New ideas for future studies of Helicobacter pylori

Helicobacter Pylori (H. Pylori) Infection Screening and Precancer Surveillance

H. pylori is an established carcinogen for the development of gastric cancer (GC), which is the second leading cause of cancer deaths worldwide.1 H. pylori is now thought to be responsible for more than 95% of all GCs, making H. pylori eradication a priority for the prevention of GC.2 GC is one of the inflammation-associated cancers. The risk of developing GC is correlated with an accumulation of genetic changes, which is in turn correlated with changes in gastric histology. GC has been recognized as linked to gastric hypochlorhydria and atrophic gastritis for more than 100 years. In 1975 Correa et al.3 proposed the existence of a cascade starting with superficial non-atrophic gastritis, through atrophic gastritis, to intramucosal cancer (then called dysplasia) and finally, to invasive cancer.

The discovery of H. pylori moved the cascade back to the cause of the progressive gastric inflammation. At that time, there was considerable focus on intestinal metaplasia, which was regarded as a possible direct precursor of cancer.4-6 The atrophic process was recognized as progressing upward from the antral-corpus junction to the corpus, leaving behind atrophic mucosa, called pyloric metaplasia or pseudopyloric mucosa, because it resembles pyloric glands but in the absence of parietal cells. However, the cells can still be identified as corpus cells by the presence of pepsinogen I, which is found only in the corpus. In animal models, pyloric metaplasia has been identified as spasmolytic polypeptide-expressing metaplasia (SPEM), based on immunohistochemical staining of trefoil factor 2. Recent human studies7, 8 have confirmed that pseudopyloric metaplasia is SPEM, thus linking the results of animal experiments and human studies in terms of cancer risk. The risk of GC can be predicted by assessing the extent and severity of corpus atrophy. Various grading systems of atrophy have been proposed, such as the Operative Link on Gastritis Assessment (OLGA), OLGA-intestinal metaplasia (OLGA-IM) and, most recently, the corpus-predominant gastritis index, which is highly correlated with SPEM.9 The risk of GC is exceedingly small in the presence of non-atrophic gastritis and progressively increases as atrophy becomes more severe. Intestinal metaplasia is no longer considered a direct precursor of GC; however, the extent and type of intestinal metaplasia are thought to be correlated with the extent and severity of atrophy.

Because of the link between cancer risk and gastric atrophy, H. pylori infection should be prevented and the bacteria should be eradicated before atrophy occurs in order to achieve the greatest reduction in cancer risk. For an individual patient this may be impossible, because atrophy may have occurred before the patient could be treated. H. pylori eradication can stop the progression of gastritis, which in turn prevents any further age-related or time-related increase in atrophy and thus reduces the risk of cancer. The degree of risk can be estimated by assessing the extent of damage already done, by using non-invasive methods such as pepsinogen test, or endoscopic or histological cancer risk-scoring systems.10 The histological scoring systems are probably the most reliable, but non-invasive tests are more practical for the prevention program at the population level. Clinical trials have revealed that after H. pylori eradication, gastric inflammation recedes – the acute inflammation within days and the chronic inflammation progressively over months to a year. Elimination of the inflammation reverses the inhibition of parietal cells caused by inflammatory cytokines, thus allowing an increase in acid secretion. Whether new parietal cells develop remains unclear, but data indicate that this maybe the case, at least to a limited extent. Data are limited as to whether intestinal metaplasia, particularly deep and extensive metaplastic epithelium, also resolves; long-term studies with repeated gastric mapping are needed to provide a definitive answer. Although it is clear that the GC risk stabilizes or, more likely, decreases as inflammation clears, studies assessing the extent and duration of improvement are needed. In addition, research is needed to define the natural history of cancer risk after H. pylori eradication as well as the changes and predictors for the changes in the natural history, and to determine whether it is possible to further reduce the risk through diet or the use of medications such as anti-inflammatory drugs or so-called gastroprotectives.11

