Peptic Ulcer Disease - Pathophysiology

SECTION 1

Historical Context & Motivation

For centuries, peptic ulcer disease (PUD) was regarded as a consequence of excessive stress, dietary indiscretion, and the overproduction of gastric acid. The prevailing dogma, "no acid, no ulcer," attributed by Schwarz in 1910, dominated clinical thinking for the better part of the twentieth century. Surgical interventions such as vagotomy and partial gastrectomy were the mainstays of therapy, reflecting the belief that acid hypersecretion was the primary—and essentially sole—etiologic factor. This paradigm profoundly shaped both research priorities and patient care, often subjecting individuals to invasive procedures that addressed symptoms without resolving the underlying cause.

1823 • Prout Identifies Gastric HCl

William Prout demonstrated that the stomach secretes hydrochloric acid, establishing the chemical basis of digestion and framing acid as the central player in mucosal injury.

1910 • Schwarz's Dictum

Karl Schwarz proposed "no acid, no ulcer," cementing the acid-centric model of peptic ulceration and guiding therapeutic strategies for decades.

1982 • Marshall & Warren Discover H. pylori

Barry Marshall and Robin Warren identified Helicobacter pylori in gastric biopsy specimens, proposing that a bacterial infection—not merely stress or diet—was the predominant cause of most peptic ulcers.

1994 • NIH Consensus Statement

The National Institutes of Health formally endorsed antimicrobial therapy for H. pylori–associated ulcers, marking a watershed shift from surgical to medical management.

2005 • Nobel Prize Awarded

Marshall and Warren received the Nobel Prize in Physiology or Medicine, validating the infectious etiology of PUD and underscoring the importance of challenging established medical paradigms.

The discovery of Helicobacter pylori fundamentally reframed the central question of peptic ulcer pathophysiology: rather than asking simply "why is there too much acid?" clinicians began asking "why has the mucosal defense failed?" This shift from a single-factor to a multifactorial model—balancing aggressive factors against protective mechanisms—is the conceptual framework that organizes modern understanding of PUD and guides both prevention and treatment.

SECTION 2

Core Principles & Definitions

Peptic ulcer disease is defined as a breach in the mucosa of the stomach or duodenum that extends through the muscularis mucosae into the submucosa or deeper layers, distinguishing it from superficial erosions that remain confined to the epithelium. The pathophysiology rests on a balance between aggressive factors that damage the mucosa and defensive factors that maintain its integrity. When the aggressive forces overwhelm the mucosal defenses, ulceration results.

Aggressive–Defensive Imbalance

Ulcers form when aggressive factors (HCl, pepsin, H. pylori, NSAIDs, bile salts) exceed the capacity of defensive mechanisms (mucus–bicarbonate barrier, mucosal blood flow, prostaglandins, epithelial cell turnover).

Helicobacter pylori Infection

H. pylori colonizes the gastric antrum and body, producing urease, cytotoxins (CagA, VacA), and inducing chronic inflammation that disrupts the mucosal barrier and alters acid secretion.

NSAID-Induced Mucosal Injury

Non-steroidal anti-inflammatory drugs inhibit cyclooxygenase (COX-1), reducing prostaglandin E₂ and prostacyclin synthesis. This diminishes mucosal blood flow, mucus secretion, and bicarbonate output, rendering the mucosa vulnerable to acid-peptic digestion.

Gastric vs. Duodenal Ulcers

Gastric ulcers are primarily associated with impaired mucosal defense (often normal or low acid), while duodenal ulcers are more frequently linked to acid hypersecretion and antral H. pylori colonization driving increased gastrin release.

Clinical Sequelae

Complications include hemorrhage (most common), perforation (free peritoneal air), penetration into adjacent organs (pancreas), and gastric outlet obstruction from chronic scarring and edema.

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KEY TAKEAWAY

Think of the gastric mucosa as a castle wall with multiple layers of defense—a mucus moat, bicarbonate ramparts, prostaglandin sentries, and blood-flow supply lines. H. pylori acts like a sappers' team burrowing beneath the wall, while NSAIDs are akin to cutting off supply lines. Acid alone is rarely sufficient to breach the wall; it is the combination of weakened defenses and persistent aggressive forces that leads to a breach—an ulcer.

SECTION 3

Visual Explanation: The Mucosal Barrier

Left panel: intact mucosal defense with continuous mucus–bicarbonate layer, surface epithelial cells, and prostaglandin-mediated blood flow. Right panel: disrupted barrier showing the ulcer crater extending through the muscularis mucosae into the submucosa, with acid penetrating into deeper tissue layers.

