22nd May 2023

Iron metabolism

Pathophysiology of iron metabolism

Iron is an essential component of the normal production and regulation of red blood cells, particularly due to its role in haemoglobin formation.

The average human has 3-6g of iron in their body, 80% of which is functional iron contained within haemoglobin and myoglobin. 20% is stored as ferritin and haemosiderin, mainly in the liver but also in the spleen and bone marrow. Only about 4mg of iron circulates in the plasma and is bound to a glycoprotein called transferrin. Free iron can be toxic to cells; in the presence of hydrogen peroxidase, free ferrous iron (Fe²⁺) is oxidised to ferric iron (Fe³⁺) creating reactive oxygen species which can cause DNA damage and cell death.

Dietary iron absorption occurs mostly in the duodenum and jejunum of the small bowel. Dietary iron can come from meat or plants. Iron from meat is termed ‘heme iron’ and 20% is absorbable. Iron from plants is ‘non-heme iron’ and only 2% is absorbable, with absorption rates worsened by co-ingestion with polyphenols (e.g. tea) or calcium, and increased with vitamin C.

Hepcidin is a peptide hormone synthesised in the liver. Hepcidin decreases intestinal iron absorption and recycling of iron from the reticuloendothelial cells. Therefore in the event of iron deficiency, hepcidin expression is decreased, resulting in increased intestinal iron absorption and recycling of iron from the reticuloendothelial cells.

Whilst the body can increase iron absorption in the event of iron deficiency, there is no regulatory pathway for iron excretion. Approximately 1mg of iron is excreted per day in men and post-menopausal women, and this increases to 2mg per day in menstruating women.

Causes of iron deficiency anaemia

Iron deficiency anaemia is the most common form of anaemia worldwide. A diagnosis of iron deficiency anaemia should prompt investigation to determine the cause.

Causes of iron deficiency can be classified by mechanism:

• Iron loss
  • Gastrointestinal bleeding e.g. gastrointestinal cancer, peptic ulcer disease, ulcerative colitis, hookworm infection, Meckel’s diverticulum, haemorrhoids
  • Menorrhagia
  • Disorders of haemostasis e.g. haemophilia
  • Blood loss from haemodialysis or frequent blood donation
  • Other blood loss, e.g. haematuria, haemoptysis
• Decreased iron intake
  • Malnutrition
  • Vegan diet
• Decreased iron absorption
  • Achlorhydria e.g. secondary to atrophic gastritis
  • Inflammatory bowel disease
  • Coeliac disease
  • Gastric or duodenal surgery
• Increased requirements
  • Pregnancy and breastfeeding
  • Growth

Iron deficiency anaemia may be asymptomatic or may present with non-specific symptoms of anaemia such as pallor, lethargy, or reduced exercise tolerance. Some symptoms more specific to iron deficiency anaemia include pica (cravings for ice or non-food items) and restless legs syndrome. Physical signs on examination may include glossitis, angular cheilitis, koilonychia or brittle nails. In cases of the rare Plummer-Vinson syndrome, there may be dysphagia due to the presence of upper oesophageal webs.

Investigating iron deficiency anaemia

Blood tests commonly used to diagnose iron deficiency anaemia include:

• Full blood count
  • Haemoglobin – low
  • Haematocrit – low
  • MCV – typically low, may be normal
  • MCH – typically low i.e. hypochromic but may be normal
  • Reticulocytes – low or normal
  • RDW– high, due to variability in size of red cells
• Blood film
  • Hypochromic, microcytic red blood cells
  • Poikilocytosis may be seen – target cells and pencil cells are commonly associated with iron deficiency anaemia.
• Iron profile
  • Ferritin – low ferritin is suggestive of iron deficiency; however ferritin is an acute phase reactant and therefore may be normal or elevated if co-existing inflammation.
  • Serum iron – low serum iron may be seen; however, this is not a reliable test in isolation
  • Serum TIBC – increased
  • Transferrin saturation – low (<16%). The percentage transferrin saturation is calculated by serum iron ÷ TIBC x 100.
  • Serum soluble transferrin receptor – increased

Additional investigations to identify a cause may include:

• OGD and colonoscopy – this is particularly important for men and post-menopausal women as occult gastrointestinal cancers are a common cause of iron deficiency anaemia. Small-bowel biopsy can also be undertaken if suspicion of coeliac disease.
• Coeliac serology
• Urinalysis – to investigate occult blood loss from the renal tract
• Helicobacter pylori testing
• Stool sample for ova and parasites if suspicion of hookworm infection
• Gynaecology workup for menorrhagia

Treatment of iron deficiency anaemia

It is important that a cause for the iron deficiency is investigated and that the underlying cause is treated, if identified.

Iron deficiency itself can be treated with oral or intravenous iron therapy. Blood transfusion may also be required in cases of severe anaemia (Hb <70g/L, or <80g/L in select patients) or in cases causing cardiovascular compromise.

Oral iron replacement with ferrous sulfate or ferrous gluconate is commonly used. Concomitant intake of calcium, tea, coffee, wine, or antacids reduces its absorption. Gastrointestinal intolerance to oral iron is common, and patients may experience nausea, constipation, and black discolouration of stool. If oral iron is tolerated, treatment is given for 3 months after the normalisation of blood tests, to ensure replacement of iron stores.

Intravenous iron can be considered if oral iron is not tolerated, failure to respond to oral iron, or in cases of intestinal malabsorption. Intravenous iron can cause anaphylaxis and therefore patients are closely monitored in an appropriate setting throughout the iron infusion.