Reduced iron export associated with hepcidin resistance can explain the iron overload spectrum in ferroportin disease

BACKGROUND & AIMS: Ferroportin disease (FD) and hemochromatosis type 4 (HH4) are associated with variants in the ferroportin‐encoding gene SLC40A1. Both phenotypes are characterized by iron overload despite being caused by distinct variants that either mediate reduced cellular iron export in FD or resistance against hepcidin‐induced inactivation of ferroportin in HH4. The aim of this study was to assess if reduced iron export also confers hepcidin resistance and causes iron overload in FD associated with the R178Q variant. METHODS: The ferroportin disease variants R178Q andA77D and the HH4‐variant C326Y were overexpressed in HEK‐293T cells and subcellular localization was characterized by confocal microscopy and flow cytometry. Iron export and cytosolic ferritin were measured as markers of iron transport and radioligand binding studies were performed. The hepcidin‐ferroportin axis was assessed by ferritin/hepcidin correlation in patients with different iron storage diseases. RESULTS: In the absence of hepcidin, the R178Q and A77D variants exported less iron when compared to normal and C326Y ferroportin. In the presence of hepcidin, the R178Q and C326Y, but not the A77D‐variant, exported more iron than cells expressing normal ferroportin. Regression analysis of serum hepcidin and ferritin in patients with iron overload are compatible with hepcidin deficiency in HFE hemochromatosis and hepcidin resistance in R178Q FD. CONCLUSIONS: These results support a novel concept that in certain FD variants reduced iron export and hepcidin resistance could be interlinked. Evasion of mutant ferroportin from hepcidin‐mediated regulation could result in uncontrolled iron absorption and iron overload despite reduced transport function.