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For further information, see CMDT Part 13-06: 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

  • 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, Crohn disease

    • 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 > 210 pg/mL

  • Serum levels in overt deficiency: < 170 pg/mL

  • Serum levels in symptomatic patients: < 100 pg/mL

  • The diagnosis is best confirmed by an elevated level of serum methylmalonic acid (>1000 nmol/L) or homocysteine (> 16.2 mmol/L)

  • The anemia of vitamin B12 deficiency is typically moderate to severe with the MCV quite elevated (110–140 fL); however, MCV may be normal

  • Peripheral blood smear is megaloblastic, defined as red blood cells that appear as macro-ovalocytes, (although other shape changes are usually present) and neutrophils that are hypersegmented

  • Reticulocyte count is reduced

  • In severe cases, white blood cell count and platelet count are reduced

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