Peptic ulcer disease

Raika Jamali M.D.

Gastroenterologist and hepatologist

Sina Hospital

Tehran University of Medical Sciences

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• Ulcers : breaks in the mucosal surface >5 mm, with depth to the submucosa

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• Health care costs of ~$10 billion / year in the US
• Despite the constant attack on the gastroduodenal mucosa by noxious agents (acid, pepsin, bile acids, pancreatic enzymes, drugs, and bacteria), integrity is maintained by a system that provides mucosal defense and repair

Oxyntic Gastric �Gland

Gastric parietal cell �undergoing transformation after stimulation

Gastroduodenal Mucosal Defense

Physiology of Gastric Secretion

Epidemiology

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• DUs occur in 6–15% of the Western population.
• The incidence of DUs declined from 1960 to 1980 and has remained stable since then.
• The death rates, need for surgery, and physician visits have decreased over the past 30 years.
• This is likely related to the decreasing frequency of Helicobacter pylori
• Eradication of H. pylori has greatly reduced the recurrence rates.
• Peak incidence : sixth decade.
• More than half of GUs occur in males
• GUs are less common than DUs, perhaps due to the higher likelihood of GUs being silent

• DUs occur most often in the first portion of duodenum (>95%) (~90% located within 3 cm of the pylorus).
• They are usually 1 cm in diameter
• Giant ulcer: >3 cm
• Ulcers depth at times reaching the muscularis propria.
• The base of the ulcer often consists of a zone of eosinophilic necrosis with surrounding fibrosis.
• Malignant DUs are extremely rare.

• GUs can represent a malignancy.
• Benign GUs are most often found distal to the junction between the antrum and the acid secretory mucosa (rare in fundus).
• Benign GUs associated with H. pylori antral gastritis
• NSAID-related GUs are not accompanied by chronic active gastritis (but have evidence of a chemical gastropathy)

Duodenal Ulcer

• H. pylori & NSAID-induced injury account for the majority of DUs
• Basal and nocturnal gastric acid secretion is increased
• Bicarbonate secretion is decreased (H. pylori ?)
• Accelerated gastric emptying of liquids ?

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Gastric Ulcer

• Majority can be attributed to either H. pylori or NSAID-induced mucosal damage
• GUs that occur in the prepyloric area are similar in pathogenesis to DUs
• Acid output (basal and stimulated) tends to be normal or decreased in GU
• Impairment of mucosal defense
• Abnormalities in resting and stimulated pyloric sphincter pressure ?
• bile acids, lysolecithin, and pancreatic enzymes (duodenal gastric reflux) ?
• Delayed gastric emptying of solids ?

H. pylori & PUD

• Gastric infection with the bacterium H. pylori accounts for the majority of PUD
• Development of gastric MALT lymphoma and gastric adenocarcinoma
• Gram-negative microaerophilic rod
• Does not invade cells
• Contains multiple sheathed flagella
• Migrates toward the more proximal segments of the stomach

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• Outer membrane protein (Hop proteins)
• Urease
• Vacuolating cytotoxin (Vac A)
• Cag pathogenicity island (cag-PAI).
• Cag A activates a series of cellular events in cell growth and cytokine production
• Urease produces ammonia from urea, an essential step in alkalinizing the surrounding pH
• Multiple strains of H. pylori exist and are characterized by their ability to express several of these factors
• Different diseases related to H. pylori infection can be attributed to different strains of the organism with distinct pathogenic features.

Epidemiology

• In developing parts of the world, 80% of the population may be infected by the age of 20,
• prevalence is 20–50% in industrialized countries

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• Risk factors:
• Poor socioeconomic status
• less education
• Birth or residence in a developing country,
• Domestic crowding,
• Unsanitary living conditions,
• Unclean food or water,
• Exposure to gastric contents of an infected individual

• Transmission of H. pylori occurs from person to person, following an oral-oral or fecal-oral route
• risk of H. pylori infection is declining in developing countries

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• Pathophysiology
• associated with a chronic active gastritis
• H. pylori is present in only 30–60% of GUs and 50–70% of DUs

H. pylori may lead to gastric secretory abnormalities

Natural history of H. pylori

Development of Non-cardia cancer is a multistage and multifactorial process

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• Atrophic gastritis + IM
• hypochlorhydria

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Host Genetic - IL-1B genotype

