Peptic ulcer disease: current concept of diagnosis and management

Abstract

Peptic ulcer disease is a common gastrointestinal disorder characterized by mucosal defects in the stomach or proximal duodenum that penetrate the muscularis mucosae. Its major etiological factors are infection with Helicobacter pylori and the use of nonsteroidal anti-inflammatory drugs, including low dose aspirin. Disease pathogenesis reflects an imbalance between aggressive luminal factors such as gastric acid and pepsin and protective mechanisms including mucus, bicarbonate secretion, prostaglandins, and mucosal blood flow. Clinically, patients may present with epigastric pain, dyspepsia, or complications like bleeding, perforation, and gastric outlet obstruction. Upper gastrointestinal endoscopy remains the diagnostic gold standard, allowing visualization, biopsy, and therapeutic intervention. Noninvasive tests are widely used to detect H. Pylori infection. Management centers on potent acid suppression with proton pump inhibitors or newer potassium competitive acid blockers, eradication of H. Pylori using evidence based combination regimens, and withdrawal or modification of ulcerogenic medications. Endoscopic hemostasis and surgery are reserved for complicated cases. Rising antibiotic resistance and increasing idiopathic ulcers represent emerging clinical challenges worldwide today

Keywords

Peptic Ulcer Disease; Helicobacter pylori; Endoscopy; Proton Pump Inhibitors; Potassium-Competitive Acid Blockers; Gastrointestinal Hemorrhage; Antibiotic Resistance; NSAIDs

Introduction

Peptic ulcer disease (PUD) refers to the formation of mucosal defects in the gastrointestinal tract—most commonly the stomach and proximal duodenum—that penetrate the muscularis mucosae[1] Historically considered a chronic, relapsing condition associated with significant morbidity and mortality, the landscape of PUD was revolutionized in the late 20th century by the discovery of Helicobacter pylori (H. pylori) by Marshall and Warren, and the subsequent development of profound acid-suppressing medications, namely proton pump inhibitors (PPIs) [2]. Despite these monumental medical advancements, PUD continues to exert a substantial burden on global healthcare systems. The global point prevalence of PUD is estimated to be approximately 5%, with a lifetime risk ranging from 5% to 10% in the general population [3]. The epidemiology of PUD is currently undergoing a dynamic shift. While the incidence of H. pylori-associated ulcers is declining in many industrialized nations due to improved hygiene and active eradication programs, this reduction is partially offset by an increasing incidence of ulcers related to the widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin, particularly among the aging population [4]. Furthermore, a third, increasingly recognized category—idiopathic or H. pylori-negative, NSAID-negative ulcers—poses new diagnostic and therapeutic dilemmas [5]. The pathogenesis of PUD is fundamentally rooted in an imbalance between aggressive luminal factors (gastric acid, pepsin) and defensive mucosal mechanisms (mucus, bicarbonate secretion, prostaglandins, mucosal blood flow) [6]. When this delicate equilibrium is disrupted, epithelial damage ensues. The contemporary management of PUD requires a multifaceted approach: accurate diagnosis, identification and removal of the offending agent, promotion of mucosal healing through potent acid suppression, and the management of complications such as hemorrhage, perforation, and gastric outlet obstruction [7].

This comprehensive review critically examines the current concepts in the diagnosis and management of PUD, synthesizing recent guidelines, evaluating the efficacy of novel therapeutics such as potassium-competitive acid blockers (PCABs), and addressing the controversies surrounding the management of antibiotic-resistant H. pylori and idiopathic ulcers.

Methods

To construct this review, a targeted literature search strategy was employed, strictly utilizing the PubMed database to ensure high academic rigor. The search strategy was designed to capture the most current and impactful research pertaining to PUD. Primary search strings included: ("Peptic Ulcer Disease"[MeSH] OR "Gastric Ulcer"[MeSH] OR "Duodenal Ulcer"[MeSH]) AND ("Diagnosis" OR "Management" OR "Therapeutics"). Additional targeted searches were conducted for "Helicobacter pylori eradication," "Potassium-competitive acid blockers," "Vonoprazan," "Endoscopic hemostasis," and "Idiopathic peptic ulcer."

Inclusion criteria prioritized systematic reviews, meta-analyses, international consensus guidelines (such as the Maastricht/Florence consensus and American College of Gastroenterology guidelines), and randomized controlled trials published between 2017 and 2024 to ensure the currency of the information. Landmark clinical trials and seminal papers published prior to 2017 were included when they provided foundational pathophysiological or historical context. Articles were restricted to those published in the English language. Data extraction focused on mechanistic pathophysiology, diagnostic accuracy of various modalities, efficacy rates of eradication regimens, and clinical outcomes of endoscopic interventions.

