Peptic ulcer

A peptic ulcer is a breach in the mucosal lining of the upper digestive system, usually in the stomach or the first part of the duodenum, that extends through the muscularis mucosa. Acid and pepsin are the main damaging agents, and the disease occurs when these overwhelm the mucosa's protective mechanisms. Worldwide, the two leading causes are infection with the bacterium Helicobacter pylori and the use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin. The term covers gastric and duodenal ulcers, which differ in location, symptom pattern, and risk of malignancy. Peptic ulcer matters because it is common, can cause life-threatening bleeding or perforation, and is one of the clearest examples of a chronic disease whose understanding was transformed by identifying a specific microbial cause and a drug-related mechanism.

This entry explains the anatomy and physiology that make ulceration possible, then examines the main causes: H. pylori, NSAIDs, and less common causes such as Zollinger–Ellison syndrome. It describes how the disease is distributed across populations and has changed over time, how it presents and is diagnosed, and what its major complications are. The later sections cover medical eradication and acid-suppression therapy, the management of drug-induced ulcers and prevention in high-risk patients, endoscopic and surgical treatment, prognosis and recurrence, the historical discovery of the bacterial cause, and unresolved questions in research and public health.

Definition, sites, and anatomy

A peptic ulcer is distinguished from an erosion by depth. An erosion stays within the epithelium, whereas an ulcer breaches the muscularis mucosae, the thin smooth-muscle layer beneath the mucosa, and extends into the submucosa or deeper. Because erosions are confined to the surface, they usually heal by epithelial regeneration, while ulcers destroy deeper tissue and must heal through granulation and scar formation (Superficial mucosal lesions, that is, erosions usually heal by epithelial regeneration and restitution, but ulcers damage the muscularis propria and smooth muscle cells do not divide/regenerate.). The size cut-off used to separate the two is not uniform. One common reference places the boundary at Erosion is <5mm. Another requires a lesion of at least 0.5 cm, while greater than 3 mm in diameter, as defined by many industry-sponsored studies, is used elsewhere. Depth, not diameter, is therefore the criterion that matters most.

Most ulcers occur in the stomach and the duodenal bulb. Gastric ulcers are located mainly along the lesser curvature, in particular at the transitional zone of corpus- to antral-type mucosa. The majority of duodenal ulcers are located in the first part of the duodenum. Within the bulb they sit on the anterior or posterior wall, and duodenal ulcers outnumber gastric ones by about four to one in one classic tabulation. Site also shifts with age: in younger people gastric ulcers tend to lie in the antrum, while in older individuals they more often appear in the upper body along the lesser curvature (In younger people, ulcers tend to be located in the antrum, whereas in older individuals, they are more likely to be located in the upper body, particularly on the lesser curvature. These high lesser curvature ulcers in older patients have been called geriatric ulcers.).

Location also predicts the type of complication. Posterior-wall duodenal ulcers erode into the gastroduodenal artery, which runs close behind the bulb, and so tend to bleed (A bleeding duodenal ulcer at the posterior wall of the duodenal bulb is most likely the result of bleeding from the gastroduodenal artery.). Anterior-wall ulcers, by contrast, have only the peritoneal cavity in front of them and tend to perforate (Acute ulcers along the anterior part of first part of duodenum usually perforate, whereas those on posterior aspect tend to cause bleeding as they erode into gastroduodenal artery.). Endoscopic data support this association: in one series of 884 patients, those situated posteriorly in the bulb were more likely to present with hemorrhage than those situated elsewhere. The same article notes that the perforation-versus-bleeding pattern was first described in the pre-endoscopy era, when site could only be determined in patients who reached surgery or autopsy (These observations were, however, made in the era before endoscopy when DU site could be determined only in patients who came to surgery or autopsy.).

Ulcers outside the stomach and duodenum are uncommon and usually occur where gastric-type mucosa is located in an abnormal position, such as Meckel's diverticulum, the rectum, or Barrett's esophagus, and after gastrojejunal anastomosis. Ulcers in the esophagus are typically linked to the ectopic gastric mucosa of Barrett's esophagus rather than to the normal squamous lining. The general rarity reflects the fact that ulceration is concentrated where acid and pepsin are delivered in high concentration, namely the stomach and the proximal duodenum, where the mucosa is specialized to withstand them. Most other segments of the gastrointestinal tract are normally not exposed to gastric juice in this way, and their lining lacks the same barrier defenses. The reflux of acid into the esophagus causes injury more often as erosive esophagitis than as a true ulcer.

Gastroduodenal defense and the balance of aggression and protection

Aggressive factors

Three principal forces damage the gastroduodenal mucosa. The first is gastric acid, secreted by parietal cells in the stomach body and fundus. The second is pepsin, a protease that is generated from pepsinogen in acidic conditions and digests proteins in the mucosal surface. The third is bile reflux from the duodenum into the stomach, which injures epithelial cells through the detergent action of bile salts and lysolecithin. Acid and pepsin act together, and the damage is greatest when both are present at high concentrations for long periods.

The duodenum is especially exposed because of the way gastric emptying works. During a meal, food buffers the acid in the stomach, so the contents that pass through the pylorus are often less acidic. Once the stomach has emptied, however, strongly acidic chyme reaches the duodenal bulb before pancreatic bicarbonate and duodenal secretions can neutralize it. The duodenal mucosa also has less thick mucus protection than the gastric lining, so the bulb has a narrow margin of safety. This timing explains why duodenal pain often appears when the stomach is empty and is relieved by eating.

Protective mechanisms

The gastroduodenal mucosa relies on several overlapping defenses. The mucus gel layer, produced mainly by surface epithelial cells and mucous neck cells, forms an unstirred layer over the epithelium. Surface cells secrete bicarbonate into this layer, creating a steep pH gradient so that the pH close to the epithelium is near neutral even when the lumen is strongly acidic. Tight junctions between epithelial cells limit back-diffusion of hydrogen ions into the tissue.

Epithelial renewal replaces damaged or lost surface cells continuously, and the gastric surface epithelium turns over within a few days. Mucosal blood flow removes acid that has penetrated the barrier, delivers bicarbonate and oxygen, and supports repair. Prostaglandins, especially PGE2 and prostacyclin, are central to this system. They stimulate mucus and bicarbonate secretion, maintain mucosal blood flow, and inhibit acid secretion from parietal cells. Because prostaglandins are produced continuously by the mucosa, anything that reduces their synthesis weakens several protective functions at once.

How the balance tips

An ulcer forms when aggressive forces overwhelm protection. Acid exposure can rise through increased parietal cell mass, hypersecretion driven by gastrin or vagal stimulation, or faster gastric emptying that delivers acid to the duodenum sooner. Protection can fall through reduced prostaglandin synthesis, impaired mucus or bicarbonate secretion, mucosal ischemia, or injury from bile reflux. Many ulcers involve both changes, and the two sides often interact: a mucosa that is already inflamed or damaged may tolerate less acid, while persistent acid exposure impairs repair.

This framework has practical consequences for treatment. Acid suppression, through drugs that reduce acid secretion, addresses the aggressive side directly. Eradicating Helicobacter pylori and withdrawing NSAIDs address the causes of mucosal inflammation and prostaglandin loss, which restore the protective side. Cytoprotective agents such as prostaglandin analogues and bismuth compounds act mainly on the defensive side. Because ulcers arise from an imbalance rather than a single defect, treatment that targets only one side may leave the other unchanged, which is one reason recurrence can occur after healing.

Helicobacter pylori infection

The organism

Helicobacter pylori is a spiral-shaped Gram-negative bacterium that selectively colonizes the gastric mucosa. Its corkscrew shape and flagella let it swim through the viscous gastric mucus toward the epithelium, where most cells sit in a thin layer of near-neutral fluid. The bacterium survives the stomach's acidic lumen mainly through large amounts of urease, an enzyme that splits urea into ammonia and carbon dioxide, which raises the pH of its immediate surroundings. Because of this, the organism can persist in a niche that most microbes cannot tolerate.

How infection leads to ulcers

Infection produces a chronic inflammatory response in the gastric wall, with neutrophils and mononuclear cells accumulating in the mucosa. The pattern of damage depends on where the bacteria settle. Antral-predominant gastritis tends to suppress the cells that release somatostatin, which removes a brake on gastrin and acid output, and this shift favours acid exposure in the duodenum. Extensive gastritis that spreads across the body of the stomach can instead cause atrophy and lower acid secretion. Ulceration seems to follow when an inflamed mucosa is exposed to acid it can no longer buffer or repair, and most infected people never reach that point. Only 10-15% of all patients infected with Helicobacter pylori develop peptic ulcer disease or gastric cancer.

