Peptic Ulcer Disease

Overview

Definition

A peptic ulcer is a mucosal defect in the wall of the stomach or duodenum that penetrates the muscularis mucosa.

Epidemiology

• Incidence:
  • Uncomplicated peptic ulcer disease (PUD): 1 case per 1,000 person-years in the general population
  • PUD complications: 0.7 cases per 1,000 person-years in the general population
• Duodenal ulcers > gastric ulcers (3:1)
• Affects men and women equally
• Duodenal ulcers occur, on average, 2 decades earlier than gastric ulcers.
• PUD rates have been falling over the past few decades.

Etiology

• Infection:
  • Helicobacter pylori or H. pylori (most common):
    • 80%–90% duodenal ulcers
    • 70%–80% gastric ulcers
  • Viruses:
    • Herpes simplex virus (HSV)
    • Cytomegalovirus (CMV)
  • Rare infections:
    • Tuberculosis (TB)
    • Syphilis
    • Mucormycosis
• Medications:
  • Non-steroidal anti-inflammatory drugs (NSAIDs; most common)
  • Medications linked to PUD or risk exacerbated by combination with NSAIDs:
    • Bisphosphonates
    • Clopidogrel
    • Corticosteroids
    • Spironolactone
  • Chemotherapy
  • Sirolimus
  • Mycophenolate mofetil
  • Potassium chloride
• Hormonal:
  • Gastrinoma (Zollinger-Ellison syndrome)
  • Antral G-cell hyperplasia/hyperfunction (gastritis)
• Post-surgical:
  • Antral exclusion
  • Gastric bypass
• Ischemic: cocaine use
• Decompensated chronic diseases:
  • Cirrhosis
  • Renal failure
  • Chronic obstructive pulmonary disease (COPD)
  • Prolonged intensive care unit (ICU) stay for any reason
• Idiopathic
• Other rare causes:
  • Annular pancreas
  • Sarcoidosis
  • Crohn’s disease
  • Radiation

Risk factors

In many cases, the listed etiologies are not enough to produce PUD. Contributing risk factors to PUD development:

• Smoking
• Alcohol
• Stress (severe illness–related, psychologic)
• Diet
• Genetic predisposition
• Blood types A and O

Pathophysiology

Anatomic location of ulcers

• Duodenal ulcer: an ulcer located in the duodenum, typically in the duodenal bulb (1st part)
• Gastric ulcer: an ulcer in the stomach lining, commonly in the lesser curvature of the stomach near the junction of the fundus and antral mucosa (or type I)

Pathophysiology

• Stomach and duodenum: 
  • Normally exposed to a toxic environment (acid + pepsin)
  • Imbalance between offending agents and defense mechanisms leads to PUD.
• Defense preventing mucosal injury:
  • Mucus-bicarbonate-phospholipid layer
  • Epithelial layer (repair of which is regulated by prostaglandins)
  • Subepithelial defense (mucosal blood flow for supply of nutrients and oxygen, disposal of noxious agents)
• Mechanisms by offending agents:
  • Increased gastric acid secretion:
    • H. pylori gastritis or inflammation: ↑ gastric acid, inhibits somatostatin, ↓ mucus
    • NSAID inhibition of COX 1 → ↓ prostaglandin (↓ mucus, ↓ mucosal blood flow, ↓ epithelial proliferation) 
    • NSAID inhibition of COX 2 → delays healing
  • Impaired duodenal bicarbonate secretion (in patients with duodenal ulcers)
  • Effects of other etiologies or risk factors:
    • Smoking → ↑ acid secretion, ↓ prostaglandin
    • Zollinger-Ellison syndrome (gastrinoma) → ↑ gastrin
    • Brain injury increases intracranial pressure, overstimulates vagus nerve → ↑ gastric acid (Cushing’s ulcer)
    • Burn injury (stress) → reduced volume, cell necrosis → gastric mucosal sloughing → impaired barrier (Curling’s ulcer)

Clinical Presentation

Asymptomatic

• 70% of PUD patients
• Older adults
• Patients taking NSAIDs
• Complication(s) (bleeding or perforation) may be the 1st clinical presentation without antecedent symptoms.

