Peptic Ulcer Disease and Related Disorders¶
Chapter 335 | Part 10: Disorders of the Gastrointestinal System · Part 10 – Gastrointestinal Disorders · Chapter 335
Key Clinical Points¶
- H. pylori eradication reduces duodenal ulcer recurrence rates by >80%.
- NSAID toxicity is related to inhibition of COX-1 isoform, not COX-2.
- 90% of patients with dyspepsia do not have ulcers; >90% of patients with PUD are asymptomatic.
- DU incidence declined from 1960-1980 and has remained stable since; death rates decreased by >50% over past 30 years.
- Gastric acid secretion occurs in three phases: cephalic, gastric, and intestinal.
- Mucosal defense is a three-level barrier: preepithelial, epithelial, and subepithelial.
- H. pylori infection is associated with antral-predominant gastritis leading to DU, or corpus-predominant gastritis leading to GU.
- Selective COX-2 inhibitors (valdecoxib, rofecoxib) were removed from market due to CV risk.
- Gastric parietal cells express H+,K+-ATPase in secretory canaliculi for acid secretion.
- Lifetime overall prevalence of PUD in the United States is ~8.4%.
DEFINITION & OVERVIEW¶
• Peptic Ulcer: Definition (Harrison's 22e): "disruption of the mucosal integrity of the stomach and/or duodenum leading to a local defect or excavation due to active inflammation." • Clinical Context: Symptom Complex: Burning epigastric pain exacerbated by fasting and improved with meals (dyspepsia). Prevalence: >90% of patients with this symptom complex do not have ulcers; >90% of patients with PUD are asymptomatic. • Epidemiology: Incidence: 4 million individuals affected per year in the US. Lifetime Prevalence: ~8.4% in the United States (slightly higher in men). Impact: Significant impact on quality of life and work absenteeism; ~15,000 deaths annually from complications.
Esophageal Manifestations of Systemic Disease¶
• Scleroderma & Connective Tissue Disorders: Pathophysiology: Hypotensive LES and absent esophageal contractility; infiltration/destruction of muscularis propria with collagen deposition; reduced interstitial cells of Cajal. Clinical Features: Severe GERD; mild dysphagia (improved by upright position/liquids). Management: Anti-inflammatory therapy; esophageal dilation for strictures. • Dermatologic Diseases: Conditions: Lichen planus, pemphigus vulgaris, bullous pemphigoid, cicatricial pemphigoid, Behçet’s syndrome, epidermolysis bullosa. Clinical Features: Blisters, bullae, ulceration, webs, and strictures in proximal esophagus. Management: Topical/systemic anti-inflammatory therapy; esophageal dilation for strictures. • Foreign Bodies & Food Impaction: Causes: Peptic stricture, carcinoma, Schatzki ring, EoE, achalasia, or inattentive eating. Clinical Features: Complete obstruction, foaming at mouth, severe chest pain. Management: Endoscopic removal; Glucagon (1 mg IV) before dislodgement; evaluate for underlying cause.
EPIDEMIOLOGY¶
• Duodenal Ulcers (DUs): Incidence: 6–15% of Western population. Trends: Incidence declined 1960-1980; death rates/surgery needs decreased by >50% over last 30 years. H. pylori Impact: Eradication reduced recurrence rates by >80%. • Gastric Ulcers (GUs): Demographics: Peak incidence in 6th decade; >50% occur in males. Clinical Note: Often silent, presenting only after complications develop. • H. pylori Prevalence: Global Trend: Declined from 50–55% to 43% (2014-2020). US Statistics: ~30% overall; rare in childhood; higher rates in those born before 1950. • Risk Factors for PUD: High Impact: H. pylori infection (OR 3.7), NSAIDs (OR 3.3). Other Factors: Chronic obstructive lung disease (2.34), chronic renal insufficiency (2.29), current tobacco use (1.99), older age (1.67), enhanced socioeconomic status (1.46), obesity (1.18), diabetes (1.13). Additional Risks: SSRIs, gastric bypass surgery, and certain ethnicities/conditions (e.g., African-American race 1.20).
