Potential Long-term Consequences of

H. pylori Infection
H. pylori infection
Weeks-moths
Chronic superficial
gastritis
Years-decades

Peptic ulcer
disease

Chronic superficial
gastritis

Lymphoproliferative
disease

Chronic atrophic
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
Advanced age
History of ulcer
Concomitant use of glucocorticoids
High-dose NSAIDs
Multiple NSAIDs
Concomitant use of anticoagulants
Serious or multisystem disease

Possible
Concomitant infection with
H. pylori
Cigarette smoking
Alcohol consumption

Disorders Associated with Peptic

Ulcer Disease
Strong association
Syatemic mastocytosis
Chronic pulmonary disease
Chronic renal failure
Cirrhosis
Nephrolithiasis
Antitrypsin deficiency

Possible association
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
cell

H. pylori

TNF-
D

acid
+

D
+

G
+

TNF-
Inflammatory IFN-
IL-8+
cell
IL-8

IL-1

SMS
ECL
+

Bacterial factors
Structure
Adhesins
Ponns
Enzymes
(urease, vac A, cag A, etc)

Host factors
Duration
Location
Inflammatory response
Genetics??

Chronic gastritis
Peptic ulcer disease
Gastric MALToma
Gastric cancer

Reported Pathophysiologic Abnormalities

in Patients with Duodenal Ulcers
Abnormality
Nocturnal acid secretion
Duodenal HCO3 secretion
Duodenal acid load
Daytime acid secretion
Pentagastrin-stimulated MAO
Gastrin sensitivity
Basal gastrin
Gastric emptying
pH inhibition of gastrin release
postprandial gastrin release
NOTE : MAO, maximal acid output

Approximate Frequency, %
70
70
65
50
40
35-40
35-40
30
25
25

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. Crhns 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

Vagus
Acetylcholine

FUNDUS

Cannaliculus

H, K ATPase
Tubulovesicles

Histamine

ECL cell

Blood vessel
D cell

Somatostatin

Somatostatin
D cell

Gastrin

Histamine

ECL cell

ANTRUM
Gastrin

Somatostatin

G cell

SCHEMATIC REPRESENTATION OF THE STEPS INVOLVED

IN SYNTHESIS OF PROSTAGLANDIN E2(PGE2) AND
PROSTACYCLIN (PGI2)
Membrane phospholipids
Phospholipase A2
Arachidonic acid
Stomach
Kidney
Platelets
Endhothelium

COX-1
housekeeping

TXA2, PGI2, PGE2

Gastrointestinal mucosal integrity
Platelet aggregation
Renal function

COX-2
inflammation

Macrophages
Leukocytes
Fibroblasts
Endothelium

PGI2, PGE2
Inflammation
Mitogenesis
Bone formation
Other functions?

COMPONENTS INVOLVED IN PROVIDING

GASTRODUODENAL MUCOSAL DEFENSE
Preepithelial
Mucus
Bicarbonate
Surface active
phospholipids
Epithelial
Cellular resistance
Restitution
Growth factors,
protaglandins
Cell proliferation
Subepithelial
Blood flow
Leukocyte

H+

Lumen
pH 1-2

Pepsin

HCO3-

Mucus gel
pH 7

HCO3Epithelium
Prostaglandin

Microcirculation

GASTRIC PARIETAL CELL UNDERGOING

TRANSFORMATION AFTER SECRETAGOGUEMEDIATED STIMULATION
Resting

Stimulated

HCI
KCI
Canaliculus
KCI

H3O+
H+, K+ -ATPase
Ca-

cAMP

Gastrin
Tubulovesicles

Active pumps

ACh

Histamine

ADHESION MOLECULES, CYTOKINE AND CHEMICAL

MEDIATOR IN LEUKOCYTE-ENDOTHELIAL INTERACTIONS
Rolling
L-selection
SLeX
SLea

P-selectin
Thrombin
Histamine
H2O2
LTC4
LTD4

E-selectin

Sticking
PAF
C5a
LTB4
IL-8

CD11/CD18
ICAM-1
IL-1
TNF
LPS

Transmigration

H2O2

IL-8
PAF

Endothelial cells
PAF
PECAM-1
Endothelial injury
Collagenase
Elastase
Activated
PMN
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
(MCP-1, TGF- 1)
Macrophage activation
ULCER SCAR

