Peptic Ulcer Disease - A Comprehensive Review

1. Definition

Bailey and Love's Short Practice of Surgery, 28th Edition

2. Sites of Occurrence

• First part of the duodenum (most common, ~95% of duodenal ulcers within the duodenal cap)
• Gastric antrum / lesser curvature (especially at or near the angularis incisura)
• Prepyloric region
• Lower oesophagus (due to reflux of acid or ectopic gastric mucosa)
• Stomal (marginal) ulcers at gastrojejunostomy sites
• Meckel's diverticulum containing ectopic gastric epithelium

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

3. Epidemiology

• Affects >4 million individuals in the United States annually
• Lifetime risk: approximately 10% for males and 4% for females
• More than 100,000 hospitalizations/year in the US related to bleeding peptic ulcer
• Duodenal ulcers are more common than gastric ulcers
• The incidence of H. pylori-associated ulcers is declining as eradication rates improve; NSAID-related ulcers are proportionally increasing, particularly in the elderly using low-dose aspirin

Robbins & Kumar Basic Pathology; Sleisenger and Fordtran's Gastrointestinal and Liver Disease

4. Aetiology and Risk Factors

4.1 Helicobacter pylori Infection

• >70% of PUD cases are associated with H. pylori infection
• H. pylori colonises the gastric antrum and first portion of the duodenum, causing chronic active gastritis as the background for ulceration
• Only 5-10% of infected individuals develop peptic ulcers, indicating a role for host factors and bacterial strain variation (e.g., CagA, VacA virulence factors)
• Mechanism of injury (Mulholland & Greenfield's Surgery):
  • Endocrine effects: increased basal serum gastrin, increased gastrin response to meals, increased responsiveness to gastrin-releasing peptide, production of N-alpha-methylhistamine, decreased somatostatin cell density and mucosal somatostatin content
  • Acid hypersecretion: increased basal and pentagastrin-stimulated acid output, abnormal gastric emptying
  • Mucosal defense impairment: decreased duodenal bicarbonate production, decreased mucosal prostaglandin production, increased epithelial cell apoptosis, disrupted epithelial barrier function, inhibited epithelial restitution
• The bacterium physically burrows through the mucosal barrier and releases urease, generating ammonium that liquefies the mucous layer and stimulates HCl secretion
• Mucosal inflammatory cells and epithelial cells release cytokines (IL-8, IFN-gamma, TNF-alpha) which stimulate gastrin release from G cells
• After H. pylori eradication: basal acid output returns to normal within 4 weeks; peak acid output declines to normal by 6 months

4.2 NSAIDs and Aspirin

• NSAIDs block cyclooxygenase (COX) enzymes, reducing mucosal prostaglandin synthesis
• Prostaglandins normally stimulate mucus and bicarbonate secretion, maintain mucosal blood flow, and promote epithelial restitution
• NSAID use is now the most common cause of gastric ulcers in the US as H. pylori rates fall
• Low-dose aspirin use in the ageing population is a significant and growing contributor

4.3 Zollinger-Ellison Syndrome (Gastrinoma)

• Gastrin-secreting tumour (usually in the pancreas or duodenal wall) causes massive, constitutive acid hypersecretion
• Results in multiple peptic ulcerations in the stomach, duodenum, and even jejunum
• In gastrinoma, acid hypersecretion is the sole aetiological factor
• High BAO (often >30 mEq/h, consistently >15 mEq/h); BAO:MAO ratio >0.6

4.4 Other Contributing Factors

Robbins & Kumar Basic Pathology; Guyton and Hall Medical Physiology; Mulholland & Greenfield's Surgery

5. Pathogenesis - The Mucosal Defence Model

Aggressive Forces:

• Hydrochloric acid (H+)
• Pepsin
• Bile salts (duodenogastric reflux)
• H. pylori toxins, enzymes (urease, proteases, phospholipases)
• NSAIDs

Defensive Mechanisms:

