Natural History and Management of HFE-hemochromatosis

Eng K. Gan, M.B.B.S.; Lawrie W. Powell, M.B.B.S., M.D., Ph.D., F.R.A.C.P., F.R.C.P.; John K. Olynyk, B.Med.Sc., M.B.B.S., M.D., F.R.A.C.P.


Semin Liver Dis. 2011;31(3):293-301. 

In This Article

Pathogenesis of Iron Overload: Hepcidin as Central Conductor29

An increase in intestinal iron absorption as either ionic iron or heme is a pathogenic characteristic of HFE-related HH.[50–53] Iron homeostasis depends on meticulous control between body iron requirements and intestinal iron absorption.[54] This process is orchestrated by the peptide hormone hepcidin, synthesized and secreted primarily by the liver.[55,56] It coordinates iron absorption, mobilization, and storage to meet the iron requirements of erythropoiesis and other iron-dependent processes.[57,58] Hepcidin inhibits iron export by binding to ferroportin found on macrophages and the basolateral surface of enterocytes, thus causing the internalization and degradation of ferroportin. In states of secondary iron excess or inflammation, increased hepcidin production results in decreased intestinal iron absorption and diminished iron release from macrophages. Conversely, iron deficiency, erythropoiesis, and hypoxia decrease hepcidin expression resulting in increased iron absorption from the intestine and release of iron from macrophage.[59–63]

In all types of HH, iron overload results from the impairment of the hepcidin-ferroportin regulatory pathway. Mutations or the absence of HFE, HJV, HAMP, and transferrin receptor-2 (TFR2) genes, reduce hepcidin expression (reviewed in more detail in Olynyk et al[51]). In almost all types of HH, reduced hepcidin production or activity results in increased expression of ferroportin protein, thereby enhancing iron export from enterocytes and macrophages. The upregulation of both iron absorption and mobilization elevates plasma transferrin saturation and non-transferrin-bound iron levels leading to iron loading of hepatocytes and other parenchymal cells, whereas macrophages remain relatively spared of iron.[64]