What are the manifestations of vitamin B12 deficiency?

Vitamin B12 Deficiency Manifestations

Vitamin B12 deficiency presents with a broad spectrum of hematological, neurological, psychiatric, and gastrointestinal manifestations that can occur independently or in combination, with neurological symptoms frequently appearing before—or even in the absence of—anemia. 1, 2

Critical Clinical Pitfall

Up to 50% of patients with "normal" serum B12 levels (180-350 pg/mL) have functional metabolic deficiency when measured by methylmalonic acid (MMA), meaning standard B12 testing alone misses half of all cases. 1, 3 This is particularly dangerous because neurological damage from subacute combined degeneration can become permanent if treatment is delayed, and this damage may progress despite normal serum B12 levels. 1, 4

Neurological Manifestations

Peripheral Nervous System

• Peripheral neuropathy with paraesthesia (pins and needles) and numbness, particularly affecting the extremities and trunk 1, 2
• Sensory loss affecting proprioceptive, vibratory, tactile, and nociceptive sensation—sensory symptoms typically appear before motor dysfunction 5, 2
• Gait ataxia and balance problems due to impaired proprioception, representing early-stage deficiency 1, 2
• Muscle weakness, abnormal reflexes, and spasticity as deficiency progresses 5

Central Nervous System

• Subacute combined degeneration of the spinal cord with extensive demyelination in the CNS, most prominently in the spinal cord, though focal demyelination also occurs in brain white matter 5, 2
• Cognitive symptoms including brain fog, concentration problems, memory difficulties, and dementia 2, 6, 7
• Optic nerve dysfunction causing blurred vision 1, 8
• Psychiatric symptoms including depression 6

Pediatric Neurological Presentations

• Developmental retardation and hypotonia in infants and children 8
• Syncope, dizziness, and convulsions 8
• Tremor and ataxia 8
• Fatigue and concentration difficulty 8

Hematological Manifestations

• Macrocytic anemia—though notably absent in one-third of cases 2, 3
• Hypersegmented neutrophils due to impaired DNA synthesis 2
• Anemia unresponsive to iron treatment, especially during pregnancy or breastfeeding 1, 2
• Abnormal blood count findings including macrocytosis, particularly in patients with restricted diets 1

Gastrointestinal Manifestations

• Glossitis (inflammation of the tongue) 1, 3

Other Clinical Features

• Fatigue and lethargy 6, 7
• Weight loss 7

Progression and Severity

Symptoms become more severe as deficiency progresses, with neurological manifestations often presenting before hematological changes. 2, 3 Vitamin B12 deficiency that is allowed to progress for longer than 3 months may produce permanent degenerative lesions of the spinal cord. 4 The mechanism by which demyelination occurs remains unclear, but axonal degeneration in distal afferent fibers of dorsal root ganglion neurons has been documented. 5

High-Risk Populations Requiring Vigilance

• Post-bariatric surgery patients (sleeve gastrectomy, Roux-en-Y gastric bypass, duodenal switch) due to reduced intrinsic factor and gastric acid 1, 3
• Patients with >20 cm distal ileum resection in Crohn's disease, who require 1000 mcg intramuscularly monthly for life 1
• Elderly patients ≥60 years, with 18.1% having metabolic deficiency and 25% of those ≥85 years having B12 <170 pmol/L 3
• Autoimmune thyroid disease patients, with prevalence of B12 deficiency ranging from 28-68% 3
• Vegans and strict vegetarians consuming no animal products 1, 4, 9
• Patients on metformin >4 months, proton pump inhibitors >12 months, H2 receptor antagonists, colchicine, phenobarbital, pregabalin, or primidone 1, 3, 9

Diagnostic Approach for Suspected Deficiency

When B12 deficiency is suspected based on clinical manifestations, measure serum B12 first. 3 If B12 <180 pg/mL (<150 pmol/L), diagnose deficiency and initiate treatment immediately. 3, 6 For borderline results (180-350 pg/mL), measure methylmalonic acid (MMA) to confirm functional deficiency, as MMA has 98.4% sensitivity and detects an additional 5-10% of patients with B12 deficiency who have low-normal B12 levels. 3 In polyneuropathy patients, 44% had B12 deficiency based solely on abnormal metabolites when serum B12 was normal. 3