Previously, peptic ulcers were primarily attributed to stress and the use of some types of medications. However, in a groundbreaking discovery, Marshall and Warren [1] identified Helicobacter pylori infection as the main cause of peptic ulcer disease (PUD). This led to the establishment of H. pylori eradication therapy as the cornerstone of peptic ulcer treatment and the prevention of their recurrence.

In recent years, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) has increased significantly in conjunction with aging populations and the increasing prevalence of musculoskeletal and cardiovascular diseases. Simultaneously, the widespread adoption of H. pylori eradication therapy and improved sanitation have contributed to a shift in the etiology of PUD. These changes have also altered the pattern of complications, such as gastrointestinal bleeding, associated with peptic ulcers.

In 2006, a nationwide study was conducted across 40 health promotion centers in South Korea. As part of this study, upper gastrointestinal endoscopies were performed on 25536 patients. The reported prevalence of gastric ulcers was 3.3%, with duodenal ulcers observed in 2.1% of cases [2,3]. This study also found that the incidence of PUD was higher among men than among women. Furthermore, the prevalence of gastric ulcers increased significantly with age, whereas the prevalence of duodenal ulcers did not show a similar correlation. Another study conducted in 2007 involved 12705 patients who underwent endoscopies. That study reported an overall prevalence of PUD of 2.4%, with gastric ulcers accounting for 61.2% of the cases and duodenal ulcers accounting for 38.8% [4].

Recent epidemiological studies in South Korea have shown a decline in the seroprevalence of H. pylori. However, the country’s shifting demographics, including an aging population, have led to increases in the prevalence degenerative musculoskeletal disorders and in the preventive use of NSAIDs for cardiovascular conditions. These factors have significantly altered the risk factors contributing to the development of peptic ulcers [5,6].

In 2020, Paik et al. [7] conducted a cross-sectional study involving 12095 participants using data from the Korean National Health and Nutrition Examination Survey and Health Professionals Follow-Up Study. Data collected by the Chronic Disease Surveillance Division of the Korea Disease Control and Prevention Agency and Ministry of Health and Welfare between 2008 and 2009 were analyzed using multivariate logistic regression to evaluate the association between PUD and various factors. Among the participants, 385 men (8.2%) and 295 women (5.4%) were diagnosed with PUD. Multivariate analysis revealed significant associations between PUD and factors such as age and psychological and psychosocial stressors in both sexes. Additionally, in men, PUD was linked to low body mass index values and insufficient physical activity in daily life.

A lower educational background has also been identified as a potential risk factor for the development of PUD, with social stress, lifestyle choices, and dietary habits contributing to its multifactorial etiology [8]. Additionally, although the prevalence of H. pylori infection has declined in many developed countries, it remains high in South Korea [9-12].

Kim et al. [13] analyzed the records of patients hospitalized for peptic ulcer bleeding (PUB) between 2006 and 2015 using data from the Korean National Health Insurance Service database. The study analyzed the standardized incidence rates of PUB alongside clinical factors such as age, sex, H. pylori infection, medication exposure, complications, and mortality. A total of 151507 PUB-related hospitalizations were recorded, with an annual rate of 34.98 cases per 100000 person-years. The incidence of PUB remained steady between 2006 and 2008 but showed a significant annual decline of 2.7% from 2008 to 2015 (p<0.05), primarily among men. Men demonstrated a higher incidence than women in the 40–70 age group; however, among individuals aged 80 years and older, women had a higher incidence than men. Interestingly, the prevalence of H. pylori infection in patients with PUB increased significantly over time, despite any substantial changes in observed NSAID or other drug exposures.

In the United States, PUD has an estimated annual prevalence ranging from 0.12% to 1.5% [14], and has shown a marked decline in complication rates over time [15-17]. From 2005 to 2014, hospitalizations associated with PUD decreased by 25.8%, while in-hospital mortality dropped by 2.4% during the same period [17]. Additionally, the age-standardized prevalence decreased from 143.4 cases per 100000 population in 1990 to 99.4 cases per 100000 in 2019; this decrease occurred alongside notable declines in both mortality rates and disability-adjusted life years. These trends underscore the significant advancements made to prevent and manage PUD.

PUD arises from an imbalance in the number of aggressive factors (e.g., gastric acid, pepsin, bile, and H. pylori infection) and external contributors (e.g., NSAIDs, inhaled tobacco smoke, and consumed alcohol) relative to the protective mechanisms of the gastric and duodenal mucosae. When these defense mechanisms are weakened, the gastric tissue becomes vulnerable to the harmful effects of gastric acid and pepsin, resulting in the formation of ulcers [18,19].

