Pathogenesis of Diseases of the Stomach Dr Paul L. Crotty Department of Pathology AMNCH, Tallaght...
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Transcript of Pathogenesis of Diseases of the Stomach Dr Paul L. Crotty Department of Pathology AMNCH, Tallaght...
Pathogenesis of Diseases of the
Stomach
Dr Paul L. Crotty
Department of Pathology
AMNCH, Tallaght
October 2008
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
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
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
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
Normal stomach• To achieve these functions
– Distensibility up to 1.5-2 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
Stomach
Stomach• Fundus/Corpus
– 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
Normal fundic type mucosa
Normal antral type mucosa
Mucosal protection system
• Mucous secretion
• Bicarbonate
• Epithelial tight junctions
• High blood flow to submucosa
• Central role of prostaglandins
Acute gastritis/Acute stress ulcer
• Depletion in mucosal protection system
• Acid/enzyme injury to gastric mucosa
• Inflammation, erosions, ulceration
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)
Acute gastritis/Acute stress ulcer
• Complications
• Ulceration
• Bleeding
• Perforation
Endoscopy
Normal antrum Acute gastritis
Acute gastritisAcute gastric stress ulcers
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
Chronic gastritis
• Type I: Autoimmune gastritis
• Type II: Helicobacter gastritis
• (Type III: Chemical gastropathy NSAIDs)
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
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
Anti-gastric parietal cell antibodies
Auto-immune gastritis
Inflammation
Loss of gastric parietal cell mass/mucosal atrophy
Increasing time
Auto-immune gastritis
Inflammation
Atrophy
Increasing time
Auto-immune gastritis
Atrophy
Increasing time
Intestinal metaplasia
Risk of dysplasia and malignancy
Early stage
Later stage: Atrophy and intestinal metaplasia
Auto-immune gastritis
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...
Helicobacter pylori
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
There is no doubt that Marshall, 46, has been one hell of a salesman. That helps explain why he is so wellknown for a discovery which stemmed from the observations of a colleague, Dr Robin Warren. In the early1980s, Warren, a pathologist at Royal Perth Hospital, had become resigned to unkind jokes from his peersabout his theory that an unusual bug he was seeing down his microscope had some role in causing stomachinflammation. No-one had taken much notice because it was such an outlandish notion. Everyone knew thatbacteria couldn't survive in the stomach's acid environment. They'd been taught so at medical school.
"When Barry spoke he was very brash, "... that I've discovered this and that you people are going to have torelearn all your medicine because we've now worked out what is really going on'," Hazell remembers. "Thevast majority of the medical profession, not only in Australia but worldwide, considered Barry to be aquack and really were extremely dismissive for a number of years."
Testing The Most Curious Subject -OneselfBy Kathryn S. Brown
One July day in 1984, Barry Marshall, a medical resident at the Fremantle Hospital in Perth, WesternAustralia, walked over to his lab bench, pulled down a beaker, and mixed a cocktail. The key ingredient:about a billion Helicobacter pylori bacteria. Marshall hoped to show that the microorganism causes ulcers.He gulped the concoction, describing it as "swamp water."
PHYSICIAN, STUDY THYSELF: Barry Marshall's daring experiment eventually garnered him awards.
One hundred years earlier, Max von Pettenkofer, a chemist in Munich, Germany, performed a similarexperiment. Von Pettenkofer was eager to prove the recently identified Vibrio cholerae bacterium couldnot, on its own, cause cholera. His cocktail ingredients: bouillon and the deadly cholerae. He, too, gulpedhis potion.Marshall was correct. He suffered an inflamed stomach. Von Pettenkofer was incorrect.
Historical
1899: Jaworski: spiral organisms in gastric washings1924: Luck and Seth:
antibiotic-sensitive urease activity in stomach1938: 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 patients1979: Fung: bacteria seen in patients with chronic gastritis1983: Warren: correlated with presence of neutrophils1983-87: Marshall sells the concept world-wide
Helicobacter
Gram negative, curved/spiral organism
Motile, flagellate organism
> 20 different species
Adapted to niche of life in the stomach
Helicobacter pylori prevalence
Bacteriology• Colonisation
– motility: flagellae– urease enzyme activity– acute infection causes transient hypochlorhydria
• Adherence– bacterial adhesins (BabA)
• Tissue Injury– lipopolysaccharide, cagA, vacA, others
Diagnosis of H. pylori infection
Diagnosis of H. pylori infection
Diagnosis of H. pylori infection
Diagnosis of H. pylori infection
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
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
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
Establishing chronic active infection
Chronic active 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)
Duodenal ulceration
- So, how does H. pylori infection in the stomach cause ulceration in the duodenum?
H. pylori live exclusively on gastric surface mucous cells.They cannot survive on intestinal epithelial cells
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 duodenumInduces gastric metaplasia in duodenumH. pylori infection of (metaplastic) gastric cellsDirect cell injury, cell death, erosion, ulceration
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
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
Peptic ulcer disease
• Complications
• Bleeding: chronic low level -> anaemia
• Massive acute bleeding
• Perforation
• Scarring -> obctruction
• Penetration -> pancreatitis
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
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