Peptic Ulcer Disease

Outline

• INTRODUCTION

• TYPES OF ULCER

• PHYSIOLOGY 

• RISK FACTORS

• CLINICAL FEATURES

• INVESTIGATION

• TREATMENT

INTRODUCTION

• Peptic ulcer disease encompasses both duodenal and gastric ulcers

• An ulcer is defined as a break in the mucosal surface > 5mm in size with depth to the sub-mucosa.

• Characteristically, it occurs in the stomach and proximal duodenum. it may also occur in the jejunum ( ZES ),or in ectopic gastric mucosa as in Meckel’s diverticulum.

• It occurs when mucosal aggressors overcome the mucosal protectors.

GASTRIC ANATOMY

• The gastric epithelial lining consists of ruggae that contain microscopic gastric glands.

• Most of the gastric glands are found within the oxyntic mucosa and contain mucous neck, parietal, chief, endocrine, and enterochromaffin cells.

• Pyloric glands contain mucous and endocrine cells (including G cells) and are found in the antrum.

PHYSIOLOGY OF GASTRIC SECRETION

• Acid secretion can be basal or stimulated. Basal acid production occurs in a circadian pattern, with highest levels occurring during the night and lowest levels during the morning hours.

• Stimulated gastric acid secretion occurs primarily in three phases (cephalic, gastric, and intestinal).
• The H-K ATPase in the parietal cells is stimulated by ACH via vagus nerve, histamine via ECL cells and gastrin via antral G-cells.
• HCl stimulates somatostatin release from D-cells which inhibit acid production.

GASTRIC AGGRESSORS

• Endogenous noxious factors such as

• HCl
• pepsinogen/ pepsin
• bile salts.

• Exogenous substances such as

• Medications
• Alcohol
• Bacteria

GASTRIC DEFENSORS

• The mucosal defense system is a 3-level barrier composed of

• Pre-epithelial: Non-stirred mucous Hco3 layer forms a pH gradient ranging from 1 to 2 at the gastric luminal surface and reaching 6 to 7 along the epithelial cell surface.

• Epithelial: Produces the mucous layer, contains ionic transporters and provides restitution. PGs play an essential role.

• Sub-epithelial: An elaborate blood supply provides HCO3–,micronutrients and oxygen while removing toxic metabolic by-products. .,

Gastric Ulcers

• Peaks between ages 55-65 years

• Commoner in males

• H. pylori and NSAIDs are a major risk factor. Concurrent use of corticosteroids increases the risk significantly.

• Benign Gus are normally found on the lesser curvature. Although they can occur anywhere in the stomach but are very rare in the fundus. They’re histologically similar to DUs.

• Gastric acid output (basal and stimulated) tends to be normal or decreased in GU patients.

Duodenal Ulcers

• Peaks between ages 25-50

• commoner in males

• DUs occur most often in the 1^st portion of the duodenum (> 95%),with~90% located within 3cm of the pylorus.

• They’re usually <1cm in diameter but can be up to 3-6cm (giant ulcer).

• Basal and nocturnal gastric acid secretion appears to be increased in DU patients

• Malignant DUs are extremely rare.

RISK FACTORS FOR ULCER

• H. PYLORI

• NSAIDS

• ALCOHOL/CAFFEINE

• SMOKING

• BLOOD GROUP/FAMILY HISTORY

• STRESS

• CHRONIC DISEASES :

• systemic mastocytosis,
• chronic pulmonary disease,
• chronic renal failure
• cirrhosis

H. PYLORI

• Gastric infection with H. pylori accounts for majority of PUD. It also plays a role in gastric mucosal-associated lymphoid tissue (MALT) lymphoma & gastric adenocarcinoma.

• H. pylori is a G-ve, micro-aerophilic rod. Most commonly found close to the mucous layer & gastric epithelium. It adheres to the gastric epithelium. Doesn’t normally invade the cells.

• H. pylori is strategically designed to survive in the stomach. Has multiple flagella, is capable of transforming to a coccoid form in adverse conditions. Produces urease, vac A, cag PAI which translocates cag to host cells. Also produce catalase, lipase, adhesins and PAF.

• H.pylori produces different virulence factors, Vac A, Cag A as well as urease and adhesion factors.

• Host: Inflammatory response to the pathogen include recruitment of neutrophils, lymphocytes and macrophages. Cag A introduced into the host cell activates cellular pathways leading to Increased cytokine production eg IL-1B.

• H.P antral infection could lead to increased acid production, increased duodenal acid and mucosal injury. Basal and stimulated gastrin release are increased in H.P infected individuals and somatostatin secretin D cells may be decreased.

• Occurs world wide.80% in developing countries & 10%in U.S

•  Transmission is from person to person, following an oral-oral orfecal-oral route.

• H.pylori infection is always associated with chronic active gastritis. Only 10-15% of the infected develop frank ulceration. Reason is unclear.In those who develop PUD, ulceration is determined by an interplay between bacterial&host factors.

