- Helicobacter Helicobacter - - - THE EASE AND DIFFICULTY THE - - PowerPoint PPT Presentation

• Helicobacter

Helicobacter -

• THE EASE AND DIFFICULTY

THE EASE AND DIFFICULTY OF A NEW DISCOVERY OF A NEW DISCOVERY

Robin Warren Robin Warren

EARLY DAYS EARLY DAYS

First reports 100 years ago First reports 100 years ago

– – considered spirochaetes considered spirochaetes

1940 Freedburg saw curved organisms 1940 Freedburg saw curved organisms in the stomach in the stomach 1954 Palmer: “Freedburg was wrong” 1954 Palmer: “Freedburg was wrong”

MEDICAL TEACHING ADAMANT MEDICAL TEACHING ADAMANT

Acid environment kills organisms Acid environment kills organisms The normal stomach is The normal stomach is sterile sterile Bacteria seen are Bacteria seen are

– – contaminant passing through contaminant passing through – – dead, or dead, or – – – – secondary to gastric lesions such as peptic ulcer secondary to gastric lesions such as peptic ulcer usually fungus or yeast in necrotic debris usually fungus or yeast in necrotic debris

Primary infection is rare Primary infection is rare

GASTRIC BIOPSIES GASTRIC BIOPSIES -----

• ---- pre 1970

pre 1970

Good quality biopsies were rare Good quality biopsies were rare Specimens were usually Specimens were usually Surgical Surgical or

• r

Post mortem Post mortem Mucosa soon autolysed in digestive juice Mucosa soon autolysed in digestive juice Helicobacter rapidly disappear Helicobacter rapidly disappear

GASTRITIS GASTRITIS -----

• ---- pre 1970

pre 1970

clinical specimens were technically inadequate clinical specimens were technically inadequate acute acute gastritis or gastritis or aplasia aplasia with pernicious with pernicious anaemia easily diagnosed but rare anaemia easily diagnosed but rare chronic chronic inflammation was difficult to: inflammation was difficult to:-

• –

– relate to the clinical findings relate to the clinical findings – – see, describe or classify see, describe or classify

MAJOR BREAKTHROUGHS IN MAJOR BREAKTHROUGHS IN THE 1970’S THE 1970’S

Numerous, small well Numerous, small well-

• fixed biopsies

fixed biopsies Histology of gastric mucosa finally seen Histology of gastric mucosa finally seen clearly by pathologists clearly by pathologists RICHARD WHITEHEAD RICHARD WHITEHEAD -

• 1972

1972

– – accurately described them accurately described them – – He defined He defined “active” gastritis “active” gastritis: :-

• specific epithelial changes and leucocyte

specific epithelial changes and leucocyte infiltration infiltration

Active Active Active

Active Active Active

WHITEHEAD’S CLASSIFICATION WHITEHEAD’S CLASSIFICATION

He designed a new He designed a new classification classification Logical, practical, descriptive Logical, practical, descriptive Set out as a tree, apparently complex Set out as a tree, apparently complex

– – But easy to use But easy to use

WHITEHEAD 1972 WHITEHEAD 1972

SIMPLIFICATION OF SIMPLIFICATION OF WHITEHEAD’S CLASSIFICATION WHITEHEAD’S CLASSIFICATION

AS USED BY ME: AS USED BY ME:-

• Severity

Severity -

• mild, moderate, severe

mild, moderate, severe “ “Active Active” ” or not

• r not

Type Type of inflammation

• f inflammation -
• acute or chronic

acute or chronic Other features Other features -

• atrophy, metaplasia

atrophy, metaplasia

BACTERIAL STAINS BACTERIAL STAINS

I was interested in stains I was interested in stains Microbiology Microbiology stains clean smears stains clean smears More difficult with More difficult with histology histology Tissues stain with bacterial stain Tissues stain with bacterial stain Exceptions: Gram and Ziehl Exceptions: Gram and Ziehl-

• Neelsen

Neelsen Silver Silver used for spirochaetes and Donovan used for spirochaetes and Donovan bodies in tissues bodies in tissues I experimented with them successfully I experimented with them successfully

BACKGROUND TO DISCOVERY BACKGROUND TO DISCOVERY

A decade of well A decade of well-

• fixed gastric biopsies

fixed gastric biopsies Whitehead's description & classification Whitehead's description & classification

– – Active gastritis Active gastritis – – My interest My interest

Bacterial stains Bacterial stains My other interests My other interests

– – Fine detail and drawing Fine detail and drawing – – Photography Photography – – Electron microscopy Electron microscopy

HELICOBACTER AND ME HELICOBACTER AND ME – – JUNE 1979 JUNE 1979

ROUTINE GASTRIC BIOPSY ROUTINE GASTRIC BIOPSY

Severe active chronic gastritis Severe active chronic gastritis Unusual blue line on the surface Unusual blue line on the surface

HIGH MAGNIFICATION HIGH MAGNIFICATION

numerous small curved bacilli numerous small curved bacilli Warthin Warthin-

• Starry stain showed bacteria clearly

Starry stain showed bacteria clearly

SILVER STAIN SILVER STAIN

• Black bacilli line the pits.
• Easily seen.

