Version May 2024
INTRODUCTION — Peptic ulcers are defects in the gastric or duodenal mucosa that extend through the muscularis mucosae (picture 1). They develop and persist as a function of the acid-peptic activity in gastric juice. Peptic ulcer disease remains an important cause of morbidity and health care costs [1].
The natural history of peptic ulcer ranges from healing without intervention to the development of complications with the potential for significant morbidity and mortality, such as bleeding and perforation. This topic will review the epidemiology, etiology, and pathogenesis of peptic ulcer disease. The clinical manifestations, diagnosis, and management of peptic ulcer disease are discussed in detail, separately. (See "Overview of complications of peptic ulcer disease".)
EPIDEMIOLOGY
Incidence and prevalence — In a systematic review of 31 published studies, the pooled incidence of uncomplicated peptic ulcer disease (PUD) was approximately one case per 1000 person-years in the general population, and the incidence of ulcer complications was approximately 0.7 cases per 1000 person-years [2].
The incidence and prevalence of PUD varies based upon the presence of Helicobacter pylori (H. pylori). Higher rates are found in countries where H. pylori infection is higher [3-6]. The incidence of PUD in H. pylori-infected individuals is approximately 1 percent per year, a rate that is 6- to 10-fold higher than for uninfected individuals [7,8]. A systematic review of seven studies from developed countries indicated a population-based one-year prevalence of PUD of 0.1 to 1.5 percent based on physician diagnosis and 0.1 to 0.19 percent based on hospitalization data [9]. A study in the United States reported an endoscopic point prevalence for peptic ulcers in asymptomatic, H. pylori-positive adults of 2 percent [10]. Other studies, in presumably asymptomatic subjects in whom H. pylori status was unknown, have reported an endoscopic point prevalence ranging from 1 and 6 percent [5,11-13].
Ulcer incidence increases with age for both duodenal ulcers (DUs) and gastric ulcers (GUs), but the incidence of uncomplicated PUD reached a plateau with age, whereas for complicated PUD, the incidence increases with age [14]. DUs occur two decades earlier than GUs, particularly in males [14].
Time trends — PUD rates have been steadily falling over the past several decades [14-22]. In several regions, rates of DUs have fallen more dramatically than for GUs [16,20]. Age-adjusted hospitalization rates for peptic ulcer disease have also declined, suggesting that the decline in H. pylori infection has had a major impact on ulcer rates [23-25]. In developed countries, the prevalence of ulcer disease in young people has declined, while nonsteroidal anti-inflammatory drug (NSAID)-related ulcers in older adults have increased due both to increased life expectancy and frequent use of aspirin and NSAIDs [16,19-22,26-29]. PUD has shifted from being a male-predominant disease in western countries to one with a nearly equal prevalence in males and females [2,9].
ETIOLOGY — Peptic ulcer disease (PUD) is associated with two major factors: Helicobacter pylori (H. pylori) infection and the consumption of nonsteroidal anti-inflammatory drugs (NSAIDs). NSAID use and H. pylori infection represent independent and also synergistic risk factors for uncomplicated and bleeding peptic ulcer disease. There are also a number of other defined mechanisms for peptic ulcer disease that are much less common but becoming more evident as the prevalence of H. pylori declines in developed countries (table 1). (See "Unusual causes of peptic ulcer disease".)
H. pylori — H. pylori affects a number of aspects of gastrointestinal physiology, including gastric acid secretion, and mucosal defense mechanisms leading to peptic ulcer disease. The prevalence of H. pylori both in the general population and in peptic ulcer patients is decreasing rapidly in developed regions, presumably due to improved hygiene and decreased H. pylori transmission in early childhood. A systematic review of H. pylori prevalence around the world showed that the highest reported H. pylori prevalence areas were in Africa (70.1 percent), South America (69.4 percent), and Western Asia (66.6 percent). Regions with the lowest reported H. pylori prevalence were Oceania (24.4 percent), Western Europe (34.3 percent), and Northern America (37.1 percent) [30].
NSAIDs, including aspirin — NSAID use is associated with a fourfold increase in the risk of peptic ulcer disease [31]. In addition, NSAIDs are associated with an increase in risk of complications from peptic ulcer disease which include gastrointestinal bleeding, perforation, and pyloric obstruction. NSAID-induced ulcers may also be more refractory to conventional therapy [32]. However, up to 40 percent of patients may not report using NSAIDs [33]. (See "Nonselective NSAIDs: Overview of adverse effects", section on 'Gastrointestinal effects'.)
