A patient on omeprazole develops hypomagnesemia and vitamin B12 deficiency after 2 years. The mechanism for B12 deficiency with long-term PPIs involves:

• A PPIs inhibit intrinsic factor (IF) secretion by parietal cells, directly blocking B12 absorption
• B PPIs competitively inhibit B12 absorption at the ileal cubilin receptor
• C PPIs are metabolized to toxic derivatives that damage the gastric mucosa reducing R-protein and IF secretion
• D Achlorhydria from PPI use impairs pepsin-mediated cleavage of B12 from R-proteins in dietary proteins; B12 bound to R-protein cannot bind IF and is not absorbed in the terminal ileum ✓

Explanation

Dietary cobalamin (B12) is tightly bound to food proteins and R-proteins (haptocorrin). Gastric acid and pepsin are required to denature food proteins and release B12 from R-proteins, allowing it to bind intrinsic factor (secreted by parietal cells) in the stomach. PPIs cause achlorhydria, impairing this critical first step — food-bound B12 cannot be released and remains bound to R-proteins, preventing IF binding and subsequent ileal absorption. PPIs do NOT inhibit IF secretion itself (parietal cells secrete both H+ and IF, but IF secretion is independent of H+/K+-ATPase). Prolonged PPI use causes B12 malabsorption of dietary B12 (not supplemental crystalline B12, which doesn't require acid digestion).

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.