Potential Long-term Consequences of

H. pylori Infection
H. pylori infection

Weeks-moths

Chronic superficial
gastritis

Years-decades

Peptic ulcer Chronic superficial Lymphoproliferative Chronic atrophic

disease gastritis disease gastritis

Gastric
adenocarcinoma
 MECHANISMS BY WHICH NSAIDs MAY
INCUDE MUCOSAL INJURY.
Endhothelial effects
•Stasis  Ischemia
• Direct toxicity
“ion trapping”
ULCER Acid
EROSIONS
Ephithelial effects ( due to
prostaglandin depletion)
•  HCI secretion
•  Mucin secretion
•  HCO3secretion
•  Surface active
phospholipid secretion
•  Epithelial cell
proliferation
HEALING (spontaneous
or therapeutic)
 Risk Factors for NSAIDs Induced
Gastroduodenal Ulceration

Established Possible
Advanced age Concomitant infection with
History of ulcer H. pylori
Concomitant use of glucocorticoids Cigarette smoking
High-dose NSAIDs Alcohol consumption
Multiple NSAIDs
Concomitant use of anticoagulants
Serious or multisystem disease
 Disorders Associated with Peptic
Ulcer Disease

Strong association Possible association

Syatemic mastocytosis
Chronic pulmonary disease
Chronic renal failure
Cirrhosis
Nephrolithiasis
 Antitrypsin deficiency
Hyperparathyroidism
Coronary artery disease
Polycythemia vera
Chronic pancreatitis
SUMMARY OF POTENTIAL MECHANISMS BY WHICH H. PYLORI
MAY LEAD TO GASTRIC SECRETORY ABNORMALITIES
Corpus
IL-8+

Inflammatory
H. pylori cell

TNF-
D –
IL-1
––
– P +–
– – SMS
acid
+ + + ECL

D G +
– + – +

TNF-
Inflammatory IFN-
IL-8+ cell IL-8
Bacterial factors Host factors
Structure Duration
Adhesins Location
Ponns Inflammatory response
Enzymes Genetics??
(urease, vac A, cag A, etc)

Chronic gastritis
Peptic ulcer disease
Gastric MALToma
Gastric cancer
 Reported Pathophysiologic Abnormalities
in Patients with Duodenal Ulcers

Abnormality Approximate Frequency, %

 Nocturnal acid secretion 70
 Duodenal HCO3 secretion 70
 Duodenal acid load 65
 Daytime acid secretion 50
 Pentagastrin-stimulated MAO 40
 Gastrin sensitivity 35-40
 Basal gastrin 35-40
 Gastric emptying 30
 pH inhibition of gastrin release 25
 postprandial gastrin release 25

NOTE : MAO, maximal acid output

 CLASSIFICATION OF GASTRITIS

I. Acute gastritis II. Chronic Atrophic Gasritis

A. Acute H. pylori infection A. Type A : Autoimmune,
B. Other acute infectious gastritides body-predominant
1. Bacterial ( other than H. pylori ) B. Type B : H. pylori - related,
2. Helicobacter helmanni antral predominant
3. Phlegmonous C. Indeterminant
4. Mycobacterial
5. Syphilitic III. Uncommon Form of Gastritis
6. Viral A. Lymphocytic
7. Parasitic B. Eosinophilic
8. Fungal C. Crhn’s disease
D. Sarcoidosis
E. Isolated granulomatous gratritis
 RISK FACTORS FOR H. pylori
INFECTION

Birth or residence in developing country

Low socioeconomic status
Domestic crowding
Unsanitary living conditions
Unclean food or water
Exposure to gastric contents of infected individual
 REGULATION OF GASTRIC ACID
SECRETION AT THE CELLULAR LEVEL
Parietal cell FUNDUS
Vagus

Acetylcholine
Cannaliculus
Histamine
 
H, K ATPase ECL cell
 Tubulovesicles
Histamine –
 – –
ECL cell
Somatostatin Somatostatin
Gastrin D cell


Blood vessel ANTRUM

Gastrin
G cell
D cell –
Somatostatin
SCHEMATIC REPRESENTATION OF THE STEPS INVOLVED
IN SYNTHESIS OF PROSTAGLANDIN E2(PGE2) AND
PROSTACYCLIN (PGI2)
Membrane phospholipids

