Discuss the causes, clinical features, investigations and management of megaloblastic anaemia, including subacute combined degeneration of the cord.

Definition

Megaloblastic anaemia is a macrocytic anaemia caused by impaired DNA synthesis with preserved RNA and protein synthesis, producing nucleocytoplasmic asynchrony — the nucleus matures more slowly than the cytoplasm, giving large cells with immature nuclei (megaloblasts) in the marrow. It results from deficiency of vitamin B12 (cobalamin) or folate, both essential for thymidylate synthesis.

Because the defect affects all rapidly dividing cells, the disorder is not confined to the marrow — the gastrointestinal epithelium and, in B12 deficiency, the nervous system are also affected.

Causes

Body stores explain the timing: B12 stores last 3–5 years, so deficiency develops insidiously; folate stores last only 3–4 months, so deficiency appears within months of inadequate intake.

Clinical Features

Haematological: gradual-onset anaemia with fatigue and dyspnoea; mild jaundice from ineffective erythropoiesis (intramedullary haemolysis), producing the characteristic "lemon-yellow" pallor; splenomegaly may be mild.

Gastrointestinal: glossitis with a smooth, beefy-red, sore tongue; angular stomatitis; anorexia, weight loss, diarrhoea; and malabsorption.

Neurological — occurs with B12 deficiency ONLY, not with folate deficiency:

• Peripheral neuropathy — symmetrical paraesthesiae in the feet and hands, the earliest neurological feature.
• Subacute combined degeneration of the cord — see below.
• Cognitive and psychiatric — irritability, poor memory, depression, and in severe cases dementia and psychosis ("megaloblastic madness").
• Optic atrophy; autonomic dysfunction.

Other: infertility, sterility, and in pregnancy folate deficiency causes neural tube defects in the fetus.

Subacute Combined Degeneration of the Cord (sacd)

Definition: demyelination of the posterior (dorsal) columns and lateral corticospinal tracts of the spinal cord due to vitamin B12 deficiency — the "combined" refers to the involvement of both tracts.

Clinical features — a classic examination case:

• Symmetrical distal paraesthesiae and numbness, beginning in the feet.
• Posterior column signs: loss of vibration sense (the earliest and most reliable), impaired joint position sense, sensory ataxia with a positive Romberg's sign, and a stamping high-stepping gait.
• Corticospinal signs: spastic weakness of the legs, brisk knee jerks, and extensor plantar responses.
• The characteristic paradox: absent ankle jerks (from the coexisting peripheral neuropathy) with extensor plantars (from corticospinal involvement) — a combination of lower and upper motor neurone signs that is highly localising. The differential for this combination is SACD, Friedreich's ataxia, taboparesis (neurosyphilis), motor neurone disease and combined pathology.
• Sphincter disturbance and impotence occur late.
• Cognitive impairment and optic atrophy may coexist.

Crucially, neurological disease may occur WITHOUT anaemia — and normal blood counts must never be used to exclude B12 deficiency in a patient with a compatible neurological picture.

Investigations

• CBC: macrocytosis with MCV often > 110 fL; anaemia; pancytopenia in severe cases.
• Peripheral smear: macro-ovalocytes and hypersegmented neutrophils (five or more lobes — an early and sensitive sign), anisopoikilocytosis.
• Reticulocyte count low — inappropriate for the degree of anaemia.
• Raised LDH and raised unconjugated bilirubin with low haptoglobin — reflecting ineffective erythropoiesis, which may be mistaken for haemolysis.
• Serum vitamin B12 and serum/red cell folate. Where B12 is borderline, measure serum methylmalonic acid (raised in B12 deficiency only) and homocysteine (raised in both B12 and folate deficiency) — this distinction is the most reliable discriminator.
• Anti-intrinsic factor antibody (specific but insensitive) and anti-parietal cell antibody (sensitive but less specific) for pernicious anaemia; also check thyroid function and screen for other autoimmune disease.
• Bone marrow (not routinely required): hypercellular with megaloblasts, giant metamyelocytes and band forms, and nuclear-cytoplasmic asynchrony.
• Schilling test — historically used to distinguish dietary deficiency from malabsorption and from intrinsic factor deficiency, by measuring urinary excretion of radiolabelled oral B12 given with and without intrinsic factor. It is now obsolete and no longer available, having been replaced by antibody testing and therapeutic trial; it is worth knowing for the examination and for its physiological logic.
• Investigate the cause: dietary history, upper GI endoscopy with biopsy (atrophic gastritis, and surveillance for the increased risk of gastric carcinoma and carcinoid in pernicious anaemia), coeliac serology, and stool examination.

Management

• Vitamin B12 replacement — parenteral (intramuscular) hydroxocobalamin or cyanocobalamin for deficiency due to malabsorption or pernicious anaemia, given as a loading course followed by lifelong maintenance injections. High-dose oral B12 is effective in dietary deficiency and in some malabsorptive states.
• Folate replacement — oral folic acid, after excluding or simultaneously treating B12 deficiency.
• Treat the underlying cause: dietary counselling and fortified foods for vegetarians, deworming, treatment of coeliac disease or bacterial overgrowth, review of metformin and proton pump inhibitors.
• Monitor response: reticulocytosis peaks at 5–7 days and is the first evidence of response; haemoglobin normalises over 6–8 weeks. Neurological recovery is slow, may take months, and is often incomplete — the longer the delay before treatment, the less complete the recovery.
• Anticipate hypokalaemia during the initial brisk erythropoietic response and monitor potassium; also anticipate a fall in iron stores as production accelerates.
• Prophylaxis: folic acid supplementation in pregnancy (periconceptional folate prevents neural tube defects), in chronic haemolysis, and in dialysis patients.