The diagram above illustrates the fundamental concept underlying peptic ulcer disease: the contrast between an intact and a disrupted mucosal barrier. On the left, the mucus–bicarbonate layer forms a continuous gel that traps secreted bicarbonate, creating a pH gradient from approximately 1–2 at the luminal surface to 6–7 at the epithelial surface. Surface epithelial cells are tightly joined and turn over rapidly, repairing minor injuries within hours. Prostaglandin E₂ sustains mucosal blood flow, which delivers bicarbonate, nutrients, and oxygen while removing back-diffusing acid. On the right, the disrupted mucosa shows a crater that has breached the muscularis mucosae—the histological hallmark that distinguishes a true ulcer from a superficial erosion. Once this layer is penetrated, submucosal arteries become exposed to acid-peptic digestion, setting the stage for potentially life-threatening hemorrhage.

SECTION 4

Pathogenic Mechanisms: H. pylori & NSAIDs

H. pylori Pathogenesis

Helicobacter pylori is a gram-negative, microaerophilic, spiral-shaped bacterium uniquely adapted to survive in the harsh gastric environment. Its colonization strategy begins with the enzyme urease, which catalyzes the hydrolysis of urea into ammonia and carbon dioxide. The ammonia creates a local alkaline microenvironment that buffers gastric acid around the organism, allowing it to survive in the mucus layer overlying the gastric epithelium. H. pylori then adheres to gastric epithelial cells via adhesins such as BabA and SabA, establishing a persistent infection that triggers both innate and adaptive immune responses.

UREASE REACTION

CO(NH₂)₂ + H₂O → 2 NH₃ + CO₂

Urea is hydrolyzed by H. pylori urease to yield ammonia (NH₃) and carbon dioxide (CO₂). The ammonia neutralizes local H⁺ ions, producing ammonium (NH₄⁺) and raising the pH in the organism's immediate vicinity. This reaction also forms the basis of the urea breath test used clinically to diagnose active infection.

The pathogenic potential of H. pylori is modulated by strain-specific virulence factors. Strains carrying the cag pathogenicity island encode a type IV secretion system that injects the CagA oncoprotein into host epithelial cells, disrupting intracellular signaling (SHP-2 phosphatase activation), promoting cytoskeletal rearrangement, and inducing pro-inflammatory cytokine release including IL-8. The VacA cytotoxin forms pores in epithelial cell membranes, induces vacuolation, and promotes apoptosis. These virulence factors amplify the inflammatory response, recruiting neutrophils and macrophages to the lamina propria. The resulting chronic active gastritis disrupts the normal feedback between antral G cells and fundic parietal cells: inflammation-driven suppression of somatostatin-producing D cells in the antrum leads to unopposed gastrin release, which stimulates parietal cell acid secretion—a key mechanism in duodenal ulcer formation.

NSAID-Induced Ulcerogenesis

Non-steroidal anti-inflammatory drugs represent the second most common cause of PUD and operate through both topical and systemic mechanisms. Topically, NSAIDs are weak acids that become non-ionized in the acidic gastric lumen, enabling them to cross the lipid bilayer of epithelial cells where they re-ionize and cause direct cellular injury—a phenomenon termed ion trapping. Systemically, and more importantly, NSAIDs inhibit cyclooxygenase-1 (COX-1), the constitutive enzyme responsible for generating prostaglandins PGE₂ and PGI₂ in the gastric mucosa. These prostaglandins stimulate mucus and bicarbonate secretion, promote mucosal blood flow, and enhance epithelial cell proliferation. Their depletion removes multiple layers of mucosal protection simultaneously, making the mucosa exquisitely vulnerable to acid-peptic injury.

Parallel pathogenic pathways converging on peptic ulcer formation. Left: H. pylori pathway progresses from colonization through urease-mediated survival, virulence factor–induced inflammation, to dysregulation of acid secretion and mucosal barrier breakdown. Right: NSAID pathway proceeds from COX-1 inhibition through prostaglandin depletion to simultaneous loss of mucus, bicarbonate, blood flow, and epithelial renewal.

SECTION 5

Classification: Gastric vs. Duodenal Ulcers

Although both gastric and duodenal ulcers fall under the umbrella of peptic ulcer disease, their pathophysiologic mechanisms, epidemiologic profiles, and clinical features differ in ways that have direct implications for diagnosis and management. Understanding these differences is essential for clinical reasoning, particularly when interpreting patient presentations and selecting appropriate diagnostic and therapeutic strategies.

