Vitamin B12 Deficiency — Causes, Megaloblastic Anaemia, Neuropathy & Treatment — Symptoms, Causes & Treatment | MyMedicPlus

Vitamin B12 (cobalamin) is an essential water-soluble vitamin required for DNA synthesis (through methylation of homocysteine to methionine and thymidine synthesis), fatty acid metabolism, and myelin synthesis. Unlike most water-soluble vitamins, B12 is stored in the liver for 3-5 years — deficiency therefore develops slowly, often presenting insidiously. B12 deficiency causes two major clinical syndromes: megaloblastic anaemia (impaired DNA synthesis in rapidly dividing cells — red blood cell precursors — causes large immature red cells); and neurological damage (demyelination of the posterior and lateral columns of the spinal cord — subacute combined degeneration — and peripheral neuropathy). B12 deficiency affects up to 6% of adults under 60 and 20% of adults over 60. It is also a significant cause of reversible cognitive impairment and dementia — often overlooked. Unlike iron deficiency, it does not always cause anaemia — neurological damage can occur with a normal blood count.

Pernicious anaemia (PA): the most common cause in developed countries — an autoimmune condition in which antibodies against gastric parietal cells and/or intrinsic factor (IF) block production of intrinsic factor, which is required for B12 absorption in the terminal ileum. PA is associated with other autoimmune conditions (thyroid disease, vitiligo, Type 1 diabetes, Addison's disease). Dietary deficiency: in strict vegans (B12 is found only in animal-derived foods — meat, fish, eggs, dairy) and some vegetarians — the most common cause globally, particularly in South Asia, where vegetarianism is prevalent. Gastric surgery / atrophic gastritis: partial gastrectomy, gastric bypass surgery, and Helicobacter pylori-associated atrophic gastritis reduce acid and IF production, impairing B12 absorption. Drug-induced malabsorption: metformin (reduces ileal B12 absorption — affects up to 20-30% of metformin users after 4+ years; mechanism involves calcium-dependent IF-B12-receptor interaction); proton pump inhibitors (PPIs) and H2-blockers (reduce gastric acid — impair protein-bound B12 release from food, though impact is modest with normal IF). Terminal ileal disease: Crohn's disease, coeliac disease, surgical resection — impairs IF-B12 complex absorption at the ileal receptor (cubam). Functional B12 deficiency: normal serum B12 but elevated methylmalonic acid (MMA) and homocysteine — reflects true cellular B12 depletion.

Haematological features: fatigue and weakness (from anaemia); pallor; breathlessness on exertion; palpitations; mild jaundice (from haemolysis of fragile megaloblastic red cells — causes lemon-yellow tinge). Neuropsychiatric features (can occur without anaemia): subacute combined degeneration of the spinal cord (SACD) — the characteristic neurological complication of B12 deficiency: symmetrical paraesthesiae (tingling, pins and needles) in hands and feet; weakness and spasticity in the legs; sensory ataxia (difficulty walking in the dark — positive Romberg test); urinary and faecal incontinence; and in severe cases, paraplegia. Peripheral neuropathy: distal stocking-glove sensory loss. Cognitive impairment and dementia: irritability, memory loss, confusion — sometimes incorrectly attributed to Alzheimer's disease (B12 deficiency is one of the treatable causes of dementia). Psychiatric features: depression, psychosis ('megaloblastic madness'). Glossitis (smooth, red, painful tongue — Hunter's glossitis). Angular cheilitis. Note: folate deficiency causes identical megaloblastic anaemia but NOT the neurological syndrome — giving folate to a B12-deficient patient without B12 will worsen neurological complications.

Full blood count (FBC): macrocytosis (large red cells — MCV above 100 fL); neutrophil hypersegmentation (5 or more lobes — classic on blood film); anaemia (Hb below normal range) in established deficiency. Note: 20-30% of patients with B12 deficiency have a normal MCV (masked by concurrent iron deficiency, or deficiency not yet advanced to anaemia). Serum vitamin B12: below 150 pmol/L confirms deficiency; 150-200 pmol/L is borderline — treat empirically if symptomatic. Serum folate and red cell folate: folate deficiency causes identical haematological picture; both should be measured together. Methylmalonic acid (MMA) and total homocysteine: more sensitive and specific markers of functional B12 deficiency — elevated MMA (above 0.28 micromol/L) confirms true tissue B12 depletion even when serum B12 is borderline; homocysteine is elevated in both B12 and folate deficiency. Intrinsic factor antibody (IFA) and anti-parietal cell antibody (PCA): IFA is highly specific for pernicious anaemia (positive in 50-60% of PA — a positive result confirms PA regardless of serum B12); PCA is sensitive but less specific (80% positive in PA). Gastric biopsy: may reveal atrophic gastritis and H. pylori in pernicious anaemia evaluation. B12 deficiency investigations are also recommended for unexplained peripheral neuropathy, cognitive impairment, and unexplained macrocytosis.