Why only some infected people develop ulcers

Several factors appear to shape this risk. Bacterial virulence is one: the CagA protein is injected directly into gastric epithelial cells through a type IV secretion system, and it is associated with long-term injury that can lead to ulcer and cancer. The VacA toxin disrupts epithelial tight junctions and dampens T-cell activity. In one series of 383 infected patients, the vacA s1 genotype was present in 91 (93.8%) of 97 patients with PUD, which points to a strong association, although the study was not designed to establish causation. Host factors also matter. Outcomes are generally attributed to the interplay of bacterial virulence, host genetic susceptibility, and host immune responses, though the specific human genes involved are still incompletely defined. Smoking is a further modifier. In a small study of 106 infected patients, cagA was significantly associated with active smoking at endoscopy, suggesting that smokers may more often harbour strains with higher-risk genotypes. Smoking and alcohol may also weaken the mucosa directly, which facilitates colonization and the development of ulcer disease.

Transmission and prevalence

Transmission occurs mainly between people in close household contact. One review concluded that in most regions, the main mechanism of spread is intrafamilial transmission, and a nationwide family study identified family members as the primary source of infection in patients. Proposed routes include oral-oral and fecal-oral spread, which are favoured by crowding, poor sanitation, and low socioeconomic status. Global prevalence has fallen: a meta-analysis estimated that the estimated global prevalence of H pylori infection decreased from 58·2% in the 1980–90 period to 43·1% in the 2011–22 period. The decline is uneven. Prevalence is lower in high-income countries and in younger people, and it has not reduced in children to the same degree as in adults. Regional variation is large; one review noted that the prevalence of H pylori infection varied from as low as 18.9% in Switzerland to 87.7% in Nigeria. Figures also differ by diagnostic method, since serological studies generally report higher rates than non-serological ones.

Eradication and recurrence

Because infection is the main driver of ulcers in many patients, its removal is the central means of preventing relapse. A Cochrane review found that overall 14% of duodenal ulcers recurred in the H. pylori eradication group compared with 64% in the no treatment group. Eradication also reduced gastric ulcer recurrence in pooled trials, although the evidence quality was rated very low. Not all studies agree: a single five-year follow-up found no significant reduction in the recurrence rate for gastric ulcers. Failure of eradication and reinfection are the main reasons for relapse. In Western settings, reinfection after successful treatment ranges between 0.5% and 2.0% per year in adults and in children older than 5 years of age, whereas in a Bangladeshi cohort the annual reinfection rate was higher, at 13%. Early relapse of the original strain, known as recrudescence, occurred within the first three months in that population.

NSAIDs, aspirin, and drug-induced injury

Nonsteroidal anti-inflammatory drugs (NSAIDs) act on two forms of the cyclooxygenase enzyme. The COX-1 form is present in most tissues, including the gastric and intestinal lining and platelets, and it runs continuously. COX-2, by contrast, is found in few tissues and is switched on by inflammation. NSAIDs achieve their anti-inflammatory and analgesic effects by blocking COX-2. The stomach's own harm, however, follows from blocking COX-1. Inhibiting COX-1 in the gastrointestinal tract reduces prostaglandin secretion and its cytoprotective effect on the gastric mucosa, which raises susceptibility to mucosal injury. Prostaglandins sustain acid-limiting, mucus and bicarbonate secretion and mucosal blood flow, so losing them weakens several defenses at once. NSAIDs also act locally: they damage cells by disrupting mucus phospholipids and cell membranes, and they uncouple mitochondrial oxidative phosphorylation. This direct injury is one reason that selective COX-2 inhibition does not remove all gastric risk.

The selective COX-2 agents (coxibs) were designed to avoid this COX-1 effect, and they do reduce gastroduodenal damage relative to traditional NSAIDs. Studies show that COX-2 inhibitors still have a low affinity for COX-1, so some risk remains. Risk also varies among individual drugs. In a pooled analysis, the relative risk of upper gastrointestinal complications for aceclofenac, celecoxib and ibuprofen is low (<2). Overall, the risk of ulcer complications such as bleeding, perforation and death is increased approximately 4-fold in NSAID users.

Risk profile

The highest-risk patients share a recognizable set of features. Concomitant corticosteroids and anticoagulants, together with high-dose and long-term NSAID use, carry the greatest risk of major gastrointestinal toxicity. Guidance lists age over 65, a history of peptic ulcer or gastrointestinal bleeding, previous gastric irritation with NSAID use, use of multiple NSAIDs or COX-2 inhibitors, and concomitant use of corticosteroids, anticoagulants and SSRIs as risk factors. Serious comorbidity also matters: patients with serious medical problems, the elderly, those on anticoagulants, steroids and aspirin, and those with previous peptic ulceration are at high risk of ulcer complications.

Low-dose aspirin and the antiplatelet dilemma

Low-dose aspirin differs mechanically from other NSAIDs. Aspirin binds COX-1 and COX-2 irreversibly, and low doses can suppress platelet COX-1 activity by 95% or more, an effect that lasts for the lifetime of the platelet because platelets cannot synthesize new enzyme. Because aspirin's gastric and cardiovascular effects overlap, the drug's benefits and harms are closely linked. Low-dose aspirin use has increased over the past decade because of its benefits in preventing cardiovascular events and possibly colon cancer. Consequently, bleeding ulcers increasingly occur in older people taking aspirin for prevention rather than in young people taking analgesics. Known risk factors for aspirin-associated bleeding include a history of peptic ulcer or ulcer bleeding, old age, renal failure, concurrent aspirin and clopidogrel use, and H. pylori infection.

This creates a clinical dilemma. Many patients who have had upper gastrointestinal bleeding continue to take low-dose aspirin for cardiovascular prophylaxis or other NSAIDs for musculoskeletal pain. Stopping antiplatelet therapy may raise the risk of thrombotic events, while continuing it may expose the patient to rebleeding, so decisions usually weigh the individual's cardiovascular risk against bleeding risk. Protective acid suppression and H. pylori management are typically used to lower the bleeding risk while aspirin continues.

Interaction with H. pylori

H. pylori and NSAIDs are both independent risk factors, and their effects appear to compound. A 2002 meta-analysis reported that both H. pylori infection and NSAID use independently and significantly increase the risk of peptic ulcer and ulcer bleeding, and there is synergism between the two for the development of peptic ulcer and ulcer bleeding. In the same analysis, H. pylori infection and NSAID use increased the risk of ulcer bleeding 1.79-fold and 4.85-fold, respectively, while the risk of ulcer bleeding rose to 6.13 when both factors were present. In practice, an individual patient's risk depends on which factors are present: a NSAID user who is also infected with H. pylori is at substantially higher risk than either exposure alone would predict.

The evidence is less settled for low-dose aspirin. One case-control study found that H. pylori infection was an independent risk factor for upper gastrointestinal bleeding in low-dose aspirin users (OR 4.7; 95% CI 2.0–10.9). A systematic review, however, concluded that the current evidence was insufficient to perform a meta-analysis and no firm conclusion could be drawn regarding the impact of H. pylori on upper GI bleeding risk in aspirin users. Eradication appears protective in practice. In one trial of aspirin users with prior bleeding, the probability of recurrent bleeding over six months was 1.9 percent with eradication therapy and 0.9 percent with omeprazole. Among aspirin users whose infection was cured, the long-term incidence of recurrent ulcer bleeding is low after H. pylori eradication.

Less common and non-H. pylori, non-NSAID causes

Zollinger–Ellison syndrome

Zollinger–Ellison syndrome is the best-known endocrine cause of peptic ulcer. Ulcers form here because a neuroendocrine tumour, usually in the pancreas or duodenum, releases large amounts of gastrin, and the gastrin drives acid output far beyond normal levels. Less than 1% of peptic ulcer disease is caused by gastrinomas. Ulcers are the usual presentation: over 90% of patients with Zollinger-Ellison syndrome develop peptic ulcers. Their distribution is informative. Ulcers usually are solitary and located in the duodenal bulb, but they may be multiple or occur more distally in the duodenum. Isolated gastric ulcers do not occur.

