Peptic Ulcer Disease

Definition

Peptic ulcer disease refers to a group of ulcerative disorders of the upper gastrointestinal  tract that require acid and pepsin for their formation. Ulcers differ from gastritis and erosions in that they extend deeper into the muscularis mucosa. The three common forms of peptic ulcers include Helicobacter pylori-associated ulcers, nonsteroidal anti-inflammatory drug-induced ulcers, and stress-related mucosal damage (also called stress ulcers).

Pathophysiology

The pathogenesis of duodenal ulcers and gastric ulcers is multifactorial and most likely reflects a combination of pathophysiologic abnormalities and environmental and genetic factors.

Most peptic ulcers occur in the presence of acid and pepsin when H. pylori, nonsteroidal anti-inflammatory drugs, or other factors disrupt normal mucosal defense and healing mechanisms. Acid is an independent factor that contributes to disruption of mucosal integrity. Increased acid secretion has been observed in patients with duodenal ulcers and may result from Helicobacter pylori infection. Patients with gastric ulcers usually have normal or reduced rates of acid secretion.

Alterations in mucosal defense induced by Helicobacter pylori or nonsteroidal anti-inflammatory drugs are the most important cofactors in peptic ulcer formation. Mucosal defense mechanisms include mucus and bicarbonate secretion, intrinsic epithelial cell defense, and mucosal blood flow. Maintenance of mucosal integrity and repair is mediated by endogenous prostaglandin production.

H. pylori infection causes gastritis in all infected individuals and is causally linked to Peptic ulcer disease. However, only about 20% of infected persons develop symptomatic Peptic ulcer disease. Most non-nonsteroidal anti-inflammatory drug ulcers are infected with Helicobacter pylori, and Helicobacter pylori eradication markedly decreases ulcer recurrence. H. pylori may cause ulcers by direct mucosal damage, impairing mucosal defense via elaboration of toxins and enzymes, altering the immune/inflammatory response, and by increasing antral gastrin release, which leads to increased acid secretion.

Nonselective nonsteroidal anti-inflammatory drugs (including aspirin) cause gastric mucosal damage by two mechanisms: (1) a direct or topical irritation of the gastric epithelium, and (2) systemic inhibition of the cyclooxygenase-1 (COX-1) enzyme, which results in decreased synthesis of protective prostaglandins.

Use of corticosteroids alone does not increase the risk of ulcer or complications, but ulcer risk is doubled in corticosteroid users taking nonsteroidal anti-inflammatory drugs concur- rently.

Epidemiologic evidence links cigarette smoking to Peptic ulcer disease, impaired ulcer healing, and ulcer-related gastrointestinal complications. The risk is proportional to the amount smoked per day. Smoking does not increase ulcer recurrence after Helicobacter pylori eradication.

Although clinical observation suggests that ulcer patients are adversely affected by stressful life events, controlled studies have failed to document a cause-and-effect relationship.

Coffee, tea, cola beverages, beer, milk, and spices may cause dyspepsia but do not increase Peptic ulcer disease risk. Ethanol ingestion in high concentrations is associated with acute gastric mucosal damage and upper gastrointestinal bleeding but is not clearly the cause of ulcers.

Clinical presentation

Abdominal pain is the most frequent symptom of Peptic ulcer disease. The pain is often epigastric and described as burning but can present as vague discomfort, abdominal fullness, or cramping. A typical nocturnal pain may awaken patients from sleep, especially between 12 am and 3 am.

Pain from duodenal ulcers often occurs 1 to 3 hours after meals and is usually relieved by food, whereas food may precipitate or accentuate ulcer pain in gastric ulcers. Antacids provide rapid pain relief in most ulcer patients.

Heartburn, belching, and bloating often accompany the pain. Nausea, vomiting, and anorexia are more common in gastric ulcers.

The severity of symptoms varies from patient to patient and may be seasonal, occurring more frequently in the spring or fall.

Pain does not always correlate with the presence of an ulcer. Asymptomatic patients may have an ulcer at endoscopy, and patients may have persistent symptoms even with endoscopically proven healed ulcers. Many patients (especially older adults) with nonsteroidal anti-inflammatory drug-induced ulcer-related complications have no prior abdominal symptoms.

Complications of ulcers caused by Helicobacter pylori and nonsteroidal anti-inflammatory drugs include upper gastrointestinal bleeding, perforation into the peritoneal cavity, penetration into an adjacent structure (e.g., pancreas, biliary tract, or liver), and gastric outlet obstruction. Bleeding may be occult or present as melena or hematemesis. Perforation is associated with sudden, sharp, severe pain, beginning first in the epigastrium but quickly spreading over the entire abdomen. Symptoms of gastric outlet obstruction typically occur over several months and include early satiety, bloating, anorexia, nausea, vomiting, and weight loss.