Thematic Sections

Etiology and Pathogenesis

The etiology of PUD is overwhelmingly dominated by two factors: H. pylori infection and the use of NSAIDs/aspirin. However, the exact mechanisms by which these factors induce ulceration differ significantly.

Helicobacter pylori

H. pylori is a Gram-negative, microaerophilic bacterium that selectively colonizes the gastric epithelium. It has evolved highly specialized mechanisms to survive the hostile, acidic environment of the stomach. Its production of urease, an enzyme that hydrolyzes urea into ammonia and carbon dioxide, creates a localized alkaline microenvironment, protecting the bacterium from gastric acid [8]. The pathogenesis of H. pylori-induced PUD involves a complex interplay between bacterial virulence factors and the host immune response. Key virulence factors include the Cytotoxin-associated gene A (CagA) and Vacuolating cytotoxin A (VacA). CagA is injected into host epithelial cells via a type IV secretion system, where it undergoes tyrosine phosphorylation and disrupts intracellular signaling pathways, leading to cytoskeletal rearrangement, altered cellular junction integrity, and increased production of pro-inflammatory cytokines like Interleukin-8 (IL-8) [9]. VacA induces the formation of intracellular vacuoles, leading to cell death, and also exerts immunosuppressive effects by inhibiting T-cell proliferation [10]. The anatomic pattern of gastritis dictates the clinical outcome. Antral-predominant gastritis, often seen in the context of high acid secretion, leads to an exaggerated release of gastrin and decreased somatostatin, predisposing the individual to duodenal ulcers [11]. Conversely, corpus-predominant or pan-gastritis leads to mucosal atrophy, intestinal metaplasia, hypochlorhydria, and an increased risk of gastric ulcers and gastric adenocarcinoma [12].

NSAIDs and Aspirin

NSAIDs are the second most common cause of PUD. The pathophysiology of NSAID-induced mucosal injury is bipartite, involving both direct topical injury and systemic effects mediated through cyclooxygenase (COX) inhibition. Weakly acidic NSAIDs remain non-ionized in the acidic gastric lumen, freely diffusing across the gastric epithelial lipid bilayer. Once inside the neutral intracellular environment, they dissociate, releasing hydrogen ions that cause uncoupling of oxidative phosphorylation, decreased ATP production, and cellular necrosis [13].

The systemic mechanism is clinically more significant. NSAIDs inhibit COX-1 and COX-2 enzymes. COX-1 is constitutively expressed and is responsible for the synthesis of prostaglandins (PGE2 and PGI2), which are crucial for maintaining the gastric mucosal barrier by stimulating mucus and bicarbonate secretion, promoting mucosal blood flow, and suppressing acid secretion [14]. The inhibition of COX-1 leads to a profound depletion of mucosal prostaglandins, rendering the mucosa highly susceptible to acid and pepsin. While selective COX-2 inhibitors (coxibs) were developed to spare gastrointestinal COX-1 and reduce ulcer risk, cardiovascular safety concerns limit their widespread use, and they are not entirely devoid of gastrointestinal toxicity [15]. Furthermore, low-dose aspirin, widely used for cardiovascular prophylaxis, irreversibly inhibits COX-1, significantly elevating the risk of bleeding ulcers, especially when combined with other antithrombotic agents [16].

 Idiopathic Peptic Ulcer Disease

An increasing proportion of PUD cases, ranging from 10% to 20% in various cohorts, are classified as idiopathic—meaning they occur in the absence of documented H. pylori infection or NSAID use [17]. The rising incidence is likely relative, reflecting the successful eradication of H. pylori in the broader population. Potential mechanisms for idiopathic ulcers include altered gastric microbiome dynamics, genetic predispositions affecting mucosal defense, psychological stress, smoking, and microvascular ischemia. These ulcers present a distinct clinical challenge, as they have higher rates of recurrence and complication compared to H. pylori-associated ulcers, and lack a targeted curative therapy beyond profound acid suppression [18].

