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Br Med Bull

Helicobacter pylori infection: an overview.

Year 1998
Farthing MJ.
Digestive Diseases Research Centre, St Bartholomew's, London, UK.
For many decades the dictum 'no acid, no ulcer' dominated thinking on the pathogenesis of peptic ulcer. When I was a medical student, not surprisingly, the standard therapy for a peptic ulcer was an antacid possibly combined with carbenoxolone. As a medical registrar, I was involved in the early studies with H2-receptor antagonists which, at the time, many of us believed would lead to the removal of peptic ulceration as a clinically important disease. It was soon evident, however, that ulcers returned rapidly when the H2-receptor antagonist was withdrawn and the concept of maintenance therapy was born. Within about 5 years of the launch of the first H2-receptor antagonist, cimetidine, two major developments occurred namely the discovery of Helicobacter pylori and the characterisation of the proton pump with the development of drugs to inhibit its action. The discovery of H. pylori not only turned the aetiopathogenesis of peptic ulceration on its head but soon emerged as a major factor in the causation of gastric cancer and mucosa associated lymphocytic tissue (MALT) gastric lymphoma. The potential clinical impact of this organism continues to expand, with suggestions that it might be involved in growth retardation in children and possibly a factor in the development of ischaemic heart disease. The high prevalence of this organism worldwide presents clinicians and other healthcare workers with a formidable challenge with regard to its control at a population level.

Helicobacter biology--discovery.

Year 1998
Buckley MJ. O'Morain CA.
Service de Hepato-Gastroenterologie, Hopital de l'Archet II, CHU, Nice, France.
The presence of gastric spirochaetal organisms was first documented over a century ago. Though repeatedly reported in the medical literature, it was felt that these spiral bacteria were merely contaminants and the reports were generally ignored by the medical community. On 22 October 1982, at a meeting of the Royal Australian College of Physicians, successful culture of these 'Campylobacterlike organisms' from gastric biopsy specimens was reported for the first time. Moreover, it was shown that their presence was associated with gastritis and, possibly, with peptic ulceration. The subsequent discovery of the pivotal role of Helicobacter pylori in a wide range of conditions has revolutionised our understanding of gastroduodenal diseases. Improvements in diagnostic and therapeutic options, combined with the gradual acceptance of the aetiological role of an infective agent in peptic disease, have led to a remarkable change in the management of gastroduodenal conditions in the past decade.

Helicobacter--species classification and identification.

Year 1998
Owen RJ.
Laboratory of Enteric Pathogens, Central Public Health Laboratory, London, UK.
The genus Helicobacter was created in 1989 with H. pylori as the type species. Since then the genus has expanded to include about 18 species. Some species were reclassified from Campylobacter, but most were newly discovered microorganisms from gastric or intestinal sites in mammalian host animals. The essential property of almost all helicobacters is the presence of sheathed flagella. Most species possess strong ureolytic ability, particularly those associated with gastric mucosa, and exhibit considerable diversity in cell morphology with respect to cell length, number and location of flagella, and presence of periplasmic fibrils. H. pylori has a global distribution and infects human gastric mucosa exclusively but there is some evidence for infection in cats. Genomes of isolates from different individuals are unusual in their diversity in gene order and sequences within individual genes. 'H. heilmannii' is another gastric spiral shaped organism less frequently infecting humans but commonly found in cat and dog gastric tissue. H. felis is important in the mouse model of infection. A range of conventional phenotypic tests as well as some new PCR based assays are available for identifying isolates of Helicobacter from clinical specimens.

Epidemiology of Helicobacter pylori: acquisition, transmission, population prevalence and disease-to-infection ratio.

Year 1998
Feldman RA. Eccersley AJ. Hardie JM.
School of Medicine and Dentistry, St Bartholomew's, London, UK.
This article focuses on factors relating to acquiring Helicobacter pylori, including re-acquiring H. pylori infection after successfully treatment. It considers variables that increase the risk of infection and explores the chances that an infected individual will develop symptomatic disease.

