Upper Gastro-intestinal tract: Inflammatory disease Paul L. Crotty TCD Medical Student Lecture...
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Transcript of Upper Gastro-intestinal tract: Inflammatory disease Paul L. Crotty TCD Medical Student Lecture...
Upper Gastro-intestinal tract: Inflammatory disease
Paul L. Crotty
TCD Medical Student Lecture
October 2007
Outline
Brief review of normal physiologyBalance between hostile and protective factorsAcute gastritis and acute stress ulcersAuto-immune gastritisHelicobacter gastritis: infection, outcomesPeptic ulcer diseaseNSAIDs and the GI tractOesophageal 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 FactorChief cells: PepsinogenEndocrine cells: Histamine, Somatostatin
Antrum surface mucous cells and mucous glands
Mucous-producing cellsEndocrine 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 gastritisAcute gastric stress ulcers
Gastritis
Chronic gastritis Type I: Auto-immune gastritis
Progressive immune destruction of GPC Terminology
Chronic superficial gastritisChronic atrophic gastritisGastric atrophyPernicious anaemia
Auto-immune gastritis
Circulating auto-antibodies (anti-GPC, intrinsic factor, proton pump)
Inflammation and atrophy involving fundus/corpusLow secretion of acid +/- enzymesCompensatory high serum gastrin levelsAssociated with other auto-immune diseases/HLASecretion of intrinsic factor decreasedAssociated 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
Gastritis
Chronic gastritis Type II:
Not auto-immune in originDifferent distribution: antral-predominantAcid 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 reservoirPerson-person:? Vomitus ? Gastro-oral ? Dental plaque
What is known about acute infection? - deliberate ingestion (Marshall) - endoscope-mediated transmissionAcute infection causes transient epigastric pain/nauseaHistology: 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)
Peptic ulcer
Ulcer: full thickness breach in the mucosaErosion: mucosal disruption but nit full thickness
Peptic ulcer: Any chronic ulcer in the GI tractin association with damage caused by acid/peptic juices
Duodenum, usually first partStomach, usually antrum/pyloric channelOGJAnastomosisMeckel’s diverticulum
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- 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 duodenumInduces gastric metaplasia in duodenumH. pylori infection of (metaplastic) gastric cellsDirect cell injury, cell death, erosion, ulceration
Duodenal ulceration
Normal duodenum Two duodenal ulcers
Left: Two duodenal ulcers: one with sentinel clotRight: 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-EllisonHyperparathyroidism
Other potential outcomes of chronic Hp infection:Multi-focal atrophic gastritis
Atrophy: mechanism?
Intestinal metaplasia: mechanism ?- teleological explanation: promote Hp clearance
DysplasiaMalignancy
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, PGF2 production- PGs protect by regulation of mucosal blood flow - NSAID effect is essentially mucosal ischaemiaAlso direct mucosal toxic effects (COX-independent)- increase pepsin activity (?)- experimentally: NSAID effect is less if neutropenic
Non-neoplastic oesophageal disease
Oesophageal varices: portal hypertensionAchalasiaMallory-Weiss oesophageal lacerationsOesophagitis
GORDallergicinfectious chemicalother
*Barrett’s oesophagus
Oesophagitis
Pathological term: inflammation of the oesophagus
Causes of oesophagitis
Gastro-oesophageal reflux disease Eosinophilic oesophagitis associated with
bronchial asthmaFungal: e.g. CandidaViral: e.g Herpes, CMV Ingestion of irritants, corrosivesChemotherapy, radiationSystemic skin diseases: e.g. pemphigoidGraft-versus host disease
Gastro-oesophageal reflux disease
Retrograde movement of stomach contents to oesophagusAcid, pepsin: direct mucosal toxicity, inflammation
Normally, reflux prevented by:lower oesophageal sphincteranatomic structureoesophageal peristaltic clearanceswallowed salivagravity
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
UlcerationHaemorrhageFibrotic strictureAspirationBarrett’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 physiologyBalance between hostile and protective factorsAcute gastritis and acute stress ulcersAuto-immune gastritisHelicobacter gastritis: infection, outcomesPeptic ulcer diseaseNSAIDs and the GI tractOesophageal disease
Oesophagitis/Gastro-oesophageal reflux disease