Transcript 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
Helicobacter gastritis: infection, outcomes
Peptic ulcer disease
NSAIDs and the GI tract
Oesophageal disease
Oesophagitis/Gastro-oesophageal reflux disease
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
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
Stomach
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
Normal fundic type mucosa
Normal antral type mucosa
Gastritis: stomach inflammation
Normal antrum
Gastritis
Gastritis: stomach inflammation
Gastritis
Acute gastritis
Chronic gastritis
Type I
Type II
Type III
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
Acute gastritis
Acute gastric stress ulcers
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
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?
 - 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
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)
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
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
- 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
Duodenal ulceration
Normal duodenum
Two duodenal ulcers
Left: Two duodenal ulcers: one with sentinel clot
Right: Ulcer with visible vessel
Chronic peptic ulcer
Chronic peptic ulceration
Complications
Haemorrhage (GU, DU)
Perforation with acute abdomen (GU, DU)
Penetration with pancreatitis (DU)
Scarring and obstruction (Pyloric channel, DU)
Subset of ulcers not related to Hp
Crohn’s disease
NSAIDs
Hypergastrinaemia:
Zollinger-Ellison
Hyperparathyroidism
Other potential outcomes of chronic Hp infection:
Multi-focal atrophic gastritis
Atrophy: mechanism?
Intestinal metaplasia: mechanism ?
- teleological explanation: promote Hp clearance
Dysplasia
Malignancy
Unanswered patho-physiological questions:
- What factors determine which course a patient will
follow with chronic Hp infection: duodenal ulceration:
multi-focal atrophic gastritis: gastric ulcer: lymphoma?
Host factors (genetic or environmental) or bacterial factors?
NSAIDs and the GI tract
-Acute gastritis, acute erosions/ulcers
-Chronic gastric ulcers
-Type III chronic gastritis: chemical gastropathy
Effects secondary to COX-1 inhibition
- inhibition of PGE2, PGI2, PGF2a production
- PGs protect by regulation of mucosal blood flow
- NSAID effect is essentially mucosal ischaemia
Also direct mucosal toxic effects (COX-independent)
- increase pepsin activity (?)
- experimentally: NSAID effect is less if neutropenic
Non-neoplastic oesophageal disease
Oesophageal varices: portal hypertension
Achalasia
Mallory-Weiss oesophageal lacerations
Oesophagitis
GORD
allergic
infectious
chemical
other
*Barrett’s oesophagus
Oesophagitis
Pathological term: inflammation of the oesophagus
Causes of oesophagitis
Gastro-oesophageal reflux disease
Eosinophilic oesophagitis associated with
bronchial asthma
Fungal: e.g. Candida
Viral: e.g Herpes, CMV
Ingestion of irritants, corrosives
Chemotherapy, radiation
Systemic skin diseases: e.g. pemphigoid
Graft-versus host disease
Gastro-oesophageal reflux disease
Retrograde movement of stomach contents to oesophagus
Acid, pepsin: direct mucosal toxicity, inflammation
Normally, reflux prevented by:
lower oesophageal sphincter
anatomic structure
oesophageal peristaltic clearance
swallowed saliva
gravity
Gastro-oesophageal reflux disease
Clinical: symptoms of heartburn
Endoscopic: red/congested mucosa
Manometric: decreased sphincter pressure
pH measurement: frequency of dips in pH <4
Pathological: microscopic evidence of oesophagitis
Clinical
Endoscopic
Microscopic
complications
Ulceration
Haemorrhage
Fibrotic stricture
Aspiration
Barrett’s oesophagus
risk of dysplasia and malignancy
Barrett’s oesophagus
As a long term complications of reflux, the
normal squamous mucosa of the oesophagus
becomes replaced by glandular mucosa
clinical importance is when it is replaced by
intestinal-type mucosa: intestinal metaplasia
can lead to dysplasia and adenocarcinoma
Summary
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