NZMA Home

Table of contents
Current issue
Search journal
Archived issues
NZMJ Obituaries
Classifieds
Hotline (free ads)
How to subscribe
How to contribute
How to advertise
Contact Us
Copyright
Other journals
The New Zealand Medical Journal

 Journal of the New Zealand Medical Association, 21-May-2004, Vol 117 No 1194

Helicobacter pylori: a historical perspective 1983–2003
Alan Fraser

1983—the beginning of a revolution

A short letter to the Lancet in 1983 by Dr Marshall reporting on the culture of a bacterium from the stomach started a revolution in our thinking about upper gastrointestinal disease.1 This report was viewed with great interest around the world. One of the centres that began research activity very soon after this report was Auckland Hospital. Dr Arthur Morris, a microbiology registrar, teamed up with Dr Gordon Nicholson, gastroenterologist. Dr Morris was keen to fulfil some of Koch’s postulates regarding Helicobacter and gastritis. He performed a self-ingestion study that has been a widely quoted paper in the area.2
The initial establishment of infection was found to require a larger than expected ‘dose’ of viable bacterium as well as needing H2-antagonists to reduce gastric acid. Abdominal pain and nausea occurred within a few days but resolved completely after 12 days. The infection proved to be difficult to eradicate. Antibiotics that had been shown to be effective in the test-tube caused only temporary suppression of the infection. It wasn’t until antibiotic combination treatments become established that the infection was finally eradicated several years later.3

Standard triple therapy—an imperfect but useful workhorse

Triple therapy with De-Nol, Metronidazole and tetracycline became the established treatment. This had modest success rates but was poorly tolerated because of side-effects and the large number of tablets that needed to be taken over 2 weeks.4 Although compliance was an issue, ulcer patients were well motivated to look for a cure for their chronic symptoms.5
Moreover, despite the drawbacks of ‘standard’ triple therapy, a large number of ulcer patients were successfully treated over a 10-year period.6 Through case-finding, both in primary care and hospital clinics, the cohort of ulcer patients was largely identified and treated.
The use of De-Nol as part of the eradication treatment was a ‘rediscovery’ of an old drug. A study at Auckland Hospital by Lane and Lee had shown that De-Nol was more effective than H2-antagonists in preventing duodenal ulcer recurrence. The reason for this observation was not apparent until the discovery of H.pylori.7
Bismuth compounds are highly bacteriocidal to H. pylori. Scanning electron microscopy studies at the University of Auckland showed the acute destructive effect of bismuth on the cell wall.9 Dr Morris was initially treated with 4 weeks of Pepto-Bismol (an old formulation of bismuth). He appeared to have been ‘cured’ based on normal histology and the absence of H. pylori on biopsies taken a week after completing treatment. Gastroscopy performed 1 year after initial ingestion showed a mild chronic inflammatory infiltrate and H. pylori was again isolated. Molecular comparison showed that this bacterium had identical molecular patterns to the original bacterium.3 Subsequent studies have confirmed that re-infection in adults is very rare.8 The re-appearance of Helicobacter after apparently successful treatment is nearly always due to recrudescence of the same strain of bacteria.

