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![H. PYLORI PATHOGENESIS
BACTERIAL VIRULENCE FACTORS
(CAG- PAI)( 37000 B-P – 29 GENES)
• Type IV secretions apparatus(1) (translocate cag A)
• Possible insertion by needle like organelle coated with a sheath (Cag 7
protein) [Rohde et al]
• Phosphorylated + binds to SHP-2 tyrosine Phosphates
Cytokine Production Growth Factor
IL- 8+ chemokines Like cellular response
(1) Odenbreit S, et al. Science 2000;287:1497-1500](https://image.slidesharecdn.com/helicobacterpylori-120616225853-phpapp01-221005085655-9c002c54/75/helicobacterpylori-120616225853-phpapp01-pdf-14-2048.jpg)
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helicobacterpylori-120616225853-phpapp01.pdf
- 1.
- 2. HISTORY OF H.PYLORI • 1890’s: Spirochetes in animal stomachs • 1900’s: Spirochetes in human stomachs • 1954: No bacteria in gastric biopsies of 1000 patients • 1975: Gram negative bacteria in 80% of GU’s (Pseudomonas) • 1983: Warren and Marshall characterize H. pylori • 2005 Nobel prize in 2005
- 3. HELICOBACTER PYLORI Background Human stomachlong considered inhospitable for bacteria Spiral shaped organisms occasionally visualized in gastric mucous layer, but no evidence of disease association Organism classified first as Campylobacter pylori Now Helicobacter pylori Other species of Helicobacter isolated from stomach, intestine of other animals Marshall and Warren culture organism from human gastric mucosa and show association with gastric inflammation DR.T.V.RAO MD 3
- 4. HELICOBACTER ( WARREN ANDMARSHAL ) • Campylobacter like organisms • Spiral shaped colonizes Gastric mucosa • Etiological agent in Gastritis and peptic ulcer • Most important bacteria. Helicobacter pylori Colonizes 50 % of the Individuals DR.T.V.RAO MD 4
- 5. WARREN AND MARSHALWINS NOBEL PRIZE DR.T.V.RAO MD 5
- 6. GENERAL CHARACTERISTICS OF HELICOBACTER DR.T.V.RAOMD 6 • Helicobacter pylori is major human pathogen associated with gastric antral epithelium in patients with active chronic gastritis • Stomach of many animal species also colonized • Urease (gastric strains only), mucinase, and catalase positive highly motile microorganisms • Other Helicobacters: H. cinnaedi and H. fenneliae • Colonize human intestinal tract • Isolated from homosexual men with proctitis, proctocolitis, enteritis, and bacteremia and are often transmitted through sexual practices
- 7. A silver stainof H. pylori on gastric mucus- secreting epithelial cells (x1000). From Dr. Marshall's stomach biopsy taken 8 days after he drank a culture of H. pylori (1985). DR.T.V.RAO MD 7
- 8. HELICOBACTER PYLORI • Gram–ve spiral shaped , motile with unipolar tuft of lopotrichus flagella DR.T.V.RAO MD 8
- 9. H. PYLORI BACTERIA •Gram negative • Spiral rod • Unipolar flagella • Microaerophilic • Urease positive* *Most important character *Scanning microscopic view of H. pylori
- 10. MORPHOLOGY & PHYSIOLOGYOF HELICOBACTER DR.T.V.RAO MD 10 • Gram-negative; Helical (spiral or curved) (0.5-1.0 um X 2.5-5.0 um); Blunted/rounded ends in gastric biopsy specimens; Cells become rod-like and coccoid on prolonged culture • Produce urease, mucinase, and catalase • H. pylori tuft (lophotrichous) of 4-6 sheathed flagella (30um X 2.5nm) attached at one pole • Single polar flagellum on H. fennellae & H. cinaedi • Smooth cell wall with unusual fatty acids
- 11. • Transmissible • Oral-oraland oral- fecal • Infects the human stomach • Produces inflammatory response • This brings up the point of the importance of “hand washing” H. PYLORI INFECTION TRANSMISSION
- 12. DYNAMICS OF H.PYLORIINFECTION DR.T.V.RAO MD 12
- 13. CULTURING AND BIOCHEMICAL CHARACTERS •Grows on chocolate agar, Campylobacter media • Grows under Microaerophilic conditions • With presence of 5 – 20% co2 • Oxidase + • Catalase – • Urease strongly +++ • H2S DR.T.V.RAO MD 13
- 14. H. PYLORI PATHOGENESIS BACTERIALVIRULENCE FACTORS (CAG- PAI)( 37000 B-P – 29 GENES) • Type IV secretions apparatus(1) (translocate cag A) • Possible insertion by needle like organelle coated with a sheath (Cag 7 protein) [Rohde et al] • Phosphorylated + binds to SHP-2 tyrosine Phosphates Cytokine Production Growth Factor IL- 8+ chemokines Like cellular response (1) Odenbreit S, et al. Science 2000;287:1497-1500
- 15. H. PYLORI PATHOGENESIS BACTERIALVIRULENCE FACTORS Ingestion Evasion + Entrance of Mucus 1 Layer (Motility + Urea I) 2 Binding 3 Insertion 4 Intra cellular pathway
- 16. HELICOBACTER PYLORI ANDPEPTIC ULCER DISEASE HISTOPATHOLOGY WITH SPECIAL STAINS .
