Helicobacter pylori and gastritis: Untangling a complex relationship 27 years on

Authors


  • Conflict of interest
    The authors have declared that they have no conflicts of interest.

Professor Benjamin C Y Wong, Department of Medicine, Queen Mary Hospital, Pokfulam Road, Hong Kong, China. Email: bcywong@hku.hk

Abstract

Since its' introduction by Warren and Marshall 27 years ago, Helicobacter pylori (HP) has become the linchpin in our understanding of important gastric conditions including gastritis, intestinal metaplasia (IM), gastric/duodenal ulcers (GU/DU), Mucosal Associated Lymphoid Tumour (MALToma) and gastric cancer. Initially named Campylobacter pyloridis, it was re-named HP when biochemical and genetic characterization of the organism showed that it was not a member of the Campylobacter genus. The finding in 1983 was seminal. It is now recognized that HP is the most common chronic human bacterial infection and it is the most common cause of gastritis. It is strongly implicated in the development of peptic ulcer disease and gastric neoplasms. In the years since its' discovery, much headway has been made in the understanding of this ubiquitous organism that had remained elusive, with much work focused on eradication, in part driven by pharmaceutical research and development. Standard triple therapy emerged to eradicate HP. However, with the emergence of HP resistance, newer regimes have been put forth that include quadruple therapy, sequential therapy and a dizzying array of other combinations bent on eradicating HP. Much less is known about the natural history of HP, the different faces of HP internationally, HP eradication and its effect on gastritis, IM, GU/DU and gastric cancer. This review will address the changing face of HP in 2011.

Time & mode of infection

Infection of HP is usually acquired in childhood while natural acquisition in adults is rare. However, this can vary depending on socio-economic class and country of origin.1,2 Children in developing countries typically acquire the infection before 10 years of age whilst in developed countries there is an age related increase in prevalence.3 Acquisition of HP infection occurs primarily during childhood, in contrast to the low acquisition rate during adulthood of 0.3–0.5% a year.1 In developed countries, the rate of loss of HP infection in any age group is equal to or greater than the rate of acquisition, leading to a decline in its overall prevalence.4–6 The major risk factor for HP infection is the socio-economic status of the family during childhood, in particular, level of sanitation and household hygiene, with the number of people in the household being important. Genetic susceptibility also appears to be significant in the acquisition of HP infection as well as its clearance.7 The mode of transmission of HP between individuals and within families remains to be elucidated; interesting myths related to oral-oral transmission of HP have been debunked when a study of couples without children revealed a low concordance of HP infection;8 currently favored mechanisms of transmission appear to be gastro-oral and faecal- oral routes.1

Natural history of infection

How often acute infection with HP spontaneously clears is uncertain. Infections in adults appear to be ostensibly long-lived. However, making firm conclusions on this issue is fraught by the increasing use of broad spectrum antibiotics and recall bias in studies looking at HP clearance (in the absence of eradication).9 Toljamo et al. reported 19% of their HP patients (15/72 patients) became negative spontaneously over a 17 year period.10 Redeen et al. described a rate of HP infection loss of 9.7% (11/113 patients) over a median follow-up of 8.4 years and underscored the probable importance of the under reporting of antibiotic use.11 Villako et al. noted a rate of loss of HP infestation on histology of 9–10% over a 6 year period.12 Moreover, the use of proton pump inhibitors (PPIs) may make the detection of HP by traditional urease-based biopsy tests and histopathological diagnosis more difficult by reducing numbers of HP in the antrum (site commonly sampled for HP) and the re-distribution of HP into the deeper layers of the oxyntic glands.13 In children and the elderly, studies suggest that spontaneous loss of HP infection may be more common.14–16 Granstom et al. demonstrated in 11 year old children, 14% had been seropositive for HP at some time during their childhood. However, at age 11 only 3% were seropositive.14 Klein et al. followed the urea breath tests of children over a shorter 18 month period and found that approximately 23% of children lost their urea breath test positivity during this time frame (from 71% to 48%).17 Banatvalas et al. found that in a study of Japanese patients, those greater than 60 years of age cleared HP seropositivity at a rate of 0.8% versus 0.1% for younger patients.16 There is some evidence in the literature that spontaneous HP loss may be related to advanced atrophic corpus gastritis.18

H. pylori in different countries

HP infection varies between countries. The predominant genotype differs greatly between regions and account for some of the gastric cancer risk seen in some population groups, such as Japan and South Korea, which tend to harbour more virulent strains.19 Socio-economic status and the acquisition and pathogenesis of HP is important especially in areas of low socio-economic status (SES) that have high rates of gastric cancer (e.g. Andean region of South America); here, the full hand of possible HP mucosal related manifestation is seen, from chronic active gastritis, to multifocal atrophy, to intestinal metaplasia, to dysplasia and finally to neoplasia.20,21 In this population, infection is acquired early in childhood with a higher proportion of virulent strains observed compared to low-risk populations.22,23 Contrasting with this scenario is that seen in Japan and South Korea, countries with populations of high SES and high gastric cancer risk. In these nations, the virulence of the prevalent HP strains tend to be high compared to populations with low gastric cancer risk.24,25 Interestingly, in most regions of Africa where SES is low, and HP infection rates high in childhood, the rate of complications including gastric cancer are low. These populations tend to be infected by HP with comparatively low virulence factors; however, dietary factors, and perhaps intestinal parasitoses may alter the immune response against HP.22,23,26,27 Finally, our analysis of HP in different regions would not be complete without a review on populations who enjoy a high SES and low gastric cancer. This includes some Western European nations, Australia and Caucasian populations in the US and Canada. In these populations, HP infections occur comparatively later and the strains involved tend to be less virulent.1,3,28 All in all, the richness of interplay between genetics, environment and HP infection is well illustrated, yet not very well elucidated.

