B12 and Folate Deficiency

Megaloblastic anaemia results from impaired DNA synthesis, causing a characteristic appearance of large red blood cells (MCV >100fL) and hypersegmented neutrophils. Vitamin B12 (cobalamin) is found in animal products and requires intrinsic factor (IF) from gastric parietal cells for absorption in the terminal ileum. Folate is found in green vegetables and absorbed in the jejunum. In the UK, Pernicious Anaemia (an autoimmune condition where antibodies attack parietal cells or IF) is the primary cause of B12 deficiency. Other causes include veganism, Crohn's disease, and metformin use. Folate deficiency is often due to poor diet, alcoholism, or increased demand (haemolysis, pregnancy). B12 deficiency is uniquely associated with subacute combined degeneration of the spinal cord (SCDSC), involving the dorsal columns and lateral corticospinal tracts. Management must prioritize B12 replacement before folate to avoid precipitating neurological crisis.

B12 and folate are essential for the conversion of homocysteine to methionine and the synthesis of thymidylate, which is required for DNA replication. Specifically, B12 is a co-factor for methionine synthase. When B12 or folate is low, DNA synthesis is delayed while cytoplasmic growth proceeds at a normal rate, leading to large, immature nuclei (nuclear-cytoplasmic dysynchrony). This results in macrocytosis and ineffective erythropoiesis. Pernicious anaemia involves Type 1 antibodies (blocking the B12-IF binding site) and Type 2 antibodies (blocking the IF-ileal receptor site). Additionally, B12 is required for the conversion of methylmalonyl-CoA to succinyl-CoA; its absence leads to an accumulation of methylmalonic acid (MMA), which is toxic to the myelin sheaths of the nervous system, leading to demyelination of the posterior and lateral columns (SCDSC).

Patients present with symptoms of anaemia (fatigue, pallor). B12 deficiency presents with neurological signs: peripheral neuropathy (glove and stocking), loss of vibration sense and proprioception (dorsal columns), and spasticity with brisk reflexes but upgoing plantars (corticospinal tracts). This 'paradox' of absent ankle jerks but upgoing plantars is classic. Psychiatric symptoms ('megaloblastic madness') including irritability and dementia can occur. Folate deficiency presents with similar haematological features but lacks the neurological involvement. It is particularly dangerous in pregnancy due to the risk of neural tube defects. Glossitis ('beefy red tongue') and jaundice (due to intramedullary haemolysis) may be seen in both.

Bloods: FBC (Hb low, MCV >100fL), Blood film (macrocytes, hypersegmented neutrophils), Serum B12, Serum Folate (Check B12 first). Autoantibodies: Anti-intrinsic factor antibodies (highly specific for Pernicious Anaemia) and Anti-parietal cell antibodies (sensitive but less specific). Special tests: Holotranscobalamin (active B12) or Methylmalonic acid (MMA) if B12 levels are borderline. Terminal ileal biopsy or imaging if Crohn's suspected.

Medical (B12): For Pernicious Anaemia or malabsorption, intramuscular Hydroxocobalamin 1mg three times a week for two weeks, followed by 1mg every 3 months for life. If neurological symptoms are present, injections are given every other day until symptoms stop improving. Dietary B12 deficiency can be managed with oral cyanocobalamin. Medical (Folate): Oral Folic Acid 5mg daily. Important: Ensure B12 levels are normal or being replaced before starting folate to prevent neurological deterioration. Conservative: Dietary advice (liver, meat, dairy for B12; green leafy vegetables for folate).