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Peptic Ulcer Disease
Fozia Akhtar Ali, MD
Paula A. Shelton, MD
image BASICS
  • Duodenal ulcer
    • Most common form of peptic ulcer
    • Usually located in the proximal duodenum
    • Multiple ulcers or ulcers distal to the second portion of duodenum raise possibility of gastrinoma (Zollinger-Ellison syndrome).
  • Gastric ulcer
    • Less common than duodenal ulcer in absence of NSAID use
    • Commonly located along lesser curvature of the antrum
  • Esophageal ulcers
    • Located in the distal esophagus; usually secondary to gastroesophageal reflux disease (GERD); also seen with gastrinoma
  • Ectopic gastric mucosal ulceration
    • May develop in those with Meckel diverticulum (1)
  • NSAID ulcers: Avoid salicylates and NSAIDs (1).
    • Alternatives include acetaminophen and tramadol. COX-2 inhibitor use is controversial due to potential cardiac risks.
    • If NSAIDs are needed, adjust to decrease risk of ulcerogenesis, and add a proton pump inhibitor (PPI) or misoprostol.
    • To reduce ulcer risk, consider testing for and eradicating Helicobacter pylori before starting therapy with NSAIDs.
  • Maintenance therapy with PPIs or H2 blockers is indicated for patients with a history of ulcer complications, recurrences, refractory ulcers, or persistent H. pylori infection.
  • Consider maintenance PPI treatment in patients with H. pylori-negative, non-NSAID-induced ulcer.
  • Imbalance between aggressive factors (e.g., gastric acid, pepsin, bile salts, pancreatic enzymes) and defensive factors maintaining mucosal integrity (e.g., mucus, bicarbonate, blood flow, prostaglandins, growth factors, cell turnover)
  • May be multifactorial
  • H. pylori infection: 90% of duodenal ulcers and 70-90% of gastric ulcers
    • Lifetime risk for peptic ulcer disease (PUD) in H. pylori-infected people: 10-20%
    • Annual risk of developing duodenal ulcer in H. pylori-infected people: ≤1%
  • Ulcerogenic drugs (e.g., NSAIDs)
  • Hypersecretory syndromes (e.g., gastrinoma)
  • Retained gastric antrum
  • Less common: Crohn disease, vascular insufficiency, radiation therapy, cancer chemotherapy, smoking
  • Predominant sex: male = female
  • Predominant age
    • 70% of ulcers occur between ages 25 to 64 years.
    • Ulcer incidence increases with age.
  • Peptic ulcer: 500,000 new cases/year
  • Recurrence: 4 million/year
  • Global incidence rate: 0.1-0.19%
  • Peptic ulcer: 2% in the United States
  • Lifetime prevalence is 5-10% for patients not infected with H. pylori; 10-20% if infected
Increased incidence of PUD in families is likely due to familial clustering of H. pylori infection and inherited genetic factors reflecting response to the organism (1).
  • H. pylori infection (1)
  • NSAID use (5-20%)
  • Tobacco use
  • Family history of ulcers
  • Stress (after acute illness, ventilator support, extensive burns, head injury)
  • Gastrinoma
  • Alcohol use
  • Medications: corticosteroids (high-dose and/or prolonged therapy), bisphosphonates, potassium chloride, chemotherapeutic agents (e.g., IV fluorouracil)
  • Gastrinoma (Zollinger-Ellison syndrome)
  • Multiple endocrine neoplasia type 1
  • Carcinoid syndrome
  • Chronic illness: Crohn disease, chronic obstructive pulmonary disease (COPD), chronic renal failure, hepatic cirrhosis, cystic fibrosis
  • Hematopoietic disorders (rare): systemic mastocytosis, myeloproliferative disease, hyperparathyroidism, polycythemia rubra vera
Physical exam for uncomplicated peptic ulcer may be unreliable and nonspecific: vital signs for hemodynamic stability, conjunctival pallor (anemia); epigastric tenderness (absent in at least 30% of older patients); guaiac-positive stool from occult blood loss (1)
Functional dyspepsia, gastritis, GERD, biliary colic, pancreatitis, cholecystitis, Crohn disease, intestinal ischemia, cardiac ischemia, GI malignancy
Initial Tests (lab, imaging)
  • Lab tests to consider when evaluating PUD:
    • CBC: Rule out anemia.
    • Fecal occult blood test
    • If multiple/refractory ulcers: Consider fasting serum gastrin to rule out gastrinoma (1).
