Symptoms of Functional Vitamin B12 Deficiency
Functional vitamin B12 deficiency presents with neurological symptoms that can occur even when serum B12 levels appear normal, making it a critical diagnostic pitfall that requires measurement of methylmalonic acid (MMA) or holotranscobalamin to detect. 1, 2
Neurological Manifestations
The neurological symptoms dominate the clinical picture and often appear before hematological changes:
Peripheral Nervous System
- Paraesthesia (pins and needles) and numbness, particularly in the extremities and trunk 3, 1
- Peripheral neuropathy with sensory loss affecting proprioceptive, vibratory, tactile, and nociceptive sensation 3
- Muscle weakness and abnormal reflexes 3
- Reduced nerve conduction velocity indicating direct peripheral motor dysfunction 3
Central Nervous System
- Gait ataxia and balance problems due to impaired proprioception (sensory ataxia), representing early-stage deficiency 3, 1
- Subacute combined degeneration of the spinal cord with extensive demyelination, most prominent in the spinal cord but also affecting brain white matter 3, 2
- Spasticity and abnormal tendon jerks 3
- Myelopathies and myelo-neuropathies 3
Cognitive and Psychiatric
- Brain fog, cognitive difficulties, and concentration problems 1, 4
- Memory issues that can progress to dementia if untreated 5
- Depression 6
- Lethargy and developmental regression (in infants) 7
Hematological Manifestations
- Macrocytic anemia, though notably absent in one-third of cases 1, 4
- Hypersegmented neutrophils due to impaired DNA synthesis 8
- Anemia unresponsive to iron treatment 1
Other Clinical Features
- Glossitis (tongue inflammation) 1, 4
- Blurred vision from optic nerve dysfunction 1
- Fatigue (though nonspecific) 4, 6
- Failure to thrive (in infants) 7
Critical Diagnostic Pitfall
Up to 50% of patients with normal serum B12 levels have functional metabolic deficiency when measured by methylmalonic acid. 1, 4 This occurs because:
- Standard total B12 tests measure both active and inactive forms 4
- Failure of intracellular transport by transcobalamin-2 can cause functional deficiency despite normal serum levels 2
- Neurological damage can become irreversible if diagnosis is delayed based solely on normal serum B12 1, 2
When to Suspect Functional Deficiency
Consider functional B12 deficiency when:
- Neurological symptoms are present with serum B12 in the borderline range (180-350 pg/mL or 150-258 pmol/L) 1, 4, 6
- Symptoms persist despite "normal" serum B12 levels 2
- Patient has risk factors: age ≥60 years (18.1% have metabolic deficiency), post-bariatric surgery, autoimmune conditions, or medications like metformin, PPIs, or H2 antagonists 1, 4
Confirmatory Testing
- Methylmalonic acid (MMA): Elevated levels confirm functional deficiency even with normal serum B12 1, 4, 6
- Holotranscobalamin (active B12): Measures biologically available B12, more sensitive than total B12 1, 4, 9
- Homocysteine: Elevated in functional deficiency but less specific 4, 2
Progression and Severity
Symptoms become more severe as deficiency progresses, with sensory symptoms typically appearing before motor dysfunction 3. The neurological damage from subacute combined degeneration can become permanent if treatment is delayed, emphasizing the need for high clinical suspicion and appropriate metabolic testing rather than relying solely on serum B12 levels 1, 2.