The physiology and pathophysiology of hepcidin

Abstract

Hepcidin, the critical iron regulatory factor, is a small peptide produced by the hepatocytes in response to increased body iron and inflammation. Circulating hepcidin controls both intestinal iron absorption and the release of iron from macrophages into plasma via a negative iron feedback system. I developed a novel competitive immunoassay for hepcidin using a polyclonal antibody produced against synthetic hepcidin. I validated the immunoassay and determined it was able to discriminate between healthy controls and selected disease groups. I compared the immunoassay against another established method of measuring hepcidin. I established that plasma hepcidin has a diurnal rhythm and that plasma hepcidin increases in response to intravenous iron in anaemic patients. Elevated levels of hepcidin in renal failure may have a role in the erythropoietin resistance observed in renal anaemia. In haemodialysis patients, hepcidin levels were significantly elevated, but there was no correlation with inflammatory markers. Elevated hepcidin was associated with anemia, but erythropoietin dose was negatively correlated with hepcidin, suggesting that erythropoietin suppresses hepcidin levels. This was confirmed in patients when hepcidin levels significantly decreased after erythropoietin treatment. The association between plasma hepcidin and other iron parameters were also examined in healthy controls after erythropoietin administration and venesection. Profound hepcidin suppression was observed after an erythropoietin dose, with peak levels reduced by 73.2%, and then gradually recovering over the following two weeks. A similar but more gradual change in hepcidin was observed after reducing hematocrit by removal of 250 mL blood. The studies suggested that the marrow–hepcidin axis is regulated by factors other than those specifically investigated. In summary, I have developed and validated a novel immunoassay for hepcidin which will allow further investigation of the vital role of this peptide in iron homeostasis and human physiology.