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Acid Peptic Disorders - Comprehensive Notes

Definition

1. Gastroesophageal Reflux Disease (GERD)
2. Peptic Ulcer Disease (PUD) - gastric and duodenal ulcers
3. Gastritis / Duodenitis
4. Stress-related mucosal injury
5. Non-ulcer (functional) dyspepsia
6. Zollinger-Ellison syndrome (rare)

A peptic ulcer is defined as a mucosal defect ≥0.5 cm in diameter that penetrates the muscularis mucosae. Smaller defects are called erosions.

• Goldman-Cecil Medicine, p. 1441

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Epidemiology

• PUD affects >4 million individuals in the US annually; lifetime risk ~10% in males, ~4% in females
• Duodenal ulcers are 2-3x more common than gastric ulcers

• 90% of peptic ulcers are caused by H. pylori infection or NSAID use

• H. pylori rates are falling in developed countries; NSAID-related gastric ulcers are rising

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Pathophysiology

Balance of Aggressive vs. Defensive Factors

Physiology of Acid Secretion

1. Gastrin (from antral G cells) → CCK-B/gastrin receptor → ↑ intracellular Ca²⁺
2. Acetylcholine (vagal postganglionic neurons) → M3 receptor → ↑ Ca²⁺
3. Histamine (from ECL cells) → H2 receptor → ↑ cAMP → PKA activation

• Katzung's Basic & Clinical Pharmacology, 16th Ed., p. 1695

H. pylori Mechanism

• Gram-negative spiral bacterium colonizing gastric antrum and body
• Prevalence: ~70% of PUD cases are H. pylori-associated; however only 5-10% of infected individuals develop ulcers (suggesting host + strain variation)
• Virulence factors: urease (generates ammonia, neutralizes local acid), cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA)
• Pathogenic mechanism:
  • Disrupts mucus layer integrity
  • Induces inflammation (gastritis) → mucosal barrier breaks down
  • Antral-predominant gastritis → ↓ somatostatin → ↑ gastrin → ↑ acid (duodenal ulcer pattern)
  • Corpus-predominant or pangastritis → ↓ acid secretion (gastric ulcer / atrophy pattern)
  • Promotes epithelial apoptosis and impairs restitution

NSAID Mechanism

• NSAIDs inhibit COX-1 enzyme → ↓ prostaglandin (PGE2, PGI2) synthesis
• Prostaglandins normally:
  • Stimulate mucus and bicarbonate secretion
  • Maintain mucosal blood flow
  • Inhibit acid secretion
• NSAIDs also have direct topical toxicity (weak acids that accumulate in epithelial cells, causing mitochondrial uncoupling)
• COX-2 selective inhibitors (coxibs) have reduced GI toxicity but increased CV risk

H. pylori vs. NSAID Ulcers - Key Differences

Other Causes

• Zollinger-Ellison syndrome: Gastrin-secreting tumor (gastrinoma) → constitutive hypergastrinemia → massive acid → multiple ulcers in stomach, duodenum, and jejunum. Suspect if ulcers are refractory, multiple, or associated with diarrhea.
• Stress ulcers: ICU patients (burns - Curling's ulcer; brain injury - Cushing's ulcer); impaired mucosal blood flow
• Other: Hypercalcemia (hyperparathyroidism, CRF) stimulates gastrin; cirrhosis; COPD; corticosteroids (reduce prostaglandins); cigarette smoking (↓ mucosal blood flow + bicarbonate)
• Robbins & Kumar Basic Pathology, p. 3905

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Clinical Features

Symptoms

• Heartburn / acid regurgitation (associated GERD or hyperacidity)
• Nausea and vomiting
• Waterbrash (sudden mouth filling with saliva)
• Anemia (chronic occult blood loss → microcytic anemia)
• Hematemesis / melena (acute bleeding)

Alarm Symptoms (Warrant Urgent Endoscopy)

• Unintentional weight loss
• Dysphagia / odynophagia
• Persistent vomiting
• Iron deficiency anemia / occult blood
• Palpable mass
• Age >55 with new-onset dyspepsia

Complications

• Bailey and Love's Short Practice of Surgery, 28th Ed.

