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Am Fam Physician. 2023;107(2):165-172

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial relationships.

Peptic ulcer disease is common, affecting 1 out of 12 people in the United States. Approximately 1 in 5 peptic ulcers is associated with Helicobacter pylori infection, with most of the rest due to nonsteroidal anti-inflammatory drug (NSAID) use. The combination of H. pylori infection and NSAID use synergistically increases the risk of bleeding ulcers more than sixfold. The H. pylori test-and-treat strategy is the mainstay of outpatient management. Patients younger than 60 years who have dyspepsia without alarm symptoms should be tested and, if positive, treated to eradicate the infection. If negative, they should be treated empirically with a proton pump inhibitor (PPI). Esophagogastroduodenoscopy is recommended for patients 60 years and older with new symptoms and for anyone with alarm symptoms. Noninvasive testing for H. pylori using a urea breath test or stool antigen test is preferred. Bismuth quadruple therapy or concomitant therapy (nonbismuth quadruple therapy) is the preferred first-line treatment for eradication because of increasing clarithromycin resistance. To lower the risk of ulcers associated with long-term NSAID use, clinicians should consider coadministering a PPI or substituting an NSAID with less effect on gastric mucosa, such as celecoxib. Eradicating H. pylori in NSAID users reduces the likelihood of peptic ulcers by one-half. Potential risks of long-term PPI use include fractures, interaction with antiplatelet medications, chronic kidney disease, Clostridioides difficile infection, dementia, and magnesium, calcium, and vitamin B12 micronutrient deficiencies.

Upper gastrointestinal symptoms such as dyspepsia (i.e., epigastric discomfort, including pain, fullness, or heartburn) are common in the outpatient setting.1,2 Although dyspepsia often occurs without underlying pathology, it can indicate the presence of peptic ulcer disease (PUD). Patients with PUD have peptic ulcers, typically in the stomach and proximal duodenum, resulting from injury caused by pepsin and gastric acid secretion.3 These ulcers can lead to epigastric pain and may be associated with bloating, abdominal fullness, nausea, or early satiety.4 Approximately 1 out of 12 people in the United States is affected by PUD.4

The effectiveness of the once standard triple therapy for H. pylori has waned because of increasing worldwide resistance to that regimen.
Bismuth quadruple therapy, composed of a PPI, bismuth, tetracycline, and metronidazole (Flagyl) or tinidazole, is the recommended first-line treatment in consensus guidelines because this regimen is not affected by increasing clarithromycin resistance.
A Canadian guideline recommends deprescribing PPIs by reducing the dose, stopping the drug, or using it only when needed for patients who have completed at least a four-week course of the PPI and had resolution of symptoms.
RecommendationSponsoring organization
Do not request serology for Helicobacter pylori. Use the stool antigen test or breath test instead.American Society for Clinical Pathology

What are Risk Factors for PUD?

Although there are several risk factors for PUD, the strongest are Helicobacter pylori infection and long-term nonsteroidal anti-inflammatory drug (NSAID) use.5,6


Historically, most peptic ulcers have been associated with H. pylori infection, but there is some evidence that this is changing.6 A cross-sectional study of more than 1 million patients undergoing esophagogastroduodenoscopy, or upper endoscopy, from 2009 to 2018 found that only one-fourth of duodenal ulcers and one-sixth of gastric ulcers were associated with H. pylori infection.5

NSAID use increases the risk of PUD, with a moderate increase for those taking a single drug in this class (odds ratio [OR] = 1.64; 95% CI, 1.43 to 1.87) and a dramatic increase for those taking multiple drugs (OR = 3.82; 95% CI, 2.16 to 6.73).7 Risk increases with duration of use. The OR is 2.46 (95% CI, 1.92 to 3.16) when taken for three years or longer vs. 1.07 (95% CI, 0.84 to 1.35) when taken for less than three months.7 The increased risk of PUD with aspirin use is similar to that seen with other NSAIDs (OR = 1.54; 95% CI, 1.37 to 1.74), whereas the risk is greater with dual antiplatelet therapy using aspirin and clopidogrel (OR = 2.62; 95% CI, 1.12 to 6.11) regardless of duration or aspirin dose.7

A meta-analysis demonstrated that concurrent H. pylori infection and NSAID use synergistically increased the risk of peptic ulcers and bleeding peptic ulcers.8 People with H. pylori infection who used NSAIDs had a 60-fold greater risk of developing peptic ulcers than noninfected people who did not use NSAIDs, and the combination increased the risk of ulcer bleeding more than sixfold.8

How Is PUD Diagnosed?

The main symptom of PUD is a gnawing or burning, episodic, nonradiating epigastric pain that is worsened by eating in those with gastric ulcers and worsened by an empty stomach (two to three hours after meals or at night) and relieved by food or antacids in those with duodenal ulcers.9,10 PUD may also be associated with bloating, abdominal fullness, nausea, or early satiety.4 History and physical examination are important to identify those who may have PUD, including a bleeding ulcer. However, a systematic review found that neither clinical impression nor computer models could adequately distinguish organic from functional disease because of their similar presentations.11 The most accurate test for diagnosing PUD is upper endoscopy, but this test is invasive and costly.


The clinician's clinical impression for PUD is modestly helpful in identifying which patients with dyspepsia have PUD (positive likelihood ratio [LR+] = 2.2; negative likelihood ratio [LR−] = 0.45).11 Specific symptoms that increase the likelihood of PUD in patients with dyspepsia include pain relieved by food (LR+ = 3.3; LR− = 0.7), nighttime awakening due to pain that is relieved by food (LR+ = 2.8; LR− = 0.6), and episodic pain (LR+ = 2.3; LR− = 0.3).10

Upper endoscopy provides direct visualization of the upper gastrointestinal tract and the ability to obtain tissue samples to test for H. pylori and malignancy.12,13 The American College of Gastroenterology (ACG) and Canadian Association of Gastroenterology recommend upper endoscopy in patients 60 years and older with new symptoms of dyspepsia or in adults of any age with alarm symptoms suggestive of malignancy or structural disease (e.g., unintended weight loss, overt gastrointestinal bleeding, iron deficiency anemia, worsening odynophagia or dysphagia, recurrent vomiting, a palpable mass, lymphadenopathy).2 Patients younger than 60 years without alarm symptoms should be tested for H. pylori and treated to eradicate the infection if the result is positive (test and treat).2

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