• Symptoms associated with iron deficiency anaemia will depend on how quickly the anaemia develops. For example, people with chronic, slow blood loss may be able to tolerate very low levels of haemoglobin with few symptoms.
• Symptoms commonly include fatigue, dyspnoea, and palpitations.
• Less common symptoms include:
• Headache.
• Tinnitus.
• Taste disturbance.
• Pruritus.
• Pica (abnormal dietary cravings, e.g. ice, clay).
• Sore tongue.
• Dysphagia (in association with oesophageal web which occurs in Patterson-Brown-Kelly or Plummer-Vinson syndromes).
• Otherwise healthy people with slow-onset anaemia may present with fatigue and dyspnoea on exertion as their only symptoms.
• Serious symptoms such as angina, marked ankle oedema, or dyspnoea at rest are unlikely at haemoglobin concentrations of more than 7 g/dL unless there is additional heart or lung pathology. Angina may occur if there is pre-existing coronary artery disease.

The description of the symptoms of iron deficiency are expert opinion from medical textbooks [Cox, 2003;Longmore et al, 2007; Provan, 2007] and a review article [Todd and Caroe, 2007].

• There may be no signs, even if the person has severe anaemia.
• Pallor may be observed even with mild anaemia:
• Less commonly:
• Atrophic glossitis.
• Angular cheilosis (ulceration of the corners of the mouth).
• Nail changes, such as longitudinal ridging and koilonychia (spoon-shaped nails).
• Tachycardia, murmurs, cardiac enlargement, and heart failure may occur if anaemia is severe (haemoglobin < 8 g/dL).

The description of the signs of iron deficiency are expert opinion from medical textbooks [Weatherall, 2003; Longmore et al, 2007].

• Check a full blood count (see Interpreting a full blood count).
• For people with a low haemoglobin and low mean cell volume (i.e. microcytic anaemia):
• For a non-pregnant person, check the ferritin level (see Interpreting ferritin levels).
• For a pregnant woman, consider checking ferritin levels. Microcytic anaemia in this group is highly likely to be due to iron deficiency and ferritin results may be less reliable in pregnancy.
• It is less clear in which groups of people vitamin B12 and folate levels should also be checked, and when this should be done. Consider particularly if the person is anaemic and:
• The anaemia is normocytic with a low or normal ferritin level.
• There is an inadequate response to iron supplements in proven iron deficiency anaemia and no reason for this (e.g. poor compliance) is apparent.
• Vitamin B12 or folate deficiency is suspected (e.g. dietary deficiency, malabsorption, lack of folate supplementation in pregnancy).
• The person is in an older age group (more at risk of pernicious anaemia).
• For more information on testing for vitamin B12 or folate levels, and interpretation of the results, see the CKS topic on Anaemia - B12 and folate deficiency.

People who are not pregnant:

• Haemoglobin level:
• The World Health Organization defines anaemia as [WHO et al, 2001]:
• In men over 15 years of age: haemoglobin (Hb) below 13 g/dL.
• In non-pregnant women over 15 years of age: Hb below 12 g/dL.
• In children of 12–14 years of age: Hb below 12 g/dL.
• However, there is variability between the criteria for iron deficiency anaemia between different studies and the normal range for haemoglobin differs between different populations in the UK, so it seems reasonable to use the lower limit of the local laboratory normal range to define anaemia [British Society of Gastroenterology, 2005].
• A low haemoglobin level by itself is poorly specific for iron deficiency as anaemia can be due to other causes. In addition, in mild iron deficiency states, the haemoglobin level may be normal [AHRQ, 2006].
• Mean cell volume:
• Decreased mean cell volume (microcytosis) — the probability of iron deficiency in anaemic people increases with decreasing mean cell volume, but no specific cut-off point can be used. Microcytic anaemia is often assumed to be due to iron deficiency, but up to a third of people will have a different diagnosis (e.g. myelodysplasia, chronic inflammation) [Galloway and Smellie, 2006; Smellie et al, 2006]. Note: reference ranges may vary between laboratories.
• Other parameters of the full blood count:
• Other red blood cell changes associated with iron deficiency include [British Society of Gastroenterology, 2005; Longmore et al, 2007]:
• Reduced mean cell haemoglobin (hypochromia).
• Increased percentage of hypochromic red cells.
• Anisocytosis (variation in the size of red blood cells).
• Poikilocytosis (presence of irregular shaped red blood cells).
• A mild thrombocytosis (increase in the number of platelets) may also be suggestive of iron deficiency [British Columbia Medical Association, 2004].

Pregnant women:

• In pregnancy a physiological reduction in haemoglobin (Hb) concentration occurs, which does not represent anaemia. There is an increase in red cell mass and plasma volume; the plasma volume increases more than the red cell mass, causing a relative Hb reduction [Baker, 2000; Letsky, 2003].
• There is a lack of agreement on the Hb level for the diagnosis of anaemia during pregnancy.
• The World Health Organization (WHO) defines anaemia as an Hb level less than 11 g/dL throughout pregnancy (this is the most widely used definition worldwide) [WHO et al, 2001].
• Mean cell volume increases by approximately 4 femtolitres in pregnancy [Letsky, 2003].

