Dr Toni Hazell offers 10 practical tips exploring the best ways to investigate and manage anaemia in adults, and how to address patient concerns

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Dr Toni Hazell

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Read this article to learn more about:

  • the diagnostic criteria of anaemia in adults
  • appropriate investigations for patients with anaemia
  • the management of iron deficiency anaemia with iron supplementation.

1. Know the definition and pathophysiology of anaemia

Anaemia is the most common haematological abnormality seen in general practice.1 NICE defines anaemia as a haemoglobin (Hb) level of:2,3

  • <130 g/l in men
  • <120 g/l in women who are not pregnant
  • <110 g/l in pregnant women.

Red blood cells are made in the bone marrow by erythropoiesis, then released into the circulation as reticulocytes, developing into mature red blood cells 1 day later. These mature cells circulate for around 3 months and are then removed by macrophages. In a healthy patient, the rate of blood cell production and the rate of loss is balanced; in a patient with anaemia this balance is disrupted, for example due to reduced production or increased destruction of red blood cells, or because of significant blood loss.1

2. Be aware of the common causes

Management of anaemia depends on finding a cause, which usually requires further blood tests. The most common cause is iron deficiency.1

Anaemia is usually classified by the mean corpuscular volume (MCV) as follows:1

  • microcytic anaemia—MCV <80 fl
  • normocytic anaemia—MCV 80–100 fl
    • hyperproliferative—reticulocyte count >2%
    • hypoproliferative—reticulocyte count <2%
  • macrocytic anaemia—MCV >100 fl
    • megaloblastic—megaloblasts and hypersegmented neutrophils on a film
    • non-megaloblastic—no megaloblasts or hypersegmented neutrophils seen.

Table 1 includes suggestions for potential differential diagnoses.

Table 1: Differential diagnoses for different types of anaemia1

Microcytic

Iron deficiency

  • Gynaecological or obstetric e.g. menorrhagia and pregnancy
  • Blood loss from the gastrointestinal (GI) tract (ulcer, malignancy, angiodysplasia, anti-inflammatory use) or other GI causes e.g. inflammatory bowel disease, parasitic GI infestation
  • Malabsorption (coeliac, post gastrectomy or bariatric surgery, Helicobacter pylori infection)
  • Blood loss from other causes e.g. blood donation, significant epistaxis
  • Insufficient dietary intake of iron (rare in the UK).

Other cause

  • Thalassaemia
  • Sideroblastic anaemia
  • Lead poisoning (rare in the UK)
  • Anaemia of chronic disease.

Normocytic

Hyperproliferative

  • Acute haemorrhage
  • Haemolytic anaemia (causes include glandular fever, toxoplasmosis, haemolytic sickle crisis and cytomegalovirus).

Hypoproliferative

  • Leukaemia
  • Aplastic anaemia
  • Red cell aplasia (causes include mumps, parvovirus, aplastic sickle crisis, glandular fever, viral hepatitis, and atypical pneumonia)
  • Anaemia of chronic disease
  • Hypothyroidism.

Macrocytic

Megaloblastic

  • B12 or folate deficiency
  • Drug induced.

Non-megaloblastic

  • Alcohol abuse
  • Myelodysplastic syndrome
  • Liver disease
  • Congenital bone marrow syndromes.

3. Take a history and examine the patient

The tradition of following the ‘history, examination, investigations’ process often gets turned on its head—GPs may be sent the result of a full blood count (FBC) requested elsewhere and it is not always clear what the indication was. Private screening services also send their abnormal results to general practice, as do extended hours and hub doctors.

If you did not request the test it is vital to take a history and examine the patient. Make sure the patient is haemodynamically stable—if they are not, or if there is recent bleeding, then you may need to arrange an emergency admission. Transfusion can be considered if the patient has a haemoglobin level of <70 g/l.4 Whether a transfusion is appropriate will depend partly on patient choice and the rate of decline of haemoglobin concentration if known; a woman with menorrhagia who has had a haemoglobin level of 65 g/l documented for the last year is less likely to need admitting than a patient with gastrointestinal (GI) symptoms whose haemoglobin level was normal 3 months ago.

