Peptic ulcers are defects or breaks in the gastric or small intestinal mucosa that have depth and extend through the muscularis mucosae. In contrast to erosions, which are small and superficial mucosal lesions, peptic ulcers can vary in size from 5 mm to several centimeters and may lead to complications such as GI bleeding, obstruction, penetration, and perforation.

The pathogenesis of peptic ulcers is multifactorial and arises from an imbalance of protective and aggressive factors such as when GI mucosal defense mechanisms are impaired in the presence of gastric acid and pepsin. Peptic ulcer disease was long considered as an idiopathic and lifelong disorder. This paradigm changed dramatically in 1984 when Marshall and Warren reported that a curved bacillus, initially named Campylobacter pyloridis and subsequently classified as H pylori, was linked to ulcers. Multiple studies have since shown that eradication of H pylori significantly reduces the rate of ulcer recurrence. Another major risk factor for peptic ulcers is the use of NSAIDs and aspirin. These medications generally exert their therapeutic and toxic effects by inhibiting the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which, in turn, impair mucosal protection and promote ulcers. The treatment of ulcer patients has been revolutionized since the development of the acid-suppressive medications such as the histamine-2 (H₂)-receptor blockers and proton pump inhibitors (PPIs), the synthetic prostaglandin misoprostol, and the selective COX-2 inhibitors. Only a small fraction of ulcers are associated with neoplasia or caused by acid hypersecretory states such as Zollinger-Ellison syndrome and other rare disorders.

The incidence of both gastric and duodenal ulcers in developed countries rapidly increased throughout the 19th century and peaked during the first half of the 20th century. Since the 1950s, however, the incidence and prevalence of both ulcers have steadily declined. There has also been a decrease in the prevalence of H pylori over recent decades, attributed to improved hygiene and widespread use of antibiotics in developed countries. Hospital discharge data for the general US population showed that the age-adjusted hospitalization rate for peptic ulcer disease and H pylori was highest among adults of age 65 years and older and decreased with each subsequent age group. These trends are thought to reflect an underlying birth cohort effect with a decrease in H pylori incidence among younger generations.

A systematic review of the literature on the epidemiology of peptic ulcer disease estimated an annual incidence ranging from 0.10% to 0.19% for physician-diagnosed peptic ulcers and from 0.03% to 0.17% for peptic ulcers diagnosed during hospitalization. In the United States, over 4 million individuals are affected by peptic ulcers, and approximately 15,000 die from ulcer complications each year. Over two-thirds of ulcer patients develop the disease between the ages of 25 and 64 years. The lifetime prevalence of peptic ulcers is 12% in men and 10% in women. The impact of peptic ulcer disease on US health care costs is substantial, with direct and indirect costs totaling over an estimated $10 billion per year. In addition, peptic ulcer complications adversely affect functional status and quality of life.

A. Causes of Peptic Ulcers

H pylori infection and the use of NSAIDs and aspirin have numerous effects on the GI tract and are the most common causes of peptic ulcers (Table 15–1). In general, both factors disrupt normal mucosal defenses and repair, making the mucosa more susceptible to acid. Suppression of gastric acid secretion using pharmacologic agents heals ulcers and reduces future complications. Only a few patients have an underlying acid hypersecretory state causing ulcers. For example, fewer than 1% of patients with duodenal ulcers have a gastrin-secreting tumor causing profound acid secretion as part of the Zollinger-Ellison syndrome. Approximately 3–5% of gastric ulcers represent malignancy including adenocarcinoma, lymphoma, or metastatic lesions. Other infections and conditions that increase ulcer formation include cytomegalovirus or herpes simplex (especially among immunosuppressed patients), tuberculosis, Crohn disease, the use of other non-NSAID medications, hyperparathyroidism, sarcoidosis, myeloproliferative disorder, and systemic mastocytosis.

Cigarette smoking also promotes the development of ulcers and may interact with H pylori and NSAIDs to increase mucosal injury. Smoking also impairs ulcer healing and increases ulcer recurrence. Several studies suggest that alcohol use and diet do not appear to increase ulcer formation, whereas emotional stress may predispose some individuals to ulcers. Critically ill patients with severe burns, physical trauma, or multiple organ failure also have an increased risk of developing gastroduodenal ulcers and associated complications. There is also an association of peptic ulcers with medical conditions such as chronic obstructive lung disease and chronic renal failure, but the mechanisms are unclear. A genetic susceptibility has been reported but is thought to stem mainly from intrafamilial infection with H pylori. Recent studies now suggest that an increasing proportion of ulcers are idiopathic, as they are not related to H pylori, NSAIDs, aspirin, acid hypersecretion, or any other known cause. In a pooled analysis of six clinical trials, for example, 27% of duodenal ulcers had no etiologic cause identified. In other studies, the proportion of idiopathic ulcers that is H pylori–negative and NSAID-negative without any other detectable causes ranges from 20% to 44%. Patients who develop bleeding from H pylori–negative and non-NSAID idiopathic ulcers have also been shown to have a nearly fourfold increased risk of recurrent GI bleeding and higher mortality as compared to patients with bleeding from H pylori–associated ulcers. These idiopathic ulcers appear to be more common in older people with comorbid conditions and have a high rate of relapse.