Clinical science of Helicobacter pylori infection: ulcers and NSAIDs.

Year 1998
Calam J.
Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
It is now clear that Helicobacter pylori is a major aetiological factor in peptic ulcer disease. About 95% of patients with duodenal ulcers and perhaps 80% of patients with gastric ulcers are infected with this bacterium and its eradication greatly diminishes recurrence of these ulcers. Many patients are still not receiving the benefit of this treatment, however. Most patients who have peptic ulcers without H. pylori infection are taking non-steroidal anti-inflammatory drugs (NSAIDs), although this may not be recognised or admitted. Such patients have to be managed by withdrawal of these agents or by giving protective agents such as misoprostol. If H. pylori is present in a patient who develops an ulcer whilst taking NSAIDs, it remains unclear whether it is beneficial to eradicate the infection, but this seems advisable in case the ulcer is due to the infection in that particular patient.

Helicobacter pylori infection and cancer.

Year 1998
Forman D.
Centre for Cancer Research, University of Leeds, Cookridge Hospital, UK.
This paper will briefly review the evidence for the role of Helicobacter pylori infection in the aetiology of gastric cancer and consider the implications of this relationship. The critical issue of whether H. pylori eradication may play a part in a strategy for the prevention of gastric cancer will then be discussed. Although this paper will largely be concerned with epidemiological evidence, it should be emphasised that an understanding of the mechanistic basis to the H. pylori-cancer relationship is also advancing rapidly and this area will be reviewed in the paper by Correa elsewhere in this issue.

Helicobacter pylori infection and gastric lymphoma.

Year 1998
Wotherspoon AC.
Department of Histopathology, Royal Marsden Hospital, London, UK.
Gastric lymphoma of mucosa associated lymphoid tissue (MALT) has characteristic clinicopathological features that are different from nodal-type B cell lymphomas. Before a lymphoma can arise within the stomach, MALT has to be acquired as part of a response to an immunological stimulus. In most instances, gastric MALT is acquired in response to infection by Helicobacter pylori. There are several features of MALT lymphoma, such as plasma cell differentiation and follicular colonisation, that suggest that these lymphomas, although demonstrated on the basis of clonality studies to be neoplastic, retain some immunological drive. In vitro studies have shown that co-culturing cells derived from low grade MALT lymphomas with H. pylori results in tumour cell proliferation in a T cell dependant manner. Clinical studies have taken this discovery further and shown that patients with early low grade gastric MALT lymphoma treated with anti-Helicobacter therapy can show regression of their tumours. It is now generally accepted that eradication of H. pylori is a central component of the management of MALT lymphoma.

Clinical significance of Helicobacter infection in children.

Year 1998
Rowland M. Drumm B.
Department of Paediatrics, University College Dublin, Ireland.
Helicobacter pylori infection of the gastric mucosa causes chronic gastritis and is associated with peptic ulcer disease and gastric carcinoma. These are conditions which usually occur in adult life. However, H. pylori is an infection which is mainly acquired in childhood. The overall prevalence of H. pylori in children is 10% in developed countries but can be as high as 30-40% in children from lower socio-economic groups. In developing countries, the prevalence of H. pylori in children ranges from 80-100%. H. pylori gastritis does not appear to be associated with symptoms in children in the absence of duodenal ulcer disease. H. pylori infection is present in the vast majority of children with duodenal ulcer disease and, as in adults, eradication of the organism results in long-term healing of duodenal ulceration. H. pylori infection acquired in childhood is now considered to be a significant risk factor for the development of gastric carcinoma. The World Health Organization has classified H. pylori as a Group 1 carcinogen. Specific epidemiological questions which need to be answered in children include the age at which infection is acquired, specific risk factors for infection, the mode of transmission and the risk of reinfection following treatment. Recently, a one week treatment regimen using colloidal bismuth subcitrate, metronidazole and clarithromycin has been shown to be effective in treating children, but compliance is important. Currently there are no guidelines on the need to treat children and a consensus is urgently required on this issue.

