What is the term for Gastroesophageal Reflux Disease (GERD) that does not respond to treatment with Proton Pump Inhibitors (PPIs)?

Refractory GERD: Definition and Management

Gastroesophageal reflux disease (GERD) that does not respond to proton pump inhibitor (PPI) therapy is termed "PPI-refractory GERD" or "refractory GERD." 1 This condition affects up to 40% of patients treated with PPIs and represents a significant clinical challenge.

Diagnostic Criteria for PPI-Refractory GERD

PPI-refractory GERD is defined by:

• Persistence of troublesome GERD symptoms despite PPI optimization for at least 8 weeks
• Ongoing documented pathologic gastroesophageal reflux 2

The American Gastroenterological Association (AGA) recommends the following approach to confirm the diagnosis:

1. Verify PPI compliance and proper administration

   • Ensure medication is taken 30-60 minutes before meals
   • Rule out poor compliance as a cause of treatment failure

2. Objective testing

   • Ambulatory reflux monitoring (preferably pH-impedance) to confirm GERD diagnosis 1
   • Upper endoscopy to evaluate for erosive esophagitis, Barrett's esophagus, or alternative diagnoses 1

Mechanisms of PPI-Refractory GERD

Several mechanisms may contribute to PPI failure:

• Weakly acidic or non-acid reflux - PPIs reduce acid but don't prevent reflux events 1
• Esophageal hypersensitivity - Normal reflux events perceived as painful 1
• Delayed gastric emptying - Contributing to increased reflux episodes
• Functional esophageal disorders - May overlap with GERD 3
• Behavioral disorders - Supragastric belching or rumination 3
• Nocturnal reflux - May be inadequately controlled by once-daily PPI 4

Management Algorithm for PPI-Refractory GERD

Step 1: Optimize PPI Therapy

• Increase to twice daily dosing 1, 5
• Consider switching to a different PPI with different metabolism 6
• Ensure proper timing (30-60 minutes before meals)

Step 2: Diagnostic Evaluation

• Upper endoscopy to rule out alternative diagnoses and assess for complications 1
• pH-impedance monitoring while on PPI therapy to determine if symptoms correlate with acid or non-acid reflux events 1
  • If positive correlation: true refractory GERD
  • If negative correlation: consider functional disorders

Step 3: Adjunctive Pharmacotherapy

Based on the GERD phenotype and diagnostic findings:

• For nocturnal symptoms: Add H2-receptor antagonist at bedtime 5
• For breakthrough symptoms: Alginate-containing antacids 1, 5
• For regurgitation or belch-predominant symptoms: Baclofen (GABA-B receptor agonist) 1, 5
• For coexistent gastroparesis: Prokinetics 1
• For esophageal hypersensitivity: Neuromodulators (tricyclic antidepressants, SSRIs) 1, 5

Step 4: Consider Non-Pharmacological Options

For patients with objectively documented GERD who remain symptomatic despite optimal medical therapy:

• Surgical options:
  • Laparoscopic fundoplication 1, 5
  • Magnetic sphincter augmentation (LINX) 1, 5
• Endoscopic options:
  • Transoral incisionless fundoplication (TIF) 1, 5
  • Radiofrequency therapy (Stretta) 6

Special Considerations

Extraesophageal Symptoms

For patients with chest pain, throat, or respiratory symptoms:

• pH/impedance monitoring is essential to detect pathological acid or non-acid reflux 1
• Lack of response to PPI therapy predicts lack of response to anti-reflux surgery 1

Functional Heartburn vs. Refractory GERD

• Patients without erosive disease on endoscopy and with physiologic acid exposure often have functional esophageal disorders 5
• These patients benefit more from neuromodulation or behavioral interventions than from escalation of acid suppression 5

Common Pitfalls to Avoid

1. Assuming GERD is ruled out if PPI therapy fails - Some patients require more intensive or longer therapy 5

2. Overuse of PPIs without documented GERD - Objective testing is essential before long-term PPI therapy 5

3. Overlooking behavioral disorders - Supragastric belching and rumination can mimic GERD symptoms 3

4. Proceeding to anti-reflux surgery without objective evidence of GERD - Lack of response to PPI therapy predicts poor surgical outcomes 1

5. Failing to consider eosinophilic esophagitis - This can mimic GERD and be PPI-responsive in some cases 1

By following this structured approach to diagnosis and management, clinicians can effectively address the challenging clinical problem of PPI-refractory GERD and improve outcomes for affected patients.