Vitamin B₁₂ Deficiency

Key Features

Essentials of Diagnosis

• Macrocytic anemia

• Megaloblastic blood smear (macro-ovalocytes and hypersegmented neutrophils)

• Low serum vitamin B₁₂ level

General Considerations

• All vitamin B₁₂ is absorbed from the diet (foods of animal origin)

• After ingestion, vitamin B₁₂ binds to intrinsic factor, a protein secreted by gastric parietal cells

• Vitamin B₁₂-intrinsic factor complex is absorbed in the terminal ileum by cells with specific receptors for the complex; it is then transported through the plasma and stored in the liver

• Three plasma transport proteins have been identified:

  • Transcobalamin I and III are secreted by white blood cells (WBC)

  • Transcobalamin II is capable of transporting vitamin B₁₂ into cells

• Approximately 90% of plasma vitamin B₁₂ circulates bound to transcobalamins I and III

• Liver stores are of such magnitude that it takes at least 3 years for vitamin B₁₂ deficiency to develop after vitamin B₁₂ absorption ceases

• Causes of vitamin B₁₂ deficiency

  • Decreased intrinsic factor production: pernicious anemia (most common cause), gastrectomy

  • Dietary deficiency (rare but seen in vegans)

  • Competition for B₁₂ in gut: blind loop syndrome, fish tapeworm (rare)

  • Decreased ileal B₁₂ absorption: surgical resection of ileum, Crohn disease of ileum

  • Prolonged use of proton pump inhibitors

  • Pancreatic insufficiency

  • Helicobacter pylori infection

  • Transcobalamin II deficiency (rare)

• Pernicious anemia is associated with atrophic gastritis and other autoimmune diseases, eg, immunoglobulin A (IgA) deficiency, polyglandular endocrine failure syndromes

Clinical Findings

Symptoms and Signs

• Causes a moderate to severe anemia of slow onset such that patients may have few symptoms relative to their degree of anemia

• Pallor and mild icterus or sallow complexion

• Glossitis and vague gastrointestinal disturbances (eg, anorexia, diarrhea)

• Neurologic manifestations

  • Peripheral neuropathy usually occurs first

  • Then, subacute combined degeneration of the spinal cord affecting posterior columns may develop, causing difficulty with position and vibration sensation and balance

  • In advanced cases, dementia and other neuropsychiatric changes may occur

  • Neurologic manifestations occasionally precede hematologic changes; patients with suspicious neurologic symptoms and signs should be evaluated for vitamin B₁₂ deficiency despite normal mean cell volume (MCV) and absence of anemia

Differential Diagnosis

• Folic acid deficiency (other cause of megaloblastic anemia)

• Myelodysplastic syndrome (other cause of macrocytic anemia with abnormal morphology)

• Other causes of peripheral neuropathy, ataxia, or dementia

Diagnosis

Laboratory Tests

• Normal vitamin B₁₂ level is > 300 pg/mL (221 pmol/L)

• Serum levels in overt vitamin B₁₂ deficiency: < 200 pg/mL (148 pmol/L)

• Serum levels in symptomatic patients: < 100 pg/mL (74 pmol/L)

• The diagnosis of vitamin B₁₂ deficiency in low or low-normal values (level of 200–300 pg/mL [147.6–221.3 pmol/L]) is best confirmed ...