 Clinical Presentation and Diagnosis

Clinical Presentation

The classic presentation of PUD is dyspepsia—specifically, burning or gnawing epigastric pain. Classically, duodenal ulcer pain manifests 2 to 3 hours postprandially and may awaken the patient at night, with transient relief upon food or antacid ingestion. Conversely, gastric ulcer pain is often exacerbated by eating, leading to early satiety, food avoidance, and weight loss [19]. However, this distinction is historically overstated and clinically unreliable. Many patients, particularly the elderly or those taking NSAIDs, remain entirely asymptomatic until they present with a severe complication. Complications occur in up to 25% of patients and include gastrointestinal hemorrhage (hematemesis, melena, or symptomatic anemia), free perforation presenting as acute peritonitis with rigid abdomen, and gastric outlet obstruction manifesting as intractable nausea, vomiting of undigested food, and profound weight loss [20].

Diagnostic Modalities

The gold standard for diagnosing PUD is upper gastrointestinal endoscopy (esophagogastroduodenoscopy, EGD). Endoscopy provides direct mucosal visualization, allowing for the precise localization, measurement, and morphological assessment of ulcers. Crucially, it facilitates biopsy sampling. Any gastric ulcer, regardless of appearance, mandates multiple biopsies from the ulcer margin and base to rule out underlying malignancy (such as gastric adenocarcinoma or lymphoma), as malignant ulcers can visually masquerade as benign peptic lesions [21]. Duodenal ulcers are rarely malignant and do not routinely require biopsy for malignancy exclusion, but mucosal sampling for H. pylori is still indicated. For H. pylori detection, endoscopic methods include the rapid urease test (RUT), histology, and bacterial culture. The RUT is highly sensitive and specific, providing rapid results by detecting the pH shift caused by H. pylori urease activity in a mucosal biopsy [22]. However, its sensitivity is significantly reduced by recent use of PPIs, bismuth, or antibiotics, which suppress bacterial load; hence, guidelines recommend withholding PPIs for two weeks prior to testing [23]. Non-invasive testing is appropriate for the initial diagnosis of H. pylori in young patients with uninvestigated dyspepsia lacking "alarm features" (e.g., weight loss, dysphagia, anemia). The Urea Breath Test (UBT) and the Stool Antigen Test (SAT) are the preferred modalities, both offering sensitivities and specificities exceeding 90% [24]. Serology (IgG testing) is no longer routinely recommended in low-prevalence areas because it cannot distinguish between active and past infections [25]. Medical Management and Eradication Strategies https://pubmed.ncbi.nlm.nih.gov/35944925/ pharmacological management of PUD hinges on acid suppression to promote mucosal healing and, if applicable, the eradication of H. pylori.

Acid Suppression Therapy

Proton Pump Inhibitors (PPIs) have been the cornerstone of PUD therapy for decades. They act by irreversibly binding to the H+/K+ ATPase enzyme on the apical membrane of parietal cells, effectively blocking the final common pathway of acid secretion [26]. Standard-dose PPI therapy (e.g., omeprazole 20 mg, pantoprazole 40 mg) for 4 to 8 weeks results in ulcer healing rates exceeding 90%. Histamine-2 receptor antagonists (H2RAs) are less efficacious than PPIs and are largely relegated to secondary roles or used in settings where PPIs are unavailable or contraindicated [27]. Recently, Potassium-Competitive Acid Blockers (PCABs), such as vonoprazan, have emerged as highly effective alternatives to PPIs. Unlike PPIs, which require acidic activation and have a short half-life necessitating pre-prandial dosing, PCABs bind reversibly to the potassium-binding site of the H+/K+ ATPase. They offer several distinct pharmacological advantages: rapid onset of action (achieving maximal acid suppression on day one), longer half-life, resistance to degradation by gastric acid, and independence from CYP2C19 genetic polymorphisms that cause variable PPI metabolism [28]. Clinical trials, such as the WATERFALL study, have demonstrated that vonoprazan is non-inferior—and in some scenarios, superior—to PPIs in healing severe erosive esophagitis and PUD [29].

Helicobacter pylori Eradication

The paradigm for H. pylori eradication has shifted dramatically due to the alarming global rise in antibiotic resistance, particularly to clarithromycin, metronidazole, and levofloxacin [30]. The traditional first-line strategy, Clarithromycin Triple Therapy (PPI + clarithromycin + amoxicillin or metronidazole for 14 days), is now obsolete in regions where clarithromycin resistance exceeds 15%—which currently includes most of North America, Europe, and Asia [31].

According to the Maastricht VI/Florence consensus and the ACG clinical guidelines, empirical first-line therapy should consist of Bismuth Quadruple Therapy (BQT) or Non-Bismuth Concomitant Quadruple Therapy.

