Peptic ulcer disease is a chronic illness manifested by recurrent ulcerations in the stomach and proximal duodenum. Acid and pepsin are thought to be crucial to ulcer development, but the great majority of peptic ulcers are directly related to infection with Helicobacter pylori or nonsteroidal anti-inflammatory drug (NSAID) use.^1,2 Gastritis is acute or chronic inflammation of the gastric mucosa and has various etiologies. Dyspepsia is continuous or recurrent upper abdominal pain or discomfort with or without associated symptoms (e.g., nausea, bloating).³ Dyspepsia may be caused by a number of diseases or may be functional.

Uncomplicated peptic ulcer disease has an incidence of more than 5 cases per 1000 persons per year, and about 10% of people living in the Western world will experience a peptic ulcer at some point during their lives.^4,5 In the United States, peptic ulcer disease costs an estimated $5.65 billion per year in total direct and indirect costs.⁶ H. pylori infection, one of the main risk factors of peptic ulcer disease, is one of the most prevalent human infections in the world, affecting at least 50% of the world’s population.⁷ The age-adjusted prevalence of H. pylori infection is decreasing in industrialized countries, likely due to an improved standard of living⁷ and the increased use of proton pump inhibitors (PPIs) and antimicrobial therapy.^2,8 This may explain the decreasing incidence of peptic ulcer disease in the United States, but this may be partially offset by the widespread use of low-dose aspirin and NSAIDs.^2,9 Over 70 million prescriptions for NSAIDs are written, and over 30 billion tablets are sold over the counter annually in the United States.¹⁰ Risk factors for ulcers not due to H. pylori or NSAIDs include antiplatelet agents, stress, Helicobacter heilmannii, cytomegalovirus infections, Behçet’s disease, Zollinger-Ellison syndrome, Crohn’s disease, cirrhosis with portal hypertension, older age, and African American ethnicity.²

Dyspepsia affects 20% to 40% of the world’s population.³ There is no consistent association with sex, age, socioeconomic status, smoking, or alcohol use; however, it is more common in people infected with H. pylori and who take NSAIDs, as well as some other medications.³

Hydrochloric acid and pepsin destroy gastric and duodenal mucosa. Mucus and bicarbonate ion secretions protect mucosa. Prostaglandins protect mucosa by enhancing mucus and bicarbonate production and by enhancing mucosal blood flow, thereby supporting metabolism. The balance between these protective and destructive forces determines whether peptic ulcer disease occurs. H. pylori bacteria or NSAIDs are thought to be the causal agents of peptic ulcer disease in most cases.^1,2 Although traditional treatment of peptic ulcers by various modalities heals most ulcers, eradication of H. pylori cures peptic ulcers in over 80% of patients whose ulcers are not associated with the use of NSAIDs.^7,11

H. pylori is a spiral, gram-negative, urease-producing, flagellated bacterium that is found living between the mucous gel and the mucosa. The bacterium’s production of urease, cytotoxins, proteases, and other compounds is thought to disturb the mucous gel and cause tissue injury. In addition, increased gastrin levels and decreased mucus and bicarbonate production are associated with H. pylori infection. Chronic active (usually asymptomatic) gastritis is an almost universal finding with H. pylori infection, but only 1% to 10% of infected people develop peptic ulcer disease.⁷ It is unclear why most infected persons do not develop symptomatic peptic ulcer disease, but it most likely reflects an interaction of factors, including characteristics of host and pathogen (different virulence of strains of bacteria). In 2005, Marshal and Warren were awarded the Nobel Prize in Physiology or Medicine for their discovery of H. pylori and its role in gastritis and peptic ulcer disease.

H. pylori is a causative agent of mucosa-associated lymphoid tissue lymphoma, and eradication of infection causes a remission in a sizable percentage of patients with low-grade tumors.⁷ In addition, H. pylori infection is a risk factor for adenocarcinoma of the stomach, and as such, the World Health Organization has classified it as a human carcinogen.⁷ However, because the prevalence of gastric cancer in the United States is very low and the H. pylori infection rate is high, other factors undoubtedly are involved. It is not clear whether eradication of the infection reduces the risk of gastric cancer.⁷ H. pylori infection has been associated with the development of iron deficiency anemia, with possible mechanisms including decreased iron absorption and/or occult blood loss from chronic gastritis. A direct cause-and-effect relationship is yet to be determined.^12,13 Improvement in the platelet count in some patients with idiopathic thrombocytopenic purpura has been demonstrated with H. pylori eradication, but much more work remains to be done in this regard.^12,14

NSAIDs inhibit prostaglandin synthesis, thereby decreasing mucus and bicarbonate production and mucosal blood flow, which allows ulcer formation. Gastrin-secreting tumors produce ulceration due to high levels of acid and pepsin production, but acid alone rarely causes ulceration. However, inhibition of acid secretion may allow ulcers to heal and is the basis for traditional ulcer treatments.

