What is the appropriate workup and treatment for an older adult suspected of having a vitamin B12 (cobalamin) deficiency?

Vitamin B12 Deficiency Workup

Initial Testing Strategy

Start with serum total vitamin B12 as the first-line test, then add methylmalonic acid (MMA) testing when results fall in the indeterminate range to confirm functional deficiency. 1

Primary Test: Total Serum B12

• Cost-effective at approximately £2 per test with rapid turnaround 1
• Interpret results as follows:
  • <180 pg/mL (<150 pmol/L): Confirms deficiency—initiate treatment immediately 1, 2
  • 180-350 pg/mL (150-258 pmol/L): Indeterminate—measure MMA to confirm functional deficiency 1, 2
  • >350 pg/mL (>258 pmol/L): Makes deficiency unlikely, but consider functional markers if high clinical suspicion 1

Alternative: Active B12 (Holotranscobalamin)

• More accurate but costs £18 per test with longer turnaround times 1
• Measures the biologically active form available for cellular use 1
• Interpretation:
  • <25 pmol/L: Confirms deficiency 1
  • 25-70 pmol/L: Indeterminate—requires MMA testing 1
  • >70 pmol/L: Makes deficiency unlikely 1

Confirmatory Testing: Methylmalonic Acid (MMA)

• MMA has 98.4% sensitivity for B12 deficiency and is more specific than homocysteine 1
• MMA >271 nmol/L confirms functional B12 deficiency 1
• Detects an additional 5-10% of patients with functional deficiency who have low-normal B12 levels 1
• Cost-effective at £3,946 per quality-adjusted life year when B12 results are indeterminate 1
• Costs £11-80 per test and requires specialized equipment 1

Critical pitfall: Standard serum B12 testing misses functional deficiency in up to 50% of cases—the Framingham Study found 12% had low serum B12, but an additional 50% had elevated MMA indicating metabolic deficiency despite "normal" serum levels 1

Who to Test: High-Risk Populations

Test patients with any of the following risk factors or clinical features 1:

Risk Factors

• Age >75 years (18.1% of those >80 years have metabolic deficiency) 1
• Metformin use >4 months 1
• PPI or H2 blocker use >12 months 1
• Gastric or intestinal resection (especially >20 cm distal ileum) 1, 3
• Bariatric surgery 1, 4
• Inflammatory bowel disease (particularly Crohn's with ileal involvement) 1, 4
• Vegan or strict vegetarian diet 4
• Autoimmune thyroid disease (prevalence of B12 deficiency ranges from 28-68%) 1

Clinical Features Warranting Testing

• Hematologic: Anemia, macrocytosis on CBC 1
• Neurological: Peripheral neuropathy, paresthesias, ataxia, cognitive difficulties, memory problems 1, 2
• Other: Unexplained fatigue, glossitis, visual problems (optic nerve dysfunction) 1

Additional Workup Components

Complete Blood Count

• Check for megaloblastic anemia, though it may be absent in one-third of cases 1
• Macrocytosis often precedes anemia and may be the earliest laboratory sign 1

Homocysteine (Optional)

• Elevated homocysteine >15 μmol/L supports B12 deficiency diagnosis 1
• Less specific than MMA—elevated in 95.9% of B12 deficiency but also in 91% of folate deficiency 1
• Falsely elevated in hypothyroidism, renal insufficiency, and hypovolemia 1

Etiologic Testing (When Deficiency Confirmed)

• Intrinsic factor antibodies: For pernicious anemia diagnosis 1
• Gastrin levels: If pernicious anemia suspected (markedly elevated >1000 pg/mL indicates pernicious anemia) 1
• Helicobacter pylori testing: To evaluate for atrophic gastritis 2
• Celiac disease screening (tissue transglutaminase antibodies and total IgA): Found in 13.3% of B12-deficient hypothyroid patients 1

Treatment Initiation

Once deficiency is confirmed, treatment choice depends on severity and presence of neurological symptoms:

With Neurological Involvement

Hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement, then maintenance of 1 mg IM every 2 months for life 3, 5

Without Neurological Involvement

Hydroxocobalamin 1 mg intramuscularly three times weekly for 2 weeks, followed by maintenance of 1 mg IM every 2-3 months lifelong 3, 5

Oral Alternative

Oral vitamin B12 1000-2000 mcg daily is as effective as intramuscular administration for most patients, including those with malabsorption 6, 1, 4

Critical warning: Never administer folic acid before treating B12 deficiency, as it may mask anemia while allowing irreversible neurological damage to progress 1, 3

Monitoring Strategy

• First recheck at 3 months after initiating supplementation 3
• Second recheck at 6 months 3
• Third recheck at 12 months 3
• Annual monitoring thereafter once levels stabilize 3
• Measure serum B12, CBC, and consider MMA/homocysteine if levels remain borderline or symptoms persist 3

Target homocysteine <10 μmol/L for optimal cardiovascular outcomes 1, 3