Prohepcidin and Hepcidin in Acute Phase Reaction Accompanying Large Cardiac Surgery

Hepcidin, a small cystein-rech peptide produced by the liver, was first described as an antimicrobial peptide (hepatic bactericidal protein) (Park et al. 2001) and subsequently discovered as a key regulator of iron homeostasis. Via regulation of ferroportin, hepcidin inhibits intestinal iron absorption and iron release from macrophages and hepatocytes (Ganz, 2006; Papanikolaou et al., 2005). Hepcidin levels are regulated by at least three independent mechanisms (Nicolas et al., 2002). Whereas both inflammation and iron loading induce hepcidin production, erythropoietic activity suppresses its production. Apart from those factors also endoplasmic reticulum stress can induce hepcidin expression (Vecchi et al., 2009). In general, the decrease of hepcidin due to the iron deficiency or enhanced erythropoiesis stimulates iron intestinal absorption. On the other hand, iron-stimulated hepcidin production prevents iron overload. Increase in hepcidin concentration due to inflammation is considered important for iron sequestration (Ganz & Nemeth, 2009). Studies of humans with severe inflammatory diseases have shown increased levels of hepcidin, suggesting that elevated hepcidin levels play a role in the anemia of inflammation (Nemeth et al., 2004; Krijt et al., 2009). Due to dominant regulation by interleukin-6 (IL-6), hepcidin was classified as a type II acute-phase protein (Nemeth et al., 2003). Increased IL-6 levels cause the binding of signal transducer and activator of transcription 3 (STAT3) to the hepcidin promoter, increasing its activity (Wrighting & Andrews, 2006). Moreover, hepcidin itself has the potential to bind bivalent metal ions (Tselepis et al., 2010) and to mediate transcriptional changes of a wide variety of genes which can play important role in inflammatory response (De Domenico et al., 2010). That is why hepcidin can be considered as important inflammatory mediator, and its measurement can be helpful in many clinical situations. Technical problems prevented reliable and routine measurements of active 25 amino acid (aa) hepcidin in plasma until 2009. Therefore there are only limited data on hepcidin in human subjects, and much of findings come from animal and in vitro models. To evaluate the time course of plasma hepcidin and its precursor prohepcidin in relation to inflammatory parameters, authors used a specific group of patients undergoing large cardiac surgery pulmonary endarterectomy (PEA) in a deep hypothermic circulatory arrest