1 Gastrology

MICROSCOPIC ANATOMY
PEPTIC ULCER DISEASE
Gastric glands
Ismael A. Lapus Jr. M.D.
 Cardia (<5%) – populated by mucous,
endocrine, and undifferentiated cells
 Fundus & Body (75%) – contains the oxyntic
GROSS ANATOMY STOMACH glands ( mucous neck, parietal, chief, endocrine
and enterochromaffin-like cells (ECL))
 Antrum & pylorus – contains the pyloric glands
composed of endocrine, mucous and gastrin
(G) cells

Oxyntic glands

- located in a gastric pit

- the most numerous and distinctive gastric glands
- responsible for secretion of acid, pepsinogen, intrinsic
factor & the bulk of gastric enzymes

GROSS ANATOMY DUODENUM

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is introduced into the

Chief cell duodenum from the stomach)
2. provide an alkaline condition
- synthesizes and secretes pepsinogen, the inactive for the
precursor of the proteolytic enzyme pepsin. intestinal enzymes to be active
- becomes active (pepsin) at low pH (<2.0) ,
- pepsin activity is significantly diminished at a pH of 4 thus enabling absorption to
and irreversibly inactivated and denatured at a pH of 7 take place
- digest peptide 3. lubricate the intestinal walls

Parietal cell
- responsible for the secretion of H ions
- contain an extensive secretory network PHYSIOLOGY
(called canaliculi) from which the HCl is
secreted by active transport (H/K+ ATPase Regulation of Gastric Acid Secretion
pump) into the stomach  Parietal cell stimulants and receptors for acid
- enzyme hydrogen potassium secretion:
ATPase (H+/K+ ATPase) is unique to
the parietal cells and transports the  Parietal cell inhibitors of acid secretion:
H+ against a concentration gradient
of about 3 million to 1, which is the
steepest ion gradient formed in the
human body

 ECL cells – synthesize and secretes Histamine

– also produces growth hormones
 G cells – secretes Gastrin
– stimulated by amino acids and gastrin
releasing peptides

Duodenum

 Brunner's glands (or Pancreal glands or

"duodenal glands")
– tubular submucosal gland found above
the hepatopancreatic sphincter
(sphincter of Odi)
– main function of these glands is to
produce a mucus-rich alkaline secretion
(containing bicarbonate) in order to:
1. protect the duodenum from the
acidic content of chyme (which
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Interplay of gastric acid secretion and inhibition at the
cellular level
Conditions of gastric acid secretion in humans
1. Basal (fasting) conditions or basal acid
output (BAO) occurs in circadian rhythm.
Lowest BAO - 5 AM - 11 AM
Highest BAO - 2 PM - 11 PM
Cholinergic input via the vagus nerve and histaminergic
input from local gastric sources are the principal
contributors to basal acid secretion
2. Maximal acid output (MAO) or peak acid output
(PAO).
In response to a stimulus such as a meal.
3 mechanisms contribute to stimulation of acid
secretion with meal:
1. Cephalovagal stimulation
- smell, sight, thought of appetizing food, taste
- stimulates gastric secretion via the vagus
nerve
2. Gastric distention
- stomach distention
- amino acids and amines stimulates
gastrin which in turn activates the parietal cell
3. Intestinal phase
- luminal distention and chemical reaction
Mucosal defense and repair from mucosal injury
1. Pre-epithelial
(1st line of defense)
- outer coating level
- mucus-bicarbonate layer (physiochemical barrier)
- mucus which is formed by water (95%) and mixture
of lipids and glycoproteins (mucin) & is secreted by
gastroduodenal surface epithelial cells
- bicarbonate which is also secreted by the gastro-
duodenal surface epithelium into the mucus gel forms a
pH gradient ranging 1 to 2 at the gastric luminal surface
and reaching 6 to 7 along the epithelial cell surface
2. Epithelial cells ( 2nd line of defense)
- Cellular level  mucus and bicarbonate production
- Cellular resistance - intracellular tight junction
- Restitution (restoration/repair of damage cells)
 requires uninterrupted blood flow and an alkaline
pH in the surrounding environment
 requires several growth factors (EGF, TFG, FGF)
- Cell regeneration (cell proliferation)
 required for large defects that can’t be repaired
 requires prostaglandins and growth factors vascular
endothelial growth factor (VEGF)
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PEPTIC ULCER DISEASE

- Disruption of mucosal integrity leading to local defect

or excavation due to active inflammation
- Seen as a break in the mucosal surface 5 mm in size
with depth to the submucosa or muscularis propia
- Usually chronic in nature

