What is the pathophysiology of Gastroesophageal Reflux Disease (GERD)?

Pathophysiology of Gastroesophageal Reflux Disease (GERD)

GERD results from abnormal reflux of gastric contents into the esophagus due to failure of the antireflux barrier, primarily through transient lower esophageal sphincter relaxations (TLESRs) and incompetence of the lower esophageal sphincter (LES), combined with impaired esophageal clearance mechanisms. 1, 2

Core Pathophysiologic Mechanisms

The Antireflux Barrier Failure

The primary defect in GERD involves breakdown of the natural antireflux barrier, which consists of the LES and the crural diaphragm at the esophageal hiatus 3, 4. The two main mechanisms of barrier failure are:

• LES incompetence occurs in approximately 80% of GERD patients with severe disease, characterized by persistently low LES pressure that allows continuous reflux of gastric contents 3
• Transient LES relaxations (TLESRs) represent inappropriate spontaneous relaxations of the LES independent of swallowing, which is the predominant mechanism in patients with normal baseline LES pressure 2, 5

Anatomical Contributors

Hiatal hernia is present in approximately 80% of patients with severe GERD and excessive esophageal acid exposure, disrupting the normal anatomical relationship between the LES and crural diaphragm 3. The presence and increasing size of hiatal hernia correlates with:

• Greater severity of esophageal acid exposure 3
• More visible mucosal damage 3
• Disruption of the intra-abdominal to intra-thoracic pressure gradient that normally protects against reflux 1

Impaired Esophageal Clearance

Once refluxate enters the esophagus, clearance mechanisms become critical to prevent mucosal damage 6:

• Primary and secondary peristalsis normally propel refluxed material back into the stomach 4, 6
• Bicarbonate-rich saliva neutralizes residual acid 6
• Deficient or delayed esophageal acid clearance allows prolonged mucosal contact with gastric contents, increasing injury risk 2, 5

The Refluxate Composition

The damaging potential of refluxed material depends on multiple factors 5, 6:

• Gastric acid concentration is the primary injurious component
• Proteolytic enzymes (pepsin) contribute to mucosal damage 5
• Bile acids from duodeno-gastro-esophageal reflux can cause injury even in the absence of acid 3
• The volume and frequency of reflux episodes determine total esophageal exposure 6

Gastric and Duodenal Dysfunction

GERD pathophysiology begins in the stomach where the refluxate is produced 6. Contributing factors include:

• Delayed gastric emptying increases the volume of gastric contents available for reflux 3
• Increased intra-abdominal pressure (from obesity, pregnancy, or other causes) promotes reflux 5, 1
• Duodenal contents refluxing into the stomach can create a more damaging mixed refluxate 3

Mucosal Integrity and Symptom Perception

The esophageal mucosa's response to refluxate determines clinical manifestations 6:

• Macroscopic changes include erosive esophagitis, strictures, and Barrett esophagus 1
• Microscopic alterations can occur without visible erosions, explaining symptoms in non-erosive reflux disease 1
• Peripheral and central neural mechanisms modulate symptom perception, with visceral hypersensitivity and hypervigilance amplifying symptom intensity even without increased acid exposure 1, 7

The Brain-Gut Axis

Stress and anxiety influence GERD through bidirectional brain-gut communication pathways involving neural, hormonal, and immunological mechanisms 7. This explains:

• Why chronic stress increases perception of reflux symptoms without changes in actual acid exposure 7
• How anxiety contributes to behavioral disorders like rumination and supragastric belching that worsen GERD 1, 7
• The role of psychological factors in treatment-refractory GERD 7

Extraesophageal Manifestations

GERD can cause symptoms through three distinct mechanisms beyond direct esophageal injury 1:

• Esophageal-bronchial reflex: Refluxate in the distal esophagus alone stimulates vagal afferents causing cough, without aspiration 1
• Microaspiration or macroaspiration: Direct irritation of the larynx and lower respiratory tract 1
• Laryngopharyngeal reflux: Backflow of gastric contents into the laryngopharynx causing hoarseness and throat symptoms 1

Critical Clinical Point

Up to 75% of patients with GERD-induced chronic cough have no gastrointestinal symptoms, making the diagnosis challenging 1. The absence of heartburn or regurgitation does not exclude GERD as the underlying cause of extraesophageal symptoms.

Pediatric Considerations

In infants and children, the pathophysiology differs slightly 1:

• Physiologic GER occurs through transient LES relaxations in up to 50% of healthy infants daily and typically resolves with maturation 1
• Pathologic GERD develops when reflux causes troublesome symptoms or complications 1
• High-risk populations (neurologic impairment, obesity, repaired esophageal atresia) have increased prevalence of severe GERD due to anatomical or functional abnormalities 1

Multifactorial Integration

The severity of GERD depends on the interplay of multiple pathophysiologic factors, with different mechanisms predominating in individual patients 6. This explains:

• Why some patients have severe symptoms with minimal mucosal damage (hypersensitivity predominates)
• Why others have extensive erosive disease with few symptoms (impaired sensation)
• Why treatment response varies based on which mechanisms are most active 6