Macrocytic Anaemias
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Anaemia is one of the most common presenting complaints to general practice. One of several ways in which anaemias can be classified, is by red cell size. As such, anaemias can be said to be:

  • Microcytic (small RBCs)
  • Normocytic (RBC size within the normal range)
  • Macrocytic (large RBCs)

In general, macrocytic anaemias occurs where there is a disorder of red blood cell synthesis, and microcytic anaemias occurs where there is a disorder of haemoglobin synthesis. 

In this article we will discuss macrocytic anaemias. An anaemia can be said be macrocyclic when the Hb is low and the MCV is high (typically >100).

  • In cases where the Hb is normal, but there are large RBCs, we refer to this as macrocytosis
  • Macrocytosis still usually warrants a diagnosis to prevent progression to macrocytic anaemia

Macrocytic anaemias can be sub-divided into:

  • Megaloblastic – deficiency of vit B12 and / or folate
  • Nonmegaloblastic – macrocytic anaemia of other cause (e.g. alcoholism, hypothyroidism, liver disease, myelodisplastic syndromes, drugs)

Megaloblastic anaemia is usually managed by identifying and treating the underlying cause, and the most important part of the diagnostic process is to differentiate megaloblastic from nonmegaloblastic anaemias.

  • It is particularly important to identify cases where myelodysplastic syndromes or myeloid neoplasm – such cases typically affect the elderly and also involve leukcoytopenia (low white cells) and / or thrombocytopenia (low platelets)

Macrocytic anaemias are common in elderly patients due to multiple factors, and as such, the incidence is expected to increase with the ageing population in the coming decades.


  • Causes:
    • Medication – 40%
      • Drugs that affect DNA synthesis – e.g. azathioprine, cyclophosphamide, sulfasalazine
      • Trimethoprim
      • Phenytoin, sodium valproate
      • Metformin
      • Antivirals – e.g. valacyclovir
    • Alcoholism – 25%
    • Vit B12 / folate deficiency – 6%
    • Liver disease – 6%
    • Myelodysplasia (MDS – myelodyslpastic syndrome – with a risk of progression to AML) – 6%
  • Megaloblastic anaemia
    • Most cases caused by pernicious anaemia
    • Peak age of onset: 60
    • Often FHx
    • Often associated with other autoimmune disorders
    • Rarely, vitamin B12 deficiency may be due to malabsorption – particularly in coeliac disease affecting the terminal ileum


Macrocytosis is a common finding on FBC (full blood count) tests.

  • It is commonly an artefact of the testing process – particularly if the sample has been left a long time before being processed
  • It is also seen in hyperglycaemia

In megaloblastic anaemias, maturation of the nucleus is delayed, which causes larger RBCs.

In liver disease, there is accumulation of cholesterol and / or phospholipids on the cell surface, which leads to larger than normal cells.

Megaloblastic anaemia

Vitamin B12 deficiency is by far the most common cause of megaloblastic anaemia. It is either caused by:

  • Insufficient dietary intake
    • Vegetarianism / vegansim
  • Malabsorption
    • Pernicious anaemia – accounts for 50% of cases of B12 deficiency
      • Or lack of intrinsic factor after gastric surgery
    • Coeliac disease (particularly of the terminal ileum)
  • HIV

Vitamin B12 is contained in animal products. The recommended daily intake is 3-30 ug/day

Folate (folic acid) deficiency is less common.

  • Folate found in green leafy vegetables and animal products
  • Recommended daily intake is 240 ug per day (400 ug in pregnancy and lactating females)
  • Folate deficiency can lead to neural tube defects in the foetus
  • Folate is absorbed by passive diffusion in the jejunum
  • Causes of folate deficiency include:
    • Poor diet
    • Alcoholism
    • Coeliac disease
    • Inflammatory bowel disease
    • Medication
      • Methotrexate
      • Trimethoprim
      • Phenytoin
      • Drug causes tend to only be apparent if there is a prolonged course and / or a high dose
  • Serum folate levels vary widely in association with diet, and as such, measuring RBC folate levels, which fluctuate less widely is considered more reliable.

