Etiology

Vitamin B12 is an essential vitamin obtained only from diet or by supplementation. Dietary sources include animal and dairy products such as meat, poultry, milk, and eggs. Stores of vitamin B12 in the liver remain in the body for years, so vitamin B12 deficiency depends on chronic, long-term deficiency.

Anything that decreases the intake or the absorption of vitamin B12 places people at risk of vitamin B12 deficiency. In general, etiologies of vitamin B12 deficiency can be categorized into:

  • Decreased dietary intake.

  • Diminished gastric breakdown of vitamin B12 from food.

  • Malabsorption from the gastrointestinal tract

Risk factors for vitamin B12 deficiency include:[31][32]

  • Older age (>65 years)

  • History of gastric resection or bypass

  • Chronic gastrointestinal illness (e.g., Crohn disease, celiac disease), bacterial overgrowth syndromes, or intestinal surgery

  • Vegan or strict vegetarian diet

  • Drugs that diminish the breakdown of vitamin B12 from food sources (e.g., H2 receptor antagonists and proton-pump inhibitors [PPIs]) or decrease absorption of vitamin B12 (e.g., metformin).

People with pernicious anemia, an autoimmune disorder that destroys parietal cells (responsible for the production of intrinsic factor required for vitamin B12 absorption), are at increased risk for vitamin B12 deficiency.

Atrophic gastritis, a chronic inflammatory condition associated with vitamin B12 deficiency, may occur secondary to autoimmune disease (e.g., Hashimoto thyroiditis) or Helicobacter pylori infection.[33][34][35][36][37][38][39]​​ Prospective study data suggest that vitamin B12 deficiency is more common in patients with autoimmune gastritis than those with H pylori-related gastritis.[40]

In patients with H pylori infection, it is unclear whether the organism, or associated atrophic gastritis, causes vitamin B12 deficiency.[41]​ There does not appear to be an association between H pylori infection and vitamin B12 deficiency in pregnant women.[42]

Anticonvulsant drugs (e.g., carbamazepine) have been associated with vitamin B12 deficiency.[43][44]​​ The exact mechanism is unclear but might include interference with absorption, plasma binding, cellular metabolism, and renal excretion.

Recreational nitrous oxide (N₂O) misuse, which is increasingly prevalent, has been linked to vitamin B12 deficiency.[45] In one systematic review and meta-analysis, up to 85% of reported recreational users were possibly or probably vitamin B12-deficient.[46] N₂O converts the active monovalent form of vitamin B12 to its inactive bivalent form. The neurologic sequelae of N₂O-induced vitamin B12 deficiency can include neuropathy and paralysis.[47]

Pathophysiology

Dietary sources of vitamin B12 (meat, poultry, dairy) are released from food by peptic acid in the stomach. Vitamin B12 binds to R-protein (haptocorrin [also known as R-binder]), forming R-B12 complex (which is stable in the gastric acidic environment). The R-B12 complex travels to the duodenum, where it is broken down (split) by pancreatic trypsin.[48]​ Free vitamin B12 then binds to intrinsic factor (IF; secreted by parietal cells of the gastric fundus and therefore lost in pernicious anemia).

The vitamin B12-IF complex is carried through the small intestine to the terminal ileum, where it attaches to IF receptors and is absorbed by endocytosis. The absorbed vitamin B12 is bound to transcobalamin. The transcobalamin-vitamin B12 complex (holotranscobalamin) is then released into the bloodstream for cell utilization.

Over 95% of dietary B12 is absorbed through the IF pathway. Any interference in this process can place the patient at risk for vitamin B12 deficiency.[Figure caption and citation for the preceding image starts]: Absorption of vitamin B12. Dietary B12 is released from food in the stomach and binds to R-protein (haptocorrin, this complex is stable in the gastric acidic environment). The R-B12 complex then travels to the duodenum, where B12 binds to intrinsic factor (IF, secreted by gastric parietal cells and therefore lost in pernicious anemia). This B12-IF complex is carried down the small intestine until the terminal ileum, where it attaches to IF receptors and is absorbed into the bloodstream bound to transcobalamin. Over 95% of dietary B12 is absorbed through the IF pathwaySukumar N et al. Investigating vitamin B12 deficiency. BMJ. 2019 May 10;365:l1865; used with permission [Citation ends].com.bmj.content.model.Caption@6a12d33f

Vitamin B12 is an essential cofactor in DNA synthesis and is closely related to folate metabolism. Specifically, vitamin B12 is an important cofactor in two biochemical processes: deficiency of vitamin B12 impairs the conversion of methylmalonic acid to succinyl co-A; deficiency of vitamin B12 or folate impairs the conversion of homocysteine to methionine. Methionine is critical in the production of S-adenosylmethionine, which is thought to be important in neural function.

Vitamin B12 and folate are thought to be integral in normal hematopoiesis and bone marrow function. Prolonged and severe deficiency in vitamin B12 can cause neurologic and hematologic disorders, and may manifest with psychiatric symptoms.[49][50]​​​

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