When HbA1c looks “too high”: two practical clarifications for endocrine screening in chelated β-thalassemia major

Dear Editor,

I read with interest the case–control study by Al-Sanabra et al. ¹ describing endocrine complications among transfusion-dependent β-thalassemia major patients receiving iron chelation therapy. The manuscript is clinically useful because it reflects routine practice: mixed chelation regimens, frequent splenectomy, and a laboratory panel spanning thyroid function, glycemic status, and bone/mineral metabolism. In settings where clinicians often need pragmatic screening strategies rather than idealized protocols, the authors’ real-world cohort offers a valuable snapshot.

The most striking signal is the glycemic profile when dysglycemia is defined by HbA1c. The authors report that 51.7% of patients had HbA1c ⩾6.5%, while 38.3% had impaired fasting glucose. ¹ This discordance could reflect clinically meaningful postprandial excursions, yet in transfusion-dependent disorders HbA1c is inherently vulnerable to distortion because it depends on erythrocyte lifespan and the age distribution of circulating red cells. Regular transfusion, hemolysis, and variable marrow activity can shift HbA1c upward or downward independent of mean glucose. Diabetes diagnostic guidance explicitly notes that factors affecting hemoglobin concentrations or erythrocyte turnover (including hemoglobinopathies and related conditions) can alter A1c interpretation and that plasma glucose-based criteria may be preferred in such settings. ² Thalassemia-specific recommendations likewise emphasize fasting glucose and oral glucose tolerance testing (OGTT), given that early dysglycemia may be predominantly postchallenge. ³

Because the manuscript’s HbA1c-defined prevalence is unusually high, a small amount of measurement context would make the central finding easier to interpret and safer to apply. Reporting the HbA1c assay platform (and whether it is susceptible to hemoglobin variants), the timing of blood sampling relative to the last transfusion, and whether phlebotomy occurred within a standardized transfusion window would help readers judge the direction and magnitude of potential bias. The dataset itself can also support a pragmatic sensitivity analysis without altering the study’s overall design: presenting a contingency table (and/or scatterplot) of fasting plasma glucose versus HbA1c categories would show whether HbA1c is systematically higher than fasting glucose in this cohort or whether the two measures identify different subgroups. If OGTT was not performed, explicitly stating that limitation is still clinically informative; if it was performed in any subset, even reporting the proportion meeting OGTT criteria would anchor the HbA1c findings to a thalassemia-appropriate reference standard. ³ Moreover, recent thalassemia literature suggests that fructosamine and glycated albumin may align with glycemia differently than HbA1c in transfusion-dependent patients.^4,5 A brief discussion of why HbA1c was selected as the primary diagnostic marker, and whether alternative markers were considered, would materially strengthen interpretation of the very high prevalence reported.

A related interpretive nuance is the reliance on ferritin as the principal iron-burden correlate for endocrine outcomes. Ferritin is practical and clinically meaningful, yet it is an imperfect proxy for tissue-specific iron deposition. Pancreatic iron has been linked to glucose dysregulation in thalassemia major and is not always mirrored by ferritin. ⁶ Given the high frequency of abnormal glycemic markers reported, ¹ explicitly noting that ferritin may under-represent pancreatic iron and that tissue iron measures (when available) can refine risk stratification would help readers avoid over-interpreting ferritin–glycemia correlations as direct mechanistic relationships.

The second bedside friction point is bone and mineral metabolism. The authors report that vitamin D levels were significantly lower in the thalassemia group than controls, with 71.7% deficient despite 43.3% receiving supplements; both hypo- and hyperparathyroidism were observed (each 11.7%), and ferritin was not significantly correlated with vitamin D or PTH. ¹ These data are clinically important, but “deficiency despite supplementation” is difficult to translate into practice without minimal operational detail. It would be helpful to specify the vitamin D metabolite measured (typically 25-hydroxyvitamin D), the deficiency threshold applied, and the supplement regimen (agent, dose, and whether supplementation reflected maintenance dosing vs repletion therapy). Contemporary expert guidance emphasizes that both 25-hydroxyvitamin D interpretation and supplementation recommendations are threshold- and context-dependent, which is precisely why reporting these details changes clinical meaning.^7,8 If supplementation was self-reported rather than prescribed, stating this explicitly would also help reconcile “supplement use” with the high deficiency prevalence.

Finally, labeling both hypo- and hyperparathyroidism in a cohort with widespread vitamin D deficiency raises the possibility that some “hyperparathyroidism” represents secondary hyperparathyroidism rather than primary gland pathology. Because management differs, readers would benefit from the biochemical criteria used for classification (PTH cutoffs, calcium and phosphate thresholds, whether albumin-corrected calcium was used, and how renal function was handled). Thalassemia-specific guidance underscores structured endocrine surveillance and careful interpretation of calcium–vitamin D–PTH patterns in the broader context of iron overload and comorbidities. ⁹ Even presenting the distribution of calcium and phosphate values alongside PTH by subgroup would make the phenotyping transparent and improve clinical actionability.

Overall, Al-Sanabra et al. ¹ provide a valuable snapshot of endocrine complications in a real-world chelated β-thalassemia major cohort. Briefly, contextualizing HbA1c measurement in transfusion-dependent patients and adding operational detail around vitamin D supplementation and parathyroid classification would strengthen clinical interpretability and reduce the risk that readers apply standard thresholds without appreciating predictable sources of misclassification.