Peptic ulcer causes

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2017 ACG Guidelines for Peptic Ulcer Disease
Guidelines for the Indications to Test for, and to Treat, H. pylori Infection
Guidelines for First line Treatment Strategies of Peptic Ulcer Disease for Providers in North America
Guidlines for factors that predict the successful eradication when treating H. pylori infection
Guidelines to document H. pylori antimicrobial resistance in the North America
Guidelines for evaluation and testing of H. pylori antibiotic resistance
Guidelines for when to test for treatment success after H. pylori eradication therapy
Guidelines for penicillin allergy in patients with H. pylori infection
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Manpreet Kaur, MD [3]

Overview

Peptic ulcer disease (PUD) results from an imbalance between mucosal defense and aggressive factors such as gastric acid, pepsin, and exogenous injury.

The principal causes are:

• Helicobacter pylori infection, about 42% of cases.
• Aspirin or NSAID use, about 36% of cases.
• Idiopathic ulcers, unrelated to either, about 22% of cases.

H. pylori and NSAIDs independently increase ulcer risk and act synergistically. PUD is rare when neither is present.

Less common causes include:

• Stress-related mucosal disease in critical illness.
• Zollinger-Ellison syndrome.
• Malignancy.
• Rare inflammatory, infectious, and anatomic causes.

Causes

Summary of causes

Category	Cause	Contribution / strength of association	Clinical clues
Infectious	Helicobacter pylori	About 42% of PUD. Historically found in 90–95% of duodenal ulcers and 70–90% of gastric ulcers.	More strongly linked to duodenal ulcer. cagA-positive strains carry higher risk.
Drug-induced	NSAIDs, including low-dose aspirin	About 36% of PUD. Independent of, and synergistic with, H. pylori.	Many NSAID ulcers are asymptomatic until bleeding or perforation.
Idiopathic	H. pylori-negative, NSAID-negative ulcer	About 22% of PUD, and rising.	Diagnosis of exclusion. High risk of rebleeding and death.
Critical illness	Stress-related mucosal disease	Mucosal lesions are found in 75–100% of ICU patients. Clinically important bleeding occurs in 1–6%.	Mechanical ventilation for more than 48 hours, coagulopathy.
Acid hypersecretory	Zollinger-Ellison syndrome (gastrinoma)	Rare.	Multiple, refractory, or atypically located ulcers.
Malignant	Gastric cancer, gastric lymphoma	Uncommon. Must be excluded.	Refractory or non-healing gastric ulcer.
Other infectious	Cytomegalovirus, herpes simplex virus, Helicobacter heilmannii	Rare.	Viral causes mainly in immunocompromised hosts.
Inflammatory / infiltrative	Crohn's disease, eosinophilic gastroduodenitis, systemic mastocytosis	Rare.	Systemic or extraintestinal features of the underlying disease.
Iatrogenic / anatomic	Radiation injury, anastomotic (marginal) ulcer, Cameron ulcer	Rare.	Prior radiation or gastric surgery. Cameron ulcer occurs with a large hiatal hernia.

Helicobacter pylori infection

Helicobacter pylori is the most common identifiable cause of PUD.

Global burden. About 57% (95% CI 44–68%) of PUD worldwide is attributable to H. pylori. This corresponds to about 3.5 million cases that could potentially be prevented by eradication.

Infection is necessary but not sufficient. An infected person has an estimated 10–20% lifetime risk of PUD, at least 3–4 times higher than an uninfected person. In a Danish population-based cohort, H. pylori infection was a major independent risk factor for PUD (OR 4.3, 95% CI 2.2–8.3).

Strain virulence. Infection with cagA-positive strains raises ulcer risk above that of cagA-negative strains. In a nested case-control study, people seropositive for both H. pylori and CagA had odds ratios of:

• 5.8 (95% CI 1.1–30.0) for duodenal ulcer.
• 4.4 (95% CI 1.8–10.5) for gastric ulcer.

The gastritis pattern determines ulcer location.

• Antral-predominant gastritis suppresses somatostatin and increases gastrin release. This causes acid hypersecretion and predisposes to duodenal ulcer.
• Corpus-predominant gastritis or pangastritis leads to gastric atrophy and low acid output. It predisposes to gastric ulcer and gastric cancer.
• In a prospective cohort of 1,526 Japanese patients, gastric cancer developed in patients with gastric ulcer but in none of those with duodenal ulcer.

