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J Clin Pathol 1990;43:353-356 353 pylori (formerly pyloridis/pylori) 1986-1989: A review J Clin Pathol: first published as 10.1136/jcp.43.5.353 on 1 May 1990. Downloaded from

A C Maddocks

Introduction needed to make further advances in the clini- In 1986 a clear and prescient review, cal field. "Campylobacter pyloridis and Other suggestions made by Goodwin et al ulceration," by Goodwin, Armstrong, and in their review and which have been followed Marshall was published in this Journal.2 What up are serological testing with clearly defined has happened since then? This short review with careful assessment of "supposed mentions some evolving areas and new controls" and double blind placebo controlled discoveries. prospective trials. The form "supposed con- "Current interest worldwide is explosive," trols" highlights the fact that some work stated Tytgat,3 but has the flow of new facts published before wide experience had been continued? Looking back at the review by gained produced false negative results. This Goodwin et al, it is striking that the in- provided ammunition for the sceptics. Most formation gained about H pylori between the of the problems related to the patchy distri- early 1980s and 1985 was considerable. The bution of the which was poorly and its chemical and ultrastructural understood, small numbers in samples, and characteristics were being explored and re- the other causes of false negative results listed striction endonuclease analysis had been used by Goodwin et al.1 It is also, of course, pos- to investigate relations among isolates. Im- sible to find positive and serology munological, serological, and epidemiological in those who claim to have no digestive studies had been done and some also related to problems. This invites speculation on the the use of . A firm association with host-parasite relation. "chronic active gastritis" was established and There have been complaints that work on H the problems raised by lack of visible macro- pylori appeared only in abstracts and scopic change at noted. Treatment conference proceedings. This has now of duodenal ulcers with plus systemic changed for the better. Over the past 12 antibiotics was already beginning to reduce months there has been a crystallisation of the relapse rate (albeit with assessment at one information and ideas in a monograph,7 re-

month). It was recognised that gastritis was views,3 and papers."' http://jcp.bmj.com/ present in the of patients with duo- denal ulcers, although it was noted that the association between gastritis and the patho- Diagnostic techniques genesis of ulcers had yet to be established. Serology, histology, and bacterial culture are There was even a prototype of the "leaking essential for research into the natural history roof' argument published by Goodwin in of the infection and the validation of other

1988.4 diagnostic techniques. For ordinary clinical on September 23, 2021 by guest. Protected copyright. diagnosis it is hoped that non-invasive, rapid, and cheaper tests will be developed which What has happened since 1986? would also be helpful for epidemiological The rapid advances made by the pioneers was studies. Obviously there will always be a need followed by a period of a much wider but for endoscopy and in some patients to slower and more amorphous growth of re- exclude malignancy, but rapid screening, and search. Recently, there has been a strong im- easy treatment follow up are very desirable petus towards the synthesis and clarification goals. of this research. There were various interest- ing comments made by Goodwin et al in their TECHNIQUES USING PRODUCTION section on future developments, including one Methods detecting the urease produced by remark which has proved prophetic: "The H pylori offer rapid and virtually specific importance of C pyloridis as a human patho- techniques for diagnostic use in outpatients gen, however, will need to be proved in great and the possibility of non-invasive treatment detail to satisfy gastroenterologists." The de- and follow up (by breath tests). These are velopment of two polarised groups of described in detail by Rathbone and Heatley.7 Department of believers and sceptics who found These tests depend on the release of labelled Bacteriology, Wright treatment, "intuitively offensive", has been from labelled . Fleming Institute, a feature of the period commented on by St Marys' Hospital Medical School, Bartlett5 and others.6 Although understand- 13C Paddington, London able, this schism (most pronounced in the Described by Graham," it was the first of this W2 1PG United States of America) probably hindered A C Maddocks group. It has the major advantage that it is acceptance of the hypothesis (that H pylori is a non-invasive and does not contain radioactive Correspondence to: Dr A C Maddocks human causing disease rather than a material. The disadvantage is that fewer Accepted for publication mere coloniser of damaged tissue) by clini- hospitals have the relatively expensive isotope 8 November 1989 cians and the well organised investigations ratio mass spectrometer needed to perform it. 354 Maddocks

