A 48-year-old woman with a 5-year history of GERD is on omeprazole 40 mg daily. She presents with fatigue, glossitis, and paresthesias in both feet. Serum B₁₂ is 180 pg/mL (normal >200), and intrinsic factor antibodies are negative. Gastric parietal cell antibodies are also negative. What is the most likely mechanism of B₁₂ deficiency in this patient?

Explanation

## PPI-Induced Vitamin B₁₂ Deficiency ### Mechanism of B₁₂ Malabsorption with PPIs **Key Point:** Proton pump inhibitors cause hypochlorhydria, which impairs the release of cobalamin (B₁₂) from food proteins and reduces intrinsic factor secretion, leading to B₁₂ deficiency after prolonged use (typically >1 year). ### Pathophysiology of B₁₂ Absorption ```mermaid flowchart TD A[Dietary B₁₂ bound to food proteins]:::outcome --> B{Normal gastric acid pH}:::decision B -->|pH 1.5-3.5| C[Pepsin releases B₁₂ from proteins]:::action C --> D[B₁₂ binds to intrinsic factor]:::action D --> E[Terminal ileum absorption]:::action E --> F[Normal B₁₂ levels]:::outcome G[PPI use: Hypochlorhydria]:::urgent --> H{pH > 4}:::decision H -->|Reduced acid| I[Pepsin inactive]:::urgent I --> J[B₁₂ remains bound to proteins]:::urgent J --> K[Reduced B₁₂ bioavailability]:::urgent K --> L[B₁₂ deficiency after 1-5 years]:::outcome ``` ### Differential Diagnosis: B₁₂ Deficiency Causes | Cause | Intrinsic Factor Antibody | Parietal Cell Antibody | Gastric Acid | Clinical Context | |---|---|---|---|---| | **Pernicious anemia** | Positive | Positive | Low | Autoimmune, B₁₂ malabsorption | | **PPI-induced** | Negative | Negative | Low | Long-term PPI use (>1 year) | | **Gastrectomy** | Negative | Negative | Absent | Post-surgical | | **Bacterial overgrowth** | Negative | Negative | Normal | Small intestine bacterial proliferation | | **Dietary deficiency** | Negative | Negative | Normal | Vegetarian/vegan diet | **High-Yield:** The absence of intrinsic factor and parietal cell antibodies rules out pernicious anemia. The clinical history of long-term PPI use (5 years) and hypochlorhydria is the key diagnostic clue. ### Clinical Pearl **Tip:** Always check B₁₂ levels and consider supplementation in patients on PPIs for >1 year, especially those with risk factors (age >50, vegetarian diet, prior GI surgery). ### Manifestations of B₁₂ Deficiency - **Hematologic:** Megaloblastic anemia, macrocytosis - **Neurologic:** Glossitis, paresthesias, subacute combined degeneration (dorsal/lateral columns) - **Psychiatric:** Cognitive changes, depression, dementia - **Gastrointestinal:** Diarrhea, loss of appetite **Warning:** Unlike folate deficiency, B₁₂ deficiency causes neurologic damage that may be irreversible if not treated promptly.