• Bismuth Quadruple Therapy (BQT): Comprises a PPI, bismuth subcitrate or subsalicylate, tetracycline, and metronidazole for 10 to 14 days. Bismuth has direct bactericidal properties and prevents bacterial adhesion, and resistance to bismuth and tetracycline remains globally low (<5%). BQT consistently achieves eradication rates of 85-90% even in areas with high clarithromycin and metronidazole resistance [32].
• Non-Bismuth Concomitant Therapy: Includes a PPI, amoxicillin, clarithromycin, and metronidazole taken simultaneously for 14 days. This is an option in settings where bismuth is unavailable, though it exposes patients to three antibiotics, increasing the risk of adverse effects [33].

A major recent breakthrough is the introduction of PCAB-based Dual Therapy. The combination of vonoprazan and high-dose amoxicillin (e.g., vonoprazan 20 mg BID + amoxicillin 1g TID for 14 days) has shown remarkable efficacy. The profound and sustained acid suppression achieved by vonoprazan maintains the intragastric pH above 6, which forces H. pylori into a replicative state, rendering it highly susceptible to the bactericidal action of amoxicillin [34]. Meta-analyses have shown that vonoprazan-based dual and triple therapies achieve superior eradication rates compared to traditional PPI-based triple therapies, with fewer side effects due to the reduced antibiotic pill burden [35]. Salvage therapy for patients who fail first-line eradication should be guided by local resistance patterns or, ideally, antimicrobial susceptibility testing (culture or molecular profiling). Levofloxacin-based therapies are common salvage regimens, but rising fluoroquinolone resistance threatens their utility [36]. Rifabutin-based triple therapy is an effective third-line or fourth-line option, though it carries a rare risk of myelotoxicity [37].

Management of NSAID-Induced Ulcers

The primary intervention for NSAID-induced PUD is the immediate cessation of the offending agent. Concurrently, a PPI should be initiated for 8 weeks [38]. If NSAID therapy cannot be discontinued due to severe rheumatological or cardiovascular indications, a switch to a selective COX-2 inhibitor (if cardiovascular risk permits) combined with high-dose maintenance PPI therapy is the recommended strategy [39]. Misoprostol, a synthetic prostaglandin E1 analog, is also effective for prophylaxis and healing but is poorly tolerated due to frequent gastrointestinal side effects such as abdominal cramping and diarrhea [40].

Management of Complications

Gastrointestinal Bleeding

Bleeding is the most common and feared complication of PUD. Acute management prioritizes hemodynamic resuscitation with intravenous crystalloids and blood transfusions if indicated. Pre-endoscopic administration of a high-dose intravenous PPI (e.g., pantoprazole 80 mg bolus followed by 8 mg/hour continuous infusion) is recommended to stabilize clot formation, as pepsin is inactivated at a pH above 6.0 [41]. Prokinetics like erythromycin may be given intravenously 30-120 minutes prior to endoscopy to clear the stomach of blood and clots, improving endoscopic visualization [42].

Endoscopy is the definitive modality for both diagnosis and hemostasis, ideally performed within 24 hours of presentation. The Forrest classification guides therapy: active spurting (Ia) or oozing (Ib) bleeding, and non-bleeding visible vessels (IIa) require endoscopic intervention. Modalities include injection therapy (dilute epinephrine), thermal coagulation (multipolar electrocoagulation, heater probe), and mechanical therapy (through-the-scope hemoclips) [43]. Current guidelines recommend dual therapy—injection of epinephrine combined with either a thermal or mechanical method—as it is superior to monotherapy in achieving initial hemostasis and preventing rebleeding. Recently, novel endoscopic tools have emerged, including Over-The-Scope Clips (OTSC) for large or fibrotic ulcers, and hemostatic powders (TC-325) as a rescue therapy for diffuse oozing [44].

 Perforation and Obstruction

Gastric or duodenal perforation presents as an acute surgical emergency. While highly selected, stable patients with sealed perforations may occasionally be managed conservatively with intravenous antibiotics, nasogastric suction, and PPIs, the standard of care remains surgical intervention. Laparoscopic closure with an omental patch (Graham patch) is the operation of choice [45]. Gastric outlet obstruction, often due to chronic scarring and fibrosis at the pylorus or duodenal bulb, may initially be managed with endoscopic balloon dilation, but definitive surgical intervention (such as antrectomy with Billroth I/II reconstruction or gastroenterostomy) is required in refractory cases.