3. Subepithelial cells ( 3rd line of defense)

- vascular level
- elaborate microvascular system providing HCO3,
micronutrients and oxygen
- removes toxic metabolic by-products

OTHER FACTORS THAT MAINTAIN MUCOSAL

INTERGRITY

NITRIC OXIDE
 stimulating gastric mucus
 increases mucosal blood flow
 maintains epithelial cell barrier

PROSTAGLANDIN
 regulate release of mucosal bicarbonate and
mucus
 inhibit parietal cell secretion
 maintains mucosal blood flow and epithelial cell
restitution
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EPIDEMIOLOGY

 Duodenal ulcer incidence is declining due to the

discovery of H. pylori as a common cause of the
lesion
 Gastric ulcers (GUs) tend to occur later in life
than duodenal ulcers (DUs)
- 6th decade of life (peak incidence)
 Male: GU > DU

PATHOLOGY

Duodenal Ulcers
 DUs occur most often in the first portion of
duodenum (>95%), with ~90% located within 3
cm of the pylorus.
 They are usually 1 cm in diameter but can
occasionally reach 3–6 cm (giant ulcer). PATHOPHYSIOLOGY
 The base of the ulcer often consists of a zone of
eosinophilic necrosis with surrounding fibrosis. Duodenal Ulcer (DU)
 Malignant DUs are extremely rare
 H. pylori and NSAID-induced injury account for
Gastric ulcer the majority
 most often found distal to the junction  Associated with increased basal and nocturnal
between the antrum and the acid secretory gastric acid secretion
mucosa (body)  Bicarbonate secretion is significantly decreased
 can represent malignancy in the duodenal bulb
 Histologically similar to DU
Gastric Ulcer (GU)

 Majority can be attributed to H. pylori infection

or NSAID induced mucosal damage
 Gastric acid output (basal or stimulated) tends
to be normal or decreased
 Impairment of mucosal defense as the cause in
the presence of minimal acid output
Exception to the rule
 GUs that occur at the pre-pyloric area or GUs in
the body associated with a DU are similar to
pathogenesis to DU

HELICOBACTER PYLORI

 Gram-negative microaerophilic rod

 Found most commonly in the deeper portions
of the mucous gel coating the gastric mucosa
or between the mucous layer and the
gastric epithelium
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 It is S-shaped (~0.5 x 3 μm in size) and contains
multiple sheathed flagella
 Resides in the antrum → proximal segments of
stomach
Epidemiology
 Developing parts of the world, 80% of the
population may be infected by the age of 20
 Factors that predispose infection
1. poor socioeconomic status and less
education
2. birth or residence in a developing
country
3. domestic crowding
4. unsanitary living conditions
5. unclean food or water
6. exposure to gastric contents of an
Infected individual
 Transmission of H. pylori occurs from person to
person, following an oral-oral or fecal-oral
route.
Pathophysiology
 Determine by bacterial and host factors
 Bacterial factors
 Structure
Mobility - flagella
Lipopolysaccharide (LPS) of gram-negative bacteria
- low immunologic activity compared to that of
other gm (-) organisms  chronic inflammation
Bacterial genome (Pathogen island) that encodes
virulence factors (Cag A and pic B) in the host cell
Vac A (virulence factor) - can cause mucosal damage
 Adhesions
 Surface factors - chemotactic for inflammatory cells
 Urease - allows the bacteria to reside in the acidic
stomach, generates NH3, which can damage the
epithelium
 Proteases and phospholipases - breakdown of 1st line
of defense
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OUTCOME
 Asymptomatic infection PROSTAGLANDIN PATHWAY
 Gastritis
 Peptic ulcer disease
 Gastric mucosal-associated lymphoid tissue
(MALT) lymphoma
 Gastric adenocarcinoma

NSAID (Non Steroidal Anti-Inflammatory Drug)

 Act as inhibitors of the enzyme CyclOoXygenase

(COX)
 2 Isoforms : COX-1 and COX-2 isoenzymes
 COX - key enzyme that controls the rate-limiting
step in prostaglandin synthesis
 Prostaglandins play a critical role in maintaining
gastroduodenal mucosal integrity and repair
– regulate release of mucosal bicarbonate
and mucus
– inhibit parietal cell secretion
– maintains mucosal blood flow and
epithelial cell restitution
 NSAID-related GUs (chemical gastropathy) is
typified by foveolar hyperplasia, edema of the
lamina propria and epithelial regeneration in
the absence of H. pylori.

