Pathophysiology of iron overload in myelodysplastic syndrome. The major cause of iron overload in MDS is the use of red cell transfusions for anemia. This leads to accumulation of macrophage iron and its subsequent export into plasma mediated by the iron export protein ferroportin on the macrophage membrane. When the capacity of plasma transferrin to bind iron is exceeded, non–transferrin-bound iron (NTBI) and its redox-active, cell-penetrating component, labile plasma iron (LPI) appear. The deleterious effects of iron overload in MDS appear to be mediated mainly by NTBI/LPI and include increased infection risk, increased mortality after hematopoietic stem cell transplantation (HSCT), accelerated transformation to acute leukemia, and damage to myocardium and other target organs. Other features unique to iron metabolism in MDS include ineffective erythropoiesis of varying degrees as well as decreased iron use by the bone marrow in patients with suppressed erythropoiesis or those undergoing myeloablation for HSCT, both of which increase transferrin saturation and NTBI. Hepcidin is a negative regulator of ferroportin expression on the macrophage and duodenal enterocyte and its suppression consequent to ineffective erythropoiesis leads to increased export of macrophage iron into plasma as well as increased absorption of iron from the gut.