NSAID and aspirin use

NSAIDs, including low-dose aspirin, are an etiologic factor in about 36% of PUD.

Mechanisms of injury. NSAIDs injure the mucosa in two ways:

• Local (topical) toxicity to the epithelium.
• Systemic inhibition of cyclooxygenase-1, which depletes gastroprotective prostaglandins.

Interaction with H. pylori. A meta-analysis of 16 studies of 1,625 NSAID users found:

• Uncomplicated PUD was more common in H. pylori-positive than H. pylori-negative users (41.7% vs 25.9%; OR 2.12, 95% CI 1.68–2.67).
• Compared with H. pylori-negative non-users, H. pylori-infected NSAID users had an ulcer OR of 61.1.
• H. pylori infection increased the risk of ulcer bleeding 1.79-fold, and NSAID use increased it 4.85-fold.

Clinical presentation. Most NSAID-induced ulcers are asymptomatic, so the first presentation may be a complication.

Idiopathic ulcers

Idiopathic ulcers are H. pylori-negative and NSAID-negative.

Frequency. They account for about 22% of PUD. Their share has risen as H. pylori prevalence has fallen:

• In Hong Kong, idiopathic ulcers rose from 4.2% to 18.8% of bleeding ulcers between 1997–1998 and 2000.
• In Asia, the proportion reached 10–30% in studies from the 2000s.

Distinguishing true from pseudo-idiopathic ulcers. Apparent idiopathic ulcers must be separated from:

• False-negative H. pylori testing. Using two or more diagnostic methods increases sensitivity. Serology is useful in patients taking proton pump inhibitors.
• Surreptitious NSAID or aspirin use. Platelet cyclooxygenase activity testing can confirm it.

Proposed mechanisms. The pathogenesis of true idiopathic ulcers is not established.

Prognosis. H. pylori-negative idiopathic bleeding ulcers carry a high incidence of recurrent bleeding and mortality.

Other specific causes

• Stress-related mucosal disease.
  • Upper gastrointestinal mucosal lesions are present in 75–100% of ICU patients, but only 1–6% develop clinically important bleeding.
  • Bleeding risk is predicted by mechanical ventilation for more than 48 hours and by coagulopathy.
  • Stress-ulcer bleeding carries an estimated mortality of 40–50%, mostly from the underlying illness.
• Acid hypersecretory states. Zollinger-Ellison syndrome is a rare but important cause of refractory gastroduodenal ulcers.
• Malignancy. Malignancy is a recognized cause of refractory ulcers. Gastric cancer and gastric lymphoma must be excluded in non-healing gastric ulcers.
• Rare causes. These include:
  • Crohn's disease.
  • Eosinophilic gastroduodenitis.
  • Systemic mastocytosis.
  • Radiation injury.
  • Cytomegalovirus or herpes simplex virus infection.
  • Helicobacter heilmannii colonization.
  • Cameron ulcers with a large hiatal hernia.
  • Anastomotic (marginal) ulcers after gastric resection.

Contributing factors

These factors increase ulcer risk but are not sole causes. Details belong in the risk factors microchapter.

• Cigarette smoking
  • Independent risk factor for PUD (OR 3.8, 95% CI 1.7–9.8).
  • Delays ulcer healing.
• Psychosocial and environmental factors. Risk is increased by psychological stress, family history of PUD, and adverse childhood circumstances such as crowded living conditions and poor water quality.
• Disaster-related stress. Evidence comes from the 2011 Great East Japan Earthquake:
  • PUD incidence rose 1.5-fold and hemorrhagic ulcers 2.2-fold.
  • Non-H. pylori, non-NSAID ulcers rose from 13% to 24% of cases.
  • Living in a refugee shelter independently predicted ulcer bleeding (OR 4.4, 95% CI 2.1–9.6).

Clinical pearls for etiologic evaluation

• Establish H. pylori status in every patient with PUD. Take a detailed, repeated NSAID and aspirin history that includes over-the-counter products.
• Do not accept a single negative H. pylori test while the patient is on a PPI. Use two or more methods, or serology.
• Before labeling an ulcer idiopathic, exclude:
  • False-negative H. pylori testing.
  • Occult NSAID or aspirin use.
  • Malignancy.
  • Zollinger-Ellison syndrome.
• A silent ulcer, especially one presenting with bleeding or perforation, should raise suspicion for NSAID use.