Feature	Gastric Ulcer	Duodenal Ulcer
Primary mechanism	Impaired mucosal defense (↓ mucus, ↓ blood flow)	Acid hypersecretion (↑ gastrin, ↓ somatostatin)
Acid output	Normal or decreased	Increased (↑ basal & maximal acid output)
H. pylori association	≈60–80% of cases	≈90–95% of cases
Typical location	Lesser curvature, antrum–body junction (incisura angularis)	Duodenal bulb (first part of duodenum, anterior wall)
Pain pattern	Worsened by eating (food → acid secretion on vulnerable mucosa)	Improved by eating, worsened 2–3 hours postprandially and at night
Weight change	Weight loss (patients avoid eating)	Weight gain (patients eat to relieve pain)
Malignancy risk	Must biopsy to rule out gastric carcinoma	Almost never malignant
Complications	Hemorrhage (left gastric artery), malignant transformation	Hemorrhage (gastroduodenal artery), perforation (anterior), pancreatitis (posterior penetration)

Comparative features of gastric and duodenal ulcers

The clinical distinction between gastric and duodenal ulcers extends to their anatomic relationships with major blood vessels, which determines the pattern of hemorrhagic complications. Posterior duodenal ulcers may erode into the gastroduodenal artery, producing massive upper GI hemorrhage, while posterior penetration can also involve the pancreas, manifesting as pancreatitis with elevated serum lipase. Anterior duodenal ulcers are more likely to perforate freely into the peritoneal cavity, producing acute peritonitis and free air under the diaphragm on upright chest radiograph. Gastric ulcers along the lesser curvature may erode into the left gastric artery, another source of significant hemorrhage.

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Clinical Pearl

The modified Johnson classification divides gastric ulcers into five types based on location and acid secretory status. Type I (lesser curvature, body) is the most common and is associated with low acid. Types II (gastric body + duodenal) and III (prepyloric) are associated with high acid output, similar to duodenal ulcers. Type IV (cardia/gastroesophageal junction) and Type V (NSAID-related, any location) round out the classification.

SECTION 6

Worked Example: Clinical Case Analysis

The following clinical scenario integrates the pathophysiologic concepts discussed above into a step-by-step diagnostic and therapeutic reasoning exercise representative of the type of clinical vignette encountered on healthcare professional licensing examinations.

Case: 52-Year-Old Man with Epigastric Pain

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Step 1 — Gather Clinical Information

A 52-year-old man presents with a 6-week history of burning epigastric pain that wakes him at night and is relieved by eating. He has a history of osteoarthritis for which he takes ibuprofen 800 mg three times daily. He denies melena, hematemesis, or weight loss. Physical examination reveals mild epigastric tenderness without peritoneal signs. Vital signs are stable.

Key features: nocturnal pain, relief with food, chronic NSAID use → high suspicion for duodenal ulcer
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Step 2 — Identify the Pathophysiologic Mechanism

The patient has two potential ulcerogenic risk factors operating simultaneously. Chronic ibuprofen use inhibits COX-1, depleting mucosal prostaglandins and compromising the mucus–bicarbonate barrier, mucosal blood flow, and epithelial renewal. Additionally, given the high prevalence of H. pylori in peptic ulcer patients, concomitant H. pylori infection must be evaluated, as the combination of NSAID use and H. pylori infection synergistically increases ulcer risk. The pain pattern—relief with food and nocturnal exacerbation—is classic for duodenal ulceration, where acid bathing an unprotected duodenal bulb causes pain that is temporarily buffered by food intake.

Dual mechanism: NSAID-induced prostaglandin depletion ± H. pylori infection
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Step 3 — Select Diagnostic Approach

For a patient over 50 with new-onset dyspepsia, upper endoscopy (esophagogastroduodenoscopy, EGD) is indicated to visualize the ulcer, assess for complications, and obtain biopsies. During EGD, biopsies should be obtained for rapid urease testing (CLO test) to detect H. pylori. If endoscopy is not immediately available, non-invasive testing with a urea breath test (¹³C or ¹⁴C) or stool antigen test can confirm H. pylori status. Importantly, proton pump inhibitors should be held for at least 2 weeks before urea breath testing to avoid false negatives.

