NON-NEOPLASTIC CONDITIONS OF THE GASTROINTESTINAL TRACT

1. NON-NEOPLASTIC CONDITIONS OF THE GASTROINTESTINAL TRACT Dr RFT McMAHON Senior Lecturer in Pathology University of Manchester Honorary Consultant Pathologist Manchester Royal Infirmary Academic Session 2011-12

2. Marshall BJ, Warren JR. Unidentified curved bacilli in the human stomach. Lancet 1984 Barry J Marshall & J Robin Warren The Nobel Prize in Physiology/Medicine 2005 "for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease"

3. The Marshall/Warren story • Perth, Australia, late 70s • Robin Warren, Histopathologist, with 20 odd cases of a peculiar bacterial infection in the stomach • Barry Marshall: young gastroenterologist in need of a project • Dual publications in the Lancet in 1983 • Minimal interest, especially from drug companies (Glaxo, SKF) • Only in late 80s, with support from Astra (PPI, omeprazole), was the importance of the infection appreciated and then the money flowed into research

4. Epidemiology • infects over half the world’s population • infection probably acquired via faecal-oral route • untreated, infection persists throughout life

5. Gastritis and practising pathologists • Bacterial (non-atrophic): Helicobacter pylori • Marshall and Warren (1984) • Many animals have helicobacter as commensals • Adaptive features allow survival in the stomach • urease • flagellae • adhesions • lipopolysaccharide coat

6. Gastritis and practising pathologists Bacterial (non-atrophic): Helicobacter pylori Clinical presentation • 80% asymptomatic • 5-15% peptic ulcer disease • 10% non-ulcer dyspepsia • 1-3% gastric adenocarcinoma • 0.5% gastric MALToma

7. Gastritis and practising pathologists Bacterial (non-atrophic): Helicobacter pylori • Outcome of Hp infection • Bacterial virulence factors (cagA, vacA, iceA) • Genetically determined host responses (IL-1) • Environmental factors • cagA particularly important

8. Helicobacter pylori and the evolution of upper GI disease in the West: Blaser 1999

9. Helicobacter pylori and upper GI pathology • What is Helicobacter pylori? • How do we recognise it? • Why is it important? • What can we do about it?

10. Helicobacter pylori and upper GI pathology What is Helicobacter pylori? • A spiral flagellated bacterium, which produces urease • Lives in the surface mucus of stomach, especially the gastric antrum • Associated with hypergastrinaemia

11. Helicobacter pylori and upper GI pathology How do we recognise it? In tissues • H&E stain: pattern of disease • Modified Giemsa stain • Warthin-Starry silver method • Immunohistochemistry

12. Helicobacter pylori and upper GI pathology How do we recognise it? H&E stain: pattern of disease • Chronic inflammation, including lymphoid follicles

13. Helicobacter pylori and upper GI pathology How do we recognise it? H&E stain: pattern of disease • Variable activity of disease (polymorphs)

14. Helicobacter pylori and upper GI pathology How do we recognise it? In tissues • H&E stain: pattern of disease • Modified Giemsa stain • Warthin-Starry silver method • Immunohistochemistry

15. Helicobacter pylori and upper GI pathology How do we recognise it? Presence of organism Giemsa H&E IHC

16. Helicobacter pylori and upper GI pathology How do we recognise it? In stomach • Culture of organism • CLO-test • C14-breath test In serum • Antibodies (will only tell if ever infected)

17. Helicobacter pylori and upper GI pathology • What is Helicobacter pylori? • How do we recognise it? • Why is it important? • What can we do about it?