H. pylori virulence factors.

Year 1998
Atherton JC.
Department of Medicine, University of Nottingham, UK.
Among people infected with Helicobacter pylori, the virulence of the infecting strain is a major determinant of who develops disease. Strains producing vacuolating cytotoxin activity are more commonly isolated from people with peptic ulcers than without. The gene encoding the toxin, vacA, varies between strains, especially in its signal sequence and mid regions. vacA genotype influences cytotoxin activity, and signal sequence type correlates closely with peptic ulceration. Infection with strains possessing cagA (cytotoxin associated gene A) is more common among people with peptic ulceration or gastric adenocarcinoma than without. cagA is a marker for the cag pathogenicity island, which includes genes necessary for the enhanced inflammation induced by pathogenic strains. Serological detection of infection with cagA+ strains is at present the best practical test for virulence. However, before a strategy of screening and selective treatment can be considered, it is important to assess whether cagA- strains are entirely non-pathogenic.

Interactions between H. pylori infection, gastric acid secretion and anti-secretory therapy.

Year 1998
McColl KE. el-Omar E. Gillen D.
Department of Medicine & Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, UK.
There is evidence of a two-way interaction between gastric acid secretion and H. pylori-associated gastritis. Gastric acid secretion influences the density of H. pylori colonisation, its distribution within the stomach and the severity of the mucosal inflammatory response to the infection. In addition, H. pylori gastritis alters gastric acid secretion. In subjects with a predominant antral gastritis, it increases acid secretion predisposing to duodenal ulcer, whereas in others with predominant body gastritis, acid secretion is impaired and the subjects have an increased risk of gastric cancer. The two-way interaction between acid secretion and H. pylori gastritis is observed when H. pylori-positive subjects are treated with proton pump inhibitor agents. The inhibition of acid secretion induces a body gastritis and this inflammation of the body mucosa inhibits acid secretion thus augmenting the anti-secretory effect of the drug. In this article, we discuss the interaction between gastric acid secretion and H. pylori gastritis and its importance in determining disease outcome.

Helicobacter pylori and gastric inflammation.

Year 1998
Bodger K. Crabtree JE.
Division of Medicine, St James's University Hospital, Leeds, UK.
H. pylori infection leads to gastric inflammation, characterised histologically by surface epithelial degeneration and infiltration of the gastric mucosa by acute and chronic inflammatory cells. H. pylori adherence, the production of a vacuolating cytotoxin and bacterial enzymes all contribute to epithelial damage. Recruitment and activation of immune cells in the underlying mucosa involves H. pylori chemotaxins, epithelial-derived chemotactic peptides (chemokines) such as IL-8 and GRO-alpha, and pro-inflammatory cytokines liberated by mononuclear phagocytes (TNF alpha, IL-1 and IL-6) as part of non-specific immunity. Antigen-specific cellular immunity results in a predominant Th1 lymphocyte response with an increase in IFN-gamma secreting T-helper cells, whilst humoral responses lead to the production of anti-H. pylori antibodies and complement activation. The complex network of cytokines implicated in these inflammatory responses include counter-regulatory elements such as IL-10 which may serve to damp down inflammation. Molecular mimicry of host structures by H. pylori, with the generation of specific immunity directed against self-antigens may also contribute to host injury. Progress in molecular biology has revealed considerable genomic diversity amongst H. pylori strains, with cag+ bacteria being associated with increased chemokine and cytokine responses and more severe degrees of gastric inflammation. Strain hetereogeneity may contribute towards the wide spectrum of disease manifestations encountered in clinical practice.

Carcinogenesis, apoptosis and cell proliferation.

