Gastric Ulcer

Etiology

Helicobacter pylori infection and NSAID-induced impairment of gastric mucosal defenses represent the most common etiologies of gastric ulcers.[7][3] Additionally, less frequent causes include hypergastrinemia associated with Zollinger–Ellison syndrome, viral infections (like cytomegalovirus), chemotherapy/immunotherapy, radiation exposure, malignancy, cigarette smoking, physiologic stress, burns, cocaine use, and Crohn’s disease.[8][3][9][10][11]

Concurrent use of glucocorticoids with NSAIDs increases ulcer risk.[3] Additional factors that heighten the likelihood of NSAID-associated peptic ulcer disease include advanced age, simultaneous anticoagulant therapy, and coexisting H pylori infection.[11] Despite varied etiologies, gastric ulcer formation shares a common pathogenic pathway characterized by disruption of the gastric mucosal barrier, which increases epithelial vulnerability to acid-mediated injury and promotes ulcer development.[12]

Epidemiology

Gastric ulcers occur less frequently than duodenal ulcers yet remain a major contributor to global morbidity and mortality. Incidence and prevalence vary according to age, sex, and geographic region. Gastric ulcers fall under the broader category of peptic ulcer disease. The lifetime prevalence of peptic ulcer disease (PUD) in the general population is approximately 10%, with an annual incidence of 0.1% to 0.2%. A Global Burden of Disease study demonstrated higher incidence, prevalence, morbidity, and mortality from peptic ulcer disease in countries with lower socio-demographic index scores. 

Countries with higher socio-demographic index scores show increasing incidence and prevalence of peptic ulcer disease, partly related to greater use of bariatric surgery for obesity management.[5] Gastric ulcer prevalence increases with advancing age, with individuals aged 70 to 74 years experiencing a disproportionate disease burden.[13] Smoking increases gastric ulcer risk, which persists despite abstinence for 4 years, compared with never-smokers.[3] Lifetime gastric ulcer risk rises 2.9-fold in patients infected with cagA-positive Helicobacter pylori strains.[14] A study by W. Hao et al reported higher incidence, prevalence, morbidity, and mortality rates in males than in females.[5]

The prevalence decreased from approximately 50% to 43% between 2014 and 2020.[14] Incolution occurs at an early age, especially in developing countries with lower socioeconomic status and crowded households.[14] 

Pathophysiology

A gastric ulcer develops due to an imbalance between injurious luminal factors and the mucosal protective mechanisms.[3]

The gastric mucosa has several defense mechanisms, including: 

• Tight junctions between gastric epithelial cells prevent the diffusion of gastric acid or pepsin to the mucosa. 
• The mucous layer, adherent to the mucosa, protects it from proteolysis by providing a physical barrier. 
• Prostaglandin-mediated blood flow, mucin production, and cellular proliferation hasten healing.[3]

Etiology-Specific Pathophysiology

The pathophysiologic mechanisms can vary depending on the underlying etiology. 

Helicobacter pylori

Helicobacter pylori is a gram-negative, S-shaped, microaerophilic, motile bacterium with a unipolar sheathed flagellum. One characteristic of this bacterium is extensive genetic variation within the same host, leading to high rates of mutation and recombination. This genomic variation is enabled by the absence of classical DNA mismatch repair pathways and by the promutagenic properties of the DNA polymerase enzyme.[14] 

Key virulence factors contributing to pathogenicity include: 

• Flagella-mediated motility: Enables penetration of the gastric mucus layer, persistence, and evasion of innate immune responses. 
• Urease: Generates ammonia to buffer gastric acid, supporting survival in a low pH environment and providing a nitrogen source.
• Adhesins: Facilitate persistent colonization despite mucosal turnover and gastric clearance.
• Nickel acquisition system: Regulates urease activity while preventing nickel toxicity. 
• CagA protein: Disrupts epithelial integrity, promotes inflammation (via IL-1 release), and is associated with carcinogenesis; neutrophilic infiltration is characteristic of chronic active gastritis.
• Vacuolating cytotoxin (VacA): Induces apoptosis, necrosis, and autophagy while suppressing adaptive immune responses.
• Modified lipopolysaccharide and flagellin: Evades innate immune recognition via altered lipopolysaccharide and flagellin compared with other gram-negative bacteria. Key virulence factors contributing to pathogenicity include:

