Definition

A peptic ulcer is a discontinuity in the entire thickness of the gastric or duodenal mucosa that extends into the muscularis mucosa or deeper. Erosions, in contrast, are more superficial lesions that do not penetrate the muscularis mucosa. PUD encompasses both gastric ulcers (occurring in the stomach) and duodenal ulcers (occurring in the duodenum).

Etiology and Risk Factors

While gastric acid and pepsin are necessary for ulcer formation, they are usually not sufficient on their own. PUD typically arises from an imbalance between aggressive factors (acid, pepsin, H. pylori, NSAIDs) and defensive factors (mucus, bicarbonate, mucosal blood flow, prostaglandins, epithelial regeneration). The primary causes are:

1. Helicobacter pylori Infection:

   • This spiral-shaped bacterium is the most common cause of PUD globally, particularly duodenal ulcers (about 90% of cases) and a significant proportion of gastric ulcers (about 70% of cases).

   • H. pylori colonizes the gastric antrum, causing chronic inflammation (Type B gastritis).

   • Mechanisms by which H. pylori contributes to ulcer formation include:

     • Production of urease, which creates a protective alkaline environment around the bacteria.

     • Production of cytotoxins (e.g., VacA, CagA) that damage epithelial cells.

     • Induction of inflammation, leading to increased gastrin release and subsequent increased acid secretion (especially in duodenal ulcer disease).

     • Weakening of the mucosal barrier.

2. Nonsteroidal Anti-inflammatory Drugs (NSAIDs):

   • NSAIDs are the second most common cause of PUD, responsible for a significant number of gastric ulcers and a smaller proportion of duodenal ulcers.

   • NSAIDs damage the gastric and duodenal mucosa through two main mechanisms:

     • Topical Irritation: Direct damage to the epithelial cells.

     • Systemic Inhibition of Prostaglandin Synthesis: NSAIDs inhibit cyclooxygenase (COX) enzymes (COX-1 and COX-2). COX-1 is constitutively expressed in the gastric mucosa and produces prostaglandins that are crucial for maintaining mucosal integrity (promoting mucus and bicarbonate secretion, maintaining blood flow, inhibiting acid). Inhibition of COX-1 reduces these protective factors. While COX-2 is primarily involved in inflammation, some COX-2 selective inhibitors can still impair mucosal healing or have systemic effects that impact the mucosa.

   • Risk factors for NSAID-induced PUD include advanced age, history of PUD, concomitant use of corticosteroids, anticoagulants, or SSRIs, high dose or prolonged use of NSAIDs, and certain comorbidities.

3. Other Less Common Causes:

   • Zollinger-Ellison Syndrome (ZES): A rare condition caused by a gastrin-producing tumor (gastrinoma), usually in the duodenum or pancreas. Excessive gastrin leads to massive acid hypersecretion, resulting in multiple, often refractory, peptic ulcers in unusual locations (e.g., post-bulbar duodenum, jejunum).

   • Stress Ulcers: Acute, superficial erosions or ulcers that can develop rapidly in the stomach or duodenum in critically ill patients with severe physiological stress (e.g., sepsis, burns, trauma, head injury, mechanical ventilation). Pathogenesis involves reduced mucosal blood flow (ischemia) and impaired mucosal defense.

   • Other Infections: While rare, other infections like Cytomegalovirus (CMV) or Herpes Simplex Virus (HSV) can cause ulcers, particularly in immunocompromised individuals.

   • Crohn’s Disease: Can affect any part of the GI tract, including the stomach and duodenum, causing ulcers.

   • Radiation Therapy: Radiation to the upper abdomen can cause ulcers.

   • Chemotherapy: Certain chemotherapeutic agents can induce mucosal injury and ulceration.

   • Vascular Insufficiency: Reduced blood flow to the gastric or duodenal mucosa can contribute to ulcer formation.

   • Cocaine Use: Associated with acute gastric and duodenal ulcers due to vasoconstriction and ischemia.

Risk Factors that Exacerbate or Contribute:

• Smoking: Impairs mucosal healing, increases acid secretion, and reduces bicarbonate production.

• Alcohol: Can irritate the gastric mucosa and may increase the risk, especially in combination with H. pylori or NSAIDs.

• Dietary Factors: While spicy foods, coffee, and acidic foods can exacerbate symptoms, they are not proven causes of PUD.

