Peptic Ulcer Disease (PUD)

Definition

• Guyton and Hall Textbook of Medical Physiology, p. 825

Sites of Occurrence

• First part of the duodenum (most frequent)
• Lesser curvature of the gastric antrum
• Stomal/marginal ulcers (at anastomoses after gastric surgery)
• Lower esophagus (in GERD or ectopic gastric mucosa)
• A Meckel's diverticulum (containing ectopic gastric epithelium)
• Rarely, the jejunum (in Zollinger-Ellison syndrome)

Figure: Causes and most frequent locations of peptic ulcer (Guyton & Hall)

Epidemiology

• Affects >4 million individuals in the US each year
• Lifetime risk: ~10% in males, ~4% in females
• Duodenal ulcers are more common than gastric ulcers
• Previously, peptic ulcer accounted for ~50% of upper GI bleeds and ~100,000 hospitalizations/year in the US
• The incidence of H. pylori-related ulcers is declining in the West; NSAID-related ulcers are becoming proportionally more common
• Robbins & Kumar Basic Pathology, p. 3903

Pathogenesis

Core Concept: Imbalance of Offense vs. Defense

• Mucus secretion (surface mucous cells, Brunner's glands)
• Bicarbonate secretion (pancreatic juice, liver bile)
• Mucosal blood flow and prostaglandins
• Feedback inhibition of acid when duodenal pH drops (secretin release, enterogastrone hormones)

1. Helicobacter pylori (H. pylori)

• Responsible for >70% of PUD cases
• A gram-negative spiral bacterium that colonizes under the mucus layer of the gastric antrum
• Breaks down the mucosal barrier via: urease (produces ammonia that damages mucosa), proteases, vacuolating cytotoxin (VacA), and CagA virulence factor
• Stimulates excessive gastrin secretion and thus acid hypersecretion
• Causes mucosal inflammation (chronic active gastritis), particularly in the antrum, which when extensive impairs protective mechanisms
• Only 5-10% of infected individuals develop ulcers - host factors and bacterial strain variation matter
• H. pylori eradication eliminates ulcer recurrence (recurrence rate falls from ~80% to ~2%)

2. NSAIDs (including aspirin)

• Inhibit COX-1 and COX-2, reducing prostaglandin synthesis
• Prostaglandins normally stimulate mucus and bicarbonate secretion, maintain mucosal blood flow, and promote epithelial repair
• NSAID-related ulcers tend to be gastric and occur in older populations
• In the US, NSAID use is becoming the most common cause of gastric ulcers as H. pylori rates fall

3. Acid Hypersecretion

• Direct cause in Zollinger-Ellison syndrome (gastrinoma) - multiple ulcers, often in unusual sites (distal duodenum, jejunum)
• Parietal cell hyperplasia
• Excessive secretory responses to stimulation
• Hypercalcemia (hyperparathyroidism, CRF) stimulates gastrin and acid

4. Other Risk Factors

• Cigarette smoking - reduces mucosal blood flow, impairs healing, increases relapse rate
• Corticosteroids (high-dose) - suppress prostaglandin synthesis
• Alcohol-related cirrhosis, COPD, chronic renal failure, hyperparathyroidism
• Psychological stress (physiological stress ulcers in ICU patients)
• Robbins Basic Pathology; Bailey & Love Surgery; Guyton & Hall

Morphology (Pathology)

• Ulcers are typically solitary, round to oval, sharply "punched-out" defects with nearly vertical walls
• The base is clean and smooth (unlike carcinoma, which is necrotic and irregular)
• Size: usually <2 cm diameter for duodenal; gastric ulcers may be larger
• Chronic ulcers penetrate into the muscularis propria and may reach the serosa
• Healing leads to residual mucosal scarring; fibrosis can cause pyloric stenosis
• "Kissing ulcers" = both anterior and posterior duodenal ulcers coexisting
• Anterior duodenal ulcers tend to perforate; posterior duodenal ulcers tend to bleed (eroding the gastroduodenal artery)

• Active ulcer base shows: necrotic fibrinoid debris (surface), inflammatory exudate, granulation tissue, fibrous scar (deepest layer)
• Adjacent mucosa shows features of chronic gastritis if H. pylori is the cause

Endoscopic Appearance

Figure: Duodenal ulcer at gastroduodenoscopy (Bailey & Love)

Clinical Features

Investigations

Non-invasive H. pylori Tests

• Urea breath test (UBT) - gold standard non-invasive test for active infection; avoid PPIs 2 weeks before
• Stool antigen test - reliable, useful for follow-up confirmation of eradication
• Serology - detects antibodies (IgG); cannot distinguish active from past infection; not reliable for post-treatment confirmation

Invasive (Endoscopic Biopsy)

• Rapid urease test (CLO test) - biopsy-based, rapid
• Histology - gold standard for confirmation and assessment of gastritis pattern
• Culture - for antibiotic sensitivity testing

