Pathogenesis Tukak Lambung

8/10/2019 Pathogenesis Tukak Lambung

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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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GASTRIC PARIETAL CELL UNDERGOING

TRANSFORMATION AFTER

SECRETAGOGUE-MEDIATED STIMULATIONStimulatedResting

Canaliculus

H+, K+-ATPaseKCI

KCI

HCI

ACh

Gastrin

HistamineTubulovesicles Active pumps

Ca-

H3O+


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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


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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)


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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


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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


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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


Apoptosis

Endothelialcell injury

Extravasatedmigration

Neutrophil embolism

HemorrhageEdema


Ischemia


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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


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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


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CONDITIONS ASSOCIATED WITH

PEPTIC ULCER

Duodenal

H.pylori

infection

NSAID

use

None knownZE, other

Gastric

H.pylori

infection

NSAID

use

None knownZE, other


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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


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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


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


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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


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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(


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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


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GASTRIC GLAND

MSC

ECL CELL

D CELL

MNC

CC

PC


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Anatomic regions of the stomach

Antrum

Pylorus

Pyloric gland

mucosa

Body

FundusLower esophagealsphincter

Oxyntic

glandmucosa

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Pathogenesis Tukak Lambung