait and Interpretation of Hemoglobin A1c Levels. JAMA 2017;317:481-2.
- Lacy ME, Wellenius GA, Sumner AE, et al. Association of Sickle Cell Trait With Hemoglobin A1c in African Americans. JAMA 2017;317:507-15.
Dr. Charbel C. Khoury is a renal fellow at the Brigham and Women’s and Massachusetts General Hospitals in Boston. He is also a Clinical Nutrition Fellow at the Brigham and Women’s Hospital.