Symptomatic

• Abdominal pain:
  • Epigastric with radiation to left or right upper quadrants
  • Sometimes radiates to the back
  • Classic duodenal ulcer pain: 2–5 hours after eating and at night (when acid is secreted without food)
  • Sometimes exacerbated by eating (pyloric channel ulcers)
• Other symptoms:
  • Nausea/vomiting
  • Early satiety
  • Postprandial fullness/bloating
  • Belching

Diagnosis

History

Review of common risk factors:

• NSAID/aspirin use
• Concomitant use of high-risk medications
• Underlying chronic disease
• Prior gastric surgery or radiation

Laboratory studies

• Anemia (occult bleeding and/or iron malabsorption)
• High fasting gastrin levels (if Zollinger-Ellison syndrome is suspected)

Esophagogastroduodenoscopy (EGD)

• Most accurate diagnostic test
• Findings:
  • Gastric ulcer: 
    • Usually solitary discrete mucosal lesions, with punched-out smooth base
    • Benign lesions have smooth, rounded edges (as opposed to irregular edges noted in malignant lesions).
    • Typically in lesser curvature
  • Duodenal ulcer:
    • Small breaks in the mucosa, often < 1 cm
    • Noted usually in the 1st part of the duodenum
• Indications for biopsy:
  • Suspected malignancy (ulcerated mass, irregular margins, abnormal mucosal folds)
  • Any gastric ulcer in areas with a high incidence of gastric cancer
  • If unusual etiology is suspected (e.g., sarcoidosis)
  • Gastric mucosal biopsy of antrum and body (in addition to the ulcer itself) for H. pylori detection

Tests for H. pylori

• Non-invasive:
  • Stool antigen assay: 
    • For initial diagnosis
    • To confirm eradication
  • Urea breath test: 
    • Patient is given radioactively labeled urea orally.
    • Urease produced by H. pylori splits urea and liberates CO₂.
    • Radioactive CO₂ is detected in the breath.
  • Serology:
    • Detection of serum IgG against H. pylori
    • Low accuracy
    • IgG remains positive after eradication.
• Invasive (require sampling of gastric mucosa):
  • Biopsy urease test: 
    • Urease produced by H. pylori liberates ammonia from urea.
    • Alkaline pH changes color of a pH reagent.
  • Histology: 
    • Accuracy improved by stains (immunohistochemical, Giemsa stains)
    • Curved, flagellated gram-negative rods are seen.
  • Bacterial culture and sensitivity

Management

Risk factor modification

• Discontinue NSAIDs.
• Stop smoking, and discontinue intake of alcohol and drugs.
• Bland diet

Medications

• H. pylori eradication:
  • A combination of an antibiotic regimen and proton pump inhibitors (PPIs):
    • Triple therapy: PPI + clarithromycin + amoxicillin or metronidazole
    • Bismuth-containing quadruple therapy: PPI + bismuth + tetracycline + metronidazole
  • Confirm H. pylori eradication after treatment.
• PPIs:
  • Uncomplicated ulcers: 
    • Given for 2 weeks (plus antibiotic treatment for H. pylori if positive)
    • Longer if the patient has indications for maintenance therapy
  • Complicated ulcers (bleeding, penetration, obstruction, or perforation):
    • Duodenal ulcer: 4–8 weeks
    • Gastric ulcer: 8–12 weeks (confirmation of ulcer healing needed)
    • Longer if the patient has indications for maintenance therapy
  • Maintenance therapy:
    • If NSAIDs or aspirin need to be continued
    • Giant ulcer (> 2 cm)
    • H. pylori negative, NSAID-negative ulcers
    • Recurrent PUD (> 2/year)

Repeat endoscopy

• Duodenal ulcers:
  • Usually not necessary
  • If symptoms persist with treatment > 4 weeks
  • If evidence of ongoing bleeding
• Gastric ulcers:
  • Persistent symptoms despite 8–12 weeks of medical therapy
  • Unclear etiology
  • Giant ulcer (> 2 cm)
  • Ulcer was suspicious for malignancy on the 1st endoscopy (even with negative biopsy).
  • Evidence of ongoing bleeding
  • Failure to eradicate H. pylori infection
  • Risk factors for gastric cancer:
    • Age > 50
    • H. pylori
    • Family history
    • Immigrants from endemic areas (Japan, Korea)
    • Gastric atrophy, metaplasia/dysplasia, adenoma

