Peptic ulcer disease is a defect in muscularis mucosa of gastrointestinal tract. Peptic ulcer is classified into 2 depending upon the location of ulcer, gastric ulcer and duodenal ulcer. The most common cause of peptic ulcer disease is H.pylori infection which is acquired in childhood but presents in adulthood. Other causes of peptic ulcer disease are chronic use of NSAID, family history of peptic ulcer disease. Persistant use of NSAIDS or chronic infection with H.Pylori results in inflammation of antral mucosa and ultimately causes the ulcer. The most common symptoms of peptic ulcer disease include episodic epigastric pain, heartburn, loss of appettite, gastroesophageal reflux, waterbrash, hematemesis and melena. Common physical examination findings of peptic ulcer disease include epigastric tenderness, tachycardia. Endoscopy is the gold standard test for the diagnosis of the peptic ulcer disease. Treatment of helicobacter pylori with antimicrobial agents is indicated for patients with gastric or duodenal ulceration. Pharmacologic therapies for peptic ulcer disease due to H. pylori is either triple or quadruple pharmacologic agents that include a Proton pump inhibitors plus a combination of antimicrobial agents.

Hundred years ago, Polish clinical researcher, professor W.Jaworski was the first to describe the spiral-shaped microorganism at Cracow Jagiellonian University but it was later confirmed in the animal by G.Bizzazero. Asklepios was the first to describe an association between GI bleeding and peptic ulcer disease. In 1982 Warren and B.J marshall cultured the organism and found a strong association between Helicobacter pylori and inflammation of gastric mucosa, not due to spicy food and stress and were awarded the noble prize.

Peptic ulcer disease is classified along three clinically distinct axes: etiology, anatomic location, and endoscopic morphology. Etiologic classification is the clinically relevant framework because it drives management. The categories are H. pylori-associated, NSAID/aspirin-induced, and idiopathic.^[1][2] The Forrest classification grades bleeding ulcers by their endoscopic stigmata of hemorrhage. It is the most clinically actionable system because it determines the need for endoscopic hemostasis and post-procedure proton pump inhibitor dosing.^[3][4] The Sakita–Miwa classification stages gastric ulcer healing; it is used mainly in research and after endoscopic submucosal dissection (ESD).^[5][6]

Peptic ulcer disease develops when aggressive luminal factors (acid, pepsin, bile) overwhelm the gastroduodenal mucosal barrier. That barrier depends on tight epithelial junctions, an adherent mucus layer, bicarbonate secretion, and prostaglandin-maintained mucosal blood flow.^[7][8] Helicobacter pylori causes chronic active gastritis, and the anatomic pattern of that gastritis determines the ulcer type. Antral-predominant gastritis produces hypergastrinemia and acid hypersecretion, which leads to duodenal ulcer. Pangastritis produces hypochlorhydria and gastric ulcer, along with a risk of atrophy and gastric cancer.^[9] NSAIDs and aspirin injure the mucosa through COX-1-mediated prostaglandin depletion and through direct topical toxicity. NSAID-associated ulcers are often painless until bleeding or perforation occurs.^[10][11] In critical illness, stress-related mucosal injury results from mucosal hypoperfusion, independent of H. pylori or NSAID exposure.^[1] H. pylori and NSAIDs act synergistically, so the combination carries greater risk of ulceration and bleeding than either factor alone.^[7]

Peptic ulcer disease (PUD) results from an imbalance between mucosal defense and aggressive factors such as gastric acid, pepsin, and exogenous injury.^[7]

The principal causes are:

• Helicobacter pylori infection, about 42% of cases.
• Aspirin or NSAID use, about 36% of cases.
• Idiopathic ulcers, unrelated to either, about 22% of cases.^[1]

H. pylori and NSAIDs independently increase ulcer risk and act synergistically. PUD is rare when neither is present.^[12]

Less common causes include:

• Stress-related mucosal disease in critical illness.^[13]
• Zollinger-Ellison syndrome.
• Malignancy.^[14]
• Rare inflammatory, infectious, and anatomic causes.^[15]

Peptic ulcer disease must be differentiated from other causes of acute upper gastrointestinal bleeding such as esophageal varices, Mallory-Weiss syndrome, gastrointestinal cancer, arteriovenous malformations, esophagitis, and esophageal ulcer. Peptic ulcer disease must also be differentiated from gastroesophageal reflux disease (GERD,pancreatitis, Zollinger-Ellison Syndrome, Cholelithiasis, gastric outlet syndrome, myocardial infarction ,pleural empyema and appendicitis.

Global age-standardized incidence, prevalence, and mortality of peptic ulcer disease (PUD) fell by 40.3%, 41.1%, and 61.5%, respectively, between 1990 and 2021.^[16] Absolute case numbers continued to rise because of population growth and aging.^[17] Men carry a higher burden than women across most age groups.^[16] In the United States, PUD-related mortality fell sharply from 2001 to 2012, plateaued, and then rose from 2018 to 2020.^[18] US racial and ethnic disparities largely track Helicobacter pylori exposure, which is highest in non-Hispanic Black and Hispanic individuals and in immigrants from endemic regions.^[19][20]

The two dominant, largely modifiable risk factors for peptic ulcer disease (PUD) are Helicobacter pylori infection and use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Together they account for roughly 70% to 78% of cases.^[1][8] These two exposures interact synergistically, so combined exposure raises ulcer bleeding risk more than either alone.^[21][2] In NSAID users, the strongest predictor of a future ulcer complication is a prior ulcer complication. Concomitant corticosteroids, anticoagulants, antiplatelet agents, or SSRIs and older age further amplify risk.^[2][8] Additional independent associations include cigarette smoking, alcohol use, male sex, diabetes mellitus, and cardiovascular disease.^[22] The proportion of idiopathic ulcers (negative for both H. pylori and NSAIDs) is rising as H. pylori prevalence declines.^[1][8]

There is no role for universal, population-based screening for peptic ulcer disease (PUD), including routine endoscopic screening, in asymptomatic average-risk adults.^[7] Instead, PUD prevention relies on targeted, risk-based testing for Helicobacter pylori (with treatment of all positive results) and on ulcer-risk assessment before starting chronic NSAID or low-dose aspirin therapy.^[19][21] The 2024 American College of Gastroenterology (ACG) guideline and the 2018 Houston Consensus Conference define the populations in whom H. pylori testing is indicated, using non-invasive urea breath testing or stool antigen testing.^[19][23] Population-wide H. pylori screen-and-treat programs are endorsed only in regions with high gastric cancer incidence.^[24]

The infection of Helicobacter pylori, a common cause of peptic ulcer disease is acquired usually during the childhood but presents in second to the fifth decade of life.Patient presents with episodic epigastric pain, indigestion, bloating, hematemesis and melena. Peptic ulcers tend to come back if untreated.

Peptic ulcer disease if not treated, the patient can develop complications like bleeding, perforation, obstruction, stricture.Chronic infection of Helicobacter pylori leads to gastric cancer, MALT lymphoma, Iron deficiency anemia, Idiopathic thrombocytopenic purpura.

Prognosis is good if the eradication therapy of Helicobacter pylori is taken. The recurrence rate of patients with peptic ulcer disease is less than 20%.

Endoscopy is the gold standard test for the diagnosis of the peptic ulcer disease.

The hallmark of peptic ulcer disease is an episodic epigastric pain which cause awakening at night.A positive history of epigastric pain, use of drugs like NSAIDs including aspirin which inhibit cyclooxygenase, use of antiplatelets, steroids and family history of peptic ulcer disease is suggestive of peptic ulcer disease. The most common symptoms of peptic ulcer disease include episodic epigastric pain, heartburn, loss of appettite, gastroesophageal reflux, waterbrash, hematemesis and melena. Less common symptoms of peptic ulcer disease include intolerance to fatty food.

