Pathogenesis Tukak Lambung
-
Upload
daniel-matius -
Category
Documents
-
view
226 -
download
0
Transcript of Pathogenesis Tukak Lambung
-
8/10/2019 Pathogenesis Tukak Lambung
1/30
Potential Long-term Consequences of
H. pylo r iInfection
H. pyloriinfection
Weeks-moths
Chronic superficialgastritis
Years-decades
Chronic superficial
gastritis
Lymphoproliferative
disease
Chronic atrophic
gastritis
Gastric
adenocarcinoma
Peptic ulcer
disease
-
8/10/2019 Pathogenesis Tukak Lambung
2/30
MECHANISMS BY WHICH NSAIDs MAY
INCUDE MUCOSAL INJURY.
Direct toxicity
ion trapping
Endhothelial effectsStasis
Ischemia Ephithelial effects ( due toprostaglandin depletion)
HCI secretion
Mucin secretion
HCO3secretion
Surface activephospholipid secretion
Epithelial cell
proliferation
HEALING(spontaneous
or therapeutic)
EROSIONS
ULCER Acid
-
8/10/2019 Pathogenesis Tukak Lambung
3/30
Risk Factors for NSAIDs Induced
Gastroduodenal Ulceration
Established Possible
Advanced age Concomitant infection withHistory 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
-
8/10/2019 Pathogenesis Tukak Lambung
4/30
Disorders Associated with Peptic
Ulcer Disease
Strong association Possible association
Syatemic mastocytosis HyperparathyroidismChronic pulmonary disease Coronary artery disease
Chronic renal failure Polycythemia vera
Cirrhosis Chronic pancreatitis
Nephrolithiasis
Antitrypsin deficiency
-
8/10/2019 Pathogenesis Tukak Lambung
5/30
SUMMARY OF POTENTIAL MECHANISMS BY WHICH H. PYLORI
MAY LEAD TO GASTRIC SECRETORY ABNORMALITIES
Inflammatorycell
Inflammatorycell
ECL
SMS
Corpus
H. pylori
acid
IL-8+
+ +
+ ++
+
+
IL-8+
TNF-IFN-
IL-8
TNF-
IL-1
GD
P
D
-
8/10/2019 Pathogenesis Tukak Lambung
6/30
Bacterial factors
StructureAdhesins
Ponns
Enzymes
(urease, vac A, cag A, etc)
Host factors
DurationLocation
Inflammatory response
Genetics??
Chronic gastritis
Peptic ulcer disease
Gastric MALToma
Gastric cancer
-
8/10/2019 Pathogenesis Tukak Lambung
7/30
Reported Pathophysiologic Abnormalities
in Patients with Duodenal Ulcers
Abnormality Approximate Frequency, %
Nocturnal acid secretion 70
Duodenal HCO3secretion 70
Duodenal acid load 65Daytime 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
-
8/10/2019 Pathogenesis Tukak Lambung
8/30
CLASSIFICATION OF GASTRITIS
I. Acute gastritis II. Chronic Atrophic GasritisA. 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 predominant3. 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
-
8/10/2019 Pathogenesis Tukak Lambung
9/30
RISK FACTORS FOR H. py lor i
INFECTION
Birth or residence in developing country
Low socioeconomic statusDomestic crowding
Unsanitary living conditions
Unclean food or waterExposure to gastric contents of infected individual
-
8/10/2019 Pathogenesis Tukak Lambung
10/30
REGULATION OF GASTRIC ACID
SECRETION AT THE CELLULAR LEVEL
ANTRUM
FUNDUSParietal cell
CannaliculusHistamine
SomatostatinSomatostatin
Histamine
Somatostatin
Gastrin
Gastrin
Vagus
Acetylcholine
Blood vessel
TubulovesiclesH, K ATPase ECL cell
ECL cell
G cellD cell
D cell
-
8/10/2019 Pathogenesis Tukak Lambung
11/30
SCHEMATIC REPRESENTATION OF THE STEPS INVOLVED
IN SYNTHESIS OF PROSTAGLANDIN E2(PGE2) AND
PROSTACYCLIN (PGI2)
Membrane phospholipids
Phospholipase A2
Arachidonic acid
COX-2inflammation
MacrophagesLeukocytesFibroblastsEndothelium
PGI2, PGE2
Inflammation
Mitogenesis
Bone formationOther functions?
