Proposed mechanism of the ferroportin disease pathogenesis. Top panel: a defect in trafficking (“loss-of-function”). Mutant protein is retained inside the cell resulting in a loss of iron export function. The efflux through the wild-type ferroportin represents only half of the normal amount and is inadequate for the macrophages processing large amounts of recycled iron. Iron accumulates in macrophages, leading to high ferritin levels, low transferrin saturation, and possibly borderline anemia. Anemia, in turn, might activate duodenal absorption, which would progressively increase transferrin saturation. Bottom panel: hepcidin resistance (“gain-of-function”). Mutations prevent hepcidin-mediated internalization and degradation of ferroportin either by interfering with hepcidin binding or by altering motifs required for internalization and degradation. As a result, an inappropriately high number of mutant ferroportin molecules is displayed on the cell surface, resulting in increased iron efflux from enterocytes and macrophages. Duodenal iron absorption increases, transferrin saturation rises, and excess iron is deposited in hepatic parenchyma and other tissues.