Diagnosis depends on showing both high gastrin and very low gastric pH. A serum gastrin level over 1000 pg/mL in the setting of gastric pH <2 is virtually diagnostic. Secretin stimulation testing helps separate gastrinoma from other causes of high gastrin, such as atrophic gastritis, renal failure, or prior vagotomy. Screening with fasting gastrin levels is advised for ulcers that are refractory to standard therapy, giant ulcers (over 2 cm), ulcers located distal to the duodenal bulb, multiple duodenal ulcers, frequent recurrences, ulcers associated with diarrhoea, and ulcers with complications. Proton pump inhibitors can also raise gastrin, so interpretation requires care. Around 60% of gastrinomas are malignant, which is why tumour localisation and staging form part of the work-up.

Stress ulceration in critical illness

Stress-related mucosal disease is a distinct entity in intensive care. Mucosal lesions are very common in these patients, but clinically important bleeding is not. Although only a small proportion (1–6%) of patients admitted to an intensive care unit (ICU) will bleed, a substantial proportion exhibit clinical risk factors. The two strongest predictors are mechanical ventilation for more than 48 h and coagulopathy. Other recognised risks include shock, sepsis, liver or renal failure, and extensive comorbidity. Stress-ulcer bleeding is a severe complication with an estimated mortality of 40–50%, mostly from decompensating an underlying condition or multiorgan failure.

The pathogenesis combines defence failure with acid exposure. Hypoperfusion of the gastric mucosa reduces protective mechanisms, while acid output may rise, which is why critically ill patients are at risk of bleeding despite no prior ulcer history. The first description of this link dates to 1823, when J. Swan associated major burns with gastric ulceration.

Other systemic and secondary causes

Several systemic conditions are associated with peptic ulcer, though the evidence for most is observational and the mechanisms are not fully established:

• Crohn's disease can involve the stomach and duodenum. Upper-tract ulcers are less common than ileal or colonic disease, and drug exposure (NSAIDs and corticosteroids) often confounds the association.
• Liver cirrhosis affects ulcers mainly through their consequences. Portal hypertension, thrombocytopenia, and coagulopathy make ulcer bleeding more likely and more severe, and portal hypertensive gastropathy may coexist.
• Behçet's disease, a systemic vasculitis, causes mucosal ulceration, most characteristically in the oral cavity, genitals, and terminal ileum. Upper gastrointestinal involvement is less typical, so the diagnosis should be considered when ulcers appear alongside other features.
• Other conditions linked to ulceration include hypercalcaemia (which can raise gastrin), chronic kidney disease, cytomegalovirus infection in immunosuppressed patients, and mast cell disease.

Smoking and alcohol

Smoking and alcohol are not primary causes in most patients but act as cofactors. Smoking impairs mucosal blood flow and bicarbonate secretion and slows healing, and it is associated with higher rates of recurrence and complications. The interplay of etiological factors in the pathogenesis of idiopathic peptic ulcer disease is poorly defined but may include a genetic predisposition, altered acid secretion, rapid gastric emptying, defective mucosal defense mechanisms, psychological stress, and smoking. Alcohol can injure the mucosa directly and, combined with NSAIDs or cirrhosis, adds to bleeding risk.

Idiopathic ulcers

Idiopathic ulcers are those with neither H. pylori infection nor gastrotoxic drug exposure. Some studies suggest approximately 20 to 25 percent of peptic ulcers are not related to either H pylori or NSAIDs. The proportion varies with the method used, and the true prevalence of H. pylori-negative peptic ulcer could have been underestimated, as it was unclear whether patients taking recent antibiotics and antisecretory treatment were excluded.

Establishing that an ulcer is idiopathic requires a systematic work-up. A detailed medication history must cover over-the-counter analgesics and traditional Chinese medicines, because surreptitious nonsteroidal anti-inflammatory drug usage is a cause of unexplained ulcer disease in up to 60% of patients. H. pylori testing needs biopsies taken off acid suppression, with both urease testing and histology negative. Hypersecretory states, especially Zollinger–Ellison syndrome, must be excluded. The management of idiopathic peptic ulcers is not defined; they appear to be more resistant to standard therapy, can be associated with more frequent complications, and those that relapse may require long-term maintenance therapy. Advanced age, serious systemic illness, and psychological stress are considered possible risk factors. Advanced age, serious systemic complication, and psychological stress are considered to be the potential risk factors for idiopathic ulcers.

Epidemiology and changing incidence

Published estimates of the burden of peptic ulcer disease vary widely, partly because sources define the disease differently. The figure most often cited is a lifetime prevalence of 5–10% and an annual incidence of 0.1–0.3% in the general population in Western countries. Global estimates are lower. One review gives a global prevalence ranging from 0.12 to 1.5%, and a separate analysis reports a lifetime prevalence of approximately 10% within the general population. Counts of people affected per year also differ. One widely cited figure puts four million people worldwide annually, while a US hospital-based analysis states that the disease affects >6 million persons in the United States each year. Definitions add further variation. The Global Burden of Disease (GBD) framework describes the disease as a mucosal break greater than 3–5 mm, with a visible depth reaching the submucosa, a threshold that does not match every clinical definition. In absolute terms, the GBD estimated approximately 8.09 million prevalent cases in 2019, a 25.82% increase from 1990, reflecting population growth and aging, while age-standardized rates moved in the opposite direction.

Age-standardized rates have fallen over the long term. Between 1990 and 2021, the GBD reported that age-standardized rates for incidence, prevalence, deaths and DALYs associated with PUD decreased by 40.3%, 41.1%, 61.5%, and 63.1%, respectively. The decline has not been uniform. One GBD analysis describes a gradual upward inclination observed in recent 15 years, which might be associated with changes in risk factors, and another notes that the decreasing tendency has plateaued in recent years. US hospitalization data show a clearer and earlier fall. Admissions decreased significantly from 222,601 in 1993 to 156,108 in 2006 (-29.9%), and the age-adjusted rate decreased 21% from 71.1/100,000 population in 1998 to 56.5/100,000 in 2005. The authors attributed much of this to a decrease in the incidence of complications caused by H. pylori infection. Public-health policy contributed as well: a federal target set in 1998 aimed at reducing hospitalizations for PUD 35% from the 1998 baseline by 2010, and mortality fell over the same period, from 3.8% to 2.7% during 1993 to 2006.

The decline in complications has been slower and less consistent than the fall in disease occurrence. Some reports describe complication rates as broadly stable, with one review noting that the global prevalence of PUD has dramatically decreased in the past decades, [but] the incidence of its complications has remained constant. Other national series show falls: a Swedish study documented a fall in the incidence of peptic ulcer perforation from 1974 to 1992 in one catchment area, and Finnish data describe incidence and complications of peptic ulcer disease requiring hospitalisation have markedly decreased. US data also show that fewer admissions can coexist with more intensive care: between 2009 and 2014, hospitalizations for PUD declined from 2,502 to 2,101, whereas the percentage of hospitalizations with procedures increased from 27.1 to 31.5 per cent.

Age and sex patterns are consistent across sources, though the details differ. Disease burden rises with age, and in the US the hospitalization rate for PUD was highest for adults >65 years of age and was higher for men than for women. GBD age-standardized prevalence increased with age, peaking at 80–84 years in both males and females. Male predominance is also reported across regions: in both sexes, the numbers and ASRs of the prevalence, incidence, deaths and DALYs were higher in males than in females over 29 years. The pattern is less uniform in some settings. A Chinese endoscopy study found that in patients under 60 years old, the prevalence of duodenal and gastric ulcers in females was markedly lower than that in males, and one GBD-based analysis found that the global prevalence of PUD was higher in females than in males on both ends of the age spectrum.

Regional differences are large. South Asia had the highest age-standardized prevalence rate in 2019, and Kiribati had the highest age-standardized prevalence rate among nations. The GBD also found positive associations between the age-standardized prevalence, incidence, death rate, DALYs and SDI, meaning that socioeconomic development and disease burden do not move in a simple inverse relationship. Quality of care follows a similar gradient, with QCI typically decreased as people aged; however, this gap was more significant among low-SDI countries. Differences in H. pylori prevalence help explain some of the variation. In a large US endoscopy cohort, the prevalence of H. pylori was 2.6-fold higher among Hispanics and 3.2-fold higher among East Asians compared with the general population. Regional patterns of NSAID use and socioeconomic conditions also shape risk, though the sources reviewed here do not quantify those links in detail.

