Iron deficiency

Iron deficiency is the most common cause of anaemia worldwide. Anaemia (American spelling anemia) is a deficiency of red blood cells and can occur either through the reduced production or an increased loss of red blood cells. To produce red blood cells, three essential elements must be present, iron, vitamin B12 and folic acid. Hence, iron deficiency anaemia is anaemia caused by the lack of iron to create red blood cells. Iron deficiency may also result in skin problems.

What are the clinical features of iron deficiency?

The signs and symptoms of iron deficiency depend on whether the patient is anaemic and if so, how fast the anaemia develops. In cases where anaemia develops over a period of time the patient can often tolerate extremely low concentrations of red blood cells (<100g/L) for some time before developing any symptoms. The first symptoms to appear are usually increased lethargy, shortness of breath and palpitations (awareness of the heartbeat).

On physical examination, hair, skin, nail and mucous membrane changes are often visible. This can occur before the patient is clinically anaemic.

• In some patients pruritus (itching) may be present.
• Nails become brittle and fragile and develop vertical stripes. Nail plate changes result in koilonychia (spoon shaped nails).
• Patients develop angular cheilitis, a condition in which painful cracks appear at the corners of the mouth.
• The tongue may become swollen and smooth and develop a burning sensation.
• Dryness of the mouth and throat making it difficult to swallow.
• Hair becomes dry, brittle and dull. Increased hair shedding may be noticed.
• Skin is abnormally pale if the patient is anaemic.

Iron deficiency may also predispose to bacterial and fungal infections such as impetigo, boils and candidiasis.

Iron deficiency

Koilonychia

Angular cheilitis

What causes iron deficiency?

There are several causes of iron deficiency. It may be due to a deficiency in iron stores.

• Deficiency in children is usually caused by the inadequate of intake of iron through their diet. This is a particular problem in premature babies and infants over the age of six months; milk is a poor source of iron. Older children are often fussy and picky eaters. Extra iron is also needed for growth in adolescents.
• Iron deficiency in women can be due to a number of factors.
  • During pregnancy the increased need for iron often exceeds a woman's dietary intake.
  • Heavy menstrual periods cause the body to lose blood faster than the body can make it.
  • Smoking and a diet low in iron.
• Lack of iron in the diet is common in vegetarians because the main dietary source of iron in red meat.
• Gastrointestinal diseases that reduce iron absorption from the intestine, e.g. Crohn disease, coeliac disease, Helicobacter infection or atrophic gastritis (which will also cause B12 deficiency).
• Use of drugs that may cause gastrointestinal bleeding, e.g. aspirin and NSAIDS.
• Bleeding due to gastritis, peptic ulceration, benign polyp or cancer in gastrointestinal tract. This possibility should be considered in asymptomatic males and postmenopausal females by testing faeces for blood.
• Excessive blood donation
• Bleeding disorders such as von Willebrand disease, a genetic condition affecting about 1% of the population

Iron deficiency also arises in sick patients with infection, inflammation or malignancy with an anaemia of chronic disease. Typical conditions include rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and chronic renal failure. This is due to reduced absorption of iron and reduced release of iron from the storage cells to the developing red cells in bone marrow.

Myelodysplasia is a rare bone marrow disesae that presents with anaemia.

What tests should be done?

Full blood count

A full, or complete, blood count (FBC, CBC) is important to detect anaemia (lowered haemoglobin (Hb) concentration).

If anaemia is due to iron deficiency the cells are smaller and contain less haemoglobin resulting in lowered red blood cell count or haematocrit, mean corpuscular volume (MCV) and mean cell haemoglobin concentration (MCH). Reticulocte haemoglobin content (Ret-Hb) is used to monitor response to iron replacement. Red cell distribution width (RDW) can reveal mixed iron and vitamin B12 deficiency as this results in red cells of variable size.

However iron deficiency can be present when these are normal.

Ferritin

Ferritin is a measure of iron stores. Low levels of ferritin less than 15 mcg μg/ml are diagnostic of iron deficiency. Levels higher than 50 mcg μg/ml in a healthy person are considered optimal.

