Vitamin B12 Deficiency — Symptoms, Causes & Treatment | MyMedicPlus

Vitamin B12 (cobalamin) deficiency causes megaloblastic anaemia, subacute combined degeneration of the spinal cord (SACD), and neuropsychiatric manifestations. Vitamin B12 is critical for DNA synthesis (as cofactor for thymidylate synthesis via the folate cycle), myelin synthesis (methylcobalamin is cofactor for methionine synthase, essential for S-adenosylmethionine and myelin production), and red blood cell maturation. Deficiency produces large, fragile red cell precursors (megaloblasts) with hypersegmented neutrophils, and progressive demyelination of the dorsal and lateral spinal columns (SACD). Serum B12 below 148 pmol/L (below 200 pg/mL) indicates deficiency; 148-300 pmol/L is borderline and warrants clinical assessment. It affects 6% of adults under 60 and 20% over 60. Vegans and vegetarians are at highest risk if unsupplemented, as B12 is found exclusively in animal-derived foods — plants contain no bioavailable cobalamin. Importantly, neurological symptoms (including SACD) may precede anaemia — a normal blood count does not exclude neurological B12 deficiency and should not delay treatment.

Pernicious anaemia (most common in non-vegans): autoimmune destruction of gastric parietal cells producing intrinsic factor (IF) required for ileal B12 absorption — positive anti-IF antibodies in 50-70%, anti-parietal cell antibodies in 90%. Dietary deficiency: strict veganism or vegetarianism without supplementation (most common cause globally). Malabsorption: Crohn's disease (ileal disease — the terminal ileum is the sole site of IF-mediated B12 absorption), gastrectomy (total or partial removes parietal cells — requires lifelong IM B12), coeliac disease. Drug-related: metformin (reduces ileal B12 absorption — affects 10-30% of users; calcium supplementation may partially reverse this), prolonged PPI use (reduces gastric acid, impairing B12 cleavage from dietary protein). Additional causes: small bowel bacterial overgrowth (bacteria consume luminal B12), ileal resection above 60 cm. Age-related: gastric atrophy increases with age, progressively reducing IF production — 20% of adults over 60 are B12 deficient. Tapeworm infestation (Diphyllobothrium latum) competes for dietary B12.

Megaloblastic anaemia: macrocytic anaemia (MCV above 100 fL), pallor, fatigue, dyspnoea, palpitations. Glossitis (smooth, red, painful tongue — Hunter's glossitis). Angular cheilitis (fissuring at corners of the mouth). Lemon-yellow pallor (combination of anaemia and haemolysis of fragile megaloblasts). Neurological — SACD: symmetrical tingling and numbness beginning in the feet, progressive ataxia (loss of balance), positive Romberg sign, loss of vibration and proprioception sense (dorsal column degeneration); spastic paraparesis and urinary incontinence (lateral column degeneration). Neuropsychiatric: depression, memory loss, cognitive decline, paranoia, and psychosis — may occur without obvious anaemia. Optic neuropathy (rare — visual loss from optic nerve demyelination). In infants born to B12-deficient mothers: failure to thrive, hypotonia, developmental regression, and encephalopathy. Critically: SACD and peripheral neuropathy can precede anaemia — a normal haemoglobin or MCV does not exclude neurological B12 deficiency and must not delay treatment.

Serum vitamin B12 below 148 pmol/L is deficient; 148-300 pmol/L is borderline (warrants clinical assessment and treatment if symptomatic). CBC: macrocytic anaemia (MCV above 100 fL), hypersegmented neutrophils (5 or more lobes — above 1 five-lobed neutrophil or above 3% five-lobed cells on the differential), pancytopenia in severe deficiency (bone marrow megaloblastosis impairs all cell lines). Methylmalonic acid (MMA) elevated: the most sensitive and specific tissue-level marker of functional B12 deficiency — elevated even when serum B12 is borderline. Homocysteine elevated: less specific (also elevated in folate deficiency, renal disease, and hypothyroidism). Anti-intrinsic factor (anti-IF) antibodies (50-70% sensitivity — high specificity, essentially diagnostic when positive) and anti-parietal cell antibodies (90% sensitivity — less specific) confirm pernicious anaemia. Folate level: check concurrently — folate deficiency also causes megaloblastic anaemia; never treat folate alone when B12 is also deficient as SACD can irreversibly worsen. Serum holotranscobalamin (active B12): the fraction bound to transcobalamin II — declines earlier than total serum B12; a sensitive early functional marker. Reticulocyte count: rises 3-7 days after starting B12 treatment — confirms haematological response.