14C urea breath test12'14 ulcers is now well recognised, as is the restric- This test uses a liquid scintillation counter tion of H pylori colonisation to gastric type which is much more widely available but the epithelial cells. The questions that arise next material is, of course, radioactive. Even are, how does Hpylori antritis relate to disease J Clin Pathol: first published as 10.1136/jcp.43.5.353 on 1 May 1990. Downloaded from though the dose is safe and very small, the in the ? What is the relation between radioactivity makes this a less attractive test gastric metaplasia, , and duodenal for follow up repeats etc. ulcers? Johnston et al showed that Hpylori can Apart from being non-invasive the other be seen by light microscopy in 96% of cases of advantage of these tests in a notoriously duodenitis associated with duodenal ulcers.'8 "patchy" condition is that they investigate the Wyatt et al'9 and Carrick et al0 explored entire mucosa rather than the small area the relation between H pylori duodenitis and provided by a biopsy specimen. ulcer formation and gastric metaplasia and heterotopic gastric mucosa. In a microscopic ENDOSCOPIC BIOPSY-UREASE TEST study of multiple duodenal and antral biopsy McNulty's observation that there is enough specimens from 137 subjects Carrick et al preformed urease present in a biopsy speci- found that the presence of duodenal H pylori men to give a rapid result when it is placed in infection was a strong risk factor for the a urea solution'5 has been followed by variants development of duodenal ulcers; cigarette from many other workers. These modifica- smoking, age, sex and use ofnon-steroidal anti- tions allow the test to be carried out in the inflammatory drugs were not significant risk endoscopy clinic in less and less time. Com- factors. Carrick et al also postulated a synergic mercial tests can be bought in (CLO-test), but role for duodenal Hpylori and endogenous acid are considerably more expensive at £2.00 per prqduction in the development of duodenal test than the £0.05 per test for home made ulceration. (Functioning acid producing tissue urease. 16 could be found most often at the edge of duodenal ulcers but was also found in subjects ANTIGENS FOR SEROLOGY: A NEW GENERATION without ulcers). They also suggested that most Although relatively crude, whole organism ofthe acid producing tissue would be destroyed antigens and lysates gave interesting early by the time the ulcer was formed. serological results, and it became obvious that The multifactorial aetiology duodenal ulcers there were some crossreactions with other is now emphasised by several groups2'22 and , notably C jejuni. This could be seems to be a theory more likely to appeal to particularly misleading in third world clinicians trained on the premise of"no acid, no countries where C jejuni infections are very ulcer" than a heavy emphasis on H pylori common. Although changing the ELISA cut infection alone. Goodwin's "leaking roof' off value and adsorbing sera have been tried, it theory is also a persuasive argument for is thought that better results could be multiple causation and "mending the roof'- http://jcp.bmj.com/ obtained by using more highly purified anti- that is, killing the bacteria, which the gens (second generation ). The urease damage, which lets in the acid, which causes the is an obvious candidate and urease rich anti- ulcer. gens have been successfully used by Bolton and Hutchinson8 and Evans et al9 and are TREATMENT recommended by the former to determine Reports on therapeutic trials of the

type on September 23, 2021 by guest. Protected copyright. IgG as a pre-endoscopy screening suggested by Goodwin et al are emerging and test. are in line with the hypothesis that continuing H pylori infection causes conditions which Gastritis allow peptic ulcers to relapse.2324 Incidentally, Although the association between cultured the use of the word "eradicated" to mean "not H pylori and histological chronic active gas- detectable" is an unfortunate and misleading tritis is accepted, there have always been feature of many articles in this area, which occasional discrepancies which have upset the could well be avoided. "gold standards". Bayersdorffer et al pro- duced a study of the topographic association HOST-PARASITE RELATION which must convince all but the most scep- There are several factors now being studied tical.'0 They studied 1000 biopsy specimens which may contribute to the pathogenicity of obtained from 10 sites in 50 patients and H pylori. Some relate to the organism, such as showed that the area of H pylori colonisation adherence factors and cytotoxin, and some to was larger than the area of gastritis. They the host defences, such as , prosta- suggest that two biopsy specimens will detect glandins, and plasma concentrations H pylori and that four should detect active which overlap with classic . chronic gastritis. Cytotoxins have been described by Leunk et Oderda et al investigated gastritis and al,25 who found intracellular vacuolisation upper in children by biopsy, when they tested Hpylori supeatant on tissue antibody, and serum pepsinogen 1 studies and culture cells. Figura et al studied the associa- showed that serum IgG concentrations and tion between cytotoxin production and ulcers.26 serum pepsinogen 1 could predict gastritis." Other cytotoxins have been obtained by sonica- tion etc, but their role is uncertain. Urease Duodenal ulcers, duodenitis, and gastric presumably exerts some toxic effect, although metaplasia its role may be more concerned with protection The association between gastritis and duodenal from the acid environment of the lumen, or (formerly Campylobacter pyloridis/pylori) 1986-1989: A review 355