These bacteria induce chronic active gastritis through epithelial injury; symptoms vary based on host factors and bacterial virulence, with cagPAI-positive strains causing more severe inflammation.[14] Patients may progress from chronic active gastritis to atrophic gastritis, intestinal metaplasia, dysplasia, and adenocarcinoma (Correa cascade), influenced by host, environmental, and microbiome factors.[14] Gastric ulcers often occur early in gastritis, though malignancy can present similarly; PUD risk rises markedly with H pylori infection, especially with concurrent NSAID use.[14]

Nonsteroidal anti-inflammatory drugs

Among NSAID users, gastric ulcer prevalence ranges from 10% to 30%. Annual incidence of peptic ulcer disease per 100,000 approaches a 4-fold increase in patients receiving NSAIDs compared with nonusers.[11] NSAID-associated ulceration develops through multiple pathogenic mechanisms.

The primary mechanism is reduced prostaglandin synthesis. NSAIDs inhibit cyclooxygenase-1, decreasing prostaglandin production and leading to reduced bicarbonate secretion, impaired mucus barrier, diminished mucosal blood flow, and decreased epithelial regeneration—key factors in maintaining mucosal integrity. Direct mucosal injury also contributes. NSAIDs increase epithelial susceptibility to acid and pepsin by disrupting mucus phospholipids, damaging cell membranes, and uncoupling mitochondrial oxidative phosphorylation, promoting ulceration.[11]

NSAIDs can be classified according to gastrointestinal risk as follows: 

• Low risk: Ibuprofen, aceclofenac, celecoxib 
• Intermediate risk: Rofecoxib, sulindac, diclofenac, meloxicam, nimesulide, ketoprofen, naproxen
• High risk: Indomethacin, tenoxicam, piroxicam, ketorolac, azapropazone [11]

The less common mechanisms include increased gastric acid secretion in Zollinger-Ellison syndrome, impaired mucosal repair and integrity due to radiation, chemotherapy, and infiltrative disease.[8] Regardless of the etiology, the final pathway is the breakdown of protective mucosal barriers and injury to the epithelial layer, resulting in ulceration and further complications. 

Histopathology

Histopathologic examination typically reveals an ulcer base with clear, sharply demarcated margins that extend through the muscularis mucosa, reflecting full-thickness loss of gastric mucosa with penetration into the submucosa. Inflammatory debris commonly overlies the epithelial surface. Acute ulcers differ from chronic ulcers by the absence of granulation tissue at the ulcer base, while chronic lesions may demonstrate fibrosis that occasionally extends into the muscularis propria. In contrast, gastric erosions involve partial loss of the gastric mucosa while preserving the muscularis mucosa.[Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. Gastritis and Gastric Ulcer. June 21, 2022]

History and Physical

Patients with gastric ulcers can have a broad range of symptoms, which can range from mild abdominal discomfort to severe pain. The most common complaint is dyspepsia (chronic or recurrent pain or discomfort centered in the upper abdomen).[3] Other common symptoms include nausea, vomiting, bloating, early satiety, heartburn, or acid regurgitation.[15][16]

The typical presentation of a patient with gastric ulcers is epigastric pain that is worse with eating (typically within 30 minutes after a meal) and often correlates with mild nausea and early satiety. Patients frequently describe this pain as sharp or burning and typically nonradiating. The pain differs from that of a duodenal ulcer, which is relieved by food and recurs 2 to 4 hours after a meal.[Yamada's Textbook of Gastroenterology. Peptic Ulcer Diseases. 27 November 2015]

Patients may also present with complications of gastric ulcers, such as upper gastrointestinal bleeding (UGIB). Gastric ulcers are the most common cause of UGIB. Additional complications can include gastric perforation or gastric outlet obstruction. Patients with gastric perforation usually present with abdominal pain and signs of peritonitis.[3] Patients with Zollinger-Ellison syndrome may present with symptoms of a gastric ulcer along with weight loss or diarrhea.[3]

In addition to the clinical history, the following key historical elements should be assessed in patients with suspected gastric ulcers.

