What is the workup for a patient with vitamin B12 (cobalamin) deficiency without anemia?

Workup for Vitamin B12 Deficiency Without Anemia

The workup for vitamin B12 deficiency without anemia should include serum active B12 (holotranscobalamin) or total B12 testing, followed by methylmalonic acid (MMA) testing for confirmation in indeterminate cases, while carefully assessing for neurological symptoms and risk factors. 1, 2

Initial Laboratory Testing

• First-line testing:

  • Active B12 (serum holotranscobalamin) OR Total B12 (serum cobalamin) 1
    • Active B12 is more accurate but more expensive (£18 vs £2 per test)
    • Either test is acceptable when suspicion arises from symptoms and risk factors

• Confirmatory testing:

  • Methylmalonic acid (MMA) when initial results are indeterminate 1, 2
    • More reliable for functional status assessment of B12
    • Not suitable as first-line due to cost (£11-80 per test)

Clinical Assessment

Neurological Symptoms to Evaluate

• Cognitive difficulties (concentration problems, short-term memory loss, "brain fog") 1
• Eyesight problems (blurred vision, visual field loss) 1
• Balance issues and falls due to proprioception impairment 1
• Impaired gait 1
• Pins and needles or numbness (paresthesia) 1
• Peripheral neuropathy symptoms 1, 3

It's critical to note that neurological manifestations can occur in the absence of anemia and may be the only presenting symptoms of B12 deficiency 3, 4. Early diagnosis and prompt treatment are essential as neurological damage can become irreversible if treatment is delayed 5, 3.

Risk Factors to Assess

• Diet low in vitamin B12 1, 2:

  • Vegan or vegetarian diet
  • Religious dietary restrictions excluding animal products
  • Limited consumption of B12-fortified foods
  • Food insecurity or difficulty preparing meals

• Medical conditions 1, 2, 6:

  • Atrophic gastritis
  • Celiac disease or other autoimmune conditions
  • Inflammatory bowel disease
  • History of gastric or small intestine resections
  • Pancreatic insufficiency

• Medication use 1, 2, 6:

  • Metformin (especially >4 months)
  • Proton pump inhibitors or H2 blockers (especially >12 months)
  • Colchicine
  • Phenobarbital
  • Pregabalin
  • Primidone

Important Considerations

• Never administer folic acid before treating B12 deficiency as this may mask hematologic manifestations while allowing neurological damage to progress 2

• Vitamin B12 deficiency left untreated for more than three months may produce permanent degenerative lesions of the spinal cord 5

• The response to treatment is inversely proportional to the severity and duration of the disease, emphasizing the importance of early diagnosis 3

• Adults over 75 years should be considered at higher risk and may warrant screening even without obvious symptoms 6

Follow-up Testing

• Follow-up testing within 3 months after supplementation to verify normalization 2
• Long-term monitoring for those with ongoing risk factors:
  • Folate status measured every 3 months until stabilization, then annually 2
  • Regular B12 level monitoring based on treatment response and risk factors

By following this structured approach to the workup of B12 deficiency without anemia, clinicians can identify and address this condition before irreversible neurological damage occurs, even in the absence of the classic hematological manifestations.