Peptic ulcer disease patient appears in severe stress due to abdominal pain. Common physical examination findings of peptic ulcer disease include epigastric tenderness, tachycardia.Perforated peptic ulcer disease patient presents with classic triad of severe epigastric tenderness, tachycardia and abdominal rigidity. Clinical signs of perforated peptic ulcer comes in 3 stages: In the initial stage within first 2 hours, the patient presents with tachycardia, epigastric pain and cool extremities. In next 2 to 12 hours, the patient presents with lower right quadrant tenderness and abdominal rigidity. In more than 12 hours, the patient presents with abdominal distension, hypotension, and pyrexia with acute circulatory collapse.

There is no specific diagnostic laboratory test for peptic ulcer disease but in the patient with the history of peptic ulcer disease, the laboratory test is used to rule out bleeding and to document the status of eradication therapy and to test refractory ulcers.

If a peptic ulcer perforates, air will leak from the inside of the gastrointestinal tract (which always contains some air) to the peritoneal cavity (which normally never contains air). This leads to “free gas” within the peritoneal cavity. If the patient stands erect, as when having a chest X-ray, the gas will float to a position underneath the diaphragm. Therefore, gas in the peritoneal cavity, shown on an erect chest X-ray or supine lateral abdominal X-ray, is an omen of perforated peptic ulcer disease. An esophagogastroduodenoscopy (EGD), a form of endoscopy, also known as a gastroscopy, is carried out on patients in whom a peptic ulcer is suspected. By direct visual identification, the location and severity of an ulcer can be described. Moreover, if no ulcer is present, EGD can often provide an alternative diagnosis.

Testing of H.pylori infection is very important for treating ulcers. H.pylori tested by 2 methods : invasive and non-invasive. Rapid urease testing is invasive test which is used as diagnostic study of choice. Stool monoclonal antigen test is one of the non-invasive test which is used to diagnose active infection.

The mainstay of treatment for peptic ulcer disease is pharmacotherapy. All patients with a gastric or duodenal peptic ulcer should be evaluated for Helicobacter pylori infection and for nonsteroidal anti-inflammatory drug (NSAID) or aspirin use, as these represent the two dominant etiologies. Treatment of H. pylori with antimicrobial agents is indicated for all patients with active gastric or duodenal ulceration who test positive for the infection.

The pharmacologic approach to H. pylori-associated PUD involves a combination of a proton pump inhibitor (PPI) or potassium-competitive acid blocker (PCAB) plus two or three antimicrobial agents. The 2024 American College of Gastroenterology (ACG) Clinical Guideline substantially revised first-line eradication strategy: standard PPI–clarithromycin triple therapy is no longer recommended empirically, given rising resistance rates to clarithromycin and levofloxacin in North America. Optimized bismuth quadruple therapy (BQT) is now the recommended first-line regimen; rifabutin-based triple therapy and vonoprazan-based regimens are endorsed as alternatives.^[19] After treatment, confirmation of eradication is mandatory using a urea breath test or monoclonal fecal antigen test at least 4 weeks after completing antibiotics and at least 2 weeks after stopping all acid-suppressive therapy. If the patient remains infected, the regimen is planned according to prior antibiotic exposure, documented resistance, and remaining treatment options.

For non-H. pylori, non-NSAID (idiopathic) ulcers, long-term acid suppression is the foundation of therapy. The use of antimicrobial therapy is discouraged among asymptomatic H. pylori carriers without an established indication.

The cornerstone of endoscopic risk stratification in peptic ulcer bleeding is the Forrest classification, first described in 1974, which categorizes ulcer stigmata and guides decisions regarding the need for endoscopic hemostasis. Pre-endoscopic risk stratification using validated scoring systems — most importantly the Glasgow-Blatchford Score (GBS) — allows identification of very-low-risk patients who may be safely managed as outpatients, as well as high-risk patients who require urgent inpatient endoscopy and intervention.^[4][25]

Surgery for peptic ulcer is principally indicated for the management of life-threatening complications, including upper gastrointestinal bleeding, perforation, and gastric outlet obstruction, as well as for ulcers that are refractory to maximal medical therapy or carry concern for underlying malignancy. Peptic ulcer disease has a lifetime prevalence in the general population of 5–10% and an annual incidence of 0.1–0.3%; despite a marked decline over the past three decades attributable to the discovery of Helicobacter pylori and the widespread use of proton pump inhibitors (PPIs), complications still arise in 10–20% of affected patients.^[26]

Bleeding ulcers are treated first with endoscopic therapy; surgery is reserved for cases of failure or recurrence after endoscopic and angiographic management. Perforated peptic ulcer is a surgical emergency; immediate repair—preferentially by laparoscopic approach in haemodynamically stable patients—is the standard of care. Elective acid-reducing surgery (e.g., vagotomy and drainage) has been largely supplanted by modern pharmacotherapy, including optimized bismuth quadruple therapy and potassium-competitive acid blocker (vonoprazan)-based regimens for Helicobacter pylori eradication.^[27]

Primary prevention of PUD focuses on: (1) identification and eradication of H. pylori infection before ulcer development; (2) gastroprotective co-therapy or substitution of safer drug classes in patients requiring NSAIDs or low-dose aspirin; (3) modification of lifestyle risk factors, including smoking cessation and reduction of excessive alcohol intake; and (4) stress ulcer prophylaxis in high-risk critically ill patients.

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Hundred years ago, polish clinical researcher professor W.Jaworski was the first to describe spiral-shaped microorganism at Cracow Jagiellonian University. Asklepios was the first to describe an association between GI bleeding and peptic ulcer disease. In 1982 Warren and B.J marshall cultured the organism and found a strong association between Helicobacter pylori and inflammation of gastric mucosa and were awarded the noble prize.

• Hundred years ago, polish clinical researcher professor W.Jaworski was the first to describe the spiral-shaped microorganism at Cracow Jagiellonian University
• In pre-16th century:
  • Hippocrates gave a detailed describtion of symptoms of peptic ulcer
  • Avicenna described the relationship between abdominal pain and mealtimes in peptic ulcer patient^[1]
• In 1586, Marcellus Donatus of Mantua described gastric ulcers by performing autopsies
• In 1688, Johannes von Murault gave detailed description of duodenal ulcers
• In 1812, Broussais found that if acute gastritis is untreated, it can lead to chronic gastritis
• In 1821, Nepveu found a relationship between gastritis and gastric cancer
• In 1857, William Brintonin described ulcer of the stomach and gastric cancer in his book
• In 1875, G.Bottcher and M. Letulle hypothesize that ulcers are caused by bacteria
• In 1880, J.Cohnheim found that ulcers may be caused by chemical factors
• In 1889, Walery Jaworski found spiral organisms in sediment washings of humans and proposed that these organisms may be involved with gastric disease
• In 1910, Moynihan wrote a book on duodenal ulcer^[2]
• In 1971, Howard Steer found H. pylori from biopsies of a patient with ulcers^[3][4]
• In late 1970, J.R Warren, a pathologist in Perth, Australia found the appearance of spiral bacteria overlying gastric mucosa^{[4]_CDC_Ulcer-5|[5]}
• In 1982 , Warren and B.J marshall cultured the organism and found a strong association between Helicobacter pylori and inflammation of gastric mucosa^{[4]_CDC_Ulcer-5|[5]}
• In an act of self-experimentation Marshall drank a petri-dish containing a culture of organisms extracted from a patient and soon developed gastritis. His symptoms disappeared after two weeks, but he took antibiotics to kill the remaining bacteria at the urging of his wife.This experiment was published in 1984 in the Australian Medical Journal^[6]
• In 1994, Parsonnet et al found an association between H. pylori and lymphomas of the gastrointestinal tract^[7]
• In 1997 Tomb et al. completed sequencing of the entire 1,667,867 base pairs of the H. pylori genome. This helped in identifying new virulence factors for the infectivity of H. pylori at the molecular level^[8]
• In 2001, Chan et al. showed that eradication of H. pylori prevents bleeding from ulcers that is caused by aspirin and non-steroidal anti-inflammatory drugs^[9]
• In 2002, European Helicobacter Pylori Study Group published the Maastricht 2-2000 Consensus Report, found a “test-and-treat” strategy for H. pylori in young patients without atypical symptoms. It suggests the use of noninvasive testing to evaluate for H. pylori ^[10]
• In 2005 Warren and Marshall awarded the Nobel Prize in Physiology or Medicine by Karolinska Institute in Stockholm for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease^[11]

