Peptic Ulcer Disease (PUD) - Causes and Treatment (Latest Guidelines 2024)

Definition

Epidemiology

• Lifetime prevalence: 8-14% of the general population
• Both incidence and prevalence have declined 31% worldwide from 1990-2019, largely due to better understanding and treatment of H. pylori and NSAID risks
• Peak incidence of complicated disease (hospitalization): ages 65-74
• PUD is the most common cause of upper GI bleeding
• Annual cost in the US: ~$6 billion USD - Yamada's Gastroenterology 7e; Sabiston Surgery, 21e

Pathophysiology: The Balance of Protective vs. Damaging Factors

Causes / Etiology

1. Helicobacter pylori (Most Common)

• Global prevalence of H. pylori ~43%
• Associated with 90% of duodenal ulcers and 70-90% of gastric ulcers
• H. pylori is a spiral-shaped, flagellate, microaerophilic gram-negative bacterium
• Mechanism: produces urease (splits urea → ammonia + bicarbonate), creating an alkaline microenvironment for survival in acidic gastric milieu
• Releases cytotoxins (e.g., CagA toxin) that destroy the mucosal barrier and underlying cells
• Its flagella allow movement through the mucus layer; mucolytic enzymes facilitate penetration
• When eradicated, ulcer recurrence becomes extremely rare - Sabiston Surgery 21e

2. NSAIDs / Aspirin (Second Most Common)

• NSAIDs inhibit cyclooxygenase (COX), reducing prostaglandin synthesis
• Prostaglandins are key mucosal protectants (stimulate mucus, bicarbonate, mucosal blood flow)
• Risk is dose-dependent and increased with advanced age, corticosteroid co-use, anticoagulants, prior PUD history

3. Zollinger-Ellison Syndrome (ZES)

• Gastrin-secreting tumor (gastrinoma), causing massive acid hypersecretion
• Think ZES when ulcers are multiple, refractory, or in unusual locations (distal duodenum/jejunum)

4. Other/Less Common Causes

• Systemic mastocytosis (histamine-driven)
• Crohn's disease
• Bisphosphonates (especially alendronate), SSRIs, potassium chloride, clopidogrel, mycophenolate
• Infections: HSV, CMV, EBV, tuberculosis, syphilis
• Ischemia, radiation, hypoxia, gastric bypass surgery
• Stress ulcers (ICU patients, burns, head trauma)
• Idiopathic ("non-H. pylori, non-NSAID ulcers" - increasing in developed countries)

Gastric vs. Duodenal Ulcers - Key Differences

Clinical Presentation

• Most common: epigastric pain/burning ("dyspepsia"), often periodic
• Duodenal ulcer pain: often relieved by food, antacids; wakes patient at night
• Gastric ulcer pain: worsened by eating
• Nausea, early satiety, bloating
• Many patients are asymptomatic until a complication develops

Complications (the "4 Ps")

Diagnosis

1. Endoscopy (EGD) - gold standard; allows direct visualization, biopsy (mandatory for gastric ulcers to rule out malignancy), and treatment of bleeding
   • 4-quadrant biopsy of gastric ulcers: sensitivity rises from 70% (1 biopsy) to 95% (4 biopsies) to 98% (7 biopsies)
2. H. pylori testing (all PUD patients must be tested):
   • Non-invasive: urea breath test (gold standard for diagnosis and test-of-cure), stool antigen test
   • Invasive (via endoscopy): rapid urease test, histology, culture
3. Plain abdominal X-ray: free air under diaphragm if perforation (upper GI contrast/barium is CONTRAINDICATED with perforation)

Treatment (2024 ACG & Current Guidelines)

Step 1: General Measures

• Stop NSAIDs if possible (or switch to COX-2 selective inhibitor + PPI)
• Smoking cessation (impairs ulcer healing)
• Avoid alcohol
• Avoid triggers

Step 2: Acid Suppression (Core of Therapy)