• Risk factors for H. pylori infection are

• birth or residence in a developing country
• domestic crowding
• unsanitary living conditions
• unclean food or water
• exposure to gastric contents of an infected individual.

NSAIDS

• The spectrum of NSAID-induced morbidity ranges from nausea and dyspepsia (prevalence reported as high as 50 to 60%) to a serious gastrointestinal complication such as frank peptic ulceration complicated by bleeding or perforation in as many as 3 to 4% of users per year.

• Acts by inhibiting PG synthesis

• About 20, 000 patients die each year( U.S) from serious GIT complications from NSAID usage.

• Unfortunately, dyspeptic symptoms do not correlate with NSAID-induced pathology.

• > 80% of patients with serious NSAID-related complications do not have preceding dyspepsia.

• Highlights the need for identifying patients with increased risk.

• Even 75mg/d of aspirin is not completely safe. Risk factors include:

Miscellaneous pathogenetic factors in PUD

• Cigarette smoking: Smokers have ulcers more frequently than nonsmokers. Smoking decreases healing rates, impair response to therapy, and increase complications such as perforation.

• Genetic predisposition:1°relatives of DU patients are 3x likely to develop an ulcer. Blood group O and non-secretor status have been implicated as genetic risk factors.

• Drugs-Bisphosphonates, cocaine KCL

• Infections-CMV, Herpes simplex

• Psychological stress. No typical PUD personality has been found.

• Ischemia

• Radiation injury

• Diet: Certain foods, alcohol & caffeine-containing beverages were thought to play a role in PUD.

• Specific chronic disorders:

• systemic mastocytosis,
• chronic pulmonary disease
• chronic kidney disease
• cirrhosis
• sarcoidosis

Clinical Features of Peptic ulcer Disease

• History: Abdominal pain is common but has a poor predictive value for the presence of either DU or GU.~ 10% of patients with NSAID-induced mucosal disease can present with a complication without antecedent symptoms.

• Epigastric pain (the most common symptom)

• Gnawing or burning
• Occurs 1-3 hours after meals
• Relieved by food or antacids
• Might occur at night (between midnight & 3 A.M )
• Might radiate to back (consider penetration)
• Maybe precipitated by meals

• Nausea

• Anorexia

ALARM SYMPTOMS IN PUD

• AGE: > 45 years

• Anorexia

• Recurrent vomiting

• weight loss

• Anaemia

• Dysphagia

• Haematemesis or Melena

Clinical Features

• Physical examination: Epigastric tenderness is the most frequent finding in patients with GU or DU. Predictive value is low.

• Physical examination is critically important for discovering evidence of ulcer complication.

• 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 succussion splash suggests gastric outlet obstruction.

PUD related complications

• G.I bleeding. Most common complication. More often in pts > 60 years old. Up to 20% bleed without prior warning symptoms or signs.

• Perforation. 2nd most common. Also more in the elderly. Penetration is a form of perforation. DUs penetrate into the pancreas GU s tend to penetrate into the left hepatic lobe. Also could form gastrocolic fistulas.

• Gastric Outlet Obstruction. Least common. Could be relative, 2°to ulcer related inflammation and Oedema of the prepyloric region, or a fixed, mechanical obstruction 2°scar formation.

Differential Diagnosis of peptic ulcer disease

• The most commonly encountered diagnosis among patients seen for upper abdominal discomfort is NUD

• Several additional disease processes that may present with "ulcer-like" symptoms include

• proximal gastrointestinal tumors

• gastroesophageal reflux disease

• pancreaticobiliary disease

• and gastroduodenal Crohn's disease.

Investigation of PUD

• In view of the poor predictive value of abdominal pain for the presence of a gastro-duodenal ulcer the clinician is often confronted with having to establish the presence of an ulcer.

• Documentation of an ulcer requires either a barium study or an endoscopic procedure.

• A large percentage of patients evaluated for dyspepsia have NUD

• Empirical treatment is appropriate if there are no alarm signs.

• Barium meal: The sensitivity of single-contrast barium meals for detecting a DU is as high as 80%, and for double-contrast, it is 90%.

• Small ulcers, previous scarring reduces sensitivity.

• Cannot differentiate between a benign and malignant GU

ENDOSCOPY

• Gold standard for examination of the UGI tract.

• It permits direct visualization of the mucosa

• Facilitates photographic documentation of a mucosal defect and tissue biopsy

• It identifies lesions too small to be detected by radiographic examination,

• Both diagnostic and therapeutic for UGIB

Investigations of H pylori infection .

• Two approaches. Invasive tests which require upper G.I endoscopy and non-invasive tests.

• Non-invasive tests include:

• Urea Breath Test
• Faecal antigen test
• Serology

Urea Breath Test (UBT)

• Most consistently accurate of the non-invasive tests.

• Depends on presence of H. pylori urease.

• Patient drinks labeled urea solution and blows into a tube.

• Labeling is with ¹³C or ¹⁴C.

• If H. pylori urease is present, urea is hydrolysed and labeled CO₂ is detected in breath sample.