• In 1992,Covacci discovered CagA gene, which encodes for a cytotoxin-associated surface protein, related with strains of H. pylori that caused duodenal ulcers and was discovered by molecular techniques were first involved in the pathogenesis of peptic ulcer disease ^[12]

• In 1868, Kussmaul discovered that an antibacterial agent containing bismuth used to treat peptic ulcers
• In 1915, Antacids are first suggested for the treatment of Peptic ulcer disease^[13]
• In 1951, J. Allende wrote a book explaining the treatment of gastric ulcers with penicillin^[14]
• 1953, Dintzis and Hastings suggested a relationship between urease and a bacterial infection,by stopping urease production in mice with antibiotics^[15]
• 1957, Charles Lieber and Andre Lefèvre explained that antibiotics decreases the production of urea to ammonia in stomach^[16]
• In 1990
  • Borody’s triple therapy became commercialized under the product name Helidac in the United States^[17]
  • Rauws and Tytgat described treatment of duodenal ulcer by eradication of H. pylori using Borody’s triple therapy that is combination of proton pump inhibitor and two antibiotics, becomes first-line therapy for eradication^[18]
  • World Congress of Gastroenterology suggested eradicating H. pylori to treatment of duodenal ulcers
  • First report of resistance of H. pylori to the antibiotic metronidazole was found^[19]
  • The resistance of H. pylori to treatment leads to the development of new regimen which includes many different antibiotic and proton pump inhibitor regimens for eradication^[10]
• In 1996 first antibiotic was developed by the Food and Drug Administration to treat peptic ulcer disease^[20]

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Peptic ulcer disease is classified along three clinically distinct axes: etiology, anatomic location, and endoscopic morphology. Etiologic classification is the clinically relevant framework because it drives management. The categories are H. pylori-associated, NSAID/aspirin-induced, and idiopathic.^[1][2] The Forrest classification grades bleeding ulcers by their endoscopic stigmata of hemorrhage. It is the most clinically actionable system because it determines the need for endoscopic hemostasis and post-procedure proton pump inhibitor dosing.^[3][4] The Sakita–Miwa classification stages gastric ulcer healing. It is used mainly in research and after endoscopic submucosal dissection (ESD).^[5][6]

• H. pylori-positive ulcers: approximately 42% of cases.^[1][2][7]
• NSAID/aspirin-induced ulcers: approximately 36% of cases.^[1][2][7]
• Idiopathic ulcers (H. pylori-negative, NSAID-negative): approximately 22% of cases. This proportion is increasing, which older schemes built on the H. pylori/NSAID dichotomy did not emphasize.^[1][8]
• Less common causes:^[2][8]
  • Acid hypersecretory states, including Zollinger-Ellison syndrome and systemic mastocytosis
  • Malignancy: gastric cancer or gastric lymphoma
  • Inflammatory: Crohn’s disease and eosinophilic gastroduodenitis
  • Infectious: cytomegalovirus or herpes simplex virus in immunocompromised hosts, and non-H. pylori Helicobacter (NHPH) infection
  • Mechanical/iatrogenic: radiation, Cameron ulcers associated with hiatal hernia, and anastomotic (marginal) ulcers after gastric resection
  • Stress ulcers in critically ill patients

Peptic ulcers occur in the stomach, most commonly along the lesser curvature, or in the duodenum, most commonly in the duodenal bulb.^[1][2] The Johnson classification subtypes gastric ulcers by location and acid output. It is of historical and surgical interest but has limited bearing on modern medical management, which depends on H. pylori status and NSAID exposure rather than acid-secretory subtype.^[9][10]

Johnson classification of gastric ulcer

Type	Location	Acid output
I	Lesser curvature, gastric body	Normal or low
II	Gastric body ulcer with active or healed duodenal ulcer	Hypersecretory
III	Prepyloric	Hypersecretory
IV	Juxtacardial/subcardial (added later)[10]	—

The Forrest classification grades bleeding peptic ulcers by endoscopic appearance. Each grade predicts rebleeding risk and directs the decision to perform endoscopic hemostasis. US endoscopists often use the descriptive terms (spurting, oozing, visible vessel, adherent clot, flat spot, clean base) interchangeably with the Forrest grades.^[11][12]

Forrest classification of bleeding peptic ulcers

Forrest class	Endoscopic finding	Approximate rebleeding risk without endoscopic therapy	Endoscopic management
IA	Active spurting	~55–90%	Endoscopic hemostasis required[3][11][12][4]
IB	Active oozing	~30%	Endoscopic hemostasis recommended[3][13]
IIA	Non-bleeding visible vessel	~43–50%	Endoscopic hemostasis required[3][11][12]
IIB	Adherent clot	~22–33%	Attempt clot removal to unmask the underlying stigma, then treat accordingly. ACG and ESGE differ on routine endotherapy (see below).[3][14][4]
IIC	Flat pigmented spot	~10%	No endoscopic therapy needed[3][12]
III	Clean base	~5%	No endoscopic therapy needed[3][12]

• High-risk stigmata (IA, IB, IIA) carry mortality of up to 11% and rebleeding rates above 40% if untreated.^[12] The adherent clot (IIB) is also grouped with the high-risk lesions, whereas the flat pigmented spot (IIC) and clean base (III) are low risk.^[15]
• Recurrent bleeding after successful hemostasis in a post hoc analysis of randomized trial data: 22.5% (IA), 17.7% (IIB), 11.3% (IIA), and 4.9% (IB).^[3]
• Documentation: the ACG/AGA 2025 quality indicators state that the Forrest class should be recorded in the procedure report, because it dictates both the need for endotherapy and post-procedure PPI dosing.^[3]
• ESGE 2026 update: introduces Forrest-stratified recommendations. These include over-the-scope clips as monotherapy for high-risk stigmata (IA/IB) and endoscopic therapy for adherent clots (IIB) when technically feasible.^[14]
• Reproducibility: interobserver agreement for Forrest stigmata is low to moderate.^[15]

This six-stage system tracks the endoscopic appearance of gastric ulcer healing over time. It remains in use in ESD and ulcer-healing research, but it has no direct implications for acute management.^[5][6]

Sakita–Miwa staging of gastric ulcer healing^[6]

Stage	Phase	Endoscopic findings
A1	Active	Mucus-coated ulcer, marginal edema, no regenerating epithelium
A2	Active	Mucus-coated ulcer with a discrete margin and less edema; a red halo and converging folds may appear
H1	Healing	Regenerating epithelium covers less than 50% of the ulcer floor, with or without converging folds
H2	Healing	Regenerating epithelium covers most of the ulcer floor
S1	Scarring	Red scar with complete re-epithelialization and visible capillaries
S2	Scarring	White scar with mature re-epithelialization

• Adherent clot (Forrest IIB): management remains unsettled. ACG did not reach a recommendation on routine endotherapy. ESGE 2026 suggests clot removal with hemostasis when the endoscopist has adequate technical competence.^[3][14][4]
• Interobserver variability: agreement is limited when distinguishing oozing from spurting, or an adherent clot from a visible vessel. This reduces the reproducibility of risk stratification.^[15]

