Iron deficiency anaemia: Diagnosis and management

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:

• In men aged over 15 years — Hb below 130g/l.
• In non-pregnant women aged over 15 years — Hb below 120 g/l.
• In children aged 12–14 years — Hb below 120 g/l.
• In pregnant women — Hb below 110 g/l throughout pregnancy. An Hb level of 110 g/l or more appears adequate in the first trimester, and a level of 105 g/l appears adequate in the second and third trimesters.
• Postpartum — below 100 g/l.

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.

• In adult men and postmenopausal women, GI blood loss is the most common cause of iron deficiency anaemia.
• Menstruation is the most common cause of iron deficiency anaemia in premenopausal women.

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:

• Cognitive and behavioural impairment in children — especially attention deficits.
• Impaired muscular performance — endurance, and exercise capacity are reduced.
• Heart failure — high-output heart failure can occur in people with severe anaemia, especially in those with a haemoglobin level less than 50 g/l.
• Adverse effects on immune status and morbidity from infection (for all age groups).

Iron deficiency anaemia in pregnancy has been associated with a number of problems, including:

• Increased morbidity for the mother and infant, and the possibility of lower birthweight.
• Preterm delivery — increased risk of preterm delivery and perinatal mortality.
• Maternal postpartum fatigue, altered cognition and depressive symptoms — this in turn may affect the woman's interactions with the infant and may negatively impact behaviour and development.
• Infant iron deficiency in the first three months of life (by a variety of mechanisms).

DIAGNOSIS

The diagnosis of anaemia caused by iron deficiency, is made through history, examination and investigations.

Take a detailed medical history, and ask about:

• Symptoms.
• Diet (to identify poor iron intake).
• Drug history (for example the use of aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, clopidogrel, or corticosteroids).
• A family history of:
• Iron deficiency anaemia
• Bleeding disorders and telangiectasia
• Colorectal carcinoma
• Haematological disorders
• A history of overt bleeding, heavy bruising or blood donation
• A history of recent illness that might suggest underlying gastrointestinal bleeding
• Menstrual history, pregnancy or breastfeeding (if appropriate).
• Travel history (increased risk of hookworm in travellers to the tropics)
• Weight loss.

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:

• Dyspnoea
• Fatigue
• Headache.

Common symptoms of anaemia include:

• Cognitive dysfunction
• Restless leg syndrome
• Vertigo.

Rare symptoms of anaemia include:

• Dysphagia (in association with oesophageal web which occurs in Patterson-Brown-Kelly or Plummer-Vinson syndromes)
• Haemodynamic instability
• Syncope

Other symptoms include:

• Dizziness, weakness
• Dysgeusia
• Irritability
• Palpitations
• Pica (abnormal dietary cravings, for example for ice or dirt)
• Pruritus
• Sore tongue
• Tinnitus
• Impairment of body temperature regulation (in pregnant women).

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:

• Pallor – this may be observed even with mild anaemia
• Atrophic glossitis
• Dry and rough skin, dry and damaged hair
• Diffuse and moderate alopecia.

Other signs of iron deficiency include:

• 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 less than 80 g/l).

There may be an absence of signs, even if the person has severe anaemia.

INVESTIGATIONS

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:

• 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 (for example poor adherence) is apparent
• Vitamin B12 or folate deficiency is suspected (for example due to dietary deficiency, malabsorption, or lack of folate supplementation in pregnancy)
• The person is in an older age group (more at risk of pernicious anaemia).

Interpreting investigation results

Anaemia is defined as a haemoglobin (Hb) level two standard deviations below the normal for age and sex:

• In men aged over 15 years — Hb below 130g/l.
• In non-pregnant women aged over 15 years — Hb below 120g/l.
• In children aged 12–14 years of age — Hb below 120g/l.
• In pregnant women — Hb below 110g/l throughout pregnancy. An Hb level of 110g/l or more appears adequate in the first trimester, and a level of 105g/100 L appears adequate in the second and third trimesters.
• Postpartum — below 100g/l.

Mean cell volume (MCV):

• • In adults, microcytosis is when the MCV is less than 80 femtolitres.

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:

• Reduced mean cell Hb (hypochromia)
• Increased percentage of hypochromic red cells
• Anisocytosis (variation in the size of red blood cells)
• Poikilocytosis (presence of irregular shaped red blood cells).