Controversies and Conflicting Evidence

Despite extensive research, several controversies persist in the management of PUD. One major area of debate surrounds the optimal duration and modality of acid suppression following endoscopic hemostasis for bleeding ulcers. While guidelines historically mandated a 72-hour continuous intravenous PPI infusion, recent randomized controlled trials and meta-analyses suggest that high-dose intermittent oral or intravenous PPIs may be non-inferior to continuous infusions in preventing rebleeding, potentially reducing hospital costs and length of stay. Another controversy involves the management of idiopathic PUD. Because the exact etiology is elusive, long-term maintenance PPI therapy is often initiated by default. However, concerns regarding the long-term adverse effects of PPIs—including potential associations with bone fractures, enteric infections (Clostridioides difficile), hypomagnesemia, and chronic kidney disease—make indefinite therapy undesirable. The risk-benefit ratio of lifelong acid suppression versus the risk of recurrent life-threatening ulcer hemorrhage in the idiopathic population remains a subject of intense debate.

Furthermore, the integration of PCABs into Western guidelines is still evolving. While heavily adopted in Asia (particularly Japan), the cost-effectiveness and long-term safety profiles of vonoprazan and similar agents in Western populations require further validation through large-scale, diverse, multi-center trials.

Limitations of Current Literature

The current body of literature on PUD possesses several limitations. First, while meta-analyses on H. pylori eradication are abundant, many primary studies suffer from significant heterogeneity in study design, regional antibiotic resistance profiles, and adherence rates, making global generalizations difficult. Efficacy data for salvage therapies are often derived from small, single-center retrospective cohorts rather than robust randomized controlled trials. Second, the literature concerning idiopathic ulcers is severely limited. Standardized diagnostic criteria to definitively rule out surreptitious NSAID use or transient H. pylori infection (which can be missed by standard biopsies) are lacking. Consequently, clinical trials evaluating therapies specifically for true idiopathic PUD are virtually nonexistent, leaving a major gap in evidence-based management for this growing patient demographic.

FUTURE DIRECTIONS

The future of PUD research and management must pivot toward precision medicine and advanced technological integration. Regarding H. pylori, the transition from empirical antibiotic selection to tailored therapy guided by molecular susceptibility testing is paramount. The development of rapid, point-of-care PCR-based tests to detect clarithromycin or levofloxacin resistance mutations in stool or gastric biopsies could revolutionize first-line treatment strategies, maximizing eradication rates and mitigating antibiotic stewardship concerns.

Research into the gastric microbiome beyond H. pylori holds immense potential. Understanding how dysbiosis contributes to mucosal susceptibility could unlock novel therapeutic targets for idiopathic ulcers, potentially involving probiotics or microbiome modulators.

In endoscopy, artificial intelligence (AI) and deep learning algorithms are being developed to aid in the real-time detection of early gastric cancer within benign-appearing gastric ulcers. Furthermore, advancements in endoscopic suturing devices and topical hemostatic agents will likely continue to shift the management of severe ulcer complications away from surgery and entirely into the realm of advanced therapeutic endoscopy.

CONCLUSION

Peptic ulcer disease remains a highly relevant clinical entity that demands a rigorous, evidence-based approach to diagnosis and management. The landscape has undeniably shifted; the triumph over H. pylori has been complicated by the specter of antimicrobial resistance, necessitating the adoption of bismuth quadruple therapies and the integration of novel, potent acid suppressants like PCABs. Simultaneously, the aging population has sustained the burden of NSAID-induced and bleeding ulcers. Endoscopy remains the linchpin of both diagnosis and emergency management, continually evolving with advanced hemostatic techniques. Addressing the rising tide of idiopathic ulcers and optimizing molecular testing for H. pylori represent the crucial next frontiers in the ongoing effort to minimize the morbidity and mortality associated with peptic ulcer disease.

