Iron is essential for every living cell in the body. It is the active component of hemoglobin, which is the main constituent of red cells, which in turn make up about 80 percent of all the cells in the human body. Additionally, iron is needed for many other enzymes involved in the transfer of electrons and flow of energy. Conversely, excess amounts of iron are harmful, resulting in the generation of oxidative stress and free radicals, and harm to organs harboring excess iron, as occurs in hereditary hemochromatosis and transfusional iron overload. As expected for such a key element of metabolism, absorption and transfer between cells is carefully controlled, and the key elements of this control have been carefully elucidated in the past 20 years, with the hepcidin-ferroportin axis being central.1 Ferroportin is the only known exporter of iron from cells, and blocking its action reduces dietary iron absorption as well as the mobilization of iron from macrophage stores in the liver and spleen. Although ferroportin inhibition seems likely to be therapeutic in some types of hereditary hemochromatosis, it is not immediately obvious why it would be beneficial in sickle cell disease (SCD) — a disorder in which the red cell is already very damaged — without inflicting iron-related problems.
The potential benefit of ferroportin inhibition in SCD stems from the critical relationship between the concentration of sickle hemoglobin (HbS) in the red cell and lag time between deoxygenation and the onset of polymerization.2 Iron deficiency has been linked to better outcomes in SCD,3 and even increased survival,4 for nearly 50 years, though the evidence has been based on observations of small series of patients. Concern about the adverse events of iron deficiency, including cognitive impairment,5 has restricted its use as a therapeutic option, though venesection is increasingly used in HbSC disease.6 In their article, Dr. Naja Nyffenegger and colleagues explore the use of vamifeport, an oral ferroportin inhibitor, in mice with SCD (HbSS Townes mice) and find a wide range of beneficial effects. In a series of careful experiments, they found that vamifeport caused reduced hemoglobin concentration in red cells, with all the downstream consequences that would be expected with a reduced rate of polymerization, including reductions in hemolysis, erythrocyte phosphatidyl serine exposure, vascular inflammation, oxidative stress, and vaso-occlusion (in the mouse perfusion model). Related to the iron restriction, they also showed that hemoglobin levels fell. Interestingly, dietary iron deficiency did not seem to reduce inflammation and hemolysis in the same way.
In Brief
Inhibition of ferroportin is emerging as another potential therapeutic option in SCD. Data are still very provisional, but it is possible that this approach might be most beneficial for patients with higher intracellular hemoglobin concentrations, such as those with HbSC and HbSS with α thalassemia.7 It might also work well with other drugs that increase hemoglobin, such as hydroxyurea. Many questions remain, however, including whether this approach is really better than dietary iron restriction or venesection, and whether there are adverse effects from iron restriction in other tissues of the body such as the brain. Still, induced iron-restricted erythropoiesis seems to be another potentially useful way to modify some of the complications in SCD. As more therapies emerge, the closer we get to the prospect of multidrug, personalized medicine in SCD, though well-designed clinical trials are needed to study this, and serious questions remain over how affordable such an approach is, particularly in low- and middle-income countries where most patients live.
Competing Interests
Dr. Rees has attended an advisory board meeting for Vifor and indicated no other relevant conflicts of interest.
