Iron is an essential element in human physiology. It has a number of important roles and yet is also very toxic to living cells. It is therefore implicated in several disease processes and a good understanding of the physiology can help appreciate their management.
As an important part of chemistry, iron can be found in the ferrous (Fe2+) or ferric (Fe3+) forms.
Functions of Iron
The physiological functions of iron include:
Oxygen transport - haemoglobin, myoglobin
Enzymes e.g. cytochrome family
The total body stores are around 4g (in an adult male). About 2.5g exists as haemoglobin in RBCs. Another 1g is found in macrophages in the spleen and liver. Only 3mg exists in the ‘mobile’ form of transferrin.
Daily losses are about 1-2mg, mainly through desquamation of skin or GI cells, and small volume blood loss. The losses of menstruation are quite a significant degree higher than this though.
As such, it can be seen that iron homeostasis is a tightly regulated process. Much of the total body iron is distributed through the body, with only a small amount in transit. The ‘flow’ or iron through the transferrin system is around 20mg per day, primarily from RBC recycling.
Iron Absorption & Transport
Iron is the most abundant element on earth. It is generally fairly widely found in food sources, and it is usually more absorption than availability that is the limiting factor. However, many staple food sources (rice, grains) lose much of their iron in processing and can result in low dietary intake in regions where they constitute the majority of food intake. Iron fortification, such as of rice, has been explored relating to this. A typical western diet will provide 15mg of iron, with only 10% actually being absorbed.
Iron is absorbed through fairly complex mechanisms in the proximal GI tract - mainly the duodenum and proximal jejunum. There is generally a distinction between iron that exists in the haem form, and the non-heam form (both Fe2+ and Fe3+ states).
Haem iron arises from ingestion of meat, and is an important source of iron for carnivores. It is more readily absorbed than non-haem iron, with the haem carrier protein being an important feature of the luminal membrane. The haem molecule is broken down within the enterocyte to bilirubin and Iron, the Fe3+ form of which binds as ferritin.
Non-haem iron is primarily from vegetables and grains and becomes ‘free iron’ in the gut. As such, non-haem iron can be susceptible to ‘capture’ from a number of coingested molecules in the GIT. These include tannins, plant derived phytates and some medications. In an acidic pH (i.e. the stomach) non-haem iron will predominate in the reduced Fe2+ state (the impact of antacids on iron handling is relevant here). Transport mechanisms exist in the enterocyte cells of the proximal GIT for absorption. Divalent Metal Transporter-1 (DMT-1) is an important channel, allowing uptake of the Fe2+ form (it is also responsible for the uptake of a number of other metals). Duodenal cytochrome B (also vitamin C Ferrireductase) is an enzyme located in the enteral border of the cell that reduces the Fe3+ iron (to Fe2+) to allow uptake through this channel
Within the intestinal cells the iron is bound to ferritin. It is reverted back to the Fe3+ state for this. Ferroportin (aka Ireg-1) is the protein channel on the capillary side of the intestinal cells that is responsible for subsequent transfer out into the blood. It is also found in large quantities on macrophages. The iron must again be in the Fe2+ state to utilise this channel.
For iron transfer, the iron is again converted to the Fe3+ form on the capillary side of the enterocytes by the enzyme hephaestin. It can now bind with the transport molecule for iron, transferrin. The molecule when it has no iron bind to it is called apo-transferrin, becoming transferrin when it has 2 Fe3+ ions bound to it.
Transferrin usually has 20-40% of the binding sites occupied by iron. This degree of iron binding is a useful measure of body iron status and has been utilised as such. Indeed, excess iron intake can lead to non-transferrin bound iron (NTBI) which may be seen in cases of iron overload (for example, repeated transfusions).
The iron is now able to be transported through the blood to be utilised around the body. The major sites for this are:
The majority (about 75%) is transported to the bone marrow and to the erythrocytes maturing there for haemoglobin synthesis. The transferrin binds to transferrin receptors on the immature erythrocytes to transfer the iron, internalising the complex and ultimately recycling the receptors.
The liver also takes up a notable amount of the transported iron (10-20%). The hepatocytes also utilise the same transferrin receptor, although they can also handle NTBI. Here it is stored in the ferric form with ferritin. Ferritin in liver cells is able to bind up to 4,500 iron ions. Iron can be release back into the circulation from the liver through similar ferroportin mechanisms as described earlier.
Whilst ferritin has a primarily intracellular role, it is recognised as being secreted in the blood and has been used as a clinical biomarker, both relating to iron status and inflammation. The serum ferritin is generally considered “iron-poor” compared to the intracellular form.
Control of Iron
Humans are unable to excrete iron, therefore levels of iron in the body must be regulated by controlling the degree of absorption.
Hepcidin is a key molecule in the control of iron. It is a peptide hormone of 25 AA length that is primarily produced by the liver (hence the name). Essentially, it can be considered as an anti-iron hormone i.e. it inhibits iron uptake and mobilisation. One mechanism of action is on ferroportin to induce internalisation of the protein, and thus reduce cellular release of iron into the blood. This includes at the enterocyte and hepatocyte locations. A similar effect happens with macrophages in the spleen, who are recycling iron from RBC degradation there.
In addition, hepcidin inhibits the absorption of iron from the small intestine.
Hepcidin release can be stimulated by:
Inflammatory cytokines (specifically IL-6)
High levels of transferrin
In essence, it is released in response to high levels of intracellular and extracellular iron (as well as inflammation) to lower iron uptake into the body. The primary governor of hepcidin is the HFE protein. This is produced by the HFE gene, also known as the haemochromatosis gene, as it is here where a genetic abnormality can lead to familial haemochromatosis.
Hepcidin release is inhibited by features linked to iron deficiency:
The exact mechanism for this feedback is not yet fully understood but appears to involve the bone morphogenetic protein (BMP) pathway.
Of note, ferroportin can be induced by high intracellular iron levels. The increased iron levels may increase expression of ferroportin mRNA.