Mechanisms of abnormal iron absorption in ferroportin disease and ferroportin-associated hemochromatosis

Ferroportin disease and ferroportin-associated hemochromatosis are both caused by pathogenic variants in the FPN1 gene, which encodes ferroportin, but their clinical consequences differ.

Panel A – Normal physiology. Ferroportin facilitates iron release/export from macrophages and intestinal enterocytes. Hepcidin (made in the liver) downregulates ferroportin.

Panel B – Ferroportin disease (FD, also called "macrophage type"), due to loss-of-function mutations in FPN1. FD is characterized by impaired iron export, especially from macrophages, as the cells cannot keep up with iron flux because ferroportin is slow to reach the cell membrane.

Panel C – Ferroportin-associated hemochromatosis (also called "hepatic type"), due to gain-of-function mutations in FPN1. In ferroportin-associated hemochromatosis, ferroportin is less sensitive to hepcidin, and iron export is not appropriately downregulated. Excess iron accumulates in the liver and other tissues.