Peptic Ulcer Disease

Pepti c Ul cer Dis ea se By: tj vasquez

parie tal cell (oxyn tic cell) -

prominent cytoplasmic tubulovescles intracellular canaliculi with microvilli H+, K+-ATPase in tubulovesicle membrane

gast ric mu cosa l defense syst em 1. 2. 3.

pre-epithelial epithelial sub-epithelial

1. pre -epit helia l defense syst em mucus-bicarbonate layer ---serves as a

physiochemical barrier to multiple molecules mucus ---- water (95%) + lipids + glycoproteins functions as a non-stirred water layer impeding diffusion of ions and molecules

bicarbonate ---- secreted into mucous gel forms a pH gradient secretion is stimulated by - calcium - prostaglandins - cholinergic input - luminal acidification

2. epithelia l defense syst em 

surface epithelial cells

1. 2. 3. 4.

mucus production epithelial cell ionic transporters intracellular tight junctions “restitution” -

migration of epithelial cells to the site of breached preepithelial barrier to restore the damage requires (1) uninterrupted blood flow (2) alkaline pH modulated by (1) epidermal growth factor (EGF) (2) transforming growth factor (TGF)α (3) basic fibroblast growth factor (FGF)

2. epithelia l defense syst em also occur in injured area are: (2) epithelial regeneration 



regulated by - prostagandins - growth factors (i) EGF (ii) TGF-α

(3) angiogenesis 

influenced by: (1) vascular endothelial growth factor (VEGF) (2) fibroblast growth factor (FGF)

3. su bepit helia l defense syst em 

HCO3- ----neutralizing acid



removal of toxic metabolic by-products



mucosal microvascular system plays a key role providing HCO3- from circulation

§ §

providing micronutrients and O2 for removal of toxic metabolic by-products

3. su bepit helia l defense syst em 

key player in defense system =

prostaglandins (1) (2) (3)

release of mucosal bicarbonate and mucus inhibition of parietal cell secretion maintenance of mucosal blood flow and epithelial cell restitution phospholipaseA2 esterified arachidonic phospholipids prostaglandins acid cyclooxygenase

phospholipaseA2 phospholipids

cox-1:

esterified arachidonic prostaglandins acid cyclooxygenase cox-2:

induced by inflammation constitutionally present in present in - stomach - macrophages - platelet - leukocytes - kidney - fibroblasts - endothelial cells - synovial cells maintaining integrity of - gastrointestinal mucosa - renal function - platelet aggregation

 COX-2 –selective NSAIDs have advantage to selectively deal with inflammation in tissue and preserve the integrity of kidney function and GI mucosa

peptic u lcer dise ase  duodenal ulcer  most oftenly seen in first portion of duodenum (>95%)  gastric ulcer  some of the ulcers in stomach may be malignant

peptic u lcer dise ase 

pathophysiology § §

Helicobacter pylori non-steroidal anti-inflammatory drugs

H. p ylo ri    

gram-negative microaerophilic rod (S-shaped) present in deeper portions of mucous gel multiple sheathed flagella coccoid form can be seen

H. p ylo ri    

    

outer membrane protein (Hop protein) urease ammonia production vacuolating cytotoxin (Vac A) genomic fragment encoding cag-PAI 

translocates Cag A into host cells



Cag A activates cell growth and cytokine production

catalase lipase adhesins platelet-activating factor pic B induces cytokines

H. p ylo ri  epidemiology:  us : ~30% overall prevalence (10% of <30 yr)  poor socioeconomic, less-educated group

 transmission:  oral - oral  fecal - oral

H. p ylo ri  pathophysiology:  almost always associated with chronic active gastritis  peptic ulcer in 10 to 15% of infected  H.pylori seen in 30 to 60% of gastric ulcer 70% of duodenal ulcer

H. p ylo ri factors in H.pylori infection 2. bacterial factors 

§ virulence factors : encoded in pathogenicity island of genome  Cag A, pic B

§ urease

mucosal damage

(1) helps bacteria to reside in stomach (2) generates NH3 epithelial damage

§ surface factors : chemotactic for PMNs, monocytes

H. p ylo ri factors in H.pylori infection 2. bacterial factors 

§ proteases & phospholipases breakdown glycoprotein-lipid complex of mucous gel

§ adhesions facilitate attachment to gastric epithelium

§ lipopolysaccharide (LPS) may play a role in promoting a smoldering chronic inflammation

H. p ylo ri  factors in H.pylori infection 2. host factors § recruitment of PMNs, T- & B-lymphocytes, macrophages and plasma cells § binding to class II MHC molecules on gastric epithelial cells § cytokine production Cag A cag-PAI    

IL-1 α/β, IL-2, IL-6, IL-8 mucosal & systemic tumor necrosis factor (TNF)α humoral response interferon (IFN)γ further compound epithelial

H. p ylo ri factors in H.pylori infection 2. host factors 

a. neutrophil-mediated production of reactive oxygen or nitrogen species b. enhanced epithelial cell turnover and apoptosis

H. p ylo ri  changes seen in H.pylori-infected individual  increased gastrin release (both basal and stimulated)  decreased # of D-cells (somatostatin-secreting cells)  increased acid secretion  direct and indirect actions of  - H.pylori  - pro-inflammatory cytokines (IL-8, TNF, IL-1)

 decreased duodenal mucosal bicarbonate production

NSAI Ds- in duced dise ase  epidemiology

 NSAIDs >30 billion over the counter/yr  70 million prescription  20,000 deaths/yr from NSAIDs-associated complications  NSAIDs-induced morbidity  nausea, dysphagia (50 to 60%)  peptic ulcer (3 to 4%)

