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Timeline of peptic ulcer disease and Helicobacter pylori

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Electron micrograph of H. pylori

This is a timeline of the events relating to the discovery that peptic ulcer disease is caused by H. pylori. In 2005, Barry Marshall and Robin Warren were awarded the Nobel Prize in Physiology or Medicine for their discovery that peptic ulcer disease (PUD) was primarily caused by Helicobacter pylori, a bacterium with affinity for acidic enivironments, such as the stomach. As a result, PUD that is associated with H. pylori is currently treated with antibiotics used to eradicate the infection. For 30 years prior to their discovery it was widely believed that PUD was caused by excess acid in the stomach. During this time, acid control was the primary method of treatment for PUD, to only partial success; among other effects, we now know that acid suppression alters the stomach milieu to make it less amenable to H. pylori infection.

Before the 1950s, there were many microbiological descriptions of bacteria in the stomach and in gastric acid secretions, lending credence to both the infective theory and the hyperacidity theory as being causes of peptic ulcer disease. A single study, conducted in 1954, did not find evidence of bacteria on biopsies of the stomach stained traditionally; this effectively established the acid theory as dogma. This paradigm was altered when Warren and Marshall effectively proved Koch's postulates for causation of PUD by H. pylori through a series of experiments in the 1980s; however, an extensive effort was required to convince the medical community of the relevance of their work. Now, all major gastrointestinal societies agree that H. pylori is the primary non-drug cause of PUD worldwide, and advocate its eradication as essential to treatment of gastric and duodenal ulcers. Additionally, H. pylori has been associated with lymphomas and adenocarcinomas of the stomach, and has been classified by the World Health Organization as a carcinogen. Advances in molecular biology in the late twentieth century led to the sequencing of the H. pylori genome, resulting in a better understanding of virulence factors responsible for its colonization and infection, on the DNA level.

Year Events
Pre 16th century


Hippocrates

1586


Gastric Ulcer

1688
1728
  • Stahl hypothesizes that some fevers are related to gastric inflammation and ulceration.[1]
1761
  • Pain is associated with stomach ulcers.[3]
1799
1812


François-Joseph-Victor Broussais

1821
1822
  • William Beaumont first demonstrates the acidity of the stomach and a relationship between acid levels and mood.[2]
1868
  • Kussmaul suggests using bismuth compounds, an anti-bacterial agent, in order to treat peptic ulcers (bismuth subsalicylate has since been used in many commercial drugs, including Pepto Bismol as part of antibacterial H. pylori treatment) The antibacterial properties of bismuth were not known until much later.[1]
1875
  • G. Bottcher and M. Letulle hypothesize that ulcers are caused by bacteria.[1]
1880
  • J. Cohnheim suggests that ulcers may be caused by chemical factors.[1]
1881
1889
  • Walery Jaworski describes spiral organisms in sediment washings of humans. He suggests these organisms might be involved with gastric disease.[1]
1892
1896


Spirochete bacteria

1905
  • F. Reigel suggests that ulcers are caused by excess acid.[1]
1906
  • Krienitz finds bacteria in the stomach of people with gastric cancer.[2]
  • Turck feeds dogs Bacillus coli and produces ulcers.[7]


Bacillus coli (E. coli)

1907
  • Berkley Moynihan suggests that acid is a cause of ulcers.[1]
1910
  • Schwartz publishes the excess acid theory of the ulcer, coining the famous phrase "no acid, no ulcer." [2]
  • Gibelli claims to be unable to reproduce Turck's study where he artificially created ulcers by feeding dogs bacteria.[1]
1913


Strepococci

1915
  • Antacids are first recommended for the treatment of PUD.[3]
  • Bacteria are associated with PUD, but it is assumed that the bacteria resides in the month.[9]
1919
  • Kasai and Kobayashi isolate spirochetes in cats and transmit them to rabbits, producing ulcers.[10]
1921
  • Luger discovers spirochetes in the gastric juice, and associates their presence with gastric cancer. [4]
1924
  • Luck and Seth discover urease in the human stomach, which they believe is naturally occurring.[11] It is now known that one of the virulence factors of H. pylori is the urease enzyme, which splits urea into ammonia