Clinical presentation

Typical symptoms

Epigastric pain is the central complaint. Patients usually describe it as burning, gnawing, or a hunger-like discomfort in the upper middle abdomen. Dyspepsia is the most prominent symptom among symptomatic patients, and pain is localized to the epigastrium in most cases, though it sometimes sits under the right or left ribs. Accompanying complaints include bloating, belching, fullness after small amounts of food, early satiety, intolerance of fatty food, nausea, and occasional vomiting. Without treatment, a painful episode may last weeks and then give way to a symptom-free period of weeks or months.

Duodenal and gastric pain

Timing relative to meals is the most useful bedside clue. Duodenal ulcer pain typically begins two to three hours after eating, sometimes given as two to five hours in other sources, when acid is secreted without a food buffer. It is usually eased by food or antacids and often wakes the patient between about midnight and 3 a.m. Gastric ulcer pain tends to come on soon after a meal. Because the pain then worsens with eating, patients may avoid food, and weight loss driven by fear of eating is considered characteristic of gastric ulcers. Vomiting is more typical of gastric disease, particularly with prepyloric or pyloric channel ulcers. Clinicians should treat these patterns as suggestive rather than diagnostic, because history alone does not reliably distinguish gastric from duodenal ulcers.

Silent ulcers and the role of NSAIDs

Many ulcers never produce symptoms, but published figures differ by definition. One summary estimates that about 70 percent of peptic ulcers are asymptomatic at a given time, whereas another estimate holds that 5 to 10 percent remain silent throughout life. In a Taiwanese screening cohort, about 11 percent of people had ulcers on endoscopy, and roughly 70 percent of those reported no symptoms. Silent ulcers are more frequent in older adults and in people taking NSAIDs, partly because NSAIDs have analgesic activity that blunts pain. Between 43 and 87 percent of patients presenting with bleeding ulcers had no preceding dyspepsia, and deaths from ulcer disease are disproportionately found among patients who had no warning symptoms. Ulcer-related complications, rather than the ulcer itself, are therefore often the first sign of disease in these groups.

Alarm features

Alarm features call for prompt endoscopic evaluation. These include overt gastrointestinal bleeding (hematemesis or melena), iron-deficiency or other anemia, clinically significant unintended weight loss, dysphagia and odynophagia, persistent or recurrent vomiting, early satiety, and a family history of upper gastrointestinal cancer. Guidelines differ on age thresholds: some recommend endoscopy for adults aged 60 or older with new dyspepsia, while others set the cutoff at 55 for ulcer patients. Signs of complications also matter. Sudden, severe, generalized abdominal pain with fever suggests perforation, pain radiating to the back may indicate penetration into adjacent structures, and tachycardia, orthostatic hypotension, or pallor suggest significant blood loss. The medication history, especially NSAIDs, aspirin, anticoagulants, and SSRIs, should be reviewed in every patient with suspected ulcer disease.

Diagnosis and investigation

Endoscopy and biopsy

Upper endoscopy (esophagogastroduodenoscopy, EGD) is the central diagnostic test. It allows direct inspection of the ulcer, tissue sampling for H. pylori and malignancy, and endoscopic treatment of bleeding in the same session. EGD allows direct visualization of gastric and duodenal ulcers, permits biopsy for detection of Helicobacter pylori infection and exclusion of malignancy, and enables endoscopic hemostasis.

Biopsy policy differs by ulcer site. Gastric ulcers carry a risk of hidden malignancy that duodenal ulcers rarely share, so gastric ulcers are biopsied routinely, while routine biopsy is not required for duodenal ulcers. Estimates of the malignancy rate in endoscopically benign-looking gastric ulcers vary, with one series reporting that 2–5 % of the benign-appearing ulcers are ultimately malignant, and a systematic review noting that about 6% of ulcers judged benign at endoscopy prove malignant on histology. The number of samples also varies by source: one guidance set advises multiple biopsies (≥8) in the base and edges of gastric ulcers, while a review notes that 3 to 4 biopsy samples are usually sufficient to diagnose cancer in gastric ulcers with 95 % sensitivity. Biopsies are also taken from the antrum and corpus, outside the ulcer edge, to test for H. pylori. Because a gastric ulcer can be malignant despite a benign appearance, follow-up endoscopy until healing is generally advised; in one review's framing, a follow-up EGD is generally recommended 6 to 12 weeks after the initiation of therapy.

Testing for H. pylori

Noninvasive tests are the main options when endoscopy is not needed. The urea breath test (UBT) is generally regarded as the most accurate. When compared with serology or stool antigen tests, the urea breath test has the highest diagnostic accuracy to identify H. pylori infection in patients without a history of gastrectomy or recent use of antibiotics or proton pump inhibitors. The stool antigen test is a close alternative: it uses an enzyme immunoassay to detect bacterial antigen in stool, and its ability to detect infection is equal to that of the urea breath test. Stool antigen testing is cheaper and avoids radioactive materials, and in lower-prevalence settings it performs comparably well. False negatives arise mainly after recent acid suppression, bismuth, or antibiotic use, and in active ulcer bleeding.

Serology measures antibodies in blood. It is inexpensive and in one study showed high sensitivity, but it is less specific and cannot confirm current infection. Antibody titers fall slowly after successful treatment, so serology is not useful for judging eradication. For this reason it is mostly used for population studies or initial diagnosis, and some guidelines recommend against routine use.

Invasive tests use biopsy material. Histology with routine staining has a reported sensitivity of 70% to 95%, which special stains improve, and it has the advantage of also assessing the mucosa for malignancy. Rapid urease testing is quick and inexpensive, but it can give false positives from other urease-producing organisms, and its sensitivity drops during active bleeding, when histology may be preferred. Culture from biopsy is slow and rarely used routinely; it is reserved for cases needing antibiotic susceptibility testing, particularly after treatment failure.

Test-and-treat versus endoscopy

Guidelines separate dyspeptic patients by age and alarm features. Alarm features include bleeding, anemia, early satiety, unexplained weight loss (>10% body weight), progressive dysphagia, odynophagia, persistent vomiting, and a family history of gastrointestinal cancer, among others. Patients with these features should undergo prompt endoscopy, as should patients over the guideline age threshold. Younger patients without alarm features may be managed by test and treat for H. pylori using a validated noninvasive test, or by an empiric trial of a proton pump inhibitor for 4–8 weeks.

The age cut-off differs between guidelines. The American College of Physicians once advised endoscopy above age 45, while later American guidance used 55, reasoning that cancer is rare in younger patients in the United States. The 2017 ACG and CAG guideline set the threshold at 60, recommending endoscopy for those aged 60 or over and not suggesting endoscopy to investigate alarm features for dyspepsia patients under the age of 60. Several evaluations question the reliability of alarm features: their identification ... has a low predictive value for GI cancer, and one-fourth of patients with malignancy and dyspepsia do not report alarm symptoms. For this reason, endoscopy is also considered when there is clinical suspicion of malignancy in the absence of alarm features, and some anxious patients may be referred for endoscopy for reassurance.

Barium studies and imaging

Barium contrast studies are a secondary option. A radiograph can suggest a benign ulcer when the crater shows radiating mucosal folds, but contrast studies cannot distinguish between benign and malignant gastric lesions with the accuracy of endoscopy and biopsy. Imaging also cannot establish H. pylori status, which requires tissue or a noninvasive test. For this reason, imaging is generally used when endoscopy is unavailable or unclear, and one primary-care guideline advises that imaging (barium swallow or CT scanning) be considered if gastroscopy is not readily available. Computed tomography is more commonly used to assess suspected complications such as perforation or obstruction, which fall outside the routine diagnostic pathway.

Bleeding

Frequency and mechanism

Bleeding is the most frequent complication of peptic ulcer disease. Peptic ulcer is thus the most common cause of nonvariceal upper gastrointestinal bleeding, accounting for 40 to 60% of cases in most populations. The annual incidence of peptic ulcer bleeding ranges between 20 to over 100 cases per 100,000 persons, and the mortality rate remains at about 10%. Incidence has been drifting downward, but non-variceal upper gastrointestinal bleeding continues to carry a substantial morbidity and mortality.

Bleeding occurs when the ulcer base erodes into a blood vessel. Duodenal ulcers on the posterior wall are the classic setting for this, because the gastroduodenal artery lies close to the ulcer base. Erosion into an artery produces pulsatile, high-volume bleeding, whereas erosion into smaller venous channels usually produces slower oozing. Ulcers that penetrate deeply carry the greatest likelihood of involving such vessels. Hemorrhage may occur along a continuum from a serious acute event associated with hemodynamic shock and high mortality to slow or intermittent blood loss leading to chronic anemia.