Epidemiology

The epidemiology of the infection was a puzzle. Dr Morris rapidly developed an ELISA antibody test and was able to demonstrate that IgG antibodies to Helicobacter were a valuable tool for epidemiology. It became apparent that H. pylori was a chronic infection with positive antibodies persisting throughout life. Early observations were that there was a higher prevalence of antibody to H. pylori with older age and a higher prevalence in Maori and Pacific Islanders.10 The seropositivity for blood donors aged 21–30 years was 24%; for 41–50 years, 53%; and 71–80 years, 68%. The ethnic differences observed in serological studies were extended with endoscopy studies of patients presenting with dyspepsia in Fiji and Tonga (93% and 78%, respectively were positive for Helicobacter).11,12 There was a high rate of ulcer disease—mostly duodenal ulcer (Fiji 28/42 and Tonga 8/18).
H. pylori is an infection acquired in early childhood. There is a higher risk of infection with lower socioeconomic living conditions. Childhood living conditions have dramatically changed in New Zealand over the last 50–60 years; consequently, acquisition of H. pylori in childhood has become much less common. This change in living standards explains the observation that H. pylori infection is more common with older age.13,14 This ‘cohort effect’ explains why Helicobacter infection is gradually becoming less common in our community independent of the effect of antibiotic treatment.
Epidemiological studies have identified some risk factors for early childhood infection. These include lack of hot running water, overcrowding and sharing a bed. Some other potential risk factors that need to be explored further are the pre-mastication of food prior to feeding infants, crowded daycare facilities, and the possible protective effect of breast-feeding. Limited data is available for New Zealand (NZ), but lower socioeconomic status has been confirmed as a risk factor.15 Serological studies of children are able to inform us of the potential burden of gastroduodenal disease in the future. Recent studies from Christchurch, Dunedin, and Auckland show that about 5% of European children become infected with H. pylori by the age of 20 years.15–17 However in contrast, almost half of Pacific Island children (living in NZ) are infected. These children will have a significant burden of gastroduodenal disease in adult life.15
Duodenal ulcer disease appears to be relatively recent consequence of H. pylori infection; perhaps only over the last 150 years. However there is good evidence available which shows that H. pylori has infected human stomachs for thousands of years. The best data on these trends in peptic ulcer disease comes from hospital admissions for ulcer bleeding or perforation.
The incidence of duodenal ulcers started to increase around 1900 and then peaked in the 1950s. Since then, there has been a gradual decline in the incidence of duodenal ulcers.14 In New Zealand, endoscopists practicing in areas with a predominantly European middle class population now rarely observe duodenal ulcers. The reasons for this remarkable change in pattern of disease are speculative, but one explanation is the trend towards higher levels of acid secretion over the last 150 years, perhaps due to improved nutrition.
When H. pylori is acquired in a stomach with low levels of acid, there is a diffuse pattern of inflammation and the potential adverse outcomes are gastric ulcer and gastric cancer. In contrast, when H. pylori is acquired in a stomach with high acid secretion, the inflammation is confined to the antrum. This leads to a further increase in acid secretion (because antral inflammation stimulates gastrin that is able to act on the healthy, responsive acid-secreting mucosa in the body of the stomach) and this high level of acid output is crucial for the formation of duodenal ulcers.
Indeed, the last 100 years has been a ‘window of opportunity’ for Helicobacter to cause duodenal ulcers. The continuation of the trend towards higher living standards is causing its gradual demise because of the interruption of transmission during childhood.
One interesting avenue of study is the use of strain types of Helicobacter to determine population migrations patterns. O’Toole et al showed that strains of Helicobacter strains from Maori and Pacific Island patients were distinctly different from strains obtained from European patients.18 The DNA profiles of the Maori and Pacific Island patients were remarkably homogeneous. Worldwide studies of DNA profiles (polymorphisms) have recently shown that the strains types from Maori and Pacific Island patients are very similar to isolates obtained from South East Asian (and to a lesser extent American Indian patients). In this worldwide study, the Polynesian isolates were the most uniform of any group studied, suggesting separate migration over at least 1000 years.19

The goal of effective and well-tolerated treatment

Metronidazole resistance became the critical factor associated with failure of standard triple therapy. The resistance rate has been observed to increase from 13% of isolates in 1986 (before eradication treatment was ever given) to around 50% in many centres.6 Metronidazole resistance is now less of a concern with the establishment of omeprazole, amoxicillin, and clarithromycin (OAC) as first-line treatment. The use of clarithyromycin was the major breakthrough in treatment combinations. Treatment became shorter (7-day duration) and more effective (eradication rates above 90%).6 The main determinant of treatment failure is now clarithromycin resistance.
Resistance rates have risen from low levels (<2%) to around 10% but may be staying stable at this level. Resistance to clarithromycin is nearly universal after failed treatment with OAC. In addition, repeating OAC has a very low chance of success (less than 10%). The preferred second-line treatment is quadruple therapy—De-Nol one tabs qid (four times daily), omeprazole 20mg bd (twice daily), tetracycline 500mg qid, and metronidazole (daily dose probably needs to be 1200 mg).6
If this treatment fails, then the merits of further attempts at eradication needs to be carefully considered. Often it is more appropriate to suggest that no further eradication treatment is attempted. Furthermore, patients with definite ulcer disease may need to accept ‘old-fashioned’ maintenance treatment with proton pump inhibitors (PPI) or H2-antagonist.