Proton Pump Inhibitors (PPIs) - First-Line

• Mechanism: irreversibly bind the H+/K+-ATPase (proton pump) at the parietal cell; require acid activation in secretory canaliculus
• Healing rate: 85% at 4 weeks, 96% at 8 weeks (superior to H2RAs)
• Examples: omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole
• Duration: 4-8 weeks for duodenal ulcers; 8-12 weeks for gastric ulcers
• Maintenance PPI: indicated for large ulcers (>2 cm), failed H. pylori eradication, or required ongoing NSAID/aspirin use

H2 Receptor Antagonists (H2RAs) - Second-Line

• Competitive inhibition of histamine H2 receptors on parietal cells
• Famotidine (most potent); cimetidine (weakest)
• Inferior to PPIs for ulcer healing; PPIs are preferred
• Note: Do NOT combine antacids or H2RAs with PPIs - the alkaline environment inhibits PPI activation

Antacids / Sucralfate

• Mucosal protectants; adjunctive role only

Step 3: H. pylori Eradication (Most Important for Long-Term Cure)

2024 ACG Clinical Guideline (Chey WD et al., Am J Gastroenterol 2024, PMID 39626064):

First-Line Regimens (Treatment-Naive, Unknown Susceptibility)

Key 2024 update: Bismuth quadruple therapy for 14 days (not 10) is the preferred regimen when antibiotic susceptibility is unknown. Clarithromycin-containing regimens should only be used if susceptibility is confirmed. Salvage regimens with clarithromycin or levofloxacin require confirmed susceptibility.

Second-Line / Salvage (Treatment-Experienced, Persistent Infection)

Test-of-Cure

• All patients should have post-treatment confirmation of eradication
• Preferred: urea breath test or stool antigen (at least 4 weeks after completing therapy, with PPI held 2 weeks prior)

Step 4: NSAID-Related Ulcer Management

Step 5: Surgical Treatment (Reserved for Complications)

1. Perforation - exploratory laparoscopy/laparotomy; omental patch (Graham patch) for closure
2. Uncontrolled hemorrhage - after failed endoscopic hemostasis
3. Gastric outlet obstruction - refractory to medical management
4. Malignancy - partial/total gastrectomy

• Highly selective vagotomy (parietal cell vagotomy): divides only acid-producing vagal branches; ulcer recurrence 10-15%; lowest dumping/diarrhea rates
• Truncal vagotomy + pyloroplasty: drainage required; higher dumping rate
• Truncal vagotomy + antrectomy: lowest recurrence (0-2%) but highest morbidity (20% postgastrectomy syndromes); reconstruction via Billroth I (gastroduodenostomy) or Billroth II (gastrojejunostomy)

Endoscopic Images of H. pylori-Associated Gastritis and PUD

Summary Treatment Algorithm

PUD confirmed (by endoscopy or clinical grounds)
        │
        ├── Test for H. pylori (ALL patients)
        │         │
        │         ├── POSITIVE → H. pylori eradication regimen (14 days)
        │         │              + PPI for 4-8 weeks (DU) or 8-12 weeks (GU)
        │         │              → Test-of-cure (UBT or stool antigen) 4+ weeks post-Rx
        │         │
        │         └── NEGATIVE → PPI therapy alone
        │                        Check for NSAID use, ZES, idiopathic
        │
        ├── NSAID-induced → Stop NSAID if possible + PPI
        │                   If NSAID needed → COX-2 inhibitor + PPI
        │
        ├── ZES → High-dose PPI + surgical/medical management of gastrinoma
        │
        └── Complications → Endoscopic hemostasis for bleeding
                             Surgery for perforation, obstruction, uncontrolled bleed

Key Sources

• Sabiston Textbook of Surgery, 21e - Chapters on Peptic Ulcer Disease and Gastric Surgery
• Yamada's Textbook of Gastroenterology, 7e - Chapter 49: Peptic Ulcer Disease
• Textbook of Family Medicine, 9e - Chapter 38
• Costanzo Physiology, 7e - Chapter 8 (Gastrointestinal Physiology)
• 2024 ACG Clinical Guideline: Chey WD et al., "ACG Clinical Guideline: Treatment of Helicobacter pylori Infection," Am J Gastroenterol 2024 (PMID 39626064) - Most current guideline available