possibly, obtaining nutrients from the inter- they did not find excess acid in patients who cellular mucus. The seems to be only had Hpylori gastritis." associated with the

and periplasm.27 Other "gastric spirals" J Clin Pathol: first published as 10.1136/jcp.43.5.353 on 1 May 1990. Downloaded from Mucinase, a which proteolyses gas- Work on Hpylori has opened up other areas of tric , was investigated by Slomiany et research, particularly other mucus related al.2" The action of this enzyme weakens the spiral organisms in man and animals. In man mucous gel and thins the barrier defending the "Gastrospirillum hominis,"39 a tightly coiled from the luminal gastric acid. gimlet-like organism (3 5-7-5 ,gm), was found The organism agglutinates red cells, and a in cases ofchronic active gastritis, mainly in the fibrillar haemagglutinin was described by gastric pits, not attached to the epithelium. It Evans et al,29 found only in bacteria cultured on produces a powerful urease. The organism has solid media. The characteristic adhesion sites, not been cultured on artificial media. It is much whose appearance is variously described as cup rarer than H pylori, occurring about once for or pedestal, may be associated with a cell every 1000 H pylori. Other similar tightly receptor glycolipid. coiled spirals are found in cats, dogs, and apes. Lingwood et al described a substance in the Campylobacter mustelae, an organism similar to lipid of red cells, human and pig stomach H pylori, is found in many ferrets' stomachs tissue, and HEp-2 cultured cells which was and infection can be associated with ulcers. specifically recognised by whole H pylori The studies by Lee of the mucosal and organisms when separated by thin layer mucus associated bacterial flora'" are well chromatography.30 The substance is thought to worth reading in the originals or in the be a novel glyceroglycolipid. It was present in beautifully illustrated chapter in the book by the human stomach antrum to a greater extent Rathbone and Heatley. The spiral shape and than in the fundus and there was less in infant urease production are shared by these mucus tissue than adult. colonising bacteria. Many of these organisms Although antibody dependent phagocytosis are found in apparently healthy animals and the takes place, the organism also directly activates Hpylori and C mustelae are unusual in that they the classical complement pathway. Bernatow- produce some minor pathological changes, ska et al suggest that this may explain the although they do not invade. For this reason inflammatory reaction produced in the tissue, Lee has referred to the group as "almost" although there is no bacterial invasion.3' normal flora. Antibody seems to have little protective effect, and patients with severe hypogammaglobulin- The missing links aemia are not particularly prone to attack by The mode of spread of H pylori is still H pylori. problematic, although there are many pointers Work on host reponses is still at an early towards person to person spread by mouth. In http://jcp.bmj.com/ stage and reports are conflicting but the picture addition to spread by electrodes during is beginning to take shape. experiments, endoscopy and biopsy equipment have been incriminated.4"42 This implies that Mucin adequate quantities of equipment and sterilis- Degradation of mucus and damage to the ing facilities to carry out endoscopy lists safely protective mucous coat are described by are essential. An elusive coccoid43 form of the Slomiany et al,2" who investigated enzymic organism is thought to be relatively resistant on September 23, 2021 by guest. Protected copyright. degradation, and by Shida et al32 and Tsuju et and may be involved in faecal-oral spread, but al,33 who looked at histological changes in evidence is so far lacking. The mode of spread mucus in H pylori infections. Thomsen et al is probably the single most important area for studied infected mucus and the possibility of new research as it holds the key to prevention, H + ion back diffusion.34 as well as being microbiologically fascinating. Prostaglandins 1 Marshall BJ, Goodwin CS. Revised nomenclature of Tissue prostaglandins are thought to have a Campylobacter pyloridis. Int J Systemat Bacteriol 1987; protective role in maintaining epithelial 37:68. 2 Goodwin CS, Armstrong JA, Marshall BJ. Campylobacter integrity. Tissue concentrations are lowered in pyloridis, gastritis, and peptic ulceration. J Clin Pathol some Hpylori infections, and although findings 1986;39:353-65. 3 Tytgat Guido NJ. Campylobacter pylori: recent develop- are variable, it is agreed that in patients with ments. Eur J Gastroenterol Hepatol 1989;1:3-41. duodenal ulcers prostaglandins are lowered.35 4 Goodwin CS. Duodenal ulcer, Campylobacter pylori, and the "leaking roof' concept. Lancet 1988;ii:1467-9. 5 Bartlett JG. Campylobacter pylori: Fact or fancy? Gastro- Gastrin enterology 1988;94:229-38. 6 Peterson WL. Antimicrobial of duodenal ulcer? Plasma gastrin is raised in healthy subjects with Hold off for now! (selecttd summary) reply by Marshall positive Hpylori, serology as well as in subjects BJ. Gastroenterology 1989;97:508-10. 7 Rathbone BJ, Heatley RV, eds. "Campylobacter pylori and with duodenal ulcer and antral colonisation.3' gastroduodenal disease". Oxford: Blackwell Scientific Levi et al put forward "the gastrin link" Publications, 1989. 8 Bolton FJ, Hutchinson DN. Evaluation of three between H pylori and duodenal ulcers as a Campylobacter pylori antigen preparations for screening unifying hypothesis.7 They contended that sera from patients undergoing endoscopy. J Clin Pathol H 1989;42:723-6. pylori stimulates gastrin release in duodenal 9 Evans DG Jr, Evans DG, Graham DY, Klein PD. A ulcer disease, and this causes the well known sensitive and specific serological test for detection of Campylobacter pylori infection. Gastroenterology 1989; increased gastric acid . They propose 96:1004-8. testing their results by following up treated 10 Bayerdorffer E, Oertrel H, Lehn N, et al. Topographic cases. association between active gastritis and Campylobacter Wagner et al contested this view because pylori colonisation. J Clin Pathol 1989;42:834-9. 356 Maddocks