18. Helicobacter pylori and upper GI pathology Why is it important? • Strongly associated with Chronic Gastritis • Strongly associated with Duodenal Ulcer • Fairly strongly associated with Gastric Ulcer • Associated with Gastric Carcinoma • Associated with Gastric MALT lymphoma • Possibly associated with diseases such as atheroma and SIDS

19. Helicobacter pylori and upper GI pathology Chronic Gastritis • Pre-infection acid output is determined by genetic, nutritional and other factors

20. Helicobacter pylori and upper GI pathology Chronic Gastritis • Pre-infection acid output is determined by genetic, nutritional and other factors • After infection, acid production is modified by H pylori-induced chronic inflammation • more virulent strains e.g. vacA and cagA lead to more active inflammation • some cytokines e.g. IL-1B and TNF-A modify parietal cell function

21. Helicobacter pylori and upper GI pathology Chronic Gastritis • Pre-infection acid output is determined by genetic, nutritional and other factors • After infection, acid production is modified by H pylori-induced chronic inflammation • more virulent strains e.g. vacA and cagA lead to more active inflammation • some cytokines e.g. IL-1B and TNF-A modify parietal cell function • Gastritis pattern related to ulcer site • pangastritis (body/antrum) with GU: low/normal acid levels • antral gastritis with DU: high acid levels

22. Phenotypes resulting from H pylori infection corpus-predominant mild pan-gastritis antrum-predominant hypochlorhydria gastric atrophy intestinal metaplasia hyperchlorhydria no significant disease gastric cancer phenotype DU phenotype

23. Helicobacter pylori and upper GI pathology Strongly associated with Chronic Gastritis - 3 main types • Type A: ‘autoimmune’, associated with autoantibodies, atrophy, intestinal metaplasia (pernicious anaemia) • Type B: ‘bacterial’, Helicobacter pylori implicated, involves antrum • Type C: ‘chemical’, NOT associated with H pylori, previous surgery/NSAID use

24. Helicobacter pylori and upper GI pathology Type A: ‘autoimmune’, associated with autoantibodies (pernicious anaemia) • Pre-neoplastic lesion, with developing atrophy and hypochlorhydria • Process of intestinal metaplasia • Dysplasia • Neoplasia

25. Helicobacter pylori and upper GI pathology Type A: atrophy and intestinal metaplasia Atrophy IM

26. Helicobacter pylori and upper GI pathology Type A:dysplasia and neoplasia dysplasia neoplasia

27. Helicobacter pylori and upper GI pathology Type B: ‘bacterial’, associated with H pylori infection • Predominantly antral gastritis, associated with duodenal ulceration • Also associated with pan-gastritis and gastric ulceration

28. Helicobacter pylori and upper GI pathology Type C: ‘chemical’, associated with reflux of biliary contents into stomach • Also seen in exposure to NSAIDs

29. Helicobacter pylori and upper GI pathology Type C: ‘chemical’ • Foveolar hyperplasia • Relative lack of inflammatory cells • Oedema • Vascular congestion • Smooth muscle

30. Helicobacter pylori and upper GI pathology Helicobacter pylori and Duodenal Ulcer • Almost all cases of DU have associated antral gastritis due to H pylori (90-95%) • Antral gastritis causes antral G-cell hyperplasia leading to hypergastrinaemia • This causes high acid levels pouring into duodenum • This causes gastric metaplasia and ulceration

31. Helicobacter pylori and upper GI pathology Helicobacter pylori and Gastric Ulcer • Usually solitary • Between 1 and 5cm in diameter • Often lesser curve at transformation zone between body and antrum

32. Helicobacter pylori and upper GI pathology Helicobacter pylori and Gastric Ulcer • A high proportion of patients with GU have H pylori infection (60-70%) • Patients with intrinsically lower acid production will develop colonisation by H pylori of the body mucosa • This leads to hypochlorhydria, lower mucosal resistance, atrophy and intestinal metaplasia • All of which predispose to gastric ulcer formation

33. Helicobacter pylori and upper GI pathology Helicobacter pylori and Gastric Carcinoma • Common in Japan, Chile and Iceland • Environmental influences ?smoked foods • Decreasing incidence • Pre-cancerous lesions • Pernicious anaemia • Neoplastic polyps • H pylori infection

34. Helicobacter pylori and upper GI pathology Helicobacter pylori and Gastric Carcinoma • Class I carcinogen • Countries with high gastric cancer incidence also have high Hp infection rates • Hp predisposes to cancer by • production of potential carcinogens e.g. nitroso-compounds in hypochlorhydric gastric juice and free radicals in inflammatory response • deficiency of anti-oxidants such as ascorbic acid in gastric juice • increased cell turnover stressing DNA repair mechanisms and perpetuating mutations