- 17.
- 18. H. PYLORI PATHOGENESIS THEROLE OF CYTOKINES I. Alter secretion of mucus II. TNF–α IL–Iß, INF- 1Y • ↑ Gastrin release Stimulate parietal cells ↑ Acid secretion I. TNF–α ↓ D cells number ↓ Somatostatin ↑ Acid secretion
- 19. PATHOLOGY AND PATHOGENESIS •H.pylori colonizes gastric mucosa • Spread by oral – oral contact • Feco oral spread prominent • Poverty and overcrowding predisposes • Poor Hygiene • Causes mild to acute gastritis • Gastric antrum - causes gastric metaplasia • Any part of the stomach can be involved • Colonizes overlying mucosa but donot invade mucosa DR.T.V.RAO MD 19
- 20.
- 21. Colonize mucosallining of stomach & duodenum in man & animals • Adherent to gastric surface epithelium or pit epithelial cells deep within the mucosal crypts adjacent to gastric mucosal cells • Mucosa protects the stomach wall from its own gastric milleu of digestive enzymes and hydrochloric acid • Mucosa also protects Helicobacter from immune response Most gastric adenocarcinomas and lymphomas are concurrent with or preceded by an infection with H. pylori Pathogenesis of Helicobacter Infections
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- 24. Multiple polar,sheathed flagella • Corkscrew motility enables penetration into viscous environment (mucus) Adhesins: Hemagglutinins; Sialic acid binding adhesin; Lewis blood group adhesin Mucinase: Degrades gastric mucus; Localized tissue damage Urease converts urea (abundant in saliva and gastric juices) into bicarbonate (to CO2) and ammonia • Neutralize the local acid environment • Localized tissue damage Acid-inhibitory protein Virulence Factors of Helicobacter
- 25. H. Pylori SpecificT Cell and B Cell Responses
- 26. MECHANISM OF H.PYLORIINFECTION DR.T.V.RAO MD 26
- 27. Urease C=O(NH2)2 + H++ 2H2O HCO3 - + 2 (NH4 +) Urea Bicarbonate Ammonium ions And then… HCO3 - CO2 + OH- Urea Hydrolysis
- 28. Tissue damage: Vacuolatingcytotoxin: Epithelial cell damage Invasin(s)(??): Poorly defined (e.g., hemolysins; phospholipases; alcohol dehydrogenase) Protection from phagocytosis & intracellular killing: Superoxide dismutase Catalase Virulence Factors of Helicobacter )
- 29. H. Pylori Pathogenesisand Application of Cutting Edge Technologies Molecular biology Genetics Imaging Cell culture models
- 30. INDICATIONS FOR NONINVASIVE TESTINGFOR H. PYLORI * • Strongly Recommended • Dyspepsia • History of/active peptic ulcer disease • Gastric MALT lymphoma • Following gastric cancer resection • Following peptic ulcer surgery • First-degree relative with gastric cancer • Long-term Non-steroidal anti-inflamatory drugs (NSAID) therapy * In the absence of alarm signs for gastric cancer or ulcer disease 1. Malfertheiner P, et al. Aliment Pharmacol Ther. 2002;16:167. 2. Talley NJ et al. Aliment Pharmacol Ther. 1999;12:1135.
- 31. TYPES OF H.PYLORI TESTS • Endoscopy • Rapid urease tests • Histology • Culture • Serologic (antibody) • Stool antigen tests •13C Urea blood test • Urea breath tests •14C-urea •13C-urea Malfertheiner P, et al. Aliment Pharmacol Ther. 2002;16:167.
