HEPCIDIN SUPPRESSION IN BETA-THALASSEMIA CARRIERS WITH IRON OVERLOAD. Preliminary reports from an ongoing study.

A certain degree of iron overload (IO) is sometimes seen in subjects with β-thalassemia trait (βTT), a mild form of non-transfusion-dependent β-thalassemia. The pathogenesis is unclear, but recently a population study in Sri Lankan children has showed that βTT is characterized by mild hepcidin suppression due to increased erythropoietic activity. This data is in accordance with previous other studies suggesting that erythropoietic drive can regulate hepcidin production, potentially acting via an erythroid-derived hormone, such as the recently identified erythroferrone (ERFE). Hepcidin is the master regulator of iron homeostasis which acts by inhibiting dietary iron absorption and iron release from macrophages, thus its suppression leads to an increased of iron availability in the body. In βTT patients, hepcidin defect may be further aggravated by genetic (i.e. mutations in hemochromatosis genes) or acquired factors (e.g. alcohol abuse or non-alcoholic liver diseases). Treatment of IO in βTT is problematic, since “standard” large-volume phlebotomies are not feasible in mildly anaemic subjects, as well as the lack of approval of oral iron chelators and of specific guidelines. Deferoxamine is the only approved therapy, but it is poorly applicable because of parenteral administration and side effects. Sporadic case reports have suggested the use of phlebotomies in βTT patients with IO, but feasibility and efficacy of such approach has not been evaluated in patients’ series. This study has been designed to better characterize factors involved in the development of IO in βTT patients, and to evaluate feasibility and efficacy of “mini-phlebotomies” in this condition. In our population, a substantial alcohol consumption (>100 g/day) appears a common acquired cofactor in βTT patients with IO, while biomolecular analysis did not reveal potentially pathogenic variants out of the known H63D and C282Y in HFE. Mean hepcidin levels were higher than those observed in the general population, suggesting that the hepcidin response to IO is conserved, while the hepcidin:ferritin ratio was lower than in age- and sex-matched normal individuals, in agreement with a relative hepcidin defect in βTT. Fifteen patients started treatment with “mini-phlebotomies”, eleven of them have reached the iron depletion and no one experienced a worsening of anaemia during the treatment, suggesting mini-phlebotomies as a valuable approach for this peculiar category of patients.