ELECTRON MICROSCOPY ELECTRON MICROSCOPY

Electron microscopy was of good quality Electron microscopy was of good quality Showed bacteria resembling Campylobacter Showed bacteria resembling Campylobacter Closely adherent to the cell surface Closely adherent to the cell surface My colleagues were finally convinced, but not My colleagues were finally convinced, but not impressed impressed

Normal epithelium Normal epithelium Normal epithelium

Electron microscopy Electron microscopy Electron microscopy

Helicobacter Helicobacter Helicobacter

MY FIRST REPORT MY FIRST REPORT

FOLLOWUP FOLLOWUP

I examined all gastric biopsies for the bacteria I examined all gastric biopsies for the bacteria

– – Not expecting to find more Not expecting to find more

Found them in almost half the biopsies Found them in almost half the biopsies

– – Usually associated with histological Usually associated with histological gastritis gastritis – – Often Often severe severe and often “ and often “active active” ”

Reporting of the organisms became routine Reporting of the organisms became routine

– – No No-

• one else believed they were of significance
• ne else believed they were of significance

DIFFICULTIES DIFFICULTIES

DISBELIEF DISBELIEF

Just a secondary infection, due to the gastritis Just a secondary infection, due to the gastritis “If it is true, why were they not recognised before?” “If it is true, why were they not recognised before?”

LABORATORY MEDICINE LABORATORY MEDICINE

No patient contact No patient contact Poor biopsies for my purposes Poor biopsies for my purposes Taken from obvious lesions, ulcer or neoplasm Taken from obvious lesions, ulcer or neoplasm Taken from any part of the stomach Taken from any part of the stomach

BARRY MARSHALL 1981 BARRY MARSHALL 1981

My findings were ready for publication My findings were ready for publication (summary, Lancet 1983) (summary, Lancet 1983) Barry, gastroenterology registrar, needed Barry, gastroenterology registrar, needed a project for publication a project for publication Sent to “that pathologist who is trying to Sent to “that pathologist who is trying to make gastritis an infection” make gastritis an infection”

BARRY MARSHALL 1981 BARRY MARSHALL 1981

He agreed to a short series of gastric biopsies He agreed to a short series of gastric biopsies Taking apparently normal antral mucosa, away Taking apparently normal antral mucosa, away from any local lesions from any local lesions He was enthusiastic He was enthusiastic Finally I had a Finally I had a clinician clinician as a collaborator as a collaborator

MAJOR STUDY 1982 MAJOR STUDY 1982

100 sequential outpatients for gastroscopy 100 sequential outpatients for gastroscopy

Formal, blind Formal, blind Detailed clinical protocol Detailed clinical protocol Biopsies for pathology and culture Biopsies for pathology and culture Tissue from “normal” antral mucosa Tissue from “normal” antral mucosa Culture using Culture using Campylobacter Campylobacter techniques techniques

UNEXPECTED RESULTS UNEXPECTED RESULTS

HISTOLOGY UNRELATED TO HISTOLOGY UNRELATED TO: :-

• Symptoms

Symptoms except except

– – Bad breath Bad breath – – Burping Burping

Gastroscopic findings Gastroscopic findings except except – – DUODENAL ULCER DUODENAL ULCER

SUCCESS SUCCESS

BACTERIA CULTURED BACTERIA CULTURED

New species New species

DUODENAL ULCER DUODENAL ULCER

Strongly related to the infection Strongly related to the infection We were surprised We were surprised

PUBLICATIONS and PAPERS PUBLICATIONS and PAPERS

1983 LANCET 1983 LANCET

My summary My summary Barry’s summary of our combined work Barry’s summary of our combined work

1983 BRUSSELS 1983 BRUSSELS

Campylobacter conference Campylobacter conference Barry presented our results Barry presented our results Skirrow enthusiastic Skirrow enthusiastic

PUBLICATIONS and PAPERS PUBLICATIONS and PAPERS

1984 LANCET 1984 LANCET

Our definitive paper presented Our definitive paper presented Delayed by disbelieving reviewers Delayed by disbelieving reviewers Skirrow repeated our work, wrote to Lancet Skirrow repeated our work, wrote to Lancet Our paper published unaltered Our paper published unaltered