• Forrest IA, IB, and IIA require endoscopic hemostatic therapy. Forrest IIC and III do not, and treating them endoscopically is not indicated.^[3][12][4]
• An adherent clot should prompt attempted removal to unmask the underlying stigma.^[14][12]
• Failing to document the Forrest class compromises post-procedure PPI dosing decisions and communication of rebleeding risk.^[3]
• Gastric ulcers require biopsy of the ulcer edge to exclude malignancy, regardless of Forrest class or Sakita–Miwa stage.^[1]
• Johnson subtype does not dictate modern medical therapy. H. pylori and NSAID status are the actionable etiologic classifiers.^[1][2]

Peptic ulcer disease develops when aggressive luminal factors (acid, pepsin, bile) overwhelm the gastroduodenal mucosal barrier. That barrier depends on tight epithelial junctions, an adherent mucus layer, bicarbonate secretion, and prostaglandin-maintained mucosal blood flow.^[1][2] Helicobacter pylori causes chronic active gastritis, and the anatomic pattern of that gastritis determines the ulcer type. Antral-predominant gastritis produces hypergastrinemia and acid hypersecretion, which leads to duodenal ulcer. Pangastritis produces hypochlorhydria and gastric ulcer, along with a risk of atrophy and gastric cancer.^[3] NSAIDs and aspirin injure the mucosa through COX-1-mediated prostaglandin depletion and through direct topical toxicity. NSAID-associated ulcers are often painless until bleeding or perforation occurs.^[4][5] In critical illness, stress-related mucosal injury results from mucosal hypoperfusion, independent of H. pylori or NSAID exposure.^[6] H. pylori and NSAIDs act synergistically, so the combination carries greater risk of ulceration and bleeding than either factor alone.^[1]

The gastroduodenal mucosal barrier has three interdependent components:^[1]

• Tight epithelial junctions that resist back-diffusion of acid and pepsin into the submucosa
• Adherent mucus layer (glycoprotein gel) that resists proteolysis and slows acid diffusion
• Bicarbonate secretion by surface epithelial cells, which neutralizes acid at the mucus-epithelial interface

Endogenous prostaglandins maintain this barrier. These are largely derived from COX-1. They sustain mucosal blood flow, stimulate mucus and bicarbonate secretion, and promote epithelial proliferation and restitution.^[5] Disruption of any of these components predisposes to ulceration, whether the cause is pharmacologic, infectious, or ischemic.

H. pylori colonizes the gastric epithelial surface, where it is shielded from luminal acid. Its spiral morphology and flagella allow it to penetrate the mucus layer.^[3] Bacterial urease hydrolyzes urea to ammonia and bicarbonate. This buffers local acid and reduces mucus viscosity, which aids bacterial motility.^[3]

Several factors mediate epithelial injury and the host immune response:^[3]

• Virulence factors, including CagA, VacA, and OipA
• Bacterial phospholipases
• The neutrophil-predominant cytokine response (IL-8, TNF-α, IL-1)

Together these produce chronic active gastritis and impair tight junctions and the mucus-bicarbonate barrier.

The anatomic distribution of gastritis largely determines the ulcer phenotype:^[3][1]

Feature	Antral-predominant gastritis	Corpus-predominant gastritis / pangastritis
Key mechanism	Antral inflammation suppresses D-cell somatostatin. This disinhibits G-cell gastrin release.	Inflammation extends into the acid-secreting corpus and causes gland atrophy.
Acid secretion	Increased. Hypergastrinemia drives histamine release from enterochromaffin-like cells, which increases parietal cell acid output.	Decreased (hypochlorhydria).
Duodenal consequence	Excess acid delivered to the duodenum causes gastric metaplasia of the duodenal bulb. This metaplastic tissue can be colonized by H. pylori and ulcerate.	None specific.
Ulcer phenotype	Duodenal ulcer	Gastric ulcer
Long-term implication	Eradication corrects the mechanism and markedly reduces recurrence.	Precursor to atrophic gastritis, intestinal metaplasia, and gastric cancer.

NSAIDs and aspirin injure the mucosa through both systemic and local mechanisms:^[4][5]

• COX-1 inhibition is the dominant systemic mechanism. It depletes protective prostaglandins, which reduces mucosal blood flow, mucus and bicarbonate secretion, and epithelial repair.
• COX-2 inhibition impairs healing and leukocyte-endothelial interactions. COX-2 is mainly inducible rather than constitutive in normal mucosa.
• Direct topical toxicity acts independently of COX inhibition. Acidic, lipophilic NSAIDs disrupt the mucus phospholipid layer and uncouple mitochondrial oxidative phosphorylation, which injures epithelial cells directly.

Prostaglandins sensitize submucosal pain fibers. As a result, NSAID-associated ulcers are more often clinically silent and are more likely to present first with bleeding or perforation.^[5]

Selective COX-2 inhibitors (e.g., celecoxib) spare COX-1 and cause less gastroduodenal toxicity than nonselective NSAIDs. The risk is reduced but not eliminated.^[4][5]

Ulcer risk increases with NSAID dose and duration, with concurrent use of multiple NSAIDs, and with combined antiplatelet therapy.^[1]

In critical illness, several factors impair mucosal perfusion and defense:^[6]

• Hypovolemia
• Reduced cardiac output
• Catecholamine-mediated splanchnic vasoconstriction
• Release of proinflammatory cytokines

These produce stress-related mucosal injury independent of H. pylori or NSAID exposure.

H. pylori infection and NSAID use each independently impair mucosal defense. Together they act synergistically, raising the risk of ulceration and ulcer bleeding above that of either factor alone.^[1]

• Testing: The H. pylori-related mechanism persists until the organism is eradicated. For this reason, H. pylori testing is recommended for all patients with active or prior peptic ulcer disease.^[7]
• Recurrence: The antral-predominant mechanism (hypergastrinemia followed by acid hypersecretion) explains why eradication is particularly effective at preventing duodenal ulcer recurrence.^[3]
• Silent presentation: NSAID ulcers are frequently painless. Consider NSAID or aspirin use in any patient whose first presentation is a bleeding or perforated ulcer without preceding dyspepsia.^[5]
• Combined risk: Ask about NSAID and aspirin use in H. pylori-positive patients, and test NSAID users for H. pylori, because the two mechanisms commonly coexist and compound each other’s risk.^[1]
• Critical illness: Stress-related mucosal disease is a distinct entity. Consider it in critically ill patients without H. pylori infection or NSAID exposure.

• The clinical contribution of COX-independent injury, such as mitochondrial toxicity and membrane damage, relative to COX-1-mediated prostaglandin depletion is not fully resolved.^[4]
• The mechanisms of ulcers that are both H. pylori-negative and NSAID-negative (“idiopathic” ulcers) are poorly defined, even though their proportion appears to be rising.^[2]
• It is incompletely characterized how strain-level virulence, such as cagA/vacA variation, interacts with host factors to determine gastric versus duodenal phenotype.^[3]

Peptic ulcer disease (PUD) results from an imbalance between mucosal defense and aggressive factors such as gastric acid, pepsin, and exogenous injury.^[1]

The principal causes are:

• Helicobacter pylori infection, about 42% of cases.
• Aspirin or NSAID use, about 36% of cases.
• Idiopathic ulcers, unrelated to either, about 22% of cases.^[2]

H. pylori and NSAIDs independently increase ulcer risk and act synergistically. PUD is rare when neither is present.^[3]

Less common causes include:

• Stress-related mucosal disease in critical illness.^[4]
• Zollinger-Ellison syndrome.
• Malignancy.^[5]
• Rare inflammatory, infectious, and anatomic causes.^[6]

