Potential Long-term Consequences of H. pylori Infection

Potential Long-term Consequences of H. pylori Infection

H. pylori infection

Weeks-moths

Chronic superficial gastritis

Years-decades

Chronic superficial gastritis

Lymphoproliferative disease

Chronic atrophic gastritis

Gastric adenocarcinoma

Peptic ulcer disease

MECHANISMS BY WHICH NSAIDs MAY INCUDE MUCOSAL INJURY.

MECHANISMS BY WHICH NSAIDs MAY INCUDE MUCOSAL INJURY.

• Direct toxicity “ion trapping”

Endhothelial effects•Stasis Ischemia

Ephithelial effects ( due to prostaglandin depletion)• HCI secretion• Mucin secretion• HCO3secretion• Surface active

phospholipid secretion• Epithelial cell

proliferation

HEALING (spontaneous or therapeutic)

EROSIONS

ULCER Acid

Risk Factors for NSAIDs Induced Gastroduodenal Ulceration

Risk Factors for NSAIDs Induced Gastroduodenal Ulceration

Established Possible

Advanced age Concomitant infection withHistory of ulcer H. pyloriConcomitant use of glucocorticoids Cigarette smokingHigh-dose NSAIDs Alcohol consumptionMultiple NSAIDsConcomitant use of anticoagulantsSerious or multisystem disease

Disorders Associated with Peptic Ulcer Disease

Disorders Associated with Peptic Ulcer Disease

Strong association Possible association

Syatemic mastocytosis HyperparathyroidismChronic pulmonary disease Coronary artery diseaseChronic renal failure Polycythemia veraCirrhosis Chronic pancreatitisNephrolithiasis Antitrypsin deficiency

SUMMARY OF POTENTIAL MECHANISMS BY WHICH H. PYLORI MAY LEAD TO GASTRIC SECRETORY ABNORMALITIES

SUMMARY OF POTENTIAL MECHANISMS BY WHICH H. PYLORI MAY LEAD TO GASTRIC SECRETORY ABNORMALITIES

Inflammatory cell

Inflammatory cell

ECL

SMS

Corpus

H. pylori

acid

IL-8+

– + – +

+ ++

+

–––+–

–

– –

IL-8+

TNF-IFN-IL-8

TNF-

IL-1

GD

P

D

Bacterial factorsStructureAdhesinsPonnsEnzymes

(urease, vac A, cag A, etc)

Host factorsDurationLocationInflammatory responseGenetics??

Chronic gastritisPeptic ulcer diseaseGastric MALTomaGastric cancer

Reported Pathophysiologic Abnormalities in Patients with Duodenal Ulcers

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 GASTRITISCLASSIFICATION 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. Indeterminant4. Mycobacterial5. Syphilitic III. Uncommon Form of Gastritis6. Viral A. Lymphocytic 7. Parasitic B. Eosinophilic8. Fungal C. Crhn’s disease

D. SarcoidosisE. Isolated granulomatous gratritis

RISK FACTORS FOR H. pylori INFECTION

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

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

SCHEMATIC REPRESENTATION OF THE STEPS INVOLVED IN SYNTHESIS OF PROSTAGLANDIN E2(PGE2) AND

PROSTACYCLIN (PGI2)

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

InflammationMitogenesisBone formationOther functions?

TXA2, PGI2, PGE2

Gastrointestinal mucosal integrityPlatelet aggregationRenal function

COX-1housekeeping

StomachKidneyPlateletsEndhothelium

COMPONENTS INVOLVED IN PROVIDING GASTRODUODENAL MUCOSAL DEFENSECOMPONENTS INVOLVED IN PROVIDING

GASTRODUODENAL MUCOSAL DEFENSE

EpitheliumHCO3

-

LumenpH 1-2

Mucus gelpH 7HCO3

-

H+ Pepsin

Prostaglandin

Microcirculation

Preepithelial• Mucus• Bicarbonate• Surface active phospholipidsEpithelial• Cellular resistance• Restitution• Growth factors, protaglandins•Cell proliferation

Subepithelial• Blood flow•Leukocyte

GASTRIC PARIETAL CELL UNDERGOING TRANSFORMATION AFTER

SECRETAGOGUE-MEDIATED STIMULATION

GASTRIC PARIETAL CELL UNDERGOING TRANSFORMATION AFTER

SECRETAGOGUE-MEDIATED STIMULATIONStimulatedResting

Canaliculus

H+, K+ -ATPase

KCI

KCI

HCI

cAMP

ACh

Gastrin

HistamineTubulovesicles Active pumps

Ca-

H3O+

ADHESION MOLECULES, CYTOKINE AND CHEMICAL MEDIATOR IN LEUKOCYTE-ENDOTHELIAL INTERACTIONS

ADHESION MOLECULES, CYTOKINE AND CHEMICAL MEDIATOR IN LEUKOCYTE-ENDOTHELIAL INTERACTIONS

Tissue injury

Oxygen radicals, Protease

Activated PMN

Endothelial injury

Endothelial cells

H2O2

PAFC5a

LTB4

IL-8

ThrombinHistamineH2O2

LTC4

LTD4

IL-1TNFLPS

L-selectionSLeX

SLea

IL-8PAF

P-selectin E-selectin ICAM-1 PAF PECAM-1

CollagenaseElastase

CD11/CD18

Rolling Sticking Transmigration

POSSIBLE MECHANISM OF ULCER RECURRENCE

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)