ETIOLOGY & PATHOPHYSIOLOGY¶
• Pathophysiological Basis: Definition: Breaks in mucosal surface >5 mm in size, with depth to the submucosa. Duodenal Ulcers (DUs): Location: >95% in first portion of duodenum; ~90% within 3 cm of pylorus. Size/Appearance: Usually ≤1 cm diameter; sharply demarcated; base often has eosinophilic necrosis and fibrosis. Malignancy: Extremely rare. Gastric Ulcers (GUs): Malignancy Risk: Can be malignant → must be biopsied upon discovery. Location: Often distal to the junction between antrum and acid-secreting mucosa. NSAID-related GUs: No chronic active gastritis; show chemical gastropathy (foveolar hyperplasia, edema of lamina propria). • H. pylori Pathogenesis: Microbiology: Gram-negative microaerophilic rod; S-shaped (~0.5–3 μm); multiple sheathed flagella. Adaptation: Produces urease to produce ammonia (alkalinizing pH); can become coccoid (dormant). Genetics: Genome: 1.65 million base pairs, ~1500 proteins. Virulence Factors: Urease: Essential for survival in acidic stomach; damages epithelial cells. Cag-PAI: Contains genes for Cag A and Pic B (induces cytokines). Vac A: Targets CD4 T cells; inhibits proliferation of B, CD8 T cells, macrophages, and mast cells. Other Factors: GGT, adhesins (BabA), proteases/phospholipases (break down mucus barrier). Impact on Acid: Can inhibit H+,K+-ATPase activity; alters gastrin release (increased) and somatostatin (decreased). Clinical Correlation: Antral-predominant gastritis → Duodenal Ulcer. _Corpus-predominant gastritis → Gastric Ulcer, atrophy, and cancer. • NSAID-Induced Disease: _Mechanism: Inhibition of COX-1 (housekeeping) and COX-2 (inflammation). Impact: Loss of prostaglandins (PGE_2, PGI_2) leads to reduced mucus/bicarbonate production and impaired blood flow. Scale: Over 30 million individuals take NSAIDs; >100 million prescriptions sold annually in the US.
Gastric Physiology and Acid Secretion¶
• Anatomy of Gastric Glands: Cardia: <5% area; contains mucous/endocrine cells. Oxyntic Mucosa (Corpus): 75% of glands; contain mucous neck, parietal, chief, endocrine, ECL, and enterochromaffin-like cells. Pyloric Glands (Antrum): Contain mucous and endocrine cells (including gastrin cells). • Parietal Cells: Structure: Located in neck/isthmus of oxyntic glands; contain tubulovesicles and apical canaliculi. Mechanism: H+,K+-ATPase expressed in membranes; requires high energy (30–40% of cell volume is mitochondria). • Mucosal Defense System: Three-Level Barrier: 1. Preepithelial: Mucus-bicarbonate-phospholipid layer (physicochemical barrier). 2. Epithelial: Surface cells secreting mucus, bicarbonate, prostaglandins. 3. Subepithelial: Robust blood flow to remove acid and provide nutrients. Key Mediators: Prostaglandins (PGE_2, PGI_2) maintain mucosal defense; Somatostatin (from D cells) inhibits G cells and ECL cells.
DIFFERENTIAL DIAGNOSIS¶
• Duodenal vs. Gastric Ulcers: Location: Duodenal ulcers are typically in the first part of the duodenum; gastric ulcers can be anywhere but must be biopsied to rule out malignancy. Morphology: DUs are usually <1 cm and sharply demarcated; GUs may show signs of chemical gastropathy if NSAID-related. • Dyspepsia vs. Peptic Ulcer: Prevalence: >90% of patients with dyspepsia do not have ulcers. Clinical Clues: Symptoms like burning epigastric pain are common to both; however, ulcer diagnosis requires confirmation via endoscopy or imaging. • Exclusionary Criteria for Dyspepsia: Rule out: GERD, biliary pain, IBS, aerophagia, and medication-related causes.
DIAGNOSTIC APPROACH¶
- Initial Screening: Identify patients >40 years old or with "Alarm symptoms" → Refer to gastroenterologist.
- Exclusionary Step: Rule out common causes (GERD, biliary pain, IBS, aerophagia, medication-related).
- Noninvasive H. pylori Testing: Rapid urease: 80–95/95–100% sensitivity; 60–90/>95% specificity. Urea breath test (UBT): >95/>95% sensitivity/specificity; useful for follow-up.
- Management of Positive H. pylori: Action: Initiate Anti-H. pylori therapy → Wait 4 weeks → Confirm eradication with UBT.
- Management of Negative H. pylori: Action: Start empiric trial of H_2 blocker.
Imaging and Endoscopy: Barium Study: Identifies "filling defects" (e.g., duodenal ulcer in first part of duodenum; gastric ulcer with distinct margins). Endoscopy: Direct visualization of mucosal integrity; required for all suspected gastric ulcers to rule out malignancy.
