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” Ephithelial effects ( due to prostaglandin depletion) •  HCI secretion •  Mucin secretion •  HCO3secretion •  Surface active phospholipid secretion •  Epithelial cell proliferation

ULCER

Acid

HEALING (spontaneous or therapeutic)

EROSIONS

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 D – – acid + D – +

TNF-
IL-1 – – – + – + + G – + – SMS ECL +

P

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

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. 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
Vagus Acetylcholine Parietal cell FUNDUS

Cannaliculus Histamine   H, K ATPase ECL cell Tubulovesicles  – Histamine  – – ECL cell Somatostatin Somatostatin D cell Gastrin  Blood vessel D 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 COX-2 inflammation Macrophages Leukocytes Fibroblasts Endothelium

TXA2, PGI2, PGE2 Gastrointestinal mucosal integrity Platelet aggregation Renal function

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+ Pepsin Lumen pH 1-2 HCO3Mucus gel pH 7 HCO3Epithelium Prostaglandin Microcirculation

GASTRIC PARIETAL CELL UNDERGOING TRANSFORMATION AFTER SECRETAGOGUE-MEDIATED STIMULATION
Resting Stimulated

HCI KCI Canaliculus H3 O + H+, K+ -ATPase CaGastrin Tubulovesicles Active pumps ACh Histamine KCI

ADHESION MOLECULES, CYTOKINE AND CHEMICAL MEDIATOR IN LEUKOCYTE-ENDOTHELIAL INTERACTIONS
Rolling Sticking
PAF C5a LTB4 IL-8

Transmigration

L-selection SLeX SLea

H2 O 2

IL-8 PAF

P-selectin
Thrombin Histamine H2O2 LTC4 LTD4

E-selectin

CD11/CD18 ICAM-1 IL-1 TNF LPS

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)

Neutrophil activation Cytokines Chemokines

Macrophage activation
ULCER SCAR

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 O2•SOD GSH

Catalase GSH-Px

H2 O

GSSG

H2O2 OCI-

Fe2+

HO•

ROO-

H. pylori
NH2CI Urease NH3

TBA-RS

Apoptosis

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

Epithelial cell
LAP NAP Tissue injury Oxygen radicals

IL-1 TNF Macrophage

IL-8

Activation 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
Oxygen radicals Elastase

Oxygen radicals Elastase

Neutrophil-endothelial cell interaction

Apoptosis

Endothelial Extravasated Neutrophil embolism cell injury migration
Hemorrhage Edema

Ischemia

Oxygen radicals 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 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

None known ZE, other

H. pylori infection

H. pylori 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 Gastritis

Gastric Ulcer Lymphoma

Acute Gastritis

Chronic Active Gastritis
Antral Predominant Gastritis
Duodenal Ulcer Lymphoma

Childhood

Old Age

Physiologic Functions of Gastric Exocrine Secretions
PRODUCT
Hydrochloric acid

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

Pepsins Gastric lipase Intrinsic factor Mucin/HCO3-

Distribution of human gastric endocrine cells in glands from the oxyntic mucosa (left) and pyloric mucosa (right)
ECL 35%

EC 25%

G 49%

EC 29%

Other 14%

D 26%

Other 3%

D 19%

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 AREA % OF TOTAL
Cardiac (<5%)

ANATOMIC COUNTERPART
Proximal stomach just below esophagogastric junction Fundus and body

EXOCRINE CELLS WITHIN GLANDS
Mucus neck

SECRETORY PRODUCTS
Mucin, PGII

Oxyntic (75%)

Mucus neck
Chief Parietal

Pyloric

Antrum and pylorus

Mucus neck

Mucin, PGI and PGII‡ PGI and PGII, ‡ leptin HCI, intrinsic factor§ 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 Oxyntic gland mucosa

Fundus

Body

Antrum
Pyloric gland mucosa

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