Peptic Ulcer Disease and H. pylori Infection

Peptic Ulcer Disease and Helicobacter Pylori Infection

• Peptic Ulcer Disease (PUD) is a break or defect in the gastric or small intestinal mucosa that penetrates the muscularis mucosae.
• Ulcer size ranges from 5 mm to several cm.
• Erosions are smaller, more superficial mucosal lesions compared to ulcers.

Epidemiology

• Uncomplicated PUD incidence: 1 case/1000 persons; Complicated PUD incidence: 0.7 cases/1000 persons.
• PUD results in 15,000 deaths/year.
• PUD impact on health costs: $10 billion/year (US).
• Duodenal ulcers predominate between 20-50 years old.
• Gastric ulcers predominate in patients older than 40 years.
• 2/3 of ulcer patients are male.
• Ulcer incidence increases with age.
• PUD rates have been falling over the past several decades.

Etiology

• Most common causes of peptic ulcers: Helicobacter pylori infection and NSAIDs and aspirin use.
• Other causes: medications (anticoagulants, potassium chloride, bisphosphonates, fluorouracil, concomitant use of steroids and NSAIDs), neoplasia, acid hypersecretory disorders
• Additional causes are hyperparathyroidism, Crohn's disease, tuberculosis, sarcoidosis, systemic mastocytosis, rare infections (CMV, herpes simplex 1, EBV in immunosuppressed patients) and vasculitis.
• Further causes: Ischemia, critically ill patients with head injury/severe burns/physical trauma/multiple organ failure, chronic pulmonary disease, cystic fibrosis, cirrhosis and renal failure.

Lifestyle Risk Factors

• Cigarette smoking promotes development of ulcers, impairs ulcer healing and increases recurrence.
• Genetic factors are important in predisposing to Hp infection or PUD without Hp infection.
• Polymorphism of C P450 may delay the metabolism of several NSAIDs.
• Emotional stress might predispose some individuals to ulcer.
• Age is a risk factor due to increased occurrence and complications with age.
• Alcohol is a risk factor, alcohol at high concentrations damages the gastric mucosal barrier (moderate consumption has been linked with improved healing).
• Diet is not the mainstay of treatment (not evidence-based).
• Caffeine is not a risk factor (no evidence).

Pathophysiology

• Imbalance of protective and aggressive factors impairs GI mucosal defense mechanisms in the presence of gastric acid and pepsin.
• The stomach produces acid and pepsin, which are potentially injurious agents that initiate digestion.
• Protective mucosal defense includes gastric mucus and bicarbonate produced by epithelial cells.
• Epithelial cells mechanism - by producing factors to maintain the barrier and allow restitution.
• Local blood flow – eliminates back diffusion of acid and supports healing.
• These mechanisms are mediated through prostaglandins and nitric oxide.

Helicobacter pylori

• The most common chronic bacterial infection in humans
• Spiral gram-negative urease-producing bacteria
• Infection affects 4.4 billion people worldwide.
• Transmission occurs via fecal-oral/oral-oral routes.
• Found in the mucus coating the gastric mucosa or between the mucus layer and the gastric epithelium.
• Urease produced by Hp helps alkalinize the surrounding pH.
• Most commonly acquired in childhood, resulting in chronic active gastritis.
• Risk factors include socioeconomic status and country of origin; prevalence is higher in developing countries compared to industrialized countries and household crowding.
• Highest H.pylori prevalence – Africa, South America, and Western Asia and lowest prevalence - Oceania, Western Europe and Northern America.
• Majority of infected persons are asymptomatic with 10-15% developing peptic ulcer disease; incidence of PUD is 1%/year in infected individuals which is 6-10 fold higher than in uninfected individuals.
• Hp infection is associated with gastritis, PUD, gastric ADK, MALT lymphoma and classified as a group 1 carcinogen in humans.
• 70-90% of patients with duodenal ulcer and 30-60% of patients with gastric ulcer have Hp infection.
• Hp eradication reduces ulcer recurrence compared with acid suppression alone, and causes mucosal injury and ulcer through inflammation and cytokines.
• Antibody production does not lead to eradication.
• Outcomes of Hp infection is based on combination of microbial (virulence) and host factors (genetic factors) and environmental factors.

