Peptic Ulcer Disease - A Comprehensive Review

1. Definition

• Bailey & Love's Short Practice of Surgery, 28th Ed.
• Guyton & Hall Textbook of Medical Physiology

2. Epidemiology

• PUD is one of the most common GI disorders worldwide. In the United States, prevalence is approximately 2% with a lifetime cumulative risk of ~10% for males and ~4% for females, peaking around age 70.
• More than 4 million individuals in the US are treated for PUD each year.
• Costs (including lost work and productivity) exceed $8 billion/year in the US.
• The incidence of PUD is falling as H. pylori infection rates decrease, but PUD in patients over 60 years has increased due to growing NSAID use.
• Duodenal ulcers (DU) are more common than gastric ulcers (GU). DU has a male predominance; GU has an equal gender incidence.
• GU patients tend to be older and are more prevalent in low socioeconomic groups and resource-poor countries.
• Robbins & Cotran Pathologic Basis of Disease, p. 719
• Schwartz's Principles of Surgery, 11th Ed., p. 1148

3. Etiology and Risk Factors

Primary Causes

Other Risk Factors

• Cigarette smoking - reduces mucosal blood flow and healing; reduces mucosal prostaglandin synthesis
• High-dose corticosteroids - suppress prostaglandin synthesis, impair healing
• Alcohol-related cirrhosis
• Chronic obstructive pulmonary disease (COPD)
• Chronic renal failure and hyperparathyroidism - hypercalcemia stimulates gastrin production and acid secretion
• Cocaine use
• Blood group O - GWAS studies confirmed the long-reported epidemiological link between O blood type and DU (the risk allele at ABO locus [rs505922] provides a molecular basis)
• Psychological stress - particularly physiological stress (trauma, burns, ICU patients)
• Genetic factors - a Finnish twin study estimated 39% of liability for PUD is explained by genetic factors; GWAS identified loci on chromosome 8q24 (PSCA gene) and 9q34 (ABO)

• Schwartz's Principles of Surgery, 11th Ed., p. 1149
• Yamada's Textbook of Gastroenterology, 7th Ed.
• Robbins & Kumar Basic Pathology

4. Pathophysiology

Figure: Causes and most frequent locations of peptic ulcer. (Guyton & Hall Textbook of Medical Physiology)

Aggressive Factors

• Hydrochloric acid (HCl)
• Pepsin
• H. pylori and its virulence factors
• NSAIDs (COX inhibition)
• Bile acids (in gastric reflux)

Defensive Factors

• Mucus-bicarbonate barrier (mucous cells, Brunner's glands)
• Mucosal blood flow (provides bicarbonate, removes acid, supports healing)
• Epithelial tight junctions and cell renewal
• Prostaglandins (stimulate mucus, bicarbonate, blood flow; inhibited by NSAIDs)
• Duodenal neutralization by pancreatic bicarbonate
• Secretin feedback (acid in duodenum stimulates secretin → pancreatic bicarbonate)
• Neural feedback (acid in duodenum inhibits gastric acid secretion and peristalsis)
• Guyton & Hall Textbook of Medical Physiology, p. 825

Role of Helicobacter pylori

1. Urease production - converts urea to NH₃ and CO₂; ammonia is directly cytotoxic and buffers the local environment, allowing bacterial survival at low pH
2. VacA (vacuolating cytotoxin A) - induces vacuolation and cell death in epithelial cells
3. CagA (cytotoxin-associated gene A) - encoded on the cag pathogenicity island (PAI); delivered via a type IV secretion system into host cells; activates NF-κB, induces IL-8, promotes inflammation and mucosal injury
4. Lipopolysaccharide (LPS) - triggers innate immune responses and PMN infiltration
5. Acid hypersecretion - H. pylori antral gastritis impairs somatostatin secretion by D cells → reduced inhibition of gastrin → elevated gastrin → increased parietal cell acid output
6. Decreased duodenal bicarbonate secretion - contributes to loss of buffering
7. Only 5-10% of infected individuals develop ulcers, indicating that host genetic factors and bacterial strain pathogenicity (cagA-positive strains) both play a role

• Schwartz's Principles of Surgery, 11th Ed., pp. 1145-1147
• Robbins & Cotran Pathologic Basis of Disease, pp. 718-720

Role of NSAIDs

• Inhibit COX-1 and COX-2 → reduce prostaglandin synthesis → decrease mucus and bicarbonate secretion, reduce mucosal blood flow
• Topical (direct) injury - many NSAIDs are weak acids that penetrate mucosal cells at low gastric pH, leading to cell damage
• COX-2-selective inhibitors (celecoxib) reduce but do not eliminate GI risk
• H. pylori infection interacts with NSAIDs/aspirin to amplify mucosal injury

