Labile Hemoglobin A_1c (LHbA_1c): From analytical interference to clinically valuable biomarker

Labile hemoglobin A_1c (LHbA_1c), the reversible Schiff base intermediate formed during early hemoglobin glycation, has long been regarded solely as an analytical interference requiring elimination for accurate HbA_1c measurement. This review synthesizes research from 2016 to 2024, examining the biochemical foundations, measurement methodologies, and emerging clinical applications of LHbA_1c. Unlike stable HbA_1c, which reflects average glycemia over 2-3 months, LHbA_1c correlates with glycemic levels over hours to days, thereby bridging a critical information gap in diabetes assessment. Recent studies demonstrate the value of LHbA_1c in detecting acute glycemic excursions, screening for hemoglobin variants, identifying preanalytical errors, and providing insights into the "glycation gap" through the LHbA_1c/HbA_1c ratio. Mathematical modeling has elucidated the kinetic relationships among glucose, LHbA_1c, and stable HbA_1c, enabling quantitative predictions of LHbA_1c behavior under various clinical scenarios. The LHbA_1c/HbA_1c ratio has emerged as a particularly versatile parameter, with values outside the reference range identifying approximately 15% of samples in which HbA_1c may not reflect expected glycemia. We argue that LHbA_1c, long dismissed as mere interference, deserves recognition as a clinically valuable parameter that, when interpreted alongside established glycemic markers, can enhance precision diabetes care. However, standardization efforts and prospective outcome studies remain essential before widespread clinical adoption.