In this article, we will discuss iron metabolism in the human body, and consider the clinical consequences when this finely balanced process is disrupted.
Iron is essential for the function of many enzymes and proteins, including haemoglobin. However, free iron is toxic to cells as it acts as a catalyst in the formation of free radicals.
In order to overcome this potential toxicity, complex regulatory systems are in place to ensure the safe absorption, transportation, and utilisation of iron.
Fig 1 – Summary of iron metabolism and storage
Iron Absorption
Absorption of iron occurs in the duodenum and upper jejunum and depends on specific carrier mechanisms. The transporter protein Divalent Metal Transporter 1 (DMT1), located on the apical surface of enterocytes, facilitates the uptake of non-haem ferrous iron (Fe2+) from the intestinal lumen.
Ferric iron (Fe3+) in the intestinal lumen must be reduced to ferrous iron (Fe2+) by duodenal cytochrome B reductase (DcytB) before uptake by DMT1.
The iron within enterocytes can either be stored as ferritin, or transferred into the bloodstream via the protein ferroportin. Once in the blood, iron is bound to the transport protein transferrin, and is mostly transported to bone marrow for erythropoiesis. Some iron is taken up by macrophages in the reticuloendothelial system as a storage pool.
Regulation
The absorption of iron is primarily regulated by a peptide called hepcidin, which is expressed by the liver. Hepcidin functions by directly binding to ferroportin, resulting in its degradation and therefore preventing iron from leaving the cell.
Hepcidin also functions by inhibiting transcription of the DMT1 gene, thus reducing iron absorption.
Iron Excretion
Firstly, it is important to note that the human body has no specific mechanism for iron excretion, and therefore regulating iron absorption to match the natural losses, is a crucial part of iron metabolism.
Approximately 1-2mg of iron is lost from the body each day from the skin and gastrointestinal mucosa. A well-balanced diet contains sufficient iron to balance this loss, as approximately 10% of the 10-20 mg of dietary iron in a balanced diet is absorbed each day.
This iron can be haem iron from animal sources, or non-haem iron from whole grains, nuts, seeds, legumes, and leafy greens.
Haem iron is more readily absorbed than inorganic iron which consists of both ferric (Fe3+) and ferrous (Fe2+) iron. Ferric iron must first be reduced to the ferrous form before it is absorbed.
Iron Recycling
On a daily basis, only a small fraction of the total iron requirement is gained from the diet. Most of the iron requirement is met from the recycling of iron within the reticuloendothelial system, which is released from storage and returned to the active pool.
Iron Storage
Iron is stored in two forms, ferritin and its insoluble derivative haemosiderin. All cells have the ability to sequester iron as either ferritin or haemosiderin. The highest concentrations of stored iron are in the liver, spleen, and bone marrow.
Clinical Relevance – Iron Deficiency
Iron deficiency is a symptom, not a diagnosis, and the clinician must always seek to find the underlying cause of the deficiency.
Deficiency can result from insufficient intake/poor absorption. It can be secondary to increased utilisation due to physiological reasons such as pregnancy, or it may be a sign of pathology such as bleeding from the GI tract.
Clinical Relevance – Hereditary Hemochromatosis (HHC)
HHC is an example of an iron metabolism disorder. It is an autosomal recessive disease characterised by excessive absorption of dietary iron. As there is no system for the excretion of excess iron, iron accumulates in tissues and organs, disrupting normal function.
The most susceptible organs include liver, adrenal glands, heart, joints, and pancreas. Patients therefore present with cirrhosis, adrenal insufficiency, heart failure, arthritis and/or diabetes.
The defective gene resides on chromosome 6 and codes for a protein called HFE. Treatment of HHC is relatively simple in the form of therapeutic phlebotomy to remove excess iron.