Pernicious anaemia/malabsorption: IM hydroxocobalamin 1 mg every 2-3 days for 2 weeks (loading — 6 injections), then 1 mg every 3 months lifelong. Neurological features present: more intensive loading — IM hydroxocobalamin daily for 2 weeks, then every 2 months (neurological regimen — UK BNF guidance). Dietary deficiency: oral cyanocobalamin 1,000-2,000 mcg daily (passive absorption at approximately 1% of any oral dose bypasses the IF requirement — effective even in pernicious anaemia). Treatment monitoring: recheck serum B12, FBC, reticulocyte count, and MMA at 6-8 weeks — confirm haematological and metabolic response. Neurological recovery: haematological normalisation within 6-8 weeks; neurological improvement is slower — may be only partial if SACD has been present for more than 6-12 months (reversibility decreases with duration). Metformin users: calcium carbonate 1,200 mg/day may partially restore ileal B12 absorption by correcting the calcium-dependent mechanism. In pregnancy: B12 replacement is safe and essential — untreated severe maternal deficiency causes neonatal neurological damage and developmental delay. Critical: never start folate alone when B12 is also deficient — folate may correct anaemia but will precipitate or worsen irreversible SACD by allowing neurological damage to continue uncorrected.

Subacute combined degeneration of the spinal cord (SACD — the most serious complication; demyelination of the dorsal columns and lateral corticospinal tracts; causes progressive bilateral limb weakness, loss of vibration and proprioception, ataxia, spastic paraparesis, and urinary incontinence; may be irreversible after 6-12 months of severe deficiency — permanent disability can result without prompt treatment; neurological improvement with B12 therapy is slower than haematological recovery and may be incomplete). Peripheral neuropathy (symmetrical sensory length-dependent neuropathy — tingling and numbness in a glove-and-stocking distribution; partial recovery with treatment). Megaloblastic psychosis (psychiatric manifestations — psychosis, paranoia, severe cognitive decline; may precede anaemia). Elevated homocysteine (an independent cardiovascular risk factor — associated with increased venous thromboembolism and stroke risk; B12 replacement normalises homocysteine). Gastric cancer risk (pernicious anaemia patients have a 3-fold increased gastric adenocarcinoma risk from chronic atrophic gastritis — requiring 3-5 yearly gastroscopic surveillance). Neonatal neurological damage (severe maternal B12 deficiency during pregnancy causes developmental delay, hypotonia, and encephalopathy in the newborn — untreated maternal deficiency is preventable with supplementation).

See a GP for: persistent and unexplained fatigue and weakness, tingling or numbness in the hands or feet, red and sore tongue (glossitis), mouth ulcers, difficulty walking or poor balance, cognitive difficulties or memory problems, or mood change — particularly in vegetarians, vegans, older adults (over 65), those with autoimmune conditions (type 1 diabetes, thyroid disease), or those on long-term metformin or proton pump inhibitors. A serum B12 level below 148 pmol/L (or borderline 148-300 pmol/L with symptoms) warrants investigation and treatment. Seek urgent neurological assessment for: subacute combined degeneration of the spinal cord — progressive bilateral limb weakness, sensory loss (absent vibration and proprioception), ataxia (poor coordination), or urinary incontinence — these neurological features of B12 deficiency require immediate B12 replacement to prevent irreversible spinal cord damage. Neurological symptoms from B12 deficiency can progress to permanent disability if not treated promptly — do not delay. Intrinsic factor antibodies should be checked to confirm pernicious anaemia, which requires lifelong 3-monthly IM hydroxocobalamin rather than oral supplementation.

Vegans and vegetarians: mandatory B12 supplementation — passive absorption of high-dose oral cyanocobalamin compensates for the absence of intrinsic factor-mediated active absorption; recommended dosing is 1,000-2,000 mcg cyanocobalamin daily (passive absorption of approximately 1% provides the required 2.4 mcg/day), or 50-100 mcg daily if serum B12 is adequate, or regular consumption of fortified plant-based foods (soy milk, fortified breakfast cereals, nutritional yeast providing at least 1.5 mcg per serving) combined with annual blood level monitoring to confirm adequacy. Annual serum B12 monitoring for all metformin users — NICE guidelines specifically recommend annual B12 monitoring after 4 years of metformin use; metformin impairs ileal calcium-dependent absorption of the intrinsic factor-B12 complex; co-prescribing calcium carbonate 1,200 mg daily may partially restore absorption. Monitor B12 annually in patients on long-term proton pump inhibitor therapy — PPIs reduce gastric acid secretion, impairing peptic liberation of protein-bound dietary B12 from food, significantly reducing absorption after years of therapy. Screen for pernicious anaemia (intrinsic factor antibody and parietal cell antibody testing) in patients with autoimmune conditions: Hashimoto's thyroiditis, Graves' disease, type 1 diabetes mellitus, vitiligo, Addison's disease, and alopecia areata — pernicious anaemia clusters with other organ-specific autoimmune diseases in up to 30% of cases. Confirmed pernicious anaemia patients require gastroscopy surveillance every 3-5 years: the underlying chronic atrophic gastritis carries a 3-fold increased risk of gastric adenocarcinoma and an elevated risk of gastric carcinoid tumours from hypergastrinaemia.