Vitamin B12 deficiency and pernicious anaemia

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Vitamin B12 is required for DNA synthesis and neurological metabolism. Deficiency causes ineffective megaloblastic erythropoiesis, macro-ovalocytes and hypersegmented neutrophils, but the MCV may be normal with early disease, concurrent iron deficiency or thalassaemia. Intramedullary destruction can raise bilirubin and LDH while reticulocytes remain inappropriately low. Neurological manifestations include symmetrical paraesthesia, loss of vibration and joint position, sensory ataxia, weakness, cognitive change, depression, psychosis and optic involvement. Their presence makes prompt treatment more important than a textbook blood-count pattern.

NICE NG239 separates confirmed, indeterminate and unlikely initial B12 results and emphasises symptoms and risk factors. Functional testing with methylmalonic acid or homocysteine can clarify indeterminate results; nitrous oxide exposure requires functional assessment because circulating B12 may not reflect intracellular activity. Cause assessment includes diet, metformin and acid suppression, coeliac and ileal disease, gastric or bariatric surgery and autoimmune gastritis. Anti-intrinsic-factor antibody is specific when positive but insufficiently sensitive to exclude autoimmune disease when negative.

Replacement route, loading and duration depend on neurological involvement and reversibility. UK practice uses hydroxocobalamin intramuscularly for neurological disease and important malabsorption. High-dose oral cyanocobalamin can be used in dietary disease and selected malabsorption situations, with at least 1 mg daily when malabsorption is suspected. Haematological recovery begins before neurological recovery; serum B12 after injection mainly proves recent treatment. Follow symptoms objectively, identify iron or folate deficiency unmasked by marrow recovery and ensure irreversible causes have a lifelong maintenance plan.

Key points

Vitamin B12 deficiency can present with neuropathy, impaired vibration or joint position, ataxia, cognitive or psychiatric change, glossitis or fatigue before anaemia or macrocytosis appears.
Take pretreatment blood when this causes no harmful delay. Interpret total or active B12 through NICE NG239 thresholds and use methylmalonic acid or homocysteine when the result is indeterminate and symptoms persist.
Nitrous oxide can produce functional deficiency despite a non-low serum B12. NICE recommends homocysteine or methylmalonic acid testing, but neurological treatment must not wait when suspicion is strong.
Autoimmune gastritis is the underlying disorder historically linked with pernicious anaemia. Anti-intrinsic-factor antibody supports it, but a negative result does not exclude the diagnosis.
Use intramuscular hydroxocobalamin when neurological disease is present or malabsorption is likely; high-dose oral replacement can be appropriate for dietary deficiency and selected malabsorption pathways under NICE guidance.
For suspected malabsorption treated orally, NICE advises at least 1 mg vitamin B12 daily. Check the exact licensed product and adherence rather than relying on low-dose supplements.
Irreversible autoimmune or anatomical malabsorption generally requires lifelong replacement. Reversible dietary or medicine-related deficiency needs cause correction, planned review and a clear stopping decision.
Do not treat folate alone until B12 deficiency has been addressed: the blood count may improve while neurological injury continues.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Autoimmune gastritis

Immune damage to gastric parietal cells reduces intrinsic factor and acid, impairing food-bound cobalamin release and terminal ileal absorption; pernicious anaemia describes the resulting autoimmune deficiency.

Gastrointestinal malabsorption

Gastrectomy, bariatric surgery, terminal ileal disease or resection, coeliac disease and pancreatic or bacterial disorders can interrupt release or absorption.

Dietary insufficiency

A vegan or severely restricted diet without reliable supplementation can deplete stores over years, particularly when pregnancy, infancy or frailty increases vulnerability.

Medicines and nitrous oxide

Metformin and acid-suppressing treatment can contribute to deficiency, while recreational or medical nitrous oxide inactivates cobalamin and causes functional neurological disease.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Absorption or function fails
Loss of intrinsic-factor-dependent uptake, inadequate intake or nitrous-oxide-mediated inactivation reduces cobalamin available to dependent intracellular enzymes.
2
DNA synthesis becomes ineffective
Impaired methionine and folate cycling disrupts nuclear maturation, producing megaloblastic erythropoiesis, intramedullary cell death and sometimes pancytopenia.
3
Myelin pathways are injured
Accumulating methylmalonic and related metabolic disturbance damages peripheral nerves, posterior columns, corticospinal tracts and cognitive or psychiatric function.
4
Tissue demand exceeds delivery
Rapid cell turnover in marrow and mucosa produces glossitis and cytopenias, while neurological injury can progress independently of haemoglobin or mean cell volume.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Neurological B12 syndromeRed flag

Symmetrical paraesthesia, impaired vibration or proprioception, sensory ataxia, weakness, cognitive change or visual symptoms with risk factors warrants prompt assessment and replacement.

Megaloblastic phenotype

Macro-ovalocytes, hypersegmented neutrophils, low reticulocytes, glossitis, raised LDH and one or more cytopenias support ineffective DNA synthesis.

