Gregory M. Vercellotti, MD
Dr. Vercellotti indicated no relevant conflicts of interest.
Gardenghi S, Ramos P, Marongiu MF, et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice. J Clin Invest. 2010;120:4466-4477.
Remarkable advances in the care of β-thalassemic patients over the past 40 years have prolonged lives and prevented organ dysfunction due to iron overload through the use of parenteral and oral iron chelators. Iron overload occurs in β-thalassemia because ineffective erythropoiesis and frequent RBC transfusions over-enhance iron absorption. It is a curious phenomenon that, in the presence of a globin chain synthesis mismatch, excess heme, erythroid hyperplasia, and anemia, the body still signals the intestine to increase iron absorption as if more iron might solve the problem. We now know that levels of hepcidin, the key regulator of iron absorption and recycling, are low in patients with thalassemia. Hepcidin is made in the liver and controls ferroportin (the “iron door”), which is found on the surface of duodenal enterocytes, macrophages, and hepatocytes. In thalassemia, hepcidin levels are lower than normal for the degree of iron overload, presumably reflecting the fact that hepcidin production decreases in the presence of increased erythropoiesis … even if that erythropoiesis is ineffective. Dr. Gardenghi et al. in Stefano Rivella’s lab at Weill Cornell Medical College provide insight into how controlling iron intake and hepcidin itself may add to the therapeutic options available to limit iron overload in organs and improve anemia in patients with β-thalassemia.
In β-thalassemic mice a moderate increase in expression of hepcidin limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. A low dietary intake of iron in thalassemic mice also positively affected erythropoiesis while reducing tissue iron levels in the liver, spleen, kidney, and heart. Interestingly, on the low iron diet, hepcidin levels decreased while erythropoietin levels increased, suggesting that hepcidin expression is more sensitive to the suppressive effect of iron restriction in states of increased erythropoiesis. Even after five months on a low iron diet, hemoglobin levels did not drop and spleen size diminished in the thalassemic mice. When very high hepcidin levels were tested, hemoglobin levels were very low and spleen iron levels were six-fold higher, suggesting that very high levels of hepcidin can inhibit release of iron from macrophages, leading to inhibition of red cell production.
According to these data, therapeutics that can increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders. However, the hepcidin level has to be just right. Supportive evidence comes from a recent report by Dr. Li et al., which showed that transferrin injections can increase hepcidin expression and improve anemia in β-thalassemic mice.1 As discussed in an accompanying commentary by Drs. Bartnikas and Fleming,2 promising new agents are in development for use in modulating hepcidin levels and possibly in iron overload states or chronic disease-related anemia in humans. Clearly, restricting iron intake as severely as was done in these mouse studies is impractical, but new iron chelators combined with “just right” amounts of hepcidin may improve organ function and prolong the lives of individuals with β-thalassemia.
- Li H, Rybicki AC, Suzuka SM, et al. Transferrin therapy ameliorates disease in beta-thalassemic mice. Nat Med. 2010;16:177-182.
- Bartnikas TB, Fleming MD. A tincture of hepcidin cures all: the potential for hepcidin therapeutics. J Clin Invest. 2010;120:4187-4190.