Vitamin B12 Deficiency


  • Vitamin B12 deficiency is related to inadequate intake or absorption of cobalamin.
  • Cobalamin is critical for central nervous system myelination, red blood cell production, immune cell cytogenesis, and DNA synthesis (1).
  • Deficiency can cause megaloblastic anemia, bone marrow dysfunction, cytopenia including lymphopenia, and diverse and potentially irreversible neuropsychiatric changes.
  • Neuropsychiatric disorders are due to demyelination of cervical, thoracic dorsal, and lateral spinal cords; white matter; and cranial and peripheral nerves.
  • Elevated MMA and homocysteine levels MMA are more sensitive and specific and persist for several days even after treatment.


Normal vitamin B12 absorption and diet recommendations

  • Vitamin B12 is a water-soluble vitamin present in animal-source foods and foods fortified with vitamin B12.
  • Dietary vitamin B12 (cobalamin) bound to food is cleaved by acids in stomach and bound to haptocorrin that are secreted in saliva (commonly known as R-factor).
  • Pancreatic proteases cleave vitamin B12 from haptocorrin.
  • In duodenum, vitamin B12 uptake depends on binding to intrinsic factor (IF) secreted by gastric parietal cells.
  • Vitamin B12-IF complex is absorbed by terminal ileum into portal circulation.
  • Small amount of ingested vitamin B12 (<1 percent) can be absorbed by passive diffusion and is the basis for use of high dose oral vitamin B12 in pernicious anemia (PA).
  • Total body stores of vitamin B12 are in 2 to 5 mg range. Most of it are stored in liver.
  • Vitamin B12 excreted in bile is effectively reabsorbed through enterohepatic circulation.
  • Typical Western diet: 5 to 30 mg/day; however, only 1 to 5 mg/day is effectively absorbed.
  • Recommend 2.4 mg/day for adults and 2.6 mg/day during pregnancy and 2.8 mg/day during lactation (most prenatal vitamins contain vitamin B12).



  • National Health and Nutrition Examination Survey documented 6.9% and 15% prevalence of B12 deficiency in U.S. adults aged 51 to 70 and >70 years, respectively (2).
  • Morbidity increases vitamin B12 deficiency occurrence, ranging from 4% to 5% in community-living elderly to about 30–40% in institutionalized subjects with multiple comorbidities.
  • Prevalence in those <60 years old is 6% versus 20% in those >60 years.
  • Increasing recognition in breastfed-only infants with vitamin B12deficient mothers
  • Among patients with clinical macrocytosis (defined as a mean corpuscular volume [MCV] >100), 18–20% were due to vitamin B12 deficiency (3).
  • Vitamin B12 deficiency due to PA is more common in people of Northern European ancestry and lower in people of African descent.

Etiology and Pathophysiology

  • Decreased oral intake
    • Vegetarians and vegans: Vitamin B12 is found in animal-source foods.
  • Decreased IF
    • PA: can be associated with autoantibodies directed against gastric parietal cells and/or IF; 15–30% of all cases; most frequent cause of severe disease; neurologic disorders are common presenting complaints.
    • 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
  • Decreased absorption
    • Crohn disease: Terminal ileal inflammation decreases body’s ability to absorb vitamin B12.
    • Chronic alcoholism: decreases body’s ability to absorb vitamin B12
    • Gluten hypersensitivity (celiac disease) intestinal villi atrophy and subsequent malabsorption
    • 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 vitamin B12 from bound proteins
  • Medications:
    • Proton pump inhibitors (PPIs), H2 antagonists, and antacids decrease gastric acidity, inhibiting vitamin B12 release from dietary protein; metformin
    • Metformin usage can cause calcium-dependent membrane inhibition, interfering with vitamin B12IF absorption.
  • Hereditary (rare): transcobalamin II deficiency

Imerslund-Gräsbeck 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 vitamin B12-IF complex and decreased vitamin B12 renal protein reabsorption.

Commonly Associated Conditions

  • Gastric abnormalities: PA, gastritis, gastrectomy/bariatric surgery
  • Small bowel disease: malabsorption syndrome, ileal resection, IBD, celiac disease
  • Pancreatic insufficiency
  • Diet: breastfed infant in vitamin B12 deficient mother, strict vegan diet
  • Medications: neomycin, metformin, PPI, histamine 2 receptor antagonists, nitrous oxide (N2O) abuse

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