Commentary on Inconsistent Hb A1c Results Observed after Implementing a New Method

This case describes how an inconsistent Hb A1c result disclosed the presence of a rare hemoglobin variant after a change of method. The variant was not seen and did not affect Hb A1c with the previous method (HPLC), but it was seen and did affect Hb A1c with the new method (capillary electrophoresis). This seems a paradox as capillary electrophoresis has a higher resolution than HPLC. Hemoglobin variants can affect the reliability of Hb A1c for (a) analytical and (b) physiological reasons. Measured Hb A1c is derived from the ratio of measured glycated and non-glycated (total) hemoglobin. If, in the case of a variant, part of the glycated hemoglobin is not measured, Hb A1c will be too low, leading to undertreatment. If part of the non-glycated hemoglobin is not measured, then the opposite applies. The common variants S, C, E, and D do not interfere with most methods, but results can be different for rare variants, as has been reported for 49 variants (1), and is unknown for many of the more than 300 β-chain variants described in the literature (2). Hb A1c depends on the glucose levels over the last 3 months but also on the lifespan of red cells. In certain physiological conditions, such as (variant-related) anemia and kidney diseases, the red cell lifespan can be significantly altered leading to under- or overtreatment. Indications for the presence of a hemoglobin variant are (a) a different pattern when Hb A1c is measured with HPLC or capillary electrophoresis, (b) a discrepancy between Hb A1c and glucose, and (c) the observation of significant changes in Hb A1c after the analytical method has changed. Healthcare professionals should be alert for the presence of a variant. Once observed, the variant should be identified, and then analytical (incorrect measurement) and physiological (altered erythrocyte lifespan) factors should be considered to warrant correct interpretation of the reported Hb A1c. The corresponding author takes full responsibility that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Nobody who qualifies for authorship has been omitted from the list. Cas Weykamp (Conceptualization-Lead, Data curation-Equal, Formal analysis-Equal, Investigation-Equal, Methodology-Equal, Validation-Equal, Writing—original draft-Lead, Writing—review & editing-Equal), and Carla Siebelder (Conceptualization-Supporting, Data curation-Equal, Formal analysis-Equal, Investigation-Equal, Methodology-Equal, Validation-Equal, Writing—original draft-Supporting, Writing—review & editing-Equal) No authors declared any potential conflicts of interest.