Surgical treatment

• Uncommon because medical therapy is very effective
• Indications for surgery:
  • Management of complications:
    • Bleeding
    • Perforation
    • Gastric outlet obstruction
  • PUD refractory to medical management
  • Non-compliance or intolerable side effects of medications
• Surgical principles:
  • Prevent ulcer complications: ulcer resection
  • Reduce acid secretion: vagotomy, antrectomy
  • Minimize postoperative physiologic disturbances: pyloroplasty to facilitate gastric emptying after vagotomy
• Procedures:
  • Highly selective vagotomy: Only the vagal branches stimulating acid secretion are transected.
  • Vagotomy and drainage (pyloroplasty or gastrojejunostomy)
  • Procedures involving partial stomach resection:
    • Vagotomy and antrectomy: removes the acid-producing portion of the stomach
    • Partial gastrectomy: removes the portion of the stomach containing the gastric ulcer
    • Reconstruction needed for a partial gastrectomy: by gastroduodenal (Billroth I) or gastrojejunal (Billroth II) anastomosis

Complications

Gastrointestinal bleeding

• Patients present with hematemesis and/or melena.
• May be chronic/low grade and present as anemia
• Acute bleeding is usually approached with endoscopic intervention.
• Dieulafoy lesion: vascular malformation in the stomach (submucosa) that ulcerates and causes massive bleeding
• Surgery may be required if unable to achieve control endoscopically.

Perforation

• Sudden onset of severe diffuse abdominal pain, peritonitis, tachycardia
• Emergent surgery is required.

Penetration

• Walled-off perforation or perforation into the retroperitoneal space
• Symptoms not as pronounced as with a free perforation; subacute onset
• Often results in an abscess formation or fistulas to the surrounding organs (colon, biliary tree, blood vessels)

Gastric outlet obstruction

• Mechanical obstruction from peri-pyloric inflammation and scarring
• 1st-line treatment is H. pylori eradication and PPIs.
• Endoscopic dilation for failure of medical management
• Surgery as a last resort

Gastric cancer

• Adenocarcinoma
• MALToma (mucosa-associated lymphoid tissue)
• Both associated with chronic H. pylori infection and atrophic gastritis

Differential Diagnosis

• Gastroesophageal reflux disease (GERD): can present with recurrent regurgitation, epigastric/substernal burning, indigestion, belching. The disease process involves an inappropriate relaxation of the lower esophageal sphincter. Gastroesophageal reflux disease can lead to mucosal damage of the lower esophagus from exposure to gastric acid.  
• Gastric cancer: can be asymptomatic in the early stages but typically presents with bloating, early satiety, dysphagia, weight loss, and cancer-related fatigue. Diagnosis is made by endoscopy with biopsy.
• Gastritis: inflammation of the gastric mucosa. H. pylori infection is also the most common culprit. Gastritis may coexist with PUD and presents with epigastric pain, nausea, and dyspepsia. Endoscopy may show mucosal irritation/atrophy, but no full-thickness ulceration.
• Cholecystitis/cholelithiasis: gallstones obstructing the cystic duct with or without associated inflammation of the gallbladder. The common presentation is the right upper quadrant and epigastric pain, nausea, and vomiting. Frequently associated with right upper quadrant or subcostal tenderness. Diagnosis is made by ultrasound.
• Viral gastroenteritis: acute self-limited illness associated with diffuse abdominal pain, vomiting, and diarrhea. May also be associated with fever. Watery diarrhea is a characteristic feature.
• Pancreatitis: inflammation of the pancreas. Pancreatitis can be acute or chronic, and usually presents with epigastric pain radiating to the back, nausea, vomiting, and bloating. Blood tests will show elevated amylase and lipase.
• Acute coronary syndrome: presents with chest pain, which is usually described as pressure across the precordium that may radiate to the neck, shoulder, jaw, back, upper abdomen, or either arm. Acute coronary syndrome can sometimes present as mostly substernal/epigastric pain, and it is important to maintain a high index of suspicion. An electrocardiogram will show changes due to myocardial ischemia/infarction.