Gastric Mucosal Oxidative Stress in Response to H. pylori

Gastric Mucosal Oxidative Stress in Response to H. pylori

H. pylori

Urease NH3

NH2CI

H2O2

O2•-

O2

H2O

HO•

Fe2+

OCI-

ROO-

GSH GSSG

CatalaseGSH-Px

Apoptosis

TBA-RS

SOD

CXC-chemokineIL-8, GRO

H. pylori-induced inflammation and inflammatory cytokine IL-8H. pylori-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

Role of neutrophil-endothelial interactions in the pathogenesis

Role of neutrophil-endothelial interactions in the pathogenesis

Gastric mucosal injury

NSAIDs

LT/PG Monocyte activation

LTC4, LTD4 LTB4

Vasospasm

TNF-

Ischemia-reperfusion

Neutrophil activation(CD11b/CD18)

Endothelial cell activation(ICAM-1)

Neutrophil-endothelial cell interaction

Oxygen radicals Elastase

Oxygen radicals Elastase

Apoptosis

Endothelial cell injury

Extravasated migrationNeutrophil embolism

Hemorrhage Edema

Oxygen radicals Elastase

Ischemia

Gastric Biopsy ProtocolGastric Biopsy ProtocolBIOPSY PROTOCOL

Topographic patterns of chronic, nonspecific gastritis

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

Reported Abnormalities in Gastric Acid Secretion and Acid Homeostasis in Peptic Ulcer Disease

Reported Abnormalities in Gastric Acid Secretion and Acid Homeostasis in Peptic Ulcer Disease

Duodenal UlcerIncreased

Mass of gastric parietal cellsMaximal acid outputPeak acid output stimulated by meals*Duration of meal-stimulated acid secretionBasal acid outputDaytime acid outputNocturnal acid outputFasting serum gastrin levels*Meal- and GRP-stimulated gastrin levels*Serum concentrations of pepsinogen I*Rate of gastric emptying for liquids

DecreasedBicarbonate production by the proximal duodenum

Gastric UlcerIncreased

Serum levels of pepsinogen IIDuodenogastric reflux

DecreasedMass of gastric parietal cellsMaximal 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

CONDITIONS ASSOCIATED WITH PEPTIC ULCER

Duodenal

H. pylori infection

NSAID use

None knownZE, other

Gastric

H. pylori infection

NSAID use

None knownZE, other

Virulence Factors of Helicobacter pylori that Promote Colonization and induce Tissue Injury

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

Proposed natural history of Helicobacter pylori infection in humans

Childhood Old Age

Chronic Active GastritisAcuteGastritisAcuteGastritis

EnvironmentalFactors

EnvironmentalFactors

MultifocalAtrophicGastritis

MultifocalAtrophicGastritis

AntralPredominantGastritis

AntralPredominantGastritis

Gastric CancerGastric Cancer

LymphomaLymphoma

LymphomaLymphoma

Gastric Ulcer

Duodenal Ulcer

Physiologic Functions of Gastric Exocrine Secretions

Physiologic Functions of Gastric Exocrine Secretions

PRODUCT FUNCTION

Hydrochloric acid Provides optimal pH for pepsin and gastric lipase (see below)

Facilitates duodenal inorganic iron absorptionNegative feedback of gastrin releaseStimulation of pancreatic HCO3- secretionSupression of ingested microorganisms

Pepsins Early hydrolysis of dietary proteinsLiberation of vitamin B12 from dietary protein

Gastric lipase Early hydrolysis of dietary triglycerideIntrinsic factor Binding of vitamin B12 for subsequentileal ab-

sorptionMucin/HCO3- Protection against noxious agents

Distribution of human gastric endocrine cells in glands from the oxyntic mucosa

(left) and pyloric mucosa (right)

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%Other

14%

ECL 35%

EC 29%

D 19%

Other 3%

G 49%

Exocrine Cells within Gastric Glands and Their Secretory Products*,†

Exocrine Cells within Gastric Glands and Their Secretory Products*,†

GLAND EXOCRINEAREA 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

Factors That May Modulate the Rate of Gastric Emptying

Meal FactorsVolume Emptying rate proportional to volumeAcidity Slowing of emptyingOsmolarity Slower emptying of hypertonic mealsNutrient density Emptying rate inversely proportional to

nutrient densityFat Slowing of emptyingCertain amino acids Slowing of emptying (e.g., L-tryptophan)

Other FactorsIleal fat Slowing of emptying (ileal “brake”)Rectal/colonic distention Slowing of emptyingPregnancy Slowing of emptying

GASTRIC GLANDGASTRIC GLAND

MSC

ECL CELL

D CELL

MNC

CC

PC

Anatomic regions of the stomachAnatomic regions of the stomach

Antrum

Pylorus

Pyloric gland mucosa

Body

FundusLower esophageal

sphincter

Oxyntic gland

mucosa