Phospholipase A2

Arachidonic acid

Stomach Macrophages
Kidney COX-1 COX-2 Leukocytes
Platelets housekeeping inflammation Fibroblasts
Endhothelium Endothelium

TXA2, PGI2, PGE2 PGI2, PGE2

Gastrointestinal mucosal integrity Inflammation
Platelet aggregation Mitogenesis
Renal function Bone formation
Other functions?
 COMPONENTS INVOLVED IN PROVIDING
GASTRODUODENAL MUCOSAL DEFENSE

Preepithelial
Pepsin Lumen
• Mucus H+ pH 1-2
• Bicarbonate
• Surface active Mucus gel
phospholipids HCO3- pH 7 HCO3-
Epithelium
Epithelial
• Cellular resistance Prostaglandin
• Restitution
• Growth factors, Microcirculation
protaglandins
•Cell proliferation

Subepithelial
• Blood flow
•Leukocyte
 GASTRIC PARIETAL CELL UNDERGOING
TRANSFORMATION AFTER SECRETAGOGUE-
MEDIATED STIMULATION
Resting Stimulated

HCI
KCI
Canaliculus
H3 O + KCI
H+, K+ -ATPase
Ca-
Gastrin

Tubulovesicles ACh Histamine

Active pumps
 ADHESION MOLECULES, CYTOKINE AND CHEMICAL
MEDIATOR IN LEUKOCYTE-ENDOTHELIAL INTERACTIONS
Rolling Sticking Transmigration

PAF
L-selection C5a
SLeX LTB4
SLea IL-8 H2 O 2 IL-8
PAF
CD11/CD18 Endothelial cells
P-selectin E-selectin ICAM-1 PAF PECAM-1
Endothelial injury
Thrombin
Collagenase
IL-1 Elastase
Histamine Activated
H2O2 TNF PMN
LTC4 LPS
LTD4 Oxygen radicals, Protease

Tissue injury
 POSSIBLE MECHANISM OF ULCER
RECURRENCE
ULCER RECURRENCE

IL-1, TNF-
(NSAID, H. pylori, stress) Neurophil Infiltration
Gastric acid

Cytokines
(IL-1, TNF-)
Chemokines Neutrophil activation
(MCP-1, TGF- 1)

Cytokines
Macrophage activation Chemokines
Monocyte infiltration
ULCER SCAR
Endothelial cell-leukocyte interaction
(ICAM-1/LFA-1, ICAM-1/Mac-1)
Gastric Mucosal Oxidative Stress
in Response to H. pylori
CXC-chemokine
IL-8, GRO H2O
O2 Catalase
GSH-Px
O2•-
SOD GSH GSSG
H2O2 HO•
Fe2+
OCI-

ROO-
H. pylori TBA-RS
NH2CI

Urease NH3 Apoptosis

 H. pylori-induced inflammation
and inflammatory cytokine IL-8
H. pylori
Epithelial cell
LAP
NAP Tissue injury

Oxygen radicals
IL-1
TNF IL-8 Activation
Macrophage Neutrophil
Chemotaxis

Transmigration

Adhesion

Venule
 Role of neutrophil-endothelial
interactions in the pathogenesis
NSAIDs

LT/PG 
Monocyte
activation
LTC4, LTD4 LTB4
TNF-

Vasospasm
Neutrophil activation Endothelial cell activation
(CD11b/CD18) (ICAM-1)

Ischemia-reperfusion Neutrophil-endothelial cell interaction Apoptosis

Oxygen radicals
Elastase
Oxygen radicals Endothelial Extravasated
Elastase Neutrophil embolism
cell injury migration
Hemorrhage Ischemia Oxygen radicals
Edema Elastase

Gastric mucosal injury

Gastric Biopsy Protocol
BIOPSY PROTOCOL
 Topographic patterns of chronic,
nonspecific gastritis

Diffuse Antral Gastritis Diffuse Corporal Atrophic Gastritis

Multifocal Atrophic Gastritis

The black areas in the schematic of diffuse corporal atrophic gastritis
and multifocal atrophic gastritis represent areas of focal atrophy and
intestinal metaplasia
Reported Abnormalities in Gastric Acid Secretion
and Acid Homeostasis in Peptic Ulcer Disease
Duodenal Ulcer
Increased
Mass of gastric parietal cells
Maximal acid output
Peak acid output stimulated by meals*
Duration of meal-stimulated acid secretion
Basal acid output
Daytime acid output
Nocturnal acid output
Fasting serum gastrin levels*
Meal- and GRP-stimulated gastrin levels*
Serum concentrations of pepsinogen I*
Rate of gastric emptying for liquids
Decreased
Bicarbonate production by the proximal duodenum
Gastric Ulcer
Increased
Serum levels of pepsinogen II
Duodenogastric reflux *Evidence suggests that this abnormality may
be a reersible consequence of exobacter
Decreased
pylori infection
Mass of gastric parietal cells
Maximal acid output GRP, gastrin-releasing peptide
 CONDITIONS ASSOCIATED WITH
PEPTIC ULCER