Hereditary factors cause a predisposition to peptic ulcer disease, as does smoking. There is an association between chronic renal failure, renal transplantation, cirrhosis, chronic obstructive pulmonary disease, and peptic ulceration, but the precise mechanism is unclear. Emotional stress may predispose to peptic ulcer disease, but diet and alcohol use do not.

Acute gastritis may be related to ischemia from severe illness (e.g., shock, trauma, severe burns, organ failure) or to the direct toxic effects of agents (e.g., NSAIDs, steroids, bile acids). H. pylori infection causes acute and chronic gastritis (both usually asymptomatic). Chronic gastritis may also be caused by autoimmune factors that destroy gastric parietal cells; this results in the loss of acid production and the loss of intrinsic factor production, which in turn cause malabsorption of vitamin B₁₂ and, hence, pernicious anemia.

Dyspepsia has multiple causes. Endoscopy of patients with dyspepsia demonstrates that about 13% have erosive esophagitis, 8% have peptic ulcer disease, and less than 0.3% have gastric or esophageal cancer.³ Other abnormalities such as gastritis, duodenitis, and gastric erosions may be present, but these may or may not be related to symptoms. About 70% to 80% of patients have no definite abnormal findings on endoscopy and are said to have “functional dyspepsia.”³ Patients with functional dyspepsia have evidence of abnormal gastric emptying, abnormal sensitivity to distention, abnormal ability of the stomach to distend with a meal, abnormalities in acid clearance, and abnormal duodenal sensitivity to acid. In addition, there appears to be an as yet poorly characterized interaction between the stomach and intestine and the central nervous system, which may contribute to symptoms.³

Burning epigastric pain is the most classic symptom of peptic ulcer disease. The pain also may be described as sharp, dull, an ache, or an “empty” or “hungry” feeling. Pain may be relieved by ingestion of milk, food, or antacids, presumably due to buffering and/or dilution of acid. Pain recurs as the gastric contents empty, and the recurrent pain may classically awaken the patient at night. Pain tends to occur daily for weeks, resolve, and then recur in weeks to months. Postprandial pain, food intolerance, nausea, retrosternal pain, and belching are not related to peptic ulcer disease. Atypical presentations are common in those >65 years old, including no pain, epigastric pain not relieved by eating, nausea, vomiting, anorexia, weight loss, and bleeding.

A change in the character of typical pain may herald a complication. Abrupt onset of severe or generalized pain may indicate perforation with peritoneal spillage of gastric or duodenal contents. Rapid onset of mid-back pain may be due to posterior penetration into the pancreas, resulting in pancreatitis. Nausea and vomiting may indicate gastric outlet obstruction from scarring or edema. Vomiting of bright red blood or coffee-ground emesis or passage of tarry or melanotic stool or hematochezia may indicate ulcer bleeding.

On physical examination, the only positive finding in patients with uncomplicated peptic ulcer disease may be epigastric tenderness. This finding is neither sensitive nor specific for the diagnosis. Other physical findings may be indicative of complications: a rigid abdomen consistent with peritonitis in perforation; abdominal distention or a succussion splash due to obstruction; or occult or gross rectal blood or blood in the nasogastric aspirate signaling ulcer bleeding.

Epigastric pain, nausea, and vomiting may be present with acute gastritis, but the most common presentation of gastritis is GI bleeding, ranging from occult blood loss in the stool to massive upper GI hemorrhage. Physical findings may be normal, may reflect only the GI bleeding, or may reflect a severe underlying associated illness (as listed earlier).

A definitive diagnosis of peptic ulcer disease cannot be made on clinical grounds alone. Uncomplicated peptic ulcer disease can be strongly suspected in the presence of a “classic” history, including epigastric burning pain; relief of pain with ingestion of milk, food, or antacids; and night pain accompanied by “benign” physical examination findings, including normal vital signs with or without mild epigastric tenderness. The differential diagnosis of epigastric pain is extensive and, in addition to peptic ulcer disease, includes gastritis, gastroesophageal reflux disease, cholelithiasis, pancreatitis, hepatitis, abdominal aortic aneurysm, gastroparesis, and functional dyspepsia. Careful history taking may elicit features that point away from peptic ulcer disease: burning pain radiating into the chest, water brash, and belching may suggest gastroesophageal reflux disease; more severe pain radiating to the right upper quadrant and around the right or left side suggests cholelithiasis; radiation through to the back indicates pancreatitis or abdominal aortic aneurysm; chronic pain, anorexia, or weight loss may indicate gastric cancer. Myocardial ischemic pain may also present as epigastric pain and should be strongly considered in the appropriate clinical setting.