Autoimmune gastritis phenotype

Autoimmune history, positive anti-intrinsic-factor antibody, glossitis and deficiency without dietary explanation supports irreversible intrinsic-factor-related malabsorption.

Post-surgical malabsorption

Gastrectomy, bariatric surgery or terminal ileal resection can make oral absorption unreliable and creates a predictable long-term replacement requirement.

Nitrous oxide toxicityRed flag

Recreational or repeated medical exposure with rapidly evolving paraesthesia, gait change or weakness suggests functional inactivation even when serum B12 is not low.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Total or active vitamin B12First step
Why
Classify the initial result within the NICE diagnostic pathway.
Interpretation and limitations
Use the assay-specific NICE thresholds and obtain the sample before replacement when safe. A result above the usual deficiency range does not exclude nitrous-oxide-mediated functional disease.
02
Methylmalonic acid or homocysteine
Why
Detect functional deficiency when the initial result is indeterminate or nitrous oxide is implicated.
Interpretation and limitations
Methylmalonic acid is more specific but rises with renal impairment; homocysteine also rises in folate deficiency. Interpret with symptoms, renal function and laboratory ranges.
03
FBC, film, reticulocytes, folate and iron studies
Why
Define marrow impact and find mixed haematinic deficiency.
Interpretation and limitations
Macrocytosis and hypersegmented neutrophils support megaloblastosis but may be absent. Low reticulocytes fit ineffective production; coexisting iron deficiency can normalise MCV and emerge during recovery.
04
Anti-intrinsic-factor antibody
Why
Identify autoimmune gastritis as an irreversible cause of malabsorption.
Interpretation and limitations
A positive result supports the diagnosis. A negative result does not exclude it; NICE recommends further cause-directed assessment when suspicion remains.
05
Coeliac and gastrointestinal assessment
Why
Find malabsorption or autoimmune gastric disease when cause remains unclear.
Interpretation and limitations
Use coeliac serology and specialist testing according to history. New dysphagia, weight loss, upper gastrointestinal symptoms or iron deficiency requires an appropriate cancer and endoscopy pathway.
06
Neurological examination
Why
Document baseline injury and provide an outcome measure independent of serum concentration.
Interpretation and limitations
Record power, reflexes, sensation, vibration, joint position, gait, cognition and vision. Focal or atypical findings may require spinal imaging or neurology assessment for another diagnosis.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Folate deficiency

Folate deficiency produces similar megaloblastosis and hypersegmented neutrophils but does not usually cause the characteristic posterior-column and peripheral neurological syndrome.

Alcohol or liver disease

Round macrocytes, target cells, liver abnormalities and exposure history favour non-megaloblastic macrocytosis, although nutritional B12 deficiency may coexist.

Myelodysplastic syndrome

Persistent macrocytosis with dysplasia, additional cytopenias, abnormal film or failure to respond to adequate replacement raises a clonal marrow disorder.

Copper deficiency

Neuropathy, anaemia and neutropenia after upper gastrointestinal surgery, excess zinc or malnutrition can mimic B12 disease and warrants copper assessment.

Other neurological disease

Diabetes, thyroid disease, spinal compression, multiple sclerosis and toxic neuropathies can resemble cobalamin-related symptoms, particularly when biochemical results are equivocal.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01NeurologicalTreat suspected neural injury promptlyFirst stepNeurological symptoms and risk factors suggest vitamin B12 deficiency or nitrous-oxide-mediated functional deficiency.

1Take B12 and functional-marker samples if immediately available, document a full neurological examination and exposure history, and stop nitrous oxide, but do not delay replacement for results.
2PreferredPreferred UK treatment is hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement, followed by the maintenance schedule when the cause is irreversible.
3EscalationEscalate rapid progression, weakness, gait or sphincter disturbance, visual change, severe psychiatric symptoms or diagnostic uncertainty to neurology and haematology while continuing supported treatment.

02Non-neurologicalMatch route to absorption and causeDeficiency is confirmed or strongly suspected without neurological involvement or physiological instability.

1First lineAlternativeFirst-line route depends on cause: use intramuscular loading when malabsorption is likely, while an adequate oral regimen is an alternative for dietary deficiency and selected patients under NICE guidance.
2For oral treatment where malabsorption is suspected, prescribe at least 1 mg daily and verify product strength, adherence and symptom response; low-dose multivitamins are not equivalent replacement.
3EscalationCheck early clinical and haematological improvement and escalate absent response to adherence, diagnosis, mixed deficiency, renal interpretation and ongoing malabsorption review.

03Find durationDetermine reversible or lifelong replacementReplacement has begun and immediate neurological risk is controlled.