The 1990s—a time of widening indications

The availability of effective and well-tolerated treatments shifted attention to indications other than peptic ulcer disease (duodenal and gastric ulcers). Patients with duodenitis, and those with evidence of duodenal scarring but no active ulcer, were also found to have a good symptomatic response—similar to patients with duodenal ulcer disease. They should be considered as part of the duodenal ulcer spectrum or ‘ulcer diathesis’. Patients presenting with bleeding peptic ulcer definitely need treatment (if H. pylori positive) but they often leave hospital without starting eradication treatment.20
The benefit of eradication treatment for patients with dyspepsia but a normal endoscopy (non-ulcer dyspepsia) is debatable. There have been at least two conflicting meta-analysis of available trials. It all depends on which trials you select! The magnitude of any effect is certainly small. Less than 15% of patients achieve symptomatic benefit (that is greater than the effect of placebo).21,22 Treatment, if given, should be directed at those with upper abdominal discomfort improved by meals (ulcer-type dyspepsia). Patients with heartburn alone are unlikely to gain any symptomatic improvement.
Uninvestigated dyspepsia is a different issue from ‘non-ulcer dyspepsia’. The ‘test and treat’ approach is a valid and successful way of managing dyspepsia in patients under 50 years in areas where the prevalence of H. pylori is over 25–30%.23–25 Some patients will have underlying peptic ulcer disease and they will be effectively treated without the need for endoscopy. The proportion of patients with dyspepsia and positive H. pylori tests and who have an underlying peptic ulcer has been debated. Studies from South Auckland showed the proportion to be as high as 40% but the proportion could be much lower in other areas.26
There is some literature suggesting that H. pylori causes a variety of non-gastrointestinal problems; However, none of these claims have been validated in the long-term. One of the most difficult contentions to prove (or disprove) is the association of H. pylori infection with coronary heart disease. There is probably no biological association, but there have been some positive studies probably because of similar confounders (such as socioeconomic status).27,28

1995 onwards—are there some good Helicobacter species that should be preserved?

The possible negative association between H. pylori and gastro-oesophageal reflux (GORD), as well as reports of aggravation of reflux oesophagitis after eradication treatment, gave some caution to the widespread treatment of H. pylori in primary care. There is no doubt that GORD is becoming more common in our community and that this change has happened at the time when the prevalence of H. pylori is decreasing. This is probably not ‘cause and effect’. Indeed, recent studies have argued against any contention that H. pylori eradication aggravates reflux.29,30 Another controversy is the potential benefit of eradication of H. pylori in patients taking long-term proton pump inhibitors (PPIs). Atrophic gastritis appears to develop at a faster rate in H. pylori-infected patients taking long-term PPIs.31
For some time, it will not be known whether this is an important association, but it cannot be considered good for patients to develop atrophic gastritis (as this is known to be the first step in a progression towards gastric cancer). Therefore, eradication treatment should be given to all patients who are likely to require long-term treatment with proton pump inhibitors.

Helicobacter and gastric cancer

Epidemiological studies have consistently shown a 2–3 fold increased risk of gastric cancer with H. pylori infection.32 Gastric cancer is generally believed to be a multi-step progression from chronic gastritis to atrophic gastritis, intestinal metaplasia to dysplasia, and subsequently to cancer. Intestinal metaplasia is more common, and occurs at an earlier age in H. pylori-infected individuals.
Furthermore, intestinal metaplasia is more common, and more extensive, in ethnic groups at higher risk of gastric cancer (eg, Maori and Pacific Islanders).33 Several large studies of gastric cancer rates after H. pylori eradication are in progress but 5–10 years of follow-up will be required before any meaningful results are obtained.34 H. pylori eradication could be a cost-effective public health strategy if large population studies show a reduction in rates of gastric cancer. Much attention has focused on an extended Maori family with familial gastric cancer related to an E-cadherin mutation.35 This important and ground-breaking research finding but should not detract from the effect of H. pylori in causing the high rates of gastric cancer in Maori and Pacific Island men.
Indeed, most estimates would attribute 50% of the gastric cancer risk to H. pylori infection.36 Therefore, eradication of this infection will always be the most easily altered risk factor for gastric cancer.

