Upper Gastro-intestinal tract: Inflammatory disease

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Upper Gastro-intestinal tract Inflammatory
disease

• Paul L. Crotty
• TCD Medical Student Lecture
• October 2007

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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

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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/toxin
  s

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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

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Stomach
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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

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Normal fundic type mucosa
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Normal antral type mucosa
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Gastritis stomach inflammation
Gastritis
Normal antrum
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Gastritis stomach inflammation
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Gastritis

• Acute gastritis
• Chronic gastritis
• Type I
• Type II
• Type III

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Gastritis

• Acute gastritis Acute stress ulceration
• acute ingestion of NSAIDs/alcohol
• severe trauma/sepsis/shock
• classically ICU patient with multi-organ failure
• extensive burns (Curlings ulcer)
• neurological disease (Cushings ulcer)
• predominantly decrease in protective factors
• risk of haemorrhage acid suppression

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Acute gastritis
Acute gastric stress ulcers
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Gastritis

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

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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

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Anti-gastric parietal cell antibodies
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Auto-immune gastritis
Inflammation
Loss of gastric parietal cell mass/mucosal atrophy
Increasing time
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Auto-immune gastritis
Inflammation
Atrophy
Increasing time
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Auto-immune gastritis
Atrophy
Intestinal metaplasia
Risk of dysplasia and malignancy
Increasing time
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Early stage
Auto-immune gastritis
Later stage Atrophy and intestinal metaplasia
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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...

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Helicobacter pylori
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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

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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
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Helicobacter
Gram negative, curved/spiral organism Motile,
flagellate organism gt 20 different
species Adapted to niche of life in the stomach
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Helicobacter pylori prevalence
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Bacteriology

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

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Diagnosis of H. pylori infection
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Diagnosis of H. pylori infection
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Diagnosis of H. pylori infection
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Diagnosis of H. pylori infection
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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

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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
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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 gt Chronic active gastritis
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Chronic active gastritis
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--gt (Acute) --gt Chronic active gastritis Differe
nt possible outcomes --gt Antral-predominant
gastritis --gt duodenal ulcer --gt Multi-focal
atrophic gastritis --gt gastric ulcer --gt
intestinal metaplasia --gt risk of dysplasia --gt
adenocarcinoma --gt Gastric lymphoma (lymphoma
of MALT)
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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 Meckels diverticulum
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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?
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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
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Duodenal ulceration
Normal duodenum Two duodenal ulcers
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Left Two duodenal ulcers one with sentinel
clotRight Ulcer with visible vessel
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Chronic peptic ulcer
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Chronic peptic ulceration

• Complications
• Haemorrhage (GU, DU)
• Perforation with acute abdomen (GU, DU)
• Penetration with pancreatitis (DU)
• Scarring and obstruction (Pyloric channel, DU)

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Subset of ulcers not related to Hp

• Crohns disease
• NSAIDs
• Hypergastrinaemia
• Zollinger-Ellison
• Hyperparathyroidism

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Other potential outcomes of chronic Hp
infection Multi-focal atrophic
gastritis Atrophy mechanism? Intestinal
metaplasia mechanism ? - teleological
explanation promote Hp clearance Dysplasia Malig
nancy
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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?
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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
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Non-neoplastic oesophageal disease Oesophageal
varices portal hypertension Achalasia Mallory-Wei
ss oesophageal lacerations Oesophagitis GORD all
ergic infectious chemical other Barretts
oesophagus
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Oesophagitis Pathological term inflammation of
the oesophagus
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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

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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
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Gastro-oesophageal reflux disease Clinical
symptoms of heartburn Endoscopic red/congested
mucosa Manometric decreased sphincter
pressure pH measurement frequency of dips in pH
lt4 Pathological microscopic evidence of
oesophagitis
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Clinical
Endoscopic
Microscopic
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complications

• Ulceration
• Haemorrhage
• Fibrotic stricture
• Aspiration
• Barretts oesophagus
• risk of dysplasia and malignancy

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Barretts 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

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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