Abstract / Summary
Non-transfusion-dependent thalassemia (NTDT) presents a clinical paradox: Patients develop significant iron overload despite minimal transfusion exposure. Iron accumulation occurs primarily through enhanced gastrointestinal absorption driven by a dysregulated hepcidin–ferroportin axis; chronic anemia and ineffective erythropoiesis raise erythroferrone, which suppresses hepatic hepcidin and permits unrestricted intestinal iron absorption. The result is progressive multi-organ iron deposition, predominantly hepatic, with cardiac, endocrine, skeletal, and renal involvement. A liver iron concentration (LIC) exceeding 5 mg/g dry weight increases the risk of thrombosis, pulmonary hypertension, endocrinopathy, and hepatocellular carcinoma. Magnetic resonance imaging (MRI) is the reference standard for organ-specific iron quantification, but its limited availability across the high-prevalence Mediterranean, Middle-Eastern, and South-Asian regions means serum ferritin-despite well-recognized limitations-remains the practical monitoring tool for most patients; this MRI-versus-ferritin trade-off is a central, unresolved controversy in NTDT care. Deferasirox is the only chelator approved for NTDT and the agent with the strongest randomized evidence, whereas data for deferoxamine and deferiprone in NTDT remain largely extrapolated from transfusion-dependent disease. Emerging disease-modifying options-most notably luspatercept, which raised hemoglobin and lowered LIC in the phase 2 BEYOND trial-alongside hepcidin-directed and gene-based strategies, may reshape management. Understanding NTDT’s distinct pathophysiology, applying resource-stratified monitoring, and initiating chelation at validated thresholds are essential to prevent irreversible complications.