Urease

1925
  • Hoffman injects a small sample from a human with PUD into a guinea pig, producing ulcers, and isolates a bacteria which he believes caused the ulcers.[12]
1936
  • First edition of the Russian Large Medical Encyclopedia suggests infection is one of the causes of PUD.[13]
1939
  • A. Stone Freedberg begins a study to look for bacteria in the human stomach at Beth Israel Hospital. He finds H. pylori. It is rumored that others cannot reproduce the results, although no negative results are published.[14]
  • James Doenges describes spirochetes in autopsies.[15]
1940
  • Freedberg and Baron observe spirochetes in autopsies.[16]
1948
  • Fitzgerald and Murphy hypothesize that PUD is caused by acid eating away mucosa, and demonstrate the effectiveness of urea as a treatment for PUD.[17]


Chemical structure of Urea

1951
  • J. Allende publishes a book describing the treatment of gastric ulcers with penicillin.[2]


Penicillin core

1953
  • Dintzis and Hastings are able to stop urease production in mice with antibiotics, suggesting a relationship between urease and a bacterial infection.[18]
1954
  • Palmer publishes a study which finds no bacteria in the human stomach. He concludes earlier discoveries were a result of contamination. Unfortunately, he chooses not to use a silver staining method, which will be later used to reveal H. pylori by Warren and Marshall. [19]


Stained tissue

1955
  • Tarnopolskaya observes that penicillin cures some peptic ulcers.[13]
  • Moutier and Cornet suggest treating gastritis with antibiotics.[13]
  • Kornberg and Davies observe that antibiotics reduce urease in cats.[20]
1957
  • Charles Lieber and Andre Lefèvre discover that antibiotics reduce gastric urea to ammonia conversion.[21]


Ammonia

1958
  • Gordon observes that penicillin cures some peptic ulcers.[13]
  • Lieber and Lefèvre present their results at the World Congress of Gastroenterology in Washington. It is not well received because of the widespread belief that bacteria cannot survive in the human stomach, due to Palmer.[23]
1959
  • Lieber and Lefèvre publish a follow-up study demonstrating that antibiotics prevent the conversion of urea to ammonia in the human stomach.[24]
  • Conway et al. call into question the extent of urease produced by bacteria in mice, as an argument against the bacterial theory of PUD.[25]
1960
  • Vital and Orrego observe campylobacter-like organisms in the stomachs of cats and dogs.[26]
  • November 16 - Lykoudis is awarded a Greek patent (#22,453) for his antibiotic treatment of PUD.[22]


Campylobacter fetus

1962
  • Susser and Stein publish a paper identifying a birth cohort phenomenon of PUD in England. This is taken as evidence for stress causing PUD.[27]
1964
  • May 4 - Lykoudis presents his antibiotic treatment for PUD at a meeting of the Medico-Surgical Society in Greece. He is largely shunned by the medical establishment.[22]
1966
1967
1968
  • November 6 - Lykoudis is fined 4,000 drachmas for treating PUD patients with his treatment, which includes antibiotics.[22]
1971
  • August 26 - Howard Steer observes H. pylori from biopsies of a patient with ulcers.[29]
1972
  • The first report of successfully using ferazolidone (an anti-bacterial agent) to treat PUD in China.[30]
1974
  • Morozov observes H. pylori; he does not connect this discovery to PUD.[13]
  • A well regarded study of PUD is published which does not mention bacteria.[29][31]
1975
  • Steer and Colin-Jones publish their results regarding H. pylori and its relation to PUD. They decide that it was Pseudomonas, a contaminant, and not related to PUD.[32]


Pseudomonas aeruginosa

1978
  • At a meeting of the American Gastroenterology Association in Las Vegas, several papers are presented which suggest that acid control via H2 blockers is ineffective at curing PUD.[33]
1979
  • Ramsey publishes a study demonstrating that bismuth can help eradicate PUD. Bismuth is an antibacterial agent, although this is not recognized by Ramsey.[34]
  • June 11 - J. Robin Warren first observes H. pylori in a gastric biopsy.[35]
  • Fung, Papadimitriou, and Matz observe H. pylori.[36]