11 Graham DY, Klein PD, Evans DJ, et al. Campylobacter patients with peptic ulcers and from patients with chronic pyloridis detected by the 13C -urea test. Lancet gastritis only. J Clin Microbiol 1989;27:225-6. 1987;i:1 174-7. 27 Bode G, Malfertheiner P, Nilius M, Lehnhardt G, 12 Bell GD, Weil J, Harrison G, et al. 14C-urea breath Ditschunheit H. Ultrastructure localisation of urease in analysis, a non-invasive test for Campylobacter pylori in outer membrane and periplasm of Campylobacter pylori.

the stomach. Lancet 1987;i: 1367-8. J Clin Pathol 1989;42:1578-9. J Clin Pathol: first published as 10.1136/jcp.43.5.353 on 1 May 1990. Downloaded from 13 Marshall BJ, Surveyor I. Carbon-14 urea breath test for the 28 Slomiany BC, Bilski J, Sarsiek, et al. Campylobacter diagnosis of Campylobacter pylori associated gastritis. pyloridis degrades mucin and undermines gastric mucosal J Nucl Med 1988;29:11-16. integrity. Biochim Biophys Res Commun 1987;144:307-14. 14 Rauws EAJ, Tytgat GNJ, Langenberg W, Royen EV. 29 Evans DG, Evans DJ Jr, Moulds JJ, Graham DY. N- Experience with 14C Urea breath test in detecting acetylneuraminyl lactose binding fibrillar haemagglutinin C pylori. In: Menge H, Gregory M, Tytgat GN, Marshall of Campylobacter pylori: a putative colonization factor BJ, eds. Campylobacter pylori. Berlin: Springer-Verlag, antigen. Infect Immun 1988;56:2896-906. 1988:151-6. 30 Lingwood CA, Law H, Pellizzari A, Sherman P, Drumm B. 15 McNulty CAM, Wise R. Rapid diagnosis of Campylo- Gastric glycerolipid as a receptor for Campylobacter bacter-associated gastritis. Lancet 1985;i:1443-4. pylori. Lancet 1989;ii:238-41. 16 McNulty CAM, Dent JC, Uff JS, Gear MWL, Wilkinson 31 Bernatowska E, Jose P, Davies H, Stephenson M, Webster SP. Detection of Campylobacter pylori by the biopsv D. Interaction of campylobacter species with antibody urease test: an assessment in 1445 patients. Gut complement and . Gut 1989;30:906-1 1. 1989;30: 1058-62. 32 Shida Y, Yoshida I, Inoto I, Suzuki S. Campylobacter pylori 17 Oderda G, Vaira D, Holton J, Dowsett JF, Ansaldi N. infection and mucin production of the gastric mucosa. Serum pepsinogen 1 and Ig G antibody to Campylobacter Gastroenterology 1989;96:A466. pylori in non-specific abdominal pain in childhood. Gut 33 Tsuju M, Kawano S, Sato N, Kamada T. Campylobacter 1989;30:912-16. pylori infection decreases the intracellular mucin of 18 Johnston BJ, Reed PI, Ali MH. Prevalence of Campylo- human gastric mucosa. Gastroenterology 1 989;96:A5 17. bacter pylori in duodenal and gastric mucosa-relation- 34 Thomsen L, Tasman-Jones C, Morris A, Wiggin T, Lee S. ship to . Scand J Gastroenterol 1988;23 Campylobacter pylori infected mucus presents a barrier to (suppl 142):69-75. ion movement- is important. 