The Sickle Effect: The Silent Titan Affecting Glycated Hemoglobin Reliability

Abstract

Hemoglobin A1c (HbA1c) is a popular invaluable tool in the diagnosis of Type 2 diabetes for red blood cells (RBCs) with a lifespan of 120 days; however, many factors, including hemoglobinopathies, affect its accuracy. Sickle cell trait, primarily a benign medical condition, is a point mutation in only one of two beta-globin genes on chromosome 11. We performed a traditional review to identify how the sickle cell trait (SCT) affects the interpretation of HbA1c and the further implications it may have on the diagnosis and management of Type 2 diabetes. A literature search was performed using PubMed®/MEDLINE® and Google Scholar with formulated keywords (sickle cell trait, HbAS, HbA1c, glycosylated hemoglobin, diabetes, RBC lifespan, race, and genetics), with the majority of results being mainly observational studies. The National Glycohemoglobin Standardization Program (NGSP) is responsible for standardizing HbA1c results and also highlights factors that can interfere with HbA1c, including hemoglobin variants. Studies that utilize only an NGSP-certified method with no clinically significant interference by HbS in patients with and without SCT showed contrasting results. Additional studies showed that persons of African ancestry, the group to which the majority of SCT patients belong, have a higher HbA1c than non-Hispanic whites (NHWs), just based on race, and a greater probability of having glucose-6-phosphate dehydrogenase (G6PD) deficiency, which lowers HbA1c. The most extensive study investigating the RBC lifespan in SCT patients showed a reduction in the cell lifespan compared to normal patients; however, other smaller studies were contradictory. Our study highlights the need for hemoglobinopathy detection before or during HbA1c measurement in populations with a high degree of African ancestry and the importance of patient notification. It also shows that SCT affects the accuracy of HbA1c, through its likely reduction of RBC lifespan and its increased association with African ancestry and G6PD deficiency. This review recommends that for SCT patients with potential Type 2 diabetes, HbA1c should be used in combination with another diagnostic tool such as fasting blood glucose, fructosamine, or glycated albumin to decrease the chances of a missed diagnosis.

Serum fructosamine and glycemic status in the presence of the sickle cell mutation

“…In a cohort of Black patients, the genetic variant (rs334) responsible for SCT was associated with higher HbA1c despite adjusting for confounders such as BMI, waist circumference and principal component factors [10,19]. Additionally, a systematic review to assess how SCT affects the interpretation of HbA1c showed conflicting results across studies, with some studies reporting lower levels of HbA1c and others reporting higher or same levels in carriers of SCT compared to non-carriers [10]. There is also evidence that high levels of HbA1c are associated with iron deficiency which we did not measure in this study [20].…”

“…While the reasons for this discrepancy are unknown, our study is one of several studies to report higher levels of HbA1c in carriers of SCT. In a cohort of Black patients, the genetic variant (rs334) responsible for SCT was associated with higher HbA1c despite adjusting for confounders such as BMI, waist circumference and principal component factors [10,19]. Additionally, a systematic review to assess how SCT affects the interpretation of HbA1c showed conflicting results across studies, with some studies reporting lower levels of HbA1c and others reporting higher or same levels in carriers of SCT compared to non-carriers [10].…”

“…However, it may not be optimal in populations with high prevalence of hemoglobinopathies [8].The presence of HbS can lead to inaccurate HbA1c measurements which consequently may lead to inacurrate estimation of past glycemia in individuals with SCT or carriers [6,9,10]. Despite the use of National Glycohemoglobin Standardization Program (NGSP)-certified devices whose assays are not affected by HbS interference, the relationship between HbA1c and SCT status is inconsistent across studies [10]. The accuracy of HbA1c may also be affected by other factors including co-existence of other hemoglobinophies (e.g.…”

“…The accuracy of HbA1c may also be affected by other factors including co-existence of other hemoglobinophies (e.g. alpha-thalassemia, glucose 6-phosphate dehydrogenase deficiency (G6PD) [10]. Thus, there is a need for alternative tests that overcome these limitations.…”

HbA1c performs well in monitoring glucose control even in populations with high prevalence of medical conditions that may alter its reliability: the OPTIMAL observational multicenter study

“…21 Second, while comorbidities that affect red cell life will alter the accuracy of any HbA1c method, the predominant hemoglobinopathy in our study population was HbAS (sickle cell) trait, and previous research has been conflicting as to whether this meaningfully alters red cell lifespan. 29 …”