Hereditary
iron overload is mainly due to mutations of the HFE gene, implicated in most cases of hereditary
hemochromatosis. Non-HFE-related hereditary
iron overload is rare. It includes hereditary
hemochromatosis related to mutations of other genes,
ferroportin disease (also known as
hemochromatosis type 4), and entities associated with specific clinical manifestations. Four genes have been implicated in hereditary
hemochromatosis: HFE and TFR2 (which codes for the second
transferrin receptor), both involved in adult forms of hereditary
hemochromatosis, and HAMP and HJV, which code for
hepcidin and hemojuvelin, respectively, and are responsible for
juvenile hemochromatosis. All types of hereditary
hemochromatosis share common clinical and
biological characteristics, including an autosomal recessive inheritance pattern, elevation of
transferrin saturation as the initial manifestation, hepatic parenchymal
iron overload, and sensitivity to therapeutic phlebotomy. They are due to hyperabsorption of
dietary iron and are linked to a deficit of
hepcidin, the principal
iron regulator in the body.
Ferroportin disease is a special dominantly inherited clinical form of
iron overload due to mutations of the SLC40A1 gene. Its expression differs significantly from that of hereditary
hemochromatosis, and its mechanism is related to impairment of
iron release from reticuloendothelial cells. Other causes of non-HFE-related hereditary
iron overload are usually associated with recognizable clinical manifestations, such as
anemia or
neurological disorders.