Iron Deficiency Anaemia

Introduction

Anaemia is defined as a haemoglobin (Hb) level of less than 130g/L for men, and less than 120g/L for non-pregnant women.

Iron deficiency anaemia (IDA) occurs when body stores of iron are low, leading to reduced production of red blood cells.

IDA is the most common cause of anaemia globally, affecting around 500 million people.¹ 

Aetiology

The three major causes of iron deficiency are:²

• Reduced absorption of iron
• Increased utilisation of iron
• Blood loss

Reduced absorption of iron

Causes of reduced absorption of iron include:

• Dietary: the main sources of dietary iron include meat, leafy green vegetables, and fortified foods including cereals and bread. Vegans, vegetarians, and those with poor or restricted diets are at risk.²
• Malabsorption: most iron absorption occurs in the small intestine. Malabsorption of iron can occur at the pre-mucosal level when digestive enzyme activity is disrupted, for example after gastrectomy or in patients with cystic fibrosis. Coeliac disease and inflammatory bowel disease result in a reduction in the mucosal surface area available for iron absorption. Intestinal resection and jejuno-ileal bypass cause inadequate absorption in the small intestine. Post-mucosal malabsorption occurs due to lymphatic obstruction in conditions such as lymphoma.³
• Drugs: drugs which reduce absorption include tetracyclines/quinolones (chelate iron) and proton pump inhibitors (decrease gastric acid that is necessary for iron absorption).²

Increased utilisation of iron

Causes of increased utilisation of iron include:⁵

• Pregnancy: increased demand due to increased blood volume as well as the needs of the fetus
• Growth spurts in children 

Blood loss

Every 2.5 ml of whole blood or 1ml of packed red blood cells contains 1mg of iron.

In comparison, only 1mg on average of iron is absorbed daily from the diet, so even modest blood loss over time can lead to iron deficiency.⁴  

In women, menorrhagia is a major cause of blood loss.

Conditions causing blood loss from the gastrointestinal system can include gastro-oesophageal reflux disease (GORD), ulcers, inflammatory bowel disease (IBD), malignancy, hookworm/schistosomiasis in tropical countries, and drugs (NSAIDs).

Other potential causes include trauma, haematuria, recurrent nose bleeds, blood donation and haemolysis.^4,5

Risk factors

Risk factors for iron deficiency anaemia include:⁵

• Pregnancy
• Menorrhagia
• Vegetarian/vegan diet
• Hookworm infection
• Haemodialysis: caused by blood loss in dialysis and poor oral absorption
• Coeliac disease
• Gastrectomy and achlorhydria (absence of gastric acid production)
• Non-steroidal anti-inflammatory use

Clinical features

Iron deficiency anaemia is often asymptomatic or causes only mild symptoms, especially if the anaemia develops gradually in otherwise healthy individuals who are able to compensate.²

History

Common symptoms of iron deficiency anaemia include:^1,5

• Dyspnoea
• Fatigue
• Headache
• Palpitations
• Pale skin or conjunctiva

Less common symptoms of iron deficiency anaemia include:^1,5

• Restless leg syndrome
• Pica (a craving non-food substances, such as ice or dirt – commonly seen in children and pregnant women)
• Tinnitus
• Pruritus
• Hair loss
• Mouth ulcers
• Vertigo/dizziness

Symptoms of underlying diseases associated with iron deficiency anaemia include:²

• Dysphagia: oesophageal malignancy, oesophageal webs associated with Plummer Vinson syndrome (a triad of atrophic glossitis, oesophageal strictures, and iron deficiency anaemia)⁵
• Dyspepsia: gastric cancer, peptic ulcer disease
• Abdominal pain: coeliac disease, intrabdominal malignancy, inflammatory bowel disease
• Change in bowel habit: bowel cancer, coeliac disease, inflammatory bowel disease
• Rectal bleeding: anal fissure, rectal cancer, haemorrhoids, inflammatory bowel disease
• Weight loss: inflammatory bowel disease, bowel cancer

Other important areas to cover in the history include:

• Last menstrual period
• Drug history: especially the use of NSAIDs

Clinical examination

Clinical findings of iron deficiency anaemia may include:²

• Conjunctival pallor
• Angular cheilitis (ulcers at the corners of the mouth)
• Atrophic glossitis (painful tongue with loss of papillae)
• Koilonychia (spoon-shaped nails)
• Dry skin and hair

In severe anaemia, there may be tachycardia, murmurs, signs of cardiomegaly, and signs of heart failure such as peripheral oedema.¹

An abdominal examination should also be carried out, to look for masses and lymphadenopathy.²

Differential diagnoses

Clinical features of iron deficiency anaemia are non-specific and may overlap with those of other causes of anaemia, so further investigations are essential to narrow the differential diagnosis.