5. Sites

• Duodenum - Most common site; first part (D1) within 2 cm of pylorus; "kissing ulcers" (anterior + posterior walls) occur
• Stomach - Lesser curve (especially at the incisura angularis); gastric antrum-body junction; high lesser curve ulcers occur with proximal migration of the antral-body junction due to parietal cell atrophy
• Gastroesophageal junction - Lower esophagus in GERD or Barrett's epithelium
• Meckel's diverticulum - When ectopic gastric mucosa is present
• Stomal/marginal ulcer - At gastrojejunostomy sites after gastric surgery (usually at jejunal/gastric mucosa junction)
• Zollinger-Ellison - Multiple ulcers in stomach, duodenum, and even jejunum

• Bailey & Love's Short Practice of Surgery, 28th Ed., p. 1174

6. Pathology (Morphology)

Figure 17.17A: Gross pathology of chronic peptic ulcer - sharply punched-out defect with radiating mucosal folds. (Robbins & Cotran Pathologic Basis of Disease, 10th Ed.)

Macroscopic Features

• Solitary in >80% of patients
• Round to oval, sharply punched-out defect with a "clean" base (peptic digestion of exudate)
• Mucosal margin is level with surrounding mucosa (unlike cancers, which have heaped-up, irregular margins)
• Size - typically <2 cm; GU tend to be larger than DU
• Folds radiate outward from the ulcer base (due to submucosal scarring)
• In chronic cases, fibrosis may produce "hourglass" deformity of the stomach

Microscopic Features (4 Zones from surface to base)

1. Zone of fibrinoid necrosis - thin layer at the surface; neutrophilic infiltrate
2. Zone of active nonspecific cellular infiltration - mononuclear cells, neutrophils
3. Zone of granulation tissue - immature vessels, fibroblasts
4. Zone of fibrosis/scar - collagenous tissue extending into the muscularis propria

• Endarteritis obliterans may be present at the base
• Larger vessels in the scarred area are thickened and occasionally thrombosed - erosion into these causes hemorrhage
• Foveolar (gastric-type) metaplasia is common in chronic duodenal peptic disease - a protective response, as gastric epithelium is more acid-resistant than intestinal epithelium
• Robbins & Cotran Pathologic Basis of Disease, pp. 719-720
• Robbins & Kumar Basic Pathology
• Bailey & Love's Short Practice of Surgery, 28th Ed.

7. Clinical Features

Symptoms

• Epigastric burning/gnawing pain, typically 2-3 hours after meals (pain when stomach is empty)
• Pain relieved by food or antacids
• Nocturnal pain (waking 1-3 AM) - highly characteristic; due to peak acid secretion during sleep
• Weight gain (eating relieves pain) or normal weight

• Epigastric pain, often precipitated or worsened by eating
• Nausea, anorexia, vomiting
• Weight loss (due to food aversion)
• Symptoms of DU and GU are often clinically indistinguishable

Alarm Features (Indicate Urgent Endoscopy)

• Dysphagia/odynophagia
• Unexplained weight loss
• Hematemesis or melena
• Palpable abdominal mass or lymphadenopathy
• Iron deficiency anemia
• Persistent vomiting
• Age >55 with recent onset of symptoms
• Family history of upper GI cancer
• Schwartz's Principles of Surgery, 11th Ed., p. 1142-1143

8. Investigations

Endoscopy (EGD - Gold Standard)

• Directly visualizes the ulcer; assesses size, location, active bleeding
• All gastric ulcers require multiple biopsies (base and rim) to exclude malignancy
• Antral biopsies for histology and CLO (Campylobacter-like organism/urease) test
• Brush cytology for gastric ulcers
• Follow-up endoscopy at 6-8 weeks for gastric ulcers to confirm healing

Tests for H. pylori

Radiology

• Erect chest X-ray - free gas under diaphragm in perforation (seen in >50%)
• Barium upper GI series - double-contrast; shows "niche" sign for DU; radiating folds toward GU crater
• CT scan - preferred for suspected perforation; more sensitive than erect CXR; differentiates from pancreatitis
• Serum gastrin - check if unusual ulcer location (distal DU, jejunal), H. pylori-negative, NSAID-negative, or multiple ulcers (to rule out ZES)
• Schwartz's Principles of Surgery, 11th Ed., p. 1143
• Bailey & Love's Short Practice of Surgery, 28th Ed.

