What are the signs and symptoms of Vitamin B12 deficiency?

Signs and Symptoms of Vitamin B12 Deficiency

Vitamin B12 deficiency presents with a wide range of hematological and neurological manifestations that can become permanent and irreversible if left untreated for more than 3 months. 1

Clinical Manifestations

Hematological Signs

• Macrocytic anemia with elevated MCV (mean corpuscular volume) 2
• Hypersegmented neutrophils on peripheral blood smear 3
• Low hemoglobin levels (typically below 13 g/dL for males, below 12 g/dL for females) 2
• Elevated reticulocyte count after initiating treatment 2

Neurological Manifestations

• Tingling and numbness in extremities (paresthesias) - reported in 54.4% of patients 2
• Subacute combined degeneration of the spinal cord - characterized by:
  • Progressive weakness of lower limbs 3
  • Loss of joint position sense 3
  • Sensory impairment 3
  • Positive Romberg's sign 3
  • Absent ankle jerks 3
• Developmental delay and seizures (particularly in infants) 4
• Headache (common in adolescents) 4
• Abnormal movements, which may appear before or paradoxically after initiating treatment 5

General Symptoms

• Fatigue (most common symptom, affecting 66.7% of patients) 2
• Pallor 3
• Failure to thrive (in infants and children) 5
• Lethargy and hypotonia 5
• Arrest or regression of developmental skills 5

Dermatological Signs

• Skin hyperpigmentation, particularly over dorsal and palmar aspects of hands and feet (rare but distinctive) 3

High-Risk Populations

Certain groups are at increased risk for vitamin B12 deficiency:

• Vegans and vegetarians (require daily B12 supplementation of 250-350 μg or weekly 1000 μg) 6
• Patients with Crohn's disease and ileal involvement/resection 6
• Post-bariatric surgery patients 6
• Patients on metformin (long-term use can contribute to B12 deficiency) 6
• Breastfed infants of vegetarian/vegan mothers 1, 5
• Elderly individuals 2

Diagnostic Considerations

Initial testing for vitamin B12 deficiency should include:

• Total B12 (serum cobalamin) or active B12 (serum holotranscobalamin) with interpretation thresholds:
  • Confirmed deficiency: Total B12 <180 ng/L or active B12 <25 pmol/L
  • Indeterminate: Total B12 180-350 ng/L or active B12 25-70 pmol/L
  • Unlikely deficiency: Total B12 >350 ng/L or active B12 >70 pmol/L 6

For indeterminate results, additional testing should include:

• Methylmalonic acid (MMA) levels
• Homocysteine levels
• Complete blood count
• Folate levels 6

Important Caveats and Pitfalls

1. Risk of permanent neurological damage: Vitamin B12 deficiency left untreated for more than 3 months may cause permanent degenerative lesions of the spinal cord. Early diagnosis and treatment are crucial. 1

2. Folic acid masking: Doses of folic acid greater than 0.1 mg per day may result in hematologic remission in patients with vitamin B12 deficiency, but will not prevent neurologic manifestations. This can mask the true diagnosis while allowing irreversible neurological damage to progress. 1

3. Paradoxical movement disorders: Abnormal movements may appear after initiating treatment in some patients, particularly infants, and can last 2-6 weeks despite neurological improvement. 5

4. Medication interactions: Most antibiotics, methotrexate, pyrimethamine, colchicine, para-aminosalicylic acid, and heavy alcohol intake can interfere with vitamin B12 absorption or diagnostic blood assays. 1

5. Increased cancer risk: Patients with pernicious anemia have about 3 times the incidence of carcinoma of the stomach as the general population. 1

6. Hyperpigmentation misdiagnosis: Skin hyperpigmentation is a rare presenting symptom of B12 deficiency and may lead to misdiagnosis if not recognized. 3

Early recognition and prompt treatment of vitamin B12 deficiency are essential to prevent irreversible neurological damage and improve both hematological and neurological outcomes.