33.1 Peptic Ulcer Disease & Gastritis

Peptic Ulcer Disease: Pathophysiology & Etiology

Peptic ulcer disease (PUD) is a mucosal defect in the stomach or duodenum that penetrates through the muscularis mucosae into the deeper layers of the gastrointestinal wall, driven by an imbalance between aggressive luminal factors (gastric acid, pepsin) and mucosal defensive mechanisms (mucus-bicarbonate barrier, mucosal blood flow, epithelial cellular regeneration, and endogenous prostaglandins).

Endogenous Mucosal Defense vs. Luminal Aggressors

• Mucosal Defensive Barrier:
  • Pre-epithelial: The mucus-gel layer enriched with bicarbonate secreted by surface foveolar cells, creating an alkaline microenvironment (pH ~7.0) at the epithelial surface despite a luminal pH of 1.0 to 2.0.
  • Epithelial: Tight junctions between gastric epithelial cells preventing back-diffusion of hydrogen ions; rapid cell turnover and restitution mediated by restitution peptides and epidermal growth factors.
  • Sub-epithelial: Microvascular mucosal blood flow that rapidly removes back-diffused acid, delivers oxygen, bicarbonate, and nutrients, and supports tissue repair.
  • Endogenous Prostaglandins (PGE2 and PGI2): Synthesized in gastric mucosa via cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. Prostaglandins stimulate mucus and bicarbonate secretion, inhibit acid secretion by parietal cells via Gi protein-coupled receptors, promote mucosal vasodilation, and stimulate epithelial renewal.

Major Etiologies of Peptic Ulcer Disease

1. Helicobacter pylori Infection:

   • Microaerophilic, Gram-negative, flagellated curved rod that colonizes the human gastric antrum and body.
   • Urease Activity: H. pylori produces copious urease, which hydrolyzes gastric luminal urea into carbon dioxide (CO2) and ammonia (NH3). Ammonia buffers local gastric acid, enabling bacterial survival, while exerting direct cytotoxicity on gastric foveolar cells.
   • Virulence Factors:
     • CagA (Cytotoxin-Associated Gene A): Translocated into host gastric epithelial cells via a Type IV secretion system, causing cytoskeletal rearrangements, cellular elongation (the "hummingbird" phenotype), disruption of tight junctions, and intense IL-8 secretion with mucosal neutrophil infiltration.
     • VacA (Vacuolating Cytotoxin A): Induces cellular vacuolization, alters mitochondrial membrane permeability, triggers epithelial apoptosis, and inhibits T-lymphocyte activation.
   • Antral-Predominant vs. Corpus-Predominant Gastritis:
     • Antral-predominant gastritis: Decreased somatostatin release from D cells leads to unchecked G-cell gastrin secretion (hypergastrinemia), stimulating parietal cells to hypersecrete hydrochloric acid, overwhelming duodenal bicarbonate defenses and producing duodenal ulcers.
     • Corpus-predominant (pangastritis): Direct mucosal destruction and progressive atrophy of acid-secreting parietal cells result in hypochlorhydria, mucosal atrophy, intestinal metaplasia, and gastric ulcers, dramatically raising the risk of gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma.

2. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) & Aspirin:

   • NSAIDs represent the second major cause of PUD. Mechanism involves both systemic and topical mucosal injury:
     • Systemic Inhibition of COX-1: Blocks mucosal synthesis of cytoprotective prostaglandin E2 (PGE2) and prostacyclin (PGI2), resulting in decreased bicarbonate and mucus secretion, reduced mucosal blood flow, and increased acid secretion.
     • Topical Caustic Effect ("Ion Trapping"): NSAIDs are weak organic acids (pKa 3-5) that remain non-ionized in acidic gastric juice, freely diffusing across the lipid membrane of gastric epithelial cells. Once inside neutral intracellular cytoplasm (pH 7.4), they ionize into charged anions and protons, becoming trapped intracellularly, disrupting mitochondrial oxidative phosphorylation and compromising membrane integrity.