If the patient is not acutely unwell, explore the patient’s history to identify potential causes of their anaemia:

  • history of blood loss or bruising
  • obstetric and gynaecological history—e.g. menorrhagia, recent delivery, or grand multiparity
  • past medical history—e.g. chronic kidney disease and inflammatory conditions; both can commonly cause an anaemia of chronic disease
  • past surgical history—e.g. bariatric surgery or other gastric or small bowel resection
  • gastrointestinal symptoms—e.g. epigastric pain, dysphagia, vomiting (coffee ground or otherwise), and melaena
  • weight loss
  • ethnicity
  • family history—e.g. of thalassaemia
  • medications, both prescribed and over the counter—e.g. anti-inflammatories, oral steroids, selective serotonin reuptake inhibitors, and anti-platelets
  • drug and alcohol use
  • other symptoms of iron deficiency anaemia—e.g. fatigue, headache, pruritus, and pica
  • other symptoms of vitamin B12 deficiency—e.g. paraesthesia, pigmented nail beds and skin creases, diarrhoea, cognitive changes, and muscle weakness
  • angina or dyspnoea (unlikely to occur in the absence of other cardiorespiratory pathology, unless the patient’s haemoglobin is <70 g/l).

Physical examinations of patients with anaemia may include the following:

  • abdominal examination for masses and organomegaly
  • rectal examination for a mass, blood, or melaena (only necessary if the patient has rectal bleeding or tenesmus3)
  • examination of the cardiovascular system, looking for any signs of heart failure
  • examination of the skin and hair for angular cheilitis and thinning hair
  • examination for signs of liver failure and jaundice
  • consideration of vaginal examination and/or speculum if there is menorrhagia with associated symptoms that merit such an examination.

4. Remember the suspected cancer guidelines

NICE Guideline (NG) 12 on Suspected cancer: recognition and referral advises that referral or investigation is considered as follows for patients who:5

  • are aged 55 years or over with upper abdominal pain and low haemoglobin (non-urgent direct access upper GI endoscopy)
    • consider referral for non-urgent direct access upper GI endoscopy
  • are aged 60 years or over with iron deficiency anaemia (IDA)
    • consider referral for a suspected cancer pathway appointment for lower GI cancer within 2 weeks
  • are aged under 50 years with rectal bleeding and IDA
    • consider referral for a suspected cancer pathway appointment for lower GI cancer within 2 weeks
  • are female, aged 55 years or over, and have visible haematuria and low haemoglobin levels
    • consider direct access pelvic ultrasound to assess for endometrial cancer.

5. Request further investigations logically

Tailor any further investigations to the most likely differential diagnoses, the most common causes, and the patient’s MCV results and symptoms. Depending on the type of anaemia identified, appropriate tests may include:

  • for microcytic anaemia—ferritin, haemoglobin electrophoresis, coeliac screen, Helicobacter pylori testing, pelvic ultrasound, faecal occult blood testing
  • for normocytic anaemia—reticulocyte count, sickle screen, thyroid function, blood film
  • for macrocytic anaemia—B12/folate levels, liver function, blood film.

The rest of this article will focus on the investigation and management of IDA—for more information, consider referring to guidance on other conditions that can cause or be related to anaemia, for example, NG8 on Chronic kidney disease: managing anaemia6 or the British Society of Gastroenterology guidelines on adult coeliac disease.7

6. Do not rule out IDA on ferritin alone

Serum ferritin is the biochemical test that most reliably correlates with relative total body iron stores,3 but ferritin is also an acute phase protein and will therefore be raised in the presence of infection, inflammation, or malignancy. Therefore, a normal ferritin level does not exclude IDA.