LATER WORK LATER WORK

Diagnosis Diagnosis CLOtest, serology and breath test invented or CLOtest, serology and breath test invented or suggested by Dr Marshall suggested by Dr Marshall Treatment Treatment Barry saw Bismuth mentioned in Osler’s Textbook of Barry saw Bismuth mentioned in Osler’s Textbook of Medicine Medicine Wondered if Denol worked by killing the bacteria Wondered if Denol worked by killing the bacteria He invented triple therapy in 1984 He invented triple therapy in 1984 Proof Proof Barry and Dr Arthur Morris used Koch’s postulates Barry and Dr Arthur Morris used Koch’s postulates Treating duodenal ulcers with triple therapy Treating duodenal ulcers with triple therapy

EXAMPLES EXAMPLES

Initial Initial acute gastritis acute gastritis, rapidly responding to treatment , rapidly responding to treatment Barry infecting himself, to fulfil Koch’s postulates Barry infecting himself, to fulfil Koch’s postulates Chronic gastritis Chronic gastritis, not responding to multiple courses of , not responding to multiple courses of therapy therapy Dr Arthur Morris, gave himself chronic gastritis to use Koch’s Dr Arthur Morris, gave himself chronic gastritis to use Koch’s postulates postulates Duodenal Duodenal ulcer due to NSAIDs ulcer due to NSAIDs My wife, who also had My wife, who also had H pylori H pylori. . After treatment for it, she After treatment for it, she could take NSAIDs could take NSAIDs Most people with Most people with H pylori H pylori are are symptomless symptomless

• Myself. When my wife was treated, she found I had bad
• Myself. When my wife was treated, she found I had bad

breath breath

DU STUDY, 1986 DU STUDY, 1986

All treated for ulcer All treated for ulcer Uncertain numbers treated for Uncertain numbers treated for H pylori H pylori

– – Blind study Blind study

Repeated biopsies Repeated biopsies

– – 12 months and 7 year follow 12 months and 7 year follow-

• up

up

Excellent for study of Excellent for study of H pylori H pylori pathology pathology

QUANTIFICATION OF GASTRITIS QUANTIFICATION OF GASTRITIS

Specific features Specific features

– – Cobblestone change Cobblestone change – – Polymorph infiltration Polymorph infiltration

Non Non-

• specific changes

specific changes

– – Mucus secretion Mucus secretion – – Lymphoid infiltration Lymphoid infiltration

Each given a value 0 Each given a value 0 – – 9, total of 36 9, total of 36

QUANTIFICATION OF GASTRITIS QUANTIFICATION OF GASTRITIS

Before and after treatment Before and after treatment Biopsy 2 weeks after treatment Biopsy 2 weeks after treatment Histogram Histogram

– – Patient numbers against pathology Patient numbers against pathology – – Total change after treatment Total change after treatment

DUODENAL ULCER DUODENAL ULCER

Distal gastric Distal gastric Gastric mucosa Gastric mucosa

– – Extends into duodenal cap Extends into duodenal cap – – Forms proximal border of duodenal ulcers Forms proximal border of duodenal ulcers

Other borders are duodenal Other borders are duodenal

– – Usually inflamed and scarred Usually inflamed and scarred – – May show gastric metaplasia with May show gastric metaplasia with H pylori H pylori

Pylorus Pylorus Pylorus

Duodenal ulcer Duodenal ulcer Duodenal ulcer

HELICOBACTER NOW HELICOBACTER NOW

The The importance of importance of H pylori H pylori is accepted is accepted worldwide worldwide Duodenal ulcer Duodenal ulcer, required treatment , required treatment Gastritis Gastritis, recognised aetiology, not the importance , recognised aetiology, not the importance WHO listing as a WHO listing as a carcinogen carcinogen Related to gastric carcinoma and MALT Related to gastric carcinoma and MALT lymphoma lymphoma Possibly associated with Possibly associated with coronary artery disease coronary artery disease Big money: drug companies and research Big money: drug companies and research Governments considering cost of total eradication Governments considering cost of total eradication

CONCLUSION CONCLUSION

Gastric bacteria: known for 100 years and ignored Gastric bacteria: known for 100 years and ignored Seen by me and linked to gastritis Seen by me and linked to gastritis

WITH DR BARRY MARSHALL WITH DR BARRY MARSHALL

we we cultured cultured H pylori H pylori linked it to linked it to duodenal ulcer duodenal ulcer fulfilled fulfilled Koch’s postulates Koch’s postulates for clinical disease and for clinical disease and eradication cures gastritis and peptic ulcer disease eradication cures gastritis and peptic ulcer disease