Megaloblastic and macrocytic anaemia: SAQ

This infant has severe vitamin B12 deficiency, acquired from the marginal stores of a strict vegan mother through exclusive breastfeeding. The macrocytic anaemia with hypersegmented neutrophils and the pancytopenia establish the megaloblastic picture, and the low serum B12 with both methylmalonic acid and homocysteine raised confirms B12 rather than folate deficiency. The developmental regression and the tremor are the neurological signs that mark the urgency, because the more severe and prolonged the neurological deficit, the less complete the recovery. [1][8]

Question 1 (10 marks)

Outline the diagnostic interpretation and the immediate management of this infant, justifying each step with the relevant evidence. [1]

A full-mark answer addresses the metabolite interpretation, the replacement agent and schedule, the two safety rules, and the family and feeding plan, each with the correct value or dose. [3]

Metabolite interpretation and diagnosis (3 marks). The macrocytic anaemia with oval macrocytes and hypersegmented neutrophils is megaloblastic until proven otherwise, and the low serum B12 confirms the cause. The methylmalonic acid is raised only in B12 deficiency, through the methylmalonyl-CoA mutase reaction that B12 catalyses, while the homocysteine is raised in both B12 and folate deficiency through the shared methionine synthase step. Both metabolites raised therefore identifies B12 deficiency and excludes folate deficiency. The mild thrombocytopenia is part of the pancytopenia of impaired DNA synthesis, in which every fast-growing cell line is affected. [5][1]

Replacement and the two safety rules (4 marks). The treatment is hydroxocobalamin by intramuscular injection, preferred over cyanocobalamin because it is retained longer. The British Society for Haematology schedule for deficiency with neurological involvement 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 first safety rule is that folic acid must never be given alone until B12 is excluded, and here it is excluded by the metabolites, so the folate can be given if the level is also low, but only alongside the B12. The second safety rule 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. [3][1]

Family and feeding plan (3 marks). The cause is the maternal vegan diet, so the mother is tested and treated with B12 and advised to supplement through the remainder of the lactation, and the family receives dietary counselling from a dietitian. The breastfeeding is continued with the infant's replacement rather than stopped, because human milk remains the best feed once the B12 is restored. A neurodevelopmental service follows the infant for the re-acquisition of the lost milestones, and the recovery of the blood count is expected within weeks while the neurological recovery proceeds over months. The family is counselled that the long-term outcome depends on the severity and the duration of the deficit before treatment. [8][9]

Question 2 (10 marks)

Explain the biochemical basis of the megaloblastic picture and the principles that govern the treatment of B12 versus folate deficiency, including the inherited causes. [5]

A full-mark answer reproduces the pathway logic and the treatment principles, distinguishing the two deficiencies and naming the inherited causes. [5]

The biochemical basis (4 marks). 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. When either vitamin is lacking, thymidine synthesis fails, DNA replication slows, and the nucleus matures more slowly than the cytoplasm, producing the large oval red cell and the hypersegmented neutrophil. B12 is also the cofactor for methylmalonyl-CoA mutase, the enzyme that converts methylmalonyl-CoA to succinyl-CoA, which is why methylmalonic acid rises only in B12 deficiency while homocysteine rises in both. [5]

Treatment principles (3 marks). For B12 deficiency the treatment is parenteral hydroxocobalamin, because the oral absorption is variable and the intramuscular route is reliable, with the longer induction for neurological involvement and the lifelong maintenance for permanent causes. For folate deficiency the treatment is folic acid 5 mg once daily by mouth for four months, or lifelong if the cause persists. The cardinal rule is that folate is never 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. Prophylactic folate is given in pregnancy at 400 micrograms daily, or 5 mg daily for high-risk pregnancies, and as a low daily dose in chronic haemolysis. [3][1]

The inherited causes (3 marks). 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. Imerslund-Graesbeck syndrome is the autosomal recessive defect of cubilin or amnionless that causes selective B12 malabsorption with persistent proteinuria, treated with lifelong parenteral B12. Congenital intrinsic factor deficiency and congenital folate malabsorption are rarer still, and these inherited causes are considered whenever the deficiency is severe, early, and unexplained by diet or malabsorption, and they demand lifelong replacement. [11][12]