GASTROESOPHAGEAL REFLUX DISEASE (GERD)

MCh Long Answer

DEFINITION

ANATOMY AND PHYSIOLOGY OF THE ANTIREFLUX BARRIER

1. Lower Esophageal Sphincter (LES) - 4-5 cm long high-pressure zone; functionally distinct from surrounding esophagus; maintains a tonic resting pressure of 10-45 mmHg; relaxes completely with swallowing via vagally mediated inhibition
2. Crural diaphragm - augments LES pressure during inspiration and with increases in intra-abdominal pressure; attached to the LES via the phrenoesophageal ligament
3. Phrenoesophageal ligament - maintains the LES in its intra-abdominal position
4. Angle of His - the oblique angle of esophageal entry into the stomach creates a flap-valve mechanism
5. Intra-abdominal segment of the esophagus - positive intra-abdominal pressure augments LES closure

• Volume clearance by primary (swallow-initiated) and secondary (distension-triggered) peristalsis
• Neutralization of residual acid by weakly alkaline swallowed saliva (bicarbonate)
• Mucin and bicarbonate secreted from submucosal glands

EPIDEMIOLOGY

• Prevalence 10-20% in the Western world; <5% in Asia
• In the United States, up to 44% may have experienced GERD symptoms; 30% report weekly symptoms
• More common in North America than Europe; higher in northern Europe than southern Europe
• Risk factors: obesity (especially central/visceral obesity), family history, positive correlation in monozygotic twins, increasing age
• Associated conditions: hiatal hernia, pregnancy, scleroderma, delayed gastric emptying, Zollinger-Ellison syndrome
• Goldman-Cecil Medicine, p. 3061
• Robbins & Kumar Basic Pathology, p. 3653

PATHOPHYSIOLOGY

Mechanisms of Reflux

• The dominant mechanism in GERD
• Vagally mediated reflex triggered by gastric distension; occurs in absence of a swallow
• Duration 10-45 seconds vs. normal swallow-induced relaxation of <8 seconds
• Frequency is increased in GERD patients compared to normals

• A persistently hypotensive LES (<6 mmHg) allows free reflux, especially with increased intra-abdominal pressure (straining, bending, postprandially)
• LES tone reduced by: alcohol, tobacco, chocolate, fats, progesterone, anticholinergics, calcium channel blockers, theophylline, nitrates

• Overcomes normal LES pressure; seen with obesity, pregnancy, straining
• May lead to rumination and supragastric belching variants

• Axial and vertical separation of the crural diaphragm from the LES abolishes the diaphragmatic augmentation of LES pressure
• The hernia sac acts as a reservoir for acid which re-refluxes during subsequent LES relaxation on swallowing
• Increases esophageal acid exposure; is found in >50% of patients with severe esophagitis

• An unbuffered pocket of acid forms in the gastric cardia in the postprandial period, escaping the buffering effect of the meal
• In GERD patients, the acid pocket is larger and more proximal; when displaced into a hiatal hernia it becomes a major source of postprandial acid reflux

• Increased intra-abdominal fat raises intragastric pressure
• Increases frequency of TLESRs
• Enhances spatial separation of crural diaphragm from LES, predisposing to hiatal hernia
• The metabolic syndrome may have an independent pro-reflux effect

• Bile salts and trypsin from duodenal contents further damage esophageal mucosa, particularly relevant in patients with severe esophagitis and Barrett's esophagus

CLINICAL FEATURES

Typical (Esophageal) Symptoms

• Heartburn (pyrosis): retrosternal burning, the cardinal symptom; worst postprandially, with bending, lying supine; relieved by antacids
• Acid regurgitation: effortless return of sour/bitter-tasting gastric contents to the throat or mouth; pathognomonic of GERD
• Dysphagia and odynophagia: suggest esophagitis, peptic stricture, or Barrett's-associated cancer
• Water brash: sudden flooding of the mouth with watery/slightly salty fluid (reflex hypersalivation)
• Belching and bloating

Atypical (Extraesophageal) Syndromes

• Chest pain: may mimic angina pectoris; should be differentiated from cardiac cause
• Chronic cough: acid-triggered laryngeal reflex arc or direct micro-aspiration
• Hoarseness/laryngitis (reflux laryngitis): posterior laryngeal erythema, subglottic edema, contact ulcers/granulomas
• Asthma/bronchospasm: GERD found in ~80% of asthmatics; may trigger bronchospasm via vagal reflex or micro-aspiration
• Dental erosion: acid dissolves enamel of posterior dentition
• Chronic sinusitis, otitis media, pharyngitis
• Globus sensation: foreign body sensation in the throat

Alarm Symptoms (Red Flags requiring urgent investigation)