1. Mucous layer - secreted by surface epithelial cells (SECs), acts as a "physiological bandage"
2. Bicarbonate secretion - creates a near-neutral pH gradient at the cell surface despite an acidic lumen; lower bicarbonate secretion in proximal duodenum is demonstrated in duodenal ulcer patients
3. Mucosal blood flow - delivers nutrients and oxygen; augmented during repair
4. Prostaglandins (PGE2, PGI2) - key mediators of mucus/bicarbonate secretion and blood flow
5. Epithelial restitution - healthy SECs migrate from the periphery to reconstitute a damaged surface layer within minutes to hours
6. Pancreatic bicarbonate - neutralises acid in the duodenum via Brunner's glands and pancreatic secretion
7. Duodenal acid feedback - rising duodenal acidity inhibits gastric secretion and emptying via neural and hormonal reflexes (secretin release stimulates pancreatic HCO3-)

Guyton and Hall Medical Physiology; Mulholland & Greenfield's Surgery; Current Surgical Therapy 14e

6. Classification of Gastric Ulcers (Modified Johnson Classification)

Current Surgical Therapy 14e

7. Pathology (Gross and Microscopic)

Gross Features:

• Sharply punched-out, circular or oval mucosal defect
• Gastric ulcers: typically on the lesser curvature; duodenal ulcers: typically on the anterior or posterior wall of the first part
• Edges are clean-cut, perpendicular (not heaped up or overhanging - features that suggest malignancy)
• Base may show a gray-white fibrinous exudate
• Surrounding mucosa shows folds radiating toward the ulcer margin (in benign ulcers)

Microscopic Features (Robbins Pathology, 4-layer pattern):

1. Superficial zone - fibrinopurulent exudate
2. Necrotic zone - coagulative necrosis
3. Granulation tissue layer - prominent, active
4. Fibrotic scar - deepest layer extending into muscularis propria or beyond

Robbins & Kumar Basic Pathology

8. Clinical Features

Symptoms:

• Epigastric pain (burning, gnawing, or aching) - the cardinal symptom
  • Duodenal ulcer: typically relieved by food (classically: hunger pain, food relief, recurrence 2-4 hours after meals); pain often wakes patient at night (2-4 AM)
  • Gastric ulcer: pain precipitated or worsened by food; this distinction is not always reliable
• Nausea and vomiting
• Heartburn / waterbrash
• Weight changes: gastric ulcer patients are often underweight; duodenal ulcer patients may gain weight (eating relieves pain)
• Bleeding: chronic blood loss presenting as microcytic (iron-deficiency) anaemia, or acute haematemesis/melaena

Note on Symptom Overlap:

Clinical Examination:

• Epigastric tenderness on palpation (most common finding)
• Succession splash (in gastric outlet obstruction)
• Peritonism (in perforation)

Bailey and Love's Short Practice of Surgery, 28th Edition; Yamada's Textbook of Gastroenterology

9. Investigation

9.1 Endoscopy (Gastroduodenoscopy) - Gold Standard

• Essential to confirm diagnosis and exclude malignancy (all gastric ulcers must be biopsied - multiple biopsies from the ulcer margin and base)
• Allows CLO (Campylobacter-like organism) test for H. pylori
• Duodenal ulcers in typical location in young patients generally do not require biopsy (very low malignancy risk)
• Follow-up endoscopy at 6-8 weeks mandatory for gastric ulcers to confirm healing

9.2 Tests for H. pylori

9.3 Gastric Acid Analysis (Rarely Used Now)

• Useful when hypergastrinemia or Zollinger-Ellison syndrome is suspected
• Normal BAO >5 mEq/h; MAO 10-15 mEq/h
• Gastrinoma: BAO often >30 mEq/h; BAO:MAO ratio >0.6

9.4 Fasting Serum Gastrin

• Elevated in ZES, chronic atrophic gastritis, renal failure
• Provocation with IV secretin (paradoxical gastrin rise in gastrinoma)

9.5 Barium Meal (Historical)

• Largely replaced by endoscopy but may be used if endoscopy is unavailable

Bailey and Love's Short Practice of Surgery, 28th Edition; Schwartz's Principles of Surgery, 11th Edition

10. Medical Management

10.1 Lifestyle Modification

• Cessation of cigarette smoking
• Avoidance of NSAIDs, aspirin (or use of selective COX-2 inhibitors + PPI cover)
• Alcohol moderation
• These measures alone are insufficient without pharmacological treatment

10.2 Proton Pump Inhibitors (PPIs)

• Standard of care for acid suppression
• Irreversibly inhibit the H+/K+-ATPase proton pump on parietal cells
• Render patients virtually achlorhydric
• Healing rates: duodenal ulcer ~90% at 4 weeks; gastric ulcer ~80-85% at 8 weeks
• Examples: omeprazole, lansoprazole, pantoprazole, esomeprazole, rabeprazole