• Genetic Predisposition: A family history of PUD may increase risk.

Pathophysiology

PUD arises from a breakdown in the balance between aggressive and defensive factors in the gastroduodenal mucosa.

• Aggressive Factors:

  • Acid and Pepsin: Hydrochloric acid denatures proteins and activates pepsin, a proteolytic enzyme. In the presence of a compromised mucosal barrier, acid and pepsin can digest the underlying tissue.

  • H. pylori: As discussed above, H. pylori directly damages the mucosa and triggers inflammation, altering the local environment to favor ulcer formation.

  • NSAIDs: Reduce the production of protective prostaglandins.

• Defensive Factors:

  • Mucus-Bicarbonate Barrier: A gel-like mucus layer traps bicarbonate ions, creating a pH gradient that protects the epithelial cells from luminal acid.

  • Epithelial Cells: Rapid turnover and migration of epithelial cells allow for quick repair of superficial damage. Tight junctions between cells prevent acid penetration.

  • Mucosal Blood Flow: Provides oxygen and nutrients, removes acid and toxins, and delivers bicarbonate.

  • Prostaglandins: Crucial for maintaining mucosal defense mechanisms.

In PUD, the aggressive factors overcome the defensive mechanisms, leading to mucosal injury and ulceration. Duodenal ulcers are often associated with increased acid secretion and impaired duodenal bicarbonate secretion, while gastric ulcers may be more related to impaired mucosal defense, even with normal or reduced acid secretion.

Clinical Manifestations

The hallmark symptom of PUD is epigastric pain, often described as burning, gnawing, or aching. However, the presentation can vary:

• Epigastric Pain:

  • Typically located in the upper abdomen, just below the breastbone.

  • Often described as a burning, gnawing, or hunger-like sensation.

  • Characteristically relieved by food or antacids in duodenal ulcers, but may be worsened by food in gastric ulcers.

  • May awaken the patient at night (especially duodenal ulcers).

  • Can be intermittent, occurring in episodes lasting days or weeks, followed by pain-free periods.

• Other Symptoms:

  • Nausea

  • Vomiting (may relieve pain)

  • Bloating or fullness

  • Early satiety (feeling full after eating little)

  • Loss of appetite

  • Weight loss (less common, may suggest complication or malignancy)

• Asymptomatic PUD: A significant proportion of patients, particularly those taking NSAIDs, may have ulcers without experiencing typical symptoms. These ulcers may only be discovered when complications occur.

Physical examination is often unremarkable, although there may be localized tenderness in the epigastrium.

Diagnosis

Diagnosing PUD involves a combination of clinical evaluation and diagnostic tests:

1. Medical History and Physical Examination: Essential for identifying symptoms, risk factors (e.g., NSAID use, H. pylori exposure), and potential complications.

2. Upper Endoscopy (Esophagogastroduodenoscopy – EGD):

   • The gold standard for diagnosing PUD.

   • Allows direct visualization of the esophageal, gastric, and duodenal mucosa.

   • Enables identification of ulcers, determination of their size, location, and appearance, and assessment for signs of bleeding.

   • Permits biopsies to be taken from the ulcer base and margins (especially for gastric ulcers to rule out malignancy) and to test for H. pylori.

3. Helicobacter pylori Testing:

   • Recommended for all patients with PUD unless the cause is clearly related to NSAID use or other factors.

   • Methods include:

     • Invasive (Endoscopy-based): Rapid urease test, histology, culture.

     • Non-invasive: Urea breath test, stool antigen test. Blood antibody tests are not recommended for initial diagnosis or confirming eradication.

4. Barium Swallow (Upper GI Series):

   • Less commonly used for primary diagnosis of PUD since the advent of endoscopy.

   • Involves swallowing barium contrast, which coats the lining of the upper GI tract, allowing ulcers to be visualized on X-rays.

   • Less sensitive than endoscopy and does not allow for biopsy or H. pylori testing. May be useful in specific situations or when endoscopy is not available or contraindicated.

5. Blood Tests: May be performed to check for anemia (due to chronic bleeding) or to screen for H. pylori antibodies (less preferred). Serum gastrin levels may be measured if Zollinger-Ellison Syndrome is suspected.

Management

Management of PUD focuses on healing the ulcer, eradicating H. pylori if present, discontinuing or modifying NSAID use, reducing gastric acid secretion, and preventing complications.