Many episodes stop without specific intervention. In upper gastrointestinal bleeding generally, bleeding is self-limited in 80% of patients, even without specific therapy. Of the remaining 20% who continued to bleed or rebleed, the mortality rate is 30% to 40%.

Endoscopic risk stratification

Endoscopy serves both diagnostic and therapeutic roles. Endoscopy can achieve primary hemostasis in more than 90% of peptic ulcer bleeding, but the appearance of the ulcer determines how urgently treatment is needed. The Forrest classification, introduced in 1974, categorizes bleeding PUs according to endoscopic stigmata of recent hemorrhage and remains widely used for risk stratification and therapeutic decision-making. Its categories run from active spurting (Ia) and oozing (Ib), through a non-bleeding visible vessel (IIa) and an adherent clot (IIb), to a flat pigmented spot (IIc) and a clean base (III). Traditional risk stratification distinguishes low-risk (Forrest IIc–III) from high-risk lesions (Forrest Ia–IIb). Interobserver agreement is generally good, though visual assessment can vary between endoscopists.

Forrest grading is usually combined with clinical scores. Such tools, including the Rockall and Glasgow-Blatchford scores, use vital signs and laboratory values rather than the lesion's appearance. Among pre-endoscopic variables, hemodynamic shock, usually defined as a systolic blood pressure <100 mmHg, often combined with tachycardia >100 beats/min, is the most powerful pre-endoscopic predictor of rebleeding. Note that the classical rebleeding figures tied to the Forrest grades are largely derived from untreated lesions and may not reflect outcomes in contemporary practice, where endoscopic hemostasis and proton pump inhibitor (PPI) therapy significantly reduce the risk of recurrence.

Rebleeding

Rebleeding is the principal concern after initial control. Rebleeding, which occurs in 10–15% of patients with peptic ulcer bleeding (PUB), is associated with a two to fivefold mortality increase, depending on the presence of other risk factors. In a Danish nationwide cohort of 19,258 patients, 10.8% rebled, and 10.2% died. Rebleeding was linked to roughly a doubling of 30-day mortality, and the highest-risk group, defined by hemodynamic instability, duodenal location and high-risk stigmata, showed 24% rebled, 50% with rebleeding failed endoscopic therapy, and 23% died.

Timing matters. In an older series, rebleeding occurred in 17% of patients, the majority within 72 hours of initial hemostasis. For this reason, clinicians monitor high-risk patients closely during the early days after treatment. When rebleeding occurs in such patients, the Danish authors recommend consultation with surgery and/or interventional radiology should be obtained prior to repeat endoscopy.

Mortality and modifying factors

Mortality figures vary by series and setting. One Syrian hospital series reported ten patients (3.4%) had died as a complication of a peptic ulcer. Across upper gastrointestinal bleeding, the cited range is a mortality rate between 2% and 15%.

Several factors worsen outcomes. Age and shock are the most consistently reported. In one prospective series of 701 patients, shock on admission was associated with a doubling of mortality figures (9.5% versus 3.7%), and the risk of a rebleed was doubled in patients over 60 years of age. Concomitant illness adds to risk: concomitant medical illness had a significant adverse effect on outcome. Comorbidity was common in the Syrian series, where the most frequent comorbidities were hypertension, diabetes mellitus, and ischemic heart disease. Anemia is less clear-cut: studies on the association between anemia and rebleeding have found conflicting results.

Antithrombotic therapy is a recognized contributor. Recent analyses list current use of antithrombotic agents and non-steroidal anti-inflammatory drugs (NSAIDs) among factors linked to early recurrent bleeding. In a cohort of cirrhotic patients with ulcer bleeding, the predictive risk factors for rebleeding were the Rockall score, units of blood transfusion, and no antibiotic prophylaxis.

Perforation, obstruction, and penetration

Perforation

Perforation occurs when an ulcer erodes completely through the gastric or duodenal wall, so that gastric or duodenal contents leave the lumen and enter the peritoneal cavity. The resulting chemical and bacterial peritonitis is a surgical emergency. Published series place the rate at roughly 2–10% of people with peptic ulcer disease, and duodenal ulcers account for most cases in many series, although the proportion varies by region. The clinical picture is typically an abrupt onset of severe upper abdominal pain that spreads across the abdomen within hours, followed by hypotension and fever. On examination, the abdomen is often rigid and board-like, bowel sounds are reduced or absent, and the white cell count is raised.

Imaging supports the diagnosis. Free gas under the diaphragm on an upright chest radiograph is the classic sign, but reported detection rates on plain films range from about 60% to 90%, so a negative film does not exclude perforation. Contrast-enhanced CT is more sensitive for small amounts of free air, which typically collects anteriorly beneath the abdominal wall or around the liver. In some patients, free fluid is the only abnormal finding, and CT occasionally fails to show free air in a minority of confirmed cases. Surgery is usually decided on clinical grounds, with resuscitation, intravenous acid suppression, and broad-spectrum antibiotics given before or during operative repair.

Mortality and predictors of poor outcome

Perforation carries a higher risk of death than bleeding, and the mortality reported in published series varies widely with setting. Estimates range from around 1–2% in some high-resource cohorts to over 20% in resource-limited settings, with a pooled figure from one review near 9%. Although the time window differs between studies, delayed presentation is the most consistently reported predictor. In an Indian cohort, symptoms lasting more than 48 hours were associated with markedly higher odds of death, and a Somali study identified delay beyond 24 hours as a risk factor. Other predictors repeatedly reported include older age, preoperative shock or hypotension, serious comorbidity, severe anaemia, and a large perforation, often defined as more than 2 cm. Operative time, the volume of intra-abdominal contamination, and the need for intensive care have also been linked to death in some analyses. Because several of these factors are linked to one another, their independent contributions are difficult to separate in observational data.

Gastric outlet obstruction

Gastric outlet obstruction is a mechanical blockage at the pylorus or the proximal duodenum that prevents gastric emptying. Peptic ulcer disease can cause it in two ways. Acute ulcers may produce inflammation and oedema that narrows the channel, and this component often responds to acid suppression and treatment of the ulcer. Chronic ulcers, particularly those near the pylorus or the duodenal bulb, lead to scarring and fibrosis that can narrow the lumen permanently and may require endoscopic dilation or surgery. Ulcers that encircle the pyloric canal are rare but can produce this scarring. Persistent vomiting, early satiety, and weight loss are typical features, and severe cases may cause electrolyte disturbance and acute kidney injury. Historically, peptic ulcer disease caused most cases of gastric outlet obstruction, but its share has fallen sharply since the introduction of proton pump inhibitors in the late 1980s, and malignancy is now the more common cause. Endoscopic biopsy is therefore used to exclude cancer whenever an ulcer is found in this location.

Penetration into adjacent organs

Penetration describes an ulcer that erodes into a neighbouring organ without causing free leakage into the peritoneal cavity. The pancreas is the organ most often reported, and antral and duodenal ulcers are the usual sources, although gastric ulcers penetrate the pancreas only rarely. Because the ulcer is contained, patients may present with atypical or localised pain, and the diagnosis may be missed if free air is absent. CT can show loss of the normal fat plane between the stomach and the pancreas, which can help distinguish penetration from perforation. Management depends on the clinical state: some penetrating ulcers without peritonitis have been treated conservatively, whereas others require surgery, particularly when there is localised peritonitis or ongoing bleeding.

Medical eradication and acid-suppression therapy

Acid suppression

Proton pump inhibitors (PPIs) such as omeprazole and esomeprazole inhibit the H⁺/K⁺-ATPase, the final common pathway of gastric acid secretion. They are prodrugs that must be activated in the acidic secretory canaliculus, and they bind the pump covalently. Acid output therefore returns only as the parietal cell synthesizes new pump molecules, which takes roughly a day. This is why twice-daily dosing is used in ulcer healing and in eradication regimens.

Potassium-competitive acid blockers (P-CABs), of which vonoprazan is the main example, bind the same enzyme reversibly and compete with potassium ions at its binding site. They need no acid activation, so they act faster and hold intragastric pH higher for longer than PPIs. A higher pH reduces acid and pepsin exposure of the damaged mucosa, which supports healing. It may also prolong the time that amoxicillin and other antibiotics spend acting on H. pylori, which is one reason acid suppression is built into eradication therapy.

