Serum hepcidin: a novel diagnostic tool in disorders of iron metabolism.

Given its potential toxicity and low bioavailability, iron metabolism in humans is a tightly regulated process. Two main levels of regulation have been described: a cellular regulation that, through the binding of iron-responsive proteins (IRPs) to iron-responsive elements in mRNA from genes encoding proteins of iron metabolism, controls the synthesis of transferrin receptor (necessary for cellular iron procurement) and ferritin (the iron storage protein), and a systemic regulation that modulates intestinal iron absorption and iron mobilization from macrophages and tissue stores. The peptide hormone hepcidin, produced by hepatocytes and acting on target cells situated both outside and within the liver, plays a key role in the systemic regulation of iron metabolism. Hepcidin was initially identified as a cysteine-rich urinary antimicrobial peptide. The subsequent observations that, in mice, hepcidin was over-expressed by hepatocytes during iron overload and that knockout animals accumulated excess iron showed that hepcidin has a role in iron homeostasis. Several studies demonstrated that hepcidin modulates the release of iron from different cell sources, including enterocytes, macrophages and hepatocytes, to plasma. Through these effects, hepcidin controls iron absorption, the recycling of iron derived from senescent and damaged erythrocytes, and the release of iron from tissue stores. These different tasks are accomplished through a unique biochemical mechanism: the interaction of hepcidin with ferroportin, a trans-membrane protein that represents the sole known cellular iron exporter in vertebrates. By triggering ferroportin internalization, ubiquitination and degradation, hepcidin blocks the release of iron from cells (Figure 1). Since ferroportin is expressed at the highest levels by iron exporting cells such as the enterocytes and macrophages, hepcidin represents a negative regulator of iron absorption and macrophage iron release. Iron homeostasis is controlled by a regulatory network involving four main components: bone marrow erythropoiesis, tissue oxygen delivery, iron stores and inflammation. The interest in hepcidin increased dramatically following the demonstration that the peptide represents the final common pathway on which the components of the regulatory network converge to control tissue iron exchange and iron absorption. In fact, increased erythropoietic activity and reduced tissue oxygen delivery suppress hepcidin production, thereby stimulating iron absorption/mobilization, whereas increased iron stores and inflammation act in the opposite way (Figure 1). Consequently, the abnormal iron status and iron homeostasis that occur in several conditions, such as in most forms of hereditary hemochromatosis, iron-loading anemias and anemia of inflammation, are mediated by a dysregulation of hepcidin production. One possible exception to this rule is type 4 hemochromatosis in which the gene encoding ferroportin, the downstream target of hepcidin, is primarily affected. However, the number of cases of ferroportin disease examined for hep-