Pedia News

Nutritional And Metabolic Aspects Of Iron

Nutritional And Metabolic Aspects Of Iron
Body iron distribution and transport
The transport and storage of iron is largely mediated by three proteins: transferrin, transferrin receptor 1 (TfR1) and ferritin.

Transferrin molecules can each contain up to two atoms of iron. Transferrin delivers iron to tissues that have transferrin receptors, especially erythroblasts in the bone marrow which incorporate the iron into haemoglobin (Figs 2.7, 3.2). The transferrin is then reutilized. At the end of their life, red cells are broken down in the macrophages of the reticuloendothelial system and the iron is released from haemoglobin, enters the plasma and provides most of the iron on transferrin. Only a small proportion of plasma transferrin iron comes from dietary iron, absorbed through the duodenum and jejunum.
Some iron is stored in the macrophages as ferritin and haemosiderin, the amount varying widely according to overall body iron status. Ferritin is a water‐soluble protein–iron complex. It is made up of an outer protein shell, apoferritin, consisting of 22 subunits and an iron–phosphate–hydroxide core. It contains up to 20% of its weight as iron and is not visible by light microscopy.
Haemosiderin is an insoluble protein–iron complex of varying composition containing approximately 37% iron by weight. It is derived from partial lysosomal digestion of ferritin molecules and is visible in macrophages and other cells by light microscopy after staining by Perls’ (Prussian blue) reaction (see Fig. 3.10). Iron in ferritin and haemosiderin is in the ferric form. It is mobilized after reduction to the ferrous form. A copper‐containing enzyme, caeruloplasmin, catalyses oxidation of the iron to the ferric form for binding to plasma transferrin. Iron is also present in muscle as myoglobin and in most cells of the body in iron‐containing enzymes (e.g. cytochromes or catalase) (Table 3.1). This tissue iron is less likely to become depleted than haemosiderin, ferritin and haemoglobin in states of iron deficiency, but some reduction of these haem‐containing enzymes may occur.
The distribution of body iron.

Regulation of ferritin and transferrin
receptor 1 synthesis
The levels of ferritin, TfR1, δ‐aminolaevulinic acid synthase (ALA‐S) and divalent metal transporter 1 (DMT‐1) are linked to iron status so that iron overload causes a rise in tissue ferritin and a fall in TfR1 and DMT‐1, whereas in iron deficiency ferritin and ALA‐S are low and TfR1 increased. This linkage arises through the binding of an iron regulatory protein (IRP) to iron response elements (IREs) on the ferritin, TfR1, ALA‐S and DMT‐1 mRNA molecules. Iron deficiency increases the ability of IRP to bind to the IREs whereas iron overload reduces the binding. The site of IRP binding to IREs, whether upstream (5′) or downstream (3′) from the coding gene, determines whether the amount of mRNA and so protein produced is increased or decreased (Fig. 3.3). Upstream binding reduces translation, whereas downstream binding stabilizes the mRNA, increasing translation and so protein synthesis.
When plasma iron is raised and transferrin is saturated, the amount of iron transferred to parenchymal cells (e.g. those of the liver, endocrine organs and heart) is increased and this is the basis of the pathological changes associated with iron loading conditions. There may also be free iron in plasma which is toxic to different organs (see Chapter 4).
Daily iron cycle. Most of the iron in the body is contained in circulating haemoglobin (see Table 3.1) and is reutilized for haemoglobin synthesis after the red cells die. Iron is transferred from macrophages to plasma transferrin and so to bone marrow erythroblasts. Iron absorption is normally just sufficient to make up for iron loss. The dashed line indicates ineffective erythropoiesis.

Hepcidin is a polypeptide produced by liver cells. It is the major hormonal regulator of iron homeostasis (Fig. 3.4a). It inhibits iron release from macrophages and from intestinal epithelial cells by its interaction with the transmembrane iron exporter, ferroportin. It accelerates degradation of ferropor­ tin mRNA. Raised hepcidin levels therefore profoundly affect iron metabolism by reducing its absorption and release from macrophages.

Control Of Hepcidin Expression
Membrane‐bound hemojuvelin (HJV) is a co‐receptor with bone morphogenetic protein (BMP) which stimulates hepci­ din expression (Fig. 3.4b). A complex between HFE and trans­ ferrin receptor 2 (TfR2) promotes HJV binding to BMP. The amount of HFE–TfR2 complex is determined by the degree of iron saturation of transferrin as follows. Diferric transferrin competes with TfR1 for binding to HFE. The more diferric transferrin, the less TfR1 is bound to HFE and more HFE is available to bind to TfR2, with consequently increased hepcidin synthesis. Low concentrations of diferric transferrin, as in iron deficiency, allow HFE binding to TfR1, reducing the amount of HFE able to bind TfR2 and thus reducing hepcidin secretion. HFE also increases BMP expression, directly increas­ ing hepcidin synthesis.
Matriptase 2 digests membrane‐bound HJV. In iron deficiency, increased  matriptase  activity therefore  results  in decreased hepcidin synthesis. Erythroblasts secrete two proteins, erythroferrone and GDF 15, which suppress hepcidin secretion. In conditions with increased numbers of early erythroblasts in the marrow (e.g. conditions of ineffective erythropoiesis, such as thalassaemia major), iron absorption is increased because of suppression of hepcidin secretion by these proteins. Hypoxia also suppresses hepcidin synthesis, whereas in inflammation interleukin 6 (IL‐6) and other cytokines increase hepcidin synthesis (Fig. 3.4a).

Dietary iron
Iron is present in food as ferric hydroxides, ferric–protein and haem–protein complexes. Both the iron content and the proportion of iron absorbed differ from food to food; in general meat, in particular liver, is a better source than vegetables, eggs or dairy foods. The average Western diet contains 10–15 mg iron daily from which only 5–10% is normally absorbed. The proportion can be increased to 20–30% in iron deficiency or pregnancy (Table 3.2) but even in these situations most dietary iron remains unabsorbed.

Iron absorption.

Iron absorption
Organic dietary iron is partly absorbed as haem and partly broken down in the gut to inorganic iron. Absorption occurs through the duodenum. Haem is absorbed through a receptor, yet to be identified, on the apical membrane of the duodenal enterocyte. Haem is then digested to release iron. Inorganic iron absorption is favoured by factors such as acid and reducing agents that keep iron in the gut lumen in the Fe2+ rather than the Fe3+ state (Table 3.2). The protein DMT‐1 is involved in transfer of iron from the lumen of the gut across the enterocyte
microvilli (Fig. 3.5). Ferroportin at the basolateral surface controls exit of iron from the cell into portal plasma. The amount of iron absorbed is regulated according to the body’s needs by changing the levels of DMT‐1 and ferroportin. For DMT‐1 this occurs by the IRP/IRE binding mechanism (Fig. 3.3), and for ferrroportin by hepcidin (Fig. 3.4a).
Ferrireductase present at the apical surface converts iron from the Fe3+ to Fe2+ state and another enzyme, hephaestin (ferrioxidase), converts Fe2+ to Fe3+ at the basal surface prior to binding to transferrin.

Hepcidin reduces iron absorption and release from macrophages by stimulating degradation of ferroportin.

Iron requirements
The amount of iron required each day to compensate for losses from the body and for growth varies with age and sex; it is highest in pregnancy, adolescent and menstruating females (Table 3.3). Therefore these groups are particularly likely to develop iron deficiency if there is additional iron loss or prolonged reduced intake.
The regulation of iron absorption.