Eradication regimens

Clarithromycin-based triple therapy (a PPI with clarithromycin and amoxicillin or a nitroimidazole) was the long-standing first-line choice, but its effectiveness has fallen as macrolide resistance has spread. The 2024 American College of Gastroenterology (ACG) update removed clarithromycin triple therapy and concomitant therapy from first-line recommendations. In the United States, clarithromycin resistance is common (over 30%), and European guidance uses a 15% threshold: PPI-based standard triple therapy is recommended only in areas with a clarithromycin-resistant strain rate of ≤15%.

Bismuth quadruple therapy (BQT), a PPI plus bismuth, tetracycline and metronidazole, is now the default when susceptibility is unknown. For treatment-naive patients, bismuth quadruple therapy for 14 days is the preferred regimen when antibiotic susceptibility is unknown. Its efficacy depends on dose and formulation: the ACG defines an "optimized" version with bismuth given at least four times daily, metronidazole at 1.5 g or more per day, and tetracycline rather than doxycycline. Substituting doxycycline for tetracycline should be avoided, and bismuth quadruple therapy contains no penicillin, so it suits patients with penicillin allergy. Concomitant (non-bismuth quadruple) therapy is not suggested over bismuth quadruple therapy in treatment-naive patients.

Other options fill specific roles. Rifabutin triple therapy and P-CAB dual therapy are a suitable empiric alternative in patients without penicillin allergy. Levofloxacin triple therapy is reserved for later lines, in patients with known levofloxacin-sensitive strains and when optimized bismuth quadruple or rifabutin triple therapies have previously been used or are unavailable.

Newer agents and regional guidance

Vonoprazan-amoxicillin dual therapy has become a major change. In a small Japanese single-arm study, vonoprazan 20 mg twice daily and amoxicillin 500 mg four times daily were given for 7 days, with an intention-to-treat eradication rate of 90%. Shorter and simpler versions are under study: a 10-day vonoprazan-amoxicillin course in a Chinese trial achieved eradication rates of >90% (PP analysis) and lower rates of adverse events compared with standard 14-day B-quadruple therapy, while in another trial a 10-day course achieved acceptable eradication in PP analysis but did not statistically meet the non-inferiority criterion. The ACG treats vonoprazan-based dual therapy as an alternative, and it is conditionally endorsed as an alternative to bismuth quadruple therapy. Because amoxicillin-based dual therapy requires taking doses three to four times daily, poor adherence remains a concern.

Guidance therefore differs by region. The ACG recommends bismuth quadruple therapy regardless of local resistance, whereas Maastricht VI/Florence guidance ties the choice to local clarithromycin rates, and a high-dose PPI-amoxicillin dual therapy, a rifabutin-containing regimen or a combination of bismuth with different antibiotics should be used after failure of initial and fluoroquinolone-containing treatment. In practice, the appropriate choice depends on local resistance, allergy status and drug availability.

Confirmation of cure

Eradication is confirmed with a test given after treatment. In the trials cited above, eradication success was determined by 13C-urea breath test at least 4 weeks after treatment. Patients are generally asked to stop PPIs for about two weeks beforehand, since acid suppression can produce false-negative results. Confirmation matters most where a cure changes management: H. pylori-associated ulcers, gastric MALT lymphoma, and resected gastric cancer, where persistent infection carries a risk of recurrence or progression.

Management of drug-induced ulcers and prevention in high-risk patients

Withdrawing or replacing the offending drug

The first step is to ask whether the NSAID or aspirin can be stopped. Guidance for an ulcer that develops during NSAID or low-dose aspirin therapy directs clinicians to consider withdrawing the drug and to re-examine the reason aspirin was prescribed, in light of how severe the ulcer was. If a patient develops a gastric or duodenal ulcer while on an NSAID or low-dose aspirin, the NSAID or aspirin consideration should be given to stopping aspirin or NSAIDs. The indication for the low-dose aspirin should be reviewed and the severity of the ulcer presentation considered.

Aspirin is the difficult case. In older Western populations it has overtaken NSAIDs as a major cause of peptic ulcer bleeding, yet patients often take it for secondary cardiovascular prevention. In one randomized comparison of continued and interrupted aspirin after endoscopic treatment, stopping the drug was associated with about tenfold higher all-cause mortality, whereas continuing it roughly doubled early rebleeding (patients who discontinued ASA had a 10-fold increased incidence of all-cause mortality compared to those who received continuous ASA therapy. On the other hand, patients receiving continuous ASA therapy had a two-fold increased risk of early rebleeding). Accordingly, the European guideline advises against interrupting low-dose aspirin given as monotherapy for secondary prevention during acute upper GI bleeding (aspirin should not be interrupted).

When an NSAID cannot be stopped, a selective COX-2 inhibitor is one alternative to a conventional NSAID plus a PPI. It is generally reserved for patients with high cardiovascular risk and, after complicated ulcers, is combined with a PPI (Selective COX-2 inhibitor monotherapy is an alternative to concomitant non-selective NSAIDs and PPI in protecting the upper GI tract from peptic ulcers and bleeding. It is recommended in patients who are at high risk of cardiovascular events and in combination with PPIs in patients who have previously had complicated gastroduodenal peptic ulcer disease.). Its cardiovascular profile is itself under scrutiny, as concerns have been raised about the cardiovascular safety of both COX-2 inhibitors and conventional NSAIDs.

Gastroprotective drugs: PPIs, misoprostol, and COX-2 inhibitors

Proton pump inhibitors are the principal preventive option. In a Japanese randomized trial of 343 patients with a prior ulcer who needed long-term NSAIDs, esomeprazole 20 mg daily cut recurrence compared with placebo (esomeprazole 20 mg once daily was significantly more effective than placebo in preventing ulcer recurrence). The protection held for both traditional NSAID and COX-2 selective users (This protective effect was observed in both traditional NSAID and selective COX-2 inhibitor users). Current Japanese guidance recommends PPIs for this group, with vonoprazan suggested as an alternative (PPIs are recommended, and VPZ is suggested to prevent NSAID-induced ulcers in patients with a history of ulcers.).

Misoprostol, a prostaglandin E1 analogue, was the first agent approved for NSAID-related ulcer prevention. In a 12-week trial in arthritis patients, duodenal ulcers occurred in 2 of 320 patients (0.6%) receiving misoprostol versus 15 of 323 patients (4.6%) in the placebo group, and gastric ulcers showed a similar reduction. Its gastrointestinal side effects, particularly diarrhea, limit its use. Comparative data favour PPIs: they are as effective as, but better tolerated than, misoprostol in preventing ulcers, and in patients who continue NSAIDs they appear to be more effective than misoprostol at healing ulcers. Enteric coating and buffering of NSAIDs, and co-therapy with sucralfate, have not been shown to prevent NSAID-related ulceration (Enteric coating or buffering of NSAIDs and co-therapy with sucralfate have not been shown to be effective in preventing NSAID-related gastric or duodenal ulceration).

For patients with a prior bleed, combining a COX-2 inhibitor with a PPI produced the lowest recurrence. In one trial, adding a PPI to celecoxib lowered 13-month recurrent bleeding to 0%, compared with 8.9% for celecoxib alone (the twice-daily addition of a PPI to twice-daily celecoxib lowered the 13-month recurrence of ulcer bleeding to 0% in the combined treatment group compared with 8.9% for celecoxib alone). Guidelines accordingly recommend concomitant COX-2 inhibitor and PPI for patients with a history of bleeding ulcers (Concomitant administration of the selective cyclooxygenase (COX)-2 inhibitor with a PPI is recommended for preventing recurrence of bleeding NSAID-induced ulcers in patients with a history of bleeding ulcers.).

Low-dose aspirin users with a prior ulcer

Here the choice lies between acid suppression and H. pylori eradication, and evidence for either is limited. Guidance differs: Japanese guidelines recommend PPIs or vonoprazan for low-dose aspirin users with an ulcer history, with an H2 receptor antagonist suggested as an alternative. Korean guidance instead recommends H. pylori treatment for such patients and adds a PPI according to ulcer severity (when patients with a history of peptic ulcer take long-term low dose aspirin, the concomitant use of a proton pump inhibitor according to the severity of the peptic ulcer is recommended.). The ACG guideline suggests offering eradication to infected low-dose aspirin users, as a conditional recommendation (Those who test positive should be offered eradication therapy to reduce the risk of ulcer bleeding).

