Diagnostic Plan: Refractory GERD on Vonoprazan with Low LES Pressure

Clinical Summary

1. True acid breakthrough / persistent pathological reflux despite vonoprazan
2. Weakly acidic or non-acid (alkaline/bile) reflux
3. Esophageal hypersensitivity
4. Functional heartburn (no true reflux)
5. A structural/motility problem driving the low LES pressure
6. An alternate or co-existing diagnosis

Step 1 - Confirm Compliance and Optimise Before Further Testing

• Verify vonoprazan dose: 20 mg once daily for active symptoms (healing dose), taken correctly
• Rule out medications that further reduce LES pressure: calcium channel blockers, nitrates, theophylline, benzodiazepines, NSAIDs, anticholinergics - ask explicitly
• Review dietary triggers: fatty foods, chocolate, citrus, carbonated drinks, coffee, alcohol, late meals, lying down after eating
• Review lifestyle: smoking (nicotine lowers LES pressure), body position in bed (head of bed elevation?)
• Rule out recent weight gain even within normal BMI range (abdominal adiposity can occur at normal BMI)

Step 2 - Upper Endoscopy (EGD) with Biopsies (First Priority if Not Recently Done)

• Persistent symptoms despite potent acid suppression
• Halitosis (raises concern for mucosal disease, bile reflux, gastroparesis)
• Evaluate for complications and alternate diagnoses

Reference: Goldman-Cecil Medicine - "endoscopy is indicated for cases with persistent symptoms... to exclude eosinophilic esophagitis, pill-induced esophagitis, stricture, Barrett esophagus, and malignancy."

Step 3 - Ambulatory 24-hour pH-Impedance Monitoring (Most Important Functional Test)

• Use wireless Bravo capsule (48-96 hours) or nasal catheter
• Determines if there is true pathological acid exposure (DeMeester score, % time pH <4)
• If normal: favors functional heartburn or hypersensitivity, not true GERD

• Combined multichannel intraluminal impedance (MII) + pH catheter
• Detects both acid and non-acid reflux events
• Evaluates symptom-reflux association (Symptom Index, Symptom Association Probability)
• If non-acid reflux episodes are temporally linked to symptoms: weakly acidic or alkaline reflux is driving symptoms - acid suppression alone will not help

Reference: Harrison's 22nd Edition - "Combined esophageal pH and impedance testing using a transnasal catheter while on PPI therapy can define if a patient with persistent or atypical symptoms has esophageal hypersensitivity or regurgitation of nonacidic or weakly acidic fluid."

Step 4 - High-Resolution Esophageal Manometry (HRM)

• LES resting pressure (confirm degree and type of hypotension)
• Transient LES relaxations (TLESRs) - the most common mechanism of reflux even in low LES pressure states
• Esophageal body motility - ineffective esophageal motility (IEM) is common in GERD and impairs acid clearance
• Hiatal hernia - manometric identification and sizing
• Rule out major motor disorders that mimic GERD:
  • Achalasia - can present with regurgitation and be misdiagnosed as GERD (very important to exclude)
  • Hypercontractile esophagus (Jackhammer)
  • Distal esophageal spasm

Reference: Washington Manual - "Esophageal manometry, particularly HRM, may identify motor processes contributing to refractory symptoms." Yamada's Gastroenterology - "Esophageal manometry is useful for detecting major motor disorders or evaluating peristalsis before antireflux surgery."

Step 5 - Gastric Emptying Study (Rule out Gastroparesis)

• Halitosis + refractory symptoms on acid suppression despite H. pylori negativity raises concern
• Delayed gastric emptying increases gastric distension, raises intragastric pressure, worsens reflux, and can cause regurgitation and halitosis independent of acid
• 20% of gastroparesis patients have pain predominance rather than nausea/vomiting

• 4-hour solid-meal gastric scintigraphy (radiolabeled technetium-99m egg meal) - gold standard
• Alternative: 13C-octanoate breath test (non-radioactive)
• Alternative: Wireless motility capsule (SmartPill) - also assesses small bowel/colon transit

Step 6 - Laryngoscopy / ENT Evaluation

• Halitosis is present - while gastroparesis and reflux are common causes, laryngopharyngeal reflux (LPR) should be evaluated
• LPR may persist or worsen even with good esophageal acid control because brief pharyngeal acid exposures are sufficient for laryngeal injury
• ENT exam: posterior laryngeal erythema, cobblestoning, vocal cord edema (Belafsky Reflux Finding Score)
• Consider dedicated hypopharyngeal-esophageal multichannel pH-impedance or pharyngeal pH probe (Restech) if LPR is suspected

Step 7 - Rumination Syndrome Assessment

• Low LES pressure + regurgitation + refractory symptoms on acid suppression are all consistent with rumination syndrome which is commonly misdiagnosed as GERD
• Diagnostic criteria (Rome IV): recurrent regurgitation of recently ingested food, not preceded by retching, cessation when material becomes acidic
• Confirmed on HRM: characteristic pattern of intra-abdominal pressure rises immediately post-prandially preceding regurgitation
• Important because this is behavioural/physiotherapy-managed - not medication-managed

Step 8 - Additional Blood Tests

Diagnostic Algorithm Summary

Refractory symptoms on vonoprazan
              ↓
Step 1: Compliance check + medication/diet/lifestyle review
              ↓
Step 2: Upper endoscopy + biopsies
    → Barrett's? EoE? Hiatal hernia? Bile reflux? Stricture?
              ↓
Step 3: 24h pH-impedance monitoring (on therapy)
    → True acid reflux? Non-acid reflux? Hypersensitivity? Functional heartburn?
              ↓
Step 4: High-resolution esophageal manometry
    → Low LES confirmed? Achalasia excluded? IEM? Rumination pattern?
              ↓
Step 5: Gastric emptying scintigraphy
    → Gastroparesis contributing to reflux/halitosis?
              ↓
Step 6: ENT / laryngoscopy for LPR
              ↓
Step 7: Blood panel (gastrin, thyroid, HbA1c, celiac screen)

Key Diagnoses to Definitively Exclude in This Patient

Note on Vonoprazan Specifically