A Short Review of Iron Metabolism and Pathophysiology of Iron Disorders

Abstract

Iron is a vital trace element for humans, as it plays a crucial role in oxygen transport, oxidative metabolism, cellular proliferation, and many catalytic reactions. To be beneficial, the amount of iron in the human body needs to be maintained within the ideal range. Iron metabolism is one of the most complex processes involving many organs and tissues, the interaction of which is critical for iron homeostasis. No active mechanism for iron excretion exists. Therefore, the amount of iron absorbed by the intestine is tightly controlled to balance the daily losses. The bone marrow is the prime iron consumer in the body, being the site for erythropoiesis, while the reticuloendothelial system is responsible for iron recycling through erythrocyte phagocytosis. The liver has important synthetic, storing, and regulatory functions in iron homeostasis. Among the numerous proteins involved in iron metabolism, hepcidin is a liver-derived peptide hormone, which is the master regulator of iron metabolism. This hormone acts in many target tissues and regulates systemic iron levels through a negative feedback mechanism. Hepcidin synthesis is controlled by several factors such as iron levels, anaemia, infection, inflammation, and erythropoietic activity. In addition to systemic control, iron balance mechanisms also exist at the cellular level and include the interaction between iron-regulatory proteins and iron-responsive elements. Genetic and acquired diseases of the tissues involved in iron metabolism cause a dysregulation of the iron cycle. Consequently, iron deficiency or excess can result, both of which have detrimental effects on the organism.

Keywords: Iron; anemia; disorders; hepcidin; metabolism.

Figure 1

The main tissues involved in the regulation of systemic iron metabolism. Duodenal enterocytes are responsible for dietary iron absorption. Upon absorption, iron circulates around the body bound to the protein transferrin and is taken up by different tissues for utilisation. The reticuloendothelial system, which includes the splenic macrophages, recycles iron from senescent erythrocytes. Among many other functions, the liver produces the hormone hepcidin. Hepcidin controls the release of iron from enterocytes and macrophages into the circulation and is regarded as the master regulator of systemic iron metabolism.

Figure 2

In the enterocytes, haem can be degraded to free iron, which enters the intracellular labile iron pool.

Figure 3

Low stomach pH and dietary ascorbic acid reduces non-haem iron from the highly insoluble Fe³⁺ form to Fe²⁺, which is more readily absorbed. Duodenal cytochrome b accepts electrons intracellularly from oxidation of ascorbic acid into dehydroascorbic acid and uses these to catalyse the reduction of Fe³⁺ to Fe²⁺.

Figure 4

Iron binding to transferrin.

Figure 5

Haem synthesis. Haem synthesis is a complex multistep reaction whose first and final steps occur in the mitochondrion, while the intermediate steps take place in the cytoplasm. Iron is imported into the mitochondrion and inserted into protoporphyrin IX to produce haem. Subsequently, haem is exported into the cytosol, where it combines with α and β globin chains formed on ribosomes to create haemoglobin.

Figure 6

Fenton reaction to produce hydroxyl radicals, which can cause membrane damage and hepatocellular damage, necrosis, liver cirrhosis, or hepatocellular carcinoma once they are in the cytoplasm.