Normal or high levels of ferritin does not exclude iron deficiency because it acts as an acute phase reactant. Levels are higher in the prescence of chronic inflammation, when erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) are elevated. Ferritin is also higher in patients with chronic kidney disease.

Other iron tests

In iron deficiency:

• Serum iron is reduced
• Iron binding capacity is increased
• Transferrin saturation is reduced, but may be elevated by oral contraceptives
• Soluble transferrin receptor (sTfR) is reduced – this reflects total body stores except if there is disease of bone marrow, but is an expensive test. It is unchanged in anaemia of chronic disease.

Retest after 3 months of iron supplementation.

Elderly patients sometimes have unexplained iron deficiency anaemia. If bowel investigation is negative, bone marrow examination may be considered.

What is the treatment for iron deficiency?

Once iron deficiency has been established, the underlying cause should be investigated and managed (e.g. correct/manage GI bleeding or menstrual blood loss, e.g. with levonorgestrel-releasing intrauterine device or tranexamic acid for a woman with heavy periods). In addition, most people will need iron replacement therapy to correct the anaemia and replenish iron stores.

Increase dietary iron

Red meat contains haem iron, which is readily absorbed. Non-haem iron sources may need the help of vitamin C in the form of fresh fruit or tablets.

Many manufactured foods contain iron; read the labels.

Calcium and tannin in tea, coffee and red wine, reduce absorption of non-haem iron, so take these several hours before a meal.

Oral iron

Iron supplementation is safe in pregnancy, infants, children and adults. It can be used in both iron deficiency anaemia and anaemia of chronic disease.

Iron preparations come in the form of tablets, oral liquids and injection. Oral preparations are most commonly used.

Oral iron preparations from reputable sources include:

• Ferrous fumarate 33% elemental iron
• Ferrous sulfate 20% elemental iron
• Ferrous gluconate 12% elemental iron

Enteric-coated and slow-release formulations are less well absorbed, but better tolerated. Taking iron with vitamin C (ascorbic acid) may increase its absorption and help replenish iron stores more quickly. Lower dose preparations are less effective.

In anaemic patients, once haemoglobin levels are corrected to within the normal range, iron replacement should be continued for a further 3 months to replenish iron stores. Aim for serum ferritin levels over 50 μg/ml.

Iron absorption is poor in the presence of grastrointestinal disease (atrophic gastritis, Helicobacter pylori infection, celiac disease, inflammatory bowel disease), chronic kidney disease and inflammatory conditions.

Interactions

Iron may interfere with the absorption of some medications, including:

• doxycycline
• fluoroquinolones
• mycophenolate mofetil
• penicillamine
• thyroid hormones.

Iron absorption is decreased by calcium, tannins (in tea and red wine) and plant phytates (cereals).

Take it at a different time of day or as advised by your pharmacist.

Side effects of iron replacement

Compliance with iron replacement therapy may be low with some patients as iron preparations are associated with a high incidence of side effects. These include nausea, constipation, diarrhoea and black stools. To reduce this:

• Take the iron preparation after meals – but iron absorption is reduced.
• Wait 30 minutes before lying down.
• Divide the dose and take it twice daily.
• If treatment is not urgent, start with one tablet twice weekly and gradually increase the dose as tolerated.

Iron injections

Intravenous injections are used in patients who cannot tolerate oral supplementation or where iron losses exceed the daily amount that can be absorbed orally. The most commonly used intravenous preparation is iron polymaltose. Other intravenous preparations include low molecular weight iron dextran, iron carboxymaltose, iron sucrose and ferric gluconate complex.

Iron polymaltose is infused over several hours and is generally well tolerated, but it may cause infusion reactions such as headache, nausea and muscle pains. Severe allergic reactions including anaphylaxis have been reported. Delayed reactions include fever and joint pain.

Intramuscular injections are now rarely used.

Intramuscular iron injections may result in longlasting brown staining (siderosis), pain, haematoma and sterile abscesses. Improvement in staining has been reported following treatment with Q-switched ruby and/or Nd/YAG laser.

Siderosis from intramuscular iron injection

Excessive iron

Excessive levels of iron can be toxic (haemosiderosis), increasing the risk of heart disease, malignancy, liver disease and diabetes. This is more likely in those carrying a gene for haemochromatosis.