Vitamin B12 Therapy

Vitamin B12 therapy replaces cobalamin to treat deficiency, which causes megaloblastic anaemia, subacute combined degeneration of the cord, peripheral neuropathy, cognitive decline and glossitis. Deficiency arises from pernicious anaemia, dietary absence (strict vegetarian diets), gastric surgery, ileal disease, drugs and nitrous oxide exposure.

Neurological damage can be irreversible if treatment is late, so prompt replacement is essential.

Mechanism. B12 is a cofactor for methionine synthase (remethylation of homocysteine) and methylmalonyl-CoA mutase. Deficiency impairs DNA synthesis and myelin maintenance.

Pharmacokinetics. Absorption needs gastric intrinsic factor and ileal receptors; a small fraction (about 1%) is absorbed passively at high oral doses, enough to treat most deficiency. Stores last 2 to 4 years; half-life in the liver is long.

Hydroxocobalamin (intramuscular).

• No neurological involvement: 1 mg three times weekly for 2 weeks, then 1 mg every 3 months.
• Neurological involvement: 1 mg on alternate days until improvement stops (up to 3 weeks or longer), then 1 mg every 2 months.
• Retained longer than cyanocobalamin; preferred in many regions.

Cyanocobalamin.

• Intramuscular or deep subcutaneous 1000 micrograms daily for 1 week, then weekly for 4 weeks, then monthly.
• Oral 1000 to 2000 micrograms daily is effective for most patients, including pernicious anaemia, if adherence is reliable; confirm response.
• Avoid in Leber hereditary optic neuropathy and in cyanide-handling impairment.

Methylcobalamin. No proven advantage over cyanocobalamin or hydroxocobalamin.

Duration. Lifelong for pernicious anaemia, gastrectomy and ileal resection; until the cause is corrected for dietary or drug deficiency (for example, metformin: continue the drug and supplement).

Prophylaxis. Vegans, after gastric bypass or ileal resection, long-term metformin or proton pump inhibitor in at-risk patients: oral 1000 micrograms daily or 1 mg intramuscularly every 3 months.

• First-line. Intramuscular hydroxocobalamin or cyanocobalamin for severe deficiency, neurological disease and malabsorption; oral cyanocobalamin for dietary deficiency and mild disease with adherence.
• Alternative. High-dose oral B12 as maintenance after loading; nasal or sublingual preparations.
• Specialist. Neurological deficiency, anaemia with cardiac failure, and nitrous oxide myeloneuropathy (B12 plus methionine, specialist).
• Emergency. Parenteral B12 and folate together in severe pancytopenia or neurological signs while tests are awaited.

Response. Reticulocytes rise in 3 to 5 days and peak at 5 to 8 days; haemoglobin rises about 10 g/L weekly and normalises by 8 weeks. Neurological recovery takes months and may be incomplete. Potassium can fall sharply as haemopoiesis restarts.

Contraindications. Hypersensitivity to cobalamin or cobalt; cyanocobalamin in Leber hereditary optic neuropathy.

Serious adverse effects. Hypokalaemia in the first days of treating severe anaemia (monitor and replace); hypersensitivity (rare); injection-site pain; acneiform eruptions; polycythaemia in polycythaemia vera may worsen; heart failure with rapid volume expansion in severe anaemia.

Major interactions. Metformin, proton pump inhibitors, H2 blockers, colchicine, neomycin and nitrous oxide reduce B12 status; chloramphenicol may delay response; folic acid alone can correct anaemia and mask neurological progression.

Common prescribing errors.

• Folic acid alone for megaloblastic anaemia.
• Oral B12 in patients with unreliable adherence and neurological signs.
• Stopping lifelong injections in pernicious anaemia.
• Not checking potassium in severe deficiency.
• Treating only with diet advice.

Special groups.

• Pregnancy: compatible; requirement slightly increased.
• Breastfeeding: compatible; maternal deficiency causes infant deficiency, so treat.
• Children: specialist dosing; investigate for inherited disorders and maternal deficiency.
• Older adults: common; check before cognitive attribution; high-dose oral effective.
• Kidney: no adjustment.
• Liver: no adjustment.
• East Africa: dietary deficiency in people with low animal-source food intake; HIV, intestinal helminth infection and tropical sprue also contribute; injections are often cheaper and more available than oral high-dose preparations.

Monitoring. Serum B12 (not useful to monitor after starting); haemoglobin and reticulocytes at 1 and 2 weeks; potassium daily for the first few days in severe cases; neurological examination; anti-intrinsic factor antibodies for diagnosis.

Referral and escalation. Neurological signs; pancytopenia; suspected gastric cancer in pernicious anaemia (endoscopy if new symptoms); no haematological response; young patients without a cause.

Comparison with alternative classes. B12 replacement is the only treatment that prevents neurological damage; folate and iron do not. Oral high-dose therapy is as effective as injection in most patients, but injections are preferred with neurological involvement.