Vitamin B12 and Folate Deficiency: Megaloblastic Anaemia

Vitamin B12 (cobalamin) and folate are both needed to make DNA. A deficiency of either causes megaloblastic anaemia, with large red blood cells. Vitamin B12 deficiency can also damage the nervous system permanently, so it must be recognised and treated promptly.

Causes of vitamin B12 deficiency

• Pernicious anaemia: an autoimmune condition with antibodies against intrinsic factor and gastric parietal cells. It is a common cause in many populations.
• Dietary: strict vegetarian or vegan diets without supplements.
• Gastric causes: gastrectomy, bariatric surgery and atrophic gastritis.
• Terminal ileum disease or resection: Crohn's disease, TB, surgery.
• Drugs: metformin, long-term PPIs, nitrous oxide misuse.
• Other: fish tapeworm and bacterial overgrowth (rare).

Causes of folate deficiency

• Poor diet: low intake of green vegetables, and alcohol excess.
• Increased needs:
  • pregnancy
  • haemolysis
  • chronic skin disease
  • dialysis
• Malabsorption: coeliac disease.
• Drugs: methotrexate, trimethoprim, phenytoin and other anticonvulsants.

Clinical features

Features of anaemia:

• tiredness
• breathlessness
• pallor, sometimes with a lemon-yellow tinge from mild jaundice

Other features:

• glossitis
• angular stomatitis

Neurological features of B12 deficiency (they can occur without anaemia):

• pins and needles
• peripheral neuropathy
• subacute combined degeneration of the spinal cord (loss of vibration sense and proprioception, unsteady gait, extensor plantar responses with absent ankle reflexes)
• memory problems
• depression
• visual problems

Investigations

• Full blood count: raised MCV (macrocytosis). There may also be low white cells and platelets.
• Blood film: oval macrocytes and hypersegmented neutrophils.
• Serum B12 and folate levels. If they are borderline, methylmalonic acid or holotranscobalamin can help.
• Intrinsic factor antibodies: specific for pernicious anaemia.
• Raised LDH and bilirubin: from ineffective red cell production.
• Other causes of macrocytosis to consider:
  • alcohol
  • liver disease
  • hypothyroidism
  • reticulocytosis
  • myelodysplasia
  • drugs

Treatment

• Vitamin B12: intramuscular hydroxocobalamin injections, as a loading course then maintenance (lifelong in pernicious anaemia). Dietary deficiency can often be treated with oral B12. Neurological involvement needs more intensive injection regimens and specialist advice.
• Folate: oral folic acid, usually for about 4 months, or longer if the cause persists.
• Important rule: if both deficiencies may be present, replace B12 before (or together with) folate. Giving folate alone can worsen the neurological damage of B12 deficiency.
• Potassium: during early treatment of severe anaemia, potassium can fall as new cells are made. Monitor it.

Prevention

• Folic acid before conception and in early pregnancy reduces the risk of neural tube defects. A higher dose is used in high-risk women, for example those on anti-epileptic drugs, with a previous affected pregnancy, or with diabetes or obesity, according to local guidance.
• B12 supplements for vegans and after bariatric surgery.
• Periodic B12 checks in long-term metformin users with symptoms.

Exam pearls

• Hypersegmented neutrophils mean megaloblastic anaemia.
• Neurological signs with macrocytosis: think B12 deficiency.
• Never treat with folate alone if B12 deficiency is possible.

See also Iron Deficiency Anaemia and the haematology chapter of our Medicine Companion.

Test yourself

5 exam-style single-best-answer questions. Choose your answer, then tap “Show answer”.

1. Which blood film finding is typical of megaloblastic anaemia?

   1. Hypersegmented neutrophils
   2. Schistocytes
   3. Target cells
   4. Sickle cells
   5. Spherocytes
   Show answer

   Answer: A. Hypersegmented neutrophils
   Hypersegmented neutrophils and oval macrocytes are typical.

2. Which antibody is specific for pernicious anaemia?

   1. Anti-CCP
   2. Anti-TPO
   3. ANA
   4. ANCA
   5. Intrinsic factor antibody
   Show answer

   Answer: E. Intrinsic factor antibody
   Intrinsic factor antibodies are highly specific; parietal cell antibodies are less specific.

3. Why must B12 be replaced before (or with) folate?

   1. No reason
   2. Folate alone can worsen neurological damage from B12 deficiency
   3. B12 is cheaper
   4. Folate blocks B12 absorption
   5. Folate is toxic
   Show answer

   Answer: B. Folate alone can worsen neurological damage from B12 deficiency
   Folate can correct the anaemia while subacute combined degeneration progresses.

4. Loss of vibration sense, extensor plantars and absent ankle reflexes suggest:

   1. Stroke
   2. Subacute combined degeneration from B12 deficiency
   3. Folate deficiency
   4. Iron deficiency
   5. Myasthenia gravis
   Show answer

   Answer: B. Subacute combined degeneration from B12 deficiency
   B12 deficiency affects dorsal columns and corticospinal tracts.

5. Which diabetes drug can cause B12 deficiency?

   1. Empagliflozin
   2. Pioglitazone
   3. Gliclazide
   4. Insulin
   5. Metformin
   Show answer

   Answer: E. Metformin
   Long-term metformin reduces B12 absorption.

More articles in Haematology

• Iron Deficiency Anaemia: Causes, Tests and Iron TreatmentMicrocytic anaemia explained: causes, ferritin and blood film, distinguishing thalassaemia trait, oral and IV iron, and when to investigate the gut.
• Thalassaemia: Genetics, Diagnosis and Transfusion CareBeta thalassaemia trait, intermedia and major, HbA2 and HPLC, transfusion and iron chelation, complications, screening and prevention.

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Disclaimer

For education and exam preparation only. This is not medical advice and must not be used to diagnose or treat patients. Always follow current clinical guidelines and the advice of qualified senior colleagues.