• Dysphagia (progressive), odynophagia
• Weight loss
• Hematemesis or melena
• Vomiting
• Anemia
• Age >45-50 with new-onset symptoms

INVESTIGATIONS

Step-up Approach

• A 4-8 week course of a PPI is a reasonable first approach in patients with typical symptoms without alarm features
• 70-80% response validates the diagnosis clinically

• Mandatory with: alarm symptoms, long-standing symptoms (>5-10 years) to screen for Barrett's, failure of PPI therapy, before antireflux surgery
• Findings graded by the Los Angeles Classification:
  • Grade A: One or more mucosal breaks <5 mm, not extending between two mucosal folds
  • Grade B: One or more mucosal breaks >5 mm, not extending between two folds
  • Grade C: Mucosal breaks extending between two or more folds, involving <75% of circumference
  • Grade D: Mucosal breaks involving ≥75% of the esophageal circumference
• Can identify: esophagitis, Barrett's esophagus, peptic stricture, Schatzki ring, tumors

• Objective measurement of esophageal acid exposure
• DeMeester score ≥14.7 is abnormal
• Normal: pH <4 for <4% of the 24-hour period
• Indicates: total acid exposure time, number of reflux episodes, correlation of symptoms with reflux (Symptom Index >50% is positive)
• Performed OFF PPI if diagnosing GERD de novo; ON PPI if evaluating adequacy of acid suppression

• Detects both acid (pH <4) and non-acid/weakly acidic reflux (impedance change without pH drop)
• Gold standard for diagnosing all forms of reflux, including those on PPI therapy
• Useful for patients with persistent symptoms on PPIs

• Not diagnostic of GERD but essential before antireflux surgery
• Identifies: LES pressure and relaxation, esophageal body peristalsis, hiatal hernia
• Rules out: achalasia, absent peristalsis (contraindications to Nissen fundoplication), scleroderma

• Demonstrates: hiatal hernia anatomy, strictures, motility disorders
• Can show free reflux but has low sensitivity (20-40%) for GERD diagnosis
• Useful preoperatively to assess esophageal length and anatomy

• Wireless capsule pH monitoring over 48-96 hours; better captures day-to-day variability
• More comfortable than catheter-based pH monitoring

• If delayed gastric emptying suspected as contributing factor

PATHOLOGY

Macroscopic (Endoscopic) Findings

• Erythema, friability, erosions, ulcerations (Los Angeles grade A-D)
• Peptic stricture (distal/Schatzki area)
• Barrett's esophagus: salmon-colored tongues or circumferential metaplastic mucosa proximal to the GEJ

Histology

• Mild GERD: often normal histology; earliest change is basal zone hyperplasia and elongation of lamina propria papillae
• Moderate-Severe: eosinophil recruitment to squamous mucosa (>15/HPF raises question of eosinophilic esophagitis), followed by neutrophil infiltration (indicates more severe injury)
• Basal cell hyperplasia and papillary elongation are markers of reflux injury
• Dilated intercellular spaces (DIS): ultrastructural finding; correlates with acid exposure even in non-erosive disease
• Robbins & Kumar Basic Pathology, p. 3655-3662

COMPLICATIONS

1. Reflux Esophagitis

• Spectrum from erythema to deep ulcers; Los Angeles Grade D with circumferential involvement can cause severe hemorrhage

2. Peptic Stricture

• Occurs in 10% of patients with untreated esophagitis
• Submucosal fibrosis from repeated injury and healing
• Presents as progressive dysphagia for solids; in distal esophagus (Schatzki ring)
• Treatment: esophageal dilation (bougie or balloon); PPI maintenance

3. Barrett's Esophagus

• Complicates chronic GERD in 7-10% of patients; represents the end-stage of GERD natural history
• Definition: Endoscopically visible replacement of normal stratified squamous epithelium by columnar metaplastic epithelium (intestinal metaplasia with goblet cells) proximal to the GEJ, confirmed on biopsy
• Classification: Long-segment (≥3 cm) and short-segment (<3 cm) Barrett's
• Risk factors for Barrett's: long-standing GERD, male sex, obesity, age >50, white race, smoking, nocturnal reflux symptoms
• Malignant potential: Annual risk of progression to adenocarcinoma is 0.5-1% per year per segment length; the dysplasia sequence is: Barrett's metaplasia → Low-grade dysplasia (LGD) → High-grade dysplasia (HGD) → Intramucosal carcinoma → Invasive adenocarcinoma
• Surveillance endoscopy: every 3-5 years for non-dysplastic Barrett's; annually for LGD
• Treatment of HGD: endoscopic mucosal resection (EMR) + radiofrequency ablation (RFA); esophagectomy reserved for submucosal/transmural invasion

4. Hemorrhage

• Acute or occult bleeding from erosions/ulcers; can cause iron deficiency anemia