Category	Cause	Contribution / strength of association	Clinical clues
Infectious	Helicobacter pylori	About 42% of PUD.[2] Historically found in 90–95% of duodenal ulcers and 70–90% of gastric ulcers.[7]	More strongly linked to duodenal ulcer. cagA-positive strains carry higher risk.[8]
Drug-induced	NSAIDs, including low-dose aspirin	About 36% of PUD.[2] Independent of, and synergistic with, H. pylori.[3]	Many NSAID ulcers are asymptomatic until bleeding or perforation.[9]
Idiopathic	H. pylori-negative, NSAID-negative ulcer	About 22% of PUD, and rising.[2][10]	Diagnosis of exclusion. High risk of rebleeding and death.[11]
Critical illness	Stress-related mucosal disease	Mucosal lesions are found in 75–100% of ICU patients. Clinically important bleeding occurs in 1–6%.[4]	Mechanical ventilation for more than 48 hours, coagulopathy.
Acid hypersecretory	Zollinger-Ellison syndrome (gastrinoma)	Rare.[5]	Multiple, refractory, or atypically located ulcers.
Malignant	Gastric cancer, gastric lymphoma	Uncommon. Must be excluded.[5]	Refractory or non-healing gastric ulcer.
Other infectious	Cytomegalovirus, herpes simplex virus, Helicobacter heilmannii	Rare.[6]	Viral causes mainly in immunocompromised hosts.
Inflammatory / infiltrative	Crohn’s disease, eosinophilic gastroduodenitis, systemic mastocytosis	Rare.[6]	Systemic or extraintestinal features of the underlying disease.
Iatrogenic / anatomic	Radiation injury, anastomotic (marginal) ulcer, Cameron ulcer	Rare.[6]	Prior radiation or gastric surgery. Cameron ulcer occurs with a large hiatal hernia.

Helicobacter pylori is the most common identifiable cause of PUD.^[2]

Global burden. About 57% (95% CI 44–68%) of PUD worldwide is attributable to H. pylori. This corresponds to about 3.5 million cases that could potentially be prevented by eradication.^[12]

Infection is necessary but not sufficient. An infected person has an estimated 10–20% lifetime risk of PUD, at least 3–4 times higher than an uninfected person.^[8] In a Danish population-based cohort, H. pylori infection was a major independent risk factor for PUD (OR 4.3, 95% CI 2.2–8.3).^[13]

Strain virulence. Infection with cagA-positive strains raises ulcer risk above that of cagA-negative strains. In a nested case-control study, people seropositive for both H. pylori and CagA had odds ratios of:

• 5.8 (95% CI 1.1–30.0) for duodenal ulcer.
• 4.4 (95% CI 1.8–10.5) for gastric ulcer.^[14]

The gastritis pattern determines ulcer location.

• Antral-predominant gastritis suppresses somatostatin and increases gastrin release. This causes acid hypersecretion and predisposes to duodenal ulcer.^[15]
• Corpus-predominant gastritis or pangastritis leads to gastric atrophy and low acid output. It predisposes to gastric ulcer and gastric cancer.^[15]
• In a prospective cohort of 1,526 Japanese patients, gastric cancer developed in patients with gastric ulcer but in none of those with duodenal ulcer.^[16]

NSAIDs, including low-dose aspirin, are an etiologic factor in about 36% of PUD.^[2]

Mechanisms of injury. NSAIDs injure the mucosa in two ways:^[9][17]

• Local (topical) toxicity to the epithelium.
• Systemic inhibition of cyclooxygenase-1, which depletes gastroprotective prostaglandins.

Interaction with H. pylori. A meta-analysis of 16 studies of 1,625 NSAID users found:^[3]

• Uncomplicated PUD was more common in H. pylori-positive than H. pylori-negative users (41.7% vs 25.9%; OR 2.12, 95% CI 1.68–2.67).
• Compared with H. pylori-negative non-users, H. pylori-infected NSAID users had an ulcer OR of 61.1.
• H. pylori infection increased the risk of ulcer bleeding 1.79-fold, and NSAID use increased it 4.85-fold.

Clinical presentation. Most NSAID-induced ulcers are asymptomatic, so the first presentation may be a complication.^[9]

Idiopathic ulcers are H. pylori-negative and NSAID-negative.

Frequency. They account for about 22% of PUD.^[2] Their share has risen as H. pylori prevalence has fallen:

• In Hong Kong, idiopathic ulcers rose from 4.2% to 18.8% of bleeding ulcers between 1997–1998 and 2000.^[10]
• In Asia, the proportion reached 10–30% in studies from the 2000s.^[7]

Distinguishing true from pseudo-idiopathic ulcers. Apparent idiopathic ulcers must be separated from:

• False-negative H. pylori testing. Using two or more diagnostic methods increases sensitivity. Serology is useful in patients taking proton pump inhibitors.^[5]
• Surreptitious NSAID or aspirin use. Platelet cyclooxygenase activity testing can confirm it.^[5]

Proposed mechanisms. The pathogenesis of true idiopathic ulcers is not established.^[7]

Prognosis. H. pylori-negative idiopathic bleeding ulcers carry a high incidence of recurrent bleeding and mortality.^[11]

• Stress-related mucosal disease.^[4]
  • Upper gastrointestinal mucosal lesions are present in 75–100% of ICU patients, but only 1–6% develop clinically important bleeding.
  • Bleeding risk is predicted by mechanical ventilation for more than 48 hours and by coagulopathy.
  • Stress-ulcer bleeding carries an estimated mortality of 40–50%, mostly from the underlying illness.
• Acid hypersecretory states. Zollinger-Ellison syndrome is a rare but important cause of refractory gastroduodenal ulcers.^[5]
• Malignancy. Malignancy is a recognized cause of refractory ulcers. Gastric cancer and gastric lymphoma must be excluded in non-healing gastric ulcers.^[5]
• Rare causes. These include:^[6]
  • Crohn’s disease.
  • Eosinophilic gastroduodenitis.
  • Systemic mastocytosis.
  • Radiation injury.
  • Cytomegalovirus or herpes simplex virus infection.
  • Helicobacter heilmannii colonization.
  • Cameron ulcers with a large hiatal hernia.
  • Anastomotic (marginal) ulcers after gastric resection.

These factors increase ulcer risk but are not sole causes. Details belong in the risk factors microchapter.

• Cigarette smoking
  • Independent risk factor for PUD (OR 3.8, 95% CI 1.7–9.8).^[13]
  • Delays ulcer healing.^[5]
• Psychosocial and environmental factors. Risk is increased by psychological stress, family history of PUD, and adverse childhood circumstances such as crowded living conditions and poor water quality.^[2]
• Disaster-related stress. Evidence comes from the 2011 Great East Japan Earthquake:
  • PUD incidence rose 1.5-fold and hemorrhagic ulcers 2.2-fold.
  • Non-H. pylori, non-NSAID ulcers rose from 13% to 24% of cases.^[18]
  • Living in a refugee shelter independently predicted ulcer bleeding (OR 4.4, 95% CI 2.1–9.6).^[19]

• Establish H. pylori status in every patient with PUD. Take a detailed, repeated NSAID and aspirin history that includes over-the-counter products.^[5][20]
• Do not accept a single negative H. pylori test while the patient is on a PPI. Use two or more methods, or serology.^[5]
• Before labeling an ulcer idiopathic, exclude:^[5][6]
  • False-negative H. pylori testing.
  • Occult NSAID or aspirin use.
  • Malignancy.
  • Zollinger-Ellison syndrome.
• A silent ulcer, especially one presenting with bleeding or perforation, should raise suspicion for NSAID use.^[9]

Peptic ulcer

Peptic ulcer disease must be differentiated from other causes of acute upper gastrointestinal bleeding such as esophageal varices, Mallory-Weiss syndrome, gastrointestinal cancer, arteriovenous malformations, esophagitis, and esophageal ulcer. Peptic ulcer disease must also be differentiated from gastroesophageal reflux disease (GERD,pancreatitis, Zollinger-Ellison Syndrome,cholelithiasis,gastric outlet syndrome,myocardial infaraction ,pleural empyema and appendicitis

