PA15.1-3 | Vitamin B12 & Folate Metabolism — Deficiency Pathogenesis — Summary & Reflection

REFLECT

Consider this scenario: a 62-year-old man with type 2 diabetes has been on metformin 1000 mg twice daily for 8 years. His annual review shows a borderline low serum B12 (190 pg/mL; laboratory reference 200–900). His neurological examination is entirely normal, and his MCV is 93 fL (normal).

1. What mechanism explains metformin-associated B12 depletion?
2. The physician wonders whether to supplement or simply monitor. What additional investigation would most precisely quantify the functional B12 status before deciding?
3. If supplementation is deferred and this patient undergoes general anaesthesia with nitrous oxide in two months for an elective procedure, what is the specific risk, and how should the anaesthetic team be informed?

Formulate your answers before comparing with the summary.

KEY TAKEAWAYS

Core concepts from this module:

B12 absorption requires the intrinsic factor relay: gastric parietal cells → IF → terminal ileum cubilin receptor → transcobalamin II. Any break in this relay (pernicious anaemia, gastrectomy, ileal disease, fish tapeworm) causes B12 deficiency after a latency of years (large stores).

The two B12-dependent enzymes:
• Methionine synthase — demethylates 5-methyl-THF; its failure creates the folate trap, blocks DNA synthesis, causes megaloblastosis.
• Methylmalonyl-CoA mutase — its failure raises methylmalonic acid, the specific biochemical fingerprint of B12 deficiency, and disrupts myelin synthesis → subacute combined degeneration.

Megaloblastosis = nuclear-cytoplasmic asynchrony → ineffective erythropoiesis (↑LDH, ↑indirect bilirubin, ↓reticulocytes) + hypersegmented neutrophils.

Neurological damage (SCD) is unique to B12 deficiency — folate deficiency causes identical haematology but NEVER posterior-column or pyramidal signs. MMA is the differentiating biochemical test.

Pernicious anaemia is autoimmune (anti-IF antibodies > anti-parietal-cell antibodies for specificity), most common in adults >50, associated with other autoimmune disorders and a slightly elevated gastric cancer risk.

Folate deficiency is faster (months), caused by poor diet/alcohol/pregnancy/malabsorption (proximal jejunum)/DHFR-inhibiting drugs. Neural tube defects are the consequence of periconceptional folate insufficiency.

Next module (H4 SDL2): translating this pathogenesis into laboratory diagnosis — blood count interpretation, BMA findings, serum assays, and the Schilling test logic.