NSAI Ds- in duced dise ase pathophysiology



(2) systemic   repair

interruption of prostaglandin synthesis impairment of mucosal defense &

(3) topical  in  

a. weak acids nonionized lipophilic form acidic condition “ion trapping” b. altering surface mucous layer back diffusion of H+ & pepsin

other f actors in a cid peptic d isease 1. cigarette smoking -

decreased healing rates impair response to therapy increased ulcer-related complications (perforation) posturated pathophysiology: § § § §

altered gastric emptying decreased proximal duodenal bicarbonate production increased risk of H.pylori infection generation of noxious mucosal free-radicals

other f actors in a cid peptic d isease  2. genetic predisposition § §

1st degree relatives of DU : x3 to develop ulcer blood group O & non-secretor : higher risk 

H.pylori binds to group O antigens

2. ? psychological stress conflicting study results 3. [diet] : no convincing study results 

4. chronic disorders

(1) systemic mastcytosis (2) chronic pulmonary disease (3) chronic renal failure (4) cirrhosis (5) nephrolithiasis

(6) α1-AT def (7) [hyperparathyroidism] (8) [coronary artery disease] (9) [polycythemia vera] (10) [chronic pancreatitis]

peptic u lcer dise ase - cl ini cal f eature s abdominal pain epigastric pain (both DU and GU)

 

- 90 min to 3 hr after meal (“awaking up from sleep”)  - relieved by antacids or food  GU: - discomfort precipitated by food  postrurated pathophysiological mechanism 5. acid-induced activation of duodenal chemical receptors 6. enhanced duodenal sensitivity to bile acid & pepsin 7. altered gastroduodenal motility 

DU:

peptic u lcer dise ase

- physi cal e xam ina tion 1. epigastric tenderness 

most frequent finding

2. tachycardia + orthostasis  

dehydration vomiting active GI bleeding

3. severe tender, board-like abdomen 

perforation

4. succussion splash 

retained fluid in stomach obstruction

gastric outlet

peptic u lcer dise ase - Dx -

1. radiographic study (barium study) a. single-contrast study b. double-contrast study

§ § § §

endoscopy serum gastrin & gastric acid analysis screening for aspirin or NSAIDs (blood or urine) H.pylori work-up a. biopsy urease tests b. non-invasive tests (serologic, breath, fecal)

peptic u lcer dise ase - compl ica tions 1. gastrointestinal bleeding  

most common complication (~15%) more often in >60 yr

2. perforation   

second most common complication (6-7%) GU into left hepatic lobe DU pancreas pancreatitis

3. gastric outlet obstruction (1-2%) 1) “relative” obstruction inflammation, edema 2) mechanical obstruction scar

peptic u lcer dise ase - compl ica tions -

changing of abdominal pain with complications penetrating ulcer (to pancreas)



2.

constant dyspepsia no relief by food or antacids pain radiating to back

  

3.

perforation sudden onset of severe generalized abdominal pain



4.

gastric outlet obstruction 

5.

pain worsening with meals, nausea, vomiting of undigested food

bleeding 

tarry stool, “coffee-ground” emesis

peptic u lcer dise ase - DDx -

1. NUD (functional dyspepsia, essential dyspepsia) 

2. 3. 4. 5.

upper abdominal pain without presence of ulcer

proximal gastrointestinal tumors gastroesophageal reflux (GER) vascular disease pancreaticobiliary disease 

chronic pancreatitis, biliary colic

6. gastroduodenal Crohn’s disease

peptic u lcer dise ase - treatmen t -

1. acid neutralizing / inhibitory drugs a.

antiacids : for symptomatic relief of dyspepsia i. ii. iii. iv.

b.

aluminum hydroxide magnesium hydroxide calcium carbonate sodium bicarbonate

H2-receptor antagonists : for active ulcer  ii.

inhibit basal and stimulated acid secretion cimetidine -

inhibits cytochrome P450

iii. ranitidine, famotidine, nizatidine

§

proton pump (H+, K+-ATPase) inhibitors (PPI)

peptic u lcer dise ase - treatmen t -

1. cytoprotective agents a. sucralfate     

insolble in water becomes a viscous paste in stomach (1) sulfate anion binds to positively charged tissue protein within ulcer bed (2) binding with growth factors (e.g. EGF) enhance prostaglandin synthesis stimulate mucous & bicarbonate secretion enhance mucosal defense & repair

b. bismuth-containing preparation 

effective against H.pylori

c. prostaglandin analogues

peptic u lcer dise ase - treatmen t 1. other drugs

a. anti-cholinergics b. tricyclic antidepressants c. licorice extract carbenoxolone

2. therapy of H.pylori -

H.pylori should be eradicated in patients with documented PUD no single drug is effective -

multiple-drug regimen -

a. triple therapy b. quadruple therapy

peptic u lcer dise ase - treatmen t -

1. therapy of NSAIDs-related injury     

goals: (1) treatment of active ulcer (2) prevention of future injury a. misoprostal (prostaglandin E1 derivative) or PPI b. high dose H2-blockers (famotidine) c. COX-2-selective NSAIDs (celecoxib, rofecoxib)

peptic u lcer dise ase - surgi cal t herapy a. b.



treatment of medically refractory disease treatment of ulcer-related complications  - gastrointestinal hemorrhage  - perforation  - gastric outlet obstruction for DU 1. 2. 3.

   

vegotomy

vegotomy + drainage highly selective vegotomy vegotomy with anterectomy

for GU antral ulcer anterectomy with Billtoth I near EG junction ulcer subtotal gastrectomy anterectomy + vegotomy