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Iron deficiency is the most common cause of anaemia and can arise from dietary deficiency, malabsorption as a result of an underlying condition, chronic blood loss – especially from the uterus or gastrointestinal tract – or increased requirement, for example, during pregnancy. Diagnosis should be confirmed by undertaking appropriate investigations, before initiating iron supplementation. The aim of treatment is to restore haemoglobin levels and red cell indices to normal, and to replenish iron stores
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WHAT IS IRON DEFICIENCY ANAEMIA?
Iron deficiency occurs as result of long-term negative iron balance. The iron deficiency spectrum ranges from iron depletion to iron deficiency anaemia.
Iron deficiency anaemia is diminished red blood cell production due to low iron stores in the body— it is the most common cause of microcytic anaemia, hypochromic anaemia, in which the two red cell indices, mean cell volume (MCV) and mean cell haemoglobin (MCH), are reduced and the blood film shows small (microcytic) and pale (hypochromic) red cells.
Anaemia is defined as a haemoglobin (Hb) level two standard deviations below the normal for age and sex:
A serum ferritin level of less than 15 micrograms/l confirms iron deficiency.
What causes iron deficiency anaemia?
The cause of iron deficiency anaemia is often multifactorial, and can be broadly be attributed to:
Dietary deficiency — rarely a cause on its own, it takes about 8 years for a normal adult male to develop iron deficiency anaemia due to a poor diet, or malabsorption resulting in no iron intake.
Malabsorption — for example due to coeliac disease, gastrectomy, Helicobacter pylori infection, or other gastrointestinal (GI) causes.
Increased loss — chronic blood loss, especially from the uterus or GI tract.
Increased requirement — physiological iron requirements are three times higher in pregnancy than they are in menstruating women, with increasing demand as pregnancy advances.
Other causes — these include: blood donation, self-harm, haematuria (rare), nosebleeds (rare), medication.
How common is iron deficiency anaemia?
Iron deficiency is the most common cause of anaemia, affecting around 500 million people worldwide.
It is a significant problem in the developed world and has a prevalence of 2–5% among adult men and postmenopausal women, and is the reason for 4–13% of referrals to gastroenterologists.
During childbearing years, there is a higher incidence of iron deficiency anaemia in women, as they lose iron through menstruation and pregnancy.
The UK prevalence of anaemia is estimated to be 23% in pregnant women and 14% in non-pregnant women.
What are the complications?
The complications of iron deficiency anaemia include:
Iron deficiency anaemia in pregnancy has been associated with a number of problems, including:
The diagnosis of anaemia caused by iron deficiency, is made through history, examination and investigations.
Take a detailed medical history, and ask about:
Examine the person to look for signs of anaemia, arrange necessary investigations and consider other causes of anaemia.
SIGNS AND SYMPTOMS
Symptoms associated with iron deficiency anaemia depend on how quickly the anaemia develops.
People with chronic, slow blood loss may be able to tolerate very low levels of haemoglobin (for example less than 70 g/l) with few symptoms.
Fatigue and mild dyspnoea after exertion may be the only symptoms in otherwise healthy people with slow onset anaemia.
Very common symptoms of anaemia include:
Common symptoms of anaemia include:
Rare symptoms of anaemia include:
Other symptoms include:
Serious symptoms such as angina, marked ankle oedema, or dyspnoea at rest are unlikely unless the haemoglobin level is less than 70 g/l, and this indicates additional heart or lung pathology.
Angina may occur if there is pre-existing coronary artery disease.
Symptoms of iron deficiency may occur without anaemia. These symptoms include fatigue, lack of concentration, and irritability.
Common or very common signs of iron deficiency include:
Other signs of iron deficiency include:
Tachycardia, murmurs, cardiac enlargement, and heart failure may occur if anaemia is severe (haemoglobin less than 80 g/l).
There may be an absence of signs, even if the person has severe anaemia.
Arrange a full blood count (FBC).
If results of the FBC show a low haemoglobin and low mean cell volume (MCV), check the ferritin level — check the ferritin level in all people with an MCV less than 95 femtolitres.
Consider checking ferritin levels for women who are pregnant, but be aware that results may be less reliable in pregnancy.
If the diagnosis is in doubt despite serum ferritin results, consider diagnostic trials of iron treatment 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 men and postmenopausal women, as they are more at risk of occult GI bleeding and malignancy and should be investigated accordingly.
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 this particularly if the person is anaemic and:
Interpreting investigation results
Anaemia is defined as a haemoglobin (Hb) level two standard deviations below the normal for age and sex:
Mean cell volume (MCV):
An MCV less than 95 femtolitres has a sensitivity of 97.6% for iron deficiency anaemia.
Interpreting investigation results (2)
Other red blood cell changes associated with iron deficiency include:
If a blood film is arranged, it may confirm the presence of microcytic hypochromic red cells and characteristic 'pencil cells', however:
A serum ferritin level of less than 15 micrograms/l confirms the diagnosis of iron deficiency.
Ferritin levels of more than 15 micrograms/l are more difficult to interpret if infection or inflammation is present, as levels can be high even in the presence of iron deficiency.
Ferritin levels are increased independently of iron status in acute and chronic inflammatory conditions, malignant disease and liver disease.
A serum ferritin concentration of greater than 100 micrograms/l usually rules out iron deficiency anaemia.
For people with no known inflammatory states and in whom the ferritin level is indeterminate (31 to 99 micrograms/l) further tests may be required to ascertain iron status.