EGD with biopsy + rapid urease test; alternative: urea breath test or stool H. pylori antigen
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Step 4 — Formulate Treatment Plan

EGD reveals a clean-based 1.2 cm ulcer in the duodenal bulb. Rapid urease test is positive. The management plan includes: (1) discontinue ibuprofen and substitute acetaminophen or a COX-2 selective inhibitor if anti-inflammatory therapy is essential; (2) initiate triple therapy for H. pylori eradication—a PPI (e.g., omeprazole 20 mg BID) plus clarithromycin 500 mg BID plus amoxicillin 1000 mg BID for 14 days; (3) continue PPI for a total of 8 weeks to allow ulcer healing; (4) if NSAID use is unavoidable, co-prescribe misoprostol (a PGE₁ analogue) or a PPI for gastroprotection.

Stop NSAID + H. pylori triple therapy × 14 days + PPI × 8 weeks total
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Step 5 — Confirm Eradication and Follow Up

After completing antibiotic therapy, eradication of H. pylori should be confirmed at least 4 weeks after completing antibiotics and 2 weeks after stopping PPI therapy. The preferred tests for confirming eradication are the urea breath test or stool antigen test. For duodenal ulcers, repeat endoscopy is generally not necessary unless symptoms persist. For gastric ulcers, repeat EGD with biopsy is recommended at 8–12 weeks to document healing and exclude malignancy, as gastric carcinoma can mimic a benign ulcer endoscopically.

Confirm eradication with urea breath test ≥4 weeks post-antibiotics; repeat EGD only for gastric ulcers

SECTION 7

Diagnostic Modalities & Therapeutic Options

The diagnostic and therapeutic landscape of peptic ulcer disease encompasses a range of modalities, each with specific advantages and limitations that inform clinical decision-making. A systematic comparison of these approaches helps clinicians select the most appropriate strategy based on clinical context, resource availability, and patient factors.

Modality	Strengths	Limitations
EGD with biopsy	Direct visualization, histologic analysis, therapeutic intervention (hemostasis), simultaneous H. pylori testing	Invasive, requires sedation, higher cost, risk of perforation (rare)
Urea breath test	Non-invasive, high sensitivity and specificity (>95%), ideal for eradication confirmation	False negatives with recent PPI, antibiotics, or bismuth use; does not visualize the ulcer
Stool H. pylori antigen	Non-invasive, can detect active infection, useful for test-and-treat strategy	Requires monoclonal antibody–based assay for optimal accuracy; affected by PPIs
Serology (IgG)	Widely available, inexpensive, not affected by PPI use	Cannot distinguish active from past infection; remains positive after eradication; not useful for confirming cure
PPI therapy	Most potent acid suppression, heals >90% of ulcers at 8 weeks, well tolerated	Long-term risks: Clostridioides difficile infection, hypomagnesemia, fractures, vitamin B₁₂ deficiency
H₂ receptor antagonists	Effective for nocturnal acid suppression, fewer long-term adverse effects than PPIs	Less potent than PPIs, tolerance develops with prolonged use (tachyphylaxis)
Misoprostol	PGE₁ analogue that directly replaces depleted prostaglandins; proven NSAID ulcer prophylaxis	GI side effects (diarrhea, cramping), abortifacient (contraindicated in pregnancy), requires QID dosing

Diagnostic and therapeutic modalities in peptic ulcer disease

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KEY TAKEAWAY

In the broader landscape of acid-peptic disorders, PPI therapy is analogous to shutting off the fire hydrant—it dramatically reduces acid output but does not repair the underlying plumbing. Eradicating H. pylori is like fixing the corroded pipe, while discontinuing NSAIDs is like removing the wrecking ball from the wall. Effective treatment of PUD requires addressing both the aggressive insult and the defensive deficit, not merely suppressing acid.

SECTION 8

Connections to Advanced GI Pathophysiology

Peptic ulcer disease serves as a foundational model for understanding several advanced concepts in gastrointestinal and hepatobiliary pathophysiology. The principles of mucosal defense, acid secretion regulation, and inflammation-driven dysplasia connect PUD to a broader spectrum of conditions including Zollinger-Ellison syndrome, gastric carcinoma, MALT lymphoma, and stress-related mucosal injury in critically ill patients.