Dietary - Low antioxidant high salt

Environmental - Smoking

Bacterial - Colonisation of

achlorhydric stomach by nitrosating species

Superficial gastritis

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Dysplasia & Cancer

H pylori infection

NSAID-Induced Disease

• prescriptions written for NSAIDs was >111 million at a cost of $4.8 billion.
• The most common drug-related toxicities in the US: NSAIDs
• The spectrum of NSAID-induced morbidity ranges from:
• Nausea and dyspepsia (50–60%)
• Peptic ulceration (15–30% of individuals taking NSAIDs regularly)
• Bleeding or perforation (1.5% of users per year)

• > 80% of patients with serious NSAID-related complications did not have preceding dyspepsia
• No dose of NSAID is completely safe
• Enteric-coated are also associated with PUD
• Established risk factors include:
• Advanced age,
• History of ulcer,
• Glucocorticoids,
• High-dose NSAIDs,
• Multiple NSAIDs,
• Anticoagulants,
• Serious or multisystem disease.
• Possible risk factors include:
• H. pylori
• Smoking
• Alcohol

NSAIDs may induce mucosal injury

Pathogenetic Factors Unrelated to� H. pylori and NSAIDs in PUD

• Smokers have ulcers more frequently
• Smoking:
• Decrease healing rates,
• Impair response to therapy
• Increase ulcer-related complications (perforation)
• Mechanisms:
• Altered gastric emptying,
• Decreased duodenal bicarbonate production,
• Increased risk for H. pylori infection,
• Generation of noxious mucosal free radicals

• Genetic predisposition
• First-degree relatives of DU patients are three times as likely to develop an ulcer
• Increased frequency in blood group O

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• Psychological stress has been thought to contribute to PUD
• Diet has also been thought to play a role in peptic diseases

• Strong association are :
• 1) Systemic mastocytosis,
• 2) Chronic pulmonary disease,
• 3) Chronic renal failure,
• 4) Cirrhosis,
• 5) Nephrolithiasis,
• 6) A1-antitrypsin deficiency.
• Possible association are:
• 1) Hyperparathyroidism,
• 2) Coronary artery disease,
• 3) Polycythemia vera,
• 4) Chronic pancreatitis

Clinical Features

• Abdominal pain is common, but has a poor predictive value for the presence of PUD
• 10% of patients with NSAID-induced mucosal disease can present with a complication without antecedent symptoms
• Typical pain pattern in DU occurs 90 min to 3 h after a meal and is frequently relieved by antacids or food.
• Pain that awakes the patient from sleep (between midnight and 3 A.M.) is the most discriminating symptom, in two-thirds
• This symptom is also present in 1/3 of patients with NUD

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• In GU, discomfort may actually be precipitated by food
• Nausea and weight loss occur more commonly in GU

• possible explanations for pain include:
• Acid-induced activation of chemical receptors in the duodenum,
• Enhanced duodenal sensitivity to bile acids and pepsin,
• Altered gastroduodenal motility

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• Dyspepsia that becomes constant, is no longer relieved by food or antacids, or radiates to the back may indicate a penetrating ulcer (to the pancreas).
• Sudden onset of severe, generalized abdominal pain may indicate perforation.
• Pain worsening with meals, nausea, and vomiting of undigested food suggest gastric outlet obstruction.
• Tarry stools or coffee-ground emesis indicate bleeding.

Physical Examination

• Epigastric tenderness is the most frequent finding (predictive value of this finding is rather low)
• Tachycardia and orthostasis suggest dehydration secondary to vomiting or active gastrointestinal blood loss.
• A severely tender, board like abdomen suggests a perforation.
• Presence of a succession splash indicates retained fluid in the stomach, suggesting gastric outlet obstruction.

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PUD-Related Complications

• Gastrointestinal Bleeding
• The most common complication
• In ~15% of PUD patients
• More often in individuals >60 y (likely due to the increased use of NSAIDs)
• Perforation
• The second most common complication
• In 6–7% of PUD patients
• Penetration is a form of perforation in which the ulcer bed tunnels into an adjacent organ.
• DUs penetrate posteriorly into the pancreas, leading to pancreatitis,
• Whereas GUs tend to penetrate into the left hepatic lobe

Gastric Outlet Obstruction

• The least common complication
• In 1–2% of patients
• Obstruction secondary to inflammation and edema often resolves with ulcer healing.
• A fixed, mechanical obstruction secondary to scar formation in the peripyloric areas requires endoscopic (balloon dilation) or surgical intervention

