What causes esophageal ulcers, particularly in patients with a history of gastroesophageal reflux disease (GERD) or Helicobacter pylori (H. pylori) infection?

What Causes Esophageal Ulcers

Esophageal ulcers are primarily caused by prolonged acid exposure from gastroesophageal reflux disease (GERD), with additional causes including medication injury (pill esophagitis), infections, and eosinophilic esophagitis. 1

Primary Causes

Gastroesophageal Reflux Disease (GERD)

• Peptic esophageal ulceration occurs when refluxed gastric acid and pepsin directly damage the esophageal mucosa, causing excavated defects where epithelial cells succumb to caustic effects 1
• The mechanism involves both direct mucosal injury from gastric juice and an immune-inflammatory response where inflammatory cytokines released from damaged epithelium trigger neutrophil migration and inflammation 2
• GERD develops when there is a decline in esophageal clearance mechanisms and anti-reflux barrier function, allowing gastric contents to remain in contact with the esophageal mucosa 2
• Transient lower esophageal sphincter relaxations independent of swallowing permit gastric contents to enter the esophagus, and when this becomes pathological (pH <4 for >6% of 24 hours), complications including ulceration can develop 3, 4

Medication-Induced Injury

• Pill esophagitis causes esophageal ulceration when medications become lodged in the esophagus and cause direct chemical injury 3
• This is a recognized cause of esophageal eosinophilia and ulceration distinct from GERD 3

Infectious Causes

• Fungal and viral infections can cause esophageal ulceration, particularly in immunocompromised patients 3
• These infections represent secondary causes that must be distinguished from primary GERD-related ulceration 3

Eosinophilic Esophagitis (EoE)

• EoE causes esophageal ulceration through immune-mediated inflammation triggered by food allergens, presenting with dysphagia, food impaction, and chest pain 3
• This condition affects predominantly atopic males (3:1 male-to-female ratio) and can occur at any age, though most commonly presents in childhood or the third to fourth decades of life 3
• Physical examination may identify comorbid allergic diseases including food allergy, asthma, eczema, and chronic rhinitis 3

Role of Helicobacter pylori

Protective Effect Against GERD

• H. pylori infection appears to provide protection against GERD rather than causing it, as the infection inhibits gastric acid production through chronic pangastritis and resulting atrophy of stomach mucosa 4, 5
• The protective mechanism may involve ammonia production by H. pylori bacteria or increased acid reabsorption by gastric epithelium 4
• Available data suggest H. pylori is not a risk factor for developing GERD and may represent a protective factor 5

Coexistence with Duodenal Ulcer Disease

• In patients with H. pylori-related duodenal ulcers, 44% have coexistent GERD, with 27.8% showing endoscopic oesophagitis and an additional 17% having abnormal pH exposure without visible oesophagitis 6
• Following H. pylori eradication in duodenal ulcer patients, the annual incidence of developing oesophagitis is 6%, with male gender and large waist circumference as risk factors 3
• The development of GERD after H. pylori eradication likely represents unmasking of pre-existing disease rather than de novo development, as patients return to normal lifestyle, gain weight, and discontinue antacids 6, 5

High-Risk Populations for Severe GERD and Complications

Pediatric Populations

• Children with neurologic impairment, history of repaired esophageal atresia, hiatal hernia, achalasia, chronic respiratory disorders, and obesity are at significantly higher risk 3
• In adults with repaired esophageal atresia, the incidence of endoscopic oesophagitis ranges from 8-19% and histological oesophagitis from 25-51%, with dysphagia affecting 39-85% of patients 3

Contributing Factors

• Global epidemics of obesity and asthma contribute to increased GERD prevalence, with GERD potentially serving as both underlying etiology and contributing factor to asthma control 3
• Hiatal hernia and more severe corpus gastritis predispose to reflux oesophagitis development 3

Complications of Esophageal Ulceration

Immediate Complications

• Esophageal ulcers can be complicated by hemorrhage, perforation, and penetration into the airway, though these occur uncommonly 1
• Bleeding is the most common complication of peptic ulcer disease and can present as hematemesis 7

Long-Term Sequelae

• Esophageal ulcers stimulate fibrous tissue production and collagen deposition, resulting in peptic stricture formation 1
• Ulcers can heal through metaplastic transformation where intestinal-type epithelium replaces damaged squamous cells, leading to Barrett's esophagus 1
• Barrett's esophagus represents a precursor lesion for esophageal adenocarcinoma, with evidence from observational studies and RCTs showing PPIs reduce this cancer risk 3

Clinical Pitfalls

Distinguishing GERD from Other Causes

• Eosinophilic esophagitis and GERD are not mutually exclusive and can coexist in the same patient, requiring careful evaluation 3
• A subgroup of patients with PPI-responsive esophageal eosinophilia demonstrates typical EoE symptoms and clinicopathologic response to PPIs, though the mechanism remains controversial 3
• Achalasia, eosinophilic gastroenteritis with esophageal involvement, and connective tissue diseases must be excluded as they can mimic GERD 3

Diagnostic Considerations

• Symptomatic response to PPI therapy does not preclude the presence of gastric malignancy, requiring additional follow-up and diagnostic testing in patients with suboptimal response or early symptomatic relapse 8
• In older patients, endoscopy should be considered to exclude malignancy 8
• Patients with suspected esophageal ulceration should undergo endoscopic evaluation to exclude anastomotic stricture, EoE, Barrett's esophagus, and esophageal cancer 3