Normal Vitamin B12 Levels
Normal vitamin B12 levels are generally defined as >350 pg/mL (>258 pmol/L), with deficiency confirmed at <180 pg/mL (<150 pmol/L) and borderline levels at 180-350 pg/mL requiring further functional testing with methylmalonic acid (MMA). 1, 2
Standard Reference Ranges
- Deficient: <180 pg/mL (<150 pmol/L) - requires immediate treatment 1, 2
- Borderline/Indeterminate: 180-350 pg/mL - measure MMA to confirm functional deficiency 1, 2
- Normal: >350 pg/mL (>258 pmol/L) - deficiency unlikely 1, 2
Critical Limitation: Serum B12 Misses 50% of Functional Deficiencies
Standard serum B12 testing fails to detect functional deficiency in up to 50% of cases, particularly in elderly patients and those with renal impairment. 1 The Framingham Study demonstrated that while 12% had low serum B12, an additional 50% had elevated MMA indicating metabolic deficiency despite "normal" serum levels. 1
Optimal Targets for Your Patient Population
For patients with history of B12 deficiency and impaired renal function, standard reference ranges are inadequate:
- Target maintenance level: >300 pmol/L (approximately >400 pg/mL) for optimal health outcomes 1
- Optimal range: 30-44 ng/mL (220-325 pmol/L) provides best benefits for cardiovascular and musculoskeletal health 1
Why Renal Function Matters
- Both MMA and homocysteine can be falsely elevated in renal insufficiency, making interpretation of functional markers challenging 1
- Use methylcobalamin or hydroxocobalamin instead of cyanocobalamin in renal dysfunction, as cyanocobalamin increases cardiovascular event risk in this population 1
- Elevated B12 >1,000 pg/mL in renal impairment is a poor prognostic marker but doesn't indicate excess 3, 4
When to Use Functional Testing (MMA)
Measure MMA when B12 is 180-350 pg/mL or when clinical suspicion remains high despite "normal" B12 levels. 1, 2
MMA Interpretation:
- MMA >271 nmol/L confirms functional B12 deficiency with 98.4% sensitivity 1
- MMA detects an additional 5-10% of patients with functional deficiency who have low-normal B12 levels 1
- In polyneuropathy patients, 44% had B12 deficiency based solely on abnormal MMA when serum B12 was normal 1
Cost-Effectiveness:
- MMA testing costs £11-80 per test and is cost-effective at £3,946 per quality-adjusted life year when B12 results are indeterminate 1
- Using MMA as first-line screening is NOT cost-effective; reserve for borderline B12 results 1
Special Considerations for History of B12 Deficiency
Patients with prior B12 deficiency require higher maintenance targets and cannot rely on serum B12 alone for monitoring. 1
If Currently Taking Supplements:
- Measure MMA as the primary test - it reflects actual cellular B12 status regardless of supplementation 1
- Serum B12 will be artificially elevated and uninformative 1
- Active B12 (holotranscobalamin) is more accurate than total B12 but costs £18 vs £2 1
Active B12 Interpretation (if measured):
- <25 pmol/L: confirmed deficiency 1
- 25-70 pmol/L: indeterminate, measure MMA 1
70 pmol/L: deficiency unlikely 1
High-Risk Populations Requiring Higher Targets
Age ≥60 years: 18.1% have metabolic deficiency; 25% of those ≥85 years have B12 <170 pmol/L despite "normal" ranges 1
Post-stroke patients: 17.3% have biochemical or metabolic deficiency; metabolic deficiency defined as B12 <258 pmol/L with elevated homocysteine or MMA 1
Metformin use >4 months: Significantly increases deficiency risk, especially at doses >1 gm/day 1, 5
Common Pitfalls to Avoid
- Never rely solely on serum B12 in patients >60 years - metabolic deficiency is common despite normal serum levels 1
- Never give folic acid before treating B12 deficiency - it may mask anemia while allowing irreversible neurological damage to progress 1
- Don't stop B12 supplements before testing - instead, measure MMA to assess functional status 1
- In renal impairment, interpret MMA and homocysteine cautiously - both can be falsely elevated 1
When Elevated B12 is Concerning
Persistently elevated B12 >1,000 pg/mL on two measurements warrants investigation for hematologic malignancy, liver disease, or solid tumors. 6, 3, 2