Peptic Ulcer

Peptic ulcer (PU) refers to inflammatory defects in the gastric or duodenal mucosa, associated with the digestive action of gastric acid and pepsin. The lesions penetrate the muscularis mucosae and may extend to deeper layers. Peptic ulcers can also occur at esophagogastric or gastrojejunal anastomoses, or in other locations such as Meckel's diverticulum containing gastric mucosa.

Epidemiology

PU is a common global condition, with a higher prevalence in males than females, and it can occur at any age. The prevalence varies across different age groups, with approximately 10% of individuals experiencing PU at some point in their lifetime. Duodenal ulcers (DU) are more common than gastric ulcers (GU). DU is more frequently observed in young and middle-aged adults, while GU is more common in older individuals. Over the past 30 years, the use of acid-suppressive drugs such as H₂ receptor antagonists (H₂RAs) and proton pump inhibitors (PPIs) has significantly reduced the incidence of PU and its complications. However, in recent years, the increased use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has led to a rise in the incidence of PU among the elderly.

Etiology and Pathogenesis

The etiology and pathogenesis of PU are multifactorial, involving an imbalance between mucosal injury and defense/repair mechanisms.

Gastric Acid and Pepsin

Pepsin plays a key role in the development of PU, with its activity dependent on the pH of gastric fluid. Pepsinogen is easily activated at a pH of 2–3, while pepsin becomes inactive at a pH above 4. Therefore, reducing gastric acid also decreases pepsin activity. The development of PU involves an imbalance between the aggressive effects of gastric acid and pepsin on the mucosa and the protective capacity of the mucosal barrier. Increased aggression or reduced defense can lead to PU formation. Both GU and DU are classified as types of PU.

Helicobacter pylori (Hp)

Hp infection is another major causative factor for PU. The infection rate of Hp in DU patients exceeds 90%, while it ranges from 60% to 90% in GU patients. Populations with a high prevalence of Hp infection also exhibit a higher prevalence of PU. Eradication of Hp promotes ulcer healing and significantly reduces recurrence.

Medications

Long-term use of aspirin, ibuprofen, indomethacin, and other NSAIDs increases the risk of PU. Other drugs, such as glucocorticoids, clopidogrel, bisphosphonates, and sirolimus, are also associated with PU development.

Mucosal Defense and Repair Abnormalities

The integrity of gastric mucosal defense and repair mechanisms is critical for maintaining mucosal health and promoting ulcer healing. Gastric mucosal biopsy, a common clinical procedure, often causes focal iatrogenic ulcers that heal rapidly without medication, demonstrating the strong self-defense and repair capacity of the gastric mucosa. Impaired defense or diminished repair ability can influence both the development and resolution of ulcers.

Genetic Susceptibility

A subset of PU patients has a significant family history, indicating genetic susceptibility.

Other Factors

Excessive alcohol consumption, chronic smoking, and stress are common triggers for PU. Gastric ulcers may also develop in patients with gastric bezoars due to prolonged mechanical irritation. Radiation therapy can cause gastric or duodenal ulcers. PU may co-occur with other diseases, such as gastrinoma, Crohn's disease, liver cirrhosis, chronic obstructive pulmonary disease (COPD), shock, severe systemic infections, acute myocardial infarction, and stroke. Rare infectious diseases, such as herpes simplex virus, tuberculosis, and cytomegalovirus infections, can also involve the stomach or duodenum, leading to ulcer formation.

Pathology

The preferred sites of PU differ depending on the underlying cause. Typical GU is often found near the gastric angle or on the lesser curvature of the antrum. GU caused by NSAIDs is commonly located on the greater curvature or in the antrum. Active PU lesions are usually solitary but can also be multiple, with a round or oval shape. Most active ulcers are less than 10 mm in diameter, with well-defined edges. The surrounding mucosa often shows congestion and edema, while the surface of the ulcer is covered with exudative white or yellow plaques. The ulcer base consists of granulation tissue. Deeper ulcers may penetrate the muscular or serosal layers of the gastric or duodenal wall. Involvement of blood vessels can lead to massive hemorrhage, while penetration of the serosa increases the risk of perforation. Healed ulcers leave behind scar tissue.

DU has a similar morphology to GU and is most commonly found in the duodenal bulb, particularly on the anterior or posterior wall near the pylorus. Recurrent DU may cause deformation of the duodenal bulb, with scar contraction leading to strictures or pseudodiverticula.

