due to mutations in ferroportin

Mammalian iron homeostasis is dominated by the fact that there is no normal excretory route for iron. Iron homeostasis is regulated at the level of intestinal absorption by the body’s demand for iron. In normal adults, iron absorption matches the rate of iron loss due to desquamification or intestinal sloughing. Iron absorption can be increased in response to increased need deriving from events such blood loss. Under most conditions, however, the rate of iron absorption by the intestine is low (1-2 mg/day) relative to total body iron (4.0 grams). Most of the iron that enters plasma results from iron export by macrophages as they recycle iron following the ingestion of aged or damaged red blood cells. Hereditary hemochromatosis (HH) presents as a disease of excessive parenchymal iron accumulation resulting from genetic disorders of iron absorption. As little as a decade ago, HH was relatively undifferentiated and was used as a generic label for primary iron overload diseases. During the past decade enormous progress has been made in understanding the genetic basis of iron overload diseases and the molecular events that result in tissue and cellular iron overload. Absorption of dietary iron by the intestine, as well as iron recycling by the macrophage, is regulated by several different physiological cues including iron load, erythropoiesis, hypoxia and inflammation. An essential component in the regulation of iron homeostasis is the secretion of the liver antimicrobial peptide hepcidin. Hepcidin is a 25 amino acid peptide secreted by the liver into the circulation. Hepcidin production is regulated transcriptionally, although the specific transcription factors remain unknown. Importantly, hepcidin synthesis is inversely correlated with iron demand; transcription of hepcidin is increased when iron stores are high and, conversely, decreased when iron stores are depleted. Hypoxia or increased erythropoiesis leads to decreased hepcidin production. Conditions of chronic inflammation, such as arthritis or cancer-associated inflammation, lead to increased production of hepcidin and decreased iron absorption resulting in an iron-limited erythropoiesis, referred to as the anemia of chronic inflammation. Much of the regulation of iron homeostasis can be explained by the observation that the molecular target of hepcidin is an iron transporter present on the surface of all iron-exporting tissues. Ferroportin-1 (Fpn, also known as SLC40A1, IREG1, MTP1) is the only identified transporter that exports iron from cells to plasma. Fpn is a membrane protein with 12 predicted transmemFrom the Dipartimento di Scienze Microbiologiche Genetiche e Molecolari, Università di Messina, Messina, Italy (IDD, GM, JK); Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah, USA (DMVW, JK).