HAMP

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Hepcidin is the peptide hormone that regulates iron metabolism. Levels are inappropriately low in haemochromatosis[1].

Prepro-hepcidin is a 84 amino acid and acts as a type II acute phase peptide coded by the HAMP gene at 19q13. Production is encouraged by pro-inflammatory cytokines, especially interleukin-6 and increased plasma and stored iron. Erythroferrone down regulates hepcidin after an acute bleed. BMP6 is the bone morphogenetic protein variant that routinely regulates hepcidin via feedback but there is also feedback via transferrin receptor 2 (TfR2) and HFE which sense extracellular iron stores. Increased erythropoietic activity suppresses hepcidin production. Erythropoietin indirectly dramatically decreases serum hepcidin, perhaps by actions on growth differentiation factor 15 (GDF15) and twisted gastrulation protein (TWSG1, a BMP-binding protein) which might interact more directly with hepcidin expression[2]. Prepro-hepcidin is processed into hepcidin-60 (prohepcidin), hepcidin-25 (Hepc25) and hepcidin-20 (Hepc20) which act as signalling molecules in iron homeostasis controlling the availability of iron for erythropoiesis. The five N-terminal amino acids are crucial for mediating its biological function and contain a copper binding site. The peptides have antimicrobial activity and thus a role in role in innate immunity. There appears to be in various disease processes a differential between pro-hepcidin and hepcidin-25 levels, with the first more directly reflecting immune activation and having no hormonal role. Hepcidin-25 decreases duodenal iron absorption and increases sequestration of iron by macrophages. This is due to binding to the transmembrane protein ferroportin which is key to exporting of iron from cells. Hepcidin bound ferroportin is internalised into cytoplasmic lysosomes and is hydrolyzed. This results in iron accumulating in cells, and hypoferraemia. This decreases iron availability to promote bacterial proliferation. Hepcidin is actively secreted in ascitic fluid, saliva, bile and pleural effusions[3]. It is also found in the urine. Hepcidin serum levels are low in iron deficiency anaemia and iron-loading anaemias, such as β-thalassemia, hypoxia and (functionally) in haemochromatosis[2]. They are high with iron overload from other causes and in iron-restricted anaemia associated with hepatic adenomas or the rare iron-refractory iron deficiency anaemia[2]. The raised levels due to failure of excretion may have a role in the anaemia of chronic renal disease and explain the supraphysiological doses of erythropetin used in this condition[2]. As an acute phase protein. levels are high with raised CRP, sepsis, burns, inflammatory bowel disease, and multiple myeloma[2].

Mutations of HAMP are associated with haemochromatosis type 2B (HFE2B, juvenile haemochromatosis, OMIM:613313).

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