Iron age: novel targets for iron overload

Abstract

Excess iron deposition in vital organs is the main cause of morbidity and mortality in patients affected by β-thalassemia and hereditary hemochromatosis. In both disorders, inappropriately low levels of the liver hormone hepcidin are responsible for the increased iron absorption, leading to toxic iron accumulation in many organs. Several studies have shown that targeting iron absorption could be beneficial in reducing or preventing iron overload in these 2 disorders, with promising preclinical data. New approaches target Tmprss6, the main suppressor of hepcidin expression, or use minihepcidins, small peptide hepcidin agonists. Additional strategies in β-thalassemia are showing beneficial effects in ameliorating ineffective erythropoiesis and anemia. Due to the suppressive nature of the erythropoiesis on hepcidin expression, these approaches are also showing beneficial effects on iron metabolism. The goal of this review is to discuss the major factors controlling iron metabolism and erythropoiesis and to discuss potential novel therapeutic approaches to reduce or prevent iron overload in these 2 disorders and ameliorate anemia in β-thalassemia.

Figure 1

Graphic representation of the interaction of the factors controlling hepcidin synthesis described in the text.

Figure 2. Graphic representation of some of the factors required to support stress erythropoiesis and modulate hepcidin synthesis in the liver

GDF11 has been associated with the increased proliferation and decreased differentiation observed in ineffective erythropoiesis.

Figure 3. Mechanisms of action of MH and TMPRSS inhibitors in HH and β-thalassemia

(A) Description of potential mechanisms of action and benefits by the use of TMPRSS6 inhibitors or minihepcidins in HH. (B) Description of potential mechanisms of action and benefits by the use of TMPRSS6 inhibitors or minihepcidins in β-thalassemia. (C) Description of potential mechanisms of action and benefits by the use of modulators of ineffective erythropoiesis in β-thalassemia. The broken line indicates a correlation that has not been demonstrated yet.