What are the consequences of long-term Proton Pump Inhibitor (PPI) use?

Consequences of Long-Term Proton Pump Inhibitor (PPI) Use

Long-term PPI use is associated with several significant adverse effects including gastrointestinal infections, nutritional deficiencies, bone fractures, and kidney problems, warranting regular review of ongoing indications and consideration of de-prescribing when appropriate. 1

Major Adverse Effects

Gastrointestinal Effects

• Clostridium difficile infection: PPIs are associated with increased risk of C. difficile-associated diarrhea, especially in hospitalized patients 2, 3
• Bacterial gastroenteritis: Higher susceptibility to enteric infections due to reduced gastric acid barrier 1
• Rebound acid hypersecretion: Patients who discontinue PPIs may experience transient upper GI symptoms due to increased acid production 4
• Stomach growths: Long-term PPI use (>1 year) increases risk of developing fundic gland polyps 5

Nutritional Deficiencies

• Vitamin B12 deficiency: Occurs particularly with higher doses and use ≥2 years due to reduced acid-dependent absorption 1, 5
• Hypomagnesemia: 71% higher risk with prolonged use, may cause serious events including tetany, arrhythmias, and seizures 1, 3
• Iron deficiency: Shows dose-dependent association after ≥1 year of continuous use 1
• Calcium absorption issues: May contribute to bone health concerns 1, 2

Bone Health Concerns

• Hip fracture risk: 20% greater risk compared to non-users 1
• Other fractures: Increased risk of clinical spine and wrist fractures, particularly with high-dose and long-term therapy (>1 year) 1, 2, 3

Kidney Effects

• Acute tubulointerstitial nephritis (TIN): Can occur at any point during PPI therapy, presenting with varying symptoms from hypersensitivity reactions to non-specific decreased renal function 2, 3

Other Significant Concerns

• Lupus erythematosus: Both cutaneous and systemic lupus have been reported, either as new onset or exacerbation of existing disease 2, 3
• Interaction with clopidogrel: PPIs may reduce clopidogrel's effectiveness by inhibiting CYP2C19 activity 2
• Small intestinal bacterial overgrowth (SIBO): Long-term PPI use may lead to SIBO and associated bowel symptoms 6
• Potential risk of gastric malignancy: Symptomatic response to PPI therapy does not preclude the presence of gastric cancer 2, 3

Appropriate Use and Monitoring

Indications for Long-Term PPI Use

• Barrett's esophagus
• Clinically significant erosive esophagitis
• Gastroprotection in high-risk users of ASA/NSAIDs
• Secondary prevention of gastric/duodenal ulcers
• Hypersecretory states (e.g., Zollinger-Ellison syndrome) 4, 1

Management Recommendations

1. Regular review of ongoing indications with clear documentation of continued need 4
2. Use lowest effective dose for shortest duration possible 4, 2, 3
3. Consider de-prescribing for patients without definitive indications for chronic use 4
4. Monitor for deficiencies in high-risk patients:
   • Magnesium levels in patients on long-term therapy or taking medications that may cause hypomagnesemia 3
   • Vitamin B12 status, particularly in elderly patients on prolonged therapy 2, 3
   • Consider bone health monitoring in elderly patients on long-term therapy 1

De-prescribing Considerations

Patients Who Should NOT Be De-prescribed

• Those with Barrett's esophagus
• Patients with eosinophilic esophagitis
• Patients with idiopathic pulmonary fibrosis
• Those at high risk for upper GI bleeding:
  • History of upper GI bleeding
  • Taking multiple antithrombotics
  • Taking aspirin/NSAIDs with additional risk factors 4

De-prescribing Approach

• Either dose tapering or abrupt discontinuation can be considered 4
• Warn patients about potential rebound acid hypersecretion symptoms 4
• Consider step-down approach: twice-daily to once-daily dosing before attempting discontinuation 1

Common Pitfalls to Avoid

1. Inappropriate continuation without clear ongoing indication
2. Failure to recognize risk factors for adverse effects
3. Overlooking monitoring in high-risk patients
4. Abrupt discontinuation without warning patients about rebound symptoms
5. De-prescribing in high-risk patients who should remain on therapy
6. Ignoring symptoms of deficiencies (B12, magnesium, iron)
7. Missing gastric malignancy in patients with suboptimal response or early symptom relapse 4, 1, 2

The decision to use PPIs long-term should be based on a clear indication for continued use, with regular reassessment of the risk-benefit ratio for each individual patient.