If clinical suspicion of IDA is strong then consider checking for other iron indices; serum iron is highly variable as it is influenced by many factors (such as inflammation and infection) and is therefore not an ideal test. More useful tests include transferrin and total iron binding concentration (TIBC). Transferrin is an iron transport protein, which increases in iron deficiency so that the available iron can be fully utilised, while TIBC is a measure of the availability of iron binding sites on transferrin. Both transferrin and TIBC will be elevated in patients with IDA and these are therefore useful second-line tests.

Some labs may also offer transferrin saturation; 30% is a normal value and it will fall in patients with iron deficiency.8

7. Consider whether further investigation of IDA is actually needed

According to NICE, the following patients—if they have had a negative test for coeliac disease—usually need no further investigation after IDA has been diagnosed:3

  • otherwise healthy young people with an obvious cause—e.g. regular blood donation
  • menstruating women with no gastrointestinal symptoms or family history of colorectal cancer
  • pregnant women (unless the anaemia is severe, there are symptoms or signs of another cause, or there is no response to iron supplementation)
  • people who are terminally ill or unlikely to tolerate further investigations, particularly if the results of such investigations would be unlikely to affect management.

For all patients who do not match the above criteria, the following investigations are recommended:3

  • urine dipstick for blood (1% of patients with IDA will have a renal tract malignancy3)
  • upper and lower GI investigations—i.e. endoscopy and colonoscopy
  • consider a stool test for parasites, if there is a relevant travel history
  • consider testing for Helicobacter pylori (if not already done), particularly in patients whose anaemia persists or recurs despite normal upper and lower GI investigations.

8. Titrate the dose of iron to what the patient can tolerate

The aim of iron treatment is to restore haemoglobin levels and iron stores. The British National Formulary suggests that patients with anaemia should have 100–200 mg of elemental iron daily;9 the elemental iron content of various preparations is shown in Table 2.

Table 2: Iron content of supplements by preparation9
PreparationDose (mg)Iron content (mg)

Ferrous fumarate

200

65

Ferrous gluconate

300

35

Ferrous sulphate

300

60

Ferrous sulphate (dried)

200

65

Reproduced from: British National Formulary. Anaemia, iron deficiency. bnf.nice.org.uk/treatment-summary/anaemia-iron-deficiency.html (accessed 26 June 2018)

NICE recommends iron supplementation with dried ferrous sulphate three times a day (or 200 mg twice daily until the clinical response is assessed after 2–4 weeks, increasing to three times daily if well tolerated or reducing to once daily if poorly tolerated), switching to ferrous gluconate if side-effects lead to poor tolerance.3 In the author’s experience, many CCGs prefer ferrous fumarate as first line due to cost issues, although NICE points out that ferrous fumarate has more elemental iron per tablet than ferrous sulphate and is therefore no more likely to be well tolerated.3

In practice, the main objective is to make sure that patients get as high a dose of elemental iron as they can tolerate. Constipation and associated abdominal pain are common when treating with iron; if patients are not warned about these symptoms in advance, they may simply stop taking the tablets. Many GPs will be familiar with cases where patients have claimed to be taking regular iron, but their last monthly prescription was issued over a year ago! In cases like these, it is important to determine whether the patient has poor adherence or if they are taking alternative over-the-counter preparations.

If a patient is not taking their iron then it is important to ask why, switch preparation if necessary, and encourage them to take as much as possible—a low dose of iron is better than none.3 It is not uncommon for patients to buy liquid iron supplements over the counter if they do not want to take tablets. While patient choice must be respected, it is important that this choice is informed and therefore patients should be advised to check how much iron is in the preparation that they are buying. Some commonly advertised liquid iron supplements, used as suggested by the manufacturer, can provide as little as 5–15 mg of iron per day.10,11

Modified-release iron is not routinely recommended by NICE as these preparations are associated with lower absorption; they are also not available on the NHS. NICE also advises against the use of compound preparations with iron and vitamin B12/folic acid/vitamin C, unless the patient’s anaemia is related to very poor diet or malnutrition. Parenteral iron preparations, which are only needed in exceptional circumstances, are usually reserved as a secondary care treatment.3

9. Check iron absorption and encourage dietary intake

The absorption of both dietary iron and supplements is reduced by the simultaneous intake of calcium, phytates (found in wholegrain cereals), polyphenols (found in tea and coffee) or by the use of a proton pump inhibitor or antacid. It is worth giving the patient information about dietary sources of iron12 as well as telling them whether they should stagger their medications so as not to take iron at the same time as calcium tablets.

