What is the pathophysiology of Peptic Ulcer Disease (PUD)?

Pathophysiology of Peptic Ulcer Disease (PUD)

The pathophysiology of peptic ulcer disease (PUD) is fundamentally characterized by an imbalance between aggressive factors (gastric acid and pepsin) and defensive mucosal protective mechanisms, leading to acid-peptic damage of the gastroduodenal mucosa and subsequent ulceration. 1, 2

Key Pathophysiological Mechanisms

Mucosal Barrier Disruption

• PUD occurs due to acid-peptic damage to the gastroduodenal mucosa, resulting in mucosal erosion that exposes underlying tissues to the digestive action of gastroduodenal secretions 1
• Ulceration represents tissue loss that breaches the muscularis mucosae, which never develops spontaneously in healthy gastroduodenal mucosa 2
• Defensive factors that normally protect the mucosa include:
  • Phospholipid surfactant layer covering the mucus bicarbonate gel
  • Mucus bicarbonate layer covering the epithelium
  • Tight junctional structures between epithelial cells that restrict proton permeability
  • Epithelial trefoil peptides that contribute to healing after injury 2

Helicobacter pylori Infection

• H. pylori is the dominant etiologic factor in PUD, causing more than 90% of ulcers when NSAIDs are excluded 3, 4
• H. pylori disrupts the protective mucous layer, allowing the underlying epithelium to be injured by gastric acid 4
• Despite high prevalence of H. pylori (>70% in some underdeveloped societies), less than 1% develop PUD, suggesting additional factors are involved 3
• This selectivity has been attributed to:
  • Pathogenic differences between H. pylori strains
  • Relative proportion of different strains in a given patient
  • Genetic host factors that favor colonization
  • Different immunologic responses that result in PUD in some individuals while only causing gastritis in others 3

Acid-Pepsin Secretion

• Historically, acid-peptic aggression was considered the overwhelming cause of PUD, supported by the dictum "no acid, no ulcer" 2
• Acid hypersecretion is an important factor in duodenal ulcer pathogenesis, with increased acid-pepsin secretion in response to various stimuli 5
• Pepsinogen I levels are better predictors of PUD than H. pylori in individual patients 3

Defensive Mechanism Impairment

• The emphasis in understanding PUD has shifted from aggressive factors to weakening/failing defensive factors that increase vulnerability of the gastroduodenal mucosa 2
• In chronic gastric ulcer of the corpus, defective defense mechanisms such as duodenogastric reflux and atrophic gastritis appear more important than aggressive factors 5

Medications and Environmental Factors

• NSAIDs and aspirin cause mucosal injury primarily by reducing mucosal defense mechanisms 2, 6
• Drug-induced ulcers occur more commonly in the stomach than the duodenum 5
• Other environmental factors contributing to PUD include:
  • Smoking
  • Emotional stress (potentially increasing acid secretion and/or decreasing mucosal defense)
  • Alcohol consumption 1, 6

Genetic Factors

• Genetic and familial factors play a role in duodenal ulcer development 5
• Heterogeneity is an important consideration in PUD pathophysiology, with abnormal functions clustered in subgroups rather than present in all patients 5

Clinical Manifestations Related to Pathophysiology

Acute vs. Chronic Ulcers

• Acute ulcers and erosions typically present with gastrointestinal bleeding or perforation, with local ischemia being the earliest recognizable gross lesion 5
• Chronic or recurrent true peptic ulcers (penetrating the muscularis mucosae) usually present with abdominal pain 5
• Approximately 50% of patients experience recurrence within a year if anti-ulcer medication is stopped 5

Complications

• Complications of PUD include perforation and bleeding, with perforation being less common (perforation:bleeding ratio of approximately 1:6) 1
• Perforation is the most common indication for emergency operation and causes about 40% of all ulcer-related deaths 1
• CT findings of perforation include extraluminal gas (97%), fluid or fat stranding along the gastroduodenal region (89%), ascites (89%), focal wall defect and/or ulcer (84%), and wall thickening (72%) 1

Therapeutic Implications

• Understanding the pathophysiology has led to targeted therapies:
  • Acid suppression with PPIs, H2-receptor antagonists
  • H. pylori eradication with antibiotics
  • Mucosal protective agents 2
• H. pylori eradication reduces ulcer recurrence, although controversies exist regarding eradication in patients requiring NSAIDs 3
• Eradication of H. pylori in PUD may cause reflux esophagitis in 25% of patients 3