PEPTIC ULCER DISEASE

Peptic UlcerDiseaseUlcers are defined as a break in the mucosal surface >5 mm in size, with depth to the

submucosa.

Objectives

• To understand the pathogenesis of Peptic ulcer disease

• To identify the role of dyspepsia in the evaluation of PUD

• To identify appropriate treatment strategies for both H pylori and NSAID associated PUD

Peptic ulcer disease• Characteristically occurs in the stomach and proximal

duodenum

• May also occur in the oesophagus (with GERD)

• in the jejunum (in Zolinger Ellison syndrome or post gastroenterostomy),

• or in ectopic gastric mucosa as in Meckels diverticulum.

• Less common causes include hypersecretory states like mastocytosis, G-cell hyperplasia

Duodenal Ulcer

• tends to peak at ages 25-75, commoner in males,

• >75% associated with H.pylori.

• Other risks: smoking, NSAIDS, family history.

• occur most often in D1 ~90% located within 3 cm of the pylorus;

• usually <1 cm in diameter, rarely 3 to 6 cm (giant ulcer).

• ulcer base often consists of a zone of eosinophilicnecrosis with surrounding fibrosis.

• Malignant DUs are extremely rare.

Gastric Ulcer

• peaks between 55-65 years.

• H. Pylori and NSAIDS are major risk factors.

• Concurrent use of corticosteroids dramatically increase the risk of ulcer.

• Benign gastric ulcers are normally found on the lesser curvature, although they can occur anywhere in the stomach, rare in the gastric fundus

• Treatment more difficult with longer treatment duration.

Pathogenesis of PUD

• In the early 20th century, the pathogenesis of the disorder was believed to be related to stress and dietary factors

• In 1971, Sir James Black identified a subtype of the histamine receptor (H2receptor) that appeared to be the principal mediator of gastric acid secretion.

• The underlying pathogenesis was found to be related to the traditional theory of imbalance between acid pepsin and mucousal resistance. (mucus, bicarbonate, prostaglandins)

Multifactorial Pathogenesis • Corrosive effect of HCL, proteolytic effect of

pepsin vs mucosal resistance

a three-level barrier

of

pre-epithelial,

epithelial, and

sub-epithelial elements

The mucosal defence system

• mucus-bicarbonate layer• physicochemical barrier

• surface epithelial cells • mucus and HCO3 production, • maintain intracellular pH, • restitution modulated by epidermal growth factor (EGF),

transforming growth factor (TGF) a, and basic fibroblast growth factor (FGF), prostaglandins

• Microvascular circulatory system• provides HCO3-, micronutrients, oxygen and

• removes toxic metabolic by-products

Gastric Acid

• Is PUD due to gastric acid hypersecretion?

• Most patients with gastric ulcers have normal –to-low acid secretion

• Most patients with DU are not hypersecretors• Small proportions are hyper secretors

• Gastric acid is required but is not commonly cause of ulcer

• In 1983, Warren and Marshall discovered H pylori infection

• The role of helicobacter pylori infection on acid-pepsin balance has led to major advances in the understanding of the aetiopathogenesis of PUD

Helicobacter pylori

•Most common chronic bacterial infection worldwide

•Found in the stomach of humans in all parts of the world.

•Transmission by fecal-oral, and oral-oral routes, iatrogenic,

•Infection occurs in childhood and persist into middle age.

does not invade the epithelial cell, may adhere tightly

capable of transforming into a coccoid form, which represents a dormant state that may facilitate survival in adverse conditions.

General Characteristics• Microaerophilic, gram-negative spiral rods

• Multiple polar sheathed flagella highly motile with rapid corkscrew motion

• Produces urease enzyme:• 100X more potent than other bacterial ureases

• Breaks down urea to NH4+ and CO2

stomach acidity possible for H. pylorito survive @ pH 2-3

Prevalence of HP in Nigeria

Author Year of

publicatio

n

Number and

population

studied

Test Prevalence of

HP

Tanko MN et al Jos, 2007 100 dyspeptics histology 79%

Smith SI et al 2004 63 dyspeptics HP DNA

(PCR)

Biopsy tissue

35%

Oluwasola AO et al 2002 25 dyspeptics

25 controls

Ig G

antibodies

88%

80%

Ndububa et al 2001 268 dyspeptic CLO/histology 73%

Holcombe C 1994 40 volunteers 80%

H pylori-mediated DU.

