However, the efficacy of this combination therapy may be less effective in FPN gain- or loss-of-function related disorders, such as in type 4 HH, where the regulation of Nrf2 on the hepcidin-FPN axis is attenuated due to the insensitivity of mutated FPN to hepcidin; and in ferroportin diseases, where FPN has higher iron-exporting activity and may be even enhanced by Nrf2 activation in macrophages. Here, HAMP is linked to hemochromatosis type 4.