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 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


Inflammation

Loss of gastric parietal cell mass/mucosal atrophy

Increasing time


Inflammation

Atrophy

Increasing time


Atrophy

Increasing time

Intestinal metaplasia

Risk of dysplasia and malignancy

Early stage

Later stage: Atrophy and intestinal metaplasia


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




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

Documents

Upper Gastro-intestinal tract: Inflammatory disease