Megaloblastic and macrocytic anaemia

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Target exams

Red flags

• A macrocytic child with developmental regression, irritability, tremor, ataxia, or loss of vibration sense has vitamin B12 deficiency until excluded, because folate deficiency does not cause neurological signs
• Never give folic acid alone until vitamin B12 deficiency is excluded, because it can precipitate or worsen subacute combined degeneration of the spinal cord
• A breastfed infant of a strict vegan or subclinically deficient mother can develop severe B12 deficiency within months, so maternal diet is part of the history of every macrocytic infant
• Severe deficiency carries a risk of hypokalaemia in the first days of vitamin replacement as the marrow resumes effective haemopoiesis, so monitor and supplement the serum potassium
• A borderline serum B12 can mislead in pregnancy or liver disease, and the methylmalonic acid and homocysteine metabolites resolve the diagnosis when the vitamin level is equivocal

Life stages

Care settings

Clinical exam formats

Board mappings

• Defines macrocytosis as a mean corpuscular volume above the age-specific reference range and distinguishes it from megaloblastic anaemia, a specific marrow pattern of impaired DNA synthesis
• Recognises that vitamin B12 deficiency in an exclusively breastfed infant of a vegan or deficient mother produces macrocytic anaemia with developmental regression and neurological signs
• States the cardinal warning that folic acid must never be given alone until vitamin B12 deficiency is excluded because it can precipitate subacute combined degeneration of the spinal cord
• Explains the folate and methionine remethylation cycle, the shared methionine synthase step needing B12, the B12-only methylmalonyl-CoA mutase step, and why methylmalonic acid rises only in B12 deficiency while homocysteine rises in both
• Differentiates megaloblastic causes (B12, folate, drug-induced, inherited) from non-megaloblastic causes of macrocytosis (reticulocytosis, liver disease, hypothyroidism, aplastic and myelodysplastic disease) using the blood film and the metabolites
• Selects hydroxocobalamin intramuscular replacement for B12 deficiency with the correct duration and maintenance schedule, folic acid for folate deficiency, and lifelong surveillance for permanent causes such as pernicious anaemia and Imerslund-Graesbeck syndrome
• Macrocytic anaemia with hypersegmented neutrophils and macro-ovalocytes on the blood film points to megaloblastic haemopoiesis from B12 or folate deficiency until proven otherwise
• Methylmalonic acid is raised in B12 deficiency only while homocysteine is raised in both B12 and folate deficiency, and this pair separates the two deficiencies when vitamin levels are borderline
• Neurological signs in a macrocytic child are B12 deficiency until excluded, and treatment is parenteral hydroxocobalamin
• Assesses the child with macrocytosis across the dietary and maternal history, the neurological examination of tone, power, reflexes, vibration and joint position sense, and the developmental assessment
• Counsels the family on the cause, the reversible nature of most paediatric deficiency, the need for a complete replacement course, and the warning that folic acid alone is dangerous when B12 is not excluded
• Builds the multidisciplinary plan of haematology, dietetics, neurodevelopmental surveillance, and the treatment of the underlying cause such as coeliac disease or pernicious anaemia
• Level 1: Recognition of the macrocytic blood film with hypersegmented neutrophils and the infant with developmental regression who needs urgent B12 and folate testing
• Level 2: Application of hydroxocobalamin replacement for B12 deficiency, folic acid for folate deficiency, metabolite interpretation, and the safe rule of never giving folate alone
• Level 3: Coordination of the diagnostic workup for inherited and autoimmune causes, lifelong maintenance for permanent deficiency, and population-level folate prophylaxis
• The biochemistry of B12 and folate, the methionine synthase and thymidylate synthase reactions, and why impaired DNA synthesis produces megaloblastic haemopoiesis
• The causes of macrocytosis in children including maternal vegan diet, goat milk feeding, malabsorption, increased demand, and drug-induced folate antagonism
• The methylmalonic acid and homocysteine interpretation, the blood film findings, and the treatment doses of hydroxocobalamin and folic acid
• Structured assessment of the macrocytic child across the dietary and family history, the pallor and jaundice of ineffective erythropoiesis, and the neurological examination of the cord and nerves
• Communication of the diagnosis, the reversible prognosis, the treatment plan, and the critical folic acid warning with the family
• Recognition and management of the severely anaemic child with cautious transfusion, hypokalaemia monitoring during early B12 treatment, and the exclusion of combined iron deficiency
• Megaloblastic anaemia as a macrocytic anaemia of impaired DNA synthesis caused by vitamin B12 or folate deficiency, presenting in infants with developmental regression and in older children with anaemia and neurological signs
• The diagnostic interpretation of the blood film, serum and red cell folate, serum B12, methylmalonic acid and homocysteine, and the cause workup including coeliac and pernicious anaemia serology
• Treatment with parenteral hydroxocobalamin or oral folic acid, the rule against folate monotherapy, and prophylactic folate in pregnancy and chronic haemolysis
• Recognition of macrocytosis on the full blood count and the distinction of megaloblastic from non-megaloblastic causes
• Application of vitamin replacement with the correct agent, route, dose and duration, and the safety rule on folate monotherapy
• Coordination of the diagnostic and dietary workup, the neurodevelopmental follow-up, and family counselling for inherited and nutritional deficiency
• Canadian approach to the macrocytic child with age-specific mean corpuscular volume interpretation and the methylmalonic acid and homocysteine metabolite pair
• Hydroxocobalamin intramuscular replacement for B12 deficiency and folic acid for folate deficiency, with mandatory folate fortification of flour as population prophylaxis
• The inherited causes of paediatric B12 and folate deficiency including transcobalamin II deficiency and Imerslund-Graesbeck syndrome, and their lifelong management