Mucosal effects of H. pylori

HP's effect on the mucosa is multiple and as our current understanding stands, it appears that patients infected with HP travel down one of two natural history “pathways” which appear to be mutually exclusive. After initial infection with HP patients usually develop acute gastritis which may spontaneously resolve with the clearing of the HP infection. However, a large majority progress to chronic active gastritis, where from thenceforth the fork in the road develops. A proportion of patients will develop antral predominant gastritis which may subsequently be complicated by duodenal ulcer(s) and/or rarely lymphoma, whilst another proportion will develop multifocal atrophic gastritis and subsequently become at risk for developing gastric ulcer(s), gastric cancer and rarely lymphoma. Why one individual during the course of their HP infection should clear the infection without the use of antibiotics is uncertain, and why individuals should arrest at any stage of this “pathway” without progressing to develop complications again is unresolved.

Gastritis

The nature of acute infections with HP are understood due to a small number of cases where investigators and/or volunteers have been intentionally infected with the bacteria.29,30 Acute gastritis results histologically in a neutrophilic gastritis followed by a gradual infiltration by all classes of inflammatory cells, including prominently lymphocytes and coupled with a transient hypochlorhydria. Post-acute gastritis, two patterns of chronic gastritis are observed and this difference in topography is associated with different diseases. Antral predominant gastritis is seen usually in conjunction with little or no gastric atrophy in duodenal ulcer disease, with normal or increased acid secretion.30–33 This is in comparison to the extensive pattern of gastritis with corpus (usually with antral) atrophy which tends to progress through intestinal metaplasia, to intestinal-type gastric cancer with hypochlorhydria, or achlorhydria.

Gastric/duodenal ulcers

The location of a peptic ulcer, when considered in association with HP infection gives the clinician the pattern and topography of HP-associated inflammation in the stomach. Duodenal ulcers are associated with antral predominant gastritis of the non-atrophic variety, hypergastrinaemia and hypersecretion of acid.30 Patients with duodenal ulcer virtually never develop body atrophic gastritis and consequently retain robust acid secretion.34,35 Conversely, gastric ulcers are thought to be associated with a chronic non-atrophic gastritis initially which progresses to chronic atrophic gastritis which involves both corpus and, invariably, the antrum and decreased acid output.36,37 Importantly, in patients with CAG, some studies have found that eradication of HP infection partially reverses the hypochlorhydria/achlorhydria seen resulting in an improvement in inflammation histologically.38–43 Annibale et al. report only 20% of their study patients reversed gastric body atrophy after HP eradication, whilst the remaining 80% retained gastric atrophic change or IM that was initially observed.44

Intestinal metaplasia & gastric cancer

Of note, patients with CAG may progress to intestinal metaplasia (IM). It should be emphasized that HP infection is not the only cause of IM. In terms of histological change, IM may represent the “point of no return.” Several studies have shown that gastric metaplastic lesions may eventually progress after HP eradication.45–47 Other researchers also report on the benefits of HP eradication in IM. Yang et al.48 found that during the second year of follow-up, patients in the eradication group achieved more regression and less development of AT and IM compared with the non-eradication controls. Whilst Lee et al. suggest that IM improves over a prolonged time frame as did a study group in Yantai, China.49,50

A possible consequence of IM is gastric cancer (GC). Less than 1–2.9% of patients who are infected with HP will develop gastric cancer, usually intestinal-type adenocarcinoma.19,51 Diffuse-type adenocarcinoma is relatively more common in populations at low risk of gastric cancer. Moreover, there appear to be significant environmental factors which contribute to the etiopathogenesis of GC, including smoking and alcohol.19 Hsu et al. studied all gastric malignancies (including adenocarcinoma and lymphoma) developed in HP-infected patients and recommended that follow-up for HP infected patients who have IM was indicated.52 More importantly, several studies have found that HP eradication was associated with a statistically significant reduction in the development of GC compared with non-eradicated HP controls, particularly in individuals that had pre-existing IM.53–55

Conclusion

Although much research and understanding have been gained in the three decades since the discovery of HP, more questions have been raised than answered. In this era of scarce economic resources, we need to further our understanding of HP and its impact on the gastric mucosa in order to target those who would benefit most from pre-emptive HP eradication, and to define the individuals who we can safely leave alone. It is also critical to understand the triggers and mechanisms by which seemingly benign chronic non-atrophic gastritis progresses to multi-focal gastritis, IM, and thereafter in some, gastric cancer. Although the discovery of HP made a very significant leap in the understanding peptic ulcer pathogenesis, the long road towards deciphering the fundamental mechanisms underlying the development of gastritis, intestinal metaplasia and gastric cancer has only just begun.

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