In pregnant women:
The differential diagnosis of microcytic anaemia includes:
Thalassaemia — for people with thalassaemia trait (alpha or beta), the mean cell volume (MCV) and mean cell haemoglobin (MCH) concentration are all reduced and are very low for the degree of anaemia.
Sideroblastic anaemias (very rare) — alcoholism can be a cause of a reversible sideroblastic anaemia. Hepatosplenomegaly is found in one third to one half of people with sideroblastic anaemia and is not present in iron deficiency anaemia.
Anaemia of chronic disease — on analysis of the full blood count (FBC), in 80% of cases, anaemia of chronic disease is normocytic and normochromic. However, in 20% of cases it can present as a microcytic, hypochromic anaemia like iron deficiency anaemia.
Lead poisoning (rare in adults) — people may have a history of risk factors, such as occupational exposures (for example, exposure to lead paint).
WHEN SHOULD I CONSIDER A DIAGNOSTIC TRIAL OF IRON TREATMENT?
If the diagnosis of iron deficiency anaemia is in doubt despite serum ferritin results, a diagnostic trial of oral iron treatment may be considered in premenopausal women with a history of menorrhagia, or pregnant women (if there is no suspicion of coeliac disease).
A trial of oral iron should be considered as the first line diagnostic test for normocytic or microcytic anaemia in pregnant women with no haemoglobinopathy.
In women with known haemoglobinopathy, serum ferritin should be checked before starting a trial of iron.
In women with unknown haemoglobinopathy status, a trial of iron should be offered. However, haemoglobinopathy screening should be undertaken without delay in accordance with the NHS sickle cell and thalassaemia screening programme guideline, but with awareness that iron deficiency can lower the haemoglobin A2 percentage.
HOW DO I MANAGE SOMEONE WITH CONFIRMED IRON DEFICIENCY ANAEMIA?
Document the likely cause — if there is no obvious cause, further investigation generally depends on the person's age and sex.
For all people with iron deficiency anaemia:
Consider stool examination to detect parasites, if appropriate from the person's travel history — faecal occult blood testing is of no benefit in the investigation of iron deficiency anaemia.
It is usually unnecessary to further investigate the following groups of people prior to treatment:
HOW DO I TREAT IRON DEFICIENCY ANAEMIA?
The aim is to restore haemoglobin levels and red cell indices to normal, and to replenish iron stores.
A dose of 65 mg elemental iron (ferrous sulfate 200mg) three times daily is needed to treat iron deficiency anaemia. However, dose-related adverse effects from taking an iron supplement are commonly experienced, which can be reduced by taking iron with food. Alternatively, lower doses may be effective and better tolerated — consider reducing the dose to ferrous sulfate 200mg (65mg elemental iron) twice a day until the clinical response is assessed after 2–4 weeks.
If ferrous sulfate is not tolerated ferrous gluconate 300mg tablets may be better tolerated than ferrous sulfate as there is less elemental iron content per tablet than ferrous sulfate.
Ferrous fumarate tablets contain more elemental iron per tablet than ferrous sulfate.
An ongoing prophylactic dose of iron (200mg ferrous sulfate daily) may be beneficial in some people who have:
Ongoing prophylaxis may also be beneficial for women who are pregnant and people undergoing haemodialysis.
WHEN SHOULD I REFER SOMEONE WITH IRON DEFICIENCY ANAEMIA?
Urgently refer people using a suspected cancer pathway for an appointment within 2 weeks if they are aged 60 years or over.
Consider an urgent referral for people using a suspected cancer pathway for an appointment within 2 weeks if they are aged under 50 years and present with rectal bleeding.
Refer to gastroenterology:
Refer women to gynaecology if:
Also refer people:
HOW DO I FOLLOW UP PEOPLE WITH IRON DEFICIENCY ANAEMIA?
Recheck haemoglobin levels (full blood count) after 2–4 weeks of iron supplement treatment to assess the person's response. The haemoglobin concentration should rise by about 20 g/100 L over 3–4 weeks.
If there is a response, check the full blood count at 2–4 months to ensure that the haemoglobin level has returned to normal.
Once haemoglobin concentration and red cell indices are normal:
Consider an ongoing prophylactic dose in people who are at risk.
HOW DO I MANAGE SOMEONE WHO HAS NOT BENEFITTED FROM INITIAL IRON TREATMENT?
Assess adherence and whether the iron treatment is tolerated — if an oral iron supplement (usually ferrous sulfate) is not tolerated, address the adverse effects:
If the person is still unable to tolerate oral iron supplements, seek specialist advice.
Refer people for specialist assessment if there is a lack of response (that is, an increase of less than 20 g/l in the haemoglobin level) after 2–4 weeks.
If the person has already had normal upper and lower gastrointestinal investigations for iron deficiency anaemia and the anaemia persists or recurs, consider testing for Helicobacter pylori, and eradicate if present.
NICE Clinical Knowledge Summaries. Anaemia – iron deficiency, 2018. https://cks.nice.org.uk/anaemia-iron-deficiency
Uprichard WO, Uprichard J. Investigating microcytic anaemia. BMJ 2013;346:f3154. https://www.bmj.com/content/346/bmj.f3154/related
Royal College of Nursing (2015). Iron deficiency and anaemia in adults. https://www.rcn.org.uk/professional-development/publications/pub-004842
British Columbia Medical Association. Iron deficiency – investigation and management, 2010 https://www2.gov.bc.ca/gov/content/health/practitioner-professional-resources/bc-guidelines/iron-deficiency
Short MW, Domagalski JE. (2013) Iron deficiency anemia: evaluation and management. Am Fam Physician 2013;87(2):98-104 https://www.aafp.org/afp/2013/0115/p98.html