H. pylori

1981
  • Yao Shi observes bacteria in the stomach, but he believes they are bacteria that are passing through the stomach and not colonizing it.[30]
  • October - Marshall and Warren successfully treat their first PUD patient with antibiotics.[37]
1982
  • Satoha et al. find evidence for an infectious cause of ulcers in rats.[38]
  • Marshall and Warren begin their first study to determine the relationship between H. pylori and PUD.[37]
  • April 8 - First successful culturing of H. pylori performed; it occurs almost by accident.[37]
  • October - Marshall discovers the bacteria he is investigating are not campylobacters, by looking at electron micrographs.[37]
  • October 2 - Marshall presents his and Warren's results at a local College of Physicians meeting. He meets with criticism, which Marshall later admits was well-founded (at least in part).[37]
1983
  • January - Two letters authored by Warren and Marshall respectively are sent to The Lancet describing their results.[37]
  • February - Gastroenterological Society of Australia rejects Marshall's abstract to present his research at their yearly conference. They deem it in the bottom 10% of papers submitted. The same abstract is accepted for presentation at a Campylobacter workshop in Brussels.[37]
  • April - Marshall and Ian Hislop begin a study to compare bismuth treatment with cimetidine. The study is abandoned because it is inconclusive.[37]
  • June - Warren and Marshall's letter appears in The Lancet.[39]
  • September - H. pylori is observed in patients outside of Australia.[37]
  • After the appearance of the letters in The Lancet, groups around the world begin isolating H. pylori.[37]


Cimetidine

1984
  • A paper describing Marshall and Warren's results is accepted by the Gastroenterological Society of Australia for presentation.[37]
  • Marshall and Goodwin attempt to infect pigs with H. pylori in an attempt to demonstrate that it causes PUD. The experiment fails.[37]
  • Marshall and Warren's paper is accepted by The Lancet in May and published in June. Many reviewers dislike the paper.[37]
  • McNulty and Watson are able to reproduce Marshall and Warren's results.[40]
  • June 12 - Marshall intentionally consumes H. pylori and becomes ill. He takes antibiotics and is relieved of his symptoms.[37]
  • Study published in China about the effectiveness of treating PUD with an antibacterial agent. [30]
1985
  • Marshall publishes the results of self-induced infection.[37]
1987
  • Morris intentionally consumes H. pylori. Like Marshall, he become ill, but unlike Marshall, he is not completely cured by antibiotics. The infection will remain with him for three years.[41]
  • An extensive study in Dublin demonstrates that eradicating H. pylori substantially reduces recurrence of ulcers.[42]
1990
  • Rauws and Tytgat describe cure of duodenal ulcer by eradication of H. pylori using a triple-therapy regimen, consisting of bismuth and two antibiotics.[43] Triple-therapy, modernized to a proton pump inhibitor and two antibiotics soon becomes first line therapy for eradication.
  • World Congress of Gastroenterology recommends eradicating H. pylori in order to cure duodenal ulcers.[44]
  • First report of resistance of H. pylori to the antibiotic metronidazole.[45] Resistance of H. pylori to treatment will lead to the development of many different antibiotic and proton-pump inhibitor regimens for eradication.[46]
1992
  • Fukuda et al. prove ingestion of H. pylori causes gastritis in rhesus monkeys.[4]
  • Covacci et al. sequence the CagA gene, which encodes for a cytotoxin-associated surface protein, which correlated strongly with strains of H. pylori that caused duodenal ulcers. This was the first description of a virulence factor for H. pylori infection determined by molecular techniques.[47]
1994
  • Fujioka et al. prove similar results as those from Fukuda et al.[4]
  • Patents for acid reducing drugs expire, removing financial incentive to resist antibiotics as treatment of PUD.[37]
  • Conference held by National Institute of Health (USA) demonstrating the general acceptance of H. pylori as cause of PUD in the US.[37]
  • Parsonnet et al. describe an association between H. pylori and lymphomas of the gastrointestinal tract. These malignant ulcers can also be treated by eradicating Helicobacter.[49]


Gastric cancer

1997
  • Tomb et al. complete sequencing of the entire 1,667,867 base pair H. pylori genome. This assists in identifying new virulence factors for the infectivity of H. pylori on the molecular level.[50] [51]
2001
2002
  • The European Helicobacter Pylori Study Group published the Maastricht 2-2000 Consensus Report, suggesting a test-and-treat strategy for H. pylori in young patients without atypical symptoms. This strategy advocates the use of non-invasive testing to evaluate for H. pylori and simply treating if found, even in the absence of ulcer disease documented on endoscopy.[46]
2005

References

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