 NSAID Mucosal Injury

1. via systemic effect
2 TYPES OF NSAID
2. via topical effect (i.e., ASA)
I. Migrate across lipid membranes of epithelial
1. Non-selective NSAID
cells, leading to cell injury once trapped
- COX 1 and 2 inhibitor
intracellularly in an ionized form
- traditional NSAID
- older class
II. Alter the surface mucous layer, permitting
back diffusion of H and pepsin, leading to
2. Selective NSAID
further epithelial cell damage
- COX 2 - inhibitor
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Non-selective NSAID
Selective NSAID (COX2 inhibitor)

100 times more selective inhibitors of COX-2 than

standard NSAIDs
Celecoxib
Enterocoxib
Meloxicam

NSAID EFFECT (COX1 inhibition)

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NSAID Less common causes of Ulcers

Infection
Established risk factors Cytomegalovirus
 advanced age Herpes simplex virus
 history of ulcer Helicobacter heilmanni
 concomitant use of glucocorticoids high-dose
+ NSAIDs Drug/Toxin
 multiple NSAIDs Bisphosphonates
 concomitant use of anticoagulants Chemotherapy
 serious or multisystem disease Clopidogrel
Crack cocaine
Possible risk factors Mycophenolate mofetil
 concomitant infection with H. pylori Potassium chloride
 cigarette smoking Glucocorticoids (when combined with NSAIDs)
 alcohol consumption
Miscellaneous
Infiltrating disease
RISK FACTORS (other than H. pylori/NSAID) Ischemia
Radiation therapy
Strong association for ulcer formation: Sarcoidosis
 systemic mastocytosis Crohn's disease
 chronic pulmonary disease Idiopathic hypersecretory state
 chronic renal failure Basophilia in myeloproliferative disease
 cirrhosis Duodenal obstruction (e.g., annular pancreas)
 nephrolithiasis
 1-antitrypsin deficiency CLINICAL FEATURES

Possible association for ulcer formation: Symptom Gastric ulcer Duodenal ulcer
 hyperparathyroidism
 coronary artery disease Epigastric pain Precipitated by frequently
 polycythemia vera (ill-defined, food intake relieved by
 chronic pancreatitis aching, hunger antacid or meal
pain) and frequently
recurs 90min -3
NOT ESTABLISHED clinical evidence as cause of ulcer hrs after meal
formation but can cause dyspepsia Awakens patient
at sleep (12Mn-
 Smoking 3AM)
 Genetics
– (Blood group O) Nausea/weight More common Less common
 Psychological stress loss
 Food
 Caffeine and alcoholic beverages
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PUD-RELATED COMPLICATIONS  DU and GU appear as a well demarcated or

discrete crater
Gastrointestinal Bleeding  GU may represent benign or malignant
 most common complication  > 3 cm, associated with mass are often
 more often in individuals >60 years old malignant
 20% bleed with preceding warning or signs  Radiographic GU must be followed by
 hematemesis, melena endoscopy and biopsy

Perforation Endoscopy
 second most common  most sensitive and specific tool for examining
 6-7% of PUD patients the upper GI tract
 elderly  direct visualization and tissue biopsy to rule out
 severely tender, boardlike abdomen malignancy and test for H. pylori
 identifies lesion too small to detect by
Penetration radiographic examination
 ulcer bed tunnels into adjacent organ
 DU - penetrate posteriorly in to pancreas
 GU - penetrate into left hepatic lobe
 Gastrocolic fistula

Gastric outlet obstruction

 least common ulcer-related complication
 ulcer related inflammation and edema in the
periplyoric area
 usually resolves with ulcer healing but a fixed
mechanical obstruction secondary to scar
formation may occur
 P.E.: succussion splash

DIFFERENTIAL DIAGNOSIS

 Non ulcer dyspepsia (NUD) or functional

dyspepsia
 GIT tumor
 Gastroesophageal reflux
 Vascular disease
 Pancreaticobiliary disease (biliary colic,
pancreatitis)
 Inflammatory disease (Crohn’s)