None known None known

NSAID ZE, other ZE, other
use NSAID
use

H. pylori H. pylori
infection infection

Duodenal Gastric
 Virulence Factors of Helicobacter pylori that
Promote Colonization and induce Tissue Injury
 Promote Colonization
 Flagella (for motility)
 Urease*
 Adherence factors
 Induce Tissue Injury
 Lipopolysaccharide
 Leukocyte recruitment and activating factors
 Vacuolating cytotoxin (VacA)
 Cytotoxin-associated antigen (CagA)
 Other membrane inflammatory protein (OipA)
 Heat shock proteins (HspA, HspB)
* Not essential for colonization
Proposed natural history of Helicobacter
pylori infection in humans
Environmental
Factors
Gastric Cancer
Multifocal
Atrophic Gastric Ulcer
Gastritis
Lymphoma

Acute Chronic Active Gastritis

Gastritis

Antral Duodenal Ulcer

Predominant
Gastritis Lymphoma
Childhood Old Age
 Physiologic Functions of Gastric
Exocrine Secretions
PRODUCT FUNCTION
Hydrochloric acid Provides optimal pH for pepsin and gastric lipase
(see below)
Facilitates duodenal inorganic iron absorption
Negative feedback of gastrin release
Stimulation of pancreatic HCO3- secretion
Supression of ingested microorganisms
Pepsins Early hydrolysis of dietary proteins
Liberation of vitamin B12 from dietary protein
Gastric lipase Early hydrolysis of dietary triglyceride
Intrinsic factor Binding of vitamin B12 for subsequentileal ab-
sorption
Mucin/HCO3- Protection against noxious agents
 Distribution of human gastric endocrine
cells in glands from the oxyntic mucosa
(left) and pyloric mucosa (right)

ECL EC EC
G
35% 25% 29%
49%

D D
Other 26% 19%
14% Other
3%
Oxyntic Mucosa Pyloric Mucosa
ECL, enterochromaffin-like (histamine); EC, enterochromaffin (serotonin);
D (somatostatin); G (gastrin)
 Exocrine Cells within Gastric Glands and
Their Secretory Products*,†
GLAND EXOCRINE
AREA CELLS
% OF ANATOMIC WITHIN SECRETORY
TOTAL COUNTERPART GLANDS PRODUCTS
Cardiac Proximal stomach Mucus neck Mucin, PGII
(<5%) just below esoph-
agogastric junc-
tion
Oxyntic Fundus and body Mucus neck Mucin, PGI and
(75%) PGII‡
Chief PGI and PGII, ‡
leptin
Parietal HCI, intrinsic
factor§
Pyloric Antrum and pylorus Mucus neck Mucin, PGII
*Pepsinogen I (PGI), includes Pg 1-5; PGII includes Pg6 and Pg7.
†Endocrine cells are also present within glands
‡PGI and PGII are colocalized in zymogen granules and are secreted concurectly
§Some intrinsic factor may also be produced in chief cells and endocrine cells
 Factors That May Modulate the Rate of
Gastric Emptying
Meal Factors
Volume Emptying rate proportional to volume
Acidity Slowing of emptying
Osmolarity Slower emptying of hypertonic meals
Nutrient density Emptying rate inversely proportional to
nutrient density
Fat Slowing of emptying
Certain amino acids Slowing of emptying
(e.g., L-tryptophan)
Other Factors
Ileal fat Slowing of emptying (ileal “brake”)
Rectal/colonic distention Slowing of emptying
Pregnancy Slowing of emptying
GASTRIC GLAND

MSC

MNC

ECL CELL

D CELL
PC

CC
 Anatomic regions of the stomach

Lower esophageal
Fundus
sphincter
Pylorus Oxyntic
gland
mucosa Body

Antrum

Pyloric gland
mucosa