10.3 H2-Receptor Antagonists

• Block histamine-stimulated acid secretion via H2 receptors on parietal cells
• Reduce acid secretion by 70-80% (ranitidine, famotidine, cimetidine)
• Less effective than PPIs; largely superseded but still used

10.4 Potassium-Competitive Acid Blockers (P-CABs)

• Newer agents (e.g., vonoprazan) that competitively bind the potassium-binding region of the proton pump
• Faster onset and more prolonged acid suppression than PPIs
• Increasingly incorporated into H. pylori eradication regimens

Guyton and Hall Medical Physiology; Bailey and Love's Short Practice of Surgery

11. H. pylori Eradication

• 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 H. pylori prevalence)

• Non-ulcer (functional) dyspepsia
• GERD
• NSAID users
• Unexplained iron-deficiency anaemia
• Populations at higher risk for gastric cancer

Eradication Regimens:

• PPI + Clarithromycin + Amoxicillin (or Metronidazole)
• Eradication rates ~70-85% (declining due to clarithromycin resistance)

• PPI + Bismuth subcitrate + Tetracycline + Metronidazole
• Eradication rates >90%; preferred in areas of high clarithromycin resistance

• PPI + Clarithromycin + Amoxicillin + Metronidazole simultaneously

Schwartz's Principles of Surgery, 11th Edition

12. Complications

12.1 Haemorrhage (Most Common Complication)

• Accounts for ~50% of upper GI bleeds historically
• Presents with: haematemesis, melaena, or iron-deficiency anaemia
• Three-quarters of bleeding peptic ulcers stop spontaneously with acid suppression and bowel rest
• One-quarter continue to bleed or rebleed - these carry nearly all mortality and morbidity

• Rockall Score (uses clinical + endoscopic criteria): score ≥3 = high risk for rebleeding/death (see table)
• Blatchford Score (no endoscopy required): score ≤1 = low risk, safe for early discharge
• High-risk endoscopic stigmata: active spurting/oozing, visible vessel (Forrest Ia/Ib/IIa), adherent clot

• Resuscitation, IV PPI (bolus + infusion)
• Early endoscopy (within 24 hours; within 12 hours for high-risk)
• Endoscopic haemostasis: injection (adrenaline), thermal coagulation (bipolar/heater probe), clips - combination therapy preferred
• Rebleeding despite endoscopic treatment: repeat endoscopy; if fails - interventional radiology (transcatheter arterial embolisation) or surgery
• Surgery: underrunning of the bleeding vessel (for duodenal ulcer) + vagotomy/pyloroplasty

Sleisenger and Fordtran's Gastrointestinal and Liver Disease; Schwartz's Principles of Surgery, 11th Edition

12.2 Perforation (Peritonitis)

• Free perforation of anterior wall ulcers into the peritoneal cavity (especially anterior duodenal ulcers)
• Classical presentation: sudden-onset severe epigastric pain ("board-like" rigidity), peritonism, absent bowel sounds
• Erect chest X-ray: pneumoperitoneum (free gas under the diaphragm) in ~70-80% of cases
• CT abdomen: more sensitive for free gas and peritoneal fluid
• Management:
  • Resuscitation (IV fluids, NG decompression, urinary catheter, IV PPI + antibiotics)
  • Emergency surgery: laparoscopic or open Graham patch repair (omentoplasty) - oversewing the perforation and covering with an omental patch
  • Concurrent H. pylori eradication reduces recurrence
  • Definitive acid-reducing surgery (vagotomy) rarely indicated in the modern era unless truly refractory

12.3 Penetration

• Ulcer erodes through the gastric or duodenal wall into an adjacent organ without free perforation
• Posterior duodenal ulcers most commonly penetrate into the pancreas (causing back pain, elevated amylase)
• Other structures: biliary tree (cholecystitis), liver, colon (gastrocolic fistula)
• Gastrocolic fistula: severe diarrhoea after every meal, foul breath, faeculent vomiting, rapid weight loss - treated with surgical repair after nutritional optimisation