9. Medical Treatment

Step 1: Test and Treat for H. pylori

• PPI (standard dose twice daily) + Clarithromycin 500 mg BD + Amoxicillin 1 g BD

• PPI BD + Bismuth subcitrate QDS + Metronidazole 400 mg QDS + Tetracycline 500 mg QDS

• PPI BD + Clarithromycin + Amoxicillin + Metronidazole (all twice daily)
• Eradication should be confirmed 4-6 weeks after completion of therapy using UBT or stool antigen (PPIs should be stopped 2 weeks prior)
• Failure after two courses warrants culture and sensitivity testing and specialist referral
• The Maastricht V/Florence Consensus guidelines provide current recommendations stratified by regional resistance patterns

• Schwartz's Principles of Surgery, 11th Ed., p. 1147

Step 2: Acid Suppression

• PPIs (omeprazole, lansoprazole, esomeprazole) - render patient effectively achlorhydric; heal all benign ulcers, the majority within 2 weeks; symptom relief within days
  • DU: 4 weeks; GU: 6-8 weeks
• H₂-receptor antagonists (ranitidine, famotidine) - historically important; effective but slower than PPIs; still used in some settings
• All gastric antisecretory agents have a high relapse rate once stopped (unless H. pylori eradicated)

Step 3: NSAID Management

• Stop NSAID if possible
• If NSAID must be continued: use lowest effective dose, add PPI; consider switching to a COX-2-selective inhibitor
• Misoprostol (prostaglandin E₁ analogue) at 200 µg QDS effectively reduces NSAID-induced ulcers (MUCOSA trial: clinical UGI events halved); limited by GI side effects (diarrhea)

Lifestyle Modifications

• Stop smoking (impairs mucosal blood flow and healing)
• Avoid known NSAIDs/aspirin unless essential
• Dietary modifications (avoid personal trigger foods)

10. Complications and Their Management

10.1 Hemorrhage (Most Common Complication)

• Most common serious complication; most peptic ulcer-related deaths are from bleeding
• Presents with hematemesis, melena, or hematochezia (massive bleed)
• Posterior DU - erosion into the gastroduodenal artery; risk of life-threatening hemorrhage

• Rockall Score (pre- and post-endoscopy): integrates age, comorbidity, diagnosis, endoscopic stigmata
  • Score 0-2: low risk (mortality <1%); score ≥8: mortality 41%
• AIMS65 score (Albumin <3, INR >1.5, altered Mental status, Systolic BP <90, age ≥65): predicts in-hospital mortality

• Resuscitation (blood transfusion; target Hb ~7-9 g/dL unless cardiovascular disease)
• High-dose IV PPI (bolus + infusion): reduces rebleeding; no acid = stable clot
• Endoscopic hemostasis - injection (epinephrine), thermal coagulation (heater probe, APC), or mechanical (clips); most (75%) stop with conservative management
• Endoscopic re-treatment for rebleeding
• Surgery (if endoscopic hemostasis fails twice): underrunning the bleeding vessel (DU); Billroth I/II gastrectomy for GU
• Sleisenger & Fordtran's Gastrointestinal and Liver Disease (Rockall score table)
• Schwartz's Principles of Surgery, 11th Ed., p. 1131

10.2 Perforation

• Incidence has changed little despite widespread PPI/eradication use
• Now predominantly affects elderly females on NSAIDs
• Most commonly: anterior DU perforating into the peritoneal cavity; posterior ulcers erode (penetrate) into the pancreas

• Sudden-onset severe generalized abdominal pain - instantaneously recognized
• Board-like (peritonitic) rigidity; abdomen immobile with respiration
• Shock, tachycardia; pyrexia develops hours later (bacterial peritonitis)
• Fluid may track to right iliac fossa mimicking appendicitis
• Atypical presentation in elderly (steroids blunt signs): higher index of suspicion required

Figure 67.12: Benign incisural gastric ulcer shown at gastroscopy. (Bailey & Love's Short Practice of Surgery, 28th Ed.)

• Erect CXR - free gas under diaphragm (>50% of cases)
• CT abdomen - most accurate; also rules out pancreatitis; serum amylase can be elevated in both (though usually lower in PUD perforation)
• ECG (to exclude inferior MI presenting as acute abdomen)

• Resuscitation + analgesia (adequate analgesia does NOT mask signs; it actually clarifies them)
• NG tube decompression, IV fluids, antibiotics
• Surgery - upper midline laparotomy (or laparoscopic approach); Graham patch repair (omental patch closure); add H. pylori eradication and PPI post-operatively
• Conservative management (Taylor's method: NG suction, IV PPIs, antibiotics) may be considered in carefully selected stable patients where perforation may have sealed spontaneously
• Bailey & Love's Short Practice of Surgery, 28th Ed., pp. 1186-1188
• Schwartz's Principles of Surgery, 11th Ed., p. 1134

10.3 Gastric Outlet Obstruction (Pyloric Stenosis)

• Most commonly associated with longstanding PUD and gastric cancer
• Results from chronic scarring/fibrosis at the pyloric channel or D1
• Presents with: repeated vomiting of undigested food, distension, succussion splash, weight loss
• Metabolic abnormality: hypochloremic hypokalemic metabolic alkalosis (loss of HCl and K+ in vomit); distinct from cancer-related obstruction (which lacks this pattern)
• Management: fluid/electrolyte correction; endoscopic balloon dilatation (first-line); surgery (antrectomy with gastrojejunostomy or Billroth II) if dilatation fails or cancer excluded
• Bailey & Love's Short Practice of Surgery, 28th Ed., p. 1190 (Summary Box)