A Human Inflammation Model for Cancer Development

It is now thought that all cancers are fundamentally genetic diseases, with GC being categorized as an inflammation-associated cancer.12 While there are many mechanisms whereby inflammation can lead to genetic instability, the presence of H. pylori itself has is associated with at least four mechanisms that lead to the genetic instability of gastric mucosa. H. pylori infection is associated with aberrant activation-induced cytidine deaminase expression, with double-strand DNA breaks, impaired DNA mismatch repair and aberrant DNA methylation. All these events have been shown to be reversible or partially reversible after H. pylori eradication.13-15 Study on the interactions between the bacterium and gastric mucosa and its relationship with the degree and extent of mucosal damage and inflammation is needed, especially in relation to repair, as they are all present in non-atrophic gastritis, which is associated with a low cancer risk. Understanding their interaction between other intragastric events and inflammatory mediators, as well as with possible carcinogens made by non-H. pylori bacteria that populate the hypochlorhydric stomach, is necessary. H. pylori eradication following the resection of early GC leads to a reduction in metachronous cancers within a soil that has already accumulated many genetic changes and is subjected to a cancer field effect.16 The fact that the risk falls after H. pylori eradication suggests that the post-treatment group is an excellent model for probing the molecular changes that occur in relation to carcinogenesis and repair.

H. pylori infection is thus an outstanding model for the study of the effects of mucosal inflammation and inflammation-induced cancer. For example, H. pylori allows the study of the molecular events involved in the chronic active inflammatory process that contribute to the multistage progression of human cancer development, including reactive oxygen, cytokines or growth factors and immune dysfunction. In human it is extremely difficult to conduct experiments on the bacterial, environmental and host interactions. However, animal models make it relatively easy to make precise changes in each component and thus provide detailed explanations and understanding of the events that may be involved in human gastric carcinogenesis. For example, H. pylori have the ability to cause double-stranded DNA breaks, which can clearly influence genetic stability. However, this ability is present irrespective of the extent and severity of the mucosal damage and the cancer risk associated with the infection (e.g., cancer risk is very low in the infection associated with an active duodenal ulcer). It is unknown whether cancer follows an imbalance in repair mechanisms and ongoing damage or whether damage is somehow differently dependent on the status of the underlying disease, and so on.

H. Pylori Eradication should Follow the Dictum “Use What Works Best Locally”

H. pylori infection is a treatable, preventable and curable infectious disease. The expected outcome of prescribed regimens should have a success rate of at least 90% with the first course of therapy.17 However, antimicrobial resistance has reduced the effectiveness of many popular regimens, which has led to a search for regimens that are highly effective in any region or population despite the presence of drug resistance. Currently, regimens that meet these criteria should use agents with rare drug-resistance. Alternatively, the ability to simply, cheaply and conveniently ascertain the resistance pattern before prescribing any therapy is needed. National guidelines need to be updated regularly and obsolete regimens should cease to be recommended.18

New Developments in the Diagnosis and Treatment of H. Pylori Infection

Diagnosis of active H. pylori infection is best made using urea breath test or stool antigen test, which yield equivalent results, and a validated laboratory-based monoclonal antibody test is also used. Serological tests (immunoglobulin G antibody detection and ELISA) are useful for screening but only in conditions of high pretest probability (e.g., an active duodenal ulcer). Molecular tests, including fluorescence in situ hybridization, can be used to detect H. pylori infection and to assess clarithromycin resistance in gastric biopsied specimens. The tests can also assess fluoroquinolone resistance, but the accuracy of commercial kits for this purpose remains unclear. Fecal antibiotic resistance tests are useful, by allowing therapy to be noninvasively tailored, based on the resistance of the bacteria. There is a need for developing a preventive or therapeutic vaccine, but the progress in this area has been slow.18

In conclusion, some authorities have suggested that the carriage of H. pylori has biological benefits as well as costs, and these benefits are not limited to the stomach. Despite claims as to the beneficial effects of the bacteria, populations in which it is naturally lacking, such as Malays, have shown no direct consequences. The bulk of evidence suggests that H. pylori is always a pathogen that all populations are better off without, and it should be marked for extinction.