The main pathogenic pathways of human hereditary iron overload disorders

The circulatory iron pool is essential for supplying iron to the erythropoietic organs and other functional sites. Entry into the bloodstream of iron from the intestine and storage sites depends largely on the presence of ferroportin and the auxiliary circulatory or cell-associated ferroxidases (such as ceroplasmin or haephestin, respectively); which help to load iron onto the transporter transferrin. The half-life and membrane activity of ferroportin are mainly dependent ont the circulating levels of hepcidin.
In the case of haemachromatosis, ferroportin-mediated iron export goes unchecked because of the loss of hepcidin or resistance to its effect. The result is circulatory iron overload followed by tissue overload as excess iron passes from the bloodstream into parenchymal cells. Here, the ratio of circulatory iron to tissue iron is high.

There are two hereditary disorders in which the underlying defects is the functional loss of the specialised iron carrier ferroportin, and aceruloplasminaemia, which is caused by the loss of a fundamental ferroxidase. Compared with the tissue iron compartment, the circulatory iron pool may be disproportionately low, and this may pose a risk for iron-restricted erythropoiesis and anaemia.

In atransferrinaemia, iron absorbed from the intestine or released from macrophages cannot be transported to the bone marrow because of the absence of transferrin. Anaemia is constant and severe. Tissue overload generally occurs as the unphysiologically high levels of non-transferrin-bound forms of iron pass into the cells.

Pietrangelo A. Hemochromatosis: An endocrine liver disease.
Hepatology 2007;46: 1291-1301