Helicobacter and the NSAID controversy

If H. pylori causes some gastric ulcers and non-steroidal anti-inflammatory drugs (NSAIDs) cause others, then surely both factors together would be worse? However, this simple notion has proved difficult to prove or disprove—with many conflicting results. An important meta-analysis has helped to resolve some issues. H. pylori-infected NSAID users are 60 times more likely to have a peptic ulcer than non-infected non-users. Furthermore, H. pylori increases the peptic ulcer risk in NSAID-users by three fold. The risk of gastric bleeding is also greater with H. pylori infection37 To ‘test and treat’ for H. pylori infection (prior to initiation of NSAID) is a proven strategy that has yet to be become popular.38
The last 20 years has seen an explosion in our knowledge of Helicobacter pylori. Over the years there have been many areas of controversy but most of the areas of debate have been resolved. It is now possible to have evidence-based practice for the management of this infection.
Author information: Alan Fraser, Associate Professor, Department of Medicine, University of Auckland, Auckland
Correspondence: Associate Professor Alan Fraser, Department of Medicine, University of Auckland, Private Bag 92019, Auckland. Fax: (09) 373 7677; email: a.fraser@auckland.ac.nz
References:
  1. Marshall B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet. 1983;i:1273–5.
  2. Morris A, Nicholson G. Ingestion of Campylobacter pyloridis causes gastritis and raised gastric pH. Am J Gastroenterol. 1987;82:192–9.
  3. Morris A. Ali MR, Nicholson G, et al. Long-term follow-up of voluntary ingestion of Helicobacter pylori. Ann Int Med. 1991;114:662-3.
  4. Fraser AG, Moore L, Ali MR, et al. An audit of low dose triple therapy for eradication of Helicobacter pylori. N Z Med J. 1996;109;290–2.
  5. Fraser AG, Moore L, Berry S, Arroll B. Eradication treatment for Helicobacter pylori in general practice. N Z Med J 1996;109:422–4.
  6. Fraser AG, Moore L, Hackett M, Hollis B. Helicobacter pylori treatment and antibiotic susceptibility: results of a 5-year audit. Aust N Z J Med. 1999;29:512–6.
  7. Lane MR, Lee SP. Recurrence of duodenal ulcer after medical treatment. Lancet. 1988; i:1147–9.
  8. Fraser AG, Schreuder V, Chua L, Moore L. Follow-up after successful eradication of H. pylori - symptoms and re-infection. J Gastro Hepatol.1998;13:555–9.
  9. Thomsen LL, Gavin JB, Tasman-Jones C. Relation of Helicobacter pylori to human gastric mucosa in chronic gastritis of the antrum. Gut. 1990;31:1230–6.
  10. Morris A, Nicholson G, Lloyd G, et al. Seroepidemiology of Campylobacter pyloridis. N Z Med J. 1986;99:657–9.
  11. Beg F, Oldmeadow M, Morris A, Nicholson G. Campylobacter pylori infection in patients undergoing endoscopy in Fiji. N Z Med J. 1998;101:140–1.
  12. Nicholson G, Morris A, Miller M, Akau'ola H. Campylobacter pylori infection in patients undergoing endoscopy in Tonga. N Z Med J. 1988;101:124.
  13. Malaty HM, El-Kasabany A, Graham DY, et al. Age at acquisition of Helicobacter pylori infection: a follow-up study from infancy to adulthood. Lancet. 2002;359:931–5.
  14. Langman M. Commentary: peptic ulcer, Susser and Stein and the cohort phenomenon. Int J Epidemiol. 2002;31:27–8.
  15. Fraser AG, Scragg R, Metcalf P, et al. Prevalence of Helicobacter pylori in different ethnic groups in New Zealand children and adults. Aust N Z J Med 1996; 26:646–51.
  16. Collett JA, Burt MJ, Frampton CM, et al. Seroprevalence of Helicobacter pylori in the adult population of Christchurch: risk factors and relationship to dyspeptic symptoms and iron studies. NZ Med J 1999;112:292–5.