Peptic ulcer disease must be differentiated from other diseases that presents with epigastric pain such as gastritis, gastroesophageal reflux disease,acute pancreatitis,prmary biliary cirrhosis,cholelithiasis,gastric outlet syndrome,myocardial infaraction ,pleural empyema,acute appendicitis ^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]}

Classification of pain in the abdomen based on etiology			Disease	Clinical manifestations									Diagnosis		Comments
				Symptoms					Signs
				Fever	Rigors and chills	Abdominal Pain	Jaundice	GI Bleed	Hypo- tension	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging
Abdominal causes	Inflammatory causes	Pancreato-biliary disorders
			Acute pancreatitis	+	−	Epigastric	±	−	±	−	−	N	Increased amylase / lipase	Ultrasound shows evidence of inflammation	Pain radiation to back
			Primary biliary cirrhosis	−	−	RUQ/Epigastric	+	−	−	−	−	N	Increased AMA level, abnormal LFTs
			Cholelithiasis	±	−	RUQ/Epigastric	±	−	−	+	+	N to hyperactive for dislodged stone	Leukocytosis	Ultrasound shows gallstone	Murphy’s sign
		Gastric causes	Peptic ulcer disease	±	−	EpisodicEpigastric	−	Gastric ulcer- melena and hematemesis Duodenal ulcer- melena and hematochezia	+ in perforated	+	+	N	Ascitic fluid LDH > serum LDH Glucose < 50mg/dl Total protein > 1g/dl	Air under diaphragm in upright CXR	Upper GI endoscopy for diagnosis
			Gastritis	±	−	Epigastric		+ in chronic gastritis	−
			Gastroesophageal reflux disease	−	−	Epigastric	−	−	−	−	−
			Gastric outlet obstruction	−	−	Epigastric	−	−	±			Hyperactive
		Intestinal causes	Acute appendicitis	+	+in pyogenic appendicitis	Starts in epigastrium, migrates to RLQ	−	−	+ in perforated appendicitis	+	+	Hypoactive	Leukocytosis	Ultrasound shows evidence of inflammation	Nausea & vomiting, decreased appetite
Extra-abdominal causes	Pulmonary disorders	Pleural empyema		+	±	RUQ/Epigastric	−	−	−	−	−	N
	Cardiovascular disorders	Myocardial Infarction		−	−	Epigastric	−	−	+ in cardiogenic shock	−	−	N
Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM=Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein

Global age-standardized incidence, prevalence, and mortality of peptic ulcer disease (PUD) fell by 40.3%, 41.1%, and 61.5%, respectively, between 1990 and 2021.^[1] Absolute case numbers continued to rise because of population growth and aging.^[2] Men carry a higher burden than women across most age groups.^[1] In the United States, PUD-related mortality fell sharply from 2001 to 2012, plateaued, and then rose from 2018 to 2020.^[3] US racial and ethnic disparities largely track Helicobacter pylori exposure, which is highest in non-Hispanic Black and Hispanic individuals and in immigrants from endemic regions.^[4][5]

• In the United States, the estimated prevalence of PUD is 103 per 100,000 and the annual incidence is 44 per 100,000.^[6] Worldwide incidence and prevalence vary, partly because H. pylori infection rates and NSAID use differ by region.^[6]
• Approximately 5–10% of people develop a peptic ulcer during their lifetime.
• Etiologic distribution of ulcers:^[6]
  • H. pylori infection: ~41.8%
  • Aspirin or NSAID use: ~36.1%
  • Idiopathic: ~22.1%
• Reported complication rates are 19.5–57.0 per 100,000 person-years for bleeding and 3.8–14.0 per 100,000 person-years for perforation.^[7]

Global age-standardized PUD burden, 1990 vs 2021 (GBD 2021)

Measure (per 100,000)	1990	2021	Relative change
Incidence	57.1	34.1	−40.3%
Prevalence	133.0	78.3	−41.1%
Mortality	7.14	2.75	−61.5%

Sources: ^[1][8]

• In the earlier GBD 2019 analysis, global age-standardized prevalence fell from 143.37 per 100,000 in 1990 to 99.40 per 100,000 in 2019.^[2] Over the same period, the absolute number of prevalent cases rose by 25.8% to about 8.09 million.^[2]
• Global age-standardized DALY rates fell by 63.1% between 1990 and 2021.^[1]

• PUD-related hospitalizations in the United States fell by 25.8% between 2005 and 2014 (National Inpatient Sample). The rate of decline slowed after 2008, and in-hospital mortality was 2.4%.^[9]
• PUD causes approximately 10,000 deaths per year in the United States.^[6]
• US age-adjusted mortality rate (AAMR) trends, 1999–2020 (37,471 PUD deaths in total):^[3]
  • 1999–2001: stable (annual percent change [APC] +0.59%)
  • 2001–2012: sharp decline (APC −11.79%)
  • 2012–2018: stable (APC +1.53%)
  • 2018–2020: increase (APC +8.45%)
• US PUD-related mortality is higher in the following groups:^[3]
  • Adults aged ≥85 years (crude mortality rate 7.63 per 100,000)
  • Men (AAMR 0.84 vs 0.71 per 100,000 in women)
  • Rural residents (AAMR 0.86 vs 0.76 per 100,000 in urban residents)
  • Residents of the Western United States (AAMR 0.87 per 100,000, the highest of any region)

• Incidence and prevalence rise with age in both sexes. They peak at ages 55–59 years in men and 65–69 years in women.^[1]
• Mortality peaks later, at ages 70–74 years in men and 75–79 years in women.^[1]

• Men had higher numbers and age-standardized rates of incidence, prevalence, deaths, and DALYs than women across most age groups in 2021.^[1][8]
• The difference has been attributed partly to estrogen’s protective effect on gastric acid secretion and gastrin release. Higher rates of smoking and alcohol use among men also contribute.^[1]

• Global H. pylori prevalence fell from 58.2% (1980–1990) to 43.1% (2011–2020).^[4]
• In North America, H. pylori prevalence is estimated at 30–40%.^[4] Infection is more common in the following groups:^[4]
  • Non-White racial and ethnic groups
  • People living in crowded or poor sanitary conditions
  • Early-generation immigrants from endemic regions
• In the Veterans Health Administration (VHA), overall H. pylori positivity was 25.8%, with marked racial and ethnic disparities that persisted despite declines in every group over time:^[5]

H. pylori positivity by race/ethnicity, US VHA (1999–2018)

Group	All ages	Age <60 years
Non-Hispanic White	20.1%	17.2%
Hispanic	36.7%	34.4%
Non-Hispanic Black	40.2%	40.7%

• Geographic variation is substantial. For example, positivity exceeds 50% among Black veterans in Alabama and Mississippi.^[5]
• In a Houston endoscopy cohort with 51.5% H. pylori prevalence, first-generation immigrant status and Black or Hispanic race/ethnicity were the strongest individual predictors of infection.^[10]
• In asymptomatic adults served by a Houston safety-net health system, overall seroprevalence was 63.9%:^[11]
  • Highest in people born in Central America (75.1%)
  • Higher in Hispanic (65.9%) than non-Hispanic White (45.0%) individuals
  • No difference in risk between second- and third-generation immigrants

• Low and low-middle sociodemographic index (SDI) regions, particularly South Asia and Sub-Saharan Africa, carry the highest prevalence and mortality burden.^[1][2]
• Oceania has been reported to have the highest age-standardized incidence and prevalence.^[1]
• Studies conflict on whether socioeconomic status, household crowding, and psychosocial stress contribute to PUD risk independently of H. pylori and NSAID use.^[12]