• antral infection leads to increased HCL production, increased duodenal acid, and mucosal injury.• ↑ acid secretion through direct and indirect actions of

proinflammatory cytokines (IL-8, TNF, and IL-1) on G, D, and parietal cells

• Basal and stimulated gastrin release are ↑ and somatostatin-secreting D cells may be decreased.

• ↓ duodenal mucosal bicarbonate production.

• gastric metaplasia in the duodenum of DU patients permits H. pylori to bind to it and produce local injury secondary to the host response.

21-Apr-20 19Pathology of H pylori

• Thus colonization of HP always results in chronic inflammation of the gastric mucosa (chronic gastritis)

• Duodenal and gastric ulcer results when the consequences of inflammation allow acid and pepsin in the stomach to overwhelm the mechanisms that protect the mucosa against these substances

21-Apr-20 21Pathology of H pylori

Why do only a few people develop clinical disease?

• Host factors• Immune response eg pleomorphism of inflammatory cytokines like IL1-B

• Genetic susceptibility: • cox 2 polymorphisms (765G>C cox2)

• sTREM (soluble triggering receptor expressed on myeloid cells in peptic ulcer disease

• etc

• Bacterial factors• HP strain

Multifactorial pathogenesis• NSAIDS

• decreases epithelial cell proliferation, growth factors,

angiogenesis,

• Environmental factors • smoking• decreased proximal duodenal bicarbonate production,

and cigarette-induced generation of noxious mucosal free radicals.

• decrease healing rates, impair response to therapy, and increase ulcer-related complications

Pathogenesis-Mucosal insults

• Most common mucosal insults are H. pylori and NSAIDS

• Uncommon causes• Hypersecretion of gastric acid

• Zollinger ellison syndrome

• Systemic mastocytosis

• Antral G cell hyperplasia

• Retained antrum syndrome

• Viral infections• CMV. HSV-1

NSAIDS

The widespread use of NSAIDS as analgesic, anti

inflammatory and anti-pyretic drugs converts the

upper GI complications into a major public health

concern • Significant health benefits in the treatment of pain and inflammation both on

and off prescription.

• Improve quality of life

• Used in both acute/chronic recurrent pain management, primary/secondary prevention of CVS/CNS events, other uses

• If oral NSAIDs are taken for at least 2 months, the risk of an • endoscopic ulcer is 1 in 5,

• of a symptomatic ulcer is about 1 in 70,

• of a bleeding ulcer is about 1 in 150,

• and of a death from a bleeding ulcer about 1 in 1300.

Endoscopic findings in NSAID Gastropathy

• Subepithelial petechial bleeds

• petechiae

• erosions

NSAID induced antral erosive gastritis with multiple exudates

PGs play a key role in gastric epithelial defense by enhancing the pre-epithelial, epithelial, post-epithelial defense mechanisms:

PGs regulate the secretion of bicarbonate and mucous, inhibit gastric acid secretion, and are important in maintaining epithelial cell restitution and mucosal blood flow.

Risk factors for ulcer complications in NSAID users

• History of previous uncomplicated ulcer

• History of previous complicated ulcer

• Advanced age @ > 60 years

• Concomitant use of:• Other NSAIDS

• Corticosteroids

• Anti-platelets

• Anticoagulants

• Significant CV disability

Clinical PresentationChronic recurrent dyspepsia ? cause

• Non-ulcer dyspepsia (Functional dyspepsia ) >50%

• Gastro-esophageal reflux disease (GERD)- 20%• Peptic ulcer disease < 20%• Gastritis (NSAID, steroids, antibiotics)• Gastric carcinoma (<2%)• Non-gastro-duodenal disease e.g..biliary,

pancreatic • Rarely-hypersecretory states:-Z- Ellison syndr,

mastocytosis

Alarm symptoms

• Recent onset symptoms in patients >45yrs

• Anaemia

• Significant Weight loss

• Recurrent vomiting

• Melaena, haematemesis

• Dysphagia

Physical examination

• Epigastric tenderness (+/-)

• RUQ tenderness may suggest a biliary etiologic

• In the presence of GAO, abdominal distension and succussion splash may be found.

• A palpable mass should raise the suggestion of a gastric malignancy.

• Involuntary guarding is indicative of peritonitis secondary to gastric perforation

Specific Investigations in a patient with suspectedPUD

Diagnosis of HP infection

• Serology: detects serum IgG antibodies.serological scar for up to 3 years. Lacks sensitivity and specificity and fails to differentiate current from past infection.