  17. Fawcett JP, Shaw JP, Cockburn M, et al. Seroprevalence of Helicobacter pylori in a birth cohort of 21-year old New Zealanders. Eur J Gastro Hepatol. 1996;4:365–70.
  18. Schmid J, Fraser AG, Hollis B, O’Toole P. Ethnic tropism of DNA fingerprints of Helicobacter pylori. Infection and Immunity. 1997;65:3708–12.
  19. Falush D, Wirth T, Linz B, et al. Traces of human migrations in Helicobacter pylori populations. Science. 2003; 299:1582–5.
  20. Garrigan K, McIntosh C, Fraser AG. Bleeding peptic ulcers: audit of eradication for H pylori. N Z Med J 1999;112:178–80.
  21. Laine L, Schoenfeld P, Fennerty MB. Therapy for Helicobacter pylori in non-ulcer dyspepsia. A meta-analysis of randomised trials. Ann Intern Med. 2001;134:361–9.
  22. Moayyedi P, Soo S, Deeks J, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database Syst Rev. 2004;(1):CD002301.
  23. Lassen AT, Pedersen FM, Bytzer P, et al. Helicobacter pylori test-and-eradicate vs. prompt endoscopy for dyspepsia patients in primary care. Lancet. 2000;356:455–60.
  24. McColl KEL, Murray LS, Gillen D, et al. Randomised trial of endoscopy with testing for Helicobacter pylori compared with non-invasive H pylori testing alone in the management of dyspepsia. BMJ. 2002; 324: 999–1002.
  25. Fraser AG, Williamsom S, Lane MR, Hollis B. Nurse-led dyspepsia clinic using the urea breath test for Helicobacter pylori. N Z Med J. 2003;116(1176). URL: http://www.nzma.org.nz/journal/116-1176/479/
  26. Fraser AG, McIntosh C, Berry S, Moore L. Can the urea breath test for H.pylori replace endoscopy for the assessment of dyspepsia in primary care? N Z Med J. 1998;111:11–4.
  27. Scragg RK, Fraser A, Metcalf PA. Helicobacter pylori seropositivity and cardiovascular risk factors in a multicultural workforce. J Epidemiol Community Health. 1996;50:578–9.
  28. Fraser AG, Scragg RK, Cox B, Jackson RT. Helicobacter pylori, Chlamydia pneumoniae and myocardial infarction. Int Med J. 2003;33:267–72.
  29. Moayyedi P, Bardhan C, Young L, et al. Helicobacter pylori eradication does not exacerbate reflux symptoms in gastro-oesophageal disease. Gastroenterology. 2001;121;1120.
  30. Schwizer W, Thumshirn M, Dent J, et al. Helicobacter pylori and symptomatic relapse of gastro-oesophageal reflux disease: a randomized controlled trial. Lancet. 2001;357:1738–42.
  31. Schenk BE, Kuipers EJ, Nelis GF, et al. Effect of Helicobacter pylori eradication on chronic gastritis during omeprazole therapy. Gut. 2000;46:615–21.
  32. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut. 2001;49: 347–53.
  33. Fraser AG, Peng SL, Jass JR. Intestinal metaplasia subtypes and Helicobacter pylori infection: a comparison of ethnic groups in New Zealand. J Gastroenterol Hepatol. 1998;13:560–5.
  34. Sung JJ, Lin SR, Ching JY, et al. Atrophy and intestinal metaplasia one year after cure of H. pylori infection: a prospective, randomized study. Gastroenterology. 2000;119:7–14.
  35. Pharoah PD, Guilford P, Caldas C. International Gastric Cancer Linkage Consortium. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology. 2001;121:1348–53.
  36. Parsonnet J, Harris RA, Hack HM, Owens DK. Should we treat H. pylori infection to prevent gastric cancer? Gastroenterology. 1997;112:1044–5.
  37. Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet. 2002;359:14–22.
  38. Chan FK, To KF, Wu JC, et al. Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial. Lancet. 2002; 359:9–13.
     
Current issue | Search journal | Archived issues | Classifieds | Hotline (free ads)
Subscribe | Contribute | Advertise | Contact Us | Copyright | Other Journals