Helicobacter pylori: human pathogen or simply an opportunist?

against retention of the external examiner system is its high cost at a time when universities are experiencing hard financial times.

Kappelman MM.

The impact of external examinations on medical education programs and students. J Med Educ 1983; 58: 300-08. Committee of Vice-Chancellors and Principals. The external examiner system for first degree and taught master’s courses. Revised code of practice. London: CVCP, 1985. Hamilton JD, Vanderwerdt JM. The accreditation of undergraduate medical education in Australia. Med J Aust 1990; 153: 541-45.

4

5

6

References

1 Piper WD. Enquiry into the role of external examiners. Stud Higher Educ 1985; 2

7

Campbell PN. Some thoughts on the role of external examiners.

8

Biochem Educ 1991; 19: 13-14. Hamilton JD, Ogunbode O. Medical education in the Nigerian experience. Lancet 1991; 338: 99-102.

9

Nicholls SH.

10: 331-42.

Nystrup J, Martenson D. Reflections on possible virtues of European medical education. Med Educ 1992; 26: 350-53.

3 Gonella JS. Internal versus external quality control: the value of external examination in medical education. J Med Educ 1983; 58:

358-59.

Alan McGuinness Gastroenterology Unit, NSW 2000, Australia (J R Graham FRACP)

Sydney Hospital, Sydney,

a

Examining. Assessment Eval Higher Educ 1985; 10: 29-34. examiner. J Geogr Higher Educ

10 Lawton R. The role of the external 1986; 10: 41-51.

Helicobacter pylori: human pathogen

It is now ten years since Marshall drank a broth of Campylobacter pyloridis (subsequently renamed Helicobacter pylorz)and then underwent gastroscopy by a colleague a few days later. This was indeed a dramatic clinical experiment and there can be little doubt that the drama of the occasion has contributed to the high profile that this organism has enjoyed over the subsequent decade. It is possible that the drama of Marshall’s selfexperiment has also lured researchers unwittingly into a less than trenchant attitude to the time-honoured scientific principles that have been generally endorsed by microbiologists in attributing disease processes to bacteria. This apparent laxness of scientific approach has not, as yet, caused patients any harm, although it may have led to a degree of inconvenience and some uncomfortable drug side-effects. With the US National Institutes of Health consensus committee recommending that "ulcer patients with H pylori infection require treatment with antimicrobial agents in addition to antisecretory drugs whether on first presentation with the illness or on recurrence",2it is timely to review the scientific data accumulated on this organism. There seems to be no dispute that H pylori is often found in the upper gastrointestinal tract, particularly in the corpus and antrum of the stomach and sometimes in the duodenal cap, when quite a number of disease processes are present. These disease processes include benign peptic ulceration, chronic gastritis, and gastric cancer. There is as yet no dispute among gastroenterologists that acid and pepsin are still prime aetiological factors in peptic ulcer disease. Benign peptic ulcers are essentially not seen in patients with atrophic gastritis and pernicious anaemia (conditions associated

community:

or

simply

an

opportunist?

with achlorhydria and negligible pepsin activity, but in which H pylori can be found quite frequently on gastric

biopsies). Antimicrobial therapy has not figured in the medical management of the Zollinger-Ellison syndrome, in which H pylori organisms are found frequently but in which a worthwhile response is seen only with the administration of proton-pump inhibitors.3 Omeprazole (as single-drug therapy) for the Zollinger-Ellison syndrome has led to disappearance of H pylori from gastric antral mucosa in most H pylori positive patients at the same time as the healing of their duodenal ulcers.4 H pylori is found in the gastric antrum of up to 100% of duodenal ulcer patients in some series, but active chronic gastritis is usually also present in these cases.5 I found (unpublished observations) that H pylori was present in a variable percentage of patients with conditions such as gastric ulcer (20%), bile reflux gastritis (25%), atrophic gastritis (33%), and active chronic (presumably peptic) gastritis (50%). In the same series, all five patients with gastric ulcers or erosions induced by non-steroidal anti-inflammatory drugs (NSAID ulcers) had detectable H pylori in biopsy samples, but none of the six patients in whom the only gastroduodenal pathology was one or more tiny, sessile, benign gastric polyps had detectable H pylori. There can surely be no dispute about the need to fulfil Koch’s postulates6 when determining that a disease is the result of an infection by a particular microorganism, especially when the organism is a bacterium. It is thus worth reminding ourselves of the four principles enunciated by Robert Koch last century: (a) the microorganism must regularly be isolated from cases of the illness; (b) it must be grown in pure culture in vitro; (c) when such a pure culture is inoculated into susceptible animal species, the typical disease must result; and (d) from such experimentally induced disease the microorganism must again be isolated. 1095