The two dominant, largely modifiable risk factors for peptic ulcer disease (PUD) are Helicobacter pylori infection and use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Together they account for roughly 70% to 78% of cases.^[1][2] These two exposures interact synergistically, so combined exposure raises ulcer bleeding risk more than either alone.^[3][4] In NSAID users, the strongest predictor of a future ulcer complication is a prior ulcer complication. Concomitant corticosteroids, anticoagulants, antiplatelet agents, or SSRIs and older age further amplify risk.^[4][2] Additional independent associations include cigarette smoking, alcohol use, male sex, diabetes mellitus, and cardiovascular disease.^[5] The proportion of idiopathic ulcers (negative for both H. pylori and NSAIDs) is rising as H. pylori prevalence declines.^[1][2]

• H. pylori is identified in approximately 42% of patients with PUD.^[1]
• Only about 10% of infected individuals develop an ulcer, compared with about 1% of uninfected individuals. This gap reflects the contribution of bacterial virulence factors, host genetics, and environmental cofactors.^[1]
• Infection is usually acquired in childhood through person-to-person transmission. It is associated with crowded living conditions and poor water quality.^[1]
• Household size is associated with PUD, but the association differs by sex.^[6]
  • In men, risk was higher with larger households.
  • In women, risk was lower in the largest households.
• Global seroprevalence has fallen from approximately 58% (1980–1990) to approximately 43% (2011–2022). United States rates are lower: about 20% by serology and about 9% by endoscopic testing in a large outpatient cohort.^[1]

NSAID-associated ulcer risk is dose- and duration-dependent:^[7]

NSAID and antiplatelet exposure and PUD risk

Exposure	Risk estimate
Single NSAID	OR 1.64 (95% CI 1.43–1.87)[7]
Multiple concurrent NSAIDs	OR 3.82 (95% CI 2.16–6.73)[7]
NSAID use under 3 months	OR 1.07 (95% CI 0.84–1.35)[7]
NSAID use for 3 or more years	OR 2.46 (95% CI 1.92–3.16)[7]
High-dose NSAID (e.g., ibuprofen ≥1200 mg/day, naproxen ≥500 mg/day) vs lower dose	GI complication rate 15% vs 4%[1]
Low-dose aspirin alone	Relative risk of GI bleeding 2–4. Pooled RCT meta-analysis (>57,000 patients): RR 2.07 for significant GI bleeding[3]
Dual antiplatelet therapy (aspirin plus clopidogrel)	OR 2.62 (95% CI 1.12–6.11), independent of aspirin dose or duration[7]

• The interaction is synergistic rather than additive. Ulcer bleeding risk is increased 1.79-fold with H. pylori alone, 4.85-fold with NSAIDs alone, and 6.13-fold with both.^[3][4]
• Among NSAID users, uncomplicated PUD is more common in H. pylori-positive than H. pylori-negative patients (41.7% vs 25.9%; OR 2.12, 95% CI 1.68–2.67).^[1]
• Eradicating H. pylori before starting long-term NSAID therapy lowers subsequent ulcer risk (RR 0.35, 95% CI 0.20–0.61, vs placebo).^[3]
• Eradication alone does not remove risk in patients at high GI risk, such as those with prior ulcer bleeding. These patients need concomitant acid suppression; see primary prevention.^[3][4]

• Prior ulcer complication: this is the single strongest predictor of a future NSAID-related ulcer complication.^[4]
• Age: age over 65–70 years identifies NSAID users who warrant prophylaxis.^[2]
• Prior PUD, whether complicated or uncomplicated.^[2]
• Concomitant drugs: antiplatelet agents, anticoagulants, corticosteroids, and SSRIs.^[2]
• Corticosteroids:
  • Corticosteroids alone are not independently ulcerogenic at doses up to prednisone-equivalent 35 mg/day for 2 months.
  • They substantially increase ulcer bleeding risk when combined with NSAIDs.^[1][4]

A large case-control study (20,622 patients) used multivariable logistic regression to identify the following independent predictors of PUD:^[5]

Independent predictors of PUD (multivariable analysis)

Factor	Adjusted OR	Modifiable
NSAID use	2.58	Yes
H. pylori positivity	2.41	Yes
Age ≥60 years	1.65	No
Corticosteroid co-administration	1.48	Yes
Cigarette smoking	1.45	Yes
Diabetes mellitus	1.42	Partially
Opium use	1.37	Yes
Male sex	1.27	No
Antiplatelet/anticoagulant use	1.25	Partially
Alcohol consumption	1.24	Yes
Cardiovascular disease	1.19	No
Gastroprotective agent use	0.71 (protective)	—

• Lower income and lower educational attainment are associated with PUD.^[6]
• Adverse childhood circumstances, such as crowding and poor water quality, are also associated with PUD.^[1]
• These associations likely act partly through H. pylori acquisition. Behavioral confounders such as smoking and alcohol use also contribute.^[6]

• Psychological and physical stress:
  • Some population studies show an association with PUD, while others show none.
  • The discrepancy likely reflects confounding by smoking, alcohol use, and socioeconomic status.
  • Proposed mechanisms are altered gastroduodenal blood flow and impaired mucosal defense.^[8][6]
• Dyspepsia in NSAID users: it is unsettled whether dyspepsia is an independent risk factor for ulcer development or simply a presenting symptom.^[4]
• Idiopathic ulcers:
  • Ulcers negative for both H. pylori and NSAIDs now represent about 22% of cases.
  • Their underlying risk factors are incompletely defined.^[1][7]

• Rare acid-hypersecretory states should be considered in patients with multiple, refractory, distal duodenal/jejunal, or recurrent ulcers, particularly when H. pylori and NSAID exposure are absent. These states include:
  • Zollinger-Ellison syndrome^[9][10][11]
  • Systemic mastocytosis
  • Retained gastric antrum after Billroth II gastrectomy
  • Chronic hypercalcemia
  • Basophilic/myeloproliferative disorders
• These conditions are causes rather than risk factors. They are covered in the causes microchapter.^[12][13]

• H. pylori infection is far from sufficient for ulcer formation: only about 10% of infected individuals develop PUD.^[1]
• Ask specifically about over-the-counter NSAID and low-dose aspirin use, because patients often do not volunteer it.^[3]
• Do not attribute an ulcer to corticosteroids alone without looking for concomitant NSAID or antiplatelet use.^[1][4]
• Risk rises sharply with NSAID use of 3 years or longer and with combined NSAIDs, anticoagulants, or corticosteroids. Reassess GI risk whenever these agents are added.^[7][4]

There is no role for universal, population-based screening for peptic ulcer disease (PUD), including routine endoscopic screening, in asymptomatic average-risk adults.^[1] Instead, PUD prevention relies on targeted, risk-based testing for Helicobacter pylori (with treatment of all positive results) and on ulcer-risk assessment before starting chronic NSAID or low-dose aspirin therapy.^[2][3] The 2024 American College of Gastroenterology (ACG) guideline and the 2018 Houston Consensus Conference define the populations in whom H. pylori testing is indicated, using non-invasive urea breath testing or stool antigen testing.^[2][4] Population-wide H. pylori screen-and-treat programs are endorsed only in regions with high gastric cancer incidence.^[5]

• Routine screening for PUD (endoscopic or non-invasive) is not recommended in asymptomatic average-risk individuals.^[1]
• H. pylori prevalence in North America is approximately 30–40%, but testing is directed at defined risk groups rather than the general population.^[2]

H. pylori is the dominant modifiable cause of PUD; all patients with a positive test for active infection should be offered treatment.^[2]

