What is the appropriate diagnostic work‑up and management for a 32‑year‑old woman with lifelong epigastric burning pain that improves with fasting, worsens with meals and lying supine, has lost 30 lb unintentionally, reports fatigue and generalized aches, and remains refractory to standard gastroesophageal reflux disease (GERD) and gastritis therapy despite prior endoscopies showing mild erosive gastritis, a small hiatal hernia, and reflux esophagitis?

Diagnostic Work-Up and Management for Refractory Epigastric Pain with Alarm Features

This patient requires urgent ambulatory pH monitoring off PPI therapy (96-hour wireless preferred) combined with esophageal manometry to definitively establish whether ongoing symptoms represent true PPI-refractory GERD, functional heartburn, or an alternative esophageal motor disorder—the 30-pound weight loss is an alarm feature that mandates this comprehensive evaluation before considering surgical intervention. 1

Critical Alarm Features Present

This patient exhibits multiple red-flag symptoms that distinguish her from uncomplicated GERD:

• Unintentional 30-pound weight loss over 3 years is an alarm feature with the best performance for identifying esophageal or gastric malignancy and mandates urgent investigation 1, 2
• Fatigue and decreased oral intake suggest systemic impact beyond simple reflux 2
• Progressive worsening over 6 years despite medical therapy indicates treatment failure requiring objective testing 1
• Lifelong symptoms since age 3 raise concern for structural abnormalities or alternative diagnoses 2, 3

Immediate Diagnostic Algorithm

Step 1: Repeat Upper Endoscopy with Comprehensive Evaluation

Perform upper endoscopy with specific attention to:

• Grade erosive esophagitis using Los Angeles classification (only Los Angeles B or greater confirms erosive reflux disease) 1
• Assess Hill grade of the flap valve at the diaphragmatic hiatus to evaluate anti-reflux barrier integrity 1
• Measure axial hiatal hernia length precisely, as size impacts surgical candidacy 1
• Inspect for Barrett's esophagus using Prague classification with biopsy if present (≥3 cm is considered long-segment) 1
• Obtain at least 5 esophageal mucosal biopsies to exclude eosinophilic esophagitis, which can masquerade as refractory GERD 1, 3
• Take at least 2 biopsies from both gastric antrum and body to maximize H. pylori detection sensitivity 2, 3

Critical pitfall: Los Angeles A esophagitis can be seen in healthy asymptomatic volunteers and does not constitute evidence of erosive reflux disease 1

Step 2: Esophageal Manometry

Perform high-resolution esophageal manometry before pH monitoring to:

• Rule out achalasia or distal esophageal spasm, which are alternative diagnoses that can present with chest pain and regurgitation 1
• Assess peristaltic function, which must be preserved for anti-reflux surgery candidacy 1
• Identify esophageal motor disorders that would contraindicate fundoplication 1

Step 3: Prolonged Wireless pH Monitoring Off PPI

Withhold PPI therapy for 2-4 weeks, then perform 96-hour wireless pH monitoring (preferred over 24-hour catheter-based) to:

• Confirm or rule out GERD objectively in this patient with refractory symptoms 1
• Phenotype the reflux pattern (acid exposure time, symptom-reflux correlation) 1
• Distinguish true PPI-refractory GERD from functional heartburn, where symptoms occur without pathologic acid exposure 1

Key diagnostic thresholds:

• Normal acid exposure time is <4.0% on all 4 days of 96-hour monitoring 1
• Abnormal acid exposure on ≥2 days predicts need for continued PPI therapy 1
• 96-hour monitoring accounts for day-to-day variability and has superior diagnostic accuracy compared to 24-hour studies 1

Additional Diagnostic Considerations

Exclude Chronic Mesenteric Ischemia

Consider CT angiography if the classic triad is present:

• Post-prandial pain (pain worsens with food intake—present in this patient) 2
• Unintentional weight loss (30 pounds—present) 2
• Food avoidance due to pain (decreased oral intake—present) 2

CTA provides 95-100% sensitivity and specificity for grading mesenteric vessel stenosis 2

Rule Out Gastric Cancer

• Age <55 years makes gastric cancer less likely but does not exclude it given the severe weight loss 1, 2
• Endoscopic visualization with biopsy is the definitive test 2, 3
• Gastric cancer is the most common cause of gastric outlet obstruction in adults 2

Management Strategy Based on Diagnostic Findings

If Erosive Esophagitis (Los Angeles B or Greater) or Long-Segment Barrett's Confirmed

• Optimize PPI dosing to twice-daily or switch to more potent agents (rabeprazole, esomeprazole, dexlansoprazole) 1
• These patients require long-term anti-reflux management and are unlikely to successfully discontinue therapy 1
• Surgical options (laparoscopic fundoplication, magnetic sphincter augmentation) are effective in carefully selected patients with proven severe erosive disease 1

If Normal Endoscopy but Abnormal pH Monitoring (Non-Erosive Reflux Disease)

• Personalize adjunctive pharmacotherapy to the reflux phenotype 1
• Alginate antacids for breakthrough symptoms 1
• Nighttime H2 receptor antagonists for nocturnal symptoms 1
• Baclofen for regurgitation-predominant symptoms 1
• Consider endoscopic therapies (transoral incisionless fundoplication) in carefully selected patients 1

If Normal Endoscopy and Normal pH Monitoring (Functional Heartburn)

This patient has reflux hypersensitivity or functional heartburn requiring:

• Pharmacologic neuromodulation (tricyclic antidepressants or SSRIs at neuromodulatory doses) 1
• Referral to behavioral therapist for cognitive behavioral therapy, hypnotherapy, or diaphragmatic breathing exercises 1
• Avoid anti-reflux surgery, as it will not benefit patients without objective reflux 1, 4

Critical Management Pitfalls to Avoid

• Never assume functional dyspepsia without first excluding organic disease through objective testing—persistent symptoms with weight loss strongly suggest alternative pathology 2, 3
• Do not proceed to anti-reflux surgery without confirming excessive esophageal acid exposure off PPI therapy, as surgery is only effective for proven GERD 1
• Missing cardiac causes of epigastric pain carries 10-20% mortality—obtain ECG and serial troponins to exclude acute coronary syndrome 2, 5
• Delaying endoscopy in patients with alarm features (weight loss, progressive symptoms) leads to poorer outcomes and missed malignancy 1, 2
• Clinical symptoms alone cannot reliably differentiate GERD, gastritis, esophagitis, and peptic ulcer disease—objective testing is mandatory 1, 2, 3

Interim Symptomatic Management During Work-Up

• Continue high-dose PPI therapy (omeprazole 40 mg twice daily, 30-60 minutes before meals) until diagnostic evaluation is complete 1
• Emphasize PPI safety to address patient concerns about long-term use 1
• Provide standardized educational material on GERD mechanisms, weight management, lifestyle modifications, and brain-gut axis relationships 1
• Elevate head of bed and avoid supine position for 3 hours after meals (symptoms worsen when lying supine) 1