It

important to recall that when Marshall experimented on himself, he developed some acute changes of gastritis-as seen at gastroscopy on the tenth day after drinking the campylobacter broth-but he did not develop a peptic ulcer.’ A single small fragmenting biopsy sample was obtained from the gastric antrum for histology and it showed increased polymorphonuclear neutrophil leucocytes in the mucosa with adherent campylobacter organisms on the surface. By the fourteenth day, all evidence of gastritis along with the organism itself had disappeared. Marshall may have fulfilled Koch’s postulates for H pylori as a cause of acute gastritis, but there is not a single report that shows that Koch’s postulates have been fulfilled for H pylori as the cause of benign gastric ulcer, benign duodenal ulcer, or a gastric malignancy. As yet, there seems to be no published series that demonstrates that antibiotic therapy alone (with any or all of ampicillin, tetracycline, metronidazole, clarithromycin) can heal benign peptic ulcers any better than placebo. A clinical trial to look at this possibility is long overdue. All published studies that purport to show healing of peptic ulcers in man by eradicating H pylori have included among the drugs given bismuth subcitrate, or a histamine-2-receptor inhibitor, or a proton-pump inhibitor, or similar, all of which have the ability to heal peptic ulcers by mechanisms unrelated to the elimination of H pylori. Indeed, most studies have reported patients in whom peptic ulcers healed despite persistence of H pylori in the gastric antrum or gastric corpus. Sung and co-workers7 implied that they used antibacterial therapy alone in treating H pylori positive gastric ulcers, but they administered bismuth subcitrate in addition to the antibiotics tetracycline and metronidazole. Antacids were also permitted for ad hoc use by the patients receiving "antibacterial therapy". It is important remember that bismuth subcitrate forms a white precipitate in gastric acid. It has a strong affinity for mucosal glycoproteins, especially in the necrotic tissue in ulcer craters. Ulcer craters become preferentially and visibly coated with a layer of polymer-glycoprotein complex that then inhibits acid back-diffusion.88 to

Considering the tens of millions of dollars that have been spent on H pylori research and treatment it is amazing that not one researcher has yet published the clinical results in ulcer patients of simply eradicating H pylori with antibiotics alone. In the absence of the normal gold standard of proof (ie, the fulfilling of Koch’s postulates) for H pylori as a cause f peptic ulcers, why have so many eminent gastroenterologists decided that H pylori can or does cause peptic ulcers? The answer lies not only in the dramatic nature of Marshall’s initial self-experiment, but also in the subsequent observation that peptic ulcers tended to relapse less often (in the absence of conventional maintenance drug therapy) if H pylori was eradicated at the time of the initial ulcer healing.9 This finding is hardly surprising, however, if one postulates that the association between H pylori and peptic ulceration is nothing more than an association between H pylori and the background mucosal inflammation in which the ulcer developed in the first place. When one takes a careful look at all the available data on H pylori in man, it is in fact quite reasonable to conclude that H pylori is nothing more than an 1096

opportunist that often chooses to reside on the surface of gastric and/or duodenal mucosa in any disease state in which there is a breach in the integrity of the mucosal barrier. This is not a new concept, having been advanced by Fallingborg and colleagues in 1992.’° This concept would logically account for the finding of H pylori in the stomachs of patients with a wide variety of disease states in which there is a disruption of the gastric mucosal barrier. These disease states include not only peptic ulcer (including Zollinger-Ellison syndrome), gastric adenocarcinoma," and gastritis (acute and chronic), but also alcoholic gastritis, 12 atrophic gastritis (including autoimmune pernicious anaemia"), NSAID ulcers, 14 lymphoma, 15 congestive gastropathy (portal hypertension),16 and Menetrier’s disease." By contrast, it is interesting that in patients with tiny benign fundic gland polyps in the stomach and in people with normal stomachs,’"’" in which there is no breach in the integrity of the gastric mucosal barrier, H pylori tends not to be found. When healthy people do spontaneously have H pylori present in their stomachs, they also have histological gastritis present as a prerequisite.lo,13 For as long as Koch’s postulates remain unfulfilled for H pylori as a cause of peptic ulcers or gastric malignancy, it is quite wrong for authoritative medical bodies to attempt to produce consensus documents that suggest that the eradication of H pylori is an essential component of preventive or healing therapy.

