Vitamin B12 Deficiency

Vitamin B12 Deficiency is a topic covered in the 5-Minute Clinical Consult.

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  • Vitamin deficiency related to inadequate intake or absorption of cobalamin (vitamin B12)
  • Cobalamin is critical for central nervous system myelination and normal functioning.
  • Deficiency can cause a multitude of symptoms and disorders including megaloblastic anemia, bone marrow dysfunction, and diverse and potentially irreversible neuropsychiatric changes.
  • Neuropsychiatric disorders are due to demyelination of cervical, thoracic dorsal, and lateral spinal cords; demyelination of white matter; and demyelination of cranial and peripheral nerves (1)[C].
  • Low vitamin B12 level can lead to elevated methylmalonic acid (MMA) and homocysteine levels (2)[C].
  • Elevated MMA causes abnormality in fatty acid synthesis affecting neuronal membrane.
  • Elevated homocysteine is neurotoxic through overstimulation of the N-methyl-D-aspartate (NMDA) receptor and toxic to vasculature through activation of coagulation system and effects on endothelium.


Normal B12 absorption

  • B12 is a water-soluble vitamin present in animal-source foods (meat, fish, eggs, milk) and foods (cereals and supplements) fortified with B12.
  • Dietary vitamin B12 (cobalamin) bound to food is cleaved by acids in stomach and bound to haptocorrin (commonly known as R-factor).
  • Duodenal proteases cleave B12 from haptocorrin.
  • In duodenum, B12 uptake depends on binding to intrinsic factor (IF) secreted by gastric parietal cells.
  • B12-IF complex is absorbed by terminal ileum into portal circulation.
  • Body’s B12 stored in liver = 50−90%
    • B12 secreted into bile from liver recycled via enterohepatic circulation
    • Delay 5 to 10 years from onset of B12 deficiency to clinical symptoms due to hepatic stores and enterohepatic circulation
  • Typical Western diet: 5 to 30 μg/day; however, only 1 to 5 μg/day is effectively absorbed.
    • Recommend 2.4 μg/day for adults and 2.6 μg/day during pregnancy and 2.8 μg/day during lactation (most prenatal vitamins contain B12).


  • Endemic area: Northern Europe, including Scandinavia; more common in those of African ancestry
  • Increasing recognition in breastfed-only infant populations with vitamin B12deficient mothers
  • Prevalence 5–20% in developed countries
    • 12% in elderly living in community
    • 30–40% in elderly in institutions, sick, or malnourished
    • 5% patients in tertiary reference hospitals
  • Prevalence by age group (3)
    • <60 years old: prevalence 6%
    • >60 years old: prevalence 20%

Etiology and Pathophysiology

  • Decreased oral intake
    • Vegetarians and vegans: B12 is found in animal source foods; however, strict vegetarians uncommonly develop deficiency because only 1 mg/day is needed, with adequate amounts present in legumes.
  • Decreased IF
    • Pernicious anemia (PA): can be associated with autoantibodies directed against gastric parietal cells and/or IF
    • Chronic atrophic gastritis: autoimmune attack on gastric parietal cells causing autoimmune gastritis and leading to decreased IF production
    • Gastrectomy: Removal of entire or part of stomach decreases number of parietal cells.
  • Decreased ileal absorption
    • Crohn disease: Terminal ileal inflammation decreases body’s ability to absorb B12.
    • Chronic alcoholism: decreases body’s ability to absorb B12
    • Ileal resection
    • Pancreatic insufficiency: Pancreatic proteases are required to cleave the vitamin B12haptocorrin bond to allow vitamin B12 to bind to IF.
    • Helicobacter pylori infection: impairs release of B12 from bound proteins
  • Medications: Proton pump inhibitors (PPIs), H2 antagonists, and antacids decrease gastric acidity, inhibiting B12 release from dietary protein; metformin
    • Metformin usage
      • Chronic metformin usage leads to vitamin B12 deficiency. Caused by calcium-dependent membrane inhibition, interfering with vitamin B12IF absorption. Years on metformin is the only predictive factor for B12 deficiency.
  • Hereditary (rare)
    • Imerslünd-Grasbeck disease (juvenile megaloblastic anemia)
    • Congenital deficiency of transcobalamin
    • Severe methylene tetrahydrofolate reductase deficiency
    • Abnormalities of methionine synthesis
  • Causes:
    • Food-cobalamin malabsorption syndrome
      • As many as 60–70% of cases
      • Primary cause in elderly
      • Pathophysiology: inability to release cobalamin from food or binding protein, especially if in the setting of hypochlorhydria
      • Seen in atrophic gastritis, long-term ingestion of antacids and biguanides, possible relationship to H. pylori infection
    • PA
      • 15–30% of all cases; most frequent cause of severe disease. Neurologic disorders are common presenting complaints.
      • Common in elderly, as high as 20%, with mild atrophic gastritis, hypochlorhydria, and impaired release of dietary vitamin B12
      • Autoimmune disease with destruction of gastric fundal mucosa cells via a cell-mediated process
      • Antigastric parietal cell antibodies: sensitivity >90%, specificity 50%; use for screening test
      • Anti-IF antibodies: sensitivity 50%
      • Associated with other autoimmune diseases
    • Insufficient dietary intake: 2% of cases; vegans or long-standing vegetarians
    • Infants born to vitamin B12deficient mothers may have deficiency or may develop it if breastfed exclusively.
    • Intestinal causes:
      • 1% of cases; prevalence depends on risk factors, such as surgical conditions.
      • Gastrectomy: due to decreased production of IF
      • Gastric bypass: appears 1 to 9 years after surgery, prevalence 12–33%
      • Ileal resection or disease
      • Fish tapeworm
      • Severe pancreatic insufficiency
    • Undetermined etiology
      • 1/10 of cases

Imerslünd-Grasbeck disease (juvenile megaloblastic anemia) caused by mutations in the amnionless (AMN) or cubilin (CUBN) genes with autosomal recessive pattern of inheritance; inadequate ileal uptake of B12-IF complex and B12 renal protein reabsorption

General Prevention

Risk factors: vegan diet, age >60 years, female, chronic atrophic gastritis, Crohn disease or other ileal disorders, chronic medication use including PPI, metformin, H2 antagonists

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