  • Indications for H. pylori testing: new-onset PUD, prior history of PUD, persistent symptoms after empiric antisecretory therapy, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, noninvestigated dyspepsia in patients <50 years of age without alarm symptoms (2)
  • H. pylori diagnostic tests: False-negative results may occur if patient was recently treated with antibiotics, bismuth, or PPIs; or in patients with active bleeding. Diagnostic yield improved by checking 2 different tests:
    • Noninvasive tests (2)[A]:
      • Serology antibody: commonly used in primary care, slow to normalize after treatment, cannot be used to document successful eradication (sensitivity, 85%; specificity, 79%)
      • Urea breath test: identifies active H. pylori infection; also used for posttreatment testing (sensitivity, >95%; specificity, >90%)
      • Stool antigen: can be used for screening and posttreatment testing (sensitivity, 91%; specificity, 94%)
    • Invasive tests:
      • Upper endoscopy with gastric biopsy; Steiner stain for direct visualization of organism (sensitivity, >95%; specificity, >95%)
      • Rapid urease test: conducted on gastric biopsies (sensitivity, 93-97%; specificity, 95%)
  • Barium or Gastrografin contrast radiography (double-contrast hypotonic duodenography): indicated when endoscopy is unsuitable or not feasible
Diagnostic Procedures/Other
Indications for upper endoscopy: patients with suspected peptic ulcers who are >55 years of age, those who have alarm symptoms, and those with ulcers that do not respond to treatment (3)[B]
First Line
  • Acid suppression: PPIs
    • Omeprazole 20 mg/day PO; lansoprazole 30 mg/day PO; rabeprazole 20 mg/day PO; esomeprazole 40 mg/day PO; pantoprazole 40 mg/day PO; dexlansoprazole 30 mg/day PO
    • Administer PPIs before breakfast.
  • H2 blockers: ranitidine or nizatidine 150 mg PO BID or 300 mg PO at bedtime; cimetidine 400 mg PO BID or 800 mg PO at bedtime; famotidine 20 mg PO BID or 40 mg PO at bedtime (4)
  • Treat ulcers for 8 to 12 weeks or until healing is confirmed in patients with complicated ulcers (4).
  • PPIs heal peptic ulcers more rapidly (4).
  • Precautions:
    • Renal insufficiency: Decrease H2 blocker dosage by 50% if CrCl <50 mL/min (2).
    • Cimetidine: Use caution with theophylline, warfarin, phenytoin, and lidocaine.
    • PPIs may decrease bone density. Obtain interval bone densitometry with long-term PPI use (5).
    • P.781

    • PPIs may cause hypomagnesemia. Consider baseline and interval levels in patients, especially for long-term use and in patients taking diuretics.
    • PPIs may be associated with increased risk of Clostridium difficile infection (5). Short-term use associated with development of community-acquired pneumonia; long-term use does not appear to have an increased risk.
    • Despite earlier concerns, PPIs do not appear to decrease the efficacy of clopidogrel (5).
  • NSAID-induced ulcers
    • Discontinue NSAID use.
    • Treat acutely with PPIs for 8 to 12 weeks; may use longer as maintenance for patients with recurrent, complicated, or idiopathic ulcers; or in patients who require long-term aspirin or NSAID use.
  • H. pylori-induced ulcers
    • H. pylori eradication regimens: Preferred duration of therapy is 14 days.
    • Triple therapy: standard dose PPI given BID plus clarithromycin 500 mg PO BID plus amoxicillin 1 g PO BID or metronidazole 500 mg PO BID in patients with allergy to amoxicillin (2)
  • Bacterial resistance: clarithromycin 10%; amoxicillin 1.4%; metronidazole 37%: Culture-guided choice of triple therapy is preferred (6).
Second Line
  • For H. pylori eradication: Use second-line therapy if first-line fails (6):
    • Bismuth quadruple therapy for 14 days
      • Bismuth subsalicylate 525 mg PO QID plus
      • Metronidazole 250 mg PO QID plus
      • Tetracycline 500 mg PO QID plus
      • Standard dose PPI PO twice daily
  • Sequential therapy
    • Standard-dose PPI PO twice daily plus amoxicillin 1,000 mg PO QID for 5 days followed by
    • Standard-dose PPI PO twice daily plus clarithromycin 500 mg PO BID plus tinidazole (or metronidazole) 500 mg PO BID for 5 days
      • Levofloxacin 250 mg PO BID may be substituted in those with PCN allergy or in areas of high clarithromycin resistance rates.
    • Another alternative salvage therapy:
      • Rifabutin 300 mg PO daily plus
      • Amoxicillin 1,000 mg PO BID plus
      • PPI orally BID
    • Alternative ulcer-healing drugs:
      • Sucralfate and antacids are additional options; however, antisecretory options are preferred.
  • Significant possible interactions:
    • Cimetidine inhibits cytochrome P450 isozymes (avoid with theophylline, warfarin, phenytoin, and lidocaine).
    • Omeprazole may prolong elimination of diazepam, warfarin, and phenytoin.
    • Sucralfate reduces absorption of tetracycline, norfloxacin, ciprofloxacin, and theophylline; it leads to subtherapeutic levels.
Pregnancy Considerations
PPIs are not associated with an increased risk for major congenital birth defects, spontaneous abortions, or preterm delivery.
Both ranitidine and esomeprazole are secreted in breastmilk; however, at considerably lower doses than those used for treatment in infants with reflux disease. Use in breastfeeding women is generally safe (7).
  • Endoscopy is indicated for patients age >50 years with new onset of dyspeptic symptoms, those who do not respond to treatment, and those of any age with alarm symptoms, such as bleeding and weight loss (8)[B].
