Serum levels, then the metabolites, then the cause
Expansion
Initial tests: serum B12 and serum folate, alongside the full blood count and blood film.
Film findings: macrocytosis, oval macrocytes, hypersegmented neutrophils (more than 5 per cent with five lobes, or any with six), and in severe cases pancytopenia with ineffective erythropoiesis, giving a raised LDH and bilirubin that can mimic haemolysis.
Pitfalls of the serum B12 assay
- Falsely low: pregnancy, oral contraceptives, folate deficiency itself, myeloma, metformin, and in about half of people with a low result there is no true deficiency
- Falsely normal despite deficiency: liver disease, myeloproliferative disease, and small intestinal bacterial overgrowth
- The active (holotranscobalamin) assay is more specific
Second line metabolites, where the result is borderline or discordant with the clinical picture
| B12 deficiency | Folate deficiency | |
|---|---|---|
| Methylmalonic acid | Raised | Normal |
| Homocysteine | Raised | Raised |
So a raised methylmalonic acid is the marker that separates them.
Finding the cause of B12 deficiency: intrinsic factor antibodies are specific but only about 50 per cent sensitive; parietal cell antibodies are sensitive but non-specific. Consider pernicious anaemia, gastrectomy, ileal disease or resection, Crohn’s, metformin, proton pump inhibitors, and a vegan diet.
Neurological disease can occur with a normal haemoglobin and a normal MCV, which is why B12 must be checked in unexplained neuropathy, cognitive decline or ataxia, and why treatment should not wait for anaemia.