is

It is understandable that no one has demonstrated Koch’s third postulate for peptic ulcer in man, but it is interesting that this postulate even eludes the experimental situation. Ross and colleagues18 found it impossible to induce gastritis in Sprague-Dawley rats that were fed daily suspensions of H pylori for seven consecutive days, despite H pylori being present on the gastric mucosa when the animals were killed three days later. In the same study, rats with artificially induced gastric ulcers were also fed daily suspensions of H pylori, and in this situation inflammation in a pre-existing gastric lesion became more intense. To produce a consensus document at this time even recommending the eradication of H pylori as an integral component of the treatment of gastritis would seem to be premature, especially when one considers that there is no consensus on the symptomatology, aetiology, or natural history of most patients in whom histological gastritis may be present. Marshall’s group’9 observed in 1994 that "duodenal ulcer may recur in patients rendered H pylori negative, due to factors other than reinfection with H pylori". Is this the first admission of a chink in helicobacter’s armour? Medical practitioners should keep an open mind until the crucial clinical experiments on H pylori have been done. Until then, no one should feel obliged to alter their preferred management of patients with benign peptic ulcer disease.

References 1

2 3

Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ. Attempt to fulfil Koch’s postulates for pyloric campylobacter. MedJ Aust 1985; 142: 436-39. Forbes G. Helicobacter pylori eradication: who, why and how in 1994? Med J Aust 1994; 161: 291-92. Saeed ZA, Evans DJ, Evans DG, et al. Helicobacter pylori and Zollinger-Ellison syndrome. Dig Dis Sci 1991; 36: 15-18.

4

et al. Antral Helicobacter pylori like organisms in different states of gastric acid secretion. Digestion 1991;

Koop H, Stumpf M, Eissele R, 48: 230-36.

K, Vaira D, Hobsley M. Duodenal ulcer, Helicobacter pylori, and gastric secretion. Gut 1994; 35: 1033-36. 6 Jawetz E, Melnick JL, Adelberg EA. Review of medical microbiology. Los Altos, California: Lange Medical Publications, 1982.

5 Chandrakumaran

7

Sung JJY, Chung SCS, Ling TKW, et al. Antibacterial treatment of gastric ulcers associated with Helicobacter pylori. N Engl J Med 1995; 332: 139-42.

8 Gilman AG, Goodman LS, Rall TW, Murad F. The pharmacological basis of therapeutics, 7th ed. New York. Macmillan, 1985. 9 Marshall BJ, Goodwin CS, Warren JR, et al. Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. Lancet 1988; ii: 1437-42.

10 Fallingborg J, Poulsen LO, Grove A, Teglbjaerg PS. Frequency of Helicobacter pylori and gastritis in healthy subjects without gastrointestinal symptoms. Scand J Gastroenterol 1992; 27: 388-90. 11 Talley NJ, Zinsmeister AR, Weaver A, et al. Gastric adenocarcinoma and Helicobacter pylori infection. J Natl Cancer Inst 1991; 83: 1734-39. 12 Uppal R, Lateef SK, Korsten MA, Paronetto F, Lieber CS. Chronic

alcoholic gastritis. Roles of alcohol and Helicobacter pylori. Arch Intern Med 1991; 151: 760-64. 13 Fong T-L, Dooley CP, Dehesa M, et al. Helicobacter pylori infection in pernicious anaemia: a prospective controlled study. Gastroenterology 1991; 100: 328-32. 14 Taha AS, Russell RI. Helicobacter pylori and non-steroidal anti-inflammatory drugs: uncomfortable partners in peptic ulcer disease. Gut 1993; 34: 580-83. 15 Stolte M. Helicobacter pylori gastritis and gastric MALT-lymphoma. Lancet 1992; 339: 745-46. 16 McCormick PA, Sankey EA, Cardin F, Dhillon AP, McIntyre N, Burroughs AK. Congestive gastropathy and Helicobacter pylori: an endoscopic and morphometric study. Gut 1991; 32: 351-54. 17 Bayerdorffer E, Ritter MM, Hatz R, Brooks W, Stolte M. Menetrier’s disease and Helicobacter pylori. N Engl J Med 1993; 329: 60. 18 Ross JS, Bui HX, del-Rosario A, Sonbati H, George M, Lee CY. Helicobacter pylori. Its role in the pathogenesis of peptic ulcer disease in a new animal model. Am J Pathol 1992; 141: 721-27. 19 Forbes GM, Glaser ME, Cullen DJE, et al. Duodenal ulcer treated with Helicobacter pylori eradication: seven-year follow-up. Lancet 1994; 343: 258-60.

