Key Facts

Vitamin B12 (cobalamin) deficiency causes megaloblastic anaemia and potentially irreversible neurological damage. Pernicious anaemia is the commonest cause in the UK.

Epidemiology

• Prevalence: ~6% of >60 years; higher in vegans (~50%)
• Pernicious anaemia: F:M 1.6:1; peak age 60–70; associated with other autoimmune conditions (thyroid, vitiligo, Addison)

Aetiology

• Pernicious anaemia (most common in UK): autoimmune atrophic gastritis → destruction of parietal cells → loss of intrinsic factor → B12 malabsorption
• Dietary: vegans, vegetarians (B12 found only in animal products)
• Malabsorption: gastrectomy, ileal resection (terminal ileum), Crohn disease (terminal ileum), bacterial overgrowth, fish tapeworm (Diphyllobothrium latum)
• Drugs: metformin, PPIs, H2 receptor antagonists, nitrous oxide (inactivates B12)

Pathophysiology

• B12 is cofactor for methionine synthase (homocysteine → methionine) and methylmalonyl-CoA mutase
• Deficiency → impaired DNA synthesis (megaloblastic change) and impaired fatty acid metabolism (neurological damage)
• Megaloblastic: defective DNA synthesis → nuclear-cytoplasmic dissociation → large immature RBCs (megaloblasts)
• Neurological: accumulation of methylmalonic acid → demyelination of dorsal columns and lateral corticospinal tracts

Haematological

• Gradual onset anaemia symptoms: fatigue, dyspnoea, pallor
• Mild jaundice (lemon-yellow tinge — from ineffective erythropoiesis/haemolysis)
• Glossitis (smooth, beefy-red tongue)
• Angular stomatitis

Neurological (may occur WITHOUT anaemia)

• Subacute combined degeneration of the cord:
  • Dorsal columns: loss of vibration sense, proprioception, positive Romberg, sensory ataxia
  • Lateral corticospinal tracts: upper motor neuron signs (hyperreflexia, extensor plantars, spasticity)
  • Peripheral neuropathy: glove-and-stocking paraesthesiae
• Cognitive: memory impairment, confusion, dementia
• Psychiatric: depression, psychosis ('megaloblastic madness')
• Optic atrophy: rare

Red Flags

• Neurological symptoms (SACD) — treat URGENTLY; may be irreversible
• Cognitive decline in elderly (consider B12 deficiency as reversible cause)
• Young patient with macrocytic anaemia (dietary, autoimmune)

Bloods

• FBC: low Hb, raised MCV (>100 fL), ± low WCC and platelets (pancytopenia in severe cases)
• Blood film: oval macrocytes, hypersegmented neutrophils (≥5 lobes), anisopoikilocytosis
• Serum B12: low (<150 ng/L)
• Methylmalonic acid (MMA): elevated (more sensitive; confirms tissue deficiency)
• Homocysteine: elevated (non-specific; also raised in folate deficiency)
• Anti-intrinsic factor antibodies: ~50% sensitive, highly specific for pernicious anaemia
• Anti-gastric parietal cell antibodies: ~90% sensitive but less specific
• Reticulocyte count: low (inappropriately)
• LDH, bilirubin: elevated (ineffective erythropoiesis/intramedullary haemolysis)
• Serum folate: check simultaneously (treat B12 first if both deficient)

Imaging/Special Tests

• MRI spine: SACD — high signal in dorsal columns and lateral corticospinal tracts on T2
• Gastroscopy: if pernicious anaemia confirmed (risk of gastric carcinoid and gastric adenocarcinoma — but routine surveillance debated)
• Schilling test: historical; no longer used

Pharmacological

No neurological involvement:

• Hydroxocobalamin 1mg IM on alternate days × 2 weeks (loading)
• Then hydroxocobalamin 1mg IM every 2–3 months for life (pernicious anaemia)

WITH neurological involvement (URGENT):

• Hydroxocobalamin 1mg IM on alternate days until no further improvement (may be several weeks/months)
• Then hydroxocobalamin 1mg IM every 2 months for life

Dietary deficiency:

• Oral cyanocobalamin 50–150mcg daily may suffice (if adherent)
• Dietary advice: fortified foods, consider lifelong supplementation for vegans

CRITICAL:

• If B12 and folate both deficient: treat B12 FIRST — giving folate alone may precipitate/worsen SACD
• Hypokalaemia may occur during early treatment (increased erythropoiesis uses potassium) — monitor

Referral Criteria

• Haematology: diagnostic uncertainty, pancytopenia, suspected MDS
• Neurology: SACD or other neurological complications
• Gastroenterology: pernicious anaemia surveillance (debated), malabsorption investigation

• Haematological: excellent response; reticulocyte rise within 5–7 days; Hb normalises in 6–8 weeks
• Neurological: if treated early, many symptoms improve; if delayed (>6 months), may be irreversible
• Pernicious anaemia: lifelong B12 replacement; ~2–3× increased risk of gastric cancer (debated surveillance)
• SACD: early treatment is critical — prognosis directly related to duration before treatment
• Dietary: excellent if supplementation maintained

B12 vs Folate Deficiency Comparison