Clinical Manifestations

Symptoms

The typical symptom of peptic ulcer is epigastric pain, which may present as dull, vague, burning, distending, severe pain, or a hunger-like discomfort. The location, nature, and severity of the pain are influenced by the site, size, and number of ulcers. The characteristics of the pain include:

A chronic course, lasting for over 10 years or longer.

Recurrent or periodic episodes, with flare-ups lasting weeks to months and showing seasonal patterns, typically occurring during seasonal transitions, such as autumn to winter or winter to spring.

Some patients experience rhythmic epigastric pain related to meals. Postprandial pain is more common in gastric ulcers (GU), while hunger pain, nocturnal pain, or pain relieved by eating is more typical of duodenal ulcers (DU).

Acid-suppressive or antacid medications can alleviate the pain.

Some patients present with dyspeptic symptoms, such as epigastric bloating, discomfort, loss of appetite, belching, and acid regurgitation, rather than typical pain. A small proportion of patients with asymptomatic ulcers exhibit no abdominal pain or dyspeptic symptoms, and their initial presentation may involve complications such as gastrointestinal bleeding or perforation. This is more common in patients of all ages who take NSAIDs long-term, particularly the elderly.

Physical Signs

During flare-ups, localized tenderness may be present in the epigastrium, subxiphoid, or right upper abdominal regions. Between episodes, physical signs may be absent.

Special Types of Ulcers

Compound Ulcers

These refer to active ulcers in both the stomach and duodenum. They are more common in males and are associated with a higher incidence of pyloric deformation, stenosis, and obstruction.

Pyloric Channel Ulcers

These ulcers cause pain shortly after meals and are prone to complications such as pyloric obstruction, bleeding, and perforation.

Postbulbar Ulcers

These ulcers occur in the descending or horizontal segments of the duodenum, most commonly in the initial part of the descending segment near the papilla, typically on the posterior or posteromedial wall. Pain may radiate to the right upper abdomen or the back.

Giant Ulcers

Ulcers with a diameter greater than 2 cm are classified as giant ulcers. They are commonly observed in elderly patients or those with a history of NSAID use. Giant duodenal bulb ulcers are often located on the posterior wall and are prone to becoming penetrating ulcers, with surrounding inflammatory masses. Pain is often severe, persistent, and radiates to the back, though asymptomatic cases may also occur in elderly individuals. Giant gastric ulcers are not necessarily malignant.

Ulcers in the Elderly and Childhood Ulcers

Ulcers in the elderly often have atypical clinical manifestations, with symptoms that are mild or absent. Pain may lack a regular pattern and may present as weight loss or anemia. Due to the widespread use of NSAIDs in this population, the incidence of ulcers in elderly individuals is increasing.

Childhood ulcers are more common in school-aged children. Pain may be peri-umbilical and accompanied by nausea or vomiting, potentially due to pyloric or duodenal edema and spasm.

Refractory Ulcers

These ulcers fail to heal despite standard anti-ulcer therapy. Possible contributing factors include:

• Persistent etiologies, such as ongoing Helicobacter pylori (Hp) infection or continued use of ulcerogenic medications like NSAIDs.
• Penetrating ulcers.
• Underlying conditions, such as Crohn's disease, gastrinoma, or post-radiation therapy.
• Diseases or medications that impair the absorption or efficacy of anti-ulcer drugs.
• Misdiagnosis, such as malignancies of the stomach or duodenum.
• Adverse factors, including smoking, alcohol abuse, and psychological stress.

Complications

Hemorrhage

Peptic ulcer is the most common cause of upper gastrointestinal hemorrhage, accounting for 50%–70% of non-variceal hemorrhage cases, with DU being more common than GU. Hemorrhage occurs when ulcers erode surrounding or deeper blood vessels, leading to varying degrees of hemorrhage. Mild cases may present with positive fecal occult blood tests or melena, while severe cases may result in massive hemorrhage, manifesting as hematemesis or dark red stools.

Perforation

Perforation occurs when an ulcer penetrates the gastric or duodenal wall. Currently, one-third to one-half of perforations are associated with NSAID use, particularly in elderly patients. Perforation may occur without prior symptoms. The clinical consequences of perforation include:

Diffuse Peritonitis Due to Free Perforation into the Abdominal Cavity

This presents as sudden, severe abdominal pain that is persistent and progressively worsens. The pain initially occurs in the upper abdomen and then spreads throughout the abdomen. Physical signs include board-like abdominal rigidity, tenderness, rebound tenderness, and absence of liver dullness. Some patients may develop shock.

