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Hepcidin: the main regulator of iron homeostasis

Iron is an essential micronutrient as it is essential for several biological processes including erythropoiesis, oxidative metabolism and cellular immune response (1, 2). As such, regulation of the absorption of iron across the epithelium of the proximal small intestine is a crucial process for maintaining body iron concentrations within the physiological range (2). During the past few years, our understanding of the molecular mechanisms controlling iron homeostasis has changed dramatically. In particular, the recent recognition of the peptide hepcidin as the main regulator of iron recycling and iron balance has revolutioned our knowledge about normal and abnormal iron metabolism (3, 4). Hepcidin is a hormone produced primarily in the liver, where its synthesis is stimulated by iron excess and inflammation, and inhibited by anemia and hypoxia. The mature bioactive form of hepcidin is a peptide of 25 amino acids that originates from a precursor (pre-prohepcidin) of 84 amino acids that undergoes two enzymatic cleavages (5). Hepcidin acts by binding to the cellular iron exporter ferroportin and inducing its internalization and degradation, thus trapping iron in enterocytes, macrophages and hepatocytes. The net effect of hepcidin is reduced absorption of dietary iron, sequestration of iron in macrophages and sequestration of iron in hepatic stores. Hepcidin excess may be the key pathogenic feature of anemia of inflammation, and hepcidin deficiency may be responsible for most cases of familial hemochromatosis (6–8). The growing clinical and laboratory interest towards hepcidin is documented by the exponential increasing number of publications referenced in PubMed during the last few years. Also, this issue of Clinical Chemistry and Laboratory Medicine includes two original articles on hepcidin (9, 10). The first paper by Floreani and colleagues (9) deals with the controversial issue of laboratory measurement of hepcidin. Indeed, few investigative tools are available and primarily include an immunodot method for measuring urinary hepcidin, urine and serum assays based on surface-enhanced laser-desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) or enzyme-linked immunosorbent assays (ELISAs) (11). However, at present, there is no consensus on the best assay method for hepcidin for every clinical application since all have potential advantages and disadvantages (12, 13). In this context, the authors assessed the performance of a SELDI-TOF MS method for quantifying hepcidin-25 (Hep-25) in plasma in 127 individuals with different disorders of iron metabolism, including hereditary hemochromatosis (HE), non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C virus (HCV) infection, and healthy controls. A positive correlation between plasma Hep25 and serum ferritin was observed in all categories, with the exception of HCV-positive patients. Moreover, in order to discriminate between HE and controls, data were analyzed with specific software and two main variables that were selected (i.e., glucose )4.8 mmol/L and a Hep-25/serum ferritin (SF) ratio F6.6) allowed for the correct diagnosis of HE to be made with remarkable performance (i.e., 100% sensitivity and 93% specificity). Based on these results, the authors concluded that the plasma Hep-25 mass spectrometry method provides measurements that reflect pathological and genetic influences, and that simple non-invasive biomarkers (glucose )4.8 mmol/L and a Hep-25/SF ratio F6.6) can predict the presence of HE. These important results, along with the inaccessibility of this method for the majority of laboratories, underline the necessity to centralize this test in a few specialized regional-reference laboratory centres. The second study by Thomas and colleagues (10) evaluated the capacity of Hep-25 (measured using mass spectrometry) to differentiate iron deficiency anemia (IDA), anemia of chronic disease (ACD) and the combined state of ironrestricted erythropoiesis (IRE)/ACD. They enrolled a total of 155 anemic patients in their study. Interestingly, the authors found that Hep-25 correlated with biochemical markers of iron deficiency (i.e., ferritin, ferritin index, transferring saturation and soluble transferring receptor), but not with hematological indices (i.e., hemoglobin, cellular hemoglobin content, the proportion of hypochromic red cells and cellular hemoglobin in reticulocytes). Therefore, Hep-25, at a cut-off of F4 nmol/L, was found to be a good marker for differentiation between IDA and ACD or ACD/IRE. However, it did not allow for the discrimination of ACD from ACD/IRE in patients with severe inflammation. Furthermore, the discrimination of ACD/IRE from ACD required combination with the reticulocyte hemoglobin content in a diagnostic plot. Thus, the authors concluded that Hep-25 is primarily an indicator of decreased body iron concentrations, but not for IRE. In conclusion, these two papers will contribute significantly to improvements in our understanding of the diagnostic role of hepcidin in disorders of iron metabolism, as well as in other life-threatening pathologies (e.g., pre-eclampsia) (14).