Disorders of iron metabolism. Part 1: molecular basis of iron homoeostasis Manuel Mun ˜oz, 1 Jose ´ Antonio Garcı ´a-Erce, 2 A ´ ngel Francisco Remacha 3 ABSTRACT Iron functions Iron is an essential micronutrient, as it is required for satisfactory erythropoietic function, oxidative metabolism and cellular immune response. Iron physiology Absorption of dietary iron (1e2 mg/ day) is tightly regulated and just balanced against iron loss because there are no active iron excretory mechanisms. Dietary iron is found in haem (10%) and non-haem (ionic, 90%) forms, and their absorption occurs at the apical surface of duodenal enterocytes via different mechanisms. Iron is exported by ferroportin 1 (the only putative iron exporter) across the basolateral membrane of the enterocyte into the circulation (absorbed iron), where it binds to transferrin and is transported to sites of use and storage. Transferrin- bound iron enters target cellsdmainly erythroid cells, but also immune and hepatic cellsdvia receptor- mediated endocytosis. Senescent erythrocytes are phagocytosed by reticuloendothelial system macrophages, haem is metabolised by haem oxygenase, and the released iron is stored as ferritin. Iron will be later exported from macrophages to transferrin. This internal turnover of iron is essential to meet the requirements of erythropoiesis (20e30 mg/day). As transferrin becomes saturated in iron-overload states, excess iron is transported to the liver, the other main storage organ for iron, carrying the risk of free radical formation and tissue damage. Regulation of iron homoeostasis Hepcidin, synthesised by hepatocytes in response to iron concentrations, inflammation, hypoxia and erythropoiesis, is the main iron-regulatory hormone. It binds ferroportin on enterocytes, macrophages and hepatocytes triggering its internalisation and lysosomal degradation. Inappropriate hepcidin secretion may lead to either iron deficiency or iron overload. INTRODUCTION Iron is an essential micronutrient, as it is required for satisfactory erythropoietic function, oxidative metabolism and cellular immune response. For a 70 kg man, total body iron is about 3500 mg (50 mg/kg body weight). Most of the iron in the body is distributed in red blood cell haemoglobin (65%; 2.300 mg). Approximately 10% is found in muscle fibres (in myoglobin) and other tissues (in enzymes and cytochromes) (350 mg). The remaining body iron is stored in the liver (200 mg), macrophages of the reticuloendothelial system (RES) (500 mg) and bone marrow (150 mg). On the other hand, the body has no active means of excreting iron, and thus regulation of absorption of dietary iron from the duodenum plays a critical role in iron homoeostasis. 1 This is extremely important as iron is essential for cellular metabolism and aerobic respiration, and cellular iron overload leads to toxicity and cell death via free radical formation and lipid perox- idation. Thus, iron homoeostasis requires tight regulation. 2e4 In this paper, we will review the main pathways of iron metabolism and their regulation (part I), whereas the causes of iron deficiency and iron overload, and the different laboratory tests to establish a correct diagnosis of iron overload, iron deficiency and anaemia, and the indications, advantages and side effects of the different options for treating iron overload and iron deficiency will be discussed in the second paper (part II) MAIN PATHWAYS OF IRON HOMOEOSTASIS Iron absorption The normal Western diet contains 15e20 mg iron in haem (10%) and non-haem (ionic, 90%) forms, of which 1e2 mg are absorbed daily mostly at the duodenum. Iron absorption is balanced against iron loss through sloughed intestinal mucosal cells, menstruation and other blood losses. Daily iron absorption may increase in response to increased iron demand (eg, growth, pregnancy or blood loss). Dietary non-haem iron primarily exists in an oxidised (Fe 3+ ) form that is not bioavailable and must first be reduced to the Fe 2+ form by a ferrir- eductase enzyme, which uses vitamin C as coen- zyme, before being transported across the intestinal epithelium. This is accomplished by a carrier protein called divalent metal transporter 1 (DMT1), which also traffics other metal ions such as zinc, copper and cobalt by a proton-coupled mecha- nism. 34 The absorption of non-haem iron can be diminished by co-administration of tretracyclines, proton pump inhibitor and antacid medication, phytates (high-fibre diets), calcium and phenolic compounds (coffee, tea). In addition, Helicobater pylori infection produces gastric atrophy, which can lead to profound iron-deficiency anaemia. 5 Haem iron is absorbed into the enterocyte by a putative, not completely identified, haem carrier protein 1. 6 Once internalised in the enterocyte, it is likely that most dietary haem is metabolised by haem oxygenase to release Fe 2+ , which enters a common pathway with dietary non-haem iron before it leaves the enterocyte 2 3 (figure 1). However, it remains uncertain whether some intact haem traverses the cell, leaving the enterocyte through the action of the recently characterised haem exporters, which are also expressed in kidney, liver and erythroblast, suggesting that they may act at those sites. 7 Plasma haem is scavenged and transported by haemopexin to hepatocytes for degradation. 1 Transfusion Medicine, School of Medicine, University of Ma ´laga, Ma ´laga, Spain 2 Hematology and Hemotherapy, University Hospital Miguel Servet, Zaragoza, Spain 3 Hematology and Hemotherapy, Complejo Hospitalario de Toledo, Toledo, Spain Correspondence to Professor Manuel Mun ˜oz, Medicina Transfusional Facultad de Medicina Campus de Teatinos, s/n 29071-Ma ´laga, Spain; mmunoz@uma.es All author contributed equally to the design, writing and discussion of this paper. Accepted 15 November 2010 Published Online First 20 December 2010 J Clin Pathol 2011;64:281e286. doi:10.1136/jcp.2010.079046 281 Best practice group.bmj.com on January 9, 2015 - Published by http://jcp.bmj.com/ Downloaded from