Iron Deficiency Anemia : Causes, Laboratory diagnosis and Treatment

Iron deficiency is the commonest cause of anaemia worldwide and is frequently seen in general practice. Iron deficiency anaemia is caused by defective synthesis of haemoglobin resulting in microcytic and hypochromic red blood cells.

Iron Deficiency Anemia : Causes, Laboratory diagnosis and Treatment

Iron metabolism

Iron is an important trace element and has a pivotal role in many metabolic processes. An average adult has 3-5 g of iron, of which two thirds is in the oxygen-carrying molecule haemoglobin.

A normal diet should provide about 15 mg of iron daily, of which 5-10% is absorbed (approximately 1 mg), principally in the duodenum and upper jejunum, where the acidic conditions help the absorption of iron in the ferrous form. The absorption of iron is helped by the presence of other reducing substances such as ascorbic and hydrochloric acid.

The body can increase its iron absorption in the face of increased demand. This usually happens during pregnancy, growth spurts, lactation and iron deficiency.

Once iron is absorbed from the bowel (duodenum and upper jejunum), it is transported across the mucosal cell to the blood. In the blood, iron is transported by transferrin to developing red cells in the bone marrow.

There are two forms of stored iron.

  • Ferritin which is a labile and readily accessible source of iron
  • Hemosiderin, an insoluble form mostly found in macrophages

The body losses about 1 mg of iron a day in faeces, urine, sweat and cells shed from the skin and gastrointestinal tract.

Women losses an additional 20 mg of iron per month during menstruation and the increased requirements of pregnancy (500-1000 mg) contribute to the higher incidence of iron deficiency in women of child bearing age.

Daily dietary iron requirements per 24 hours

Male 1 mg
Adolescence 2-3 mg
Female (reproductive age) 2-3 mg
Pregnancy 3-4 mg
Infancy 1 mg
Maximum bioavailability from normal diet about 4 mg

Clinical features of iron deficiency

  • Symptoms depend on how quickly anaemia develops. In cases of chronic, slow blood loss, the body adapts to increasing anemia and patients can often tolerate extremely low levels of haemoglobin with remarkably few symptoms.
  • Most patients complain about an increase in lethargy and dyspnoea. More unusual symptoms include headache, tinnitus, and taste disturbances.
  • There may be several skin, nail and other epithelial changes in chronic iron deficiency.
  • Skin atrophy occurs in about a third of patients, and (rarely nowadays) nail changes such as koilonychias (a spoon-shaped nail) can lead to brittle, flattened nails.
  • Patients may also complain of angular stomatitis, in which painful cracks appear at the corner of the mouth, sometimes accompanied by glossitis.
  • Although rare, oesophageal and pharyngeal webs may be a feature of iron deficiency anaemia (consider this in middle-aged women with dysphagia). These changes are thought to be due to the reduction of iron-containing enzymes in the epithelium and gastrointestinal tract.
  • Tachycardia and cardiac failure may occur with severe anaemia, regardless of cause, and prompt remedial action should be taken in such cases.

Predisposing factor in the development of iron deficiency

  • Age: infants (especially if history of prematurity); adolescents; postmenopausal women; old age
  • Drug history: especially aspirin and non-steroidal anti-inflammatories
  • Gastrointestinal tract: appetite or weight changes; changes in bowel habit; bleeding from rectum/melena; gastric or bowel surgery
  • Physiological: pregnancy; infancy; adolescence; breast feeding; age of weaning
  • Renal: haematuria (rarer cause)
  • Reproduction: menorrhagia
  • Sex: increased risk in women
  • Social history: diet, especially vegetarians

Causes of iron deficiency anaemia

  • Angiodysplasia
  • Carcinoma: stomach, colorectal
  • Haemorrhoids (rarely)
  • Hereditary haemorrhagic telangiectasia (rare) Malabsorption
  • Hiatus hernia (ulcerated)
  • Inflammatory bowel disease
  • Menorrhagia
  • Oesophageal varices
  • Oesophagitis
  • Peptic ulcer
  • Coeliac disease
  • Atrophic gastritis (also may result from iron deficiency)
  • Physiological
  • Growth spurts (especially in premature infants)
  • Pregnancy Dietary
  • Vegans
  • Elderly Worldwide commonest cause of iron deficiency is hookworm infection

Laboratory investigations

  • A complete blood count and a film should be taken. These confirm anaemia; the recognition of iron deficiency indices is usually straightforward (low haemoglobin concentration, low mean cell volume, low mean cell haemoglobin concentration, low mean cell haemoglobin concentration).
  • The blood film will show microcytic hypochromic red cells. Hypochromic anaemia occurs in other disorders, such as anaemia of chronic diseases, sideroblastic anaemias and in thalassemia.
  • Some modern analysers can determine the percentage of hypochromic red cells that may be high before the anaemia develops (it is worth noting that a decrease in the concentration of haemoglobin is a late feature of iron deficiency).

Further haematinic assays may be necessary to help distinguish the type.

Diagnostic difficulties arise when more than one type of anaemia is present for example, iron deficiency and folate deficiency in malabsorption, in a population where thalassemia is present, or during pregnancy, when interpretation of red cell indices may be difficult.

Haematinic assays will demonstrate reduced serum ferritin concentration in a simple iron deficiency. However, as an acute phase protein, the concentration of serum ferritin in inflammatory or malignant diseases may be normal or even elevated.

A prime example of this is rheumatoid disease, in which active disease may result in spuriously elevated serum ferritin concentration masking the underlying iron deficiency caused by gastrointestinal bleeding following non-steroidal analgesic therapy.

Confusion in liver disease may also occur, as the liver contains stores of ferritin that are released after hepatocellular damage, resulting in increased serum ferritin concentrations. In cases where the estimate of ferritin is likely to be misleading, the soluble transferrin receptor (sTfR) assay may help in the diagnosis. In iron deficiency anemia, transferrin receptors are found in greater numbers on the surface of red cells; a proportion of receptors are shed into the plasma and can be measured using commercial kits. Unlike serum ferritin, sTfR does not cause inflammatory disorders and can therefore help to distinguish between anemia due to inflammation and iron deficiency.

  • Sampling of bone marrow diagnosis is rarely performed with a simple iron deficiency, but if the diagnosis is questionable, a marrow aspiration may be performed to prove that there are no bone marrow stores.

When diagnosing iron deficiency anaemia, the underlying cause should be investigated and treated. For example, menstrual blood loss or gastrointestinal bleeding, the history will often suggest the possible cause of the bleeding. Where no obvious cause exists, further investigation will usually depend on the patient's age and sex. Possible gastrointestinal blood loss in male patients and postmenopausal women is investigated through gastrointestinal tract visualization (endoscopic or barium studies). In male and postmenopausal women, possible gastrointestinal blood loss is investigated by visualization of the gastrointestinal tract (endoscopic or barium studies). Faecal occult blood is of no value in the investigation of iron deficiency.

Diagnosis of iron deficiency anaemia

Management of Iron deficiency Anaemia

Effective management of iron deficiency relies on

      I.            Proper management of the underlying cause (e.g. gastrointestinal or menstrual blood loss)

  • Effective iron replacement therapy should result in an increase in haemoglobin concentration of approximately 1 g / l per day (about 20 g / l every three weeks), but this varies from patient to patient.
  • Once the concentration of haemoglobin is within the normal range, the iron replacement should continue for three months to replenish the iron stores.

   II.            Iron replacement therapy.

  • Oral iron replacement therapy with a gradual replenishment of iron stores and the restoration of haemoglobin is the preferred treatment.
  • Oral ferrous salts are the treatment of choice (ferric salts are less well absorbed) and usually take the form of ferrous sulfate 200 mg three times daily (providing an elemental iron per day of 65 mg or 3 195 mg).
  • Alternative preparations are ferrous gluconate and ferrous fumarate.

However, all three compounds are associated with a high incidence of side effects, including nausea, constipation and diarrhoea. These side effects may be reduced by taking tablets after meals, but even milder symptoms are associated with poor compliance with oral iron supplementation.

Failure of response to oral iron therapy

Poor compliance is the main reason for failure to respond to oral iron therapy. However, if the losses (for example, bleeding) exceed the amount of iron absorbed daily, the concentration of haemoglobin will not increase as expected; this will also be the case in the combined deficiency states.

The presence of underlying inflammation or malignancy may also result in a poor response to therapy. Finally, an incorrect diagnosis of iron deficiency anaemia should be considered in patients who do not respond adequately to iron replacement therapy.

Intravenous and intramuscular iron preparations

Parenteral iron may be used when the patient cannot tolerate oral supplements for example, when patients have severe gastrointestinal side effects or when losses exceed the daily amount that can be absorbed orally.

Iron sorbitol injection is a complex made up of iron, sorbitol and citric acid. Treatment is a course of deep intramuscular injections. The dose varies from patient to patient and depends on (a) the initial concentration of haemoglobin and (b) body weight.

10-20 deep intramuscular injections are usually given over two to three weeks.

Besides being painful, injections also lead to skin staining at the site of injection and arthralgia and are best avoided.

Intravenous preparation (Venofer ®) is available for use in selected cases and under strict medical supervision, for example on the day-to-day haematology unit (risk of anaphylaxis or other reactions).

Alternative treatments

Blood transfusion is not indicated unless the patient has decompensated due to a decrease in haemoglobin concentration and needs a faster increase in haemoglobin, for example, in cases of worsening of angina or serious coexisting pulmonary disease. In cases of iron deficiency with severe acute bleeding, blood transfusion may be required.

Prevention

In cases where dietary absorption is likely to be matched or exceeded, additional sources of iron, such as prophylactic iron supplements during pregnancy or after gastrectomy, or breastfeeding, or the use of formula milk during the first year of life (rather than cow's milk, which is a poor source of iron) should be considered.

References

  • ABC OF CLINICAL HAEMATOLOGY Second Edition Edited by DREW PROVAN Senior Lecturer, Department of Haematology, Bart’s and the London, Queen Mary’s School of Medicine and Dentistry, London
  • The source of the detail in the table is the British National Formulary, No 32(Sep), 1995.

 

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