Specialized Testing: Gastrin Levels: Obtain fasting serum gastrin if: - Multiple ulcers or unusual locations (e.g., severe esophagitis). - Resistant to therapy with frequent recurrences. - Suspected Zollinger-Ellison Syndrome (ZES) (e.g., hypercalcemia, family history of neuroendocrine tumors). Zollinger-Ellison Screening: - Ultrasound (Sensitivity: 0–28% primary; 15–77% metastatic). - Selective angiography (Sensitivity: 35–68% primary; 96–100% metastatic). - SASI (Sensitivity: 55–78%). - OctreoScan (Sensitivity: 55–77% primary; 90–100% metastatic).
H. pylori Detection Methods¶
• Invasive Tests: Rapid urease: 80–95/95–100% (Simple, but false negative with recent PPI/antibiotic use). Culture: 76-90/100% (Time-consuming; allows determination of antibiotic susceptibility). • Noninvasive Tests: Urea breath test: >95/>95% (Simple, rapid; useful for follow-up).
MANAGEMENT & TREATMENT¶
- Acid Suppression Therapy: Antacids: Mylanta, Maalox, Tums, Gaviscon → 100–140 meq/L every 1 and 3 h after meals and hs. H2 receptor antagonists: Cimetidine, Famotidine. Proton pump inhibitors (PPIs):
- Omeprazole: 20 mg/d
- Lansoprazole: 30 mg/d
- Rabeprazole: 20 mg/d
- Pantoprazole: 40 mg/d
- Esomeprazole: 20 mg/d
- Dexlansoprazole: 30 mg/d
- Mucosal Protective Agents: Sucralfate: (Used for mucosal protection). Misoprostol: 200 μg qid.
- H. pylori Eradication Therapy: Decision Point: Based on Clarithromycin resistance level. Low Resistance (<15%):
- Clarithromycin triple: PPI (standard/double), Clarithromycin (500 mg), Amoxicillin (1 g) or Metronidazole (500 mg tid).
- Bismuth quadruple: PPI, Bismuth subcitrate (120–300 mg) or subsalicylate (300 mg), Tetracycline (500 mg), Metronidazole (250–500 mg). High/Unknown Resistance (>15%):
- Bismuth quadruple.
- Non-bismuth 4-drug: PPI, Clarithromycin, Amoxicillin, Nitroimidazole.
- Levofloxacin 4-drug: PPI, Levofloxacin (500 mg), Amoxicillin, Bismuth.
- Rifabutin 3-drug: PPI, Rifabutin (300 mg), Amoxicillin.
- NSAID Management: No CV Risk:
- No GI risk → Traditional NSAID.
- GI risk present → Coxib or Traditional + PPI/Misoprostol. Active Ulcer:
- Discontinue NSAID → Start H2 blocker or PPI.
Flowchart: Empirical approach to Helicobacter pylori eradication (if sensitivity unknown) * Step 1: Assess Clarithromycin Resistance. * If Low (<15%): * Option A: Bismuth 4-drug → Fail → Levofloxacin 4/3-drug → Fail → Clarithromycin 3/4-drug → Fail → Rifabutin 3-drug. * Option B: Clarithromycin 3-drug → Fail → Bismuth 4-drug → Fail → Levofloxacin 4/3-drug → Fail → Rifabutin 3-drug. * If High (>15%) or Unknown: * Option A (Bismuth available): Bismuth 4-drug → Fail → Levofloxacin 4/3-drug → Fail → Rifabutin 3-drug. * Option B (Non-bismuth): Non-bismuth 4-drug → Fail → Bismuth 4-drug → Fail → Levofloxacin 4/3-drug → Fail → Rifabutin 3-drug. * Option C: Levofloxacin 4/3-drug → Fail → Bismuth 4-drug → Fail → Rifabubin 3-drug.
