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...resistance. Although alternative rescue regimens been advocated, the best strategy would be to prevent disease, especially in the case of gastric cancer for which there is still no treatment. One approach is to inhibit the first step in the pathogenic process--adhesion of the organism to the host tissue. Another and probably a better approach is vaccination, but clinical trials have so far been unsuccessful. There is still a large uncertainty in relation to how H. pylori causes disease. Knowledge from genomics, proteomics, and the relationship between polymorphism of the bacterium and the host, as well as the continuing investigation of the role played by important virulence factors in the outcome of the disease, will help both in understanding pathogenesis of disease and in the design of the best vaccine.
Keywords: Helicobacter, peptic ulcer, gastric cancer, management, adhesion, genome, proteome, VacA, CagA
1. Introduction
Helicobacter pylori emerged into prominence in 1983 when it was first isolated from the human stomach by Warren and Marshall (1). Warren believed it was the cause of gastritis and gastric ulcers and tentatively suggested this. This suggestion was met with disbelief by the majority of the medical profession as a paradigm was already in place to explain ulcer development--too much spicy food, too much smoking and too much acid. At that time, the treatment was surgical--selective vagotomy or partial gastrectomy. With time and accumulating evidence, there was a paradigm shift and currently the majority of the medical profession now believes that H. priori is the principle cause of gastric ulcers--and more besides. The treatment now is a short course of antibiotics combined with anti-acid medication.
H. pylori is a micro-aerobic gram negative bacillus that is found in over 50% of the world's population, making it one of the commonest infections. It is acquired in childhood although the route(s) of transmission remain undefined (2). The organism has a highly variable genetic make-up, which underpins the relationship between the type of the infecting strain and the clinical outcome. Type I strains carry an assemblage of virulence markers and are more likely to be found in patients with disease than are Type II strains, which are relatively less virulent. This genetic heterogeneity can also be used to identify separate variants of H. pylori and these variants are geographically distributed according to ethnic background and historically recognised population migrations (3). Although the first Helicobacter to be isolated, H. priori is now only one member of the Genus, as similar species have been isolated from a range of animals as diverse as the cheetah, the tamarin, the mouse and the dolphin (4).
The majority of individuals colonised by H. pylori are asymptomatic although histologically they will have gastritis. A proportion of patients will develop peptic ulcers (duodenal and gastric ulcers) and a smaller proportion will develop gastric cancer. Globally H. pylori is the major cause of gastric cancer and has been classified as a Class I carcinogen by the WHO. In duodenal ulcer, the organism is found principally in the antrum of the stomach (2) and the acid load in the stomach, induced by the presence of the organism, is high. In gastric ulcer, the converse is true--the organism is not confined to the antrum but can be found throughout the stomach (antrum and fundus) and the amount of acid in the stomach is low. This latter finding is due to death of the acid producing cells that are found mainly in the fundus of the stomach, caused by the presence of the organism. Conditions of persistent inflammation with low acid in the stomach, along with various other co-factors, such as a diet poor in vitamin C, may eventually lead to gastric cancer.
In order to understand the diseases caused by H. pylori, it is necessary to understand the host/pathogen interaction. However, a complete understanding of the pathogenesis of disease is still a long way off, although a clearer picture of the manifold effects of H. pylori on the host and the contribution of the host to development of disease is slowly emerging. H. pylori Type I stains possess a gene called cagA--a virulence marker and an indicator for the presence of a Cag pathogenicity island (PAI). This is a collection of about 30-40 genes, which are necessary for the synthesis of a Type IV secretion apparatus. Virtually, all strains also possess a gene, which synthesises a vacuolating cytotoxin--vacA. However, only Type I strains secrete the vacA cytotoxin. Type II strains lack cagA and do not secrete vacA. Type I strains are associated with more severe gastroduodenal disease compared to type II strains.
