Albertine Donker

Chapter 1 14 Hepcidin is the key regulator of systemic iron homeostasis Cells involved in iron homeostasis are duodenal enterocytes, erythroid precursors, hepatocytes and macrophages. The duodenal enterocyte absorbs 1-2 mg per day to balance the small amount of iron that the human body losses via the desquamation of epithelia. Once inside the enterocyte, iron is stored by ferritin or released into the plasma. After oxidation by ferroxidases, iron is loaded to transferrin (Tf) for transport in the plasma. Iron binding to transferrin prevents the formation of unbound iron that is highly toxic because it catalyzes the formation of oxidative radicals. Transferrin binds to specific transferrin receptors, expressed on all iron-containing cells, but mainly on erythroid precursors in the bone marrow, and on hepatocytes. In the bone marrow iron is used for erythropoiesis, in the liver iron is stored in hepatocytes as ferritin or hemosiderin. However, the majority of iron in the circulation is derived from the recycling of senescent erythrocytes (20- 25 mg of iron per day). In physiological circumstances, intestinal iron absorption is enhanced in situations of increased iron demands (for example during periods of rapid growth in infancy, childhood and pregnancy and during periods of blood loss e.g. menses). 11 On the other hand, iron absorption is depressed in case of (imminent) IO. Importantly, the human body cannot excrete iron in a regulated way. Therefore, effective communication and fine-tuning between enterocytes, erythroid precursors, hepatocytes and macrophages is crucial in order to prevent both ID and IO. Hepcidin, a 25-amino acid peptide hormone, has emerged as the key regulator of systemic iron homeostasis ( Figure 1 ). 11,15,17-19 Hepcidin, encoded by HAMP , is mainly produced and secreted by hepatocytes, circulates in the bloodstream and is excreted by the kidneys. By binding to the (only known) cellular iron exporter FNP and inducing its internalization and degradation, hepcidin regulates the iron dietary iron uptake by the intestines and the release of recycled iron from senescent erythrocytes. 11,15,17,18 The synthesis of hepcidin is controlled by certain physiologic and pathologic triggers that reflect circulating and stored iron levels, erythropoietic activity, hypoxia and inflammatory signals. 11,15,20,21 Many clinical factors are known to influence circulating hepcidin levels. Impaired renal function, therapy with oral or parenteral iron supplements, systemic infections and inflammatory diseases cause an increase of hepcidin levels while on the opposite anemia (especially iron deficiency anemia (IDA)), treatment with erythropoiesis stimulating agents, chronic