Year 1998
Correa P. Miller MJ.
Department of Pathology, Louisiana State University Medical Center, New Orleans 70112-1393, USA.
Biological agents, especially viruses, have been linked to the carcinogenesis process in major human cancers, especially lymphomas (retroviruses), hepatocarcinomas (hepatitis viruses) and carcinomas of the female genital organs (papilloma viruses). Chronic infection and inflammation have long been suspected to play a role in human carcinogenesis. Helicobacter pylori is the first bacterial infection recognized as a human carcinogen, essentially on the basis of epidemiological evidence of causality. Contrary to most other recognized human carcinogens, experimental evidence of carcinogenesis is lacking. As a consequence, mechanistic explanations of H. pylori carcinogenesis at this point in time are hypothetical.

Clinical practice--breath tests.

Year 1998
Bell GD.
Gastroenterology Department, Sunderland District General Hospital, UK.
The underlying principle of the two non-invasive radio-labelled urea breath tests is similar. Both are positive when the patient's stomach is colonised by Helicobacter pylori because the organism's urease enzyme splits the orally administered urea isotope to labelled CO2 which is then detected in the expired breath. The tests thus reflect active infection and are ideally suited to monitoring the success or failure of different eradication therapies as well as studying rates of acquisition and re-infection/late recrudescence post treatment. [13C]-urea should always be used in children since it is the stable non-radioactive isotope but the [14C]-urea breath test is suitable for most adults, since the dose of radioactivity is minimal.

Current regimens for treatment of Helicobacter pylori infection.

Year 1998
Harris A.
Kent and Sussex Hospital, Royal Tunbridge Wells, UK.
The aim of treatment of Helicobacter pylori is eradication of the bacterium from the foregut. Treatment is difficult because of the bacterium's habitat and acquired resistance to commonly used antibiotics. Dual therapy, the 2 week combination of omeprazole or ranitidine bismuth citrate and either amoxycillin or clarithromycin, eradicates H. pylori in 50-80% of patients. Classical triple therapy is commonly associated with side effects, is highly dependent on patient's compliance, and is significantly less effective in the presence of metronidazole-resistant strains of H. pylori, where eradication may be 50%. One week, twice daily, proton pump inhibitor (PPI)-based triple therapy regimens eradicate about 90% of H. pylori and are associated with mild side effects. Second line regimens include 7 days treatment with omeprazole and 3 times daily amoxycillin and metronidazole or a PPI-based quadruple therapy regimen. In some cases, the bacterium defeats all attempts at eradication.

Is there a rationale for eradication of Helicobacter pylori? Cost-benefit: the case for.

Year 1998
Moayyedi P. Axon AT.
Gastroenterology Unit, Leeds General Infirmary, UK.
Screening and treating the community for Helicobacter pylori would have seemed inconceivable 5 years ago. This has now become a real possibility given that H. pylori is a major risk factor for gastric carcinoma. Screening should not be introduced, however, before the costs and benefits of the programme are established. It has been estimated that 1:30-1:60 of the UK population die from an H. pylori related disease. If treating H. pylori were to reduce premature mortality, then this would be a persuasive argument for a screening strategy. The financial costs of screening and treating H. pylori are significant but this would be partially offset by savings that would accrue from reducing dyspepsia in the community. Indeed, decision analysis models suggest H. pylori screening is cost-effective. The potential benefits are enormous and prospective randomised trials are urgently required to establish whether such a programme is worthwhile.

Helicobacter pylori eradication cost-benefit: the case against.

Year 1998
Patchett SE.
Digestive Diseases Research Centre, St Bartholomew's, London, UK.
Helicobacter pylori is an important human pathogen, implicated in the pathogenesis of peptic ulcer disease, gastric cancer, and perhaps also in other non-gastrointestinal disease. There is little doubt that in peptic ulcer disease at least, there is a strong argument for its eradication on both clinical and economic terms. The majority of subjects infected with Helicobacter pylori never develop clinically overt disease, and it is this group that the clinical and financial benefit of eradication needs to be closely examined.

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