What are the signs and symptoms of vitamin B12 deficiency?

Signs and Symptoms of Vitamin B12 Deficiency

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 often appearing before—or even without—hematological changes. 1

Critical Clinical Pitfall

A major diagnostic trap is that normal serum B12 levels do not exclude functional B12 deficiency—up to 50% of patients with "normal" serum B12 have metabolic deficiency when measured by methylmalonic acid (MMA). 1, 2 This means you cannot rely on serum B12 alone to rule out deficiency, particularly in high-risk populations. 2

Neurological Manifestations

Neurological symptoms are often the first and most concerning presentation:

• Peripheral neuropathy with pins and needles, numbness, or tingling (paresthesia), particularly in the extremities and trunk, is a hallmark symptom that can occur even with normal serum B12 levels. 1, 2

• Sensory loss affecting proprioceptive, vibratory, tactile, and nociceptive sensation typically appears before motor dysfunction. 1, 2

• Gait ataxia and balance problems due to impaired proprioception can represent early-stage deficiency, leading to falls. 1, 2

• Subacute combined degeneration of the spinal cord with extensive demyelination in the CNS is a severe manifestation that can become irreversible if treatment is delayed. 1, 2, 3

• Muscle weakness, abnormal reflexes, and spasticity occur as deficiency progresses. 1

• Blurred vision related to optic nerve dysfunction can occur. 1

• Brain fog, cognitive difficulties, concentration problems, and memory issues are common neuropsychiatric symptoms. 2, 4

Critical warning: Neurological damage can occur even before anemia develops and may progress despite normal serum B12 levels. 1 If untreated for longer than 3 months, permanent degenerative lesions of the spinal cord may develop. 3

Hematological Manifestations

Blood-related symptoms may be absent in one-third of cases, but when present include: 2

• Macrocytic anemia with elevated mean corpuscular volume (MCV >100 fL). 1, 5

• Abnormal findings on blood count including anemia or macrocytosis, especially in patients with restricted diets. 1

• Hypersegmented neutrophils due to impaired DNA synthesis. 2

• Anemia unresponsive to iron treatment, especially during pregnancy or breastfeeding. 1, 2

Other Clinical Features

• Fatigue is the most commonly reported symptom, present in approximately 67% of patients. 5

• Glossitis (inflammation of the tongue) is a possible symptom. 1

• Depression may be present. 4

High-Risk Populations Requiring Vigilance

Screen for B12 deficiency in patients with these risk factors: 1, 4, 6

• Dietary factors: Vegan or vegetarian diets, limited consumption of fortified foods, food allergies to eggs/milk/fish, or eating disorders. 1

• Gastrointestinal conditions: Atrophic gastritis, celiac disease, post-bariatric surgery (sleeve gastrectomy, Roux-en-Y gastric bypass, duodenal switch), or >20 cm distal ileum resection in Crohn's disease. 1

• Autoimmune conditions: Thyroid disease, Sjögren syndrome, type 1 diabetes. 1

• Medications: Metformin (especially >4 months use), proton pump inhibitors or H2 receptor antagonists (>12 months), colchicine, phenobarbital, pregabalin, primidone, or methotrexate. 1, 6

• Age: Adults >60 years have 18.1% prevalence of metabolic deficiency; 25% of those ≥85 years have low B12. 7

Diagnostic Approach When Symptoms Present

When B12 deficiency is suspected based on symptoms:

1. Initial test: Serum B12 level (<180 pg/mL confirms deficiency; 180-350 pg/mL is indeterminate; >350 pg/mL makes deficiency unlikely). 7, 4

2. For indeterminate results (180-350 pg/mL): Measure methylmalonic acid (MMA) to confirm functional deficiency—MMA has 98.4% sensitivity and detects an additional 5-10% of patients with deficiency who have low-normal B12 levels. 7

3. Complete blood count: Check for megaloblastic anemia, though it may be absent in one-third of cases. 2, 3

4. In patients with neurological symptoms and normal B12: Consider measuring MMA or holotranscobalamin, as neurological symptoms can occur with normal serum B12 levels. 2, 8

Never delay treatment while waiting for confirmatory testing if clinical suspicion is high and neurological symptoms are present, as irreversible damage can occur. 1, 3