B. Helicobacter pylori Infection

H pylori is a spiral gram-negative urease-producing bacterium that can be found in the mucus coating the gastric mucosa or between the mucus layer and gastric epithelium. Multiple factors enable the bacterium to live in the hostile stomach acid environment, including its ability to produce urease, which helps alkalinize the surrounding pH. H pylori infection is most commonly acquired in childhood and results in a chronic active gastritis that is usually lifelong without specific treatment. Risk factors for acquiring H pylori include low socioeconomic status, household crowding, and country of origin. The prevalence of H pylori varies among different countries and is significantly higher in developing than in industrialized countries. The majority of infected persons remain asymptomatic, but approximately 10–15% develop peptic ulcer disease during their lifetime. In addition to causing chronic gastritis and peptic ulcers, H pylori has been associated with the development of gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. In 1994, the International Agency for Research on Cancer classified H pylori as a group 1 carcinogen and a definite cause of gastric cancer in humans.

Infection with H pylori increases the risk of peptic ulcers and GI bleeding from threefold to sevenfold. Depending on the population, H pylori is present in up to 70–90% of patients with duodenal ulcers and up to 30–60% of gastric ulcers. Multiple clinical studies show that H pylori eradication reduces ulcer recurrence to less than 10% as compared with recurrences of 70% with acid suppression alone. H pylori generally causes mucosal injury and ulcer complications through inflammation and cytokines. Despite a vigorous systemic and mucosal humoral response, antibody production does not lead to eradication of the infection.

H pylori is a highly heterogeneous bacterium. A combination of microbial and host factors determines the outcome of H pylori infection. The virulence of the organism, host genetics, and environmental factors affect the distribution and severity of gastric inflammation and level of acid secretion. Several H pylori virulence factors have been associated with gastric atrophy, intestinal metaplasia, and risk of disease. For example, the presence of H pylori virulence factors that affect the induction of proinflammatory cytokine release or adhesion to the epithelial cell partly explain geographic differences in the incidence of gastric cancer. Several of these bacterial virulence factors include the Cag pathogenicity island (cagPAI), the vacuolating cytotoxin (VacA), and the blood group antigen-binding adhesin (BabA) and are associated with a more severe clinical outcome. Other virulence factors include H pylori neutrophil-activating protein and cell-wall polysaccharide. H pylori that express the cytotoxin-associated gene A (CagA-positive strains) reportedly represent virulent strains having greater interactions with humans. Several genes in a genomic fragment that make up a cagPAI encode components of a type IV secretion island that translocates CagA in host cells and affects cell growth and cytokine production. CagA is a highly antigenic protein that is associated with a prominent inflammatory response by eliciting interleukin-8 production. H pylori strains that also express active forms of VacA or the outer membrane proteins BabA and OipA are similarly associated with a higher risk of diseases than are strains that lack these factors.

C. Aspirin and NSAIDs

Aspirin and NSAIDs are among the most frequently used drugs worldwide. NSAIDs are used to treat pain and inflammation, whereas aspirin is being increasing used for primary and secondary prevention of cardiovascular events. Unfortunately, these drugs have substantial GI toxicity and are associated with the development of peptic ulcers and life-threatening GI bleeding. Endoscopic studies have shown that up to 15–30% of patients on NSAIDs develop gastric and duodenal ulcers. Epidemiologic studies also suggest that the risks of ulcer complications and death among regular NSAID users are 3–10 times higher as compared with those not taking these drugs. More than 107,000 hospitalizations in the United States are attributed to NSAIDs each year. The elderly are at particularly increased risk, and one study found that the adjusted hospitalization rate for ulcer complications was 16.7 per 1000 person-years among elderly Medicaid patients on NSAIDs, in contrast to a rate of 4.2 among nonusers, with an attributable rate of 12.5 excess hospitalizations for ulcer disease per 1000 person-years among users.