Concept in PUD	Advanced Connection
H. pylori chronic inflammation → gastric atrophy → intestinal metaplasia	Correa cascade: sequential progression from chronic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → gastric adenocarcinoma (intestinal type)
H. pylori–driven chronic immune stimulation in the lamina propria	MALT lymphoma: marginal zone B-cell lymphoma arising from mucosa-associated lymphoid tissue; low-grade forms may regress with H. pylori eradication alone
Gastrin-mediated parietal cell stimulation in PUD	Zollinger-Ellison syndrome: gastrin-secreting tumor (gastrinoma) causing massive acid hypersecretion, multiple ulcers (often distal duodenum/jejunum), and diarrhea; associated with MEN-1
Prostaglandin-mediated mucosal blood flow in normal defense	Stress ulcers (Curling & Cushing): mucosal ischemia in burns/trauma (Curling) and vagal-mediated acid hypersecretion in CNS injury (Cushing); stress ulcer prophylaxis with PPIs in ICU patients
Acid-peptic injury to esophageal and duodenal mucosa	GERD and Barrett esophagus: chronic acid reflux causes esophageal squamous-to-columnar metaplasia, a premalignant condition; parallels the metaplasia-dysplasia-carcinoma sequence in the stomach

Connections between PUD concepts and advanced GI pathophysiology

The concept of the Correa cascade deserves particular attention because it illustrates how a treatable infectious disease (H. pylori gastritis) can, over decades, progress through a well-characterized sequence of histologic changes to gastric adenocarcinoma. This metaplasia–dysplasia–carcinoma sequence is not unique to the stomach; analogous progressions occur in Barrett esophagus (intestinal metaplasia → dysplasia → esophageal adenocarcinoma) and in inflammatory bowel disease (chronic colitis → dysplasia → colorectal carcinoma). Understanding PUD as the entry point to this cascade underscores the importance of H. pylori eradication not only for ulcer healing but for cancer prevention.

SECTION 9

Practice Problems

Question 1: CONCEPTUAL

Explain why the dictum "no acid, no ulcer" is an oversimplification of peptic ulcer pathophysiology. What additional factors must be considered in the current multifactorial model?

Show answer

While gastric acid is a necessary cofactor for peptic ulceration—ulcers do not form in the absence of acid—it is rarely sufficient on its own. The current model recognizes that ulcers arise from an imbalance between aggressive factors (acid, pepsin, H. pylori, NSAIDs, bile salts) and defensive factors (mucus–bicarbonate barrier, mucosal blood flow, prostaglandins, epithelial cell turnover). Most patients with gastric ulcers have normal or even low acid output, indicating that impaired mucosal defense, rather than excess acid, is the primary driver. The discovery of H. pylori demonstrated that a bacterial infection undermines multiple layers of mucosal defense, and NSAID use depletes prostaglandins that are critical for maintaining the integrity of the barrier.

Question 2: BASIC CALCULATION

A patient's fasting gastric pH is measured at 1.3, and the pH at the epithelial surface beneath the mucus layer is 6.7. Calculate the fold-difference in hydrogen ion concentration between these two sites, recalling that pH = −log[H⁺].

Show answer

The hydrogen ion concentration at pH 1.3 is [H⁺] = 10⁻¹·³ ≈ 5.01 × 10⁻² M. At pH 6.7, [H⁺] = 10⁻⁶·⁷ ≈ 2.00 × 10⁻⁷ M. The fold-difference is (5.01 × 10⁻²) ÷ (2.00 × 10⁻⁷) ≈ 250,000-fold. This enormous concentration gradient across a layer only ≈0.5 mm thick underscores the remarkable efficiency of the mucus–bicarbonate barrier. This gradient is maintained by continuous bicarbonate secretion by surface epithelial cells and the gel-like properties of mucus that limit back-diffusion of H⁺ ions.

Question 3: INTERMEDIATE

A 68-year-old woman on long-term aspirin therapy for secondary stroke prevention develops melena. EGD reveals a gastric ulcer on the lesser curvature. H. pylori testing is negative. Discuss the pathophysiologic mechanism of her ulcer, and explain why simply stopping aspirin may not be clinically appropriate. What gastroprotective strategy would you recommend?

Show answer

Aspirin irreversibly acetylates COX-1, reducing synthesis of prostaglandins PGE₂ and PGI₂ in the gastric mucosa. This diminishes mucus and bicarbonate secretion, reduces mucosal blood flow, and impairs epithelial cell proliferation—removing multiple layers of mucosal defense simultaneously. The location on the lesser curvature is typical for Type I gastric ulcers associated with impaired defense. Simply stopping aspirin may not be appropriate because she requires it for secondary stroke prevention; discontinuation increases her thrombotic risk. The recommended strategy is to continue aspirin at the lowest effective dose while co-prescribing a PPI (e.g., omeprazole or pantoprazole) for long-term gastroprotection. Misoprostol is an alternative but is often poorly tolerated due to diarrhea and cramping. Follow-up EGD at 8–12 weeks with biopsy is essential to confirm healing and exclude malignancy.