NSAIDs and Aspirin

• 15-30% of patients taking NSAIDs develop gastric/duodenal ulcers.
• NSAIDs complications results in 20,000 deaths/year
• Inhibit COX-1 and COX-2, decreasing prostaglandin (PG) synthesis.
• COX-1 is the rate-limiting enzyme for PG.
• PG maintains mucosal blood flow and increases secretion of mucus and bicarbonate.
• Inhibition of COX-1 by NSAIDs impairs mucosal protection and leads to ulcers.
• PUD and GI bleeding risk is based on dose, duration and type of NSAIDS.
• Risk is higher in patients older than 60 years, history of PUD, taking CS/anticoagulants, with important comorbid diseases.
• H.pylori infection is a synergistic risk factor for PUD.
• COX-2 inhibitors reduce GI complications but are associated with coronary side effects.
• Other GI complications: dyspepsia, ulcerations and strictures of the small intestine, acute colitis, exacerbations of IBD, ulcers, strictures or perforation of the colon.

Zollinger-Ellison Syndrome

• Gastrinoma = neuroendocrine tumor that secretes gastrin in excess.
• Leads to severe peptic ulcer disease, abdominal pain, and diarrhea.
• Usually located in the pancreas or proximal small bowel.
• Diagnosis requires High fasting serum gastrin > 1000 pg/mL and stomach pH < 2.0.
• Gastrin can be increased in atrophic gastritis/patients on PPI.
• Secretin test can be used for diagnosis.
• 20-25% of patients have MEN 1 syndrome.

Specific Ulcer Types

• Cameron ulcer – found in patients with large hiatal hernias and gastric ulcers; usually asymptomatic, may cause occult/overt bleeding.
• Anastomotic ulcer – occurs in patients with partial gastrectomy; ischemia and chronic inflammation from biliary reflux may be the cause.
• Dieulafoy ulcer – characterized by a singular bleeding focus with minimal mucosal disruption.

Clinical Findings: Symptoms and Signs

• Epigastric pain is the classic symptom described as "dull," "empty," or "hunger-like."
• Nausea and vomiting are nonspecific.
• Associated symptoms: bloating, early satiety, abdominal fullness.
• Duodenal ulcer pain is sometimes relieved by food ingestion and may awaken patients at night.
• Gastric ulcer pain is exacerbated by eating and might be accompanied by nausea, anorexia, and weight loss.
• 70% of ulcer patients report no or few symptoms, and 30% of patients with an ulcer seen on endoscopy describe no abdominal pain ("silent ulcer").
• Additional manifestations: melena, hematemesis, anemia, hematochezia, orthostatic hypotension (ulcer bleeding), persistent vomiting (obstruction).
• Other symptoms are acute worsening or generalized pain (ulcer penetration/perforation), early satiety/anorexia/unexplained weight loss (possible cancer) and upper abdominal pain with penetration to the back (penetration).
• Physical exam is unreliable and often normal.
• Tenderness on deep palpation.
• Tachycardia and orthostatis can be seen in patients with significant bleeding; pallor; and inquire about stool characteristics.
• Rigid abdomen with diffuse rebound tenderness suggests ulcer perforation with peritonitis.
• Large amounts of intra-abdominal air leads to hypertympany over the liver.

Laboratory Findings

• Uncomplicated ulcer presents with normal complete blood count.
• Iron deficiency anemia may be present.
• Acute perforation may lead to leukocytosis.

Endoscopy

• Gold-standard for diagnosing peptic ulcers through direct visualization.
• Biopsy specimens can be obtained during endoscopy.
• 5% of gastric ulcers are malignant, so every gastric ulcer should be biopsied.
• Hemostasis therapy can be applied to active bleeding ulcers.

Barium Studies

• Safer and cheaper than endoscopy, but have limited accuracy.
• Do not permit biopsy and have no therapeutic options.

Diagnostic Tests for Helicobacter pylori

• Noninvasive tests are serologic testing, urea breath test, stool antigen test.
• Invasive tests (endoscopy with biopsy) are rapid urease test, histologic study, culture.

Noninvasive Tests

• Serologic tests (serum immunoassays for IgG antibodies to Hp) are inexpensive, low sensitivity/specificity, should not be used to confirm successful cure after treatment; results can be positive in patients with active or prior infection.
• Urea breath and stool antigen tests can be used for screening and confirming cure; both have high sensitivity and specificity.
• Recent use of PPIs, bismuth, or antibiotics can increase false-negative results during testing.

Invasive Tests

• Rapid urease test: a biopsy is taken from the antrum of the stomach; high sensitivity and specificity.
• Histology: has high sensitivity and specificity.
• Culture: not routinely performed and expensive.

Indications for Helicobacter pylori Testing

• Established indications: Gastric marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), active peptic ulcer disease or past history if cure of H. pylori has not been documented, early gastric cancer.

Differential Diagnosis

• GERD, Functional dyspepsia, Neoplasia (anorexia, significant weight loss, upper endoscopy with biopsy) and Biliary tract disease (abdominal ultrasound)
• Other potential diagnoses are Hepatitis, Pancreatitis, Appendicitis, Mesenteric ischemia, Myocardial ischemic pain, Pneumonia.