35. Stages in the development of gastric carcinoma(after Correa) normal gastric mucosa H pylori superficial gastritis atrophic gastritis intestinal metaplasia Precancerous lesions dysplasia carcinoma

36. Helicobacter pylori and upper GI pathology Helicobacter pylori and Gastric Carcinoma • Early gastric cancer: confined to mucosa and submucosa, LN negative • Rare in UK, relatively common in Japan • 5 year survival 85%

37. Helicobacter pylori and upper GI pathology Helicobacter pylori and Gastric Carcinoma Gross appearances Histology

38. Helicobacter pylori and upper GI pathology Helicobacter pylori and Gastric Carcinoma • Late gastric cancer: fungating, exophytic growth pattern • Malignant ulcer with raised rolled edges, loss of rugae • Diffusely infiltrative pattern • 5 year survival 30% (full thickness, LN-) • 5 year survival 5% (full thickness, LN+)

39. Helicobacter pylori and upper GI pathology Helicobacter pylori and Gastric Carcinoma Spread of gastric carcinoma • Direct: pancreas, colon, liver spleen • Lymphatic: local and regional LN, Virchow’s node • Blood: liver, lungs • Transcoelomic: omentum, mesentery, ovary (Krukenberg)

40. Helicobacter pylori and upper GI pathology Helicobacter pylori and Gastric MALT Lymphoma • Mucosa Associated Lymphoid Tissue arises in the stomach as a result of Hp infection • Lymphoma arising in gastric MALT is a result of Hp infection as shown by • positive sero-epidemiological correlations • animal models • complete regression of lymphoma following eradication of Hp

41. Helicobacter pylori and upper GI pathology H pylori and Gastric MALT Lymphoma • Mucosa Associated Lymphoid Tissue arises in the stomach as a result of Hp infection Lymphoid follicle

42. Helicobacter pylori and upper GI pathology H pylori and Gastric MALT Lymphoma • Mucosa Associated Lymphoid Tissue arises in the stomach as a result of Hp infection Infiltrate of B cells Lympho-epithelial lesion

43. Helicobacter pylori and upper GI pathology What can we do about it? • Treat with antiulcer drugs, especially PPIs • Treat with antibiotics: currently clarithromycin • Resistance may develop • Reinfection may occur • If recurrence, consider culture and sensitivity • Some strains more virulent, leading to ulceration, carcinoma and MALToma

44. INFLAMMATORY BOWEL DISEASE • What is inflammatory bowel disease? • What does it include? • What are its mimics? • What is the differential diagnosis?

45. INFLAMMATORY BOWEL DISEASE What is inflammatory bowel disease? • Chronic inflammatory conditions of unknown aetiology affecting the gastrointestinal tract

46. INFLAMMATORY BOWEL DISEASE What does inflammatory bowel disease include? Two main forms of idiopathic IBD • Crohn’s disease • Ulcerative colitis

47. INFLAMMATORY BOWEL DISEASE IDIOPATHIC IBD Pathogenesis • Genetics • Environment • Constitutional Susceptibility

48. INFLAMMATORY BOWEL DISEASE IDIOPATHIC IBD - Pathogenesis Genetics • Twin Studies: monozygotic > dizygotic • Family Studies: CD > UC • Shared risk loci on chromosomes 3, 7 and 12, CD on chromosome 16, UC on chromosomes 2 and 6 • Involvement of genes implicated in immunoregulation • Associations with Turner’s syndrome, Ank Spon, PSC

49. INFLAMMATORY BOWEL DISEASE IDIOPATHIC IBD - Pathogenesis Environment • Microbes: mycobacteria, viruses, normal bowel flora • Short Chain Fatty Acids: major source of metabolic fuel for epithelium • Cigarette smoke - UC: stopping smoking induces relapses - CD: smoking increases relapse rate - possible role in arterial insufficiency in CD

50. INFLAMMATORY BOWEL DISEASE IDIOPATHIC IBD - Pathogenesis Constitutional Susceptibility • Defects of mucosal defences - may convert commensals into pathogens - modification of secretory mucins - may expose the gut to pathogens - increased intestinal permeability