Reference Tables¶
TABLE 335-1 Causes of Ulcers Not Caused by Helicobacter pylori and NSAIDs Pathogenesis of Non-Hp and Non-NSAID Ulcer…¶
Harrison's 22e, p.2522
- Pathogenesis of Non-Hp and Non-NSAID Ulcer Disease
- Infection
- Cytomegalovirus
- Herpes simplex virus
- Helicobacter heilmannii
- Drug/Toxin
- Bisphosphonates
Checkpoint inhibitor - Chemotherapy
- Clopidogrel
- Crack cocaine
- Glucocorticoids (when combined with NSAIDs)
- Mycophenolate mofetil
- Potassium chloride
- Miscellaneous
- Basophilia in myeloproliferative disease
- Duodenal obstruction (e.g., annular pancreas)
- Infiltrating disease
- Ischemia
- Radiation therapy
- Eosinophilic infiltration
- Sarcoidosis
- Crohn’s disease
- Idiopathic hypersecretory state
TABLE 335-3 Drugs Used in the Treatment of Peptic Ulcer Disease¶
Harrison's 22e, p.2524
| DRUG TYPE/ MECHANISM |
EXAMPLES | DOSE |
|---|---|---|
| Acid-Suppressing Drugs | ||
| Antacids | Mylanta, Maalox, Tums, Gaviscon |
100–140 meq/L 1 and 3 h after meals and hs |
| Cimetidine | ||
| Famotidine | ||
| Proton pump inhibitors | Omeprazole | 20 mg/d |
| Lansoprazole | 30 mg/d | |
| Rabeprazole | 20 mg/d | |
| Pantoprazole | 40 mg/d | |
| Esomeprazole | 20 mg/d | |
| Dexlansoprazole | 30 mg/d | |
| Mucosal Protective Agents |
TABLE 335-2 Tests for Detection of Helicobacter pylori TEST Invasive (Endoscopy/Biopsy Required) Rapid urease Histology…¶
Harrison's 22e, p.2524
| TEST | SENSITIVITY/ SPECIFICITY, % |
COMMENTS |
|---|---|---|
| Invasive (Endoscopy/Biopsy Required) | ||
| Rapid urease | 80–95/95–100 | Simple, false negative with recent use of PPIs, antibiotics, or bismuth compounds |
| 60–90/>95 | ||
| Culture | 76-90/100 | Time-consuming, expensive, dependent on experience; allows determination of antibiotic susceptibility |
| Noninvasive | ||
| 74.4/59 | ||
| Urea breath test | >95/>95 | Simple, rapid; useful for early follow-up; false negatives with recent therapy (see rapid urease test) |
| >95/>95 | ||
| Sucralfate | ||
| Prostaglandin analogue | Misoprostol | 200 μg qid |
| Bismuth subsalicylate (BSS) |
TABLE 335-4 Recommended First-Line Therapies for H. pylori Infection REGIMEN Clarithromycin triple (Only in patients…¶
Harrison's 22e, p.2527
| REGIMEN | DRUGS (DOSES) | DOSING FREQUENCY | DURATION (DAYS) | FDA APPROVAL |
|---|---|---|---|---|
| Clarithromycin triple (Only in patients without prior exposure to macrolides, incidence of clarithromycin <15%, or either of the above unknown) |
PPI (standard or double dose) | bid | 14 | Yesa |
| Clarithromycin (500 mg) | ||||
| Amoxicillin (1 g) or metronidazole (500 mg tid) | ||||
| PPI (standard dose) | bid | 10–14 | ||
| Bismuth subcitrate (120–300 mg) or subsalicylate (300 mg) | qid | |||
| Tetracycline (500 mg) | qid | |||
| Metronidazole (250–500 mg) | qid (250 mg) tid to qid (500 mg) |
|||
| Concomitant | PPI (standard dose) | bid | 10–14 | No |
| Clarithromycin (500 mg) | ||||
| Amoxicillin (1 g) | ||||
| Nitroimidazole (500 mg)c | ||||
| PPI (standard dose) | bid | 5–7 | ||
| PPI, clarithromycin (500 mg) + nitroimidazole (500 mg)c | bid | 5–7 | ||
| Hybrid | PPI (standard dose) + amoxicillin (1 g) | bid | 7 | No |
| PPI, amoxicillin, clarithromycin (500 mg), nitroimidazole (500 mg)c | bid | 7 | ||
| PPI (standard or double dose) + amoxicillin (1 g) | bid | 5–7 | ||
| Levofloxacin (500 mg) | qd | |||
| Amoxicillin (1 g) | bid | |||
| Levofloxacin sequential | PPI (standard or double dose) + amoxicillin (1 g) | bid | 5–7 | No |
| PPI, amoxicillin, levofloxacin (500 mg qd), nitroimidazole (500 mg)c | bid | 5–7 | ||