• Urea breath test:• C13 requires expensive mass spectrometry, and C14

uses radioactivity.• Patient ingests carbon labelled 13c or 14c• Urease of HP hydrolyses the urea and liberates co2 which

is absorbed and exhaled in the breath • Labelled co2 is collected and quantified

Other tests for HP• Histology

• Giemsa, warthin-stary

• Multiple biopsies, sampling error, prior antibiotic reduce sensitivity

• Rapid urease (CLO, PyloriteK, HPfast):

• Biopsy specimen placed in medium containing a coloured pH indicator

• cheap , quick and specific. Poor sensitivity

The urease enzyme produced by the Helicobacter cause a colour change in a small reagent tube, usually within minutes. A+C+ = Antrum is positive, Corpus is positive

• Fecal antigen test. detection of antigen shed in stools.

• Culture: Gold standard. Slow and laborious. Lacks

sensitivity.• DNA probes /PCR on gastric tissue/ gastric juice

• Urinary excretion of 15N ammonia

Fibre-optic Endoscopy

• Diagnosis of HP

• Visualization and biopsy of ulcer• In gastric ulcers “do it right first time”

• 4 good biopsy from ulcer margin

• I from base

• Prognosis

• Treatment of ulcer

Pre pyloric ulcerswithin 2 to 3 cm of the pylorusmay have a different pattern of healingmay heal more slowlymay be more likely to recur

Giant ulcersover 2cm in diameterheals slowly, recurrenttreat for >12 weeks10% incidence of malignancymay be assoc with NSAID use

Barium studies of upper GI

• DU appears as a well-demarcated crater, most often seen in the bulb. • single-contrast barium meals and double-contrast

study(sensitivity 80% vs 90% )

• Decreased sensitivity (small ulcers (<0.5 cm), presence of previous scarring, or in postoperative patients.

• GU may represent benign or malignant disease., • discrete crater with radiating mucosal folds originating from

the ulcer margin. • 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 Xray are malignant by endoscopy or surgery..

• Other investigation in dyspeptic patients• Abdominal USS

• Haematological/Biochemical tests

• Stool tests- occult blood

• Others as needed

Treatment goals and therapeutic options

• Goals• Subjective improvement• Healing of ulcer crater• Treatment of HP infection• Preventing complications

• Therapeutic options• Choice of therapy will depend on a drug availability

(bismuth),cost, antibiotic resistance pattern, side effect, dosing and compliance and prevalence of gastric cancer. PPI are important adjunct to RX as the increase the bioavailability and stability of the antibiotics.

Drug THERAPY.

• First Line therapy• ‘PPI+Clarith(500mg)+Amox(1gm) or Metrod (500mg) all BD-7-

14days.

• Eradication rates 70-85%.

• Quadruple therapy-PPI (bd)+bismuth+Metrod+Tetracy (qid) all given for 10-14days. Eradication rates 75-93%.Useful in penicillin allergy and increasing Clarith resistance in some countries. (Katelaris PH Gastroent 2002)

• Second line therapy-• levofloxacin based or rifabutin based or Furazolidone-based

Other treatment options

• Sequential therapy (2x5, 3x5)A PPI + amoxicillin 1 g twice dly x 5/7 followed by the PPI + clarithromycin 500 mg + tinidazoleor metronidazole 500 mg bd for 5 days

• Concomitant therapyPPI + amoxicillin 1 g, clarithromycin 500 mg + tinidazole or metronidazole 500 mg twice daily for

7-14 days

• Others: Mucosal protective agents used in place of PPI in some programmes. Octreotide, a somatostatin analogue used as part of quadriple therapy

Problems that limit effectiveness of eradication therapy

• Genetic factors (CYP 2C19 polymorphysms

(rapid, intermediate and poor metabolizers of PPIs)

• Antibiotic resistance (esp with metronidazole and clarithromycin). *Amoxycillin resistance, an emerging problem

• Adverse drug effects

• Patient compliance

• Drug substitution eg Ampicillin for amoxycillin,

Follow up of patients after eradication of infection

• Breath tests:Recent treatment with PPI/ antibacterials may suppress H.pylori and cause a false negative breath test. Thus, delay for at least 4 weeks after treatment is completed.

• Fecal antigen tests

• Endoscopy

• Serological tests: not useful as antibody titers decline over 6-12 months

Diet and PUD

• Drink a lot of milk!

• Don’t eat spices!

• Don’t eat fried foods!

• Don’t eat pepper!

• Current evidence suggest that• Stress spicy food, alcohol are insignificant risks.

• frequent ingestion of milk is associated with increased acid secretion.

