Hepcidin Levels in Sickle Cell Disease (SCD)

Sickle cell disease (SCD) refers to a group of inherited disorders characterized by the presence of sickle hemoglobin (HbS) that are associated with episodes of acute illness and progressive organ damage. The most common variant of SCD, sickle cell anemia (HbSS), refers to homozygosity for the β S allele, with most of the remaining patients having sickle hemoglobin C disease (HbSC) and sickle beta thalassemia (HbSβ-thalassemia).

SCD may be associated with iron overload that occurs following repeated red blood cell (RBC) transfusions. However, in patients with beta thalassemia major, iron overload occurs due to both repeated RBC transfusions and hyperabsorption of iron. The hyperabsorption of iron in beta thalassemia occurs due to ineffective erythropoiesis and subsequent downregulation of hepcidin. Thalassemia intermedia and major are the most studied human models of hepcidin modulation by ineffective erythropoiesis alone and the combined and opposite effect of both ineffective erythropoiesis and transfusion dependent iron overload, accordingly. Regular transfusions induce massive iron loading but inhibit erythropoietic drive. Accordingly, hepcidin production is higher in thalassemia major than in thalassemia intermedia although still inappropriate to the massive transfusional iron loading that partially counteracts the erythropoietic-dependent hepcidin down-regulation (Origa R et al, 2007; Kattamis A et al, 2006; Camberlein E et al, 2008). No differences in the steady-state levels of hepcidin was observed when HbSS patients (N = 40) were compared with healthy hemoglobin AA (HbAA)controls (N = 30) (85.3 ± 30 l μg/L vs. 83.5 ± 40 l μg/L) (Ezeh C et al, 2005).

Hepcidin is a 25-amino acid peptide produced mainly in the liver and is the major physiological regulator of body iron stores and serum iron. It negatively regulates egress of iron from cells, such as intestinal epithelial cells and macrophages. Growth differentiation factor-15 (GDF-15) and twisted gastrulation protein homolog 1(TWSG1), two transforming growth factor-β (TGF-β) superfamily members released from erythroid precursors, have been proposed to contribute to hepcidin suppression in thalassemia, although it remains unresolved whether GDF-15 and TWSG1 are markers of ineffective erythropoiesis or mediators of hepcidin suppression in vivo.

With the presence of a thalassemia gene, patients with HbSβ-thalassemia (HbSβ0-thalassemia and HbSβ+-thalassemia) may have an increased tendency to absorb excess iron compared to patients with HbSS.