J. TACK, M.D., Ph.D.

TARGID

University of Leuven

Leuven, Belgium

www.targid.eu

PEPTIC ULCER DISEASEFrom stress to infection

Animal research

Clinical observations: Higher prevalence in taxi drivers

Higher prevalence in officers than in soldiers at the war front

PEPTIC ULCER DISEASEArguments in favor of stress

Psychosomatic Medicine 1991

PEPTIC ULCER DISEASEAnimal studies of stress pathways

Psychosomatic Medicine 1991

PEPTIC ULCER DISEASEHuman studies of the role of stress

• Born 1951 Kalgoorlie, Australia• Graduated Medical school in Perth,

Australia, 1975• Internship and residency at Queen Elizabeth

II Medical Centre, Perth 1975-1979

• Training in internal medicine at Royal Perth Hospital from 1979 onwards; aimed at becoming a rheumatologist

• Gastroenterology division 1981; proposal to do some research project:

• Analysis of 20000 endoscopy reports or• Collaborate with Dr. Warren on bacteria

in the stomach

HELICOBACTER PYLORIBarry Marshall

• 1979: noticed bacteria on gastric biopsies showing chronic gastritis

• Showed the biopsies to 2 colleagues who "did not see any bacteria" 

• Confirmed presence by electron microscopy

• Searched for similar cases; collected them and observed bacteria

• Met with Barry Marshall 1981

HELICOBACTER PYLORIRobin Warren

• Found the bacteria in 13/13 patients with duodenal ulcer and 24/28 patients with gastric ulcer

• After 6 months, Barry Marshall moved to the hematology ward. Meanwhile, they set up a 100 patient trial

• In June 1982, Barry Marshall was to be rotated to Port Hedland, 2000 km north of Perth

• Aim of the trial:• Presence in health and diseased stomach• Correlation with type and severity of disease• Culture• Follow-up of disease and infection status

HELICOBACTER PYLORIWarren & Marshall

• All attempts to culture failed• Easter 1982: sample left for 5 days (instead

of routine 2); culture growth obtained• Trial finalised May 1982

• Barry Marshall took the data to Port Hedland and analysed them there:• Significant correlation with presence of gastritis

• Significant correlation with presence of peptic ulcer (gastric but especially duodenal)

HELICOBACTER PYLORIWarren & Marshall

HELICOBACTER PYLORIWarren & Marshall

Duodenal ulcer Gastric ulcer

H. pyloriNSAIDCancer (Zollinger Ellison)Other

92% 70%

5% 1%2%

25%

3%

2%

• Data presented in October 1982 at local College of Physicians meeting; largely negative responses

• Barry Marshall took a job as senior registrar Gastroenterology at Fremantle Hospital end of 1982

• Drafted letter for Lancet; decided to submit two letters: one with Warren’s initial observations of bacteria and one with Warren & Marshall’s joint work

• Letters published June 1983

HELICOBACTER PYLORIWarren & Marshall

• Wrote abstract for Gastroenterological Society of Australia in Perth, February 1983: rejected

• Applied for NHMRC grant: rejected• Looked for grants from manufacturers of

ulcer drugs: rejected, except for manufacturer of bismuth preparation DeNol

• Confirmed antimicrobial effect of DeNol in cultures, not with cimetidine

• Submitted 100 patient paper to Lancet January 1984

HELICOBACTER PYLORIWarren & Marshall

• Confirmed antimicrobial effect of DeNol in cultures, not with cimetidine

• April 1983: small prospective treatment study with DeNol vs. Cimetidine; histology improvement with DeNol

• Observed synergism of bismuth with metronidazole

HELICOBACTER PYLORIWarren & Marshall

Mildly active, moderately chronic Hp related gastritis without intestinal metaplasia in the antrum

Active Hp related gastritis – neutrophils infiltrating the crypt lining (higher magnification)

Positive Immunohistochemical staining with an antibody directed against Helicobacter pylori

Special stain (modified Steinert) showing Helicobacter pylori colonies on the surface and in the pits

1. The organism must always be found in diseased subjects but not in healthy ones

2. The organism must be isolated from diseased animals and grown in pure culture away from the animal

3. The organism isolated in pure culture must initiate and reproduce the disease when reintroduced into susceptible subjects

4. The organism should be re-isolated from the experimentally infected animals

CHRONIC GASTRITISKoch’s postulates

• Attempts to infect pigs failed• Marshall inoculated himself in 1984

• No approval from EC or spouse

• initial biopsy was negative• he inoculated himself with H. pylori

cultured from a patient with excellent response to metronidazole

• He became sick after 7 days (nausea, vomiting, epigastric pain)

• New endoscopy on day 10: positive

CHRONIC GASTRITISKoch’s postulates

1. The organism must always be found in diseased subjects but not in healthy ones

2. The organism must be isolated from diseased animals and grown in pure culture away from the animal

3. The organism isolated in pure culture must initiate and reproduce the disease when reintroduced into susceptible subjects

4. The organism should be re-isolated from the experimentally infected animals

CHRONIC GASTRITISKoch’s postulates

• Lancet paper published June 1984• Obtained funding from NHMRC end of 1984

for a clinical trial• Marshall took a staff position in Virginia,

USA in 1985

• Travelled back to Australia 1987

• Nobel prize in 2005

HELICOBACTER PYLORIWarren & Marshall