 

 

REFERENCES

1. Lanas A, Chan FKL. Peptic ulcer disease. Lancet. 2017;390(10094):613-624. DOI: 10.1016/S0140-6736(16)32404-7. https://pubmed.ncbi.nlm.nih.gov/28242110/
2. Malfertheiner P, Megraud F, Rokkas T, Gisbert JP, Liou JM, Schulz C, Gasbarrini A, Atherton JC, Machado JC, Amieva M, et al. Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report. Gut. 2022;71(9):1724-1762. DOI: 10.1136/gutjnl-2022-327745. https://pubmed.ncbi.nlm.nih.gov/35944925/
3. Ford AC, Sperber AD, Corsetti M, Camilleri M. Peptic ulcer disease. Lancet. 2020;396(10257):1156-1166. DOI: 10.1016/S0140-6736(20)30114-6. https://pubmed.ncbi.nlm.nih.gov/32910903/
4. Sostres C, Gargallo CJ, Arroyo MT, Lanas A. Peptic ulcer bleeding risk. The role of Helicobacter pylori infection in NSAID/low-dose aspirin users. Am J Gastroenterol. 2015;110(5):684-689. DOI: 10.1038/ajg.2015.98. https://pubmed.ncbi.nlm.nih.gov/25869391/
5. Charpignon C, Lesgourgues B, Pariente A, Campillo B, Goria O, Boulay G, et al. Peptic ulcer disease: one in five is related to neither Helicobacter pylori nor aspirin/NSAID intake. Aliment Pharmacol Ther. 2013;38(8):946-954. DOI: 10.1111/apt.12465. https://pubmed.ncbi.nlm.nih.gov/24004044/
6. Narayanan M, Reddy KM, Marsicano E. Peptic Ulcer Disease and Helicobacter pylori infection. Mo Med. 2018;115(3):219-224. DOI: 10.1016/j.mcna.2020.08.001. https://pubmed.ncbi.nlm.nih.gov/30228726/
7. Kavitt RT, Lipowska AM, Anyane-Yeboa A, Gralnek IM. Diagnosis and Treatment of Peptic Ulcer Disease. Am J Med. 2019;132(4):447-456. DOI: 10.1016/j.amjmed.2018.12.009. https://pubmed.ncbi.nlm.nih.gov/30611829/
8. Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev. 2006;19(3):449-490. DOI: 10.1128/CMR.00054-05. https://pubmed.ncbi.nlm.nih.gov/16847081/
9. Hatakeyama M. Helicobacter pylori CagA and gastric cancer: a paradigm for macromolecular injection-transmitted human disease. Nat Rev Cancer. 2014;14(3):158-168. DOI: 10.1038/nrc3659. https://pubmed.ncbi.nlm.nih.gov/24561443/
10. Cover TL, Blaser MJ. Helicobacter pylori in health and disease. Gastroenterology. 2009;136(6):1863-1873. DOI: 10.1053/j.gastro.2009.01.073. https://pubmed.ncbi.nlm.nih.gov/19457415/
11. McColl KE. Pathophysiology of duodenal ulcer disease. Eur J Gastroenterol Hepatol. 1997;9(1):9-12. DOI: 10.1097/00042737-199701000-00003. https://pubmed.ncbi.nlm.nih.gov/9031893/
12. Dixon MF. Pathophysiology of Helicobacter pylori infection. Scand J Gastroenterol Suppl. 1994;201:7-10. DOI: 10.3109/00365529409091386. https://pubmed.ncbi.nlm.nih.gov/8047833/
13. Bjarnason I, Scarpignato C, Holmgren E, Olszewski M, Rainsford KD, Lanas A. Mechanisms of Damage to the Gastrointestinal Tract From Nonsteroidal Anti-Inflammatory Drugs. Gastroenterology. 2018;154(3):500-514. DOI: 10.1053/j.gastro.2017.10.049. https://pubmed.ncbi.nlm.nih.gov/29274864/
14. Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself? Physiol Rev. 2008;88(4):1547-1565. DOI: 10.1152/physrev.00004.2008. https://pubmed.ncbi.nlm.nih.gov/18923189/
15. Chan FK, Lanas A, Scheiman J, Berger MF, Nguyen H, Goldstein JL. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet. 2010;376(9736):173-179. DOI: 10.1016/S0140-6736(10)60673-3. https://pubmed.ncbi.nlm.nih.gov/20638563/
16. McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med. 2006;119(8):624-638. DOI: 10.1016/j.amjmed.2005.10.039. https://pubmed.ncbi.nlm.nih.gov/16887404/
17. Chung CS, Chiang TH, Lee YC. A systematic approach for the diagnosis and treatment of idiopathic peptic ulcer disease. Korean J Intern Med. 2015;30(5):559-570. DOI: 10.3904/kjim.2015.30.5.559. https://pubmed.ncbi.nlm.nih.gov/26354049/