12.4 Gastric Outlet Obstruction (Pyloric Stenosis)

• Caused by oedema (acute, reversible) or fibrotic stenosis (chronic, irreversible) due to longstanding ulcer at the pylorus or first part of duodenum
• Presents with: projectile non-bilious vomiting, succession splash, early satiety, profound weight loss
• Metabolic consequence: hypochloraemic, hypokalaemic metabolic alkalosis with paradoxical aciduria
• Investigation: endoscopy (confirms diagnosis, exclude malignancy), barium meal (shows pyloric narrowing), serum electrolytes
• Management:
  • Correct fluid/electrolyte imbalance (IV saline + KCl)
  • NG decompression and gastric lavage
  • H. pylori eradication + PPI
  • Endoscopic balloon dilatation (for fibrous stenosis)
  • Surgery (gastrojejunostomy or antrectomy with Billroth reconstruction) if endoscopic therapy fails

Bailey and Love's Short Practice of Surgery, 28th Edition

13. Surgical Treatment

13.1 Procedures for Acid Reduction:

• Truncal vagotomy - division of both vagal trunks at the oesophageal hiatus; eliminates cephalic-phase acid stimulation; requires drainage procedure (pyloroplasty or gastroenterostomy) because it causes gastric atony
• Selective vagotomy - division of only the gastric branches of the vagus; less morbidity than truncal; also requires drainage
• Highly selective (proximal gastric) vagotomy - denervates only the acid-secreting fundus/corpus, preserving antral/pyloric innervation; no drainage needed; lowest complication rate
• Antrectomy - removes the gastrin-secreting antrum; combined with vagotomy for best results (Billroth I or II reconstruction)
• Pyloroplasty (Heineke-Mikulicz) - full-thickness longitudinal incision through the pylorus closed transversely, used as a drainage procedure accompanying vagotomy

13.2 Post-Surgical Complications ("Post-gastrectomy Syndromes"):

• Dumping syndrome (early/late)
• Diarrhoea (postvagotomy)
• Small stomach syndrome / early satiety
• Recurrent (stomal) ulceration
• Gastrocolic fistula
• Afferent loop syndrome
• Alkaline reflux gastritis

Bailey and Love's Short Practice of Surgery, 28th Edition; Current Surgical Therapy 14e

14. Special Situations

Peptic Ulcer in Pregnancy

• Pregnancy generally has a protective effect on PUD - elevated progesterone reduces acid secretion and motility; higher prostaglandin levels protect the mucosa
• Symptoms often improve during pregnancy and relapse post-partum
• Treatment: antacids, sucralfate (preferred, not absorbed); PPIs if necessary (omeprazole, generally considered safe in 2nd/3rd trimester); H. pylori eradication deferred until after delivery (antibiotics restricted)

Creasy & Resnik's Maternal-Fetal Medicine

Stress Ulcers (Curling's and Cushing's Ulcers)

• Curling's ulcer: stress ulcers associated with severe burns (reduced plasma volume and mucosal ischaemia)
• Cushing's ulcer: stress ulcers associated with head injury or intracranial hypertension (vagally mediated acid hypersecretion)
• Both may perforate and bleed; prophylaxis with PPI or H2 blockers is standard in ICU patients

15. Summary

Key References

• Bailey and Love's Short Practice of Surgery, 28th Edition (Chapter 67 - Peptic Ulceration)
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease (Chapter 20 - UGI Bleeding / Peptic Ulcer)
• Robbins & Kumar Basic Pathology (Chapter 13 - Gastrointestinal Tract)
• Guyton and Hall Textbook of Medical Physiology (Chapter 67 - Peptic Ulcer)
• Schwartz's Principles of Surgery, 11th Edition (Chapter 26 - Stomach and Duodenum)
• Mulholland and Greenfield's Surgery, 7th Edition (Chapter 45 - Peptic Ulcer Disease)
• Current Surgical Therapy, 14th Edition (Benign Gastric Ulcer; Perforated Peptic Ulcer sections)
• Creasy & Resnik's Maternal-Fetal Medicine (Peptic Ulcer Disease in Pregnancy)

Recent Evidence Note (2025-2026): A 2026 systematic review in Gastroenterology (PMID 41236450) quantified the substantial disease burden of H. pylori beyond gastric cancer, including peptic ulcer morbidity and mortality, arguing for wider mass eradication strategies. A 2025 meta-analysis (PMID 40281437) documented the prevalence and patterns of PUD in Africa, highlighting the continued high H. pylori contribution in lower-income regions. These findings reinforce the continued centrality of H. pylori eradication in global PUD management.