Pernicious anaemia

  • The term pernicious refers to the slow and insidious onset nature of the condition
    • Large amounts of B12 are stored in the liver – typically 5-10 years supply – and thus any deficiency can take many years to manifest itself
  • Intrinsic factor is normally secreted by the gastric parietal cells and absorbed in the terminal ileum
  • B12 binds to intrinsic factor and is absorbed with it
  • B12 is a coenzyme that produces methionine from homocysteine – which converts folic acid into its active form
  • So, whenever B12 is deficient, folic acid cannot be utilised
  • Prevalence of about 10-50 per 100 000 in European populations, less in Asians.
  • Destruction of the parietal cells leads to lack on intrinsic factor production and autoantibodies against intrinsic factor


Macrocytosis in itself is often aysmtpoamtic. Presentation of macrocytic anaemia can include:

  • Fatigue
  • SOB – particularly on exertion
  • Angina
  • Headache
  • Palpitations
  • Neurological symptoms
    • Reduced sensation
    • Tingling sensations in the limbs (parasthesia)
    • In severe cases, symptoms can involve ataxia, decreased propriception and vibration sense
  • In severe cases there may be signs of cardiac failure
  • Textbook physical signs of anaemia:
    • Pallor (nail beds, tongue and conjunctiva)
    • Bounding pulse
    • Systolic (pulmonary) flow murmur


It is often discovered when a patient present with vague symptoms of lethargy, tiredness, and  has a FBC performed. Once macrocytosis has been confirmed, consider further investigation, including:

  • If a blood film has not already been performed – perform a blood film
    • If reticulocytes are ABSENT, this suggests a non-megaloblastic cause – i.e. alcoholism, hypothyroidism or liver cause
    • If reticulocytes are increased, this indicates rapid turnover of reticulocytes
    • The presence of target cells indicate a non-megaloblastic cause
    • May help identify a myelodysplastic syndrome
  • Vit B12 levels
    • Low <200 pg/ml
    • Indeterminate 200 – 300 pg/ml
    • Normal >300 pg/ml
  • Folate levels (consider ‘red cell folate’ if available as opposed to ‘serum folate’ as it is more reliable)
    • Normal >4 ng/ml
    • Low <2 ng/ml
  • TFTs
  • LFTs
    • For liver disease and / or alcoholism
  • Coeliac serology (if indicated)

If no obvious cause can be found – consider referral to haematology.

Also note that homocysteine levels are often raised in folate and B12 deficiency, and that a homocysteineuria can exist when B12 deficiency exists. It is not routinely clinically useful to check for these, but these tests are sometimes performed by alternative medicine practitioners and patients may present to you with these results.


Depends on the cause

  • Pernicious anaemia / B12 deficiency
    • Vit B12 IM injections every 3 months (may be lifelong if pernicious anaemia, may be short term if another cause can be rectified (e.g. poor nutrition)
  • Folate deficiency
    • Folic acid 5mg daily for 4 months (oral)
    • If B12 and folate deficiency occur concurrently you MUST treat the B12 deficiency first, or you can aggravate B12 deficiency and risk causing degeneration of the spinal cord

When to refer to haematology

  • Neurological symptoms
  • Pregnancy
  • Suspected haematological malignancy
  • No cause can be identified

When to refer to gastroenterology

  • Suspected malabsorption (other than pernicious anaemia) – e.g. coeliac disease or inflammatory bowel disease


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Dr Tom Leach

Dr Tom Leach MBChB DCH EMCert(ACEM) FRACGP currently works as a GP and an Emergency Department CMO in Australia. He is also a Clinical Associate Lecturer at the Australian National University, and is studying for a Masters of Sports Medicine at the University of Queensland. After graduating from his medical degree at the University of Manchester in 2011, Tom completed his Foundation Training at Bolton Royal Hospital, before moving to Australia in 2013. He started almostadoctor whilst a third year medical student in 2009. Read full bio

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