Megaloblastic and macrocytic anaemia: Viva

Branch 1: Confirming the diagnosis

The candidate should recognise the classic infantile vitamin B12 deficiency, with the macrocytic anaemia, the hypersegmented neutrophils, the developmental regression, and the tremor, in the breastfed infant of a strict vegan mother. A strong candidate states that the breastfeeding infant is wholly dependent on maternal stores, that a marginal vegan supply is depleted within months, and that the developmental regression is the sign that lifts the case out of an ordinary anaemia and marks the urgency. The candidate should add that the methylmalonic acid raised with the homocysteine raised confirms B12 rather than folate deficiency. [8][9]

If the examiner presses on the separation of the two deficiencies, the candidate should give the metabolite logic precisely. Methylmalonic acid rises only in B12 deficiency, because B12 is the cofactor for methylmalonyl-CoA mutase, while homocysteine rises in both deficiencies, because the methionine synthase step is shared and requires both vitamins. The candidate should note that the metabolites resolve the diagnosis when the serum B12 is borderline, which it often is, because the assay is confounded by pregnancy and liver disease. [5]

Branch 2: The biochemical basis

If the examiner moves to the mechanism, the candidate should explain the folate and methionine remethylation cycle. Folate enters the cycle as 5-methyltetrahydrofolate and donates its methyl group to homocysteine in a reaction catalysed by methionine synthase, which uses B12 as its cofactor, regenerating tetrahydrofolate and producing methionine. The tetrahydrofolate then feeds the thymidylate synthase reaction that produces thymidine for DNA synthesis. [5]

The candidate should explain why the lack of either vitamin produces the megaloblastic picture. When thymidine synthesis fails, DNA replication slows, the nucleus matures more slowly than the cytoplasm, and the cell grows large but cannot divide, producing the macro-ovalocyte and the hypersegmented neutrophil and, in the severe case, the pancytopenia. A strong candidate links the marrow picture of nuclear-cytoplasmic asynchrony to the peripheral blood film and explains why a single missing vitamin enlarges every fast-growing cell line. [1]

Branch 3: Treatment and the safety rules

If asked for the treatment, the candidate should name parenteral hydroxocobalamin as the agent of choice and give the British Society for Haematology schedule. For deficiency with neurological involvement the schedule is hydroxocobalamin 1000 micrograms intramuscularly on alternate days for up to three weeks, or until no further improvement, followed by maintenance of 1000 micrograms every two to three months. The candidate should state that hydroxocobalamin is preferred over cyanocobalamin because it is retained longer, and that the oral route is reserved for selected maintenance only. [3]

The candidate should then give the two safety rules that the examiner will test. The first is that folic acid must never be given alone until B12 is excluded, because it can precipitate or worsen subacute combined degeneration of the cord by driving the B12-dependent neurological injury while the marrow improves. The second is that the serum potassium is monitored and supplemented in the first days, because the resuming marrow takes up potassium and a severe hypokalaemia can develop. A strong candidate adds that any combined iron deficiency is treated with elemental iron once the vitamin replacement is under way. [1][3]

Branch 4: The inherited causes and the family

If the examiner moves to the inherited causes, the candidate should name transcobalamin II deficiency and Imerslund-Graesbeck syndrome. Transcobalamin II deficiency is the autosomal recessive transport defect that produces a normal serum B12, because the vitamin is carried on transcobalamin I, but severe cellular deficiency with failure to thrive, pancytopenia, and neurological signs, treated with high-dose parenteral B12 to saturate the missing carrier. [11]

Imerslund-Graesbeck syndrome is the autosomal recessive defect of cubilin or amnionless that causes selective B12 malabsorption with persistent proteinuria, because cubilin also reabsorbs protein in the proximal tubule, and it is treated with lifelong parenteral B12. A strong candidate closes by stating that the prognosis is excellent when the deficiency is caught early and replaced before permanent neurological injury, that the family receives dietary counselling and the mother is treated and advised to supplement, and that the neurodevelopmental service follows the infant for the re-acquisition of the lost milestones. [12][2]