1. Eradication of Helicobacter pylori:

   • Recommended for all patients with H. pylori-associated PUD.

   • Typically involves a combination of a proton pump inhibitor (PPI) and two or three antibiotics for 7-14 days. Various regimens exist (e.g., standard triple therapy, bismuth quadruple therapy), and the choice depends on local antibiotic resistance patterns and patient factors.

   • Confirmation of eradication after treatment (using urea breath test or stool antigen test) is important, especially for complicated ulcers or persistent symptoms.

2. Management of NSAID-Induced PUD:

   • Discontinue the NSAID if possible. Ulcers often heal with acid suppression alone after stopping the NSAID.

   • If NSAID use is necessary (e.g., for chronic pain or inflammation), strategies to reduce risk include:

     • Using the lowest effective dose of the NSAID.

     • Considering a COX-2 selective NSAID (lower GI risk but potential cardiovascular risk).

     • Co-prescribing a PPI or misoprostol for gastric mucosal protection.

   • Treat with acid-suppressing medication (usually a PPI) for an appropriate duration to ensure healing.

3. Acid Suppression:

   • Proton Pump Inhibitors (PPIs) are the most effective medications for reducing gastric acid secretion and promoting ulcer healing. They are the mainstay of treatment for both H. pylori-associated (as part of eradication therapy) and NSAID-induced PUD.

   • H2-Receptor Blockers (H2RAs) are less potent than PPIs but can also be used to reduce acid secretion and promote healing, particularly for duodenal ulcers.

   • Antacids provide rapid, temporary symptom relief but do not promote ulcer healing.

4. Lifestyle Modifications:

   • Smoking cessation is strongly recommended, as smoking impairs ulcer healing and increases the risk of recurrence and complications.

   • Moderate alcohol consumption may be acceptable, but excessive intake should be avoided.

   • While not primary causes, avoiding foods that consistently trigger symptoms may be helpful for individual patients.

5. Management of Complications: Requires specific interventions (see below).

6. Follow-up:

   • Repeat endoscopy is usually recommended for gastric ulcers after a period of treatment to confirm healing and ensure that the lesion was not malignant.

   • Repeat endoscopy is generally not necessary for uncomplicated duodenal ulcers if H. pylori has been eradicated and symptoms resolve.

Complications

PUD can lead to serious, potentially life-threatening complications:

1. Bleeding:

   • The most common complication.

   • Can manifest as hematemesis (vomiting blood), melena (black, tarry stools), or hematochezia (bright red blood in stool, less common, usually indicates rapid transit).

   • Can lead to anemia (chronic slow bleeding) or hypovolemic shock (acute severe bleeding).

   • Requires urgent endoscopic intervention (e.g., injection therapy, thermal coagulation, clipping) to achieve hemostasis, often followed by high-dose IV PPIs.

2. Perforation:

   • Occurs when the ulcer erodes through the entire wall of the stomach or duodenum, leading to leakage of gastric or duodenal contents into the peritoneal cavity.

   • Causes sudden onset of severe, generalized abdominal pain, rigidity (board-like abdomen), and signs of peritonitis.

   • A surgical emergency requiring immediate intervention to close the perforation.

3. Penetration:

   • Occurs when the ulcer erodes into an adjacent organ (e.g., pancreas, liver, biliary tract).

   • Causes severe, constant pain that is not relieved by food or antacids and may radiate to the back.

   • Diagnosis may require imaging (CT scan). Management depends on the site of penetration and may involve medical therapy or surgery.

4. Gastric Outlet Obstruction:

   • Occurs when an ulcer in the pyloric channel or duodenum causes inflammation, edema, scarring, or stricture, blocking the passage of food from the stomach into the duodenum.

   • Symptoms include nausea, vomiting (often large volumes of undigested food), early satiety, bloating, and weight loss.

   • Management may involve nasogastric tube decompression, IV fluids, PPIs, and sometimes endoscopic balloon dilation or surgery.

5. Malignancy:

   • Gastric ulcers, particularly those that are large or located in certain areas, can be malignant. Biopsies are essential to rule out cancer.

   • Duodenal ulcers are rarely malignant.

   • Chronic H. pylori infection is a significant risk factor for gastric adenocarcinoma and MALT lymphoma.