• Prior history of PUD
• Medication history- use of NSAIDs, aspirin, steroids, proton pump inhibitors (PPI) or potassium-competitive acid blockers (PCAB), antiplatelets, anticoagulants, and any vasoconstricting medications
• Prior surgical or endoscopic history, particularly prior bariatric surgery
• Any signs of overt gastrointestinal bleeding, including melena, hematemesis, coffee-ground emesis, hematochezia, or hematochezia. (Clinicians should remember that up to 15% of patients who present with hematochezia along with hemodynamic instability have a brisk upper gastrointestinal bleed.) [15]
• Diarrhea (keeping Zollinger-Ellison syndrome as a differential diagnosis) 
• Syncope or loss of consciousness (as it could indicate the beginning of shock or concurrent anemia)
• Exertional fatigue or shortness of breath, which could indicate anemia due to bleeding from an ulcer or iron deficiency anemia associated with H pylori
• Prior cardiac disease history, as specific cardiological pathologies may mimic a gastric ulcer

Vital signs should be assessed in all patients with suspected gastric ulcers. The most common physical examination finding is epigastric tenderness. Some patients may demonstrate the “pointing sign,” indicating the epigastric region as the focal area of pain. Symptoms often persist for weeks to months before patients seek medical attention.[Yamada's Textbook of Gastroenterology. Peptic Ulcer Diseases. 27 November 2015][17]

Evaluation

For patients presenting with upper abdominal pain/dyspepsia, the following blood laboratory tests are recommended:

• Complete metabolic profile
• Complete blood count
• Troponins
• Type and screen
• Coagulation profile
• Lipase
• Serum or urine pregnancy test in premenopausal women
• Serum lactate (in specific scenarios where shock or mesenteric ischemia is suspected) [17]

Additionally, the following are the imaging studies that are beneficial to exclude other differential diagnoses and complications of gastric ulcers:

• Chest x-ray to rule out pneumonia or pleural effusions, which could mimic upper abdominal pain. 
• An abdominal computerized tomography (CT) scan with intravenous contrast to rule out pancreatitis or gastric perforation. Older patients (65 years or older) occasionally lack signs of peritonitis. Hence, clinicians should have a low threshold for considering cross-sectional imaging, eg, a CT scan.[17]
• Electrocardiogram to rule out myocardial infarction. 

These tests help exclude other differential diagnoses, but do not confirm a gastric ulcer. The most accurate test for diagnosing a gastric ulcer remains an esophagogastroduodenoscopy (EGD).[16][3]

For patients with gastric ulcers presenting with UGIB, hemodynamic evaluation is critical. The Glasgow Blatchford score may be used in the emergency department to triage patients for hospital admission (Glasgow Blatchford score >1) or discharge with outpatient follow-up (Glasgow Blatchford score 0 to 1, very low risk category).[18]

Treatment / Management

Patients with suspected gastric ulcers without alarm features or overt UGIB

Management of gastric ulcers initially focuses on increasing gastric pH to promote mucosal healing, most effectively achieved with proton pump inhibitors (PPIs). Suppression of gastric acid supports restoration of epithelial integrity and reduces ongoing injury. Subsequent management aims to eliminate factors that damage the gastric mucosa. Appropriate therapy includes eradication of Helicobacter pylori when identified, smoking cessation, substitution of nonulcerogenic alternatives for NSAIDs, avoidance of concurrent NSAID use with glucocorticoids or anticoagulants, and treatment of underlying conditions, eg, CMV infection or Crohn’s disease.[3] Evaluation then turns to the need for esophagogastroduodenoscopy, which remains the most accurate diagnostic modality for gastric ulcers and allows acquisition of gastric biopsies to assess for H pylori infection, gastritis, and gastric malignancy.

Patients with suspected gastric ulcers and alarm features

Recognition of alarm symptoms necessitates expedited endoscopic evaluation. Alarm features include unintentional weight loss, gastrointestinal bleeding, age over 60 years, persistent vomiting, and symptoms refractory to H pylori testing and treatment.[3] When endoscopy confirms a gastric ulcer, biopsy of the surrounding mucosa becomes essential to exclude gastritis, H pylori infection, and malignancy.

