Vitamin B12 Deficiency: Diagnosis and Treatment
Diagnostic Approach
Start with serum total B12 as the first-line test, then use methylmalonic acid (MMA) to confirm functional deficiency when results are indeterminate. 1
Initial Testing Algorithm
- Serum B12 <180 pg/mL (<150 pmol/L): Confirms deficiency—initiate treatment immediately 1, 2
- Serum B12 180-350 pg/mL (150-258 pmol/L): Indeterminate range—measure MMA to confirm functional deficiency 1, 2
- Serum B12 >350 pg/mL (>258 pmol/L): Makes deficiency unlikely, but consider MMA if high clinical suspicion remains 1
Confirmatory Testing with MMA
MMA >271 nmol/L confirms functional B12 deficiency with 98.4% sensitivity, detecting an additional 5-10% of patients with deficiency who have low-normal B12 levels 1. This is critical because standard serum B12 testing misses functional deficiency in up to 50% of cases 1. MMA is more specific than homocysteine for B12 deficiency, with MMA elevated in only 12.2% of folate-deficient patients versus 91% for homocysteine 1.
When to Screen
Screen patients with at least one risk factor AND one clinical symptom 2:
Risk Factors:
- Age >75 years (18.1% have metabolic deficiency; 25% of those ≥85 years have B12 <170 pmol/L) 1
- Metformin use >4 months 1, 3
- PPI or H2 blocker use >12 months 1, 3
- Ileal resection >20 cm or ileal Crohn's disease 1, 4
- Post-bariatric surgery 1, 4
- Vegan/strict vegetarian diet 1, 5
- Atrophic gastritis, celiac disease, or autoimmune conditions 1, 3
Clinical Symptoms:
- Fatigue, cognitive difficulties, memory problems, "brain fog" 1, 2
- Peripheral neuropathy (tingling, numbness, paresthesias) 1, 3, 2
- Balance issues, sensory ataxia, gait disturbances 3, 2
- Glossitis (tongue inflammation) 1, 3
- Blurred vision, optic nerve dysfunction 1, 3
- Macrocytic anemia or elevated MCV on CBC 1, 2
Treatment Protocols
For Patients WITHOUT Neurological Involvement
Hydroxocobalamin 1 mg intramuscularly three times weekly for 2 weeks, then 1 mg IM every 2-3 months for life 4, 3. Oral B12 1000-2000 mcg daily is equally effective for most patients and costs less 1, 5, but IM administration ensures compliance and bypasses absorption issues 4.
For Patients WITH Neurological Involvement
Hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement, then 1 mg IM every 2 months for life 4, 3. Neurological symptoms often present before hematological changes and can become irreversible if untreated 1. Tongue symptoms (glossitis, tingling, numbness) represent neurological involvement and require this aggressive protocol 4.
Special Populations
- Ileal resection >20 cm: Prophylactic hydroxocobalamin 1000 mcg IM monthly for life, even without documented deficiency 1, 4
- Post-bariatric surgery: 1000-2000 mcg/day oral OR 1000 mcg/month IM indefinitely 1, 4
- Crohn's disease with ileal involvement >30-60 cm: Annual screening and prophylactic supplementation 1, 4
- Pregnancy/lactation: 4.5-5 mcg/day 1
Formulation Selection
Use hydroxocobalamin or methylcobalamin instead of cyanocobalamin in patients with renal dysfunction, as cyanocobalamin requires renal clearance of the cyanide moiety and is associated with increased cardiovascular events (HR 2.0) in diabetic nephropathy 1, 4.
Monitoring Strategy
Initial Monitoring
- Recheck at 3 months: Assess serum B12, CBC for resolution of megaloblastic anemia, and MMA if levels remain borderline 4
- Recheck at 6 months: Ensure continued improvement 4
- Recheck at 12 months: Confirm stabilization 4
- Annual monitoring thereafter once levels stabilize 1, 4
Target Levels
- Serum B12 >300 pmol/L (>400 pg/mL) for optimal health 1
- Homocysteine <10 μmol/L for optimal cardiovascular outcomes 1, 4
- MMA <271 nmol/L confirms adequate treatment 1, 4
Critical Pitfalls to Avoid
Never administer folic acid before treating B12 deficiency, as folic acid may mask anemia while allowing irreversible neurological damage to progress, including subacute combined degeneration of the spinal cord 4, 3, 6, 7. This is the single most important clinical pitfall.
Do not rely solely on serum B12 to rule out deficiency, especially in patients >60 years where metabolic deficiency is common despite normal serum levels 1. Up to 50% of patients with "normal" serum B12 have metabolic deficiency when measured by MMA 1.
Do not stop monitoring after one normal result, as patients with malabsorption or dietary insufficiency often require ongoing supplementation and can relapse 4. Patients with pernicious anemia, ileal resection >20 cm, or post-bariatric surgery require lifelong supplementation 4, 6, 7.
Do not discontinue treatment in high-risk patients even if levels normalize, as the underlying cause persists and deficiency will recur 4, 6.
Vitamin B12 deficiency that progresses for longer than 3 months may produce permanent degenerative lesions of the spinal cord 6. Early recognition and aggressive treatment of neurological symptoms is essential to prevent irreversible damage 1, 3.