People who are not pregnant:

• Serum ferritin level is the biochemical test which most reliably correlates with relative total body iron stores. Low levels indicate low iron stores. However, the test is difficult to interpret if infection or inflammation is present, as levels can be high even in the presence of iron deficiency [WHO et al, 2001].
• A serum ferritin level of less than 15 microgram/L confirms the diagnosis of iron deficiency anaemia [British Society of Gastroenterology, 2005; Smellie et al, 2006].
• A serum ferritin concentration of greater than 100 microgram/L usually rules out iron deficiency [Smellie et al, 2006; Killip et al, 2007]. However, expert feedback suggests that this may not be the case if a person has certain inflammatory diseases (e.g. malaria, tuberculosis) as the ferritin can be raised above 100 microgram/L even in the presence of iron deficiency anaemia.
• Ferritin levels of more than 15 micrograms/L are more difficult to interpret as they can be influenced by the presence of co-existing disease:
• Coexisting diseases in which ferritin levels may be misleading include rheumatoid disease, liver disease, malignancy, hyperthyroidism, kidney disease, or heavy alcohol intake. Feedback from expert reviewers suggests that this may also be the case with any disease in which C-reactive protein, erythrocyte sedimentation rate or globulins are increased [British Columbia Medical Association, 2004; Provan, 2007; Zimmerman and Hurrell, 2007].
• Expert opinion varies as to the level of ferritin which is diagnostic of iron deficiency anaemia in people with chronic inflammation. The British Society of Gastroenterology suggest a diagnostic cut-off of serum ferritin of 50 micrograms/L in people who have coexisting disease [British Society of Gastroenterology, 2005]; other reviews concerning the laboratory diagnosis of iron deficiency anaemia concluded that the likelihood of iron deficiency does not start to decrease until ferritin levels are higher than 70 micrograms/L in people with inflammatory or liver disease [Guyatt et al, 1992; Smellie et al, 2006].
• If inflammation is suspected to be spuriously affecting the ferritin result, practitioners need to consider other markers of inflammation (e.g. white blood cell count, platelets, C-reactive protein) or measures of iron status (e.g. iron, total iron binding capacity), and seek advice from haematology or clinical biochemistry if in doubt about selection of further tests and interpretation of results.

Pregnant women:

• Serum ferritin level is considered to be a reliable indicator of iron deficiency in the first trimester (in the absence of infection, inflammation, or excessive alcohol consumption); however serum ferritin levels fall in the second and third trimesters independent of iron stores [Mungen, 2003].

Recommendations on investigating suspected iron deficiency anaemia, and interpreting results are based on expert opinion from a World Health Organization guideline [WHO et al, 2001], a national guideline [British Society of Gastroenterology, 2005], a US guideline [AHRQ, 2006], a Canadian guideline [British Columbia Medical Association, 2004], medical textbooks [Letsky, 2003; Longmore et al, 2007; Provan, 2007], and review articles [Guyatt et al, 1992; Baker, 2000; Mungen, 2003 Galloway and Smellie, 2006; Smellie et al, 2006; Killip et al, 2007; Zimmerman and Hurrell, 2007].

• Feedback from expert reviewers and a paper on investigating iron status in microcytic anaemia [Galloway and Smellie, 2006] suggest that if the diagnosis of iron deficiency anaemia is in doubt despite serum ferritin results, a diagnostic trial of oral iron treatment is appropriate in premenopausal women with a history of menorrhagia, or pregnant women (if there is no suspicion of coeliac disease).
• A diagnostic trial of iron treatment should not be used for postmenopausal women as they are more at risk of occult gastrointestinal bleeding and malignancy [Baker, 2000].
• For more information about iron treatment, see Treating iron deficiency anaemia.
• For more information about when to test to confirm a response to treatment, see Monitoring during treatment.

This recommendation is based on expert opinion from review articles [Baker, 2000; Galloway and Smellie, 2006] and CKS reviewers.

• The differential diagnosis of microcytic anaemia includes:
• Thalassaemia.
• Sideroblastic anaemias.
• Some anaemias of chronic disease.
• Lead poisoning (rare in adults).
• Thalassaemia and sideroblastic anaemia are both associated with an accumulation of iron, so tests will show an increase in serum iron and ferritin, and a low total iron-binding capacity.
• For people with thalassaemia trait (alpha or beta), the mean cell volume, mean cell haemoglobin, and mean cell haemoglobin concentration are all reduced and are very low for the degree of anaemia.

Information on the differential diagnosis of iron deficiency anaemia is based on expert opinion from review articles [Hoffbrand et al, 2001; Killip et al, 2007] and a medical textbook [Longmore et al, 2007].