Peptic Ulcer Disease

Noman Shehzad

parietal cell (oxyntic cell)

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

gastric mucosal defense system

1. pre-epithelial pre2. epithelial 3. sub-epithelial sub-

1. pre-epithelial defense presystem mucus-bicarbonate layer ---- serves as a mucusphysiochemical barrier to multiple molecules mucus ---- water (95%) + lipids + glycoproteins
functions as a non-stirred water layer impeding nondiffusion of ions and molecules

bicarbonate ---- secreted into mucous gel

forms a pH gradient secretion is stimulated by - calcium - prostaglandins - cholinergic input - luminal acidification

2. epithelial defense system

 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 prepreepithelial 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) (3) basic fibroblast growth factor (FGF)

2. epithelial defense system

 also occur in injured area are: (1) epithelial regeneration
 regulated by - prostagandins - growth factors (i) EGF (ii) TGFTGFinfluenced by: (1) vascular endothelial growth factor (VEGF) (2) fibroblast growth factor (FGF)

(2) angiogenesis


3. subepithelial defense system

   ----neutralizing HCO3- ----neutralizing acid removal of toxic metabolic by-products by-

mucosal microvascular system plays a key role (1) providing HCO3- from circulation (2) providing micronutrients and O2 for removal of toxic metabolic by-products by-

3. subepithelial defense system

 key player in defense system =

prostaglandins
(1) release of mucosal bicarbonate and mucus (2) inhibition of parietal cell secretion (3) maintenance of mucosal blood flow and epithelial cell restitution phospholipaseA2 esterified arachidonic phospholipids prostaglandins acid cyclooxygenase

phospholipaseA2 phospholipids

esterified arachidonic prostaglandins acid cyclooxygenase cox-2:

cox-1:

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 COXselectively deal with inflammation in tissue and preserve the integrity of kidney function and GI mucosa

peptic ulcer disease

 duodenal ulcer  most oftenly seen in first portion of duodenum (>95%)  gastric ulcer  some of the ulcers in stomach may be malignant

peptic ulcer disease

 pathophysiology
1. Helicobacter pylori 2. non-steroidal anti-inflammatory drugs nonanti-

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

H. pylori
    outer membrane protein (Hop protein) urease J ammonia production vacuolating cytotoxin (Vac A) genomic fragment encoding cag-PAI cag  translocates Cag A into host cells Cag A activates cell growth and cytokine production

    

catalase lipase adhesins platelet-activating factor plateletpic B induces cytokines

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

 transmission:
 oral - oral  fecal - oral

H. pylori
 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. pylori
 factors in H.pylori infection 1. bacterial factors
a. virulence factors : encoded in pathogenicity island
of genome  Cag A, pic B J mucosal damage

b. urease

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

c. surface factors : chemotactic for PMNs, monocytes

H. pylori
 factors in H.pylori infection 1. bacterial factors
d. proteases & phospholipases
breakdown glycoprotein-lipid complex of glycoproteinmucous gel

e. adhesions
facilitate attachment to gastric epithelium

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

H. pylori
 factors in H.pylori infection 2. host factors
a. recruitment of PMNs, T- & B-lymphocytes, T- Bmacrophages and plasma cells b. binding to class II MHC molecules on gastric epithelial cells c. cytokine production I Cag A I cag-PAI cag    ILIL-1 / , IL-2, IL-6, IL-8 IL- IL- ILmucosal & systemic tumor necrosis factor (TNF) humoral response interferon (IFN) further compound epithelial damage

H. pylori
 factors in H.pylori infection 2. host factors
d. neutrophil-mediated production of reactive neutrophiloxygen or nitrogen species e. enhanced epithelial cell turnover and apoptosis

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

 decreased duodenal mucosal bicarbonate production

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

NSAIDsNSAIDs-induced disease

  repair

pathophysiology
interruption of prostaglandin synthesis impairment of mucosal defense &

(1) systemic

(2) topical
 in a. weak acids nonionized lipophilic form acidic condition ion trapping b. altering surface mucous layer back diffusion of H+ & pepsin