Iron deficiency classically causes microcytic hypochromic anaemia characterised by small and pale red blood cells on blood film.  

Other causes of microcytic anaemia include thalassemia, a genetic defect of haemoglobin production common in certain parts of the world such as the Mediterranean coast and sideroblastic anaemia, a congenital or acquired inability to integrate iron into haemoglobin. Both diseases cause microcytosis and hypochromia.

Anaemia of chronic disease is caused by ongoing inflammation in conditions such as:

• Inflammatory arthritis
• Cancer
• Kidney disease
• Infections (e.g. tuberculosis and HIV)

Anaemia of chronic disease usually causes normocytic anaemia, but in 20% of cases can cause normochromic microcytic anaemia.

Hyperchromic microcytic anaemia is rare and caused by hereditary spherocytosis, a genetic red cell membrane defect. Other rarer causes of microcytic anaemia are lead toxicity and copper deficiency.^5,8

Investigations

Confirming iron deficiency

Full blood count

Typical findings on a full blood count (FBC) in iron deficiency anaemia include:^1,5

• Low Hb: <130g/L for men, <120g/L for non-pregnant women
• Low MCV: <95fl is microcytic with a 97.6% sensitivity for iron deficiency
• Reduced mean corpuscular haemoglobin (MCH): <27.5 picograms/red cell indicates hypochromia
• Reduced MCHC
• Increased red cell distribution width (RDW): indicates variation in the size of red blood cells

Ferritin

If the full blood count reveals a low Hb and MCV, a ferritin level should also be assessed.

The presence of low serum ferritin can help to confirm an iron-deficient state. However, as ferritin is an acute phase reactant (i.e. it rises in inflammatory states), patients who are iron deficient may appear to have normal (or even raised) serum ferritin levels in the context of acute inflammation (e.g. infection, autoimmune disease).

Transferrin saturation and total iron-binding capacity (TIBC)

Transferrin saturation and TIBC can be useful to confirm iron deficiency, particularly in the context of inflammation (e.g. infection, inflammatory disorder).

Typical findings in iron deficiency anaemia include:

• Low transferrin saturation: as there is less iron to saturate the transferrin
• Raised total iron-binding capacity (TIBC): there is an increased capacity to bind iron due to reduced levels of iron

Blood film

Typical findings on a blood film including hypochromic cells, which differ in size (anisocytosis), and shape (poikilocytosis).²

B12 and folate

B12 and folate are often checked in all patients presenting with anaemia to rule out B12/folate deficiency, which typically presents with macrocytic anaemia.

B12 and folate levels should be checked:¹

• in patients presenting with normocytic/macrocytic anaemia and low or normal ferritin
• in patients who have not demonstrated an adequate response to iron treatment¹

Investigation of an underlying cause

Investigation to identify an underlying cause of iron deficiency anaemia is not always necessary in the following patient groups:

• Younger healthy patients with a clear cause for iron deficiency (e.g. a history of blood donation)
• Menstruating young women with no history of gastrointestinal symptoms or family history of colorectal cancer
• Pregnant women (unless the anaemia is severe, there is no response to iron therapy, or there are concerning features in the history)

In all other cases, the following investigations should be performed:

• Coeliac serology: tissue transglutaminase antibody
• Urine dipstick: to screen for haematuria
• Stool examination: to detect parasites if the patient has recently travelled to high-risk areas

Further gastrointestinal investigations (e.g. endoscopy, colonoscopy) to exclude chronic blood loss from gastrointestinal malignancy should be considered for patients meeting any of the following criteria:

• 60 years or over
• Premenopausal women with bowel symptoms
• Family history of gastrointestinal cancer
• Persistent anaemia despite treatment

Checking for occult blood in stool is of no benefit in investigating iron deficiency anaemia.^1,2

Management

Referral to specialist services

Referral to specialist services may be required depending on the suspected underlying pathology causing iron deficiency anaemia:¹