10. Monitor the patient’s haemoglobin and keep referral in mind

According to NICE, the following process should be observed for monitoring during treatment with iron:3

  • haemoglobin concentration should be checked by FBC 2–4 weeks after starting iron; it should rise by approximately 20 g/l in 3–4 weeks
    • if there is a response, recheck the FBC in 2–4 months to ensure that the haemoglobin level has returned to normal
  • once haemoglobin concentration and red blood cell indices are normal:
    • continue treatment for 3 months to ensure replenishment of iron stores, and then stop
    • after iron has been stopped, monitor the patient’s FBC every 3 months for 1 year
    • check again after a further year, and again if symptoms of anaemia return.

It is not necessary to keep checking ferritin levels, unless there is any concern that the diagnosis may not be correct.3

If there is no response to treatment with iron (and the patient is actually taking the tablets!), consider a different formulation or refer for specialist advice. If adherence is being affected by adverse effects, these should be addressed; for example, by offering co-prescription of a laxative for patients experiencing constipation or reassurance for patients concerned about black stools.3

Some patients who are at particular risk of recurrent IDA might benefit from a small prophylactic dose (e.g. one tablet daily of whichever formulation they prefer). This includes patients who have:

  • had a gastrectomy or bariatric surgery
  • a poor diet that is unlikely to change
  • menorrhagia and do not want their heavy periods treated (or cannot tolerate available treatments)
  • malabsorption
  • a condition where further treatment is not appropriate (e.g. terminal illness or frailty).

Dr Toni Hazell

Part-time GP, Greater London

References

  1. Zaiden R. BMJ best practice—assessment of anaemia. London: BMJ, 2018. Available at bestpractice.bmj.com/topics/en-gb/93
  2. NICE. Anaemia—B12 and folate deficiency. NICE Clinical Knowledge Summary. NICE, 2018. cks.nice.org.uk/anaemia-b12-and-folate-deficiency#!topicsummary (accessed 26 June 2018).
  3. NICE. Anaemia—iron deficiency. NICE Clinical Knowledge Summary. NICE, 2013. cks.nice.org.uk/anaemia-iron-deficiency#!topicsummary (accessed 26 June 2018).
  4. NICE. Blood transfusion. NICE Guideline 24. NICE, 2015. Available at: www.nice.org.uk/ng24
  5. NICE. Suspected cancer: recognition and referral. NICE Guideline 12. NICE, 2015. Available at: www.nice.org.uk/ng12
  6. NICE. Chronic kidney disease: managing anaemia. NICE Guideline 8. NICE, 2015. Available at: www.nice.org.uk/ng8
  7. Ludvigsson J, Bai J, Biagi F et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut 2014; 63 (8): 1210–1228.
  8. Kelly A, McSorley S, Patel P, Talwar D. Interpreting iron studies. BMJ 2017; 357: j2513.
  9. British National Formulary. Anaemia, iron deficiency treatment summary. NICE, 2018. bnf.nice.org.uk/treatment-summary/anaemia-iron-deficiency.html (accessed 26 June 2018).
  10. A Nelson & Co Ltd. Spatone® original. www.spatone.com/en/our-range/spatone/spatone-original (accessed 26 June 2018).
  11. Salus (UK) Ltd. Floradix® liquid iron. floradix.co.uk/product/floradix-liquid-iron/ (accessed 26 June 2018).
  12. British Dietetic Association. Food fact sheet—iron. BDA, 2017. Available at: www.bda.uk.com/foodfacts/iron_food_fact_sheet.pdf