EDUCATION :: HEMOGLOBIN A1C
A practical approach for your lab’s A1c testing & why your methodology matters
By Matthew C. Wagner, PhD A
lthough a hemoglobin A1c (HbA1c) measurement for evaluating patient glycemic control is well established for diagnosis and monitoring in patients with normal
hemoglobin, this does not speak to the sizeable minority (~7% worldwide1
) of patients with abnormal hemoglobin, for whom
the HbA1c test may not be appropriate. These patients possess hemoglobinopathies; genetic mutations affecting the structure (hemoglobin variants), and/or production (thalassemias) of he- moglobin A, resulting in assay interference, altered glycation dynamics, and/or changes to red blood cell (RBC) lifespan that result in a different relationship between the patient’s glycemic status and the measured HbA1c. Some patients with multiple mutations even lack any normal hemoglobin A (Hb A) and, hence, produce no HbA1c. The 2018 American Diabetes Association update to the Stan- dards of Medical Care in Diabetes first broached this topic with new recommendations, stating that recent evidence “describe[ed] potential limitations in A1c measurements due to hemoglobin variants, assay interference, and conditions associated with red blood cell turnover…”2
This update addresses the laboratory
phenomenon of occasional patient samples giving no A1c result, non-physiologic results, or clinically discordant values. However, these recommendations can be seen to place the laboratory in an unfortunate position: the lab may either rou-
30 | SEPTEMBER 2023
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tinely perform additional hemoglobinopathy testing on all A1c screening samples or produce results that may be incorrect for a portion of their patients, risking a diabetes misdiagnosis that significantly impacts these patients’ health. Here we will explore the impact of these recommendations, the reasoning behind them, and show how labs can mitigate the risk of invalid testing through careful A1c methodology choice. The intrinsic nature of Hb A in HbA1c formation makes it unsurprising that structural variants may interfere with detec- tion and measurement of the glycated form, either analytically (in methods unable to distinguish/separate the variant) or clinically (altering the formation or retention of the glycated hemoglobin) as noted in a previous issue of this publication.3 Very often manufacturers, supported by the NGSP,4
indicate
no analytical interference from common variants for their methods, but this does not speak to the clinical interference caused by the systemic effects of the variant. In explaining their new recommendations, the ADA noted a study in which Hb S trait (heterozygous Hb S) patients have a systemically lower HbA1c value by 0.3%, 5
found in African American populations6
even despite the noted higher A1c value where the variant is
common. A subsequent study found a similar shift in Hb E trait patients.7,8
While these shifts are relatively small, possibly only impacting cases on the borderline of diagnostic cutoff, there
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