Introduction
Peptic Ulcer Disease (PUD) is a prevalent gastrointestinal disorder characterized by sores or ulcers forming in the lining of the stomach or the first part of the small intestine (duodenum). Understanding the multifactorial etiology and complex pathogenesis of PUD is essential for effective prevention and treatment. This review examines the diverse causes and mechanisms behind PUD, extending beyond the well-known roles of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs (NSAIDs).
Etiology of Peptic Ulcer Disease
Helicobacter pylori Infection
Helicobacter pylori is a spiral-shaped bacterium that colonizes the stomach lining, causing chronic inflammation and leading to ulcer formation. More than 90% of duodenal ulcers and approximately 70% of gastric ulcers are associated with H. pylori infection.
- Pathogenesis: H. pylori disrupts the mucosal barrier by producing urease, which hydrolyzes urea to ammonia, neutralizing stomach acid and allowing the bacterium to survive. It also induces an inflammatory response, damaging the gastric epithelium. The bacterium’s virulence factors, such as CagA and VacA, are critical in this process. CagA is associated with increased inflammation and a higher risk of ulceration and gastric cancer, while VacA induces cell damage and apoptosis.
- Epidemiology: H. pylori infection is more common in developing countries, with a prevalence of up to 80% in some regions. Improved sanitation and antibiotic use have led to a decline in prevalence in developed countries. Transmission often occurs in childhood, with crowded living conditions and poor hygiene being significant risk factors.
NSAID Use
NSAIDs, including aspirin, are another major cause of PUD. They inhibit cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis, which is essential for maintaining the gastric mucosal barrier.
- Mechanism: NSAIDs cause direct mucosal damage and impair mucosal defense mechanisms by inhibiting prostaglandin production, leading to reduced mucus and bicarbonate secretion and increased gastric acid secretion. The suppression of prostaglandin synthesis by NSAIDs disrupts the mucosal barrier, making the stomach lining more susceptible to damage by gastric acid. Additionally, NSAIDs can cause topical injury to the gastric epithelium.
- Risk Factors: Concurrent use of corticosteroids, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs), and a history of PUD increases the risk of NSAID-induced ulcers. Other risk factors include older age, high-dose or long-term NSAID use, and the presence of comorbid conditions such as cardiovascular disease and rheumatoid arthritis.
Other Contributing Factors
- Zollinger-Ellison Syndrome: A rare condition characterized by gastrin-secreting tumors (gastrinomas) leading to excessive gastric acid production and recurrent ulcers. Gastrinomas are typically found in the pancreas or duodenum and result in markedly elevated levels of gastrin, causing hypersecretion of gastric acid and severe peptic ulceration. Patients with Zollinger-Ellison syndrome often present with multiple, refractory ulcers and require specialized diagnostic and therapeutic approaches.
- Physiological Stress: Severe stress from trauma, surgery, or critical illness can cause stress ulcers due to mucosal ischemia and impaired defense mechanisms. Stress-related mucosal disease (SRMD) often occurs in critically ill patients and is characterized by superficial mucosal erosions. Factors contributing to SRMD include hypoperfusion of the gastrointestinal tract, reperfusion injury, and the release of inflammatory mediators.
- Lifestyle Factors: Smoking, excessive alcohol consumption, and a diet high in spicy foods may exacerbate ulcer formation. Smoking has been shown to impair mucosal healing and increase gastric acid secretion, while alcohol can directly damage the gastric mucosa and disrupt its barrier function. Although spicy foods are often blamed for causing ulcers, they are more likely to exacerbate existing symptoms rather than being a direct cause.
- Genetic Factors: There is evidence suggesting a genetic predisposition to PUD. A family history of ulcers increases the risk, indicating that genetic factors may influence susceptibility.
- Infectious Agents Other than H. pylori: Besides H. pylori, other infectious agents like cytomegalovirus (CMV) and herpes simplex virus (HSV) have been implicated in ulcer formation, particularly in immunocompromised individuals.
- Medications: Beyond NSAIDs, other medications such as bisphosphonates, potassium chloride, and certain chemotherapeutic agents can cause mucosal damage and lead to PUD.
Pathophysiology of Peptic Ulcer Disease
Imbalance Between Aggressive and Protective Factors
PUD results from an imbalance between aggressive factors (gastric acid, pepsin, bile salts) and protective factors (mucus, bicarbonate, blood flow, prostaglandins).
- Aggressive Factors: Excess gastric acid and pepsin can digest the mucosal lining, leading to ulcer formation. Bile salts can disrupt the mucosal barrier and exacerbate the damage. Pepsin, a proteolytic enzyme activated by gastric acid, plays a significant role in mucosal injury and ulcer formation. Factors such as hypersecretion of gastric acid, increased pepsin activity, and bile reflux into the stomach contribute to the pathogenesis of PUD.
- Protective Factors: Mucus and bicarbonate form a protective barrier on the mucosal surface. Adequate blood flow delivers oxygen and nutrients essential for mucosal repair and maintains an optimal pH. Prostaglandins play a crucial role in maintaining mucosal integrity by stimulating mucus and bicarbonate secretion, enhancing mucosal blood flow, and promoting epithelial cell regeneration. Disruption of these protective mechanisms can lead to ulcer formation.
Role of Helicobacter pylori
H. pylori infection disrupts the balance by increasing gastric acid secretion and inducing an inflammatory response. The bacterium's virulence factors, such as CagA and VacA, further damage the mucosa. H. pylori also interferes with the normal regulation of gastric acid secretion, leading to hypergastrinemia and increased acid output. The chronic inflammation caused by H. pylori infection can result in atrophic gastritis and intestinal metaplasia, further increasing the risk of ulceration and gastric cancer.
Impact of NSAIDs
NSAIDs compromise the mucosal defense by inhibiting COX-1, which is involved in the production of protective prostaglandins. This results in reduced mucus and bicarbonate secretion, impaired blood flow, and increased acid secretion. The direct topical effect of NSAIDs on the gastric epithelium can cause additional mucosal injury. The combined effects of systemic prostaglandin inhibition and topical mucosal damage significantly increase the risk of PUD in NSAID users.
Pathophysiological Insights from Studies
- Inflammatory Mediators: Recent studies highlight the role of inflammatory cytokines, such as TNF-α and IL-1β, in the pathogenesis of PUD. These cytokines contribute to mucosal inflammation and ulcer formation by promoting leukocyte infiltration and disrupting the epithelial barrier.
- Epithelial Restitution and Angiogenesis: The process of epithelial restitution and angiogenesis is crucial for ulcer healing. Growth factors like VEGF and EGF are essential for promoting cell proliferation and new blood vessel formation in the ulcer bed. Impaired angiogenesis and delayed restitution can lead to chronic ulceration.
Conclusion
Understanding the etiology and pathogenesis of peptic ulcer disease is crucial for developing effective prevention and treatment strategies. While Helicobacter pylori infection and NSAID use remain the primary causes, other factors such as Zollinger-Ellison syndrome, physiological stress, genetic predisposition, and lifestyle choices also play significant roles. By addressing these underlying causes and maintaining a balance between aggressive and protective factors, healthcare providers can better manage and prevent peptic ulcer disease.
References
- Lanas, Angel, and Francis KL Chan. "Peptic ulcer disease." The Lancet 390.10094 (2017): 613-624.
- Kavitt, Robert T., et al. "Diagnosis and treatment of peptic ulcer disease." The American journal of medicine 132.4 (2019): 447-456.
- Sverdén, Emma, et al. "Peptic ulcer disease." BMJ 367 (2019).
