Background: Glycated hemoglobin (HbA1c) is the internationally recognized gold standard to assess long-term glycemic control in patients with diabetes mellitus. However, its efficacy is fundamentally undermined in thalassemia syndromes, which are one of the most prevalent inherited hemoglobin disorders worldwide due to ineffective erythropoiesis, altered red blood cell biology, chronic hemolysis, reduced red blood cell (RBC) lifespan, and confounding factors related to transfusion. Despite precise glycemic monitoring being clinically time-sensitive and urgent for thalassemia patients, who have significantly raised risk of endocrine disorders such as diabetes mellitus, a universally recognized clinical framework for addressing this diagnostic challenge remains absent.
Objectives: This comprehensive review critically analyzes the mechanisms through which different thalassemia subtypes, including α-thalassemia, β-thalassemia major (transfusion-dependent), β-thalassemia intermedia (non-transfusion-dependent), and compound hemoglobinopathies, influence HbA1c measurement across accepted analytical system. This research further assesses the evidence base for alternative glycemic indicators in thalassemia populations and presents evidence-informed clinical recommendations.
Methods: A narrative systematic review was performed using PubMed/MEDLINE, the Cochrane Library, Embase, and Google Scholar to identify peer-reviewed publications from 2000 to 2025, with particular emphasis on those published post-2015. The search terms used were thalassemia, hemoglobin A1c, glycated hemoglobin, HbA1c interference, fructosamine, glycated albumin, continuous glucose monitoring, hemoglobinopathy, diabetes mellitus, iron overload, and erythrocyte lifespan.
Results: The alpha-thalassemia trait does not substantially affect HbA1c assessment in standard high-performance liquid chromatography (HPLC) techniques. Conversely, HbH disease causes significant measurement errors in cation-exchange HPLC systems due to peak co-elution. The β-thalassemia trait is linked to a statistically significant, yet clinically minor, decrease in HbA1c levels, primarily resulting from a decrease in hemoglobin concentration. Transfusion-dependent β-thalassemia compromises the accuracy of HbA1c measurement through several procedures including Glycated albumin, fructosamine, and continuous glucose monitoring (CGM) offer clinically relevant, although not flawless, alternatives for glycemic evaluation in thalassemia settings.
Conclusion: Clinicians treating thalassemia patients with suspected or co-existing diabetes must exercise caution when interpreting HbA1c results, identify method-specific analytical limits, and consistently use alternative glycemic monitoring strategies. Efficient multidisciplinary coordination among diabetologists, hematologists, and clinical laboratorians is essential for achieving optimal glycemic surveillance and reducing the risk of both under- and over-treatment of diabetes among patients with thalassemia.