1. Pathogenesis of Diseases of the Stomach
Dr Paul L. Crotty
Department of Pathology
AMNCH, Tallaght
October 2008

2. Classification of Disease by Aetiology
Congenital
Acquired
Infection
Physical/Trauma
Chemical/Toxic
Circulatory disturbances
Immunological disturbance
Degenerative disorders
Iatrogenic
Idiopathic
Multifactorial
Various: radiation, nutritional deficiency, psychosomatic
Pre-neoplastic/ Neoplastic

3. Stomach: classification by aetiology
Congenital: Congenital pyloric stenosis
Acquired
Infection: Helicobacter gastritis
Physical/Trauma:
Chemical/Toxic: Acute gastritis/Acute stress ulcer
Circulatory disturbances: (Acute gastritis/Acute stress ulcer)
Immunological disturbance: Autoimmune gastritis
Degenerative disorders
Iatrogenic:
Idiopathic:: Hypertrophic gastropathy
Multifactorial:
Pre-neoplastic/ Neoplastic:
Intestinal metaplasia,-> dysplasia -> intetsinal type adenocarcinoma
Signet ring cell carcinoma
GI stromal tumours, lymphoma, other

4. Stomach: classification by aetiology
Congenital: Congenital pyloric stenosis
Acquired
Infection: Helicobacter gastritis PEPTIC ULCER DISEASE
Physical/Trauma:
Chemical/Toxic: Acute gastritis PEPTIC ULCER DISEASE
Circulatory disturbances: Acute gastritis
Immunological disturbance: Autoimmune gastritis
Degenerative disorders
Iatrogenic:
Idiopathic:: Hypertrophic gastropathy
Multifactorial: PEPTIC ULCER DISEASE
Pre-neoplastic/ Neoplastic:
Intestinal metaplasia,-> dysplasia -> intetsinal type adenocarcinoma
Signet ring cell carcinoma
GI stromal tumours, lymphoma, other

5. Normal stomach Functions
Food reservoir with regulated delivery to small intestine
Defence against ingested bacteria, toxins
Mixing of food, initiation of digestion of nutrients
Defence against auto-digestion
Role in vitamin B12 absorption: intrinsic factor

6. Normal stomach To achieve these functions
Distensibility up to litres
Pyloric sphincter, coordinated contraction
Production of hydrochloric acid
Muscle contraction -> churning effect
Production of digestive enzymes (pepsin)
Mucosal protection system
Intrinsic factor production
Neural, endocrine coordination

7. Stomach

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

9. Normal fundic type mucosa

10. Normal antral type mucosa

12. Mucosal protection system
Mucous secretion
Bicarbonate
Epithelial tight junctions
High blood flow to submucosa
Central role of prostaglandins

13. Acute gastritis/Acute stress ulcer
Depletion in mucosal protection system
Acid/enzyme injury to gastric mucosa
Inflammation, erosions, ulceration

14. Acute gastritis/Acute stress ulcer
Risk factors
Aspirin, NSAIDs
Alcohol (acute excess)
Heavy smoking
Chemotherapy
Acute ill patients/ ICU
trauma, sepsis, shock
extensive burns (Curling’s ulcer)
Neurological disease (Cushing’s ulcer)

15. Acute gastritis/Acute stress ulcer
Complications
Ulceration
Bleeding
Perforation

16. Endoscopy
Acute gastritis
Normal antrum

17. Acute gastritis
Acute gastric stress ulcers

18. Stomach: classification by aetiology
Congenital: Congenital pyloric stenosis
Acquired
Infection: Helicobacter gastritis
Physical/Trauma:
Chemical/Toxic: Acute gastritis/Acute stress ulcer
Circulatory disturbances: (Acute gastritis/Acute stress ulcer)
Immunological disturbance: Autoimmune gastritis
Degenerative disorders
Iatrogenic:
Idiopathic:: Hypertrophic gastropathy
Multifactorial:
Pre-neoplastic/ Neoplastic:
Intestinal metaplasia,-> dysplasia -> intetsinal type adenocarcinoma
Signet ring cell carcinoma
GI stromal tumours, lymphoma, other

19. Chronic gastritis Type I: Autoimmune gastritis
Type II: Helicobacter gastritis
(Type III: Chemical gastropathy NSAIDs)

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

21. 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

22. Anti-gastric parietal cell antibodies

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

24. Auto-immune gastritis
Inflammation
Atrophy
Increasing time

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

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

27. Chronic 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...

28. Helicobacter pylori

29. 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

33. 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
: Marshall sells the concept world-wide

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

35. Helicobacter pylori prevalence

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

38. Diagnosis of H. pylori infection

39. Diagnosis of H. pylori infection

40. Diagnosis of H. pylori infection

41. Diagnosis of H. pylori infection

42. 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

43. 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

44. 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

45. Chronic active gastritis

46. Different possible outcomes --> Antral-predominant gastritis
--> (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)

47. 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?

48. 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
- 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

49. Peptic ulcer disease
Ulcer: full thickness breach in mucosa extendinf to submucosa (at least)
Erosion: partial thickness breach in mucosa
Peptic ulcer: chronic ulcer secondary to acid/enzymes anywhere in GI tract
first part of duodenum
stomach, antrum or prepyloric
other distal oesophagus, Meckel’s diverticulum

50. Peptic ulcer disease Helicobacter pylori infection
chronic use of aspirin, NSAIDs
heavy smoking
corticosteroids
hyperacidity: Zollinger-Ellison syndrome
in patients with:
cirrhosis, COPD, CRF, hyperparathyroidism

51. Peptic ulcer disease Complications
Bleeding: chronic low level -> anaemia
Massive acute bleeding
Perforation
Scarring -> obctruction
Penetration -> pancreatitis

52. Hypertrophic gastropathy
Thickened stomach wall, thickened folds
Menetrier’s disease
expansion of foveolae, increased mucin
can lead to protein loss into lumen
Hypertrophic-hypersecretory gastropathy
increased fundic glands
Hyperplasia of glands secondary to Zollinger-Ellison syndrome
gastrinoma -> hyperacidity -> ulcers

53. Stomach: classification by aetiology
Congenital: Congenital pyloric stenosis
Acquired
Infection: Helicobacter gastritis PEPTIC ULCER DISEASE
Physical/Trauma:
Chemical/Toxic: Acute gastritis PEPTIC ULCER DISEASE
Circulatory disturbances: Acute gastritis
Immunological disturbance: Autoimmune gastritis
Degenerative disorders
Iatrogenic:
Idiopathic:: Hypertrophic gastropathy
Multifactorial: PEPTIC ULCER DISEASE
Pre-neoplastic/ Neoplastic:
Intestinal metaplasia,-> dysplasia -> intetsinal type adenocarcinoma
Signet ring cell carcinoma
GI stromal tumours, lymphoma, other