• Pt should wait for at least 4 weeks after completion of eradication therapy before repeating test to prevent false –ve result.

Faecal Antigen Test

• Depends on detection of H. pylori antigen in stool.

• This test is more accurate than antibody testing and less expensive than urea breath tests.

• Also requires about 4 weeks after eradication therapy before re-testing to assess eradication.

Serology

• The simplest of the tests.

• Measures specific IgG levels in serum by ELISA or immunoblot. Accurate in very good hands but commercial kits perform poorly.

• IgG persist for years and cannot differentiate old from new infection.

• Serology can distinguish between cag⁺ and cag^- strains. Could be useful in determining prevalence and virulence of H. pylori infection .

Invasive/ Endoscopic Tests 

Rapid urease test:

• Considered the endoscopic diagnostic test of choice. Three kits( CLO test, Hp fast, and Pyloritek)are commercially available, each containing a combination of a urea substrate and a pH-sensitive indicator. One large or two small antral biopsy specimens are placed in therapid urease test kit. If H. pylori are present, bacterial urease converts urea to ammonia, which changes pH and produces a color change. This often occurs within minutes but can require upto 24h.

• Histology is done if the rapid test is negative and a high suspicion for H pylori persists (presence of a duodenal ulcer).

• It is considered the criterion standard for diagnosis of H. pylori. It is accurate provided a special stain (e.g. modified Giemsa or silver stain) permitting optimal visualization of H. pylori is used.

• It yields additional information including the degree and pattern of inflammation, atrophy, metaplasia and dysplasia.

• Culture is most specific but sensitivity is low because H. pylori is difficult to isolate.

Special Investigations

• These are used in refractory PUDs.

• Include serum gastrin estimation, gastric acid analysis, and sham feeding. Obtaining serum gastrin is useful in patients with recurrent, refractory, or complicated PUD and is useful in patients with a family history of PUD to screen for Zollinger-Ellison syndrome.

• A secretin stimulation test can be performed to distinguish Zollinger-Ellison syndrome from other conditions with a high serum gastrin, such as achlorhydria and antisecretory therapy with a proton pump inhibitor.

• Also, screening for aspirin or NSAID ( blood or urine )in complicated or refractory H. pylori-negative PUD.

Treatment

• Provide symptom relief

• Promote ulcer healing

• Prevent ulcer recurrence and complications: Documented eradication of H. pylori in patients with PUD is associated with a dramatic decrease in ulcer recurrence to 4% (as compared to 59%) in GU patients and 6% (compared to 67%) in DU patients.

Drugs commonly used in acid peptic disorders

Acid Neutralizing/Inhibitory drugs.

• Antacids: Used mainly for symptomatic relief of dyspepsia. Most commonly used agents are mixtures of aluminum hydroxide & magnesium hydroxide.

• AlOH causes constipation & phosphate depletion.

• Mg OH may cause loose stool.

H2 RECEPTOR ANTAGONISTS

• Cimetidine

• Ranitidine

• Famotidine

• Nizatidine.

• Cimetidine has weak anti- androgenic effect &  can induce gynaecomastia & impotence. It inhibits cytochrome P450. Careful monitoring in concurrent use with warfarin,phenytoin&theophylline.

• Famotidine& Nizatadine do not affect cytochromep 450

• SE: pancytopenia, neutropenia, anaemia & thrombocytopenia..

PROTON PUMP INHIBITORS:

• Omeprazole

• Lansoprazole

• Pantoprazole

• Rabeprazole

• Esomeprazole.

Cytoprotective Agent: Sucralfate. Complex sucrose salt Insoluble & forms a paste in the stomach & duodenum. Should be avoided in CRF ( contains AlOH)

Bismuth preparations

Prostaglandin analogues eg misoprostol

H. Pylori eradication regimen

• Triple therapy:

1. PPI + Clarithromycin+ Metronidazoleor Amoxycillin
2. H2RA +Clarithromycin+ Metronidazoleor Amoxycillin
3. Bismuth subsalicylate + Metronidazole+ TCN

• Quadruple therapy
• Bismuth salt
• + PPI
• + TCN
• + METRONIDAZOLE

Recommendations for Treatment of NSAID-Related Mucosal Injury

• Active ulcer
• NSAID discontinued. H2 receptor antagonist or PPINSAID continued + PPI

• Prophylactic therapy

• Misoprostol
• Selective COX-2 inhibitor
• PPI

• H. pylori infection eradication if active ulcer present or there is a past history of peptic ulcer disease

Surgical Treatment for Peptic Ulcer Disease

• INDICATIONS:

• Bleeding PUD not controlled by endoscopic treatment
• GOO
• Perforation
• Penetration

The appropriate surgical procedure depends on the location and nature of the ulcer.

• Many authorities recommend simple over sewing of the ulcer with treatment of underlying H pylori infection
• Additional surgical options for refractory or complicated PUD include vagotomy and pyloroplasty, vagotomy and antrectomy with gastroduodenal reconstruction (Billroth I) or gastrojejunal reconstruction (Billroth II), or a highly selective vagotomy.

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