Direct comparisons are informative but not conclusive. Among aspirin users with a bleeding history, one trial found no difference in rebleeding between eradication and a PPI (there was no difference in the incidence of recurrent bleeding between the H. pylori eradication group and the group taking the PPI). Eradication failure and concurrent NSAID use account for most recurrences in these patients (Failure of eradication and concomitant use of NSAIDs, however, account for most cases of recurrent bleeding with low-dose aspirin.). A separate trial found that co-therapy with a PPI (lansoprazole 30mg daily) significantly reduced the risk of rebleeding in high-risk patients taking low-dose aspirin when compared with those taking aspirin and placebo (1.6 vs. 14.8%, P=0.008). Because of this uncertainty, a universal test-and-treat approach for all aspirin users is probably not justified, and testing is more often targeted at those with a prior ulcer or additional bleeding risk factors such as age 70 or older or concurrent anticoagulants or NSAIDs (H. pylori testing and eradication should be offered to low dose aspirin users with a history of peptic ulcer or with other risk factors for gastrointestinal bleeding, including being aged 70 years or more, and concomitantly using of anticoagulants, NSAIDs, or non-aspirin antiplatelet drugs.).

Endoscopic and surgical treatment

Endoscopic hemostasis and risk stratification

Endoscopy is both the diagnostic test and the first treatment for a bleeding ulcer. The Forrest classification, first published in 1974, grades the endoscopic appearance of the ulcer base from active spurting (Ia) and oozing (Ib), through a non-bleeding visible vessel (IIa) and an adherent clot (IIb), to a flat pigmented spot (IIc) and a clean base (III). Lesions Ia, Ib and IIa are generally treated with endoscopic therapy together with high-dose proton pump inhibitor (PPI) treatment. IIc and III are usually managed with acid suppression alone, while IIb is a contested intermediate category, because the adherent clot can hide the lesion and clot removal can provoke bleeding. Endoscopic techniques include injection of dilute epinephrine, thermal coagulation and mechanical clipping, often used in combination. Hemostasis failure is most common in Forrest Ia lesions and in duodenal ulcers. After successful treatment, a continuous high-dose PPI infusion for up to 72 hours reduces rebleeding, particularly from gastric ulcers, and lowers the need for further endoscopy, transfusion and surgery.

Rebleeding and the indications for intervention

Rebleeding is the principal concern in the first days after hemostasis. In one retrospective series of 386 patients with high-risk stigmata, 48 rebleeds occurred within three days, and the predictors included albumin, prothrombin time, shock, hematemesis or melena, and Forrest class. Reported rebleeding rates for IIa and IIb lesions in some series fall roughly between 17% and 31%, and a commonly cited estimate is that about one in five patients rebleeds after apparently successful endoscopic hemostasis, with a several-fold rise in mortality. The usual sequence is repeat endoscopy with a second hemostatic attempt after the first rebleed. If a second endoscopic attempt fails, transcatheter angiographic embolization or surgery is considered. Persistent bleeding that cannot be controlled by endoscopy or medication is the main indication for operative intervention.

Surgery as the last resort

Surgery is reserved for complications that endoscopy and drugs cannot control. These include failed hemostasis after repeated endoscopy and angiography, and perforation, which requires operation in most cases. Perforation affects roughly 2% to 10% of patients with peptic ulcer, with mortality reported as high as about 10%. Because the operation is performed under emergency conditions, the surgeon's first priority is usually to close the perforation and control contamination rather than to address the underlying acid disorder.

Surgical options for perforation

The Graham patch, introduced in 1937 after earlier work by Cellan-Jones in 1929, closes the perforation with several interrupted full-thickness sutures and lays a vascularized pedicle of greater omentum over the defect, tying the sutures over it. In the modified Graham patch, the perforation is closed first and the omentum is then secured over the closed defect; this reduces the risk of leakage from the suture line, though the knots may create a narrow contact surface between omentum and duodenum. Reported postoperative leak rates after these techniques have been roughly 3% to 7%. Primary closure, with or without an omental patch, is generally reserved for smaller perforations, often under about 2 cm. Larger defects may require conversion to laparotomy. Laparoscopic omental patch repair has been performed since the early 1990s and is considered feasible and safe in selected cases. Some perforations, particularly small, early and clinically stable ones, can be managed without immediate operation.

Historical operations

Before the omental patch became standard, perforated ulcers were treated by open gastrectomy or simple suture. Elective surgery for chronic or recurrent ulcer was also once common. Procedures such as truncal vagotomy with drainage and parietal cell vagotomy were used to reduce acid secretion. Gastric resection and vagotomy were largely displaced by acid suppression and eradication of bacterial infection, but they remain part of the historical record of ulcer surgery.

Prognosis, recurrence, and special populations

Recurrence and the role of eradication

Recurrence depends mainly on two factors: whether H. pylori is cleared, and whether NSAIDs continue to be taken. In a retrospective series of 223 patients diagnosed between 2016 and 2021, the five-year recurrence rate was 30.9%, and the authors judged effective H. pylori elimination to be the most decisive factor, with age, drug exposure, and chronic disease also contributing. The five years recurrence rate of PUD was 30.9%. Effective elimination of H. pylori is by far the most critical factor influencing the relapse of PUD, even though age, drugs, and the prevalence of chronic diseases also impact its recurrence.

Rebleeding after eradication appears uncommon in observational data. In a prospective cohort of 1,000 patients cured of H. pylori after a bleeding episode, the cumulative rebleeding incidence was 0.5%, and maintenance anti-ulcer (antisecretory) therapy is not necessary if eradication is achieved. However, NSAID intake or H. pylori reinfection may exceptionally cause rebleeding in H. pylori-eradicated patients. Randomized comparisons show a clearer contrast in small samples: in one trial, rebleeding occurred in 0 of 29 patients given omeprazole plus amoxicillin, against 6 of 22 given omeprazole alone. Rebleeding occurred significantly less often in the dual therapy group than in the omeprazole group (0/29 versus 6/22 or 27%; p < .01).

The evidence is not uniform. In contrast, in the 5 randomized trials in chronic NSAID users, H pylori eradication did not reduce the risk of ulcers or ulcer complications. Patients who continue NSAIDs therefore remain at risk even after cure, which is why drug exposure figures prominently in recurrence analyses.

Age, comorbidity, and mortality

Mortality after ulcer bleeding is concentrated in older and more medically complicated patients. In a Swedish hospital series covering 1984 to 2004, incidence decreased from 62.0 to 32.1 per 100 000 inhabitants between 1984 and 2004. Over the same period, in-hospital mortality did not fall, and the authors attributed this to a population that was older and carried more comorbidity, which offset gains from better drug and endoscopic therapy. Age above 65 years (OR: 1.11, 95% CI: 1.02–1.23) and number of comorbidities (OR: 6.00, 95% CI: 2.56–17.4) were independent risk factors for in-hospital mortality.

The age gradient is steep at the oldest ages. A study of very elderly patients with bleeding ulcers found that patients aged 80 years or greater had the highest risk of rebleeding and death. In a Danish population-based cohort of perforated ulcers, standardized 30-day mortality rose from 8.9% in patients under 65 to 44.6% in those aged 80 and over. Standardized 30-day mortality was 8.9% among patients younger than 65 years rising to 44.6% among patients aged 80+ years. Among patients with bleeding ulcers who survive endoscopic hemostasis, a series from 1993 to 2003 recorded 284 rebleeding episodes (8.8%) and 229 in-hospital deaths (7.1%), with predictors including advanced age, comorbidity, and in-hospital rebleeding.

Comorbidity also shapes long-term survival. The study demonstrated that peptic ulcer bleeding is associated with long-lasting excess mortality. The main predictors for long-term mortality were old age, comorbidity, male sex, severe anaemia and tobacco use. Cardiovascular disease illustrates the pattern in older populations: in a Chinese national survey of elderly adults, CVD was significantly associated with an increased PU risk (OR = 1.31, 95%CI 1.03–1.66, p = 0.04), while an observed mortality difference reflected the presence of cardiovascular comorbidity rather than ulcer status alone.

Ulcers without H. pylori infection carry their own prognostic signal. In a study of bleeding ulcers, the overall 30-day mortality was positively correlated to older age, underlying comorbid illnesses, in-hospital bleeding recurrence and the absence of H. pylori infection.