| Levofloxacin (250 mg) | qd | 7–10 | ||
| PPI (double dose) | qd | |||
| Nitazoxanide (500 mg) | bid | |||
| Doxycycline (100 mg) | qd |
TABLE 335-5 Salvage Therapies for H. pylori Infection REGIMEN Bismuth quadruple¶
Harrison's 22e, p.2530
| REGIMEN | DRUGS (DOSES) | DOSING FREQUENCY | DURATION (DAYS) | FDA APPROVAL |
|---|---|---|---|---|
| Bismuth quadruple | PPI (standard dose) | bid | 14 | Noa |
| Bismuth subcitrate (120–300 mg) or subsalicylate (300 mg) | qid | |||
| Tetracycline (500 mg) | qid | |||
| Metronidazole (500 mg) | tid or qid | |||
| PPI (standard dose) Levofloxacin (500 mg) Amoxicillin (1 g) |
bid qd bid |
14 | ||
| Concomitant | PPI (standard dose) | bid | 10–14 | No |
| Clarithromycin (500 mg) | bid | |||
| Amoxicillin (1 g) | bid | |||
| Nitroimidazole (500 mg) | bid or tid | |||
| PPI (standard dose) Rifabutin (300 mg) Amoxicillin (1 g) |
bid qd bid |
10 | ||
| High-dose dual | PPI (standard to double dose) | tid or qid | 14 | No |
| Amoxicillin (1 g tid or 750 mg qid) | tid or qid |
TABLE 335-7 Guide to NSAID Therapy No CV risk (no Traditional NSAID aspirin)¶
Harrison's 22e, p.2530
| NO/LOW NSAID GI RISK | NSAID GI RISK | |
|---|---|---|
| No CV risk (no aspirin) |
Traditional NSAID | Coxib or Traditional NSAID + PPI or misoprostol Consider non-NSAID therapy |
| Traditional NSAID + PPI or misoprostol if GI risk warrants gastroprotection Consider non-NSAID therapy |
TABLE 335-6 Recommendations for Treatment of NSAID-Related Mucosal Injury¶
Harrison's 22e, p.2530
| CLINICAL SETTING | RECOMMENDATION |
|---|---|
| Active ulcer | |
| NSAID discontinued | H receptor antagonist or PPI 2 |
| NSAID continued | PPI |
| H. pylori infection | Eradication if tests positive for H. pylori |
TABLE 335-8 When to Obtain a Fasting Serum Gastrin Level Multiple ulcers Ulcers in unusual locations; associated with…¶
Harrison's 22e, p.2535
- Multiple ulcers
- Ulcers in unusual locations; associated with severe esophagitis; resistant
to therapy with frequent recurrences; in the absence of nonsteroidal anti-
inflammatory drug ingestion or Helicobacter pylori infection - Ulcer patients awaiting surgery
Severe or refractory GERD
GERD associated with diarrhea - Extensive family history for peptic ulcer disease
- Postoperative ulcer recurrence
- Basal hyperchlorhydria
- Unexplained diarrhea or steatorrhea
Diarrhea improved with PPI - Hypercalcemia
- Family history of pancreatic islet, pituitary, or parathyroid tumor
- Prominent gastric or duodenal folds
TABLE 335-9 Sensitivity of Imaging Studies in Zollinger-Ellison Syndrome¶
Harrison's 22e, p.2536
| SENSITIVITY, % | ||
|---|---|---|
| STUDY | PRIMARY GASTRINOMA |
HEPATIC METASTATIC GASTRINOMA |
| Ultrasound | 0–28 | 15–77 |
| 0–59 | ||
| Selective angiography | 35–68 | 96–100 |
| 70–90 | ||
| SASI | 55–78 | N/A |
| 20–25 | ||
| OctreoScan | 55–77 | 90–100 |
| 28–86 |
TABLE 335-10 Classification of Gastritis I. Acute gastritis¶
Harrison's 22e, p.2538
- I. Acute gastritis
A. Acute Helicobacter pylori infection
B. Other acute infectious gastritides
1. Bacterial (other than H. pylori)
2. Helicobacter heilmannii
3. Phlegmonous
4. Mycobacterial
5. Syphilitic
6. Viral
7. Parasitic
8. Fungal
II. Chronic atrophic gastritis
A. Type A: Autoimmune, body-predominant
B. Type B: H. pylori–related, antral-predominant
C. Indeterminate
III. Uncommon forms of gastritis
A. Lymphocytic
B. Eosinophilic
C. Crohn’s disease
D. Sarcoidosis
E. Isolated granulomatous gastritis
F. Russell body gastritis