Penetration into Adjacent Solid Organs

This occurs when ulcers penetrate into surrounding organs such as the liver, pancreas, or spleen. Chronic symptoms may include a change in pain patterns, with pain becoming persistent or refractory. Pancreatic involvement may cause back pain and elevated serum amylase levels.

Fistula Formation into Hollow Organs

DU may penetrate the common bile duct, resulting in biliary fistulas, while GU may penetrate into the duodenum or transverse colon, forming intestinal fistulas.

Pyloric Obstruction

Pyloric obstruction can be partial or complete, depending on the severity. Clinical manifestations include epigastric distension and pain, worsening after meals, and relief after vomiting. Vomitus may contain undigested food. Severe vomiting can lead to dehydration, hypochloremic hypokalemic alkalosis, weight loss, and malnutrition. Physical examination may reveal visible gastric peristalsis or succussion splash. Pyloric obstruction is often caused by recurrent DU or pyloric channel ulcers, with temporary obstruction resulting from inflammatory edema and smooth muscle spasm resolving after ulcer healing or medical treatment. Persistent or progressive obstruction may result from severe scarring, adhesions to surrounding tissues, or malignancy, leading to gastric outlet stenosis or deformation.

Malignant Transformation

Recurrent and long-standing GU carries a higher risk of malignant transformation, while DU rarely undergoes malignant changes. Gastroscopy with biopsy aids in distinguishing between benign and malignant ulcers.

Auxiliary Examinations

Upper Gastrointestinal Endoscopy and Biopsy

Upper gastrointestinal (GI) endoscopy is the preferred diagnostic method and the "gold standard" for peptic ulcer (PU) diagnosis. It provides the following information:

• Confirmation of the presence, location, and staging of the lesion.
• Differentiation between benign and malignant ulcers.
• Evaluation of treatment effectiveness.
• Hemostatic treatment for patients with concurrent bleeding.
• Dilation or stent placement for patients with associated stenosis or obstruction.
• Assessment of the gastric or duodenal wall, ulcer depth, relationships with surrounding organs, and the number and size of lymph nodes using endoscopic ultrasound.

Routine biopsies should be taken from the edges of gastric ulcers (GU). While there is no consensus on the number of biopsy specimens required, biopsies from four different areas around the ulcer are generally sufficient for diagnosis. Some GUs are difficult to distinguish as benign or malignant under endoscopy, necessitating multiple biopsies, pathological examinations, or even further evaluation with endoscopic ultrasound or fine-needle aspiration. For non-healing GUs where malignancy cannot be excluded, multiple-site biopsies are recommended. Follow-up endoscopy after 8 weeks of standard treatment is advised, with additional biopsies and pathological examinations if necessary, until complete ulcer healing is confirmed.

X-ray Barium Contrast Imaging

The use of upper GI barium contrast imaging has declined with the widespread adoption of endoscopy, but it retains specific diagnostic value in certain cases:

• Assessment of gastric motility.
• For patients with contraindications to endoscopy.
• For those unwilling to undergo endoscopy or in settings where endoscopy is unavailable.

Double-contrast barium imaging can effectively display the morphology of the gastrointestinal mucosa. The direct signs of ulcers on barium imaging include niches and converging mucosal folds, while indirect signs include spasmodic notches on the gastric greater curvature, stenosis, duodenal bulb irritability, and deformities of the bulb. However, barium imaging is less effective than endoscopy and does not allow for pathological diagnosis through biopsy.

CT Scan

CT imaging is valuable for diagnosing penetrating ulcers or perforations. It can reveal inflammatory changes, masses, or fluid collections around the perforation and is more sensitive than upright chest X-rays in detecting free air. CT also aids in the differential diagnosis of pyloric obstruction. After oral contrast administration, CT may show gastric wall discontinuity, exudation around the perforation, or wall thickening.

Laboratory Tests

Helicobacter pylori (Hp) Testing

Hp testing is recommended for all patients with a history of PU, regardless of whether the ulcer is active or in the scarring phase.

Other Tests

Complete blood count and fecal occult blood tests can help identify active bleeding associated with the ulcer.

