What is the treatment for vitamin B12 (cobalamin) deficient anemia?

Treatment of Vitamin B12 Deficient Anemia

For B12 deficiency anemia with neurological symptoms, administer hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement occurs, then transition to maintenance dosing of 1 mg IM every 2 months for life. 1, 2

Initial Treatment Protocol

With Neurological Involvement

• Hydroxocobalamin 1 mg IM on alternate days until neurological symptoms stop improving 1, 2
• This aggressive approach is critical because neurological damage can become irreversible if undertreated 1, 3
• Neurological symptoms include peripheral neuropathy, paresthesias, gait disturbances, cognitive impairment, and subacute combined degeneration of the spinal cord 1

Without Neurological Involvement

• Hydroxocobalamin 1 mg IM three times weekly for 2 weeks as the loading phase 1, 2
• This standard regimen is sufficient when only hematologic manifestations are present 1

Alternative Dosing (FDA-Approved Cyanocobalamin)

The FDA label for cyanocobalamin provides an alternative regimen: 100 mcg IM daily for 6-7 days, then 100 mcg on alternate days for seven doses, then every 3-4 days for 2-3 weeks 4. However, recent evidence suggests this may be inadequate for many patients, and 1000 mcg dosing retains significantly more vitamin with no additional cost or toxicity 5.

Maintenance Therapy

All patients require lifelong maintenance therapy once the underlying cause is malabsorption-related (pernicious anemia, ileal resection, bariatric surgery, atrophic gastritis) 1, 2.

Standard Maintenance Regimen

• Hydroxocobalamin 1 mg IM every 2-3 months for life 1, 2
• For patients with neurological involvement: Hydroxocobalamin 1 mg IM every 2 months 1
• Some patients may require monthly injections (1000 mcg) to meet metabolic requirements 1, 5

Monitoring Schedule

• Recheck at 3 months, 6 months, and 12 months during the first year 1
• Measure serum B12, complete blood count, methylmalonic acid (if B12 remains borderline), and homocysteine 1
• Target homocysteine <10 μmol/L for optimal outcomes 1
• Once stabilized, annual monitoring is sufficient 1

Oral Therapy Considerations

High-dose oral B12 (1000-2000 mcg daily) is as effective as IM therapy for most patients and should be considered when malabsorption is not severe 5, 6, 7. A 2024 prospective study demonstrated that oral cyanocobalamin 1000 mcg daily reversed B12 deficiency in 88.5% of pernicious anemia patients within 1 month 6.

However, IM administration remains preferred for:

• Severe neurological symptoms requiring rapid correction 3, 7
• Confirmed malabsorption (pernicious anemia, ileal resection >20 cm, post-bariatric surgery) 1, 4
• Patients who fail oral therapy 3

Choice of B12 Formulation

Hydroxocobalamin is the preferred formulation over cyanocobalamin based on guideline recommendations 1. Key advantages include:

• Superior tissue retention 1
• Established dosing protocols across all major guidelines 1
• Safer in renal dysfunction (cyanocobalamin requires renal clearance of cyanide and is associated with increased cardiovascular events in diabetic nephropathy, HR 2.0) 1

Methylcobalamin is an acceptable alternative to hydroxocobalamin, particularly in renal dysfunction 1.

Critical Warnings and Pitfalls

Never Give Folic Acid Before B12

Never administer folic acid before or without adequate B12 treatment 1, 2. Folic acid can mask the megaloblastic anemia while allowing irreversible neurological damage (subacute combined degeneration of the spinal cord) to progress 1, 2. Always check and treat B12 deficiency first 2.

Do Not Stop Treatment Prematurely

• Never discontinue B12 supplementation even if levels normalize, as patients with malabsorption require lifelong therapy 1
• Stopping injections after symptom improvement can lead to irreversible peripheral neuropathy 1

Avoid Cyanocobalamin in Renal Disease

Use hydroxocobalamin or methylcobalamin instead of cyanocobalamin in patients with renal dysfunction (GFR <60 mL/min) 1. Cyanocobalamin accumulation increases cardiovascular risk in this population 1.

Special Populations

Post-Bariatric Surgery

• 1000 mcg IM monthly for life or 1000-2000 mcg oral daily 1
• These patients have permanent malabsorption and require indefinite supplementation 1

Ileal Resection

• Prophylactic B12 injections (1000 mcg IM monthly) for life if >20 cm of distal ileum resected 1
• Even without resection, Crohn's disease involving >30-60 cm of ileum requires annual screening and prophylactic supplementation 1

Thrombocytopenia

• IM administration is safe with platelet counts >50 × 10⁹/L 1
• For platelets 25-50 × 10⁹/L: use smaller gauge needles (25-27G) and apply prolonged pressure (5-10 minutes) 1
• For platelets <10 × 10⁹/L: consider platelet transfusion support before IM injection 1

Route of Administration

Avoid intravenous administration as almost all vitamin will be lost in urine 4. Use intramuscular or deep subcutaneous injection 4. The preferred IM site is the deltoid or vastus lateralis; avoid the buttock due to sciatic nerve injury risk 1.