Differential Diagnosis

• NUD, also known as functional dyspepsia is typified by upper abdominal pain without the presence of an ulcer
• Proximal gastrointestinal tumors,
• Gastroesophageal reflux,
• Vascular disease,
• Pancreaticobiliary disease (biliary colic, chronic pancreatitis),
• Gastroduodenal Crohn's disease

Diagnostic Evaluation

• In view of the poor predictive value of abdominal pain for the presence of an ulcer, documentation of an ulcer requires either a radiographic (barium study) or an endoscopic procedure
• Double-contrast study
• Detection rates as high as 90%
• Sensitivity for detection is decreased in small ulcers (<0.5 cm), presence of previous scarring, or in postoperative patients
• Ulcers >3 cm in size or those associated with a mass are more often malignant.
• Up to 8% of GUs that appear to be benign by radiographic appearance are malignant by endoscopy or surgery.
• Radiographic studies that show a GU must be followed by endoscopy and biopsy

A benign duodenal ulcer A benign gastric ulcer

Endoscopy

• The most sensitive and specific approach for examining the upper gastrointestinal tract
• Facilitates tissue biopsy to rule out malignancy (GU) or H. pylori
• Identifies lesions too small to detect by radiography
• Evaluates atypical radiographic abnormalities
• Determines if an ulcer is a source of blood loss

a benign duodenal ulcer a benign gastric ulcer

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• Serum gastrin and gastric acid analysis (sham feeding) may be needed in individuals with complicated or refractory PUD (Zollinger-Ellison Syndrome).
• Screening for aspirin or NSAIDs (blood or urine) may also be necessary in refractory H. pylori–negative PUD patients.

Treatment

• Acid suppression
• Eradication of H. pylori
• Therapy/prevention of NSAID-induced disease

Acid Neutralizing/Inhibitory Drugs

• Antacids
• They are now rarely, used as the primary therapeutic agent
• Mixtures of aluminum hydroxide and magnesium hydroxide
• Should not be used in CRF, because of possible hypermagnesemia, and chronic neurotoxicity
• Calcium carbonate can lead to milk-alkali syndrome (hypercalcemia, hyperphosphatemia with possible renal calcinosis and progression to renal insufficiency).

H2 Receptor Antagonists

• Cimetidine, ranitidine, famotidine, and nizatidine have different potency,
• Inhibit basal and stimulated acid secretion
• Cimetidine
• May have weak antiandrogenic side effects (reversible gynecomastia & impotence)
• Inhibit cytochrome P450, (warfarin, phenytoin, and theophylline)
• Confusion and elevated levels of serum aminotransferases, creatinine, and prolactin
• Tolerance to H2 blockers
• Pancytopenia

Proton Pump (H+,K+-ATPase) Inhibitors

• Omeprazole, esomeprazole, lansoprazole, rabeprazole, and pantoprazole are benzimidazole derivatives that covalently bind and irreversibly inhibit H+,K+-ATPase
• The most potent acid inhibitory agents
• Maximum acid inhibitory effect between 2 and 6 h after administration
• Duration of inhibition lasting up to 72–96 h
• It can take 2 and 5 days for gastric acid secretion to return to normal levels once these drugs have been discontinued

• Before a meal
• No carcinoid tumor development in humans
• Gastrin levels return to normal levels within 1–2 weeks after drug cessation
• IF production is also inhibited, but vitamin B12-deficiency anemia is uncommon
• Interfere with absorption of drugs such as ketoconazole, ampicillin, iron, and digoxin
• Hepatic cytochrome P450 can be inhibited by omeprazole & lansoprazole

• Warfarin, diazepam, atazanavir, and phenytoin concomitantly with PPIs
• Associated with a higher incidence of community-acquired pneumonia

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• Tenatoprazole: longer half-life and inhibits nocturnal acid secretion
• Potassium-competitive acid pump antagonists (P-CABs), inhibit gastric acid secretion via potassium competitive binding of the H+,K+-ATPase.