DIAGNOSTIC EVALUATION

Double contrast barium study

 90% detection rate for duodenal ulcer
 Sensitivity for detection is decreased in:
– small ulcers (< 0.5 cm)
– presence of previous scarring
– post-operative patients
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TREATMENT
Antacids
 Neutralization of secreted acid
 Mixture of AlOH and MgOH (AlMgOH), Ca
carbonate, Na bicarbonate
 Possible adverse effects:
 AlOH produce constipation, phosphate depletion,
chronic neurotoxity
 MgOH produce diarrhea and hypermagnesemia in
renal failure patients
Ca carbonate can lead to milk-alkali syndrome
(hypercalcemia, hyperphosphatemia with possible renal
calcinosis and progression to renal insufficiency)
 a bicarbonate can induce systemic alkalosis
H2 Receptor Antagonists
 Cimetidine, ranitidine, famotidine, and
nizatidine
 Significantly inhibit basal and stimulated acid
secretion at therapeutic doses
 Patients may develop tolerance to H2 blockers,
a rare event with PPIs
 Reversible systemic toxicities with H2 receptor
blocker: pancytopenia, neutropenia anemia and
thrombocytopenia
 Cimetidine and ranitidine (to a lesser extent)
can bind to hepatic cytochrome P450 hence
careful monitoring of drugs such as warfarin,
phenytoin, and theophylline is indicated with
long-term usage.
Proton Pump Inhibitor (PPI)
 Omeprazole, esomeprazole, lansoprazole,
rabeprazole, pantoprazole
 Most potent acid inhibitory agents , blocks the
final pathway for acid
production
 Covalently bind and irreversibly inhibit H+,K+-
ATPase
 Upon entering the parietal cell, they
are protonated and trapped within the acid
environment of the tubulovesicular and
canalicular system
 Proton pumps need to be activated for these
agents to be effective
 Efficacy is maximized if they are administered
immediately before a meal
 Given for 6-8 weeks for gastric ulcer and 4
weeks for duodenal ulcer to achieve complete
ulcer healing

Advantages of Proton Pump Inhibitor
 Potently inhibit all phases of gastric acid secretion
 Onset of action is rapid (maximum acid inhibitory
effect between 2 and 6 h after administration)
 Long duration of inhibition lasting up to 72–96 h
 Progressive acid inhibition in repeated daily dosing
 Basal and secretagogue-stimulated acid production is
inhibited by >95% after 1 week of therapy
 Half-life of PPIs is ~18 h; thus, it can take between 2
and 5 days for gastric acid secretion to return to normal
levels once these drugs have been discontinued
Cytoprotective Drugs
Sucralfate
 Insoluble in water and becomes viscous paste
within the stomach and duodenum
 Actions
 Physiochemical barrier
 Promotes trophic action by binding growth
factors
 Enhances prostaglandin synthesis
 Stimulate mucous and bicarbonate secretion
 Enhances mucosal defense and repair
 Adverse event
 Aluminum induced neurotoxicty
Bismuth-Containing Preparation
 Mechanism is unclear
 ulcer coating
 prevention of further pepsin/HCl induced
damage
 binding of pepsin
 stimulation of prostaglandins
 bicarbonate and mucous secretion
 Adverse events
 black stool, constipation, darkening of
tongue
 neurotoxicity
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Prostaglandin analog

 Misoprostol (Cytotec)
 Mechanism
 enhancement of mucosal defense
 repair
 enhances mucous bicarbonate secretion
 stimulate mucosal blood flow
 decrease mucosal cell turnover NSAID-Related Gastric or Duodenal Injury
 Adverse events
 diarrhea
 uterine bleeding and contraction

Helicobacter pylori eradication

Cardiovascular Risk of NSAID:

 COX 2 associated with increased cardiovascular

events
 NSAID – Na and H20 retention Hypertension
 Withdrawal from the market: Rofexocib,
Valdecoxib Lumiracoxib
 Currently available: Celecoxib, Enterocoxib,
Meloxicam, Parecoxib
 COX 1 is dominant source of Thromboxane A2
 COX 2 is the dominant source of Prostacycline
I2
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Primary Prevention for GI Risk of NSAID Used

Guide to NSAID Therapy

Cardiovascular No/Low NSAID NSAID GI Risk

setting GI Risk

No CV risk Traditional Cox-2 inhibitor

(no aspirin) NSAID OR
Traditional
NSAID + PPI
Consider non-
NSAID therapy

Traditional Traditional
NSAID + PPI if NSAID + PPI
GI risk warrants
gastro
protection

Consider non- Consider non-

NSAID therapy NSAID therapy

Established risk factors: advanced age, history of ulcer ,

concomitant use of glucocorticoids, high-dose NSAIDs,
multiple NSAIDs, concomitant use of anticoagulants,
serious or multisystem disease

Possible risk factors: concomitant infection with H.

pylori, cigarette smoking, alcohol
consumption

SURGICAL MANAGEMENT

Elective

 decrease indication due to effective

pharmacologic and endoscopic approaches for
the treatment of acid peptic disease
 treatment of medical refractory disease
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 endoscopically and medically unresponsive

Urgent or Emergent bleeding
 ulcer related complication (bleeding,  failed endoscopic intervention (balloon
perforation, penetration, gastric outlet dilatation) for gastric outlet obstruction
obstruction)

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