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Upper Gastro-intestinal tract: Inflammatory disease

Upper Gastro-intestinal tract: Inflammatory disease. Paul L. Crotty TCD Medical Student Lecture October 2007. Outline. Brief review of normal physiology Balance between hostile and protective factors Acute gastritis and acute stress ulcers Auto-immune gastritis

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Upper Gastro-intestinal tract: Inflammatory disease

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  1. Upper Gastro-intestinal tract: Inflammatory disease Paul L. Crotty TCD Medical Student Lecture October 2007

  2. Outline • Brief review of normal physiology • Balance between hostile and protective factors • Acute gastritis and acute stress ulcers • Auto-immune gastritis • Helicobacter gastritis: infection, outcomes • Peptic ulcer disease • NSAIDs and the GI tract • Oesophageal disease • Oesophagitis/Gastro-oesophageal reflux disease

  3. Gastro-intestinal tract • Important to review normal physiology • Functions: • mechanical: directional motility/reservoir • digestion of food/absorption of nutrients/fluid • regulated processes: neural/hormonal input • protection: auto-digestion/bacteria/antigens/toxins

  4. Regional specialisation • Oesophagus • tube to separate from respiratory system • Stomach • 1.2-1.5l reservoir, starts digestion • Small intestine • main site for digestion and absorption • Large intestine • water resorption

  5. Stomach

  6. Stomach • Fundus/Corpus • surface mucous cells and deep glands with • Parietal cells: Hydrochloric acid, Intrinsic Factor • Chief cells: Pepsinogen • Endocrine cells: Histamine, Somatostatin • Antrum • surface mucous cells and mucous glands • Mucous-producing cells • Endocrine cells (G cells): Gastrin

  7. Normal fundic type mucosa

  8. Normal antral type mucosa

  9. Gastritis: stomach inflammation Gastritis Normal antrum

  10. Gastritis: stomach inflammation

  11. Gastritis • Acute gastritis • Chronic gastritis • Type I • Type II • Type III

  12. Gastritis • Acute gastritis: Acute stress ulceration • acute ingestion of NSAIDs/alcohol • severe trauma/sepsis/shock • classically: ICU patient with multi-organ failure • extensive burns (Curling’s ulcer) • neurological disease (Cushing’s ulcer) • predominantly decrease in protective factors • risk of haemorrhage: acid suppression

  13. Acute gastritis Acute gastric stress ulcers

  14. Gastritis • Chronic gastritis • Type I: Auto-immune gastritis • Progressive immune destruction of GPC • Terminology • Chronic superficial gastritis • Chronic atrophic gastritis • Gastric atrophy • Pernicious anaemia

  15. Auto-immune gastritis • Circulating auto-antibodies (anti-GPC, intrinsic factor, proton pump) • Inflammation and atrophy involving fundus/corpus • Low secretion of acid +/- enzymes • Compensatory high serum gastrin levels • Associated with other auto-immune diseases/HLA • Secretion of intrinsic factor decreased • Associated with low serum B12/ megaloblastic anaemia

  16. Anti-gastric parietal cell antibodies

  17. Auto-immune gastritis Inflammation Loss of gastric parietal cell mass/mucosal atrophy Increasing time

  18. Auto-immune gastritis Inflammation Atrophy Increasing time

  19. Auto-immune gastritis Atrophy Intestinal metaplasia Risk of dysplasia and malignancy Increasing time

  20. Early stage Auto-immune gastritis Later stage: Atrophy and intestinal metaplasia

  21. Gastritis • Chronic gastritis • Type II: • Not auto-immune in origin • Different distribution: antral-predominant • Acid secretion increased (some normal) • Serum gastrin normal (some increased) • Concept crystallised with discovery of the role of...