5. Esophageal Adenocarcinoma

• Barrett's esophagus is the precursor; incidence has risen 6-fold over the past 3 decades in Western countries
• Prognosis depends on stage at diagnosis

6. Respiratory Complications

• Aspiration pneumonitis, lung abscess, pulmonary fibrosis (in severe, long-standing cases)

MANAGEMENT

Step 1: Lifestyle Modifications

• Weight reduction in overweight/obese patients (most evidence-based lifestyle intervention)
• Head of bed elevation (15-20 cm) or use of a wedge - for nocturnal symptoms
• Avoidance of precipitating foods: fatty foods, chocolate, coffee, alcohol, carbonated beverages, spicy foods, mint
• Postprandial posture: avoid lying down within 3 hours of meals
• Smoking cessation
• Avoidance of tight-fitting garments
• Small, frequent meals

Step 2: Medical Therapy

• Mylanta, Maalox: provide rapid but short-term symptom relief; neutralize acid
• Gaviscon (alginate + antacid): forms a viscous mechanical raft barrier floating on gastric contents; reduces postprandial proximal acid pocket exposure; used PRN

• Ranitidine 150 mg BD, Famotidine 20-40 mg BD, Cimetidine 400 mg BD
• Suppress histamine-mediated acid secretion; partial efficacy; useful for mild symptoms and as adjunct
• Develop tachyphylaxis with continuous use
• Superior to placebo; inferior to PPIs

• Irreversibly inhibit the H+/K+-ATPase pump (the final common pathway of acid secretion)
• Most potent acid-suppression agents available
• Agents: Omeprazole 20 mg, Lansoprazole 30 mg, Pantoprazole 40 mg, Rabeprazole 20 mg, Esomeprazole 20-40 mg; all given 30-60 minutes before the first meal of the day
• Standard dosing: Once daily for 4-8 weeks for non-erosive reflux disease
• Twice-daily dosing for Grade C/D esophagitis, refractory cases; results in more rapid endoscopic healing
• Long-term maintenance: Required for most patients with erosive esophagitis and Barrett's; titrate to lowest effective dose
• Efficacy: Superior to H2RAs for healing esophagitis and maintaining remission; no major differences in efficacy between different PPIs
• Long-term adverse effects (low magnitude): Hypomagnesemia, vitamin B12 deficiency, Clostridioides difficile infection, community-acquired pneumonia, hip fracture/metabolic bone disease, small intestinal bacterial overgrowth

• Vonoprazan (40 mg), Tegoprazan
• Reversibly inhibit the H+/K+-ATPase; faster onset of action, more sustained pH elevation, not dependent on meal timing
• Particularly effective for nocturnal acid breakthrough and refractory GERD
• A recent 2026 meta-analysis (Koo & Fass, PMID 41524830) confirmed P-CABs are superior to PPIs for nighttime GERD symptoms

• Metoclopramide: increases LES tone and promotes gastric emptying; dopamine antagonist
• High-quality evidence to support its use as monotherapy or adjunct is lacking; extrapyramidal adverse effects (tardive dyskinesia with long-term use) argue against routine use - Goldman-Cecil Medicine, p. 3137
• Domperidone: similar mechanism with less CNS penetration; useful in gastroparesis-associated GERD

• GABA-B agonist; reduces frequency of TLESRs
• Useful adjunct in refractory GERD with documented TLESRs; limited by CNS adverse effects (somnolence, dizziness)

Step 3: Endoscopic Therapies

• Stretta procedure: Radiofrequency energy applied to the LES to induce collagen deposition and LES remodeling; reduces TLESRs; moderate evidence
• Transoral incisionless fundoplication (TIF): Endoscopic reconstruction of the gastroesophageal valve; less invasive than surgery
• LINX device (Magnetic sphincter augmentation): A ring of interlinked titanium beads with magnetic cores encircling the LES; opens with swallowing pressure but resists reflux; laparoscopically placed; effective for PPI-dependent GERD without large hiatal hernia

Step 4: Surgical Treatment

1. Patient's preference to discontinue lifelong PPI therapy despite good symptomatic response
2. Persistent, troublesome regurgitation despite PPI therapy (PPIs do not stop volume reflux)
3. Documented non-acid/weakly acidic reflux as the cause of symptoms (PPI failure)
4. Complications: Barrett's esophagus, peptic stricture (in conjunction with treatment)
5. Young patients in whom lifelong pharmacological therapy is undesirable
6. Non-compliance or intolerance of medical therapy

• Objective documentation of pathologic reflux (pH ± impedance monitoring)
• HRM to assess LES pressure and esophageal body peristalsis (exclude achalasia; weak peristalsis may favor partial fundoplication)
• OGD to assess Barrett's, stricture, hiatal hernia anatomy
• Barium swallow to assess esophageal length (rule out short esophagus)
• Gastric emptying study if gastroparesis suspected