Other rare causes — Although some NSAID-negative, H. pylori-negative ulcers are due to specific causes, such as gastrinoma or viral infections, others remain in the idiopathic category (table 1). Unusual causes of peptic ulcer disease are discussed in detail separately. (See "Unusual causes of peptic ulcer disease".)
RISK FACTORS — The presence of Helicobacter pylori (H. pylori) or use of nonsteroidal anti-inflammatory drugs (NSAIDs) alone is not likely to be sufficient for ulcer formation. Although gastritis is consistently observed with H. pylori infection and NSAIDs consistently inhibit mucosal prostaglandin production, the yearly incidence of clinical ulcer disease among subjects at risk is only approximately 1 percent for both categories of ulcer [7,8,34]. There are a number of risk factors for ulcer disease.
Smoking — Smoking is an independent risk factor for symptomatic and asymptomatic peptic ulcer disease (PUD) [35]. PUD risk progressively increases with increasing pack-years of cigarette smoking [36]. A population-based study found that the prevalence of ulcer disease in current and former smokers was almost twice as high as non-smokers [37]. Smoking more than 15 cigarettes per day compared with never smoking increased the risk of a perforated ulcer more than threefold [38]. In addition, ulcers in smokers appear to be more difficult to treat and may be associated with a higher rate of recurrence [39-42]. The deleterious effects of smoking may be due to its impact on the balance of mucosal aggressive and protective factors [43]. However, in patients with H. pylori, smoking does not appear to be a risk factor for ulcer relapse once H. pylori has been eradicated [44-46].
Alcohol — Alcohol in high concentrations damages the gastric mucosal barrier. Alcohol consumption is related to the development of complicated and uncomplicated ulcer disease. In a large population based study, heavy drinking (more than 42 drinks per week) increased the risk of a bleeding ulcer fourfold (RR = 4.4; 95% CI 2.3–8.3) compared with drinking less than one drink per week in high concentrations and also stimulates acid secretion [47]. In addition, contents of alcoholic beverages other than alcohol are also strong stimulants of acid secretion.
Genetic factors — Host genetic factors appear to be important in predisposing to H. pylori infection and to disease outcomes such as duodenal ulcers (DU) and gastric cancer. Genes that encode for cytokines account for the individual responses to H. pylori infection. Genetic variations in pro-inflammatory cytokines (eg, IL-1B, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha) and anti-inflammatory cytokines (IL-10) are associated with PUD [48]. A genome-wide association study in Japan found that specific genetic variations in the Prostate Stem Cell Antigen are associated with gastric ulcer, duodenal ulcer, and gastric cancer [49]. Genetic polymorphism related to synergy between host (TNF-alpha promoter) and bacterial (induced by contact with epithelium, or the iceA1 gene) factors have been related to DU in children [50].
There is also evidence for a genetic predisposition to PUD that is independent of any predisposition to H. pylori infection [51,52]. An illustrative report found high concordance of a self-reported ulcer history in monozygotic compared with dizygotic twins regardless of whether they were reared apart or together [53]. Cross-twin, cross-trait correlations for monozygotic and dizygotic twins indicated that genetic effects for peptic ulcer were independent of genetic influences for H. pylori. Hyperpepsinogenemia linked to elevated serum pepsinogen group A has also been noted in patients with familial clustering of PUD [52]. Genetic predisposition due to a polymorphism of cytochrome P450 2C9 may delay the metabolism of several NSAIDs, with a prolonged duration of drug effect, enhancing the ulcerogenic effect [54].
Blood groups O and A, the Lewis phenotype Le (a + b-), and non-secretors of ABH in particular have been associated with an increased risk of peptic ulcers [55,56]. However, other studies have failed to find any association of blood group O with H. pylori infection or with peptic ulcer [57-59]. Studies suggest that strains of H. pylori from different areas of the world may have different binding affinities for gastric epithelium accounting for these seemingly contradictory results seen with blood group studies from different countries [60]. (See "Pathophysiology of and immune response to Helicobacter pylori infection".)
Other
●Diet – Dietary factors have been hypothesized to account for some of the regional variation of ulcer disease, possibly related to toxins generated with storage of certain foods or from protective effects of certain foods [61,62]. A prospective study of a cohort of 47,806 males found no association between the type or amount of fat intake and the risk of DU [63]. However, high consumption of fruits and vegetables, dietary fiber, and vitamin A were associated with a reduced risk of ulcer disease.