H. pylori has both direct and indirect effects on the host, which eventually lead to the development of disease. The helical shape of the organism facilitates its penetration of the mucus layer covering the gastric epithelium. The next step in the infection is its ability to bind to gastric epithelium. The organism expresses a number of ligands through which it binds to the host cells. Once bound, H. pylori expresses a number of enzymes that affect the quality of the mucus barrier and directly damage the host cell. Urease expression results in hydrolysis of urea and a release of ammonia, which disrupts the mucus layer and has a direct cytotoxic effect. The organism also secretes phospholipase, which further disrupts the mucus layer. The loss of this protective barrier allows the stomach acid and digestive enzymes to have direct access to the gastric epithelium. In addition, Type I strains will secrete VacA and the cagA protein will be injected into host cells, which will result in further damage to the host epithelium, and ultimately will induce the release of chemotactic cytokines, which recruit inflammatory cells to the area. The release of reactive oxygen species and cytotoxic proteins from the inflammatory cells leads to additional damage to the host epithelium. H. pylori also has indirect effects on the host that also lead to damage. As the host mounts an acquired immune response to the presence of the organism, antibodies are produced that cross-react with host cells and these can induce antibody mediated cell death. Finally, by interrupting the negative feedback loop that regulates the amount of acid produced by the stomach, very high levels of acid may cause further damage to the gastric epithelium that is now unprotected by the mucus layer that covers it.
In addition to microbial virulence factors, both host and environmental factors contribute to disease. Within the host, certain polymorphisms related to cytokine production and acid secretion are associated with more severe disease compared to other host polymorphisms. Most severe disease occurs when certain microbial virulence markers (e.g. cag, vac) are present in a susceptible host genetic background. Environmental, host and microbial factors implicated in H. pylori disease are summarised in Table 1.
As mentioned earlier, H. pylori is a global pathogen that causes severe gastroduodenal diseases i.e. peptic ulcer disease and gastric cancers, leading to a significant morbidity and mortality. Although peptic ulcer disease is treated by a short course of antibiotics combined with anti-acid medication, there is a worrying increase in the prevalence of antibiotic resistance. Moreover, when gastric cancer is diagnosed, it is often too late. There are several strategies to overcome these problems. Several alternative rescue regimens have been advocated to treat peptic ulcer disease. Additionally, there is increasing interest in the role of host polymorphisms related to drug metabolism and how these polymorphisms affect success of therapy. One of the best strategies would be to prevent disease by using a vaccine. However, clinical trials have been unsuccessful. One novel approach is to inhibit the first step in the pathogenic process adhesion of the organism. Although a considerable amount of knowledge has been acquired since its first isolation, there are still large areas of uncertainty in relation to how H. pylori causes disease. A key area of current interest is host/pathogen interaction and the mechanism of disease causation. Knowledge of the genome sequence of H. pylori and the development of molecular techniques, such as micro-arrays, has allowed expression of bacterial genes during an actual infection to be investigated. Additionally, this information can also be used to identify potential vaccine candidates and to investigate evolution of the organism and its interaction with its environment. The relationship between polymorphism in the bacterium and the host and how they interact to enhance disease potential are reviewed in the case of gastric cancer. Moreover, over the past year, other roles for VacA and cagA, two of the most important virulence factors, have been discovered, which will increase our knowledge of pathogenesis. Finally, although H. pylori is related principally to gastroduodenal disease, there are many other species of Helicobacter from a whole range of different animal species. These non-pylori Helicobacter species are of engaging interest because of their possible relationship to the pathogenesis of inflammatory bowel disease and liver cancer. Certainly, some of these Helicobacter species can induce colitis and liver cancer in rodent models of infection and the question is whether they may be related to human forms of these two diseases.
2. Management of peptic ulcer disease
The major group of individuals in which eradication of H. pylori is undertaken, and for which there is a clear benefit, is with peptic ulcer disease. The currently accepted management for the eradication of H. pylori...
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