Neutrophil activation
Cytokines
Chemokines

Monocyte infiltration
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

O2

H2O

Catalase
GSH-Px

O2SOD
H2O2

GSH
Fe2+

GSSG

HO

OCIROOH. pylori

TBA-RS
NH2CI

Urease

NH3

Apoptosis

H. pylori-induced inflammation
and inflammatory cytokine IL-8
H. pylori
Epithelial cell
LAP
NAP
IL-1
TNF
Macrophage

Tissue injury
Oxygen radicals
IL-8

Activation
Neutrophil
Chemotaxis

Transmigration
Adhesion
Venule

Role of neutrophil-endothelial
interactions in the pathogenesis
NSAIDs
LT/PG
LTC4, LTD4

Monocyte
activation

LTB4
TNF-

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

Ischemia-reperfusion
Oxygen radicals
Elastase

Neutrophil-endothelial cell interaction

Oxygen radicals
Elastase

Apoptosis

Endothelial
Extravasated
Neutrophil embolism
cell injury
migration
Hemorrhage
Edema

Ischemia

Gastric mucosal injury

Oxygen radicals
Elastase

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
Decreased
Mass of gastric parietal cells
Maximal acid output

*Evidence suggests that this abnormality may

be a reersible consequence of exobacter
pylori infection
GRP, gastrin-releasing peptide

CONDITIONS ASSOCIATED WITH

PEPTIC ULCER
NSAID
use

None known
ZE, other

NSAID
use

H. pylori
infection

H. pylori
infection

Duodenal

Gastric

None known
ZE, other

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
Environmental
Factors
Factors

Multifocal
Multifocal
Atrophic
Atrophic
Gastritis
Gastritis

Acute
Acute
Gastritis
Gastritis

Childhood

Gastric
GastricCancer
Cancer
Gastric Ulcer
Lymphoma
Lymphoma

Chronic Active Gastritis

Antral
Antral
Predominant
Predominant
Gastritis
Gastritis

Duodenal Ulcer
Lymphoma
Lymphoma

Old Age

Physiologic Functions of Gastric

Exocrine Secretions
PRODUCT
Hydrochloric acid

Pepsins
Gastric lipase
Intrinsic factor
Mucin/HCO3-

FUNCTION
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
Early hydrolysis of dietary proteins
Liberation of vitamin B12 from dietary protein
Early hydrolysis of dietary triglyceride
Binding of vitamin B12 for subsequentileal absorption
Protection against noxious agents

Distribution of human gastric endocrine

cells in glands from the oxyntic mucosa
(left) and pyloric mucosa (right)
ECL
35%

Other
14%

EC
25%

EC
29%

G
49%

D
26%

Oxyntic Mucosa

Other
3%

D
19%

Pyloric Mucosa

ECL, enterochromaffin-like (histamine); EC, enterochromaffin

(serotonin); D (somatostatin); G (gastrin)

Exocrine Cells within Gastric Glands and

Their Secretory Products*,
GLAND
AREA
% OF
TOTAL

EXOCRINE
CELLS
ANATOMIC
COUNTERPART

WITHIN
GLANDS

Cardiac Proximal stomach

Mucus neck
(<5%)
just below esophagogastric junction
Oxyntic Fundus and body
Mucus neck
(75%)
PGII
Chief PGI and PGII,
leptin
Parietal
HCI, intrinsic
factor
Pyloric
Antrum and pylorus
Mucus neck

SECRETORY
PRODUCTS
Mucin, PGII

Mucin, PGI and

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
Acidity
Osmolarity
Nutrient density
Fat
Certain amino acids
(e.g., L-tryptophan)
Other Factors
Ileal fat
Rectal/colonic distention
Pregnancy

Emptying rate proportional to volume

Slowing of emptying
Slower emptying of hypertonic meals
Emptying rate inversely proportional to
nutrient density
Slowing of emptying
Slowing of emptying

Slowing of emptying (ileal brake)

Slowing of emptying
Slowing of emptying

GASTRIC GLAND
MSC
MNC
ECL CELL
D CELL
PC

CC

Anatomic regions of the stomach

Lower esophageal
sphincter
Pylorus

Fundus
Oxyntic
gland
mucosa

Antrum
Pyloric gland
mucosa

Body