  • At endoscopy:
    • Biopsy stomach for H. pylori testing (CLO test).
    • Biopsy margin of gastric ulcer to exclude malignancy.
    • Interventions to stop active bleeding or prevent rebleeding in those with certain stigmata include injection with epinephrine, heater probe treatment, or placement of endoscopic clips (3).
  • Indications for surgery: Ulcers that are refractory to treatment and patients at high risk for complications (e.g., transplant recipients, patients dependent on steroids/NSAIDs); surgery also may be needed acutely to treat perforation and bleeding refractory to endoscopic therapy (8).
  • Surgical options:
    • Duodenal ulcers: truncal vagotomy and drainage (pyloroplasty/gastrojejunostomy), selective vagotomy (preserving the hepatic and/or celiac branches of the vagus) and drainage, or highly selective vagotomy (3)
    • Gastric ulcers: partial gastrectomy, Billroth I or II
    • Perforated ulcers: laparoscopy/open patching (3)
Admission Criteria/Initial Stabilization
  • Discontinue ulcerogenic agents (e.g., NSAIDs) (1).
  • Bleeding peptic ulcers
    • Stable: Give PPI to reduce transfusion requirements, need for surgery, and duration of hospitalization (9).
    • Unstable: Fluid/packed RBC resuscitation followed by emergent esophagogastroduodenoscopy (EGD); use IV PPI.
    • Insufficient evidence for concluding superiority, inferiority, or equivalence of high-dose PPI treatment over lower doses in peptic ulcer bleeding (5)[A]
  • Oral PPIs are as effective as IV after endoscopic treatment (9).
  • Perforated peptic ulcers: Free peritoneal perforation with bacterial peritonitis is a surgical emergency (3).
Patient Monitoring
  • H. pylori eradication: expected in >90% (with double antibiotic regimen): Confirm eradication by urea breath test.
  • Acute duodenal ulcer: Monitor clinically.
  • Acute gastric ulcer: Confirm healing via endoscopy after 12 weeks (if biopsy not done initially) to confirm that the lesion is benign.
  • Tobacco cessation
After H. pylori eradication (10):
  • Low ulcer relapse rate; if relapse, consider surreptitious use of NSAIDs.
  • Reinfection rates <1% per year
  • Low risk of rebleeding
  • Decreased NSAID ulcer recurrence (10)
1. Ramakrishnan K, Salinas RC. Peptic ulcer disease. Am Fam Physician. 2007;76(7):1005-1012.
2. Saad R, Chey WD. A clinician's guide to managing Helicobacter pylori infection. Cleve Clin J Med. 2005;72(2):109-110,112-113,117-118.
3. Bertleff MJ, Lange JF. Perforated peptic ulcer disease: a review of history and treatment. Dig Surg. 2010;27(3):161-169.
4. Gill SK, O'Brien L, Einarson TR, et al. The safety of proton pump inhibitors (PPIs) in pregnancy: a meta-analysis. Am J Gastroenterol. 2009;104(6): 1541-1545.
5. Neumann I, Letelier LM, Rada G, et al. Comparison of different regimens of proton pump inhibitors for acute peptic ulcer bleeding. Cochrane Database Syst Rev. 2013;(6):CD007999.
6. Luther J, Higgins PD, Schoenfeld PS, et al. Empiric quadruple vs. triple therapy for primary treatment of Helicobacter pylori infection: systematic review and meta-analysis of efficacy and tolerability. Am J Gastroenterol. 2010;105(1):65-73.
7. Marshall JK, Thompson AB, Armstrong D. Omeprazole for refractory gastroesophageal reflux disease during pregnancy and lactation. Can J Gastroenterol. 1998;12(3):225-227.
8. Laine L, Jensen DM. Management of patients with ulcer bleeding. Am J Gastroenterol. 2012;107(3):345-360.
9. Yen HH, Yang CW, Su WW, et al. Oral versus intravenous proton pump inhibitors in preventing re-bleeding for patients with peptic ulcer bleeding after successful endoscopic therapy. BMC Gastroenterol. 2012;12:66.
10. Gisbert JP, Calvet X, Cosme A, et al. Long-term follow-up of 1,000 patients cured of Helicobacter pylori infection following an episode of peptic ulcer bleeding. Am J Gastroenterol. 2012;107(8): 1197-1204.
11. Yuan Y, Padol IT, Hunt RH. Peptic ulcer disease today. Nat Clin Pract Gastroenterol Hepatol. 2006;3(2):80-89.
  • K27.9 Peptic ulc, site unsp, unsp as ac or chr, w/o hemor or perf
  • K26.9 Duodenal ulcer, unspecified as acute or chronic, without hemorrhage or perforation
  • K25.9 Gastric ulcer, unspecified as acute or chronic, without hemorrhage or perforation
Clinical Pearls
  • In patients with PUD, H. pylori should be eradicated to assist in healing and to reduce the risk of gastric and duodenal ulcer recurrence.
  • Upper endoscopy is indicated in patients with suspected peptic ulcers who are >55 years of age, those who have alarm symptoms, and those who do not respond to treatment.