Aspirin and other NSAIDs generally exert their therapeutic and toxic effects by inhibiting COX-1 and COX-2 isoenzymes, which, in turn, decrease prostaglandin synthesis. COX-1 is the rate-limiting enzyme for GI prostaglandins that normally help maintain mucosal blood flow and increase secretion of mucus and bicarbonate. Inhibition of COX-1 impairs mucosal protection and leads to ulcers. The risks of peptic ulcers and GI bleeding are dependent on the dose, duration, and type of NSAID. Several other factors have also been shown to increase the development of peptic ulcers among NSAID users. They include increasing age, a previous history of GI bleeding or ulcers, and concomitant use of steroids. In a meta-analysis, the pooled relative risks for ulcer complications ranged from 1.6 to 9.2, according to the individual NSAID, with a pooled relative risk of 1.6 for aspirin. Even very low doses of aspirin have been associated with ulcers and GI bleeding, suggesting that there are no true safe doses of aspirin. A case-control study, for example, found that low-dose aspirin and nonaspirin NSAIDs both significantly increased the risk of ulcer bleeding with odds ratios of 2.4 and 7.4, respectively.

A. Symptoms and Signs

Epigastric pain is the classic symptom associated with peptic ulcer disease. The pain is often described as a gnawing, dull, aching, “empty,” or “hunger-like” sensation. The classic pain associated with duodenal ulcer is sometimes relieved with ingestion of milk, food, or antacids but recurs 2–4 hours after eating and may also awaken the patient at night. In contrast, most patients with gastric ulcers report that eating exacerbates the pain. During fasting, they may have relief of their symptoms, which then recur shortly after eating. As a result, some gastric ulcer patients experience nausea, avoidance of food/anorexia, and even weight loss.

Peptic ulcer symptoms tend to recur at intervals of weeks or months. An acute worsening or change in the pain characteristic such as generalized pain may arise from ulcer penetration or perforation. Alarm symptoms such as melena, hematemesis, guaiac-positive stools, and unexplained anemia suggest possible ulcer bleeding, while persistent vomiting may represent obstruction. Early satiety, anorexia, and unexplained weight loss may arise from a cancer. Patients with upper abdominal pain with radiation to the back may have penetration, while those with severe or worsening abdominal pain may have perforation. However, many ulcer patients present with few or no symptoms until the development of complications such as GI bleeding, perforation, penetration, and obstruction. In one study, abdominal pain was absent in over 30% of older patients with peptic ulcers seen on upper endoscopy. Less common symptoms such as nausea and vomiting may arise from a gastric outlet obstruction with ulcer edema or scarring.

The physical examination is unreliable and often normal, although some ulcer patients have epigastric tenderness to deep palpation. Occult or gross blood may be detected in the setting of bleeding ulcers. Tachycardia and orthostasis may be found in patients with significant bleeding or dehydration, while a rigid abdomen with diffuse rebound tenderness may reflect ulcer perforation with peritonitis. Rarely, a distended abdomen or a succession splash can be noted in patients with an ulcer that is complicated by outlet obstruction.

The majority of duodenal ulcers develop in the bulb or pylori channel. Patients with duodenal ulcers tend to have a younger age of onset, often between 30 and 55 years of age on average. These duodenal ulcer patients also have an increased parietal cell mass and acid secretion (with increased average basal and nocturnal gastric acid secretion). Bicarbonate secretion has been reported to be impaired among patients with active duodenal ulcers. It is thought that the imbalance between duodenal acid load and buffering capacity leads to the development of small islands of gastric metaplasia in the duodenal bulb. Colonization of these islands by H pylori subsequently leads to duodenitis and duodenal ulcer.

In the stomach, most benign ulcers are found in the antrum and lesser curvature of the stomach at the junction of the body and antrum. Gastric ulcers often occur later in life, usually among patients between the ages of 55 and 70 years with a peak incidence in the sixth decade. Patients with gastric ulcers often have normal or decreased acid secretion. A few patients present with both gastric and duodenal ulcers are found to have increased acid secretion. The gastric ulcers in these patients tend to be located in the distal antrum or pyloric channel.

B. Endoscopy

Definitive diagnosis of peptic ulcers can be made with upper endoscopy. Endoscopy has a much higher diagnostic yield than barium contrast radiology and enables biopsy specimens to be obtained for evaluation of H pylori infection and underlying malignancy. Because up to 5% of gastric ulcers are malignant, it is generally recommended that biopsy samples be taken from the ulcer margin or that a follow-up endoscopy be scheduled 12 weeks after starting acid-suppressive medications to document complete healing. Ulcers greater than 3 cm in size and those that are associated with a mass are more likely to be malignant. In contrast, the incidence of malignant duodenal ulcers is extremely low; thus, they do not routinely require biopsy. Actively bleeding ulcers or ulcers at high risk for rebleeding can also be treated during endoscopy with hemostasis therapy.

Patients suspected of having an ulcer who present with alarm symptoms, such as GI bleeding, early satiety, and unexplained weight loss, and those who are elderly should undergo prompt evaluation with endoscopy. Patients who are found to have multiple ulcers, refractory ulcers, or ulcers in unusual locations, such as postbulbar or jejunum, or who have diarrhea and weight loss should also be considered for evaluation of Zollinger-Ellison syndrome.