Peptic ulcer disease (gastric ulcer and duodenal ulcer) is a common clinical problem. The lifetime prevalence of peptic ul-cer disease is 5 % to 10 %. The most important risk factors are infection with H. pylori, NSAID ingestion, and the unopposed hypergastrinemia of Zollinger Ellison syndrome. A number of "myth"factors are clearly not associated with the development of ulcers: stress, personality, occupation, alcohol consump-tion, and diet.

Pathophysiology

Peptic ulcer disease was once thought of simply as a prob-lem of hypersecretion of acid and pepsin. However, it is now clear that an ulcer is the end result of an imbalance between aggressive and defensive factors in the gastroduodenal mucosa. H. pylori, NSAIDs, and acid secretory abnormalities are the major factors that disrupt this equilibrium. Whereas acid pep-tic injury is necessary for ulcers to form, acid secretion is nor-mal in almost all patients with gastric ulcers and increased in approximately one third of patients with duodenal ulcers. Zollinger Ellison syndrome accounts for 0.1% of patients who present with peptic ulcer disease. A defect in bicarbonate pro. duction, and hence acid neutralization in the duodenal bulb, is also seen in patients with duodenal ulcer disease. This abnor-mality resolves with eradication of H. pylori if it is present.

Duodenal and gastric ulcers develop in a minority of pa-tients infected with H. pylori. Acute infection results in short. lived acid hyposecretion that then resolves despite persistence of the organism. Chronic infection increases the basal gastrin, the gastrin response to a meal, basal acid output, and gastrin stimulated acid output. Regulation of antral G cells may be al-tered by abnormalities in the ability of adjacent somatostatin-producing D cells to shut down gastrin release. All of these ab-normalities resolve after eradication of the organism. Gastric ulcers may develop in the setting of intense gastritis associated with certain strains of H. pylori. The development of duodenal ulcers is more complex and probably involves enhanced gastric acid secretion caused by dysregulation of somatostatin and gas-trin: gastrin release is increased, whereas the inhibitory influ-ence of somatostatin is diminished. This results in duodenal gastric metaplasia and subsequent H. pylori colonization and in-flammation in the duodenum. Duodenal bicarbonate production is also inhibited by H. pylori infection.

NSAII)s clearly predispose patients to ulcers, both duode-nal and gastric, as well as to complications of ulcer disease, in-cluding hemorrhage, perforation, and obstruction. The risk for gastric ulcers is somewhat greater than that for duodenal ulcers. It is estimated that symptomatic ulceration occurs in 2% to 4 % of patients treated with NSAIDs for 1 year. Many more individuals will develop asymptomatic ulcers of uncertain significance. NSAID-induced ulceration occurs with all NSAIDs, except for the newer cyclooxygenase-2 selective a-gents such as celecoxib (Celebrex), regardless of enteric coat-ing or delivery as a prodrug formulation. The risk of NSAID-induced ulceration and complications is dose related and in-creases with age older than 60, concurrent corticosteroid use, increasing duration and dose of therapy, anticoagulant thera-py, and a history of prior ulcer disease.

Clinical Presentation

Dyspepsia, the classic symptom of peptic ulcer disease, is defined as a pain centered in the upper abdomen or discomfort characterized by fullness, bloating, distention, or nausea. Symptoms may be chronic, recurrent, or of new onset. Dys-pepsia is a common clinical problem and may be seen in 25 % to 40% of adults. Only 15% to 25% of patients with dyspepsia are found to have a gastric or duodenal ulcer. Other causes of dyspepsia include gastroesophageal reflux disease, gastric can-cer, and gastroparesis. Up to 60 % of patients have no definite diagnosis and are classified as having functional dyspepsia, a condition most likely related to an abnormal perception of events in the stomach caused by afferent visceral hypersensi. tivity.

Diagnostic Approach

There are four possible diagnostic approaches to the pa-tient with dyspepsia: ¢Ùa short trial of empirical antisecretory therapy; ¢Úimmediate endoscopy; ¢Ûnoninvasive testing for H. pylori infection followed by antibiotic treatment of positive patients; ¢Üempirical antibiotic therapy for H. pylori without testing for H. pylori infection. There are no randomized con-trolled clinical trials that allow the physician to make evidence- based decisions in the H. pylori era.

Immediate endoscopic evaluation without a trial of empiri-cal therapy is indicated for individuals with obvious systemic symptoms such as weight loss, bleeding, nausea, and vomiting as well as in indivduals with new-onset dyspepsia older than age 45 to 50 years in whom gastric neoplasia is a consideration. If a gastric ulcer is found at endoscopy, multiple biopsies and brush cytology are required to exclude a malignancy. En-doscopy is also indicated in patients who fail to respond to the empirical therapy. There is no longer any role for barium radio-graphy in the evaluation of dyspepsia, because of its poor sen-sitivity and specificity. Initial noninvasive testing for H. pyl0ri followed by antimicrobial therapy in patients with positive fea-tures is a cost-effective approach for patients younger than age 45 years with uncomplicated dyspepsia. The rationale for this is that ulcer disease, if present, will heal and future ulcer diathesis is eliminated. However, a decision to treat empirically patients with dyspepsia with antibiotics for presumed H. pylori infection without proof of infection is not supported by any model and should never be done. Indiscriminate use of antimi-crobial therapy may also be associated with illnesses related to alteration of normal human flora, increased resistance of H. pylori and other bacteria that are not a target of therapy, and a host of adverse effects such as Clostridium difficile colitis.