Diagnosis

A chronic course, periodic episodes, rhythmic epigastric pain, and a history of NSAID use are key historical features suggestive of PU. Upper GI endoscopy confirms the diagnosis. For patients unable to undergo endoscopy, upper GI barium contrast imaging can be used for diagnosis. The presence of a niche on imaging supports the diagnosis of an ulcer, although it is challenging to distinguish between benign and malignant ulcers using this method.

Differential Diagnosis

Other Diseases Causing Chronic Epigastric Pain

While a diagnosis of PU may be established, some patients continue to experience symptoms even after ulcer healing. In such cases, it is necessary to evaluate whether predisposing factors have been addressed and to consider the possibility of coexisting conditions, such as chronic liver, biliary, or pancreatic diseases, functional dyspepsia, or other abdominal disorders.

Gastric Cancer

Gastric ulcers identified on upper GI endoscopy should be carefully distinguished from malignant ulcers. Typical malignant ulcers often have irregular shapes, are larger than 2 cm, and feature irregular edges, uneven bases, and necrotic debris.

Gastrinoma (Zollinger-Ellison Syndrome)

Gastrinoma is a neuroendocrine tumor of the stomach, intestines, or pancreas. Gastrin, secreted by G cells in the gastric and proximal small intestinal mucosa, promotes gastric acid secretion, cell proliferation, and gastrointestinal motility. Gastrinoma is characterized by multiple ulcers, atypical locations, frequent ulcer complications, poor response to standard anti-ulcer therapy, diarrhea, hypersecretion of gastric acid, and elevated serum gastrin levels.

Gastrinomas are typically small, with approximately 80% located within the "gastrinoma triangle," which is defined by the confluence of the cystic and common bile ducts, the junction of the second and third parts of the duodenum, and the junction of the neck and body of the pancreas. Less common locations include the stomach, liver, bones, heart, ovaries, and lymph nodes. Over 50% of gastrinomas are malignant, and metastases may be present at diagnosis.

When gastrinoma is suspected, serum gastrin levels should be measured. Enhanced CT, MRI, or PET-CT imaging can help identify the tumor. Proton pump inhibitors (PPIs) can reduce gastric acid secretion and control symptoms. Surgical resection of the tumor is recommended whenever possible.

Treatment

The goals of peptic ulcer (PU) treatment include eliminating the underlying causes, controlling symptoms, promoting ulcer healing, preventing recurrence, and avoiding complications.

Pharmacological Treatment

Since the 1970s, pharmacological treatment of PU has undergone three major milestones: the introduction of H₂-receptor antagonists (H₂RAs), proton pump inhibitors (PPIs), and Helicobacter pylori (Hp) eradication therapy. These advances have significantly improved ulcer healing rates, reduced the incidence of complications, and minimized the need for surgical intervention.

Inhibition of Gastric Acid Secretion

H₂-Receptor Antagonists (H₂RAs)

H₂RAs remain one of the mainstays of PU treatment. They are effective, convenient to use, moderately priced, and have minimal adverse effects with long-term use. Commonly used H₂RAs include famotidine, nizatidine, and ranitidine. The 6-week healing rates for gastric ulcers (GU) and duodenal ulcers (DU) with H₂RAs are reported to be 80%–95% and 90%–95%, respectively.

Table 1 Common H₂RAs

Proton Pump Inhibitors (PPIs)

PPIs are the first-line drugs for treating PU. After absorption into the bloodstream, PPIs reach the gastric parietal cells and accumulate in the acidic environment of the acid-secreting canaliculi. There, they are converted into active forms that bind to and inhibit the proton pump (H⁺-K⁺-ATPase), thereby suppressing gastric acid secretion. PPIs can control ulcer symptoms within 2–3 days and are more effective than H2RAs for refractory ulcers. The 4-week healing rates for typical gastric and duodenal ulcers are 80%–96% and 90%–100%, respectively.

Table 2 Common PPIs

It is important to rule out gastric cancer when treating GU with PPIs, as these drugs can alleviate symptoms of malignant ulcers and mask the disease. PPIs are acid-dependent and unstable in acidic gastric juices; therefore, the protective enteric coating of oral formulations should remain intact. The enteric coating dissolves in the small intestine (pH ≥ 6), allowing the drug to be absorbed into the bloodstream.