Older patients and the gap between incidence and complications

Incidence has fallen in most countries, but the decline has not been even across age groups. The age-standardized incidence rate (ASIR) decreased from 57.14 (95% CI: 48.61–66.73) per 100,000 population in 1990 to 34.10 (95% CI: 29.13–38.97) per 100,000 population in 2021. Among people aged 70 and over, the absolute number of cases rose from about 1.07 million in 1990 to about 1.61 million in 2019, even as age-specific prevalence declined. Despite an increasing number of cases, the prevalence of PUD among the elderly has exhibited a steady decline, with an EAPC of -1.47. A rising population share of older adults, together with greater use of NSAIDs, low-dose aspirin, and anticoagulants, helps explain why complications persist. The increasing proportion of elderly persons in the general population and the associated increases in the use of NSAIDs, low-dose aspirin, and anticoagulants might increase the risk of peptic ulcer complications.

Low-resource settings

Declines in incidence have been steepest in the poorest regions. The largest decreases in age-standardized prevalence, incidence, DALY and death rates from 1990 to 2019 occurred in the low-SDI and low-middle-SDI quintiles. Lower-income settings nonetheless face a particular problem with delayed care. Analyses of the global burden note that delays in diagnosis and treatment could have prolonged the disease course or increased complications of PU. Late presentation thus raises the likelihood that an ulcer reaches the stage of bleeding or perforation before it is treated, with the outcomes described above.

Discovery and history of understanding

Early descriptions and the acid-digestion era

Stomach pain and bleeding that may have come from ulcers appear in ancient medical writing, but these accounts could not separate ulcers from other gastric disorders. By the eighteenth century, anatomists such as Giovanni Battista Morgagni were describing ulcerated lesions of the stomach found at autopsy, which established the lesion as a pathological entity rather than only a clinical complaint. The nineteenth century brought the chemistry of digestion into focus. In 1824, William Prout identified hydrochloric acid in gastric juice, and in 1836 Theodor Schwann isolated pepsin, the enzyme that digests protein in the acidic stomach. William Beaumont's observations between 1825 and 1833 of a patient with a permanent gastric fistula, Alexis St. Martin, gave direct evidence of gastric secretion and its digestive action in a living person. Physicians then reasoned that ulceration resulted from the stomach digesting itself. Julius Cohnheim's autodigestion theory of the 1870s, which proposed that acid and pepsin acted on tissue weakened by local ischemia, became the foundation of the acid-peptic model that dominated the field for the next century.

The surgical era and the shift to acid suppression

Under this model, the logical treatments were to reduce acid or to remove the acid-producing tissue. Theodor Billroth performed the first gastrectomy for cancer in 1881 and, in 1885, described a partial resection with gastrojejunostomy that was applied to ulcer disease. In the twentieth century, surgery also included vagotomy, which cut the vagal supply that stimulates acid secretion; John Dragstedt popularized the procedure in the 1940s. Medical management in the early decades relied on the Sippy regimen of 1915, which combined frequent feeding of milk and cream with alkaline antacids. This treatment relieved symptoms but did little to prevent recurrence. The discovery of histamine receptor antagonists in the 1970s, notably cimetidine, and later the introduction of proton-pump-inhibitor drugs in the late 1980s, allowed acid to be suppressed far more effectively. Even so, these drugs controlled the consequences of acid rather than its underlying cause, so ulcers healed and then relapsed in many patients once treatment stopped. Because no infectious or other cause was identified, ulcer disease was regarded as a chronic, recurrent condition that required lifelong management.

The discovery of Helicobacter pylori

In 1979, the Australian pathologist Robin Warren noticed curved bacteria in inflamed gastric biopsies. Working with the physician Barry Marshall, he found that these organisms were present in most patients with gastritis, and in 1982 they succeeded in culturing the bacterium, which was later named Helicobacter pylori. Their early reports were met with skepticism, partly because the acid-peptic model was so well established. In 1984, Marshall drank a culture of the organism, developed gastritis, and recovered after treatment with antibiotics, a self-experiment that strengthened the case for a causal role. A 1994 National Institutes of Health consensus conference recommended antibiotic treatment for patients with H. pylori-associated ulcers, marking a formal change in clinical practice. Most ulcers came to be reclassified as infectious diseases with an inflammatory basis, rather than as a chronic condition driven by acid alone. Warren and Marshall received the 2005 Nobel Prize in Physiology or Medicine for this discovery. The reclassification changed the framing of the disease: eradicating the bacterium reduced recurrence sharply, and the later recognition of NSAIDs as a second major cause further refined the understanding of why ulcers form.

Unresolved questions and current research

Idiopathic ulcers are the least settled part of the picture. Estimates of how many ulcers lack both an H. pylori infection and an NSAID or aspirin exposure vary widely. In a French hospital-based cohort, about 21.6% of patients had neither factor. By contrast, an Italian study put the prevalence of idiopathic ulcers at about 4%. Part of this spread reflects method. The true prevalence may have been underestimated when patients who had recently taken antibiotics or antisecretory drugs were not excluded, because these can produce false-negative tests. Another part reflects the shrinking pool of infected people: the decline of H. pylori infection in the South Korean population is considered a likely reason for the rising share of ulcers unrelated to the bacterium.

The causes of idiopathic ulcers remain largely unknown. Proposed contributors include a genetic predisposition, altered acid secretion, rapid gastric emptying, defective mucosal defenses, psychological stress, and smoking, and several studies link advanced age and serious systemic illness to them. Undisclosed drug use is an important confounder. One review found that surreptitious NSAID use may account for unexplained ulcers in up to 60% of patients, which is why a careful drug history, including over-the-counter analgesics and traditional medicines, is a necessary first step. Diagnostic work also requires repeating H. pylori testing off acid suppression and antibiotics, and excluding hypersecretory states such as Zollinger–Ellison syndrome. Management remains undefined: these ulcers appear more resistant to standard therapy, may be associated with more frequent complications, and relapsing cases may need long-term maintenance treatment.

The question of aspirin-associated ulcers illustrates the uncertainty about whether eradication should be used prophylactically. The Helicobacter Eradication Aspirin Trial (HEAT), conducted in UK primary care, randomised older adults on aspirin with a positive breath test to eradication or placebo. Over follow-up of 26,668 person-years, there were 44 episodes of bleeding probably or definitely due to peptic ulcers, 18 in the eradication group and 26 in the control group. The overall primary analysis was not significant, with a hazard ratio of 0.69 (95% CI 0.38 to 1.25; p = 0.22). The reported benefit emerged only after a split analysis, which was introduced under a modified analysis plan: a significant reduction in the first 2.5 years, which was lost in the period after the first 2.5 years. The authors themselves noted that eradication protects against aspirin-associated peptic ulcer bleeding, but this might not be sustained in the long term. Because the trial compared eradication with placebo rather than with maintenance acid suppression, the relative merits of the two strategies in high-risk aspirin users, and the value of a long-term combined approach, remain open. Reviews also stress that the early advantage appeared to be lost with longer follow-up, and that the causal role of H. pylori in aspirin-related bleeding has not been fully established.

Rising antibiotic resistance now shapes both treatment and public health policy. Clarithromycin resistance has substantially increased, now exceeding the 15% threshold in all WHO regions, where international guidelines discourage empirical clarithromycin-based therapy. In a Korean nationwide series, clarithromycin resistance rose from 8.5% (2005–2010) to 16.0% (2011–2012), then to 17.8% (2017–2018). A pooled analysis found an overall clarithromycin resistance rate of 27.53% worldwide, though the authors noted substantial variation caused by differing prescribing patterns and breakpoints. Resistance to other agents is also increasing: from 2006 to 2016, resistance to clarithromycin, metronidazole and levofloxacin rose across all WHO regions. The World Health Organization's 2017 priority pathogen list included clarithromycin-resistant H. pylori, which made susceptibility-guided selection of regimens, rather than empirical use of older regimens, a central goal. Surveillance is uneven: inadequate monitoring in developing countries and the lack of uniform testing methods can produce discrepancies between regions and underestimate resistance.

The debate over population-wide screening and treatment compared with targeted testing has not been resolved. Proponents of screen-and-treat strategies emphasise that H. pylori is a established cause of gastric cancer, so eradication in high-incidence regions may prevent more than ulcers. Opponents point out that most infected people never develop ulcers, that mass programmes add costs for testing, endoscopy and drugs, and that widespread antibiotic use risks further resistance and adverse drug effects. Test-and-treat approaches in younger patients with uncomplicated dyspepsia are generally favoured in low-prevalence settings, but they do not address the rising idiopathic group, and the balance between overtreatment and missed diagnosis continues to be debated among guideline bodies and health systems.

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