Treatment

• All ulcer patients should be tested and treated for Hp.
• NSAIDs should be discontinued.
• Patients with upper GI bleeding suspected of having an ulcer should be started on IV PPI.

Proton Pump Inhibitors (PPIs)

• PPIs block acid secretion by irreversibly binding and inhibiting the hydrogen-potassium ATPase on the luminal surface of the parietal cell.
• PPIs include: omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole.
• PPI 40 mg twice daily for 8 weeks heals 85% of NSAIDs induced gastric ulcer and 90% of duodenal ulcer.
• Administer 30 minutes before a meal.
• Rare side effects include Clostridium difficile infection, pneumonia, and bone fracture.

Histamine2 Receptor Antagonists and Cytoprotective Agents

• Histamine 2 (H2)-receptor antagonists: Cimetidine, Ranitidine, Famotidine, Nizatidine
• H2-receptor antagonists are inferior compared to PPI, but are superior compared to placebo; useful in patients who cannot tolerate PPI
• Ranitidine 300 mg twice daily for 8 weeks - heals 70% of ulcers
• Sucralfate which is a sucrose salt that binds to tissue proteins and form a protective barrier that decreases exposure of epithelium to acid, bile salts and pepsin. A side effect is constipation.
• Misoprostol –a prostaglandin E1 analog – inhibits gastric acid secretion, stimulates bicarbonate and mucus secretion, enhances mucosal blood flow; 200 mg twice daily has a similar effect to H2-rec blockers (side effect includes diarrhea); contraindicated in pregnant women.

Eradication Therapy for Hp

• I. Triple Therapy (often used as first-line therapy).
  • PPI standard dose (Lansoprazole 30 mg, Omeprazole 20 mg, Pantoprazole 40 mg, Rabeprazole 20 mg, Esomeprazole 20 mg) or double the standard dose - administered twice daily.
  • Clarithromycin 500 mg, twice daily.
  • Amoxicillin 1 g twice daily for 14 days.
  • Use Metronidazole 500 mg three times daily for penicillin-allergic patients.
• II. Clarithromycin Sequential Therapy
  • PPI standard dose + Amoxicillin 1 g - twice daily for 5 days, followed by PPI standard dose + Clarithromycin 500 mg + Tinidazole/Metronidazole 500 mg twice daily for the next 5 days.
• III. Quadruple Bismuth Therapy (usually the second-line therapy)
  • PPI standard dose – twice daily.
  • Bismuth subsalicylate 300 mg or bismuth subcitrate 120 mg - four times daily.
  • Metronidazole 500 mg three times daily.
  • Tetracycline 500 mg, four times daily for 10-14 days.
• IV. Levofloxacin – Based Triple Therapy (salvage therapy).
  • PPI high dose - twice daily.
  • Levofloxacin 500 mg once daily.
  • Amoxicillin 750 g three times daily for 14 days.
• Eradication Confirmation: Tests must be done1 month after treatment.

Complications

• GI bleeding is present in 15% of peptic ulcers: hematemesis, melena, or hematochezia.
• Perforation occurs in 7% of ulcers causing severe abdominal pain and a rigid abdomen from peritonitis.
• Penetration can cause pancreatitis/hepatitis.
• Obstruction occurs in 2% -- inflammation and edema in the prepyloric area.

Upper Gastrointestinal Bleeding (UGB)