• Widely accepted as the gold standard antireflux procedure for patients with good esophageal motility
• Steps: 5-port laparoscopic approach; mobilization of the gastroesophageal junction; posterior crural repair (crural closure with non-absorbable sutures); complete posterior mobilization of the fundus (division of short gastric vessels - "floppy" Nissen); 360° wrap of the gastric fundus around the distal 2-3 cm of the esophagus; wrap sutured to the esophagus and stomach with 3 interrupted non-absorbable sutures; bougie (56-60 Fr) passed to calibrate wrap tension
• "Floppy" Nissen - key concept: a loose, 2-3 cm wrap over a large bougie prevents dysphagia and gas bloat syndrome
• Outcomes: >90% long-term symptomatic control; equivalent to continued PPI therapy for erosive esophagitis healing; however, persistent regurgitation responds better to surgery than medical therapy - Goldman-Cecil Medicine, p. 3186

• Toupet fundoplication (270° posterior wrap): preferred when esophageal peristalsis is weak or absent; lower incidence of postoperative dysphagia
• Dor fundoplication (180° anterior wrap): less antireflux efficacy; often used after Heller myotomy for achalasia
• Belsey Mark IV (240° anterior transthoracic wrap): transthoracic approach; historical interest; used for short esophagus requiring esophageal lengthening

• For patients with true esophageal shortening (short esophagus)
• A neoesophagus is fashioned from the gastric cardia using a stapler, then a fundoplication is performed around it

• Considered in morbidly obese (BMI >35) patients with GERD; addresses both obesity and reflux simultaneously; particularly advantageous over fundoplication in this population

• Laparoscopic approach is the standard; comparable efficacy to open surgery with less morbidity, shorter hospital stay, and faster recovery

• Dysphagia (early): common in first 6-8 weeks; usually resolves; rarely requires dilation
• Gas-bloat syndrome: inability to belch or vomit; bloating; caused by excessive wrap tightness
• Wrap failure/migration: herniation of the wrap into the chest; recurrent reflux symptoms; requires reoperation
• Esophageal perforation: rare intraoperative complication
• Slipped wrap: fundus slips below the wrap (Nissen slippage); causes recurrent reflux and dysphagia simultaneously
• Splenomegaly, splenic injury: during short gastric vessel division

SPECIFIC SITUATIONS

GERD in Pregnancy

• Extremely common (up to 80% of pregnancies); caused by progesterone-mediated LES relaxation and uterine pressure
• Managed with lifestyle modification, antacids (safe), sucralfate, H2RAs (Category B), and PPIs if severe (used with caution; omeprazole has most safety data)

GERD in Scleroderma

• Absent LES tone and esophageal aperistalsis; severe reflux
• Fundoplication is contraindicated due to aperistalsis; Roux-en-Y is preferred in selected cases
• Medical management is the mainstay; high-dose PPIs

GERD and Barrett's Esophagus

• PPIs are the medical therapy of choice; do NOT prevent progression to adenocarcinoma but reduce symptoms and maintain mucosal healing
• Antireflux surgery controls GERD symptoms in 90% of patients but Barrett's esophagus rarely regresses and cancer risk is not eliminated
• Endoscopic surveillance is mandatory regardless of whether medical or surgical therapy is chosen
• Yamada's Textbook of Gastroenterology, p. 1153

Refractory GERD (Persistent Symptoms on Double-Dose PPI)

1. Compliance and timing of PPI administration assessed
2. Impedance-pH monitoring ON PPI to document breakthrough acid reflux vs. non-acid reflux vs. functional heartburn
3. HRM to reassess LES and motility
4. Trial of P-CAB or adjunct baclofen
5. Consider surgical evaluation if pathologic acid/non-acid reflux confirmed

SUMMARY TABLE

REFERENCES

• Goldman-Cecil Medicine International Edition, Chapter 124: Esophageal Disorders (Gary W. Falk and David A. Katzka)
• Robbins & Kumar Basic Pathology, Chapter 13: Gastrointestinal Tract - Reflux Esophagitis and Barrett Esophagus
• Maingot's Abdominal Operations: Antireflux Surgery - Procedure Selection
• Sleisenger & Fordtran's Gastrointestinal and Liver Disease: Surgical Therapy for GERD
• Yamada's Textbook of Gastroenterology, 7th ed.: Barrett Esophagus - General Management Recommendations
• Koo TH, Fass R. Potassium-competitive acid blockers for nighttime GERD symptoms. Esophagus. 2026 Apr. PMID: 41524830 - Systematic review confirming P-CAB superiority over PPIs for nocturnal GERD symptoms.