3. Other Etiologies & Risk Factors:

   • Cigarette Smoking: Impairs mucosal blood flow, inhibits pancreatic bicarbonate secretion, impairs ulcer healing, and accelerates ulcer recurrence.
   • Severe Physiological Stress (Stress Ulcers): Seen in critically ill ICU patients (Curling ulcers associated with severe extensive burns; Cushing ulcers associated with elevated intracranial pressure or severe head trauma triggering intense vagal hyperstimulation and massive acid hypersecretion).
   • Hypersecretory States: Zollinger-Ellison syndrome (gastrinoma), systemic mastocytosis (massive histamine release).
   • Medication Interactions: Concurrent systemic corticosteroids, anticoagulants, antiplatelet agents (clopidogrel), and SSRIs markedly potentiate NSAID-induced gastrointestinal ulceration and bleeding.

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Duodenal vs. Gastric Ulcers: Clinical & Diagnostic Distinction

Careful chronobiologic history and risk assessment differentiate duodenal from gastric ulcerations:

[!IMPORTANT] Anatomic Complication Pearls for Board Exams:

• Anterior duodenal ulcers are in direct contact with the peritoneal cavity; perforation causes sudden catastrophic peritonitis and pneumoperitoneum (free air under the diaphragm).
• Posterior duodenal ulcers erode directly into the gastroduodenal artery, precipitating massive, life-threatening upper gastrointestinal hemorrhage.
• Gastric ulcers along the lesser curvature can erode directly into the left gastric artery.

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Dyspepsia Evaluation & Upper Endoscopy (EGD) Indications

Dyspepsia is defined as one or more postprandial symptoms: postprandial fullness, early satiety, and epigastric pain or burning. The Joint Guidelines of the American College of Gastroenterology (ACG) and Canadian Association of Gastroenterology (CAG) establish clear management pathways based on age and alarm features.

Guideline-Directed Indications for Upper Endoscopy (EGD)

1. Age ≥60 Years:
   • All patients aged 60 years or older presenting with new-onset or persistent dyspepsia must undergo prompt diagnostic esophagogastroduodenoscopy (EGD), regardless of whether alarm features are present, due to the high baseline incidence of upper gastrointestinal malignancy in this demographic.
2. Alarm Features ("Red Flags") at Any Age:
   • The presence of any alarm feature warrants immediate EGD, irrespective of patient age:
     • Progressive dysphagia (difficulty swallowing) or odynophagia (painful swallowing);
     • Unintentional, unexplained weight loss (>10% of baseline body weight);
     • Persistent, intractable vomiting;
     • Evidence of gastrointestinal bleeding (hematemesis, "coffee-ground" emesis, melena, hematochezia);
     • Unexplained iron deficiency anemia (microcytic hypochromic indices, low ferritin);
     • Palpable epigastric abdominal mass or lymphadenopathy (Virchow node [left supraclavicular], Sister Mary Joseph nodule [periumbilical], Irish node [left anterior axillary]);
     • Family history of upper gastrointestinal tract malignancy in a first-degree relative.
3. Patients Aged <60 Years Without Alarm Features:
   • In younger patients without alarm signs, invasive endoscopy is not initially recommended. The preferred approach is non-invasive testing for Helicobacter pylori ("test-and-treat" strategy). If testing is positive, eradicate the infection. If testing is negative or symptoms persist after proven eradication, initiate an empiric trial of once-daily proton pump inhibitor (PPI) therapy for 4 to 8 weeks.

Endoscopic Biopsy Protocol for Gastric Ulcers

• Mandatory Biopsy: Because benign gastric ulcers and malignant ulcerated gastric adenocarcinomas can appear macroscopically indistinguishable on endoscopy, all gastric ulcers must be biopsied at index EGD.
• Sydney Protocol: Minimum of 4 to 6 quadrant biopsies taken from the raised, rolled ulcer margins and the base to exclude malignancy, plus antral and corpus mucosal biopsies for H. pylori.
• Surveillance Endoscopy: All patients with gastric ulcers must undergo repeat surveillance EGD 8 to 12 weeks after completion of acid suppression therapy to verify complete histologic and endoscopic ulcer healing. Failure of a gastric ulcer to heal completely after 8 to 12 weeks of high-dose PPI therapy strongly suggests occult malignancy and mandates repeat deep biopsies or surgical wedge resection.

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Diagnostic Testing for Helicobacter pylori

Diagnostic tests are divided into non-invasive active tests, non-invasive non-active serology, and endoscopic invasive tests. Testing should only be performed if the clinician intends to treat positive results.