Evidence to support the use of a bland diet or dietary restrictions to prevent PUD are lacking. Although certain foods, beverages, and spices cause dyspepsia, there are no convincing data that such specific foods cause, perpetuate, or reactivate peptic ulcers. There is no evidence that coffee consumption is a risk factor for ulcer disease, although increased consumption may be associated with a higher rate of infection with H. pylori [64-66]. In one series, coffee increased dyspepsia in subjects with nonulcer dyspepsia, but not in those with DU when compared with controls [67].
●Psychologic factors – Two lines of evidence suggest an association between psychosocial factors and ulcer pathogenesis. First, in prospective studies, poorly tolerated stress or depressive symptoms at baseline increase the risk of ulcer development over the next 9 to 15 years [68]. Other psychosocial factors, such as work-related stress, social problems, and post-traumatic stress disorder, are also predictive of subsequent ulcer disease [69-72]. Second, several studies have established that peptic ulcer complications become much more prevalent during periods of natural disaster or societal catastrophe [68,73,74].
The pathophysiologic mechanisms accounting for the effects of stress on the ulcer formation have not been defined. These effects could be mediated by both altered behaviors and by altered physiology. A population-based prospective study in Denmark that included 3379 individuals demonstrated that psychological stress increased the incidence of peptic ulcer in part by influencing health risk behaviors [69]. Stress had similar effects on ulcers associated with H. pylori infection and those unrelated to H. pylori or NSAID use. Stress also increases acid secretion, but the effects are more prominent in patients with DU compared with controls [75]. As a result, one must consider not only the stressor, but the individual's physiological and psychosocial response to the stress; deleterious effects may only be evident in a subset of predisposed individuals. Stress, anxiety, and depression have also been observed to impair endoscopic healing and to promote relapse of endoscopically diagnosed ulcers [68,76,77]. The effects of stress seem to be reversible; patients who develop an ulcer following traumatic life events, but who are psychologically stable, tend to do well after the stress has resolved [68].
However, the finding a relationship between psychosocial factors and ulcer disease does not establish causality. One study found that anxiety and neuroticism were high in a group of DU patients at the outset, but normalized in relapse-free patients at the end of a 10-year follow-up period [78]. In some cases, psychological features may be the result and not the cause of the disease process.
●Sleep and sleep apnea – Disturbances in sleep may be a risk factor for ulcer disease, complications of peptic ulcer disease, and ulcer recurrence [79,80]. In a large retrospective study that included 7096 patients with sleep apnea and 28,384 age- and sex-matched controls, in adjusted analysis, patients with sleep apnea were twice as likely as controls to develop gastrointestinal bleeding during a follow-up period of four years [79]. In another study, females who slept more than nine hours a day by self-report had a lower incidence of ulcer disease than females who slept less than nine hours. A similar nonsignificant trend was seen in males [81].
●COVID-19 infection – Gastrointestinal bleeding is frequently reported in patients with COVID-19, and peptic ulcer disease is the most common cause of gastrointestinal bleeding [82]. The clinical presentation of patients is similar to those presenting without COVID-19 infections, and ulcers are found in one-half of the patients [83]. In a meta-analysis, overall mortality was high at 19.1 percent (95% CI 12.7-27.6 percent) and pooled mortality secondary to gastrointestinal hemorrhage was 3.5 percent (95% CI 1.3–9.1 percent). The risk of rebleeding was high at 11.3 percent (95% CI 6.8–18.4 percent). The majority of patients can be managed conservatively, and only one-third of patients undergoing upper endoscopy required therapeutic intervention to stop bleeding. Mortality from gastrointestinal bleeding was low in this population, and most deaths were unrelated to bleeding and were caused by other complications of the disease [83].
●Checkpoint inhibitor-induced gastritis and ulcer disease – Immune checkpoint inhibitors are increasingly used in oncology, and they have been associated with severe gastritis, gastric ulcers, and gastrointestinal bleeding. These ulcers and gastritis may not respond to proton pump inhibitor therapy, and corticosteroid therapy is needed in severe cases. The incidence and risk factors remain unclear.
PATHOPHYSIOLOGY — Considering the acid-peptic environment of the stomach and the noxious agents that are ingested, ulcers are surprisingly uncommon, reflecting the effectiveness of the protective mechanisms that govern gastric mucosal function and repair. Primary malfunction of these secretory, defense, or repair mechanisms is a very uncommon cause of ulcer, if it occurs at all. Most ulcers occur when the normal mechanisms are disrupted by superimposed processes such as Helicobacter pylori (H. pylori) infection and the ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs, via inhibition of prostaglandin synthesis, affect the amount of gastric acid generated, the integrity of the mucosal barrier, the amount of bicarbonate and glutathione generated, and the rate of mucosal blood flow. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity".)