TXA2, PGI2, PGE2Gastrointestinal mucosal integrityPlatelet aggregationRenal function
COX-1housekeeping
StomachKidneyPlateletsEndhothelium
-
8/10/2019 Pathogenesis Tukak Lambung
12/30
COMPONENTS INVOLVED IN PROVIDING
GASTRODUODENAL MUCOSAL DEFENSE
Epithelium
HCO3-
LumenpH 1-2
Mucus gelpH 7HCO3
-
H+ Pepsin
Prostaglandin
Microcirculation
Preepithelial
Mucus
Bicarbonate
Surface active
phospholipids
Epithelial
Cellular resistance
Restitution
Growth factors,
protaglandins
Cell proliferation
Subepithelial
Blood flow
Leukocyte
-
8/10/2019 Pathogenesis Tukak Lambung
13/30
GASTRIC PARIETAL CELL UNDERGOING
TRANSFORMATION AFTER
SECRETAGOGUE-MEDIATED STIMULATIONStimulatedResting
Canaliculus
H+, K+-ATPaseKCI
KCI
HCI
ACh
Gastrin
HistamineTubulovesicles Active pumps
Ca-
H3O+
-
8/10/2019 Pathogenesis Tukak Lambung
14/30
ADHESION MOLECULES, CYTOKINE AND CHEMICAL
MEDIATOR IN LEUKOCYTE-ENDOTHELIAL INTERACTIONS
Tissue injury
Oxygen radicals, Protease
ActivatedPMN
Endothelial injury
Endothelial cells
H2O2
PAFC5aLTB4IL-8
Thrombin
HistamineH2O2LTC4LTD4
IL-1TNFLPS
L-selectionSLeXSLea
IL-8
PAF
P-selectin E-selectin ICAM-1 PAF PECAM-1
CollagenaseElastase
CD11/CD18
Rolling Sticking Transmigration
-
8/10/2019 Pathogenesis Tukak Lambung
15/30
POSSIBLE MECHANISM OF ULCER
RECURRENCE
Gastric acid
IL-1
, TNF-
(NSAID, H.pylori, stress)Neurophil Infiltration
ULCER RECURRENCE
Neutrophil activation
CytokinesChemokines
Monocyte infiltration
Macrophage activation
ULCER SCAR
Cytokines(IL-1
, TNF-
)Chemokines
(MCP-1, TGF-1)
Endothelial cell-leukocyte interaction(ICAM-1/LFA-1, ICAM-1/Mac-1)
-
8/10/2019 Pathogenesis Tukak Lambung
16/30
Gastric Mucosal Oxidative Stress
in Response to H. py lor i
H. pylori
Urease NH3
NH2CI
H2O2
O2-
O2H2O
HOFe2+
OCI-
ROO-
GSH GSSG
CatalaseGSH-Px
Apoptosis
TBA-RS
SOD
CXC-chemokineIL-8, GRO
-
8/10/2019 Pathogenesis Tukak Lambung
17/30
H. py lor i-induced inflammation
and inflammatory cytokine IL-8
H. pylori
LAP
NAP
Epithelial cell
Tissue injury
Oxygen radicals
Adhesion
Neutrophil
Chemotaxis
Transmigration
Venule
Activation
Macrophage
IL-8IL-1TNF
-
8/10/2019 Pathogenesis Tukak Lambung
18/30
Role of neutrophil-endothelial
interactions in the pathogenesis
Gastric mucosal injury
NSAIDs
LT/PG Monocyte
activationLTC4, LTD4 LTB4
Vasospasm
TNF-
Ischemia-reperfusion
Neutrophil activation(CD11b/CD18)
Endothelial cell activation(ICAM-1)
Neutrophil-endothelial cell interaction
Oxygen radicalsElastase
Oxygen radicalsElastase
Apoptosis
Endothelialcell injury
Extravasatedmigration
Neutrophil embolism
HemorrhageEdema
Oxygen radicalsElastase
Ischemia
-
8/10/2019 Pathogenesis Tukak Lambung
19/30
-
8/10/2019 Pathogenesis Tukak Lambung
20/30
Topographic patterns of chronic,
nonspecific gastritis
The black areas in the schematic of diffuse corporal atrophic gastritis
and multifocal atrophic gastritis represent areas of focal atrophy and
intestinal metaplasia
Diffuse Antral Gastritis Diffuse Corporal Atrophic Gastritis
Multifocal Atrophic Gastritis
-
8/10/2019 Pathogenesis Tukak Lambung
21/30
Reported Abnormalities in Gastric Acid Secretion
