- 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 sterile sterile The normal stomach is 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 ----- ----- pre 1970 pre 1970 GASTRIC BIOPSIES Good quality biopsies were rare Good quality biopsies were rare Specimens were usually Surgical Surgical or or Specimens were usually Post mortem Post mortem Mucosa soon autolysed in digestive juice Mucosa soon autolysed in digestive juice Helicobacter rapidly disappear Helicobacter rapidly disappear
GASTRITIS ----- ----- pre 1970 pre 1970 GASTRITIS clinical specimens were technically inadequate clinical specimens were technically inadequate acute gastritis or gastritis or aplasia aplasia with pernicious with pernicious acute anaemia easily diagnosed but rare anaemia easily diagnosed but rare chronic inflammation was difficult to: inflammation was difficult to:- - chronic – 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- -fixed biopsies fixed biopsies Numerous, small well Histology of gastric mucosa finally seen Histology of gastric mucosa finally seen clearly by pathologists clearly by pathologists RICHARD WHITEHEAD - - 1972 1972 RICHARD WHITEHEAD – 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 classification classification He designed a new 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 - - mild, moderate, severe mild, moderate, severe Severity “ Active ” or not or not Active ” “ Type of inflammation of inflammation - - acute or chronic acute or chronic Type Other features - - atrophy, metaplasia atrophy, metaplasia Other features
BACTERIAL STAINS BACTERIAL STAINS I was interested in stains I was interested in stains Microbiology stains clean smears stains clean smears Microbiology More difficult with histology histology More difficult with Tissues stain with bacterial stain Tissues stain with bacterial stain Exceptions: Gram and Ziehl- -Neelsen Neelsen Exceptions: Gram and Ziehl Silver used for spirochaetes and Donovan used for spirochaetes and Donovan Silver 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- -fixed gastric biopsies fixed gastric biopsies A decade of well 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- -Starry stain showed bacteria clearly Starry stain showed bacteria clearly Warthin
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 one 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 clinician clinician as a collaborator as a collaborator Finally I had a
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 Campylobacter Campylobacter techniques techniques Culture using
UNEXPECTED RESULTS UNEXPECTED RESULTS HISTOLOGY UNRELATED TO : :- - HISTOLOGY UNRELATED TO Symptoms except except Symptoms – Bad breath Bad breath – – Burping Burping – Gastroscopic findings except except Gastroscopic findings – 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
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