- 32. • Detects activeinfection • Sensitive and specific • Non-radioactive • No special handling requirements • Easy to collect and handle sample • Not indicated in pediatric population 13C UREA BREATH TEST 1. Graham DY et al. Am J Gastroenterol. 2001;96:1741. 2. Leodolter A et al. Am J Gastroenterol. 1999;94:2100.
- 33. LABORATORY DIAGNOSIS • Diagnosedby Invasive and Non Invasive tests • Invasive, Endoscopic Biopsy of Gastric mucosa • Microscopy – Biopsy • Culture • Staining by special stains • Gram staining • Culture more sensitive 3 – 7 days • Biopsy testing for urease detection in urea medium DR.T.V.RAO MD 33
- 34. Laboratory Identification Recoveredfrom or detected in endoscopic antral gastric biopsy material; Multiple biopsies are taken Many different transport media Culture media containing whole or lysed blood Microaerophilic Grow well at 37oC, but not at 25 nor 42oC Like Campylobacter, does not use carbohydrates, neither fermentatively nor oxidatively
- 35. DIAGNOSIS BY NONINVASIVE METHODS • Serology ELISA • Urea breath test patient swallows urea solution In this test patient drinks urea solutions labeled with an isotope carbon If H.pylori is present in the urea is converted to ammonia and co2 in the breath measured. DR.T.V.RAO MD 35
- 36. SUGGESTED GUIDELINES FOR TREATMENTOF PATIENTS WITH GI OR ULCER DISEASE History & Physical Exam Peptic ulcer disease Undifferentiated dyspepsia Symptoms of GERD Use of NSAIDs or aspirin Positive Eradication therapy Confirmation of cure Test for H. pylori Malfertheiner P, et al. Aliment Pharmacol Ther. 2002;16:167.
- 37. SUGGESTED GUIDELINES FOR TREATMENTOF PATIENTS WITH GI OR ULCER DISEASE History & Physical Exam Peptic ulcer disease Undifferentiated dyspepsia Symptoms of GERD Use of NSAIDs or aspirin Positive Eradication therapy Confirmation of cure Negative Treat for PUD, Initiate PPI therapy, or discontinue NSAIDs Test for H. pylori Malfertheiner P, et al. Aliment Pharmacol Ther. 2002;16:167.
- 38. TREATMENT • Use ofantibiotics, bismuth salts • Ingestion of Bismuth subsalicylate • Antibiotics Tetracycline's and metronidazole for two weeks • Use of Omeprazole • Clarithromycin • Do not treat for Asymptomatic colonization • Drug resistance is a growing problem DR.T.V.RAO MD 38
- 39. • Antibiotic treatmentdoes not always completely inhibit or kill H. pylori with potential for antibiotic resistance. Resistance to antibiotics is the single most important factor for declining H. pylori eradication rates. • In Japan, resistance to antibiotic drugs has increased 400% while in Taiwan, it is 500%. This means that those who are infected while in these countries may find the bacterium rather resistant to their antibiotic treatments. EMERGING DRUG RESISTANCE IN H.PYLORI DR.T.V.RAO MD 39
- 40. EPIDEMIOLOGY OF HELICOBACTERINFECTIONS DR.T.V.RAO MD 40 • Developed Countries: • United States: 30% of total population infected • Of those, ~1% per year develop duodenal ulcer • ~1/3 eventually have peptic ulcer disease(PUD) • 70% gastric ulcer cases colonized with H. pylori • Low socioeconomic status predicts H. pylori infection • Developing Countries: • Hyperendemic • About 10% acquisition rate per year for children between 2 and 8 years of age • Most adults infected but no disease • Protective immunity from multiple childhood infections
- 41. H.PYLORI CONTINUES TOBE AN IMPORTANT PATHOGEN • H. pylori is a transmissible, infectious disease with potentially serious outcomes • H. pylori infection may be asymptomatic or cause dyspepsia • Eradication therapy can cure H. pylori infection and prevent morbidity and downstream events such as PUD and gastric cancer • Patients with symptoms of upper-GI disease, and who use aspirin or NSAIDs should be tested for H. pylori infection
- 42. • Programme Createdby Dr.T.V.Rao MD for Medical and Health Care Workers in the Developing World • Email • [email protected] DR.T.V.RAO MD 42