Population	Guideline support	Comment
Current or past peptic ulcer disease (without documented eradication)	ACG 2024; Houston 2018	Highest-yield indication; test all patients diagnosed with PUD[2][4]
Uninvestigated dyspepsia in patients not meeting criteria for endoscopy	ACG/CAG 2017; ACG 2024; Houston 2018	Non-invasive test-and-treat preferred over empiric endoscopy in patients <60 years without alarm features[6][2]
Starting or on long-term NSAID or low-dose aspirin therapy	ACG 2024; ACG 2017	H. pylori and NSAIDs act synergistically on ulcer and ulcer-bleeding risk[2][7]
Unexplained iron deficiency anemia; immune thrombocytopenic purpura	ACG 2024	Extra-gastric indications[2]
Gastric MALT lymphoma; gastric premalignant conditions; history of gastric cancer or endoscopic resection of early gastric cancer	ACG 2024; Houston 2018 (MALT lymphoma)	Premalignant/malignant indications[2][4]
Adult household members of a person with a positive non-serologic test	ACG 2024; Houston 2018	Newly endorsed by ACG in 2024[2][4]
Family history of gastric cancer; first-generation immigrants from high-prevalence/high-incidence regions; higher-risk racial or ethnic groups	ACG 2024; Houston 2018	Gastric cancer–prevention indications[2][4]
Family history of PUD	Houston 2018 only	Not adopted by ACG[4]

• Use a test of active infection: urea breath test, stool antigen test, or biopsy-based testing during endoscopy.^[2]
• Hold proton pump inhibitors for 2 weeks before urea breath or stool antigen testing to avoid false-negative results.^[2]
• Serology cannot distinguish active from past infection and has a low positive predictive value in low-prevalence populations; a positive serology should not by itself trigger treatment.^[8][9]
• Confirm eradication at least 4 weeks after completing therapy with a non-serologic test.^[2]

• Patients aged ≥60 years with dyspepsia should undergo endoscopy; patients <60 years should undergo non-invasive H. pylori testing and treatment rather than empiric endoscopy.^[6]
• For patients with dyspepsia and alarm features (vomiting, GI bleeding, unexplained iron deficiency, weight loss) or risk factors for gastric cancer, prompt endoscopy with biopsies — rather than test-and-treat — is recommended.^[2]
• A lower age threshold may be considered in populations at higher gastric cancer risk.^[2]
• The American Society for Gastrointestinal Endoscopy (ASGE) instead recommends initial endoscopy for new-onset dyspepsia at age ≥50 years or with alarm features, and bases test-and-treat versus empiric PPI therapy in younger patients on local H. pylori prevalence (test-and-treat preferred if prevalence >20%) — an age threshold that differs from the ACG 60-year cutoff.^[10][11]

Template:Family tree/summary= Test-and-treat approach to uninvestigated dyspepsia

Uninvestigated dyspepsia

Age ≥60 years, alarm features, or gastric cancer risk factors?

Yes: EGD with biopsies

No: urea breath or stool antigen test

Positive: treat, then confirm eradication ≥4 weeks later

• Before initiating chronic NSAID therapy, assess ulcer risk factors: age >65 years, high-dose NSAID, prior uncomplicated ulcer, and concurrent aspirin, corticosteroids, or anticoagulants; a prior complicated ulcer or more than 2 risk factors confers high risk.^[3]
• H. pylori infection and NSAID use independently and synergistically increase the risk of peptic ulcer and ulcer bleeding.^[7]
• In the HEAT trial (long-term aspirin users ≥60 years with a positive urea breath test), eradication reduced hospitalization or death from peptic ulcer bleeding during the first 2.5 years of follow-up (HR 0.35, 95% CI 0.14–0.89); the benefit was not sustained with longer follow-up.^[12][13]
• Test for H. pylori before long-term NSAID or low-dose aspirin therapy and treat if positive.^[2]
• Selection of gastroprotective strategies is covered in Peptic ulcer disease primary prevention.

• Population screen-and-treat for gastric cancer prevention is recommended in regions with high gastric cancer incidence (e.g., East Asia), ideally in young adults before development of atrophic gastritis and intestinal metaplasia.^[14][5][15]
• The 2025 Taipei Global Consensus II recommends prioritizing H. pylori screening in high-risk populations and supports family-based testing, since transmission occurs primarily within households.^[16] The 2025 AGA Clinical Practice Update recommends opportunistic (not universal) H. pylori screening for US individuals at increased gastric cancer risk, including first-generation immigrants from high-incidence regions, possibly other non-White racial and ethnic groups, those with a first-degree relative with gastric cancer, and those with hereditary gastrointestinal polyposis or cancer syndromes.^[17]
• Population screening is not recommended in low-incidence settings such as the United States; targeted testing of higher-risk groups is preferred.^[2][5]

• The Houston Consensus Conference endorses testing based on family history of PUD, which ACG has not adopted.^[4][2]
• Routine H. pylori testing is not recommended for patients on long-term PPI therapy or with reflux symptoms alone; this Houston Consensus statement was not approved by the external validation group and has not been adopted by the ACG. Testing for reflux symptoms is reasonable only when patients are otherwise at high risk for H. pylori-related disease.^[18]
• In a US validation cohort (n=942), individual risk-factor statements from ACG and the Houston Consensus Conference had generally low predictive performance for H. pylori infection; first-generation immigrant status and Black or Hispanic race/ethnicity performed best, and a combined model performed better than any single factor.^[18]
• The optimal age threshold for test-and-treat versus endoscopy varies across societies (ACG/CAG 60 years; ASGE 50 years) and with regional gastric cancer incidence.^[6][10][2]
• The 2017 ACG/CAG dyspepsia guideline does not recommend endoscopy for alarm features alone in patients <60 years, whereas the 2024 ACG H. pylori guideline recommends endoscopy with biopsies for dyspepsia with alarm features.^[6][2]

Helicobacter pylori infection is a common cause of peptic ulcer disease which is acquired usually during childhood but presents in second to fifth decade of life. Patient presents with episodic epigastric pain, indigestion, bloating,hematemesis and melena. If not treated, patients can develop complications like bleeding, perforation, obstruction or stricture. Chronic infection of helicobacter pylori leads to gastric cancer, MALT lymphoma, iron deficiency anemia, Idiopathic thrombocytopenic purpura. Peptic ulcers tend to recur if left untreated. Prognosis is good if the eradication therapy of Helicobacter pylori is taken.The recurrence rate of patients with peptic ulcer disease is less than 20%.

• The infection of Helicobacter pylori , common cause of peptic ulcer disease is acquired usually during the childhood, mainly in those who have low socioeconomic status, increased number of siblings and similar infection in the mother.^[1][2][3]
• The duodenal ulcer occurs in second to fifth decade of life. where as gastric ulcer occurs in the 4th decade of life.
• Peptic ulcer disease starts with symptoms such as episodic epigastric pain, indigestion, bloating.
• Without treatment, the patient will develop symptoms of perforation like severe abdominal pain. Chronic infection leads to gastric atrophy, gastric metaplasia and ultimately leads to gastric cancer and MALT lymphoma.^[4]

• Bleeding is the commonest complication.
  • Sudden large bleeding can be life threatening.
  • Bleeding occurs when the ulcer erodes one of the blood vessels around the stomach.^[5][6]
• Perforation
  • Perforation is most common occur at the duodenal bulb (62%), followed by the pyloric region (20%), and the gastric body (18%).
  • Erosion of the gastro-intestinal wall by the ulcer leads to spillage of stomach or intestinal content into abdominal cavity leading to fatal consequences.
  • Perforation at the anterior surface of stomach leads to acute peritonitis, initially chemical and later bacterial peritonitis.
  • Often, the first symptom is a sudden intense abdominal pain.
  • Posterior wall perforation leads to pancreatitis, pain in this situation often radiates to back.
  • Penetration is also a form of perforation, when the ulcer continues into adjacent organs such as liver and pancreas.^[7][8]
• Obstruction
  • Occurs as a result of stricture and scarring narrowing in the duodenum leading to gastric outlet obstruction.

Chronic Helicobacter pylori infection leads to:

• Gastric cancer
• MALT lymphoma
• Iron deficiency anemia
• Idiopathic thrombocytopenic purpura

• Prognosis is good if the eradication therapy of Helicobacter pylori is taken.
• The recurrence rate of patients with peptic ulcer disease is less than 20%.

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