Diagnostic Tests for H.pylori H. pylori testing is essen-tial in patients with peptic ulcer disease. A negative test will focus the subsequent diagnostic evaluation on other causes of peptic ulcer disease, such as NSAID consumption or gastrino-ma. Furthermore, a negative test precludes antimicrobial ther-apy. Diagnostic tests for the detection of H. pylori infection are subdivided into noninvasive and invasive techniques. Im-munoglobulin G serologic testing is the noninvasive test of choice for the diagnosis of H. pylori infection in the untreated patient. Serologic tests may remain positive for up to 3 years after bacterial eradication, limiting its role in the documenta-tion of eradication. In the 13Cot 14Clabeled urea breath test, H. pylori urease' splits off labeled carbon dioxide, which may be detected in the breath of a patient. The urea breath tests are more accurate than serologic tests but more expensive and less widely available. The urea breath test is the noninvasive test of choice to document successful H. pylori eradication after antibi-otic therapy. Patients should not receive proton pump in-hibitors for at least 14 days before administration of breath tests to avoid false-negative results. If endoscopy is performed, the diagnosis is made by the rapid urease test or histology. In the rapid urease test, mucosal biopsies are directly inoculated into a urea-containing media with a pH-sensitive indicator that changes color when ammonia is metabolized from urea by the urease of the organism. Recent treatment with antibiotics or proton pump inhibitors will decrease the yield of both of these biopsy tests.

Treatment

Cost precludes routine post-treatment testing in all pa-tients. Instead, cure of infection should only be sought in se-lected patients: complicated peptic ulcer disease (i. e. , bleed-ing, perforation or obstruction). MALT lymphoma, or after resection of early gastric cancer. Because antibiotic treatment suppresses the organism even if it is not eradicated, confirma-tion of cure should only be done 4 weeks after completion of therapy.

Initial Treatment of Peptic Ulcer Disease A number of excellent treatment options are available for the healing of pep-tic ulcers. Antacids are highly effective agents for healing ulcers and controlling symptoms. However, from a practical perspec-tive, the inconvenient dosing frequency and adverse effects of therapy limit the use of antacids to symptom control only. Antacids neutralize acid that is already secreted. This increases intragastric pH, which also inactivates pepsin. The greatest buffering capacity is achieved when antacids are given 1 hour after eating(Table 21).

H2-receptor antagonists remain a mainstay of ulcer thera-py. Acid secretion is decreased by competitively and selectively inhibiting the H2 receptor of the parietal cell. There are four different H2receptor antagonists: cimetidine, ranitidine, famo-tidine, and nizatidine, All of these compounds act by the same mechanism but have different relative potencies for inhibiting gastric acid secretion; cimetidine is the least potent, whereas famotidine is the most potent. As a consequence of inhibiting gastric acid secretion, gastric pH rises and pepsin activity de-creases. This class of drugs is uniformly safe and well tolerat-ed, although the risk of adverse effects is slightly increased with cimetidine because of binding to cytochrome P450 and hence increased drug interactions. H2 receptor antagonists heal 90% to 95% of duodenal ulcers and 88% of gastric ulcers at 8 weeks. Given as a single full dose at bedtime, each of the avail-able compounds (cimetidine, 800 mg; ranitidine, 300 mg; famotidine, 40 mg;and nizatidine, 300 mg) has a comparable efficacy for ulcer healing.

The proton pump inhibitors omeprazole and lansoprazo1e are substituted benzimidazoles that bind irreversibly to the H+, K+-ATPase enzyme of the gastric parietal cell, thereby blocking the final step of gastric acid secretion in response to any type of stimulation, resulting in long-lasting inhibition of gastric acid secretion. For gastric secretory activity to be re-stored, new enzyme needs to be resynthesized, which normally takes 2 to 5 days. The proton pump inhibitors are remarkably well tolerated. Adverse effects are uncommon and are typically no more common than those experienced with placebo. The proton pump inhibitors achieve duodenal ulcer healing rates at 4 weeks that typically are noted at 8 weeks with H2-receptor antagonists. Omeprazole, 20 mg once daily, and lansoprazole, 15 mg daily, result in healing rates of 90% to 100% at 4 weeks. In addition to accelerating duodenal ulcer healing, the proton pump inhibitors typically relieve symptoms more rapidly than H2-receptor antagonists. In contrast to the dramatic accel-eration of healing of duodenal ulcers with proton pump in-hibitors, gastric ulcer healing is essentially comparable to that from H2 receptor antagonists at 8 weeks, Furthermore, dou-bling of the dosage used for duodenal ulcer therapy (ornepra-zole, 40 mg daily; lansoprazole, 30 mg daily) is required to achieve comparable healing rates, which results in higher costs to the patient.

Sucralfate is a complex salt of sucrose sulfate and alu-minum hydroxide that is as effective as H2 receptor antagonists in the treatment of duodenal ulcer disease. It is insoluble in water; and in the acid milieu of the stomach, sucralfate is bro-ken down into sucrose sulfate and an aluminum salt. There, it becomes a gel-like substance that binds to both defective and normal mucosa in the stomach and the duodenum. Sucralfate has little or no effect on acid secretion and acts through several different mucosal protective mechanisms. It binds to mucosal surfaces and acts as a physical barrier to the diffusion of acid, pepsin, and bile acids. Sucraifate is as effective as Ha receptor antagonists in the treatment of duodenal ulcer disease. The drug is well tolerated with few adverse effects. The evidence for efficacy in gastric ulcer disease is less compelling. The cor-rect dose is lg four times a day, which makes it less convenient than other agents for treating peptic ulcer disease.