18. Quan C, Talley NJ. Management of peptic ulcer disease not related to Helicobacter pylori or NSAIDs. Am J Gastroenterol. 2002;97(12):2950-2961. DOI: 10.1111/j.1572-0241.2002.07076.x. https://pubmed.ncbi.nlm.nih.gov/12492176/
19. Vakil N. Peptic Ulcer Disease. N Engl J Med. 2010;362(16):1544-1545. DOI: 10.1056/NEJMvcm0805164. https://pubmed.ncbi.nlm.nih.gov/20410515/
20. Svanes C. Trends in ulcer disease epidemiology. Epidemiol Rev. 2000;22(2):290-297. DOI: 10.1093/oxfordjournals.epirev.a018040. https://pubmed.ncbi.nlm.nih.gov/11218378/
21. Sugano K, Tack J, Kuipers EJ, Graham DY, El-Omar EM, Miura S, Haruma K, Asaka M, Uemura N, Malfertheiner P. Kyoto global consensus report on Helicobacter pylori gastritis. Gut. 2015;64(9):1353-1367. DOI: 10.1136/gutjnl-2015-309252. https://pubmed.ncbi.nlm.nih.gov/26187502/
22. Vaira D, Perna F. How useful is the rapid urease test for evaluating the success of Helicobacter pylori eradication therapy? Nat Clin Pract Gastroenterol Hepatol. 2007;4(11):600-601. DOI: 10.1038/ncpgasthep0958. https://pubmed.ncbi.nlm.nih.gov/17978832/
23. Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol. 2017;112(2):212-239. DOI: 10.1038/ajg.2016.563. https://pubmed.ncbi.nlm.nih.gov/28071659/
24. Gisbert JP, Pajares JM. Stool antigen test for the diagnosis of Helicobacter pylori infection: a systematic review. Helicobacter. 2004;9(4):347-368. DOI: 10.1111/j.1083-4389.2004.00235.x. https://pubmed.ncbi.nlm.nih.gov/15270750/
25. Burucoa C, Delchier JC, Courillon-Mallet A, de Korwin JD, Mégraud F, Zerbib F, Raymond J, Fauchère JL. Comparative evaluation of 29 commercial Helicobacter pylori serological kits. Helicobacter. 2013;18(3):169-179. DOI: 10.1111/hel.12030. https://pubmed.ncbi.nlm.nih.gov/23241103/
26. Sachs G, Shin JM, Briving C, Wallmark B, Hersey S. The pharmacology of the gastric acid pump: the H+,K+ ATPase. Annu Rev Pharmacol Toxicol. 1995;35:277-305. DOI: 10.1146/annurev.pa.35.040195.001425. https://pubmed.ncbi.nlm.nih.gov/7598465/
27. Strand DS, Kim D, Peura DA. 25 Years of Proton Pump Inhibitors: A Comprehensive Review. Gut Liver. 2017;11(1):27-37. DOI: 10.5009/gnl15502. https://pubmed.ncbi.nlm.nih.gov/27840364/
28. Sugano K. Vonoprazan fumarate, a novel potassium-competitive acid blocker, in the management of gastrointestinal disorders. Aliment Pharmacol Ther. 2018;47(1):99-109. DOI: 10.1111/apt.14414. https://pubmed.ncbi.nlm.nih.gov/29082552/
29. Laine L, DeVault K, Katz P, et al. Vonoprazan Versus Lansoprazole for Healing and Maintenance of Healing of Erosive Esophagitis: A Randomized Trial. Gastroenterology. 2023;164(1):61-71. DOI: 10.1053/j.gastro.2022.09.041. https://pubmed.ncbi.nlm.nih.gov/36240833/
30. Savoldi A, Carrara E, Graham DY, Conti M, Tacconelli E. Prevalence of Antibiotic Resistance in Helicobacter pylori: A Systematic Review and Meta-analysis in World Health Organization Regions. Gastroenterology. 2018;155(5):1372-1382. DOI: 10.1053/j.gastro.2018.07.007. https://pubmed.ncbi.nlm.nih.gov/30003817/
31. Fallone CA, Chiba N, van Zanten SV, Fischbach L, Gisbert JP, Hunt RH, et al. The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults. Gastroenterology. 2016;151(1):51-69. DOI: 10.1053/j.gastro.2016.04.006. https://pubmed.ncbi.nlm.nih.gov/27102658/
32. Ford AC, Qume M, Moayyedi P, Arents NL, Lassen AT, Logan RF, et al. Helicobacter pylori "test and treat" or endoscopy for managing dyspepsia: an individual patient data meta-analysis. Gastroenterology. 2005;128(7):1838-1844. DOI: 10.1053/j.gastro.2005.03.024. https://pubmed.ncbi.nlm.nih.gov/15940616/