Endoscopy (OGD/EGD)

• Direct visualization, localization, biopsy
• All gastric ulcers must be biopsied (at least 6-10 targeted biopsies) to exclude malignancy - gastric cancer can mimic benign ulcer, and PPIs can heal the ulceration without treating the underlying malignancy
• Repeat endoscopy with biopsy after treatment to confirm healing of gastric ulcers

Imaging

• Barium meal (upper GI series): historically used; ulcer shown as a niche/crater; largely superseded by endoscopy for most cases

Treatment

1. NSAID-Associated PUD

• Stop the NSAID if possible (or switch to a selective COX-2 inhibitor with a PPI)
• PPI (e.g., omeprazole) for 4-8 weeks - heals most ulcers
• Test for H. pylori and eradicate if co-present

2. H. pylori Eradication

• Documented PUD (active or historical) - regardless of whether NSAIDs are also used
• Gastric MALT lymphoma (60-90% achieve complete remission with eradication alone)
• After endoscopic resection of early gastric cancer
• Uninvestigated dyspepsia in patients <60 years (test-and-treat if local prevalence >20%)
• Pre-NSAID therapy (reduces GI bleeding risk)
• Unexplained iron-deficiency anemia or ITP

• Eradication rates with initial therapy: ~80-90%; ~20-30% fail due to antibiotic resistance (especially clarithromycin and metronidazole resistance)
• Confirm eradication with UBT or stool antigen 4-6 weeks after completing therapy (wait 2 weeks off PPI)
• Sabiston Textbook of Surgery; Harrison's Principles of Internal Medicine 22E

3. Acid Suppression Alone (Maintenance)

• H. pylori-negative, non-NSAID ulcers - long-term PPI therapy
• Zollinger-Ellison syndrome - high-dose PPI indefinitely (unless tumor resectable)

Complications

1. Bleeding (Most Common)

• Most common complication; accounts for ~50% of upper GI bleeds
• Posterior DU may erode the gastroduodenal artery (catastrophic hemorrhage)
• Presents as hematemesis, melena, or hemodynamic instability
• Rockall Score stratifies risk of rebleeding and mortality:

• Management: resuscitation, urgent OGD, endoscopic hemostasis (injection, thermal, clips); H. pylori eradication postoperatively reduces recurrence from 20% to near zero
• Sleisenger and Fordtran's GI and Liver Disease

2. Perforation

• Anterior DU perforates most often (into the peritoneal cavity)
• Classic presentation: sudden severe epigastric pain, board-like rigid abdomen, free air under the diaphragm on erect CXR
• Treatment primarily surgical (oversewing of perforation + peritoneal lavage); conservative management (Teylor's method) in selected patients
• Perforated gastric ulcer must be excised and sent for histology to exclude malignancy

3. Pyloric Stenosis / Gastric Outlet Obstruction

• Results from chronic scarring and fibrosis from repeated ulcer healing
• Presents with: large volume vomiting, succussion splash, visible peristalsis, hypochloraemic hypokalaemic metabolic alkalosis
• Most commonly associated with longstanding PUD or gastric cancer
• Treatment: nasogastric decompression, IV fluid/electrolyte correction, then definitive endoscopic or surgical intervention

Surgery (Now Rarely Done Electively)

• Billroth I (distal gastrectomy with gastroduodenostomy)
• Billroth II / Pólya (distal gastrectomy with gastrojejunostomy)
• Highly selective vagotomy (preserves gastric emptying)
• Long-term complications of gastric surgery: dumping syndrome, bile reflux gastritis, B12 deficiency, iron-deficiency anaemia, stomal/marginal ulcers

Differential Diagnosis

• Acute cholecystitis / cholelithiasis
• Pancreatitis
• Gastric carcinoma (must always be excluded in gastric ulcers)
• GERD / esophagitis
• Functional dyspepsia
• Appendicitis (atypical presentations)
• Ischemic bowel disease (elderly)
• IBD (Crohn's disease can involve upper GI tract)

Key Clinical Pearls

1. No acid = no ulcer: PPIs are the backbone of both healing and maintenance therapy
2. All gastric ulcers must be biopsied: malignancy cannot be excluded on appearance alone, and PPIs can heal the surface without treating the cancer
3. H. pylori eradication changes natural history: reduces recurrence from ~80% to ~2%
4. Posterior DU bleeds; anterior DU perforates - relates to anatomical proximity to the gastroduodenal artery
5. NSAID ulcers are increasing as a proportion in developed countries as H. pylori prevalence declines; often silent until a complication occurs
6. Zollinger-Ellison should be suspected in H. pylori-negative, non-NSAID refractory ulcers - check fasting serum gastrin
7. Eradication confirmation is mandatory (UBT or stool antigen 4-6 weeks post-treatment)