Diagnosis

The physical examination may reveal epigastric tenderness between the umbilicus and the xiphoid process that less commonly radiates to the back.

Routine laboratory tests are not helpful in establishing a diagnosis of uncomplicated Peptic ulcer disease. The hematocrit, hemoglobin, and stool hemoccult tests are used to detect bleeding.

The diagnosis of Helicobacter pylori infection can be made using endoscopic or nonendoscopic tests. The tests that require upper endoscopy are more expensive, uncomfortable, and require a mucosal biopsy for histology, culture, or detection of urease activity. The nonendoscopic tests include serologic antibody detection tests, the urea breath test, and the stool antigen test. Serologic tests detect circulating immunoglobulin G directed against Helicobacter pylori but are of limited value in evaluating posttreatment eradication. The urea breath test is based on urease production by Helicobacter pylori.

Testing for Helicobacter pylori is only recommended if eradication therapy is considered. If endoscopy is not planned, serologic antibody testing is reasonable to determine Helicobacter pylori status. The urea breath test is the preferred nonendoscopic method to verify Helicobacter pylori eradication after treatment.

The diagnosis of Peptic ulcer disease depends on visualizing the ulcer crater either by upper gastrointestinal radiography or endoscopy. Radiography may be the preferred initial diagnostic procedure in patients with suspected uncomplicated Peptic ulcer disease. If complications are thought to exist or if an accurate diagnosis is warranted upper endoscopy should be performed. If a gastric ulcer is found on radiography, malignancy should be excluded by direct endoscopic visualization and histology.

Desired outcome

The goals of treatment are relieving ulcer pain, healing the ulcer, preventing ulcer recurrence, and reducing ulcer-related complications. In Helicobacter pylori-positive patients, the goals are to eradicate the organism, heal the ulcer, and cure the disease with a cost-effective drug regimen.

Treatment

Nonpharmacologic treatment

Patients with Peptic ulcer disease should eliminate or reduce psychological stress, cigarette smoking, and the use of nonsteroidal anti-inflammatory drugs (including aspirin). If possible, alternative agents such as acetaminophen, a nonacetylated salicylate (e.g., salsalate), or COX-2 selective inhibitor should be used for pain relief.

Although there is no need for a special diet, patients should avoid foods and beverages that cause dyspepsia or exacerbate ulcer symptoms (e.g., spicy foods, caffeine, alcohol).

Pharmacologic treatment

Eradication of Helicobacter pylori is recommended for Helicobacter pylori-infected patients with gastric ulcers, duodenal ulcers, ulcer-related complications, and in some other situations. Treatment should be effective, well tolerated, easy to comply with, and cost-effective.

First-line eradication therapy is a proton pump inhibitor (Proton pump inhibitor)-based three-drug regimen containing two antibiotics. Most clinicians prefer clarithromycin and amoxicillin, reserving metronidazole for back-up therapy. The Proton pump inhibitor should be taken 15 to 30 minutes before meals along with the two antibiotics. Although an initial 7-day course provides minimally acceptable eradication rates, longer treatment periods (10 to 14 days) are associated with higher eradication rates and less antimicrobial resistance.

First-line treatment with quadruple therapy using a Proton pump inhibitor (with bismuth, metronidazole, and tetracycline) achieves similar eradication rates as Proton pump inhibitor-based triple therapy and permits a shorter treatment duration (7 days). However, this regimen is often recommended as second-line treatment when a clarithromycin-amoxicillin regimen is used initially. All medications except the Proton pump inhibitor should be taken with meals and at bedtime.

If the initial treatment fails to eradicate Helicobacter pylori, second-line empiric treatment should: (1) use antibiotics that were not included in the initial regimen; (2) include antibiotics that do not have resistance problems; (3) use a drug that has a topical effect (e.g., bismuth); (4) be extended to 10 to 14 days. Thus, if a Proton pump inhibitor-clarithromycin-amoxicillin regimen fails, therapy should be instituted with a Proton pump inhibitor, bismuth subsalicylate, metronidazole, and tetracycline for 10 to 14 days.

Conventional treatment with standard dosages of H₂-receptor antagonists (H₂RA) or sucralfate alone (without antibiotics) relieves ulcer symptoms and heals most gastric and duodenal ulcers in 6 to 8 weeks. Proton pump inhibitors provide comparable healing rates over 4 weeks. However, when conventional antiulcer therapy is discontinued after ulcer healing, most Helicobacter pylori-positive patients develop a recurrent ulcer within 1 year.

Maintenance therapy with a Proton pump inhibitor, low-dose H₂RA, or sucralfate  may be indicated for patients who have a history of ulcer-related complications, a healed refractory ulcer, failed Helicobacter pylori eradication therapy, or who are heavy smokers or nonsteroidal anti-inflammatory drug users.