19 Wyatt JI, Rathbone BJ, Dixon MF, Heatley RV. Gastroenterol Int 1988;1 (suppl 1):759. Campylobacter pyloridis and acid induced gastric meta- 35 Taha AS, McKinlay AW. Uphadhyay R, Kelly R, Russell plasia in the pathogenesis of duodenitis. J Clin Pathol RJ. Prostaglandins and Campylobacter pylori. Lancet 1987;40:841-8. 1989;ii:800-1. 20 Carrick J, Lee A, Hazell S, Ralston M, Daskalopoulos G. 36 Smith JTL, Founder RE, Evans DJ, Graham DY, Evans Campylobacter pylori duodenal ulcer and gastric meta- DG. Inappropriate 24 hour hypergastrinaemia in asymp- plasia: possible role of functional heterotopic tissue in tomatic C pylori infection. Gut 1989;30:A732-3. ulcerogenesis. Gut 1989;30:790-7. 37 Levi S, Haddad G, Ghosh P, et al. Campylobacter pylori and 21 Graham DY. Campylobacter pylori and . duodenal ulcers: the gastrin link. Lancet 1989;i:1 167-8. Gastroenterologv 1989;96:615-25. 38 Wagner S, Schuler A, Gebel M, Freise J, Schmidt FW. 22 Wyatt JI. Campylobacter pylori duodenitis and duodenal Campylobacter pylorn and acid secretion. Lancet 1989; ulceration. In: Rathbone BO, Heatley RV, eds. ii:562. Campylobacter pylori and Gastroduodenal disease. Oxford: 39 Anonymous. Gastrospirillum hominis. [Editorial.] Lancet Blackwell Scientific, 1989:117. 1989;ii:252-3. 23 Marshall BJ, Goodwin CS, Warcon JR, et al. Prospective 40 Lee A, Hazell SL. Campylobacter pylori in health and double blind trial of duodenal relapse after eradication of disease; an ecological perspective. Microb Ecol Health Dis Campylobacter pylori. Lancet 1988;ii:1437-42. 1988;1:1-16. 24 Rauws EAJ, Langenberg W, Houthoff HJ, Zanen HC, 41 Karim QN, Rao GG, Taylor M, Baron JH. Routine cleaning Tytgat GNJ. Campylobacter pyloridis-associated chronic and elimination of Campylobacter pylori from endoscopic active antral gastritis. A prospective study ofits prevalence biopsy forceps. J Hosp Infect 1989;13:87-90. and the effects of antibacterial and antiulcer treatment. 42 Rokkas T, Pursey C, Uzoechina E, et al. Non-ulcer dyspep- Gastroenterology 1988;94:33-40. sia and short term De-Nol therapy: a placebo controlled 25 Leunk RD, Johnson PT, David BC, Kraft WG, Morgan trial with particular reference to the role ofCampylobacter DR. Cytotoxic activity in broth culture filtrates of pylori. Gut 1988;29:1386-91. Campylobacter pylori. I Med Microbiol 1988;26:93-9. 43 Megraud F. Campylobacter pylori: recent developments. 26 Figura N, Guguelmetti P, Rossolini A, et al. Cytotoxin Microbiological characteristics of Campylobacter pylori.

production by Campylobacter pylori strains isolated from Eur J Gastroenterol Hepatol 1989;1:5-12. http://jcp.bmj.com/ on September 23, 2021 by guest. Protected copyright.