1Review diet, medicines, surgery, ileal and coeliac disease and test anti-intrinsic-factor antibody when autoimmune gastritis is suspected; a negative antibody does not close the assessment.
2AlternativeContinue lifelong intramuscular replacement for autoimmune gastritis or complete terminal ileal or gastric loss; a monitored oral alternative may suit other causes according to NICE and absorption reliability.
3EscalationEscalate new upper gastrointestinal symptoms or unexplained iron deficiency in autoimmune gastritis to appropriate gastroenterology and suspected-cancer assessment.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Rapidly restores active vitamin B12 in neurological deficiency and bypasses unreliable gastrointestinal absorption.

Hydroxocobalamin with neurological involvement

Give 1 mg intramuscularly on alternate days until no further improvement, then 1 mg every 2 months when the underlying cause is irreversible.

Obtain diagnostic samples first only when this causes no delay. Hypersensitivity is uncommon but possible; acneiform eruptions and injection-site reactions occur, and serum B12 after treatment should not guide neurological recovery.

Loads body stores and maintains replacement where autoimmune, anatomical or other clinically important malabsorption makes oral delivery unreliable.

Hydroxocobalamin without neurological involvement

Give 1 mg intramuscularly three times a week for 2 weeks, then 1 mg every 2 to 3 months when ongoing maintenance is required.

Confirm cause and whether maintenance is lifelong. A brisk marrow response can expose iron or folate deficiency, and rare hypokalaemia has been described during severe haematological recovery.

Treats dietary deficiency and selected malabsorption when a sufficiently high dose and reliable adherence can deliver clinical response.

Oral vitamin B12

When oral replacement is selected and malabsorption is suspected, NICE advises at least 1 mg daily; use the current product and cause-specific follow-up plan.

Over-the-counter products vary in content. Do not use a low-dose supplement for neurological disease or unreliable absorption, and change route if symptoms or blood counts fail to improve.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Irreversible neurological disability

Delayed replacement can leave persistent sensory loss, gait impairment, weakness, sphincter disturbance, cognitive change or visual symptoms despite later blood-count recovery.

Severe ineffective erythropoiesis

Intramedullary precursor destruction can cause marked anaemia, jaundice, raised LDH and pancytopenia, occasionally mimicking haemolysis or marrow malignancy.

Pregnancy and infant harm

Maternal deficiency can impair fetal development and breastfed infants may develop anaemia, developmental regression or neurological injury when maternal stores are inadequate.

Gastric neoplasia association

Autoimmune gastritis is associated with gastric adenocarcinoma and neuroendocrine tumour risk, so new upper gastrointestinal symptoms require appropriate specialist assessment.

Recurrent lifelong deficiency

Irreversible malabsorption causes relapse when maintenance replacement stops, even though serum B12 initially rises and the full blood count normalises.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Document neurological findings at baseline and review symptom trajectory at the NICE follow-up interval; blood concentration after injection does not measure nerve recovery.
Check FBC and reticulocyte or haemoglobin response when haematological disease was present, and investigate an absent or incomplete response rather than extending loading blindly.
Assess iron and folate when marrow recovery is limited or a second deficiency is plausible, particularly after gastrointestinal surgery or autoimmune gastritis.
Confirm that irreversible causes have a coded lifelong maintenance plan, recall arrangement and route that the patient can access reliably.
For reversible dietary or medicine-associated causes, confirm correction of the cause and make a documented review or stopping decision rather than discontinuing automatically.
Safety-net worsening gait, weakness, sphincter symptoms, visual change, confusion and recurrent paraesthesia for urgent reassessment.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Normal MCV does not protect nerves

Neurological deficiency can precede macrocytosis, and concurrent iron deficiency can normalise the average red-cell size. Clinical features must drive assessment.

Pernicious anaemia names an outcome

Autoimmune gastritis is the underlying pathology; intrinsic-factor loss can cause deficiency before anaemia, and the autoimmune disease has consequences beyond haemoglobin.

A negative antibody is not exclusion

Anti-intrinsic-factor antibody supports autoimmune gastritis when positive but has limited sensitivity, so persistent suspicion requires further cause assessment.

Nitrous oxide changes the test logic

It inactivates cobalamin intracellularly. Serum B12 can therefore mislead, while methylmalonic acid or homocysteine and the exposure history reveal functional deficiency.

Blood recovers before nerves

Reticulocytes and haemoglobin may improve quickly, whereas sensory and gait recovery can take months and may remain incomplete after delayed treatment.

11Common pitfallsFrequent interpretation and management errors.

01
Excluding B12 deficiency because haemoglobin and MCV are normal.
02
Waiting for every result before treating a progressive neurological syndrome.
03
Using serum B12 alone to exclude nitrous-oxide-mediated functional deficiency.
04
Calling a negative anti-intrinsic-factor antibody definitive exclusion of autoimmune gastritis.
05
Giving folic acid alone before B12 deficiency is addressed.
06
Stopping replacement in irreversible malabsorption after the FBC normalises.
07
Monitoring serum B12 instead of objective neurological and haematological recovery.