The dilemma of glycemic control: Hemoglobin A1c or fructosamine as a measurement related to serum iron

Abstract

Abstract Hemoglobin A1c (HbA1c) is widely recognized as the gold standard biomarker for assessing long-term glycemic control in individuals with diabetes mellitus. However, its measurement is impacted by hematological factors that influence erythrocyte lifespan, hemoglobin composition, and plasma protein glycation. Notably, anemia, iron deficiency, and variations in hemoglobin variants can significantly alter HbA1c levels regardless of glycemic status, which makes clinical interpretation more difficult, especially in pediatric populations where such hematological disturbances are common. While published research highlights the impact of iron deficiency anemia, emerging evidence suggests that elevated serum iron and other hematologic parameters may also influence the reliability of HbA1c. Instead, fructosamine, which reflects shorter-term glycemic control, is less influenced by these variables and may serve as a useful proxy for glycemic control.In this prospective cohort study, we enrolled 93 pediatric patients (≤18 years) with type 1 and type 2 diabetes to investigate how hematologic parameters influence discrepancies between glucose estimates derived from HbA1c and fructosamine, a short-term glycemic marker affected to a lesser extent by hematological variables. We defined the discrepancy variable, X, as the difference between fructosamine-based and HbA1c-based estimated blood glucose (BG), calculated using formulas from Nathan et al. and Kang et al., respectively. Demographic data collected included age, gender, ethnicity (Hispanic/non-Hispanic), height, weight, BMI, BMI percentile, age at diabetes diagnosis, type of diabetes, and other comorbid conditions. Participants underwent comprehensive hematological profiling, including serum iron, hemoglobin (Hb), erythropoietin, hemoglobin F (HbF), reticulocyte count, and total iron-binding capacity (TIBC).Spearman's correlation revealed a significant positive association between serum iron and X (r = 0.312, p = 0.003). A multiple linear regression model which controlled for potential confounders, including BMI, diabetes type, Hb, erythropoietin, TIBC, and reticulocyte count, confirmed serum iron as the only independent variable that influenced X. Other variables, including hemoglobin (Hb), erythropoietin, hemoglobin F (HbF), reticulocyte count, and total iron-binding capacity (TIBC) showed no significant association with X, also indicating that these variables do not affect HbA1C or fructosamine.The implications of these findings are complex and varied. On one hand, they challenge established literature in the sense that only iron deficiency impairs HbA1c accuracy, emphasizing the necessity for clinicians to consider both low and high iron states when interpreting HbA1c results in pediatric diabetes management. These findings also challenge the traditional view that only iron deficiency affects HbA1c reliability, suggesting that elevated iron may also distort HbA1c—possibly through altered erythrocyte dynamics or glycation kinetics. This highlights the need for clinicians to consider both high and low iron states in interpreting HbA1c, particularly in pediatric patients with hematologic variability. Our results also support the use of fructosamine as a glycemic marker, especially in populations with underling hematologic abnormalities. Fructosamine levels remained the same across variations in multiple hematologic variables, highlighting the clinical value of using fructosamine adjunctively in pediatric diabetes management, particularly for patients with hematologic issues. Further research is necessary to clarify the mechanisms and pathways by which serum iron and other hematological factors influence hemoglobin glycation and erythrocyte interactions. Longitudinal studies with larger sample sizes could confirm these findings and alter clinical guidelines, which may ultimately improve the accuracy of diagnoses and increase positive outcomes in pediatric populations with similar hematological and endocrinological conditions.