L13: Macrocytic Anaemia

Macrocytic anaemia is defined by an MCV greater than 100 fL. The most clinically important causes are megaloblastic anaemia (folate or vitamin B12 deficiency) and non-megaloblastic causes (alcohol, liver disease, hypothyroidism, drugs, myelodysplastic syndrome).

Megaloblastic anaemia results from impaired DNA synthesis. Both folate and vitamin B12 are essential for nucleotide synthesis: folate provides one-carbon units for thymidylate synthesis (via thymidylate synthase) and purine synthesis, while B12 is required for the methionine synthase reaction that regenerates the active form of folate (5-methylTHF → THF). Deficiency of either causes delayed nuclear maturation relative to cytoplasmic development — cells grow large but cannot divide efficiently. The result is macrocytic red cells, hypersegmented neutrophils (five or more lobes; pathognomonic), and pancytopenia in severe deficiency.

Vitamin B12 (cobalamin) absorption requires a multi-step process. Dietary B12 is bound by haptocorrin (R-binder) in the stomach, then transferred to intrinsic factor (IF) — a glycoprotein secreted by gastric parietal cells — after haptocorrin is cleaved by pancreatic proteases in the duodenum. The B12-IF complex is absorbed exclusively in the terminal ileum via cubam receptors. In plasma, B12 is carried by transcobalamin II (active transport fraction) and haptocorrin. Hepatic stores of B12 are substantial (2–3 mg), lasting 3–5 years if absorption ceases.

Pernicious anaemia is the most common cause of B12 deficiency in adults. It is an autoimmune condition in which antibodies destroy gastric parietal cells (anti-parietal cell antibodies in ~90% of patients) and/or block IF (anti-IF antibodies in ~50%). Gastric parietal cell loss causes achlorhydria and loss of IF → failure of B12 absorption. Other causes of B12 deficiency: atrophic gastritis (Helicobacter pylori or autoimmune), gastrectomy, terminal ileum disease (Crohn's disease, resection), strict vegan diet (no animal products), and fish tapeworm (Diphyllobothrium latum).

Vitamin B12 deficiency uniquely causes neurological disease: subacute combined degeneration of the spinal cord (demyelination of the dorsal and lateral columns), peripheral neuropathy (numbness, paraesthesia), and cognitive impairment/dementia. Folate deficiency does NOT cause neurological disease; this distinction is clinically critical because treating B12 deficiency with folate alone corrects the blood picture but allows neurological damage to progress.

Folate deficiency causes: poor dietary intake (especially in alcohol dependence), increased requirements (pregnancy, haemolytic anaemia, dialysis), malabsorption (coeliac disease), and drugs that inhibit dihydrofolate reductase (methotrexate, trimethoprim).

Non-megaloblastic macrocytosis. Alcohol causes macrocytosis by a direct toxic effect on red cell membrane lipids and often by concurrent folate deficiency. Liver disease causes macrocytosis through lipid abnormalities. Myelodysplastic syndrome (MDS) is a clonal stem cell disorder causing dysplastic haematopoiesis, macrocytosis, and cytopenias; it may transform to acute myeloid leukaemia.

Treatment: vitamin B12 deficiency is treated with intramuscular hydroxocobalamin (or oral cyanocobalamin in dietary deficiency where absorption is intact). Folate deficiency is treated with oral folic acid 5 mg daily. In megaloblastic anaemia where the cause is uncertain, B12 must be corrected before or alongside folate to prevent masking neurological disease.