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This is a clinician-written, evidence-based summary aligned to the 2026 MLA Content Map. It is intended for medical students and junior doctors preparing for the UKMLA. Always cross-reference with NICE guidance, local protocols, and clinical judgement.
Key points
- Macrocytic megaloblastic anaemia: raised MCV (>100 fL), hypersegmented neutrophils on blood film, low serum B12
- Commonest cause in UK is pernicious anaemia — autoimmune destruction of gastric parietal cells; anti-intrinsic factor antibodies are diagnostic (high specificity)
- Other causes: dietary (vegan/vegetarian), malabsorption (terminal ileum disease — Crohn's), gastrectomy, metformin
- Neurological complications: subacute combined degeneration of the cord (dorsal columns + lateral corticospinal tracts), peripheral neuropathy — may be IRREVERSIBLE if untreated
- Treatment: IM hydroxocobalamin — loading 1 mg on alternate days for 2 weeks, then 1 mg every 3 months lifelong if pernicious anaemia
Overview
Vitamin B12 (cobalamin) is essential for DNA synthesis, red blood cell maturation, and neurological function. Deficiency leads to megaloblastic anaemia (impaired DNA synthesis causes nuclear-cytoplasmic asynchrony in developing red cells) and potentially irreversible neurological damage. Absorption of B12 requires intrinsic factor (produced by gastric parietal cells) and an intact terminal ileum. In the UK, the commonest cause is pernicious anaemia — an autoimmune condition causing parietal cell destruction and loss of intrinsic factor production.
Epidemiology
Pernicious anaemia affects approximately 1 in 1,000 people in the UK. It is more common in women, those aged over 60, and those of Northern European descent. There is a strong association with other autoimmune conditions (thyroid disease, vitiligo, Addison's disease). Dietary deficiency is increasingly recognised in vegans and the elderly. B12 deficiency from terminal ileal disease (Crohn's) or surgical resection is another important cause.
Clinical Features
Symptoms
Fatigue, lethargy, breathlessness — insidious onset over months
Glossitis — painful smooth red tongue
Paraesthesiae — tingling or numbness in hands and feet (peripheral neuropathy)
Cognitive impairment, mood disturbance, and confusion — especially in the elderly
Unsteadiness or ataxia (dorsal column involvement)
Visual disturbance (optic neuropathy — rare)
Symmetrical weakness in the legs (corticospinal tract involvement)
Signs
Pallor and mild jaundice (lemon-yellow tinge from ineffective erythropoiesis and haemolysis)
Glossitis — smooth beefy-red tongue
Angular stomatitis
Reduced vibration sense and proprioception in lower limbs (dorsal column signs)
Positive Romberg test, sensory ataxia
Upper motor neurone signs: upgoing plantars, brisk reflexes (lateral corticospinal tracts)
Investigations
First-line
FBC and blood filmMacrocytic anaemia (MCV >100 fL), oval macrocytes, HYPERSEGMENTED NEUTROPHILS (≥5 lobes — highly characteristic of megaloblastic anaemia)
Serum B12Low (<200 ng/L). Note: B12 levels can be borderline/unreliable; methylmalonic acid (MMA) and homocysteine are more sensitive
Serum folateCheck concurrently — must exclude combined deficiency. Treating B12 deficiency with folate alone can precipitate subacute combined degeneration
Second-line
Anti-intrinsic factor antibodiesHIGH specificity (~100%) for pernicious anaemia but sensitivity only ~50%. Positive result = diagnostic
Anti-parietal cell antibodiesHigh sensitivity (~90%) but LOW specificity — present in ~10% of normal population; less useful than anti-IF
LDH and bilirubinBoth raised in megaloblastic anaemia (ineffective erythropoiesis causes intramedullary haemolysis)
Reticulocyte countLow (impaired red cell production). Rises after B12 replacement — peak reticulocyte response at 5–7 days
Specialist
Methylmalonic acid (MMA)Raised in B12 deficiency (not folate). Useful when B12 levels are borderline
HomocysteineRaised in both B12 and folate deficiency
Bone marrow biopsyRarely needed — shows megaloblastic erythropoiesis. Only if diagnostic uncertainty
OGDConsider in pernicious anaemia — risk of gastric carcinoid and gastric adenocarcinoma (atrophic gastritis)
1
B12 replacement — no neurological involvement
- IM hydroxocobalamin 1 mg on alternate days for 2 weeks (loading)
- Then IM hydroxocobalamin 1 mg every 3 months (maintenance — lifelong if pernicious anaemia)
- If dietary deficiency: oral cyanocobalamin 50–150 µg daily between meals, or IM as above
2
B12 replacement — WITH neurological involvement
- IM hydroxocobalamin 1 mg on alternate days until no further improvement (may need several weeks)
- Then IM hydroxocobalamin 1 mg every 2 months (more frequent maintenance)
- Refer urgently to haematology — neurological damage may be irreversible if delayed
3
Monitoring and follow-up
- Recheck FBC at 8 weeks — MCV should normalise
- Monitor potassium during initial replacement — hypokalaemia can occur as new red cells are produced
- Lifelong B12 injections if pernicious anaemia — no need to recheck B12 levels once on treatment
- Screen for associated autoimmune conditions: TFTs (thyroid disease common in pernicious anaemia)
4
Important prescribing points
- NEVER give folic acid alone if B12 deficiency is suspected — may correct anaemia but precipitate or worsen neurological damage (subacute combined degeneration)
- Always replace B12 first (or concurrently) before giving folic acid
Complications
- Subacute combined degeneration of the cord: Demyelination of dorsal columns (loss of proprioception and vibration) and lateral corticospinal tracts (UMN weakness). Classic exam scenario — may be IRREVERSIBLE
- Peripheral neuropathy: Symmetrical glove-and-stocking sensory loss
- Dementia and cognitive impairment: B12 deficiency is a reversible cause of dementia — always check
- Increased risk of gastric cancer: Pernicious anaemia associated with atrophic gastritis — slight increased risk of gastric adenocarcinoma and carcinoid
- Neural tube defects: B12 deficiency in pregnancy increases risk (as with folate deficiency)
UKMLA Exam Tips
- 1Hypersegmented neutrophils on blood film = megaloblastic anaemia (B12 or folate deficiency) — this is the classic film finding
- 2Anti-intrinsic factor antibodies = diagnostic of pernicious anaemia (high specificity). Anti-parietal cell antibodies are sensitive but NOT specific
- 3NEVER give folate alone if B12 deficiency is possible — will worsen neurological damage. Always give B12 first or concurrently
- 4Subacute combined degeneration = B12 deficiency affecting dorsal columns + lateral corticospinal tracts. Exam buzzwords: loss of vibration sense, positive Romberg, upgoing plantars
- 5LDH and bilirubin are raised in megaloblastic anaemia (intramedullary haemolysis) — do NOT confuse with haemolytic anaemia
- 6Reticulocyte count rises within 2–3 days of B12 replacement, peaks at day 5–7 — useful marker of response
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