Description

Normal vitamin B₁₂ absorption

• 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 (commonly known as R-factor).
• Duodenal 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.
• Body’s vitamin B₁₂ stored in liver: 50–90%
  • Vitamin B₁₂ secreted into bile from liver recycled via enterohepatic circulation
  • Delay 5 to 10 years from onset of vitamin B₁₂ deficiency to clinical symptoms due to hepatic stores and 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).

Epidemiology

Prevalence

• 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
• Prevalence in those <60 years old is 6%, and in those >60 years old, it is 20%.

Etiology and Pathophysiology

• Decreased oral intake
  • Vegetarians and vegans: Vitamin B₁₂ is found in animal source foods.
• 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
• 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)
• Causes:
  • Food-cobalamin malabsorption syndrome
    • 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
    • Antigastric parietal cell antibodies: sensitivity >90%, specificity 50%; use for screening test
  • Insufficient dietary intake: 2% of cases; vegans or long-standing vegetarians
  • Infants born to vitamin B₁₂deficient mothers 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

Genetics
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 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
• Pancreatitis: 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