BOOKSHELF

Science and the

quiet

world. One might have expected this to lead him to get scientists and others to integrate genetic

modern

art

The role of medical research in health care.-David Weatherall. New York: W W Norton. 1995. Pp 378.$25. ISBN 0-393037444.

and environmental studies and put an end to the spurious nature versus nurture controversy. Instead he asks : "should we be concentrating our Be patient. That is the message of important tool for identifying women efforts, both in teaching medical stuDavid Weatherall’s new book Science ; at high risk and hence focusing our dents and in medical research, more and the Quiet Art. After all, it took screening programs". on controlling our environment and over 1300 years before Galen’s theoHe oversimplifies the problem. In: lifestyle and less on laboratory studies ries based on observations of blood most of those destined to get that try to understand the causes and . flow in animals and gladiators were the weak links will be somatic cell mechanisms of our common killers?". corrected by Vesalius, another 100 mutations acquired only in the organ Framing the question in this way is before Harvey described the circulaor tissue undergoing malignant transnot going to lead to any fundamental another 300 revand before his For formation. most it will be tion, organs, changes in either education or olutionary ideas formed the basis of difficult if not impossible to detect research. There is, moreover, no modern cardiology. The pace has them before transformation. Indoubt of how Weatherall would but we have a still herited mutations in a long quickened, specific gene, answer it. Public health measures and to before which will be the "weak links" in go fully way improvements in social conditions today’s major diseases. Weatherall a small proportion of cancers, are have accounted for substantial declines in morbidity and premature guides us through the progress made theoretically detectable in any nuclein diabetes mellitus, pernicious ated cell, but it will not be easy to test mortality in infectious diseases in the anaemia, and infectious diseases, and for all of them. Moreover, as he past century, but Weatherall hastens lucidly describes the complexity of points out in relation to screening for to add that scientific medical discoveries have made gains through cardiovascular disease, cancer, and genetic susceptibility to breast canAck"in for vaccinations and antibiotics. In disdisorders. our enthusiasm cer, neurodegenerative preventive efforts to reduce environMacfarlane medicine we must not we the taunts of paraging forget,that nowledging mental contributors to disease he says Ivan be women to a Burnett, Rene Dubos, Illich, may exposing many and Thomas McKeown, who in turn life of unnecessary worry". He also "in some cases, such as those of psychiatric and rheumatic disorders, called the total conquest of disease recognises that, with the commercial"dream" or "mirage" and accused isation of disease-related genes, "Our there is no evidence that our environnew pharmacopeia will not be ment plays a major role". 12 pages physicians of "hubris" and a "mechanistic" approach, Weatherall, like cheap". He does not point out that later, however, he admits "environLewis Thomas and Peter Medawar, is the ability to acquire proprietary ’., ment doubtless plays a major role in confident that medical research can rights is often a result of millions of generating psychiatric disease". He think through the complexities. For dollars and pounds of publicly supacknowledges that infectious disease is more frequent in poor and ask he and does not view takes the instance, ported research, optimistic that "if cancers result from chains of whether the exorbitant prices should crowded conditions and that there is events ... we may be able to control : a socioeconomic gradient in infant be tolerated by the public. the disease by breaking only one link : Weatherall astutely describes how mortality, but seems to say that we in the chain". Although the book was will be able to discover the biological our genetic make-up evolved in ai written before the discovery of the different environment totally from causes and mechanisms and then BRCA1 gene, Weatherall predicted our civilised one, leaving us ill-presuccessfully prevent or treat everyone that such a gene would give us "an pared to cope biologically with the with diseases for which the poor are

i

cancer,

only

understanding

;

1

i

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