In β-thalassemia major, organ damage in untransfused patients results from iron overload. However, even in transfusion-dependent patients, iron overload occurs. Which mechanism explains iron overload despite low dietary iron in transfused thalassemia patients?

• A Increased DMT-1 expression in intestinal enterocytes due to chronic hypoxia
• B Suppression of hepcidin by erythroferrone released from expanded erythroid progenitors, causing unchecked intestinal iron absorption ✓
• C Increased HAMP gene expression decreasing ferroportin degradation
• D Decreased transferrin synthesis leading to non-transferrin-bound iron accumulation

Explanation

In thalassemia, ineffective erythropoiesis (massive death of erythroid precursors in marrow) leads to release of erythroferrone (ERFE) from erythroblasts. Erythroferrone suppresses hepcidin production in hepatocytes. With low hepcidin, ferroportin is not degraded, allowing continued intestinal iron absorption even in the setting of iron overload. This 'iron hunger signal' from the expanded erythroid compartment overrides iron stores, leading to progressive overload despite reducing dietary iron. Each unit of transfused blood also adds approximately 200-250 mg iron.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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