Description

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).

Epidemiology

• 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
  • <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 absorption
  • Crohn disease: Terminal ileal inflammation decreases body’s ability to absorb B₁₂.
  • Chronic alcoholism: decreases body’s ability to absorb B₁₂
  • Gluten hypersensitivity (Celiac disease) causes 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 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.
    • Metformin use was associated with an increase in MMA and worsening neuropathy score in patients with type 2 diabetes.
• Hereditary (rare)
  • Imerslund-Gräsbeck disease (juvenile megaloblastic anemia)
  • Congenital deficiency of transcobalamin
  • Severe methylene tetrahydrofolate reductase deficiency
  • Abnormalities of methionine synthesis
  • Mutations in the gene for intrinsic factor, genes encoding the vitamin B₁₂ transporting transcobalamins, and genes involving intracellular vitamin B₁₂ metabolism.
• 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
  • Pernicious anemia
    • 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

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 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