Treatment duration depends on ulcer characteristics. Proton pump inhibitor therapy twice daily for 8 weeks is indicated for ulcers larger than 2 cm or those requiring endoscopic hemostasis, while twice-daily therapy for 4 weeks suffices for smaller, uncomplicated lesions.[3] Clinical studies demonstrate superior healing rates with proton pump inhibitors compared with H2 receptor antagonists or sucralfate.[3] 

Patients presenting with overt UGIB

Initial management of patients with overt upper GI bleeding depends on the patient's hemodynamic stability and should focus on resuscitation. Intravenous crystalloids can be used for patients with suspected hemorrhagic shock. Blood transfusion is recommended for patients with a hemoglobin level <7g/dl (or 8g/dl in patients with cardiac disease). ACG guidelines do not make a recommendation for or against pre-endoscopic antisecretory therapy with PPI in patients presenting with upper GI bleeding. It is recommended that patients undergo an endoscopic evaluation within 24 hours of presentation. 

During endoscopy, gastric ulcers are graded using the Forrest classification; this provides an estimate of the risk of ulcer bleeding and helps guide management. Several endoscopic therapies are available for hemostasis, including epinephrine injection, monopolar/bipolar cautery, argon plasma coagulation, through-the-scope (TTS) or over-the-scope (OTS) clip placement. When epinephrine is used for hemostasis, it should be combined with another hemostatic intervention.[18]

The following criteria are used in the Forrest classification:

• Ia: jet arterial bleeding, 90% rebleeding risk
• Ib: oozing, 50% rebleeding risk
• IIa: visible vessel, 25% to 30% rebleeding risk
• IIb: adherent clot, 10% to 20% rebleeding risk
• IIc: black spot in the ulcer, 7 to 10% rebleeding risk
• III: clean based, 3% to 5% rebleeding risk [19]

High-dose PPI therapy is recommended for 3 days following successful hemostatic therapy of a bleeding ulcer. High-risk patients with UGIB due to ulcers who received endoscopic hemostatic therapy followed by short-term high-dose PPI therapy in the hospital should continue on twice-daily PPI therapy until 2 weeks after the index endoscopy. 

In case of gastric ulcer bleeding refractory to endoscopic therapy, a consultation request to the interventional radiology for transcatheter arterial embolization is reasonable [20]. Surgical management may be needed when endoscopic therapy is inadequate or not indicated. Indications for surgical intervention include perforation, uncontrolled bleeding, severe gastric outlet obstruction, and ulcers not healed with medical therapy. (A1)

Treatment of patients with h.pylori infection

For confirmed H pylori infection (urea breath test, fecal antigen test, or endoscopic biopsy), current American College of Gastroenterology (ACG) guidelines recommend optimized bismuth quadruple therapy.

Optimized bismuth quadruple therapy includes: 

• Proton pump inhibitor (standard dose) twice daily
• Bismuth subcitrate (120-300 mg) or subsalicylate (300 mg) 4 times daily
• Tetracycline (500 mg) 4 times daily
• Metronidazole (500 mg) 3 to 4 times daily [21]

The optimized quadruple bismuth therapy may be used in both treatment-naive patients and as a salvage therapy. Another benefit of this therapy is that it can be used in patients with penicillin allergy.[21] Physicians or other healthcare prescribers should always refer to local antibacterial resistance patterns and protocols when treating bacterial infections, eg, H pylori. Confirmation of cure (urea breath test, fecal antigen test, or endoscopic biopsy) is an essential step in the treatment of H pylori. Confirmation of cure should be performed 4 weeks after completion of H pylori therapy.[21] 

Differential Diagnosis

Differential diagnoses that should be considered when evaluating clinical features of a gastric ulcer include: 

• Cardiovascular disease, eg, angina, myocardial infarction, pericarditis
• Upper gastrointestinal pathology, eg, functional dyspepsia, esophagitis, gastritis, gastric cancer [3] 
• Biliary disease, eg, symptomatic cholelithiasis, choledocholithiasis, or cholangitis
• Pancreatitis (acute or chronic) 
• Small bowel pathology, eg, obstruction, internal hernia, intussupection
• Vascular etiologies, eg, acute mesenteric ischemia, aortic dissection [17]

Prognosis

Most patients with gastric ulcers experience a favorable prognosis. Uncomplicated gastric ulcers typically heal within 8 weeks when patients adhere to acid-suppressive therapy, receive appropriate treatment for Helicobacter pylori infection when present, and avoid agents that provoke mucosal injury.[3]

Complications

Complications associated with gastric ulcers include: 

• Gastrointestinal bleeding
• Gastric perforation
• Gastric outlet obstruction
• Gastric malignancy [22]