If a blood film is arranged, it may confirm the presence of microcytic hypochromic red cells and characteristic 'pencil cells', however:

• Hypochromia may also occur in haemoglobinopathies (such as thalassaemia)
• In pregnancy, a physiological reduction in 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, leading to haemodilution and a fall in the haematocrit from 40% to 33%
• Normal pregnancy is also associated with a slight increase in MCV (by approximately 4 femtolitres) and for milder cases of iron deficiency, the MCV may not fall below the normal range.

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:

• Serum ferritin level is a reliable indicator of iron deficiency in the first trimester.
• In the second and third trimesters it is of limited use, as serum ferritin levels fall independently of iron stores.
• A serum ferritin concentration less than 15 micrograms/l indicates iron depletion in all stages of pregnancy, and treatment should be considered when levels fall below 30 micrograms/l, as this indicates early iron depletion, which will continue to fall unless treated.

DIFFERENTIAL DIAGNOSIS

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:

• Screen for coeliac disease — if positive, refer for further investigations.
• Test the urine for blood.

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:

• Otherwise healthy young people in whom the history clearly suggests a cause — for example, regular blood donors.
• Menstruating young women with no history of gastrointestinal symptoms or family history of colorectal cancer.
• Pregnant women, unless the anaemia is severe, the history and examination suggest an alternative cause of iron deficiency (for example inflammatory bowel disease), or there is no response to iron supplementation.
• People who are terminally ill or unable to undergo invasive investigations.
• People who refuse further investigations.

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.

Ongoing supplementation

An ongoing prophylactic dose of iron (200mg ferrous sulfate daily) may be beneficial in some people who have:

• Recurring anaemia (such as in an elderly person) and further investigations are not indicated or appropriate
• An iron-poor diet — for example, vegans
• Malabsorption – for example, coeliac disease
• Menorrhagia
• Had a gastrectomy.

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:

• All men and postmenopausal women with iron deficiency anaemia unless they have overt non-gastrointestinal bleeding.
• Men with a haemoglobin (Hb) level less than 120g/l and postmenopausal women with an Hb level less than 100g/l should be investigated more urgently, as lower levels of Hb suggest more serious disease.
• All people aged 50 years or over with marked anaemia, or a significant family history of colorectal carcinoma, even if coeliac disease is found.
• Premenopausal women if they are aged under 50 years and have colonic symptoms, a strong family history (two affected first-degree relatives or just one first-degree relative affected before the age of 50 years) of gastrointestinal cancer, or persistent iron deficiency anaemia despite treatment.

Refer women to gynaecology if:

• Menorrhagia is unresponsive to medical management
• She has postmenopausal bleeding
• For women aged over 55 years — refer urgently using a suspected cancer pathway for an appointment within 2 weeks
• For women aged under 55 years — consider referring urgently using a suspected cancer pathway for an appointment within 2 weeks
• She is pregnant and has significant symptoms and/or severe anaemia (haemoglobin less than 70 g/l), or late gestation (over 34 weeks), or if there is failure to respond to a trial of oral iron.

Also refer people:

• If coeliac serology is positive — refer to gastroenterology
• If they have profound anaemia with signs of heart failure
• If they are unable to tolerate, or are not responding to, oral iron treatment
• Who have initially responded to iron treatment but develop anaemia again without an obvious underlying cause
• When the type of anaemia is in doubt
• When further haematological investigations, such as bone marrow examination or an investigation of bleeding state, cannot be carried out in primary care.

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:

• Continue iron treatment for 3 months to aid replenishment of iron stores, and then stop.
• Then monitor the person's full blood count every 3 months for 1 year.
• Recheck after a further year, and again if symptoms of anaemia develop subsequently.
• If haemoglobin or red cell indices drop below normal, prescribe iron supplements.

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:

• Offer a laxative to people with constipation
• Offer reassurance to people who have black stools
• Recommend the person takes iron with or after meals
• Reduce the dose frequency of the iron supplement (for example one or two tablets daily)
• Give a different iron formulation or salt with a lower content of elemental iron

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.

ACTIVITIES

• Run a report on all patients coded as having iron deficiency.

• Review case notes to ensure that there is a documented reason for the iron deficiency and formal diagnosis.

• Review/follow up all patients with no formal diagnosis.

Resources

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