Potassium-Competitive Acid Blockers (P-CABs)

P-CABs inhibit acid secretion by competitively binding to the H⁺-K⁺-ATPase enzyme at the parietal cell membrane. Unlike PPIs, P-CABs are stable in acidic environments, do not require acid activation, act more rapidly, exhibit minimal inter-individual variability, and have fewer adverse effects. Their efficacy in healing GU and DU, as well as in preventing ulcers induced by long-term NSAID or low-dose aspirin use, is comparable to that of PPIs.

Eradication of H. pylori

Hp eradication is recommended for all Hp-positive PU patients, regardless of whether the ulcer is active or in remission. Eradication of Hp significantly reduces ulcer recurrence rates.

Gastric Mucosal Protection

Bismuth Compounds

Bismuth compounds form colloidal suspensions in acidic solutions and combine with proteins at the ulcer base to create a protective barrier against gastric acid and pepsin. Although PPIs are more cost-effective and widely used, bismuth compounds remain an integral part of quadruple therapy for Hp eradication. Common side effects include blackened tongue and stools. Since the kidneys are the primary route of bismuth excretion, these drugs are contraindicated in patients with renal dysfunction.

Weakly Alkaline Antacids

Common options include magnesium aluminum carbonate, aluminum phosphate, sucralfate, and aluminum hydroxide gel. These agents neutralize gastric acid and provide rapid, temporary pain relief but are insufficient for ulcer healing. They are no longer considered primary or standalone treatments for PU.

Treatment Regimens and Duration

To achieve ulcer healing, acid-suppressive therapy is typically administered for 4–6 weeks. The recommended treatment duration for DU with PPIs is 4 weeks, while GU requires 6–8 weeks. The duration of P-CAB therapy requires further evidence but can be referenced against PPI regimens. Hp eradication therapy, which lasts 1–2 weeks, may overlap with the 4–8 weeks of acid-suppressive therapy or follow its completion.

Maintenance Therapy

Most patients can discontinue treatment after GU healing. However, in cases of recurrent ulcers, further evaluation for underlying causes is necessary, in addition to maintenance therapy. Maintenance therapy involves long-term administration of low doses of H2RAs or PPIs. The duration varies by individual, ranging from 3–6 months to 1–2 years or longer, depending on the clinical condition.

Patient Education

Patients are encouraged to ensure adequate rest and reduce mental stress. Improvements in dietary habits, smoking cessation, and avoidance of alcohol, strong tea, and coffee are advised. Unnecessary NSAID use and other gastric irritants should be discontinued. If NSAIDs or other medications must be taken, they should be consumed with food or after meals, and gastroprotective agents may be recommended under medical guidance.

Endoscopic and Surgical Treatment

Endoscopic Treatment

Endoscopic interventions for PU bleeding include spraying fibrin glue on the ulcer surface, injecting 1:10,000 adrenaline at the bleeding site, clipping the bleeding point, and thermal coagulation. In some cases, a combination of these methods is employed. When combined with continuous intravenous PPI infusion, the success rate for controlling active PU bleeding exceeds 95%. Endoscopic features and treatment strategies for ulcer bleeding are outlined in relevant guidelines.

Table 3 Endoscopic features and treatment strategies for PU bleeding

For PU-associated pyloric deformities or stenosis causing obstruction, endoscopic balloon dilation is the first-line treatment. Multiple dilation sessions may be required to relieve the obstruction.

Surgical Treatment

Advances in PPI use and endoscopic techniques have significantly reduced the need for surgical intervention in PU and its complications. However, surgery is considered in the following situations:

• Massive gastrointestinal hemorrhage that fails to respond to pharmacological, endoscopic, or vascular interventional treatments.
• Acute perforation or chronic penetrating ulcers.
• Scar-induced pyloric obstruction unresponsive to endoscopic treatment.
• Suspected malignant transformation of GU.

Surgical intervention aims not only to remove the ulcer lesion but also to permanently reduce gastric acid and pepsin secretion. Postoperative complications may include gastric bleeding, duodenal stump rupture, anastomotic leakage or fistula formation, postoperative obstruction, dumping syndrome, bile reflux gastritis, anastomotic ulceration, and iron deficiency anemia.

Prognosis

Effective pharmacological treatment can achieve ulcer healing rates exceeding 95%. The mortality rate of PU among young and middle-aged patients is nearly zero. In elderly patients, deaths are primarily due to severe complications, particularly massive hemorrhage or acute perforation, with an overall mortality rate of less than 1%.