Route of B12 replacement depends on the cause. Pernicious anaemia and malabsorption syndromes (terminal ileal disease, gastric surgery): parenteral hydroxocobalamin (1 mg IM) is required as oral absorption is bypassed. Loading: 1 mg IM on alternate days for 2 weeks (6 injections total). Maintenance: 1 mg IM every 3 months (lifelong). Neurological features require more intensive initial loading (alternate days for 3 weeks). Dietary deficiency (vegan/vegetarian): oral cyanocobalamin 50-150 mcg daily (supplements); alternatively, high-dose oral hydroxocobalamin 1 mg daily achieves adequate serum levels through passive absorption even without IF (approximately 1% passive absorption); regular dietary fortified foods (fortified plant milks, breakfast cereals, nutritional yeast). Metformin-induced deficiency: annual B12 monitoring in long-term metformin users (especially at high doses, above 1.5 g/day, or after 4+ years); oral supplementation usually sufficient unless symptomatic. Folate supplementation: should be given concurrently with B12 in megaloblastic anaemia but must not replace B12 treatment. Response to treatment: reticulocytosis peaks at 5-7 days; Hb normalises within 8 weeks; neurological improvement occurs over months (up to 12-18 months) — early treatment achieves more complete neurological recovery.

Untreated or prolonged vitamin B12 deficiency causes serious, potentially permanent organ damage. Neurological complications are the most severe: subacute combined degeneration of the spinal cord (SACD) — bilateral demyelination of the dorsal and lateral spinal columns — causes progressive spastic paraparesis, loss of proprioception and vibration sense, and sensory ataxia; peripheral neuropathy produces glove-and-stocking sensory loss and neuropathic pain; neuropsychiatric manifestations include cognitive impairment, depression, and dementia (particularly in elderly patients). Neurological damage from B12 deficiency is reversible if treated early — deficits present for more than 12–18 months may be only partially reversible or permanent. Haematological: megaloblastic anaemia (macro-ovalocytes, hypersegmented neutrophils, raised MCV) causes progressive fatigue, pallor, dyspnoea on exertion, and palpitations; severe anaemia can precipitate cardiac decompensation in the elderly. Hunter's glossitis (smooth, sore, beefy-red tongue from atrophic papillae) impairs eating and nutrition. In pregnancy, severe maternal B12 deficiency causes neural tube defects, low birth weight, and neonatal neurological complications — breastfed infants of B12-deficient mothers are at risk of megaloblastic anaemia and developmental delay. Bone marrow suppression in severe cases causes pancytopaenia (anaemia, leucopaenia, thrombocytopaenia), increasing infection and bleeding risk. Pernicious anaemia — the most common cause of B12 deficiency in adults — carries a 3-fold increased risk of gastric cancer due to associated chronic atrophic gastritis and achlorhydria.

Vegans and strict vegetarians should supplement B12 consistently — without supplementation, 40-86% develop deficiency over time. A daily supplement of at least 10 mcg (or 2,000 mcg weekly) is recommended by most vegan organisations and clinical guidelines. Fortified foods (plant-based milks with B12, fortified cereals, nutritional yeast) provide meaningful B12 but supplementation ensures adequacy. Long-term metformin users should have B12 checked every 1-3 years — particularly those at higher doses, older patients, and those with symptoms of peripheral neuropathy. Patients with H. pylori-associated atrophic gastritis should have it tested and treated — restoration of gastric mucosa can improve B12 absorption. Annual B12 monitoring is recommended for patients post-gastrectomy, post-bariatric surgery, and with established inflammatory bowel disease affecting the terminal ileum. Importantly, folate supplementation without B12 in at-risk patients should be avoided — it corrects anaemia but worsens neurological damage.

See a GP for investigation of B12 deficiency if you have: persistent fatigue with pallor, breathlessness, or palpitations; tingling or numbness in hands or feet (peripheral neuropathy); difficulty walking, balance problems, or unsteadiness; memory impairment, confusion, or depressive symptoms; a smooth, red, sore tongue; or you are a strict vegan or vegetarian not supplementing B12. Seek urgent review if you have neurological symptoms (tingling, weakness, gait problems) — neurological damage from B12 deficiency is more easily reversible if treated early; once fixed deficits develop, recovery is incomplete. People on long-term metformin, PPIs, or who have had gastrointestinal surgery should have periodic B12 monitoring as part of routine follow-up. If you are pregnant and vegan or vegetarian, B12 supplementation is essential — severe B12 deficiency in pregnancy causes neural tube defects, low birth weight, and neonatal neurological complications.