                      H. PYLORI DIAGNOSTIC WORKUP

                      Patient with Suspected PUD / Dyspepsia
                                       │
                ┌──────────────────────┴──────────────────────┐
                ▼                                             ▼
       Age >=60 OR Alarm Signs                       Age <60, No Alarm Signs
                │                                             │
                ▼                                             ▼
      DIAGNOSTIC EGD + BIOPSY                       NON-INVASIVE ACTIVE TEST
      • Rapid Urease Test (CLOtest)                 • Stool Antigen Test (SAT) OR
      • Histology (Giemsa / W-Starry)               • 13C-Urea Breath Test (UBT)
      • Rule out malignancy                         • MUST HOLD PPI x 1-2 weeks
                                                    • MUST HOLD Antibiotics/Bismuth x 4 wk
                                                    • NEVER USE SEROLOGY (IgG EIA)!

Comparison of H. pylori Diagnostic Modalities

[!WARNING] Crucial Pre-Test Washout Rules to Prevent False Negatives:

• Proton Pump Inhibitors (PPIs) suppress bacterial metabolic activity and reduce bacterial density, causing false-negative UBT, stool antigen, and CLOtest results. PPIs must be stopped for at least 1 to 2 weeks prior to active testing.
• Bismuth compounds and systemic antibiotics suppress H. pylori numbers and must be stopped for at least 4 weeks prior to testing.
• Safe symptomatic alternatives: H2-receptor antagonists (famotidine) and antacids do not interfere with urease-based tests and can be used up to 24 to 48 hours before testing.

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ACG Guideline-Directed Eradication Regimens

Historically, clarithromycin-based triple therapy (PPI + clarithromycin + amoxicillin) was the standard regimen. However, extensive nationwide surveillance has demonstrated North American clarithromycin resistance rates between 20% and 30%, resulting in treatment failure rates exceeding 30% to 40%. Consequently, clinical practice guidelines from the ACG have dethroned triple therapy as the empiric choice.

ACG First-Line Regimens

Patient Counseling & Adverse Effects

• Bismuth Subsalicylate: Causes harmless, temporary black discoloration of the tongue and stool (bismuth sulfide precipitation); patients must be reassured this is not melena. Tinnitus can occur from salicylate toxicity.
• Metronidazole: Severe disulfiram-like ethanol intolerance (nausea, violent vomiting, flushing, tachycardia); patients must strictly avoid all alcohol during therapy and for 72 hours following completion. Causes metallic dysgeusia.
• Tetracycline: Pill esophagitis, cutaneous photosensitivity, gastrointestinal distress. Strictly contraindicated in children <8 years and during pregnancy/lactation due to permanent dental staining and bone growth inhibition.

Mandatory Confirmation of Eradication (Test-of-Cure)

• Rule: Every patient treated for Helicobacter pylori infection must undergo a formal test-of-cure to confirm bacterial clearance.
• Timing: Perform test-of-cure at least 4 weeks after completion of antibiotic therapy AND at least 1 to 2 weeks after stopping PPI therapy.
• Test Modality: Use either the 13C-urea breath test or laboratory-based stool antigen test (or repeat mucosal biopsy if undergoing surveillance EGD for a gastric ulcer). Serum antibody testing must never be used.

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NSAID-Associated Ulcer Prevention & Risk Stratification

Chronic NSAID use confers a four- to five-fold increased risk of upper gastrointestinal ulceration and bleeding. Clinicians must risk-stratify patients prior to initiating long-term NSAID therapy.

Gastrointestinal Risk Stratification for NSAID Therapy

• High Risk: History of a prior complicated ulcer (perforation, obstruction, bleeding); OR multiple (>2) moderate risk factors.
• Moderate Risk: Age ≥65 years; high-dose NSAID therapy; concurrent use of aspirin, systemic corticosteroids, or anticoagulants (warfarin, DOACs); history of an uncomplicated peptic ulcer.
• Low Risk: Age <65 years with no risk factors.

