Why do PPIs reduce B12 Levels?

Gastric acid inhibitors [Proton Pump Inhibitor (PPIs) & Histamine 2 receptor antagonists (H2RAs)] is associated with vitamin B12 deficiency; especially in the elderly. 

WHY??? Vitamin B12 absorption requires peptic enzymes to cleave dietary B12 from dietary proteins and to allow for absorption in the distal Ileum.

THEORY: This is performed primarily by pepsin, which requires gastric acid to activate it from its pepsinogen precursor. Therefore in the setting of reduced gastric acid secretion, vitamin B12 will not be cleaved and can not bind to R-proteins in the stomach. This step is required to protect vitamin B12 from pancreatic digestion. Also, parietal cells which generate HCl (via K+/H+ APTase pump) produce intrinsic factor, a compound required for vitamin B₁₂ absorption in the distal ileum. (see image on right)

NOTE: conditions associated with vitamin B12 deficiency (ie, thyroid disease, Helicobacter pylori infection, alcohol abuse, smoking, atrophic gastritis, and achlorhydria), may be confounding!

REFERENCES

1. Lam JR, Schneider JL, Zhao W, Corley DA. Proton Pump Inhibitor and Histamine 2 Receptor Antagonist Use and Vitamin B12 Deficiency. JAMA. 2013;310(22):2435-2442. doi:10.1001/jama.2013.280490.
2. Festen, HP. Intrinsic factor secretion and cobalamin absorption. Physiology and pathophysiology in the gastrointestinal tract. Scand J Gastroenterol Suppl. 1991; 188():1-7.
3. Howden, CW. Vitamin B12 levels during prolonged treatment with proton pump inhibitors. J Clin Gastroenterol. 2000 Jan;30(1):29-33.