Anaemia - B12 and folate deficiency
Exam Tips
- In OSCEs, link macrocytosis + hypersegmented neutrophils to megaloblastic anaemia, then separate B12 from folate by neurological findings (present in B12, not typical in isolated folate deficiency).
- State clearly that folic acid must not be started alone until B12 deficiency is excluded or co-treated.
- Pernicious anaemia clues: older patient, autoimmune background, positive intrinsic factor antibodies, need for lifelong IM hydroxocobalamin.
- If serum B12 is borderline but suspicion is high, use methylmalonic acid/homocysteine and clinical context rather than a single test value.
- Image anchor for revision: peripheral blood film showing macro-ovalocytes and hypersegmented neutrophils; and schematic of B12 absorption (stomach intrinsic factor to terminal ileum), e. g. standard figure in Hoffbrand haematology megaloblastic chapter.
Definition
Vitamin B12 deficiency anaemia and folate deficiency anaemia are megaloblastic macrocytic anaemias caused by impaired DNA synthesis in rapidly dividing bone-marrow precursors. They typically present with raised MCV (often >100 fL) and low haemoglobin for age/sex, and B12 deficiency may additionally cause neurological dysfunction even when anaemia is mild or absent.
Pathophysiology
Folate and cobalamin are required for thymidylate and purine synthesis, so deficiency causes defective nuclear maturation with relative preservation of cytoplasmic growth (nuclear-cytoplasmic asynchrony), producing megaloblasts, macro-ovalocytes, and hypersegmented neutrophils. Ineffective erythropoiesis leads to intramedullary destruction of precursors (low reticulocyte response, raised LDH, indirect hyperbilirubinaemia). B12 deficiency also disrupts methylmalonyl-CoA metabolism and myelin maintenance, explaining peripheral neuropathy, posterior column signs, and subacute combined degeneration. Body stores explain tempo: B12 stores (about 2-5 mg) can delay presentation for years, whereas folate stores (about 10-12 mg) can be depleted within months.
Risk Factors
- Pernicious anaemia (autoimmune atrophic gastritis with intrinsic factor deficiency)
- Older age (risk rises with age; very high prevalence in the very elderly)
- Vegan diet or severe malnutrition
- Gastric surgery (partial/total gastrectomy) or ileal disease/resection
- Malabsorption (coeliac disease, Crohn disease, tropical sprue, blind loop syndrome, fish tapeworm, giardiasis)
- Drugs reducing B12 absorption or availability: metformin, proton pump inhibitors, H2-receptor antagonists, colchicine, nitrous oxide exposure
- Folate-antagonist or folate-depleting drugs: methotrexate, trimethoprim, sulfasalazine, anticonvulsants, nitrofurantoin, excess alcohol
- Increased folate requirement: pregnancy, lactation, haemolytic states, malignancy, chronic inflammatory disease, dialysis
Clinical Features
Symptoms
- Gradual fatigue, exertional dyspnoea, reduced exercise tolerance
- Palpitations, dizziness, headaches
- Sore tongue or mouth (glossitis), reduced appetite, weight loss
- Neurocognitive symptoms in B12 deficiency: paraesthesia, gait unsteadiness, memory and concentration problems
- Mood or psychiatric disturbance (less common; severe cases may present with psychosis)
Signs
- Pallor and tachycardia; flow murmur in significant anaemia
- Smooth beefy glossitis and angular cheilitis
- Mild jaundice from ineffective erythropoiesis
- Reduced vibration/proprioception, sensory ataxia, positive Romberg sign (B12 deficiency)
- Peripheral neuropathy, spasticity or extensor plantar responses in advanced B12 neurological disease
- Features suggesting underlying cause: vitiligo/other autoimmune disease, malnutrition, or stigmata of malabsorption
Investigations
Management
Lifestyle Modifications
- Address cause and nutrition: improve intake of B12- and folate-rich foods, reduce harmful alcohol use, and treat malabsorption where possible
- Safety-net for neurological symptoms and pregnancy planning; ensure folic acid prophylaxis advice is individualized pre-conception
- Review long-term medicines (for example metformin, acid suppression, folate antagonists) and balance risks/benefits
Pharmacological Treatment
Vitamin B12 replacement
- Hydroxocobalamin 1 mg intramuscularly 3 times weekly for 2 weeks (initial treatment if no neurological involvement)
- Hydroxocobalamin 1 mg intramuscularly on alternate days until no further neurological improvement, then 1 mg every 2 months (if neurological involvement)
- Hydroxocobalamin 1 mg intramuscularly every 2-3 months long term (maintenance for irreversible causes such as pernicious anaemia)
- Cyanocobalamin oral 50-150 micrograms daily in diet-related deficiency when absorption is intact
Do not delay treatment in suspected severe deficiency with neurological signs. In pernicious anaemia, treatment is usually lifelong. Monitor clinical response and blood count; early reticulocyte rise is expected.
Folate replacement
- Folic acid 5 mg orally once daily for 4 months (typical adult treatment)
- Folic acid up to 15 mg daily in malabsorption states (specialist-guided)
- Pregnancy prevention dosing: folic acid 400 micrograms daily pre-conception to 12 weeks; 5 mg daily if high-risk (for example previous neural tube defect, certain antiepileptics, diabetes, BMI >=30)
Critical safety point: exclude or treat coexisting B12 deficiency before giving folic acid alone, as isolated folate can correct anaemia while neurological injury from B12 deficiency progresses.
Supportive/adjunctive care
- Potassium replacement only if clinically indicated by measured hypokalaemia
Rarely, brisk marrow response can unmask hypokalaemia after starting therapy; check electrolytes in severe cases.
Surgical / Interventional
- No routine surgical treatment for the deficiency itself; surgery is only relevant to underlying causes (for example prior gastric or ileal resection).
Complications
- Heart failure or cardiopulmonary strain in severe anaemia (especially older adults)
- Peripheral neuropathy, ataxia, cognitive impairment, and rarely optic atrophy or severe psychiatric disturbance in B12 deficiency
- Neural tube defects in pregnancy with low maternal folate or B12
- Subfertility/sterility (often reversible after replacement)
- Pancytopenia from ineffective marrow production in severe nutritional deficiency
- In pernicious anaemia, increased long-term risk of gastric malignancy and coexistence with autoimmune endocrinopathies
Prognosis
Haematological recovery is usually rapid and excellent with correct replacement and treatment of the underlying cause; reticulocytosis typically appears within about a week and haemoglobin rises over weeks. Neurological outcomes depend on duration before treatment: early therapy may reverse deficits, but delayed treatment can leave permanent impairment. Prognosis is best with lifelong adherence in irreversible causes (for example pernicious anaemia) and regular review for associated autoimmune disease and gastric risk.
Sources & References
🏥BMJ Best Practice(1)
✅NICE Guidelines(1)
- Anaemia - B12 and folate deficiency[overview]