Iron Metabolism

1. Iron
2. Iron Absorption
3. Iron Storage
4. Excess Iron
5. Iron Deficiency
6. Quiz

Iron is an important element in the normal functioning of the body where it is used as a component of haemoglobin and myoglobin for oxygen transport, and as a co-factor in detoxification, respiration and metabolic pathways.

Iron is obtained from the diet and is recycled within the body. Iron deficiency can be due to insufficient iron in the diet, loss of iron in blood (e.g. menstruation or a gastric ulcer) or functional iron deficiency in chronic disease (when less iron is released from the body's stores). The body has no way to eliminate iron, meaning that a buildup of iron can also be dangerous. This is seen in conditions such as hereditary haemochromatosis, or in patients receiving many blood transfusions and can lead to organ damage.

Iron is an element that is used in the body for a variety of functions. Its most important use is for carrying oxygen as a component of haemoglobin (the oxygen carrying pigment in red blood cells) and myoglobin (the oxygen carrying pigment in muscle cells). It is also a key co-factor in many enzymes involved in detoxification and the Krebs cycle.

Iron Absorption

In the body, iron is mostly found in one of two oxidation states: ferrous (Fe²⁺) and ferric (Fe³⁺) iron.

Iron is taken in through diet in two forms; haem and non-haem. Haem is made up of Fe²⁺ ions and is found in meat such as beef, liver and chicken, whereas non-haem is both Fe²⁺ and Fe³⁺, and is found in raisins, oats, spinach and fortified cereals. Iron must be in the ferrous form to be absorbed in the duodenum and upper jejunum.

Iron absorption is inhibited by some chemicals found in everyday food items; i.e. tannins in tea/red wine, or phytates found in chapattis. This works by binding non-haem iron in the intestine so that it cannot be absorbed. Note that antacids can also reduce iron absorption. On the other hand, vitamin C found in citrus fruits can help increase the absorption of iron by reducing ferric to ferrous iron. This is why patients on iron supplements are encouraged to take their tablets with a glass of orange juice.

Diagram: Shows the absorption of non-haem iron in the duodenum and jejunum. Fe²⁺ and haem iron can be absorbed easily, while Fe³⁺ has to be reduced before being absorbed. Iron can be stored in the enterocytes as ferritin, or released into the blood bound to transferrin

SimpleMed Original by Dr. Tom Bradley

The conversion into the ferrous form of iron happens via the reductase enzyme on the apical surface of the enterocytes lining the bowel. The Fe²⁺ ions are taken up by a transporter protein DMT1 into the enterocyte. Haem iron is taken up by a separate poorly understood process.

Once the Fe²⁺ is within the enterocyte it can be stored as ferritin (a soluble iron & protein complex) in the form of Fe³⁺, or transported into the bloodstream by the protein ferroportin. The Fe²⁺ needs to be oxidised back into ferric (Fe³⁺) iron by an enzyme called hephaestin. Now in the correct form, the ferric iron is bound by transferrin and so can be transported around the body to sites where it is needed, in particular to bone marrow where erythropoiesis takes place. (see haematopoiesis and the spleen article).

When the Fe³⁺ iron bound to transferrin reaches the target cell, it binds to a transferrin receptor on the cell surface membrane and causes the process of receptor-mediated endocytosis to occur. The Fe³⁺ is reduced to Fe²⁺inside its endosome. Following this, it is transported into the cytoplasm through the same DMT1 transporter as on the enterocytes in the gut. Once in the cytoplasm, mitochondria can utilise it to produce cytochrome enzymes. Unused Fe2+ is stored in cells as the protein ferritin, which is able to release iron in a controlled manner when needed, after which the Fe2+ can leave via the transporter ferroportin.

Iron Storage

Iron is stored in two different forms: the previously mentioned  usable and soluble ferritin form within cells (which allows iron to enter and leave through pores in the iron-protein complex) and the insoluble hemosiderin form which consists of ferritin complexes clumped together. The latter often accumulates in macrophages in the liver, bone marrow and spleen.

Most of the iron in the body is obtained from recycling old erythrocytes, which explains the limited requirement of iron in our diet. The erythrocytes are phagocytosed by macrophages in the reticuloendothelial system, returning the iron to the blood via transferrin, or storing it within the macrophage as ferritin.

Iron absorption needs to be regulated carefully as both a deficiency and an excess of iron can be harmful to the body. The balance is maintained through regulation of absorption, bodily stores of iron and the rate of erythropoiesis. Note there is no active mechanism for the excretion of iron from the body! The enterocytes sense the iron levels being absorbed from diet and adjust the channel protein transcription accordingly.

Absorption of iron is regulated by hepcidin, a small protein made by the liver which can bind to and cause the degradation of ferroportin and also inhibits DMT1 gene transcription. Overall, hepcidin inhibits dietary iron from entering the bloodstream. The synthesis of hepcidin is increased during iron overload to reduce the levels taken in. Conversely its synthesis is decreased when there is an increased rate of erythropoiesis. This enables the bone marrow to be supplied with enough iron to produce new erythrocytes.

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