10.4 Malignant Transformation

• Duodenal ulcers do NOT undergo malignant transformation
• Gastric ulcers: Two scenarios
  1. Benign chronic gastric ulcer undergoes malignant transformation - rare
  2. An ulcer assessed endoscopically as benign proves on biopsy to be malignant - more common; hence all gastric ulcers must be biopsied
• The underlying risk: H. pylori → chronic gastritis → atrophy → intestinal metaplasia → dysplasia → adenocarcinoma (Correa cascade)
• Bailey & Love's Short Practice of Surgery, 28th Ed.

10.5 Penetration

• Posterior gastric/DU erodes into adjacent structures without free perforation:
  • Posterior DU → pancreas (causes pancreatitis; amylase rises)
  • Gastric ulcer → splenic artery (risk of hemorrhage), transverse colon (gastrocolic fistula)
• Pain becomes constant, radiates to the back; loses meal periodicity

11. Surgical Treatment

Historic Surgical Procedures (now rarely for elective use)

• Bailey & Love's Short Practice of Surgery, 28th Ed., Table 67.2

Post-Gastrectomy Syndromes (~30% of patients)

• Early dumping (20-30 min post-prandially): hyperosmolar chyme dumps into small intestine → fluid shifts → vasomotor symptoms (flushing, palpitations, dizziness) + GI symptoms (cramps, diarrhea)
• Late dumping (1-3 hours post-prandially): hypoglycemia secondary to reactive insulin surge
• Bilious vomiting/bile reflux gastritis
• Small stomach syndrome: early satiety, weight loss
• Diarrhea (especially post vagotomy)
• Malnutrition/malabsorption: iron, B12, folate deficiency; post-gastrectomy osteoporosis (calcium malabsorption)
• Malignant transformation: increased gastric remnant cancer risk after Billroth II

12. Special Situations

Zollinger-Ellison Syndrome (ZES)

• Gastrin-secreting tumor (gastrinoma), usually in the duodenum or pancreas (the "gastrinoma triangle")
• 25% associated with MEN-1
• Massive acid hypersecretion → multiple ulcers in atypical locations (distal duodenum, jejunum), refractory to standard treatment
• Diagnosis: fasting serum gastrin >1000 pg/mL (diagnostic) or secretin stimulation test (paradoxical gastrin rise >200 pg/mL)
• Treatment: high-dose PPI; surgical resection; octreotide for metastatic disease

NSAID-Induced Ulcer Prevention

• COX-2 inhibitors + PPI: most effective prophylaxis in high-risk patients
• Misoprostol: effective but poorly tolerated

PUD in Pregnancy

• Covered briefly by Creasy & Resnik; PPIs (omeprazole) generally safe; avoid misoprostol (uterotonic); H. pylori eradication may be deferred post-partum

13. H. pylori Eradication - Indications (ACG Guidelines)

• Active peptic ulcer disease (gastric or duodenal)
• Confirmed history of PUD not previously treated for H. pylori
• Gastric MALT lymphoma (low grade)
• After endoscopic resection of early gastric cancer
• Uninvestigated dyspepsia (depending on prevalence)

• Nonulcer dyspepsia
• GERD
• Persons using NSAIDs
• Unexplained iron deficiency anemia
• Populations at higher risk for gastric cancer
• Schwartz's Principles of Surgery, 11th Ed., Table 26-8

14. Summary (Key Points)

Recent Evidence (PubMed, 2024-2026)

• A 2025 systematic review and meta-analysis (PMID: 40281437) reported on the prevalence and patterns of PUD across Africa, noting high H. pylori rates as a dominant etiological driver in that region.
• A 2026 systematic review (PMID: 41236450) in Gastroenterology quantified the broader disease burden of H. pylori beyond gastric cancer, strengthening the evidence for mass eradication strategies to reduce PUD burden globally.

• Robbins & Cotran Pathologic Basis of Disease, 10th Ed. (Kumar et al.), pp. 718-720
• Robbins & Kumar Basic Pathology, pp. 3903-3910
• Sleisenger & Fordtran's Gastrointestinal and Liver Disease, pp. 305+
• Schwartz's Principles of Surgery, 11th Ed., pp. 1125-1136, 1143-1152
• Bailey & Love's Short Practice of Surgery, 28th Ed., pp. 1174-1190
• Guyton & Hall Textbook of Medical Physiology, pp. 825-828
• Yamada's Textbook of Gastroenterology, 7th Ed., Chapter 49