Gastric acid hypersecretion — Gastric ulcers involving the gastric body or distal antrum, and gastric ulcers associated with concurrent duodenal ulcers (DU) have normal or even increased levels of acid secretion. Although only a minority of DU subjects have true acid hypersecretion, high-normal or modestly elevated values appear to be a defining characteristic of patients with DU, whether or not they are infected with H. pylori.
The majority of patients infected with H. pylori develop pangastritis, which over time is associated with a reduction in gastric acid secretion. However, approximately, 10 to 15 percent of patients with the infection develop an antrum predominant gastritis which is associated with decreased antral somatostatin concentrations and increased basal and stimulated gastric acid secretion [84-86]. Somatostatin secretion by the antral D cells is a feedback mechanism by which gastrin secretion is regulated. Inhibition of somatostatin secretion may involve cytokines induced by H. pylori infection. Host genetic factors can also influence the cytokine response to H. pylori infection and predispose to ulcer disease [84,85,87-89].
Increased acid secretion is also an important factor in some patients with ulcer recurrences following successful H. pylori eradication. Abnormalities in gastrin and somatostatin secretion and most abnormalities of acid secretion usually normalize within one year of H. pylori eradication [84,89]. However, a small study found higher basal and pentagastrin-stimulated acid secretion in patients with recurrent ulcers following successful H. pylori eradication, as compared with patients without recurrent ulcers [90]. (See "Association between Helicobacter pylori infection and duodenal ulcer", section on 'Pathogenesis of ulcer formation'.)
Among H. pylori-negative subjects, a subset have acid hypersecretion without hypergastrinemia [88,91]. The mechanisms of acid hypersecretion in these patients have not been defined. One study of six patients with non-H. pylori, non-NSAID DU found increased gastrin response to a meal (but not fasting hypergastrinemia) and increased peak gastric acid secretion [92]. Some subjects with non-H. pylori, non-NSAID hypersecretion may have a component of muscarinic-dependent, vagal hyperactivity, although this element is difficult to quantify. In the absence of H. pylori or gastrinoma, fasting hypergastrinemia is only rarely found in hypersecretory DU patients, sometimes linked to antral G-cell hyperfunction [93].
Impaired duodenal bicarbonate secretion — The majority of DU patients have impaired duodenal bicarbonate secretion. The combination of increased gastric acid secretion and reduced duodenal bicarbonate secretion lowers the pH in the duodenum, which promotes the development of gastric metaplasia (ie, the presence of gastric epithelium in the first portion of the duodenum) [94]. Excess acid secretion in gastrinoma patients is also associated with marked gastric metaplasia in the duodenum.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Peptic ulcers (The Basics)" and "Patient education: H. pylori infection (The Basics)" and "Patient education: Gastritis (The Basics)")
●Beyond the Basics topics (see "Patient education: Peptic ulcer disease (Beyond the Basics)" and "Patient education: Helicobacter pylori infection and treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Estimates of the annual incidence of peptic ulcer disease (PUD) range from 0.1 to 0.3 percent. PUD incidence in Helicobacter pylori (H. pylori)-infected individuals is approximately 1 percent per year, a rate that is 6- to 10-fold higher than for uninfected subjects. The incidence of PUD increases with age for both duodenal and gastric ulcers. (See 'Incidence and prevalence' above.)
●Peptic ulcer disease is associated with two major factors: H. pylori infection and the consumption of nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are also associated with an increase in risk of complications from peptic ulcer disease which include gastrointestinal bleeding, perforation, and gastric outlet obstruction. (See 'Etiology' above.)
●Smoking is a risk factor for PUD. Alcohol in high concentrations damages the gastric mucosal barrier. Host genetic factors appear to be important in predisposing to H. pylori infection but can also influence the risk of PUD through other mechanisms. Dietary factors have been hypothesized to account for some of the regional variation of ulcer disease, possibly related to toxins generated with storage of certain foods or from protective effects of certain foods. However, evidence to support the use of a bland diet or dietary restrictions to prevent PUD are lacking. (See 'Risk factors' above.)
●Most ulcers occur when the normal secretory, defense, or repair mechanisms of the stomach are disrupted by superimposed processes such as H. pylori infection and the ingestion of NSAIDs. (See 'Pathophysiology' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Andrew H Soll, MD, who contributed to an earlier version of this topic review.
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