33. Gisbert JP, Calvet X. Review article: non-bismuth quadruple (concomitant) therapy for eradication of Helicobacter pylori. Aliment Pharmacol Ther. 2011;34(6):604-617. DOI: 10.1111/j.1365-2036.2011.04770.x. https://pubmed.ncbi.nlm.nih.gov/21745235/
34. Suzuki S, Gotoda T, Kusano C, Iwatsuka K, Moriyama M. The Efficacy and Tolerability of a Triple Therapy Containing a Potassium-Competitive Acid Blocker Compared With a 14-Day PPI-Based Low-Dose Amoxicillin and Clarithromycin Therapy. Am J Gastroenterol. 2016;111(7):949-956. DOI: 10.1038/ajg.2016.182. https://pubmed.ncbi.nlm.nih.gov/27140024/
35. Jung YS, Kim TH, Choi KD, Lee H, Jung EK. Efficacy of vonoprazan-based triple therapy for Helicobacter pylori eradication: a systematic review and meta-analysis. J Gastroenterol Hepatol. 2017;32(9):1552-1561. DOI: 10.1111/jgh.13783. https://pubmed.ncbi.nlm.nih.gov/28370216/
36. Gisbert JP, Morena F. Systematic review and meta-analysis: levofloxacin-based rescue regimens after Helicobacter pylori treatment failure. Aliment Pharmacol Ther. 2006;23(1):35-44. DOI: 10.1111/j.1365-2036.2006.02737.x. https://pubmed.ncbi.nlm.nih.gov/16393278/
37. Gisbert JP, Calvet X. Review article: rifabutin in the treatment of refractory Helicobacter pylori infection. Aliment Pharmacol Ther. 2012;35(2):209-221. DOI: 10.1111/j.1365-2036.2011.04937.x. https://pubmed.ncbi.nlm.nih.gov/22126421/
38. Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, McGowan J. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev. 2002;(4):CD002296. DOI: 10.1002/14651858.CD002296. https://pubmed.ncbi.nlm.nih.gov/12519573/
39. Chan FK, Wong VW, Suen BY, Wu JC, Ching JY, Hung LC, et al. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet. 2007;369(9573):1621-1626. DOI: 10.1016/S0140-6736(07)60749-1. https://pubmed.ncbi.nlm.nih.gov/17499604/
40. Graham DY, Agrawal NM, Roth SH. Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial. Lancet. 1988;2(8623):1277-1280. DOI: 10.1016/s0140-6736(88)92892-0. https://pubmed.ncbi.nlm.nih.gov/2904005/
41. Barkun AN, Almadi M, Kuipers EJ, Laine L, Sung J, Tse F, et al. Management of Nonvariceal Upper Gastrointestinal Bleeding: Guideline Recommendations From the International Consensus Group. Ann Intern Med. 2019;171(11):805-822. DOI: 10.7326/M19-1795. https://pubmed.ncbi.nlm.nih.gov/31634917/
42. Rahman R, Nguyen DL, Sohail U, McKnight W, Parekh NK. Pre-endoscopic erythromycin administration in upper gastrointestinal bleeding: an updated meta-analysis and systematic review. Ann Gastroenterol. 2016;29(3):312-317. DOI: 10.20524/aog.2016.0045. https://pubmed.ncbi.nlm.nih.gov/27366032/
43. Gralnek IM, Camus Duboc M, Garcia-Pagan JC, et al. Endoscopic diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH): European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2021;53(3):300-332. DOI: 10.1055/a-1369-5274. https://pubmed.ncbi.nlm.nih.gov/33561884/
44. Schmidt A, Gölder S, Goetz M, Meining A, Lau J, von Delius S, et al. Over-the-scope clips are more effective than standard endoscopic therapy for patients with recurrent bleeding of peptic ulcers. Gastroenterology. 2018;155(3):674-686. DOI: 10.1053/j.gastro.2018.05.037. https://pubmed.ncbi.nlm.nih.gov/29803838/
45. Søreide K, Thorsen K, Harrison EM, Bingener J, Møller MH, Ohene-Yeboah M, Søreide JA. Perforated peptic ulcer. Lancet. 2015;386(9996):1288-1298. DOI: 10.1016/S0140-6736(15)00276-7. https://pubmed.ncbi.nlm.nih.gov/26460663/