Prevention Strategies

1. Proton Pump Inhibitor Co-Therapy: Standard-dose PPI once daily co-prescribed with the NSAID significantly reduces both gastric and duodenal ulcer recurrence and bleeding complications.
2. COX-2 Selective Inhibitors (Celecoxib): Selectively inhibits inducible COX-2 while sparing constitutive mucosal COX-1, reducing endoscopic ulcer incidence by 50% compared to non-selective NSAIDs. However, celecoxib confers increased cardiovascular thrombotic risk (myocardial infarction, stroke) at higher doses and does not eliminate ulcer risk when combined with low-dose aspirin.
3. Misoprostol (Cytotec):
   • Synthetic prostaglandin E1 (PGE1) analog that directly replaces deficient mucosal prostaglandins, stimulating bicarbonate and mucus secretion and maintaining mucosal blood flow.
   • Dosing: 200 mcg PO four times daily with food.
   • Adverse Effects: High incidence of dose-dependent crampy abdominal pain and explosive diarrhea (seen in 20% to 30% of patients), which severely limits adherence.
   • Black Box Warning: Strictly contraindicated in women of childbearing potential and pregnancy due to potent uterotonic properties causing uterine contractions, vaginal bleeding, and spontaneous abortion.

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Zollinger-Ellison Syndrome (ZES / Gastrinoma)

Zollinger-Ellison syndrome is a clinical syndrome caused by a gastrin-secreting neuroendocrine tumor (gastrinoma), characterized by severe gastric acid hypersecretion resulting in refractory peptic ulcer disease and chronic secretory diarrhea.

Epidemiology & Clinical Manifestations

• Epidemiology: 75% to 80% are sporadic neuroendocrine tumors; 20% to 25% occur in association with Multiple Endocrine Neoplasia Type 1 (MEN1) syndrome (triad of parathyroid adenomas, pituitary adenomas, and pancreatic neuroendocrine tumors).
• Localization: Over 70% of gastrinomas arise within the anatomic "gastrinoma triangle" bounded by the junction of the cystic duct and common bile duct superiorly, the junction of the second and third portions of the duodenum inferiorly, and the neck and body of the pancreas medially.
• Hallmark Clinical Presentations:
  • Refractory, persistent, or rapidly recurrent peptic ulcer disease despite guideline-directed PPI therapy and confirmed H. pylori eradication;
  • Multiple peptic ulcers occurring simultaneously;
  • Ulcers located in atypical anatomic sites: the distal duodenum (post-bulbar) or proximal jejunum;
  • Peptic ulcer disease accompanied by severe, chronic watery secretory diarrhea (large volumes of hydrochloric acid overwhelm duodenal neutralization, denaturing pancreatic enzymes and inactivating pancreatic lipase, causing acid-induced malabsorption and secretory enteropathy; diarrhea completely resolves with high-dose gastric acid suppression).

Diagnostic Evaluation Algorithm

1. Fasting Serum Gastrin (FSG):
   • The initial screening test of choice. Must be measured while fasting and ideally with the patient off PPI therapy for at least 1 to 2 weeks (or on H2-blockers):
   • FSG >1,000 pg/mL (normal <100 pg/mL) combined with a gastric pH <2.0 is virtually pathognomonic for Zollinger-Ellison syndrome.
   • Caveat: Documenting gastric pH <2.0 is mandatory to distinguish gastrinoma from secondary hypergastrinemia caused by achlorhydria (such as autoimmune atrophic gastritis or chronic PPI suppression, where lack of acid eliminates negative feedback on G cells).
2. Secretin Stimulation Test (Confirmatory for Borderline Cases):
   • Indicated when fasting serum gastrin is non-diagnostically elevated between 110 and 1,000 pg/mL with gastric pH <2.0.
   • Intravenous secretin (2 clinical units/kg) is administered, and serum gastrin levels are measured at 2, 5, 10, 15, and 30 minutes.
   • Diagnostic Response: In normal parietal cells, secretin inhibits gastrin release. In gastrinoma cells, secretin stimulates secretin receptors, causing a paradoxical rise in serum gastrin of >120 pg/mL over baseline (confirms Zollinger-Ellison syndrome).
3. Tumor Localization:
   • Somatostatin Receptor PET/CT (68Ga-DOTATATE PET/CT): The gold standard imaging modality with >90% sensitivity for identifying primary gastrinomas and metastatic hepatic lesions.
   • Endoscopic Ultrasound (EUS) is highly sensitive for identifying tiny pancreatic and duodenal wall tumors.