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Haematology & Oncology

B12 and Folate Deficiency

B12 or folate deficiency impairs DNA synthesis and can cause megaloblastic cytopenias; B12 deficiency additionally threatens the nervous system, so it must be recognised and replaced promptly, especially before or alongside folic acid.

In a nutshell

B12 and folate deficiency impair DNA synthesis and can cause megaloblastic anaemia, but B12 deficiency can also cause neuropathy, sensory ataxia, myelopathy, cognitive or psychiatric symptoms without anaemia or macrocytosis. Take blood first, treat suspected neurological B12 deficiency promptly, and never give folic acid alone when B12 deficiency is possible.

Classic presentation

Fatigue, glossitis or macrocytosis with low B12 or folate; B12 deficiency may additionally present with pins and needles, impaired gait, sensory ataxia, cognitive symptoms or risk factors such as autoimmune gastritis, gastrointestinal surgery, metformin, restrictive diet or nitrous oxide use.

Key points

  • Both B12 and folate deficiency impair DNA synthesis and can produce macro-ovalocytes, hypersegmented neutrophils and pancytopenia.
  • Do not exclude B12 deficiency because the FBC is normal: neurological symptoms can precede anaemia or macrocytosis.
  • Use total or active B12 initially; active B12 is preferred in pregnancy, while methylmalonic acid or homocysteine helps with indeterminate results or suspected nitrous-oxide toxicity.
  • Current NICE thresholds for total B12 are less than 180 nanograms per litre as confirmed deficiency, 180 to 350 as indeterminate and above 350 as deficiency unlikely; follow local laboratory validation.
  • Autoimmune gastritis and total gastrectomy or complete terminal-ileal resection require lifelong intramuscular B12; oral or intramuscular treatment may be chosen for reversible or dietary causes.
  • Treat B12 before or alongside folate, stop recreational nitrous oxide, and follow symptoms at 3 months or earlier when severe or during pregnancy.

First-line investigation

FBC and blood film with total or active B12 and serum folate; take samples before treatment, but do not delay B12 in suspected megaloblastic anaemia with neurological symptoms.

Management

Recognise neurological or severe disease

  • Take diagnostic blood samples but start B12 promptly when suspected megaloblastic anaemia is accompanied by neurological symptoms, and escalate severe anaemia or pancytopenia.1,3

Confirm deficiency and identify its cause

  • Use total or active B12, serum folate and cause-directed testing, with methylmalonic acid or homocysteine for indeterminate results or nitrous-oxide-related deficiency.1,6

Replace B12 by route and cause

  • Use lifelong intramuscular B12 for autoimmune gastritis or complete loss of gastric or terminal-ileal absorption; use oral or intramuscular replacement for other causes according to symptoms, malabsorption and adherence.1,7

Treat folate and correct modifiable causes

  • Treat folate after B12 has been checked or replacement has started, address diet and malabsorption, review medicines and stop recreational nitrous oxide.1,4,7

Escalate pregnancy, autoimmune or persistent neurological disease

  • Use active B12 in pregnancy, follow up earlier, consider specialist input for pregnancy, autoimmune gastritis, major gastrointestinal surgery, uncertain cause or neurological deterioration.1,3

Review symptoms and safety-net recurrence

  • Review at 3 months or earlier when severe and at 1 month in pregnancy or breastfeeding; adjust oral treatment or switch route if symptoms remain functionally significant, and continue lifelong treatment for irreversible causes.1

Exam traps

  • B12 deficiency can occur without anaemia or macrocytosis, so a normal FBC does not exclude it.
  • Folate deficiency does not cause the classic B12 myelopathy; neurological symptoms make B12 treatment urgent.
  • Do not give folic acid alone before checking or addressing B12 deficiency.
  • A negative intrinsic-factor antibody does not exclude autoimmune gastritis.
  • Do not routinely repeat the initial B12 test during intramuscular replacement; assess symptoms and clinical response instead.
  • Recreational nitrous oxide can cause functional B12 deficiency even when serum B12 is not clearly low.

Illustrations

Megaloblastic blood filmPeripheral blood film showing macro-ovalocytes and a hypersegmented neutrophil, typical of vitamin B12 or folate deficiency.Sheikh A et al., Cureus 2025, CC-BY-4.0 · CC-BY-4.0
Folate cycle and B12-dependent reactionsDiagram of the folate cycle and B12-dependent reactions, showing why B12 deficiency affects myelin as well as DNA synthesis.PassFinals · original
Subacute combined degeneration of the cordCross-sectional diagram of the spinal cord highlighting dorsal and lateral column involvement in B12 deficiency.PassFinals · original

Key sources

  1. NICE, Vitamin B12 deficiency in over 16s: diagnosis and management (NG239)
  2. NHS, Vitamin B12 or folate deficiency anaemia
  3. NHS, Vitamin B12 or folate deficiency anaemia: diagnosis
  4. NHS, Vitamin B12 or folate deficiency anaemia: treatment
  5. NHS, Vitamin B12 or folate deficiency anaemia: causes
  6. NICE, Coeliac disease: recognition, assessment and management (NG20)
  7. British National Formulary, online prescribing information

This page is exam revision material, not medical advice, and must not be used for patient care. Always check drug doses against the BNF and current guidance. Full disclaimer.