First Reported Case of Hemoglobin Graz in the United States: Implications for Misleading Hemoglobin A_1c Results

Routine serum studies in a female patient with sustained prediabetic glycated hemoglobin A_1c (HbA_1c) levels, controlled on metformin, yielded an unexpected finding: an elevated HbA_1c value of ≥14.9% (≥139 mmol/mol) (normal reference range, <5.7% to <39 mmol/mol). Estimated average glucose (EAG) (normal reference range, <126 mg/dL to <7 mmol/L) is a linearly corresponding blood glucose value calculated from HbA_1c measurements that reflects the average glycemic status over the preceding 3 months. Caution must be used when the EAG provided by the HbA_1c does not align with blood glucose values obtained around the same period. Our patient carries a rare heterozygous pathogenic variant affecting the β subunit called hemoglobin Graz (Hb Graz), characterized by a histidine for leucine substitution, resulting in clinically silent Hb abnormalities. Individuals without diabetes carrying the Hb Graz pathogenic variant exhibit significantly higher HbA_1c values when analyzed by high-performance liquid chromatography. Alternative methods of quantifying glycemic control are suggested if the possibility of a confounding variable exists, such as when a HbA_1c-blood glucose mismatch occurs or unexplainable HbA_1c levels are detected.