Vitamin B12 Replacement Therapy
Treatment Protocol Based on Neurological Involvement
For patients with vitamin B12 deficiency and neurological symptoms (paresthesias, gait disturbance, cognitive impairment), administer hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement occurs, then transition to maintenance therapy with 1 mg intramuscularly every 2 months for life. 1, 2
For patients without neurological involvement, give hydroxocobalamin 1 mg intramuscularly three times weekly for 2 weeks, followed by maintenance therapy of 1 mg intramuscularly every 2-3 months lifelong. 1, 3, 2
Why This Matters
The distinction between neurological and non-neurological presentations is critical because neurological damage from B12 deficiency can become irreversible if not treated aggressively. 1 The alternate-day dosing for neurological cases ensures rapid tissue saturation to halt progression of demyelination. 1
Formulation Selection
Use hydroxocobalamin as the preferred formulation over cyanocobalamin, particularly in patients with renal dysfunction. 1, 2
- Hydroxocobalamin has longer tissue retention compared to cyanocobalamin 2
- In patients with diabetic nephropathy or impaired renal function, cyanocobalamin is associated with a 2-fold increased risk of cardiovascular events (HR 2.0) due to accumulation of the cyanide moiety that requires renal clearance 1
- Methylcobalamin or hydroxocobalamin should be used instead in renal dysfunction 1, 2
The FDA label for cyanocobalamin specifies 100 mcg dosing 4, but this is outdated—current evidence strongly supports 1000 mcg dosing for superior tissue retention with no additional cost or toxicity. 5
Route of Administration
Intramuscular or deep subcutaneous injection is required for patients with malabsorption conditions (pernicious anemia, ileal resection >20 cm, post-bariatric surgery, inflammatory bowel disease). 1, 2, 4
- Preferred injection sites are the deltoid or vastus lateralis 2
- Avoid the buttock due to risk of sciatic nerve injury; if used, only inject in the upper outer quadrant with the needle directed anteriorly 1
- Avoid intravenous administration as almost all vitamin will be lost in urine 4
Oral therapy with 1000-2000 mcg daily can be considered for patients with normal intestinal absorption or dietary insufficiency. 3, 6
- Oral high-dose B12 (1-2 mg daily) is as effective as intramuscular administration for correcting anemia and neurologic symptoms in patients without severe malabsorption 6
- However, intramuscular therapy leads to more rapid improvement and should be prioritized in severe deficiency or severe neurologic symptoms 6
Special Population Dosing
Post-bariatric surgery patients: 1 mg intramuscularly every 3 months OR 1000-2000 mcg orally daily, indefinitely 1, 3, 2
Ileal resection >20 cm or Crohn's disease with ileal involvement >30-60 cm: Prophylactic treatment with 1000 mcg intramuscularly monthly for life, even without documented deficiency 1, 3
Patients with thrombocytopenia:
- Platelet count >50 × 10⁹/L: Standard IM administration is safe 1
- Platelet count 25-50 × 10⁹/L: Use smaller gauge needles (25-27G) and apply prolonged pressure (5-10 minutes) at injection site 1
- Platelet count <10 × 10⁹/L: Consider platelet transfusion support before IM administration 1
Monitoring Strategy
First year monitoring schedule: Check serum B12, complete blood count, and homocysteine at 3,6, and 12 months after initiating treatment. 1, 3, 2
After stabilization: Annual monitoring of B12 levels and homocysteine. 1, 3
Target homocysteine level: <10 μmol/L for optimal cardiovascular outcomes. 1, 2
What to Measure at Follow-Up
- Serum B12 levels as the primary marker 1
- Complete blood count to evaluate for resolution of megaloblastic anemia 1
- Methylmalonic acid if B12 levels remain borderline (>271 nmol/L confirms deficiency) 1, 3
- Homocysteine as an additional functional marker 1, 2
Critical Pitfalls to Avoid
Never administer folic acid before treating B12 deficiency—this can mask the anemia while allowing irreversible neurological damage (subacute combined degeneration of the spinal cord) to progress. 1, 3
Do not discontinue B12 supplementation even if levels normalize—patients with malabsorption require lifelong therapy. 1, 3
Do not stop monitoring after one normal result—patients can relapse and require ongoing supplementation. 1
Do not "titrate" injection frequency based on serum B12 or MMA levels—instead, adjust based on clinical symptoms and whether the patient remains symptom-free. 7
Individualized Dosing Considerations
While standard maintenance is every 2-3 months, clinical experience suggests up to 50% of patients require more frequent administration (ranging from twice weekly to every 2-4 weeks) to remain symptom-free. 7 If neurological symptoms recur (paresthesias, gait disturbances, cognitive changes), increase injection frequency or switch from oral to injectable form. 1, 3