H. pylori plays a central role in ulcer formation by utilizing its helical structure and flagella to penetrate the gastric mucus layer and colonize the gastric epithelium. This bacterium also produces ammonia and bicarbonate, via its urease activity, enabling it to survive in the acidic gastric environment and to also reduce mucus viscosity and thereby enhance its mobility. The resulting inflammatory response further compromises the gastric mucosa [20]. Increased acid production, often due to antral involvement, is implicated in duodenal ulcer formation [21].

Protective mechanisms, including mucus and bicarbonate secretion, mucosal blood flow, and epithelial cell regeneration, are vital for mucosal integrity, but are often disrupted by external factors [19]. NSAID-induced PUD occurs through multiple pathways, including damage to the gastric mucosal lipid layers, mitochondrial dysfunction, and the blockade of cyclooxygenase enzymes (COX-1 and COX-2) [22]. COX-1 is a constitutive enzyme essential for protective functions such as maintenance of the gastrointestinal mucosa and renal homeostasis. In contrast, COX-2 is minimally present during the resting state but is quickly induced when inflammation occurs [6]. The blockade of COX-1 reduces prostaglandin synthesis, impairing mucus and bicarbonate production, epithelial regeneration, and mucosal blood flow, thus exposing the mucosa to acidic and enzymatic damage. Stress-related mucosal injuries, often triggered by critical illness, involve reduced perfusion, catecholamine surges, and inflammatory mediators, which collectively impair mucosal defenses and exacerbate injuries [19,21-24].

Endoscopy remains the cornerstone of a PUD diagnosis, allowing direct visualization of ulcers and confirmation of H. pylori infection via biopsies and urease testing. It is particularly recommended for patients presenting with alarm symptoms, such as gastrointestinal bleeding, weight loss, or persistent vomiting, to exclude malignancies and other differential diagnoses [25,26].

In regions with a low prevalence of gastric cancer, noninvasive testing for H. pylori is often favored for younger patients with dyspepsia. However, in high-prevalence areas like South Korea, more aggressive diagnostic strategies, including follow-up endoscopy for PUD, are warranted to confirm healing and rule out the presence of a malignancy [27,28].

Management of PUD involves identifying and mitigating risk factors, such as NSAID use and H. pylori infection, in conjunction with pharmacological interventions. Smoking cessation strategies are also essential because smoking impairs ulcer healing. Proton pump inhibitors (PPIs) are the mainstay of treatment owing to their potent acid-suppressing effects. In recent years, potassium-competitive acid blockers (P-CABs) have emerged as highly effective alternatives that offer rapid acid suppression without the need for proton pump activation. Both therapies demonstrate excellent safety profiles, efficacious ulcer healing, and prevention of recurrence [29-32]. In a recent meta-analysis, P-CABs demonstrated efficacies equivalent to that of lansoprazole for healing peptic ulcers, with a comparable safety profile relative to common adverse events. However, their use was associated with a heightened risk of serious adverse events compared with lansoprazole [33].

Refractory ulcers, constituting 5%–10% of cases, require more intensive treatment strategies, including high-dose PPIs or newer P-CABs. Idiopathic ulcers, the prevalence of which is increasing globally, often respond well to long-term PPI therapy but warrant thorough evaluation to exclude the possibility of malignancies or other rare causes such as Zollinger–Ellison syndrome [34-36].

H. pylori eradication is a cornerstone of PUD management, particularly for duodenal ulcers [37]. Current guidelines recommend combination therapy involving antisecretory agents and multiple antibiotics tailored to resistance patterns and patient history [25,26,38,39]. Although clarithromycin-based triple therapy was once the treatment standard, rising resistance rates have shifted preferences toward bismuth-based quadruple regimens or concomitant therapies that are administered for at least 10 days to maximize efficacy [40-43]. Despite eradication rates of 81.2%–88.5% reported in Europe, similar regimens (levofloxacin-based, sequential, non-bismuth-based quadruple, and bismuth-containing quadruple therapies) have yielded rates of <85%, globally, raising concerns about the effects of antibiotic resistance [44,45]. Levofloxacin-based regimens achieve eradication rates of 77%–84%, but increasing resistance has led to them being recommended as second-line therapies rather than first-line options [25,26,38,46,47]. Alternative strategies, such as sequential, hybrid, and high-dose amoxicillin dual therapies, have shown eradication rates of 80%–88% when implemented as first-line treatment options [26,38,45].

The incidence and complications of PUD have shown a declining trend; however, H. pylori infection and NSAID use remain significant risk factors. Advances in the use of PPIs and P-CABs have improved treatment outcomes, particularly for patients with H. pylori-related ulcers who are undergoing eradication therapy and for those who are being treated to prevent NSAID-related ulcers. However, the increasing prevalence of antibiotic resistance has diminished the efficacy of traditional therapies, emphasizing the need for novel antibiotic combinations and broader application of bismuth-based regimens. The development of novel treatment strategies to overcome resistance and the exploration of innovative anti-ulcer therapeutics are critical.