and Acid Homeostasis in Peptic Ulcer DiseaseDuodenal UlcerIncreased
Mass of gastric parietal cellsMaximal acid outputPeak acid output stimulated by meals*Duration of meal-stimulated acid secretionBasal acid outputDaytime acid output
Nocturnal acid outputFasting 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 duodenumGastric UlcerIncreased
Serum levels of pepsinogen IIDuodenogastric reflux
Decreased
Mass of gastric parietal cellsMaximal acid output
*Evidence suggests that this abnormality may
be a reersible consequence of exobacter
pylori infection
GRP, gastrin-releasing peptide
-
8/10/2019 Pathogenesis Tukak Lambung
22/30
CONDITIONS ASSOCIATED WITH
PEPTIC ULCER
Duodenal
H.pylori
infection
NSAID
use
None knownZE, other
Gastric
H.pylori
infection
NSAID
use
None knownZE, other
-
8/10/2019 Pathogenesis Tukak Lambung
23/30
Virulence Factors of Helicobacter pylor ithat
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
-
8/10/2019 Pathogenesis Tukak Lambung
24/30
Proposed natural history of Helicobacter
py lor iinfection in humans
Childhood Old Age
Chronic Active GastritisAcuteGastritis
EnvironmentalFactors
MultifocalAtrophic
Gastritis
AntralPredominantGastritis
Gastric Cancer
Lymphoma
Lymphoma
Gastric Ulcer
Duodenal Ulcer
-
8/10/2019 Pathogenesis Tukak Lambung
25/30
Physiologic Functions of Gastric
Exocrine Secretions
PRODUCT FUNCTIONHydrochloric acid Provides optimal pH for pepsin and gastric lipase
(see below)
Facilitates duodenal inorganic iron absorption
Negative feedback of gastrin releaseStimulation of pancreatic HCO3- secretion
Supression of ingested microorganisms
Pepsins Early hydrolysis of dietary proteins
Liberation of vitamin B12from dietary proteinGastric lipase Early hydrolysis of dietary triglyceride
Intrinsic factor Binding of vitamin B12for subsequentileal ab-sorption
Mucin/HCO3- Protection against noxious agents
-
8/10/2019 Pathogenesis Tukak Lambung
26/30
Distribution of human gastric endocrine
cells in glands from the oxyntic mucosa
(left) and pyloric mucosa (right)
Oxyntic Mucosa
ECL, enterochromaffin-like (histamine); EC, enterochromaffin (serotonin);
D (somatostatin); G (gastrin)
Pyloric Mucosa
EC
25%
D
26%Other14%
ECL
35%EC
29%
D
19%Other
3%
G
49%
E i C ll ithi G t i Gl d d
-
8/10/2019 Pathogenesis Tukak Lambung
27/30
Exocrine Cells within Gastric Glands and
Their Secretory Products*,
GLAND EXOCRINE
AREA CELLS% OF ANATOMIC WITHIN SECRETORYTOTAL COUNTERPART GLANDS PRODUCTS
Cardiac Proximal stomach Mucus neck Mucin, PGII(
-
8/10/2019 Pathogenesis Tukak Lambung
28/30
Factors That May Modulate the Rate of
Gastric Emptying
Meal FactorsVolume Emptying rate proportional to volume
Acidity Slowing of emptying
Osmolarity Slower emptying of hypertonic meals
Nutrient density Emptying rate inversely proportional tonutrient 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
-
8/10/2019 Pathogenesis Tukak Lambung
29/30
GASTRIC GLAND
MSC
ECL CELL
D CELL
MNC
CC
PC
-
8/10/2019 Pathogenesis Tukak Lambung
30/30
Anatomic regions of the stomach
Antrum
Pylorus
Pyloric gland
mucosa
Body
FundusLower esophagealsphincter
Oxyntic
glandmucosa