• Source: proximal to the ligament of Treitz.
• Peptic ulcer is the most common cause of nonvariceal UGB (40 - 60% of cases).
• Rebleeding increases mortality rate 10-fold.
• 1 out of 6 patients with an ulcer will bleed.
• Mortality rate is 14%.
• Risk factors: use of low-dose aspirin, antiplatelet agents, NSAIDs, and corticotherapy.
• Hematemesis: vomiting of fresh blood or clots.
• Melena: dark black stools with a distinctive smell.
• Hematochezia is fresh blood or clots per rectum.
• Patients with bleeding ulcers usually do not have pain.
• Other symptoms are dizziness or syncope (hemodynamic instability).
• Evaluate vital signs, presence/absence of shock, and hypovolemia.
• Look for tachycardia (HR > 100/min), postural hypotension (10% blood volume loss) and shock (20% blood volume loss causes poor outcome).
• Inquire about medical comorbidities and medication: anticoagulants, antiplatelet agents, aspirin, NOAC, NSAIDs.
• Hb, hematocrit levels may be low.
• Check for high blood urea nitrogen compared to creatinine and sodium/potassium levels.
• Consider electrocardiogram.
• Common sources include: peptic ulcer disease (50%), duodenal/gastric ulcers, esophagogastric varices, Mallory Weiss tear, esophagitis and erosive duodenitis.
• Treatment: Two peripheral intravenous access catheters and Crystalloid fluids (normal saline/lactate Ringer) to maintain normal blood pressure and Oxygen therapy.
• Perform elective endotracheal intubation with ongoing severe hematemesis, and consider blood transfusions with a Hb target = 7 - 9 g/dL (RESTRICTIVE TRANSFUSION).
• With coagulopathy, focus on INR < 2.5 via transfusion of fresh frozen plasma/vitamin K.
• When low platelet count (<50,000), consider platelet transfusion.
• PPIs used to maintain a gastric pH > 6 (prevents fibrinolysis of an ulcer clot).
• Initiate iv PPI in patients with UGI bleeds before endoscopy.
• 80 mg bolus followed by 8 mg/h infusion for 72 h
• For diagnosis, prognosis and therapy perform an endoscopy.
• Early upper GI endoscopy recommended within 24 hours of presentation after hemodynamic resuscitation or very early upper Gl endoscopy (< 12 h) is used in patients with hemodynamic instability despite ongoing attempts of volume resuscitation.
• Methods for treatment during endoscopy include:
  • Injection therapies – usually uses epinephrine to reduce blood flow.
  • Contact thermal therapies (bipolar cautery).
  • Mechanical treatments (hemoclips).
  • Hemostatic nanopowder (procoagulant).
• Forrest Classification is a classification system used to describe peptic ulcers, helps to prognosticate and risk stratify patients based on stigmata of recent hemorrhage and decide on discharge versus close inpatient monitoring.
• Endoscopic hemostasis (high risk for persistent bleeding or rebleeding) is used for IA, I B and IIA and endoscopic clot removal to remove underlying active bleeding.
• IIC and III do not require endoscopic treatment as they carry a low risk for rebleeding.
• Epinephrine injection is not recommended as monotherapy and should be used with other endoscopic hemostasis modalities.
• For active bleeding not controlled by standard endoscopic hemostasis therapies, the use of a topical hemostatic spray is recommended.
• 70-80% of rebleeds occur within the first 3 days, thus: repeat endoscopy and if endoscopy fails to stop the bleeding – surgery and interventional radiology are equivalent options.
• Perforation symptoms consist of severe abdominal pain, rigidity of the abdomen, peritoneal irritation, hemodynamic shock and a chest radiograph that shows free air under the diaphragm in order to prepare for emergency surgery.
• Stenosis is a rare complication where an ulcer in the duodenal bulb/pyloric channel has important edema and inflammation.
• Stenosis symptoms include nausea, vomiting, and gastric stasis.
• Management includes: nasogastric tube aspiration, administration of iv PPI (80 mg bolus, and then 8mg/h in continuous infusion); eradication of Hp or withdrawal of NSAIDs

Functional Dyspepsia

• 20% of the population reports symptoms.
• Does not affect survival, substantial health care costs, and affects quality of life.
• Majority of patients have functional dyspepsia (idiopathic or non-ulcer).
• Symptoms include postprandial fullness, early satiety, bloating, and/or epigastric pain.
• The diagnosis is based on symptoms & + evaluation to exclude other organic causes.
• Rome IV criteria for functional dyspepsia: one or more postprandial fullness, early satiety, epigastric pain or burning.
• Rule out structural disease (including upper endoscopy).
• DD: GERD, gastroparesis, IBS, etc.
• Pathophysiology (not well understood): motility disorder, visceral hypersensitivity, altered gut microbiome, duodenal inflammation and immune activation, hypothalamic – pituitary – adrenal axis and stress, psychosocial dysfunction
• Dyspepsia secondary to organic disease is PUD, GERD, HP infection, medication (NSAID, iron, vitamin D, antibiotics, calcium channel blockers), gastroesophageal malignancy, biliary pain, pancreatitis, infiltrative diseases and systemic disorders).
• In order to manage perform: test and treat H. pylori infection, perform PPI for 4-8 weeks, prescribe Tricyclic antidepressant (in patients with no improvement of symptoms after 8 weeks of PPI).

Remember

• Helicobacter pylori infection and NSAIDs use are the major risk factors for peptic ulcers.
• Only 15% of infected HP patients will develop PUD.
• Serology is not helpful to verify whether Hp has been eradicated.
• Endoscopy – gold standard for diagnosis.
• Peptic ulcer is the most common cause of nonvariceal UGB.
• Initial treatment of UGB aims at hemodynamic stabilization.
• Biopsy samples must be obtained from every GASTRIC ulcer.