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Investigations

1. Upper GI Endoscopy (Gold Standard)

• First-line investigation for suspected APD
• Can diagnose ulcers, erosions, gastritis, malignancy
• Immediate indications: alarm symptoms, overt GI bleeding
• In gastric ulcers: multiple biopsies mandatory to exclude malignancy
• Biopsies from antrum: histology + CLO (Campylobacter-like organism) test for H. pylori
• "U-manoeuvre" to inspect lesser curvature, incisura, and GOJ

2. Tests for H. pylori

Note: Stop PPIs 2 weeks and antibiotics 4 weeks before urea breath test or stool antigen test to avoid false negatives.

3. Barium Meal (Upper GI Series)

• Now largely replaced by endoscopy
• Gastric ulcer: niche/crater with Hampton's line (thin lucent line = ulcer margin); radiating mucosal folds
• Duodenal ulcer: deformed duodenal cap/bulb ("cloverleaf" deformity in chronic disease)
• Cannot differentiate benign from malignant

4. Laboratory Tests

• CBC: microcytic anemia (chronic blood loss)
• Serum gastrin: elevated in Zollinger-Ellison syndrome (>1000 pg/mL); measure after stopping PPI
• Serum calcium / PTH: rule out hyperparathyroidism if multiple/refractory ulcers
• LFTs, renal function: assess comorbidities affecting drug choice
• Coagulation screen (if bleeding)

5. Radiology

• Erect CXR: free air under diaphragm in perforation (seen in ~80%)
• CT abdomen: better for perforation, penetration, obstruction, malignancy staging

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Treatment

General Principles

1. Relieve symptoms
2. Heal the ulcer
3. Eradicate H. pylori (if present)
4. Prevent recurrence and complications

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A. Agents That Reduce Intragastric Acidity

1. Proton Pump Inhibitors (PPIs) - First-Line

• Mechanism: Irreversible covalent inhibition of H⁺/K⁺-ATPase on parietal cell canalicular membrane. Prodrugs activated in acidic environment of canaliculus → sulfenamide derivative binds covalently to cysteine residues on proton pump.
• Must be taken 30-60 minutes before meals (proton pumps must be active for drug to work)
• Duration of action exceeds plasma t½ (>24h due to irreversible binding); acid secretion resumes only when new proton pumps are synthesized (~18h)

• Katzung's Basic & Clinical Pharmacology, 16th Ed., p. 1698

2. H2-Receptor Antagonists (H2RAs)

• Mechanism: Competitive antagonists of histamine at H2 receptors on parietal cells → ↓ cAMP → ↓ acid secretion
• Less effective than PPIs; used for mild-moderate disease or maintenance

3. Antacids

• Neutralize secreted HCl; rapid symptom relief but no ulcer healing
• Magnesium hydroxide (laxative), aluminum hydroxide (constipating), calcium carbonate
• Best used as symptom rescue, not primary therapy
• Magnesium-containing antacids can cause diarrhea; aluminum-containing can cause constipation

4. Anticholinergics (Muscarinic Antagonists)

• Pirenzepine (selective M1 antagonist): reduces acid but with significant anticholinergic side effects; largely obsolete

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B. Agents That Enhance Mucosal Defense

1. Sucralfate

• Aluminum salt of sulfated sucrose; at pH <4, forms viscous paste that adheres to ulcer base, protecting it from acid and pepsin
• Stimulates PGE synthesis and mucus secretion
• Must be taken on empty stomach, 1h before meals
• Does not inhibit acid; requires acid-free gap from antacids/PPIs
• Use: DU, NSAID prophylaxis, stress ulcer prevention
• SE: Constipation, aluminum accumulation (renal failure)

2. Misoprostol

• Synthetic PGE1 analogue → ↑ mucus and bicarbonate secretion, ↓ acid secretion, ↑ mucosal blood flow
• Indicated for NSAID-induced ulcer prevention
• Dose: 200 mcg QID with food
• SE: Diarrhea (30%), abdominal cramps; contraindicated in pregnancy (uterotonic)

3. Bismuth Compounds (Bismuth Subcitrate / Subsalicylate)

• Topical effects: coats ulcer base; bactericidal against H. pylori
• Used as part of quadruple therapy for H. pylori eradication
• SE: Black stools, constipation; long-term high-dose bismuth encephalopathy