• Urgent referral (within 2 weeks) for suspected bowel cancer: patients aged 60 and over with iron deficiency anaemia, or aged 50 and over with rectal bleeding
• Non-urgent gastroenterology referral for upper and lower gastrointestinal investigations (see criteria above)
• All patients with positive coeliac serology should be referred to gastroenterology for endoscopic biopsy

Other referral pathways may be indicated depending on the probable cause of the iron-deficiency anaemia, for example, a referral to urology for microscopic or gross haematuria. Women with postmenopausal bleeding should be referred to gynaecology urgently within 2 weeks.¹

Correction of iron deficiency¹ 

Oral iron supplementation

The cause of anaemia should be identified and treated if possible. If dietary deficiency is felt to be contributory, advice to increase intake of iron-rich food and a dietitian referral may be useful.

Iron supplementation should be prescribed (e.g. oral ferrous sulphate 200mg two to three times a day) and treatment should be continued for three months after the iron deficiency is corrected to replenish stores.

Iron tablets may have side effects such as nausea, gastrointestinal irritation, and constipation or diarrhoea. It is important to counsel the patient that these usually settle over time and can be managed by taking the tablet with food. Lower doses may be better tolerated.

Changing the formulation may also help with side effects. Ferrous gluconate has less elemental iron than sulphate or fumarate and may be more acceptable. Safe storage should be emphasised as overdose can be fatal.

Full blood count monitoring is required to assess the response to supplementation. A haemoglobin rise of 2g/100ml would be expected by four weeks.

Intravenous iron supplementation

Intravenous iron is reserved for those with true intolerance of oral iron (e.g. inflammatory bowel disease) or those who fail to respond to oral iron supplementation. Intravenous iron produces a more rapid response and better repletion of stores than oral iron but has side effects including arthralgia and myalgia.

There is a risk of anaphylaxis associated with intravenous iron replacement, so it should only be administered where there are adequate resuscitation facilities.⁵

Complications

Complications of iron deficiency anaemia include:¹

• Cognitive and behavioural impairment in children
• Reduced exercise capacity and endurance
• High-output heart failure
• Immunodeficiency
• In the context of pregnancy, it can lead to increased morbidity for mother and infant, increased risk of preterm delivery and perinatal mortality

Key points

• Iron deficiency anaemia (IDA) can develop due to reduced absorption of iron, increased utilisation of iron and blood loss.
• IDA is often asymptomatic, but symptoms may include fatigue, dizziness, dyspnoea, pallor, restless legs and pica.
• Iron deficiency anaemia is typically microcytic (low MCV) and hypochromic (low MCH).
• Characteristic cell morphology on blood film includes poikilocytosis and anisocytosis.
• Patients over 60 and those 50 and older with rectal bleeding should be referred urgently for an endoscopy to exclude bowel cancer.
• First-line treatment of IDA involves oral iron supplementation, side effects include nausea, gastrointestinal irritation, and constipation or diarrhoea.
• Intravenous iron is reserved for patients with true intolerance of oral iron (e.g. inflammatory bowel disease) or those who fail to respond to oral iron.
• Complications of iron deficiency anaemia include cognitive/behaviour impairment in children, reduced exercise capacity, heart failure and immunodeficiency. 

Reviewer

Dr BK Sinha

General Practitioner

Editor

Dr Chris Jefferies

References

1. NICE CKS. Anaemia – Iron Deficiency. Last revised Sep 2018. Available from: [LINK]
2. Patient.info Iron-deficiency Anaemia. Last edited 28 Jul 2020. Available from: [LINK]
3. Saboor, M., Zehra, A., Qamar, K., & Moinuddin. Disorders associated with malabsorption of iron: A critical review. Published 2015. Pakistan journal of medical sciences, 31(6), 1549–1553. Available from: [LINK]
4. Miller J. L. Iron deficiency anemia: a common and curable disease. Published 2013. Cold Spring Harbor perspectives in medicine, 3(7), a011866. Available from: [LINK]
5. BMJ Best Practice. Iron deficiency anaemia. Last reviewed Jul 2020. Available from: [LINK]
6. Patient.info. Plummer-Vinson syndrome. Last edited 27 Jan 2017. Available from: [LINK]
7. C Heitz. License: [CC BY]. Available from: [LINK]
8. Gotter, A. Microcytic Anemia. Last reviewed 6 Nov 2018 by Deborah Weatherspoon. Available from: [LINK]
9. Erhabor Osaro. Iron deficiency anaemia blood film. License: [CC BY-SA]. Available from: [LINK]