At what vitamin B12 (B12) level should repletion be started?

Vitamin B12 Repletion Thresholds

Vitamin B12 repletion should be initiated when serum B12 levels fall below 350 ng/L (or 258 pmol/L), even if the patient is asymptomatic, to prevent potential irreversible neurological complications. 1

Understanding B12 Deficiency Thresholds

The interpretation of vitamin B12 levels follows specific thresholds:

• Confirmed deficiency: Total B12 <180 ng/L or active B12 <25 pmol/L
• Indeterminate (requires further testing): Total B12 180-350 ng/L or active B12 25-70 pmol/L
• Unlikely deficiency: Total B12 >350 ng/L or active B12 >70 pmol/L 1

It's crucial to understand that serum B12 testing alone has limitations. Even with "normal" B12 levels (200-500 pg/mL), 5-10% of patients may have functional B12 deficiency as indicated by elevated metabolites 1. This is why additional testing is recommended for indeterminate results.

Confirming Indeterminate Results

For patients with indeterminate B12 levels (180-350 ng/L), additional testing should include:

• Methylmalonic acid (MMA) - 98.4% sensitivity for B12 deficiency
• Homocysteine levels - 95.9% sensitivity for B12 deficiency
• Complete blood count - to assess for macrocytic anemia 1, 2

Special Considerations

Several important clinical scenarios warrant special attention:

1. Neurological symptoms: Patients with neurological symptoms should be treated even with "normal" serum B12 levels, as demonstrated by cases of B12-responsive leukoencephalopathy in patients with serum B12 levels as high as 447 pg/mL 3

2. High-risk populations: More aggressive screening and earlier intervention should be considered for:

   • Elderly patients (>75 years)
   • Patients on metformin (>4 months)
   • Patients on proton pump inhibitors (>12 months)
   • Vegans or strict vegetarians
   • Patients with malabsorption disorders
   • Patients with gastric or small intestine resections 4

3. Masked deficiency: B12 deficiency can be masked by folate supplementation, which may correct the hematologic abnormalities while allowing neurological damage to progress 5

Treatment Approach

Once deficiency is identified or suspected:

• Oral supplementation: High-dose vitamin B12 (1500-2000 mcg daily) is effective for most patients, even those with malabsorption issues, due to 1-2% absorption via passive diffusion 1, 4

• Intramuscular therapy: Consider for patients with severe deficiency or severe neurological symptoms, as it leads to more rapid improvement 4

• Duration: Initial treatment for 3 months, followed by assessment of response by measuring serum B12 levels 1

Monitoring Response

• Assess response after 3 months by measuring serum B12 levels
• Monitor platelet count until normalization
• For long-term therapy, periodically assess B12 levels 1

Key Takeaway

The threshold of 350 ng/L represents a clinically significant cutoff that balances the risk of missing functional deficiency against unnecessary treatment. Given the safety profile of vitamin B12 supplementation and the potential for irreversible neurological damage with untreated deficiency, this conservative approach is warranted 1, 3.