4. Rebamipide, Ecabet (Less common)

• Enhance prostaglandin synthesis and scavenge free radicals; used mainly in Asia

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C. H. pylori Eradication Therapy

• Active gastric or duodenal ulcer
• History of PUD (even if not currently active)
• Gastric MALT lymphoma
• After resection of early gastric cancer
• Uninvestigated dyspepsia (test-and-treat in low-risk patients <55 yrs)
• First-degree relatives of gastric cancer patients
• Prior to long-term NSAID therapy

First-Line Regimens

• PPI (standard dose BD) + Clarithromycin 500 mg BD + Amoxicillin 1g BD
  • Eradication rate: ~70-85% (declining due to clarithromycin resistance)

• PPI + Clarithromycin 500 mg BD + Metronidazole 400 mg BD

• Bismuth 120 mg QID + Tetracycline 500 mg QID + Metronidazole 400 mg TID + PPI BD

• PPI + Amoxicillin + Clarithromycin + Metronidazole (all simultaneously)

• PPI BD + Levofloxacin 500 mg OD + Amoxicillin 1g BD

Post-Eradication Confirmation

• Urea breath test or stool antigen test at least 4-6 weeks after completing therapy and ≥2 weeks after stopping PPI
• Endoscopic confirmation (with repeat biopsy) reserved for gastric ulcers at follow-up to confirm healing and exclude malignancy
• Bailey and Love's Short Practice of Surgery, 28th Ed., p. 8920-8921

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D. Management of NSAID-Induced Ulcers

1. Stop NSAID if clinically possible
2. If NSAID must be continued:
   • Switch to COX-2 selective inhibitor (lower GI risk)
   • Add PPI (preferred) or misoprostol
3. Treat with PPI for 4-8 weeks (gastric ulcers heal more slowly than duodenal)
4. Test and treat H. pylori if positive (both factors are additive in risk)

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E. GERD Treatment

1. Lifestyle: Weight loss, head-of-bed elevation, avoid late meals, alcohol, caffeine, fatty foods, chocolate, tobacco
2. PPI OD (before breakfast) - most effective; use lowest effective dose for maintenance
3. H2RA (nocturnal): add to PPI for breakthrough nocturnal symptoms
4. Antireflux surgery (Nissen fundoplication): for medically refractory GERD or in young patients wanting to avoid lifelong drugs; laparoscopic approach
5. Prokinetics (metoclopramide, domperidone): adjunctive; improve LES tone and gastric emptying

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F. Stress Ulcer Prophylaxis

• Indicated in ICU patients with: mechanical ventilation >48h, coagulopathy, burns (>35% BSA), head injury, shock
• Preferred agent: PPI IV (pantoprazole 40 mg OD)
• Alternative: H2RA IV (famotidine)
• Sucralfate: nasogastric route; some evidence for lower pneumonia risk (less acid suppression)

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G. Zollinger-Ellison Syndrome

1. High-dose PPI (omeprazole 60-120 mg/day or equivalent) - controls acid hypersecretion
2. Localize and resect the gastrinoma if feasible (CT, MRI, octreotide scan / somatostatin receptor scintigraphy)
3. Long-term PPI maintenance if tumor non-resectable

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H. Surgical Treatment

• Emergency: Perforation (patch repair / laparoscopic washout), uncontrolled bleeding (endoscopy ± surgery), obstruction
• Elective: Rare - medically refractory ulcers, suspicion of malignancy

• Truncal vagotomy + pyloroplasty: Reduces acid (vagal denervation) + drainage procedure
• Highly selective (proximal) vagotomy: Denervates acid-secreting body only, preserves pyloric function; lowest complication rate
• Billroth I (gastroduodenostomy) or Billroth II (gastrojejunostomy): partial gastrectomy with reconstruction

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Summary Table: Key Drug Classes

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• Goldman-Cecil Medicine, International Ed. (Chapter 125)
• Bailey and Love's Short Practice of Surgery, 28th Ed. (Chapter 67)
• Katzung's Basic and Clinical Pharmacology, 16th Ed. (Chapter 62)
• Goodman & Gilman's The Pharmacological Basis of Therapeutics (Chapter 53)
• Robbins & Kumar Basic Pathology