Macrocytic anaemia with neurological signs: B12, folate and the methylmalonic acid trap
Meera, a 71-year-old retired teacher, presents with six months of progressive fatigue, a sore tongue and tingling in both feet. She has become unsteady and her daughter has noticed occasional confusion. She has been a strict vegan for 15 years and takes no supplements. Examination shows glossitis, reduced vibration sense and proprioception in the toes, brisk knee reflexes with extensor plantars, and a broad-based gait. Haemoglobin is 8.4 g/dL, MCV 122 fL, white cell count 3.2 × 10⁹/L, platelets 98 × 10⁹/L; the film shows oval macrocytes and hypersegmented neutrophils. Lactate dehydrogenase is 780 U/L and indirect bilirubin 38 µmol/L. Serum vitamin B12 is 84 pg/mL, serum folate 18 ng/mL, methylmalonic acid 4.2 µmol/L (raised) and total homocysteine 48 µmol/L (raised). Anti-intrinsic factor antibodies are positive. She asks whether a folate tablet from the pharmacy would be enough.
1. Explain how vitamin B12 deficiency produces a megaloblastic anaemia and why lactate dehydrogenase and bilirubin are raised.
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Vitamin B12 is a cofactor for methionine synthase, which converts homocysteine to methionine using methyltetrahydrofolate as the methyl donor. This reaction also regenerates tetrahydrofolate, which is required for thymidylate synthesis and therefore DNA replication. In B12 deficiency, folate becomes trapped as methyltetrahydrofolate, thymidylate production falls and DNA synthesis is impaired. Erythroid precursors show nuclear–cytoplasmic asynchrony, producing large cells with immature nuclei, the megaloblasts. Similar changes affect other rapidly dividing cells, explaining the low white cell count, low platelets and glossitis. Many of these abnormal red cells are destroyed within the marrow, a process called ineffective erythropoiesis or intramedullary haemolysis. This releases lactate dehydrogenase and raises indirect bilirubin, while haptoglobin may be low. The reticulocyte count is usually low despite the anaemia. The combination of a high MCV, hypersegmented neutrophils, raised LDH and raised indirect bilirubin is a classic picture of megaloblastic anaemia.
2. The patient has both raised methylmalonic acid and raised homocysteine. Why does this pattern point to B12 rather than folate deficiency, and why does it matter clinically?
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Methylmalonyl-CoA mutase requires adenosylcobalamin, a B12 coenzyme, to convert methylmalonyl-CoA to succinyl-CoA. When B12 is deficient, methylmalonic acid accumulates; folate deficiency does not raise methylmalonic acid. Methionine synthase requires methylcobalamin and folate, so homocysteine rises in either deficiency. Therefore a raised methylmalonic acid with a raised homocysteine strongly supports B12 deficiency, while folate deficiency would raise homocysteine alone. In this patient the low serum B12 and positive anti-intrinsic factor antibodies confirm pernicious anaemia. The clinical importance is that giving folate alone can correct the anaemia and the high MCV while failing to treat the neurological damage, and it may unmask or worsen subacute combined degeneration. Folate supplementation without B12 can also precipitate a rapid fall in serum B12. Treatment must be with B12, usually parenterally, before or alongside any folate.
3. Explain the neurological findings and why parenteral hydroxocobalamin is preferred over oral supplements in this patient.
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Vitamin B12 is required for myelin synthesis and maintenance. Deficiency causes demyelination of the dorsal columns, corticospinal tracts and peripheral nerves. Dorsal column involvement produces loss of vibration sense and proprioception with sensory ataxia and a broad-based gait; corticospinal involvement produces brisk reflexes and extensor plantars; peripheral neuropathy produces tingling and reduced sensation. The combination is subacute combined degeneration of the spinal cord. Cognitive changes can also occur. Pernicious anaemia is caused by autoantibodies against intrinsic factor or gastric parietal cells, so oral B12 absorption is unreliable because the ileal receptor-mediated pathway is blocked. Intramuscular hydroxocobalamin bypasses this step and is preferred for neurological involvement, often given frequently at first and then at maintenance intervals. High-dose oral cyanocobalamin can be effective in some patients through passive absorption, but it is less dependable in pernicious anaemia with neurological disease. Potassium should be monitored during early treatment because rapid erythropoiesis can cause hypokalaemia.