Defective release of Hepcidin not defective synthesis is the primary pathogenic mechanism in HFE-Haemochromatosis.
Recent findings indicate a principal role for Hepcidin in iron homeostasis. Hepcidin is also thought to play a vital role in the pathogenic mechanism of anaemia in patients with inflammation or chronic disease. Under normal conditions influx and efflux of iron from duodenal enterocytes is regulated by Ferroportin. Ferroportin is a Hepcidin binding protein expressed in duodenal enterocytes. Hepcidin is a peptide synthesised in the liver and is the main regulator of iron homeostasis. It is a defensin like protein and exhibits anti-microbial and anti-fungal activity. The Hepcidin gene is principally expressed in hepatocytes but to a lesser extent in neutrophils and macrophages. Hereditary Haemochromatosis is caused by disruption of iron homeostasis due to mutations in the HFE gene (C282Y or H63D). Unrestricted uptake of iron by duodenal enterocytes causes iron overload which is the hallmark of the disease. Current thinking is that defective Hepcidin synthesis or defective iron-sensing mechanisms leading to Hepcidin deficiency is the cause of iron overload in HFE-Haemochromatosis. Thus HFE-Haemochromatosis has been described as an endocrine disease. Basal levels of Hepcidin appear to be normal in HFE-Haemochromatosis patients. This contradicts current theories of defective Hepcidin synthesis as the cause of Hereditary HFE-Haemochromatosis. We propose that the defect in HFE-Haemochromatosis is the loss of Hepcidin surge in response to intake of dietary iron and is not as a result of reduced synthesis.
Arnold
Jayantha
J
Department of Gastroenterology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex, UB1 3HW, United Kingdom. jayanthaarnold@hotmail.com <jayanthaarnold@hotmail.com>
Sangwaiya
Arvind
A
Bhatkal
Bharati
B
Arnold
Ahran
A
D000900:Anti-Bacterial Agents / Q000378:metabolism*; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D006432:Hemochromatosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D019190:Iron Overload / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D008954:Models, Biological; D009154:Mutation
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins