ABC of Clinical haematology: Iron deficiency anaemiaBMJ 1997; 314 doi: https://doi.org/10.1136/bmj.314.7077.360 (Published 01 February 1997) Cite this as: BMJ 1997;314:360
- Rebecca FrewinAndrew HensonDrew Provan
Iron deficiency is the commonest cause of anaemia worldwide and is frequently seen in general practice. The anaemia of iron deficiency is caused by defective synthesis of haemoglobin, resulting in red cells that are smaller than normal (microcytic) and contain reduced amounts of haemoglobin (hypochromic).
Diagnosing iron deficiency is usually straightforward–the major challenge is determining the cause of the anaemia
Iron has a pivotal role in many metabolic processes, and the average adult contains 3-5 g of iron, of which two thirds is in the oxygen-carrying molecule haemoglobin.
A normal Western diet provides about 15 mg of iron daily, of which 5-10% is absorbed, principally in the duodenum and upper jejunum, where the acidic conditions help the absorption of iron in the ferrous form. Absorption is helped by the presence of other reducing substances, such as hydrochloric acid and ascorbic acid. The body has the capacity to increase its iron absorption in the face of increased demand–for example, in pregnancy, lactation, growth spurts, and iron deficiency.
Once absorbed from the bowel, iron is transported across the mucosal cell to the blood, where it is carried by the protein transferrin to developing red cells in the bone marrow. Iron stores comprise ferritin, a labile and readily accessible source of iron, and haemosiderin, an insoluble form found predominantly in macrophages.
About 1 mg of iron a day is shed from the body in urine, faeces, sweat, and cells shed from the skin and gastrointestinal tract. Menstrual losses of an additional 20 mg a month and the increased requirements of pregnancy (500-1000 mg) contribute to the higher incidence of iron deficiency in women of reproductive age.
Clinical features of iron deficiency
The symptoms accompanying iron deficiency depend on how rapidly the anaemia develops. In cases of chronic, slow blood loss, the body adapts to the increasing anaemia, and patients can often tolerate extremely low concentrations of haemoglobin–for example, <70 g/l–with remarkably few symptoms. Most patients complain of increasing lethargy and dyspnoea. More unusual symptoms are headaches, tinnitus, and taste disturbance.
On examination, several skin, nail, and other epithelial changes may be seen in chronic iron deficiency. Atrophy of the skin occurs in about a third of patients, and nail changes such as koilonychia (spoon shaped nails) result in brittle, flattened nails. Patients may also complain of angular stomatitis, in which painful cracks appear at the angle of the mouth, sometimes accompanied by glossitis. Although uncommon, oesophageal and pharyngeal webs can be a feature of iron deficiency anaemia (consider this in middle aged women presenting with dysphagia). These changes are believed to be due to a reduction in the iron-containing enzymes in the epithelium and gastrointestinal tract.
Risk factors in development of iron deficiency
Age–Infants (especially if history of prematurity); adolescents; postmenopausal women; old age
Sex–Increased risk in women
Renal–Haematuria (rarer cause)
Gastrointestinal tract–Appetite or weight changes; changes in bowel habit; bleeding from rectum/melaena; gastric or bowel surgery
Drug history–Especially aspirin and non-steroidal anti-inflammatories
Social history–Diet, especially vegetarians
Physiological–Pregnancy; infancy; adolescence; breast feeding; age of weaning
Increasing tachycardia and worsening cardiac failure indicate cardiac decompensation from the worsening anaemia, and in such cases prompt remedial action should be taken.
When iron deficiency is confirmed a full clinical history including leading questions on possible gastrointestinal blood loss or malabsorption (as in, for example, coeliac disease) should be obtained. Menstrual losses should be assessed, and the importance of dietary factors and regular blood donation should not be overlooked.
Diet alone is seldom the sole cause for iron deficiency anaemia in Britain except when it prevents an adequate response to a physiological challenge–as in pregnancy, for example.
Causes of iron deficiency anaemia Reproductive system
Inflammatory bowel disease
Carcinoma: stomach, colorectal
Angiodysplasia hereditary haemorrhagic telangiectasia (rare)
Atrophic gastritis (also may result from iron deficiency)
Growth spurts (especially in premature infants)
Worldwide commonest cause of iron deficiency is hookworm infection
Investigations in iron deficiency anaemia
Full clinical history and physical examination
Full blood count and blood film examination
Haematinic assays (serum ferritin, vitamin B12, folate)
Urea and electrolytes, liver function tests
Faecal occult bloods
Midstream urine (occult blood loss)
Fibreoptic and/or barium studies of gastrointestinal tract
Pelvic ultrasound (females, if indicated)
A full blood count and film should be taken. These will confirm the anaemia; recognising the indices of iron deficiency is usually straightforward (reduced haemoglobin concentration, reduced mean cell volume, reduced mean cell haemoglobin, reduced mean cell haemoglobin concentration). The blood film shows microcytic hypochromic red cells. Hypochromic anaemia occurs in other disorders, such as anaemia of chronic disorders and sideroblastic anaemias and in globin synthesis disorders, such as thalassaemia. To help to differentiate the type, further haematinic assays may be necessary. Difficulties in diagnosis arise when more than one type of anaemia is present–for example, iron deficiency and folate deficiency in malabsorption, in a population where thalassaemia is present, or in pregnancy, when the interpretation of red cell indices may be difficult.
Haematinic assays will demonstrate reduced serum ferritin concentration in straightforward iron deficiency. As an acute phase protein, however, the serum ferritin concentration may be normal or even raised in inflammatory or malignant disease.
A prime example of this is found in which active disease may result in a spuriously raised serum ferritin concentration masking an underlying iron deficiency caused by gastrointestinal bleeding after non-steroidal analgesic treatment. There may also be confusion in liver disease as the liver contains stores of ferritin that are released after hepatocellular damage, leading to raised serum ferritin concentrations. In cases where ferritin estimation is likely to be misleading, it can be helpful to determine the serum iron concentration and total iron binding capacity, which are reduced and raised respectively in uncomplicated iron deficiency. In common with serum ferritin estimation, however, these measures are often difficult to interpret when inflammation is present.
Diagnosis of iron deficiency anaemia
Diagnostic bone marrow sampling is seldom performed in simple iron deficiency, but if the diagnosis is in doubt a marrow aspirate may be carried out to demonstrate absent bone marrow stores.
When iron deficiency has been diagnosed, the underlying cause should be investigated and treated. Often the history will indicate the likely source of bleeding–for example, menstrual blood loss or gastrointestinal bleeding. If there is no obvious cause further investigation generally depends on the age and sex of the patient. In male patients and postmenopausal women possible gastrointestinal blood loss is investigated by performing faecal occult bloods and visualisation of the gastrointestinal tract (endoscopic or barium studies). Faecal occult bloods are useful screening tests (sensitivity 50-75% in the detection of colorectal cancer), but a negative result should not preclude other investigations of the gastrointestinal tract.
Effective management of iron deficiency relies on (a) the appropriate management of the underlying cause (for example, gastrointestinal or menstrual blood loss) and (b) iron replacement therapy.
Oral iron replacement therapy with gradual replenishment of iron stores and restoration of haemoglobin is the preferred treatment. Oral ferrous salts are the treatment of choice (ferric salts are less well absorbed) and should take the form of ferrous sulphate 200 mg three times daily (providing 65 mgx3 = 195 mg elemental iron/day). Alternative preparations include ferrous gluconate and ferrous fumarate. All three compounds, however, are associated with a high incidence of side effects, including nausea, constipation, and diarrhoea. These side effects may be reduced by taking the tablets after meals, but even milder symptoms account for poor compliance with oral iron supplementation. Modified release preparations have been developed to reduce side effects but in practice prove expensive and often release the iron beyond the sites of optimal absorption.
Effective iron replacement therapy should result in a rise in haemoglobin concentration of around 1 g/l per day (about 20 g/l every three weeks), but this varies from patient to patient. Once the haemoglobin concentration is within the normal range, iron replacement should continue for three months to replenish the iron stores.
Failure to respond to oral iron therapy
The main reason for failure to respond to oral iron therapy is poor compliance. However, if the losses (for example, bleeding) exceed the amount of iron absorbed daily, the haemoglobin concentration will not rise as expected; this will also be the case in combined deficiency states.
The presence of underlying inflammation or malignancy may also lead to a poor response to therapy. Finally, an incorrect diagnosis of iron deficiency anaemia should be considered in patients who fail to respond adequately to iron replacement therapy.
Intravenous iron preparations
Intravenous iron preparations are available in Britain on a named patient basis only
These preparations are frequently associated with side effects, some of which are severe–such as anaphylaxis
They should therefore be given only under close medical supervision and when full resuscitation facilities are available
The rise in haemoglobin concentration is no faster with parenteral iron preparations than with oral iron 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 if the losses exceed the daily amount that can be absorbed orally.
Iron sorbitol injection is a complex of iron, sorbitol and citric acid. Treatment consists of a course of deep intramuscular injections. The dosage varies from patient to patient and depends on (a) the initial haemoglobin concentration and (b) body weight. Generally, 10-20 deep intramuscular injections are given over two to three weeks. Apart from being painful, the injections also lead to skin staining at the site of injection and arthralgia.
Blood transfusion is not indicated unless the patient has decompensated due to a drop in haemoglobin concentration and needs a more rapid rise in haemoglobin–for example, in cases of worsening angina or severe coexisting pulmonary disease. In cases of iron deficiency with serious ongoing acute bleeding blood transfusion may be required.
When absorption from the diet is likely to be matched or exceeded by losses, extra sources of iron should be considered–for example, prophylactic iron supplements in pregnancy or after gastrectomy or encouragement of breast feeding or use of formula milk during the first year of life (rather than cows' milk, which is a poor source of iron).
Drs A G Smith and A Amos provided the photographic material and Dr A Odurny provided the radiograph. The source of the detail in the table is the British National Formulary, No 32(Sep), 1995.
Rebecca Frewin is registrar in haematology at the Southampton University Hospitals NHS Trust.
The ABC of clinical haematology is edited by Drew Provan, consultant haematologist and honorary senior lecturer at the Southampton University Hospitals NHS Trust, and Andrew Henson, clinical research fellow, university department of primary care, Royal South Hants Hospital, Southampton.