Question 4: APPLIED

A patient treated for H. pylori–associated duodenal ulcer with standard triple therapy (PPI + clarithromycin + amoxicillin × 14 days) returns 6 weeks later. A urea breath test performed 2 weeks after completing the PPI is positive. Discuss possible reasons for treatment failure and outline the next-line eradication regimen, explaining the pharmacologic rationale.

Show answer

Treatment failure most commonly results from clarithromycin resistance, which has risen to 15–20% or higher in many populations. Other causes include poor patient compliance with the multidrug regimen, inadequate acid suppression (which reduces antibiotic efficacy in the gastric environment), or concurrent use of agents that reduce antibiotic effectiveness. The next-line approach is bismuth quadruple therapy: a PPI plus bismuth subsalicylate plus metronidazole plus tetracycline for 14 days. Bismuth has direct antimicrobial activity against H. pylori, disrupts the bacterial biofilm, and acts synergistically with the antibiotics. Alternatively, levofloxacin-based triple therapy (PPI + levofloxacin + amoxicillin) may be used, though fluoroquinolone resistance is an increasing concern. The pharmacologic rationale for switching antibiotic classes is to circumvent macrolide resistance. If available, culture-based or PCR-based susceptibility testing can guide targeted therapy for refractory infections.

Question 5: CRITICAL THINKING

H. pylori infection is present in roughly 50% of the world's population, yet only 10–20% of infected individuals develop peptic ulcers, and fewer than 1–3% develop gastric carcinoma. Propose a pathophysiologic framework that accounts for this discrepancy, integrating bacterial virulence factors, host genetic susceptibility, and environmental cofactors.

Show answer

The variable clinical outcomes of H. pylori infection can be explained by a three-way interaction among bacterial, host, and environmental factors. On the bacterial side, strains harboring the cag pathogenicity island (CagA⁺) and the s1/m1 allele of VacA are significantly more virulent, inducing greater IL-8 release, neutrophil infiltration, and epithelial damage than CagA⁻ strains. Host genetic polymorphisms in cytokine genes—particularly IL-1β (IL-1B-31C and IL-1RN*2 alleles) that produce higher levels of the potent acid-suppressing cytokine IL-1β—predispose to more severe corpus gastritis, accelerating the Correa cascade toward atrophy and carcinoma. Conversely, individuals with lower IL-1β expression tend to develop antral-predominant gastritis with preserved or increased acid secretion, predisposing to duodenal ulcers rather than cancer. Environmental cofactors include high dietary salt (which enhances CagA expression and promotes atrophic gastritis), smoking (which impairs mucosal blood flow and healing), low antioxidant intake, and co-infection with other pathogens. This framework explains the geographic variation in disease outcomes—for instance, the high gastric cancer rates in East Asia correlate with high prevalence of CagA⁺ strains, high-salt diets, and susceptible host IL-1β genotypes.

SUMMARY

Peptic Ulcer Disease — Summary

Summary

Peptic ulcer disease arises from an imbalance between aggressive factors (gastric acid, pepsin, Helicobacter pylori, NSAIDs) and defensive factors (the mucus–bicarbonate barrier, mucosal blood flow, prostaglandins, and epithelial cell turnover). H. pylori undermines defense through urease-mediated survival, CagA/VacA virulence factors, and chronic inflammation that dysregulates gastrin–somatostatin feedback. NSAIDs inhibit COX-1, depleting mucosal prostaglandins and simultaneously reducing mucus, bicarbonate, and blood flow.

Gastric ulcers primarily reflect impaired defense with normal or low acid, while duodenal ulcers are more strongly linked to acid hypersecretion driven by antral H. pylori infection. Diagnosis relies on EGD with biopsy for visualization and histology, supplemented by the urea breath test or stool antigen test for H. pylori detection. Treatment targets both aggressive and defensive elements: H. pylori eradication with triple or quadruple antibiotic therapy, PPI-mediated acid suppression, NSAID cessation, and prostaglandin replacement with misoprostol when NSAIDs cannot be avoided. PUD connects to the broader spectrum of GI pathophysiology through the Correa cascade (gastritis → atrophy → metaplasia → dysplasia → carcinoma), MALT lymphoma, and Zollinger-Ellison syndrome.