Treatment of ulcers not associated with HP

(usually associated with NSAIDS)

• Discontinue drug if possible,

• concurrent use of PPI, H2RA,or cytoprotective agents (misoprostol)

• Use of selective cyclooxygenase 2 (COX 2) inhibitors

Preventive strategies-General rules

Targeting modifiable risk factors1. Use the lowest effective dose for the shortest period of time

2. Avoid concomitant therapy with corticosteroids, triple AAA

3. Use safer NSAIDS (coxibs, diclofenac, aceclofenac and ibuprufen)

4. Less use of NSAIDS with the highest GI toxicity

5. Eradicate H-pylori infection in patients with prior ulcer history

Enteric coated or buffered ASA formulations

Will this reduce the risk of UGIE?

Yes will reduce dyspepsia and improve tolerability

No, will not reduce the risk of ulceration and GI bleeding which is caused by a systemic effect on prostaglandin reduction

Parenteral or rectal administration of NSAIDS

Will this reduce the risk of UGIE?

No, will not reduce the risk of Gastroduodenal ulceration or GI bleeding which is caused by a systemic effect on prostaglandin reduction

Complications of PUD

• BleedingRisk factors for bleeding include 1. multimorbid patients,2. associated NSAID intake3. no previous history of ulcer disease (DUSUK study group-Scand J gastroenterol, 1997)

• Penetration

• Perforation

• Gastric outlet obstruction

nsaid (1) the risk of gastric ulceration is

increased to a greater extent than that of duodenal ulceration

(2) the risk of bleeding varies with the individual NSAID; for example, the relative risk of bleeding is greatest with azapropazone and piroxicam and less with ibuprofen

(3) the risk of bleeding is dose dependent

(4) multiple cofactors contribute to the risk of ulcer bleeding associated with NSAIDs.

-age greater than 75 years,

-history of heart disease,

-history of peptic ulcer, and

- history of previous gastrointestinal bleeding

were independent predictors of NSAID-induced complications.[

Group Relative Risk

Control[*]

1.0

Aspirin[†]

1.5-2.5

Other NSAIDs[†]

4-7

COX-2 Inhibitors 1.3-1.5

Key early decisions in the medical management of acute upper gastrointestinal bleeding

Triage Admit to hospital versus discharge from emergency roomAdmit to ICU versus monitored bed versus unmonitored hospital bedEmergency versus routine gastroenterology consultSurgical consult or not

Intensive monitoring Nasogastric tube insertion or notCentral venous line or Swann-Ganz catheter or notFoley insertion or not

General supportive therapy Endotracheal intubation or notTransfuse packed erythrocytes or notTransfuse other blood products or notPPI therapy or notOctreotide therapy or not

Endoscopy Emergency versus elective endoscopyEGD versus colonoscopyEndoscopic therapy or notSpecific modality of endoscopic therapy

UGIB-PRESENTATION

Probable Source of GI Bleeding Within the Gut

Clinical Indicator

Probability of Upper GI

Source

Probability of Lower GI Source

Hematemesis Almost certain

Rare

Melena Probable Possible

Hematochezia Possible Probable

Blood-streaked stool

Rare Almost certain

Occult blood in stool

Possible Possible

• Endoscopic hemostatic therapy is indicated for patients with high-risk stigmata (active bleeding or a visible vessel in an ulcer bed).

• Epinephrine injection alone provides suboptimal efficacy and should be used in combination with another method.

• No single method of endoscopic thermal coaptive therapy is superior to another.

• Clips, thermocoagulation, or sclerosant injection should be used in patients with high-risk lesions, alone or in combination with epinephrine injection.

• A new promising endoscopic application is the use of a chemical compound which, when sprayed as nanopowder on active bleeding, can lead to immediate hemostasis, with coverage of the bleeding ulcer with a powder layer.

Endoscopic management.

REFRACTORY ULCERS

• — Ulcers are considered refractory if healing is not evident after 8 to 12 weeks of therapy; the latter time frame is most appropriate for larger gastric ulcers (GU) • Persistent HP infection• NSAID• Heavy smoking• Carcinoma• hypergastrinoma

• refractory symptoms vs refractory ulceration.. Persistent symptoms in the absence of an active ulcer on endoscopy suggest that other etiologies for the pain should be sought

Current/future research

• With the decoding of the HP gene, several antigens are being targeted for HP vaccination.

• Vaccination in animal models confers protection against re-infection.

• Vaccination against HP using DNA sequences encoding urease A and B subunits are in the pre-clinical stages.

Summary