Cytoprotective Agents

• Sucralfate
• Binding primarily to sites of active ulceration
• Physicochemical barrier
• Promoting a trophic action by binding growth factors such as EGF
• Enhancing prostaglandin synthesis
• Stimulating mucous and bicarbonate secretion
• Enhancing mucosal defense and repair
• Avoid in CRF to prevent aluminum-induced neurotoxicity.
• Hypophosphatemia
• Gastric bezoar formation

• Bismuth
• Ulcer coating;
• Prevention of further pepsin/HCl-induced damage;
• Binding of pepsin;
• Stimulation of prostaglandins, bicarbonate, and mucous secretion
• Black stools,
• Constipation,
• Darkening of the tongue
• Neurotoxicity

Prostaglandin Analogues

• Enhance mucous bicarbonate secretion,
• Stimulate mucosal blood flow
• Decrease mucosal cell turnover.
• The most common toxicity noted with this drug is diarrhea (10–30%).
• Uterine bleeding and contractions
• Contraindicated in pregnancy

Therapy of H. pylori

• PUD who are found to be H. pylori–positive by serology or breath testing.
• Gastric MALT lymphoma
• Patients with NUD, to prevent gastric cancer?
• Patients with GERD requiring long-term acid suppression?
• 14 days provides the greatest efficacy
• Promote ulcer healing,
• Prevent ulcer recurrence and complications
• Diminished recurrent ulcer bleeding

• The most complication with amoxicillin is pseudomembranous colitis (<2%)
• Tetracycline has been reported to cause rashes,hepatotoxicity and anaphylaxis
• Resistant to amoxicillin, and tetracycline is uncommon
• Quadruple therapy
• Antibiotic-resistant strains are the most common cause for treatment failure in compliant patients

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• Second-line therapy include:
• (levofloxin, amoxicillin, PPI) for 10 days
• (furazolidone, amoxicillin an PPI)
• Then culture and sensitivity of the organism
• Cigarette smoking
• Sequential therapy:5 days of amoxicillin + PPI, followed by an additional 5 days of PPI + tinidazole + clarithromycin

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• If H. pylori present, eradication is recommended for 14 days, followed by continued acid-suppressing drugs for 4–6 week
• Test of choice for documenting eradication is the urea breath test (UBT).
• Stool antigen assay (off PPI)
• Multiple biopsies of a GU should be taken initially; even if these are negative for neoplasm, repeat endoscopy to document healing at 8–12 weeks should be performed, with biopsy if the ulcer is still present.
• ~ 70% of GUs eventually found to be malignant undergo significant (usually incomplete) healing.

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• A GU that fails to heal after 12 weeks and a DU that does not heal after 8 weeks of therapy should be considered refractory
• Poor compliance
• Persistent H. pylori infection
• NSAID use
• Smoking
• Malignancy (For a GU)
• Hypersecretory state such as ZES, (fasting gastrin or secretin stimulation test )

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• Ischemia
• Crohn's disease
• Amyloidosis
• Sarcoidosis
• Lymphoma
• Eosinophilic gastroenteritis
• Infection [CMV, tuberculosis, or syphilis].
• Higher dose is also effective in maintaining remission.
• Surgical intervention

Surgical Therapy

• Elective, for medically refractory disease,
• Or as urgent/emergent, for an ulcer-related complication

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• GIB unresponsive or refractory to endoscopic intervention + IV PPI, will require surgery (~5% of transfusion-requiring patients)

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Specific Operations for Duodenal Ulcers

• Surgical treatment is designed to decrease gastric acid secretion by Vagotomy

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• 1) vagotomy and drainage (by pyloroplasty, gastroduodenostomy, or gastrojejunostomy to compensate for the vagotomy-induced gastric motility disorder)
• 2) highly selective vagotomy (which does not require a drainage procedure)
• 3) vagotomy with antrectomy in prepyloric ulcers and refractory to medical therapy (lowest rates of ulcer recurrence but the highest complication rate)

Operations for Gastric Ulcers

• Antrectomy (including the ulcer) with a Billroth I anastomosis is the treatment of choice for an antral ulcer.
• Vagotomy is performed only if a DU is present
• Ulcers located near the esophagogastric junction require subtotal gastrectomy with a Roux-en-Y esophagogastrojejunostomy (Csende's procedure).
• A less aggressive approach, including antrectomy, intraoperative ulcer biopsy, and vagotomy (Kelling-Madlener procedure

Surgery-Related Complications

• More aggressive surgical procedures have a lower rate of ulcer recurrence but a greater incidence of gastrointestinal dysfunction
• Recurrent Ulceration
• Afferent Loop Syndromes
• Dumping Syndrome
• Postvagotomy Diarrhea
• Bile Reflux Gastropathy
• Maldigestion and Malabsorption
• Gastric Adenocarcinoma