Transcript Pathogenesis of Diseases of the Stomach

Pathogenesis of Diseases of
the Stomach
Dr Paul L. Crotty
Department of Pathology
AMNCH, Tallaght
October 2008
Classification of Disease by Aetiology
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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
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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
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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
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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
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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
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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
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Complications
Ulceration
Bleeding
Perforation
Endoscopy
Normal antrum
Acute gastritis
Acute gastritis
Acute gastric stress ulcers
Stomach: classification by aetiology
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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
Intestinal metaplasia
Risk of dysplasia and malignancy
Increasing time
Early stage
Auto-immune gastritis
Later stage: Atrophy and intestinal
metaplasia
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 well
known for a discovery which stemmed from the observations of a colleague, Dr Robin Warren. In the early
1980s, Warren, a pathologist at Royal Perth Hospital, had become resigned to unkind jokes from his peers
about his theory that an unusual bug he was seeing down his microscope had some role in causing stomach
inflammation. No-one had taken much notice because it was such an outlandish notion. Everyone knew that
bacteria 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 to
relearn all your medicine because we've now worked out what is really going on'," Hazell remembers. "The
vast majority of the medical profession, not only in Australia but worldwide, considered Barry to be a
quack and really were extremely dismissive for a number of years."
Testing The Most Curious Subject Oneself
By Kathryn S. Brown
One July day in 1984, Barry Marshall, a medical resident at the Fremantle Hospital in Perth, Western
Australia, 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 similar
experiment. Von Pettenkofer was eager to prove the recently identified Vibrio cholerae bacterium could
not, on its own, cause cholera. His cocktail ingredients: bouillon and the deadly cholerae. He, too, gulped
his potion.
Marshall was correct. He suffered an inflamed stomach. Von Pettenkofer was incorrect.
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
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?
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- deliberate ingestion (Marshall)
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- endoscope-mediated transmission
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• 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
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
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
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?
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
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
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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
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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
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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