Hepcidin and β-thalassemia major

In this issue of Blood, Pasricha et al evaluated serum hepcidin and its putative pathological suppressor growth differentiation factor-15 (GDF-15) in patients with β-thalassemia major before and after transfusion, in the context of erythropoietic activity and iron loading. The study offers insight into dynamic regulation of hepcidin in this disease, reinforces the likely contribution of hepcidin to iron loading between transfusions, and highlights the potential clinical utility of hepcidin measurements in the management of patients with β-thalassemia major.¹ 

Iron overload is the major cause of morbidity and mortality in patients with moderate to severe β-thalassemia. Iron overload is also seen in patients with other anemias with ineffective erythropoiesis, including patients with congenital dyserythropoietic anemias. Although erythrocyte transfusions are frequently the predominant source of iron (each milliliter of packed erythrocytes contains about 1 mg of iron), it is now widely appreciated that even non–transfusion-dependent thalassemia patients often develop lethal iron overload.²  The discovery of the pathological suppression of the iron-regulatory hormone hepcidin in β-thalassemia and other iron-loading anemias^3-5  provided an explanation for these counterintuitive observations. Hepcidin deficiency allows increased intestinal iron absorption, often to rates similar to those in severe hereditary hemochromatosis.

In iron-loading anemias, hepcidin is thought to be regulated by the opposing influences of erythropoietic activity, which suppresses hepcidin, and iron loading, which increases hepcidin.⁶  Pasricha et al¹  clearly demonstrated that even in β-thalassemia major patients, who are highly iron overloaded, serum hepcidin levels are lower than would be expected because of the exuberant erythropoiesis. The reduction of erythropoietic activity by erythrocyte transfusions partially relieved the suppression of hepcidin. The observed average doubling of serum hepcidin after transfusion is a mirror image of the average 50% reduction in serum erythropoietin and contrasts with the very minor posttransfusion changes in serum ferritin levels. Thus, the effect of transfusions on hepcidin is due to the correction of anemia and the associated decrease in erythropoietin concentrations (see figure) and is not related to the iron content of transfused erythrocytes.

The study also demonstrated that the posttransfusion suppression of erythropoiesis was less effective in men than women, and this was reflected by the lower posttransfusion hepcidin in men compared with women. The explanation for gender difference likely lies in men having a higher blood volume; thus, the male patients received a lower transfusion dose per unit blood volume. In addition, as men naturally have higher hemoglobin (Hb) levels than women, higher Hb concentrations may be required in men to suppress erythropoietic drive. The authors suggest that treatment guidelines may need to be adjusted to account for gender differences in blood volume, and hepcidin may be helpful in assessing the effectiveness of the transfusion regimen.

Why is hepcidin suppressed in ineffective erythropoiesis? Based on studies in patients with β-thalassemia and other iron-loading anemias, as well as related animal models and cellular studies, it has been proposed that erythropoietin-stimulated erythroblasts produce secreted mediators that act on the liver to suppress hepcidin production. Dying erythroblasts or erythroblasts that fail to mature appropriately may further contribute to secretion of hepcidin suppressors, perhaps explaining the paradoxical lack of iron overload in patients with expanded erythroblasts but normal maturation, such as in untransfused chronic hemolytic anemias.

GDF-15 has been proposed as a hepcidin suppressor in β-thalassemia.⁷  GDF-15 is secreted by late and apoptotic erythroblasts, and its levels are greatly elevated in human β-thalassemia patients, although not in a thalassemia mouse model. A definitive demonstration of the role of GDF-15 in hepcidin suppression in thalassemia is still missing, and it seems that GDF-15 does not play a role in physiological hepcidin suppression after hemorrhage.^8,9  In the current study, GDF-15 levels were greatly elevated before transfusion, as expected. After transfusion, GDF-15 decreased by 25% to 35%, but still remained extremely high compared with normal levels. Although the current study does not provide evidence for a specific hepcidin suppressor, it highlights the importance of this regulation in β-thalassemia. The nature of the hepcidin-suppressive erythroblast-derived mediators (erythrokines) is an active area of research, with important implications for the diagnosis and treatment of iron-loading anemias.