Peptic Ulcer

Disease
parietal cell (oxyntic cell)
- prominent cytoplasmic tubulovescles
- intracellular canaliculi with microvilli
- H+, K+-ATPase in tubulovesicle membrane
gastric mucosal defense
system
1. pre-epithelial
2. epithelial
3. sub-epithelial
1. pre-epithelial defense
system
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. epithelial defense
system
 surface epithelial cells
1. mucus production
2. epithelial cell ionic transporters
3. intracellular tight junctions
4. “restitution”
- migration of epithelial cells to the site of breached pre-
epithelial 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. epithelial defense
system
 also occur in injured area are:
(1) epithelial regeneration
 regulated by - prostagandins - growth
factors (i) EGF (ii) TGF-α
(2) angiogenesis
 influenced by: (1) vascular endothelial
growth factor (VEGF) (2) fibroblast growth
factor (FGF)
3. subepithelial defense
system
 HCO3- ----neutralizing acid
 removal of toxic metabolic by-products

 mucosal microvascular system plays a key

role
(1) providing HCO3- from circulation
(2) providing micronutrients and O2 for removal
of toxic metabolic by-products
 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
phospholipids arachidonic prostaglandins
acid
cyclooxygenase
 phospholipaseA2
esterified
phospholipids arachidonic prostaglandins
acid
cyclooxygenase

cox-1: cox-2:
constitutionally present in induced by inflammation
- stomach present in
- platelet - macrophages
- kidney - leukocytes
- endothelial cells - fibroblasts
maintaining integrity of - synovial cells
- 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 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
H. pylori
 gram-negative microaerophilic rod (S-shaped)
 present in deeper portions of mucous gel
 multiple sheathed flagella
 coccoid form can be seen
H. pylori
 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. pylori
 epidemiology:
 us : ~30% overall prevalence (10% of <30 yr)
 poor socioeconomic, less-educated group

 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  mucosal damage
b. urease (1) helps bacteria to reside in stomach
(2) generates NH3  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
mucous 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,
macrophages and plasma cells
b. binding to class II MHC molecules on gastric
epithelial cells
c. 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 damage
H. pylori
 factors in H.pylori infection
2. host factors
d. neutrophil-mediated production of reactive
oxygen or nitrogen species
e. enhanced epithelial cell turnover and
apoptosis
H. pylori
 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
NSAIDs-induced disease
 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%)
NSAIDs-induced disease
 pathophysiology
(1) systemic
 interruption of prostaglandin synthesis
 impairment of mucosal defense &
repair
(2) topical
 a. weak acids nonionized lipophilic form
in acidic condition

 “ion trapping”
 b. altering surface mucous layer
back diffusion of H+ & pepsin
other factors in acid-
peptic disease
1. cigarette smoking
- decreased healing rates
- impair response to therapy
- increased ulcer-related complications (perforation)
- posturated pathophysiology:
(1) altered gastric emptying
(2) decreased proximal duodenal bicarbonate production
(3) increased risk of H.pylori infection
(4) generation of noxious mucosal free-radicals
other factors in acid-
peptic
 2. geneticdisease
predisposition
(1) 1st degree relatives of DU : x3 to develop ulcer
(2) blood group O & non-secretor : higher risk
 H.pylori binds to group O antigens
3. ? psychological stress
 conflicting study results
4. [diet] : no convincing study results
5. chronic disorders
(1) systemic mastcytosis (6) α1-AT def
(2) chronic pulmonary disease (7) [hyperparathyroidism]
(3) chronic renal failure (8) [coronary artery disease]
(4) cirrhosis (9) [polycythemia vera]
(5) nephrolithiasis (10) [chronic pancreatitis]
peptic ulcer disease
- clinical features -
 abdominal pain
 epigastric pain (both DU and GU)
 DU: - 90 min to 3 hr after meal
(“awaking up from sleep”)
 - relieved by antacids or food
 GU: - discomfort precipitated by food
 postrurated pathophysiological mechanism
1. acid-induced activation of duodenal chemical
receptors
2. enhanced duodenal sensitivity to bile acid & pepsin
3. altered gastroduodenal motility
peptic ulcer disease
- physical examination -
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  gastric outlet
obstruction
peptic ulcer disease
- Dx -
1. radiographic study (barium study)
a. single-contrast study
b. double-contrast study
2. endoscopy
3. serum gastrin & gastric acid analysis
4. screening for aspirin or NSAIDs (blood or urine)
5. H.pylori work-up
a. biopsy urease tests
b. non-invasive tests (serologic, breath, fecal)
peptic ulcer disease
- complications -
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 ulcer disease
- complications -
 changing of abdominal pain with complications
1. penetrating ulcer (to pancreas)
 constant dyspepsia
 no relief by food or antacids
 pain radiating to back
2. perforation
 sudden onset of severe generalized abdominal pain
3. gastric outlet obstruction
 pain worsening with meals, nausea, vomiting of
undigested food
4. bleeding
 tarry stool, “coffee-ground” emesis
peptic ulcer disease
- DDx -
1. NUD (functional dyspepsia, essential dyspepsia)
 upper abdominal pain without presence of ulcer
2. proximal gastrointestinal tumors
3. gastroesophageal reflux (GER)
4. vascular disease
5. pancreaticobiliary disease
 chronic pancreatitis, biliary colic
6. gastroduodenal Crohn’s disease
peptic ulcer disease
- treatment -
1. acid neutralizing / inhibitory drugs
a. antiacids : for symptomatic relief of dyspepsia
i. aluminum hydroxide
ii. magnesium hydroxide
iii. calcium carbonate
iv. sodium bicarbonate
b. H2-receptor antagonists : for active ulcer
 inhibit basal and stimulated acid secretion
i. cimetidine
- inhibits cytochrome P450
ii. ranitidine, famotidine, nizatidine
c. proton pump (H+, K+-ATPase) inhibitors (PPI)
peptic ulcer disease
- treatment -
2. 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 ulcer disease
- treatment -
3. other drugs
a. anti-cholinergics
b. tricyclic antidepressants
c. licorice extract carbenoxolone
4. 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 ulcer disease
- treatment -
5. 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 ulcer disease
- surgical therapy -
a. treatment of medically refractory disease
b. treatment of ulcer-related complications
 - gastrointestinal hemorrhage
 - perforation
 - gastric outlet obstruction

 for DU vegotomy
1. vegotomy + drainage
2. highly selective vegotomy
3. vegotomy with anterectomy
 for GU
 antral ulcer  anterectomy with Billtoth I
 near EG junction ulcer  subtotal gastrectomy
 anterectomy + vegotomy