Vitamin B12 Deficiency

Description

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).

Epidemiology

Prevalence

• 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

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 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