  22. Helicobacter pylori

  23. Chronic gastritis • Type II: Helicobacter pylori gastritis • evidence for role of H. pylori in gastritis/ulcer • epidemiology • 90% of patients with duodenal ulcer • 70% with gastritis/gastric ulcer (80-90% if not taking NSAIDs) • treatment effect • Hp clearance leads to ulcer healing • High recurrence after ulcer healing without Hp clearance • experimental ingestion

  24. Historical 1899: Jaworski: spiral organisms in gastric washings 1924: Luck and Seth: antibiotic-sensitive urease activity in stomach 1938: Doenges: spirochaetes in autopsy stomach (40%) But the dogma was that: The stomach was sterile, all isolates were ‘contaminants’ 1975: Steer: bacteria seen in 80% of gastric ulcer patients 1979: Fung: bacteria seen in patients with chronic gastritis 1983: Warren: correlated with presence of neutrophils 1983-87: Marshall sells the concept world-wide

  25. Helicobacter Gram negative, curved/spiral organism Motile, flagellate organism > 20 different species Adapted to niche of life in the stomach

  26. Helicobacter pylori prevalence

  27. Bacteriology • Colonisation • motility: flagellae • urease enzyme activity • acute infection causes transient hypochlorhydria • Adherence • bacterial adhesins (BabA) • Tissue Injury • lipopolysaccharide, cagA, vacA, others

  28. Diagnosis of H. pylori infection

  29. Diagnosis of H. pylori infection

  30. Diagnosis of H. pylori infection

  31. Diagnosis of H. pylori infection

  32. Transmission • Not well understood: no animal reservoir • Person-person:? Vomitus ? Gastro-oral ? Dental plaque • What is known about acute infection? • - deliberate ingestion (Marshall) • - endoscope-mediated transmission • Acute infection causes transient epigastric pain/nausea • Histology: Acute neutrophilic gastritis

  33. Acute Helicobacter infection - Epithelial cells are the initial sensor of contact with pathogen - Bacterial factors: cagA, (?others) induce IL-8 secretion by the gastric epithelial cells (also IL-6, IL-7, IL-15) - IL8: chemotactic, activates neutrophils - IL-6, IL-7, IL-15: activate antigen-specific response -Bacterial lipopolysaccharide: directly chemotactic -Acute neutrophilic response

  34. Establishing chronic active infection However H. pylori remains intra-luminal, so - Neutrophil response fails to clear bacterium - Bacterial persistence sets up T-cell dependent response: lymphocytes, plasma cells - Neutrophil response persists => Chronic active gastritis

  35. Chronic active gastritis

  36. --> (Acute) --> Chronic active gastritis Different possible outcomes --> Antral-predominant gastritis --> duodenal ulcer --> Multi-focal atrophic gastritis --> gastric ulcer --> intestinal metaplasia --> risk of dysplasia --> adenocarcinoma --> Gastric lymphoma (lymphoma of MALT)

  37. Peptic ulcer Ulcer: full thickness breach in the mucosa Erosion: mucosal disruption but nit full thickness Peptic ulcer: Any chronic ulcer in the GI tract in association with damage caused by acid/peptic juices Duodenum, usually first part Stomach, usually antrum/pyloric channel OGJ Anastomosis Meckel’s diverticulum

  38. Duodenal ulceration H. pylori live exclusively on gastric surface mucous cells. They cannot survive on intestinal epithelial cells - So, how does H. pylori infection in the stomach cause ulceration in the duodenum?

  39. How does H. pylori infection in the stomach cause ulceration in the duodenum? Compare DU versus Non-DU patients with Hp infection DU patients have - lower IL-1beta production - higher acid output - more antral-predominant gastritis - high Gastrin with failure of feedback inhibition - increased parietal cell mass Delivery of excess acid into duodenum Induces gastric metaplasia in duodenum H. pylori infection of (metaplastic) gastric cells Direct cell injury, cell death, erosion, ulceration

  40. Duodenal ulceration Normal duodenum Two duodenal ulcers

  41. Left: Two duodenal ulcers: one with sentinel clotRight: Ulcer with visible vessel

  42. Chronic peptic ulcer

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