Most uncomplicated nonsteroidal anti-inflammatory drug-induced ulcers heal with standard regimens of an H₂RA, Proton pump inhibitor, or sucralfate (Table Oral Drug Regimens Used to Heal Peptic Ulcers or Maintain Ulcer Healing) if the nonsteroidal anti-inflammatory drug is discontinued. If the nonsteroidal anti-inflammatory drug must be continued, consideration should be given to reducing the nonsteroidal anti-inflammatory drug dose or switching to acetaminophen, a nonacetylated salicylate, a partially selective COX-2 inhibitor, or a selective COX-2 inhibitor. Proton pump inhibitors are the drugs of choice when nonsteroidal anti-inflammatory drugs must be continued because potent acid suppression is required to accelerate ulcer healing. If Helicobacter pylori is present, treatment should be initiated with an eradication regimen that contains a Proton pump inhibitor. Patients at risk of developing serious ulcer-related complications while on nonsteroidal anti-inflammatory drugs should receive prophylactic cotherapy with misoprostol or a Proton pump inhibitor.

TABLE. Drug Regimens to Eradicate Helicobacter pylori

Drug 1 Drug 2 Drug 3 Drug 4 Proton pump inhibitor-based three-drug regimens Omeprazole 20 mg twice daily or lansoprazole 30 mg twice daily or pantoprazole 40 mg twice daily or esomeprazole 40 mg daily or rabeprazole 20 mg daily Clarithromycin 500 mg twice daily Amoxicillin 1 g twice daily or metronidazole 500 mg twice daily   Bismuth-based four-drug regimens Omeprazole 40 mg twice daily or lansoprazole 30 mg twice daily or pantoprazole 40 mg twice daily or esomeprazole 40 mg daily or rabeprazole 20 mg daily or Standard ulcer-healing dosages of an H2-receptor antagonist taken for 4– 6 wk (see Table 28-2) Bismuth subsalicylate 525 mg 4 times daily Metronidazole 250– 500 mg 4 times daily Tetracycline 500 mg four times daily or amoxicillin 500 mg four times daily, or clarithromycin 250– 500 mg 4 times daily a Although treatment is minimally effective if used for 7 days, 10– 14 days of treatment is recommended. The antisecretory drug may be continued beyond antimicrobial treatment in the presence of an active ulcer. b In the setting of an active ulcer, acid suppression is added to hasten pain relief.

Patients with ulcers refractory to treatment should undergo upper endoscopy to confirm a nonhealing ulcer, exclude malignancy, and assess Helicobacter pylori status. Helicobacter pylori-positive patients should receive eradication therapy. In Helicobacter pylori-negative patients, higher Proton pump inhibitor doses (e.g., omeprazole 40 mg/day) heal the majority of ulcers. Continuous Proton pump inhibitor treatment is often necessary to maintain healing.

TABLE. Oral Drug Regimens Used to Heal Peptic Ulcers or Maintain Ulcer Healing

Drug Duodenal or Gastric Ulcer Healing (mg/dose) Maintenance of Duodenal or Gastric Ulcer Healing (mg/dose) Proton pump inhibitors Omeprazole 20– 40 daily 20– 40 daily Lansoprazole 15– 30 daily 15– 30 daily Rabeprazole 20 daily 20 daily Pantoprazole 40 daily 40 daily Esomeprazole 20– 40 daily 20– 40 daily H2-receptor antagonists Cimetidine 300 four times daily 400 twice daily 800 at bedtime 400– 800 at bedtime Famotidine 20 twice daily 40 at bedtime 20– 40 at bedtime Nizatidine 150 twice daily 300 at bedtime 150– 300 at bedtime Ranitidine 150 twice daily 300 at bedtime 150– 300 at bedtime Promote mucosal defense Sucralfate (g/dose) 1 four times daily 1– 2 twice daily 2 twice daily 1 four times daily

Evaluation of therapeutic outcomes

Patients should be monitored for symptomatic relief of ulcer pain as well as potential adverse effects and drug interactions related to drug therapy.

Ulcer pain typically resolves in a few days when nonsteroidal anti-inflammatory drugs are discontinued and within 7 days upon initiation of antiulcer therapy. Most patients with uncomplicated Peptic ulcer disease will be symptom-free after treatment with any one of the recommended antiulcer regimens.

The persistence or recurrence of symptoms after several weeks of treatment suggests failure of ulcer healing or Helicobacter pylori eradication, or an alternative diagnosis such as gastroesophageal reflux disease.

Most patients with uncomplicated Helicobacter pylori-positive ulcers do not require confirmation of ulcer healing or Helicobacter pylori eradication.

High-risk patients on nonsteroidal anti-inflammatory drugs should be closely monitored for signs and symptoms of bleeding, obstruction, penetration, and perforation.

Follow-up endoscopy is justified in patients with frequent symptomatic recurrence, refractory disease, complications, or suspected hypersecretory states.