Outpatient clinics often encounter some take the carbon 13 breath test results found to have H. pylori infection, but the value is not high, the patient himself does not have gastric disease, and there is no discomfort in the population, such patients should be sterilized? It is the patient’s trouble, but also the doctor’s trouble. Our guidelines believe that this category of people can not kill the bacteria. However, after reading this article today, I believe that H. pylori should be killed, regardless of the value, whether the patient has gastric disease or not, or whether the patient has uncomfortable symptoms, as long as there is no contraindication to taking bactericidal drugs, it should be recommended to kill. The results of the study are presented below for the reference of doctors and patients.
Helicobacter pylori (Hpylori, Hp) infection is associated with a variety of diseases, including gastritis and gastric adenocarcinoma. There is no clear conclusion on whether Hp clearance prevents cancer or only reduces its risk of development. In addition, some studies have suggested that H. pylori infection may also have some benefits for the body (e.g., reduced risk of obesity or childhood asthma), but the evidence is also not yet strong.
A recent review published in Gastroenterology reviews the impact of Hp infection and summarizes the benefits and challenges associated with Hp clearance.
I. Hp: the primary cause of gastric cancer
Hp infection is the primary cause of gastric cancer, but the bacterium itself is not sufficient to cause gastric cancer and requires the involvement of other factors, and Hp is not the only cause of gastric cancer; Epstein-Barr virus infection, host genetic abnormalities, autoimmune gastritis, and proximal cancers associated with esophageal adenocarcinoma also account for 3-5% of gastric adenocarcinomas. Thus, even in the absence of Hp infection, gastric adenocarcinoma does not disappear completely.
Gastric cancer is the leading cause of cancer deaths worldwide. in November 2014, WHO published a working paper entitled “H. pylori eradication as a preventive measure for gastric cancer”. in early 2015, the Kyoto global consensus opinion on Hp gastritis was published.
The opinion states that gastritis should be defined as an infectious disease regardless of whether the patient is symptomatic or not, and regardless of complications such as peptic ulcer and gastric cancer; that Hp-infected individuals should be given eradication treatment unless the patient’s own condition does not allow it; and that Hp eradication reduces the risk of gastric cancer. The degree of risk reduction depends on the duration of bacterial infection, the severity of the infection, and the degree of atrophic damage.
In conclusion, the issue at hand is how to eradicate Hp in the most effective and cost-efficient manner. however, Hp eradication may be feasible in some countries, but is difficult for developing countries (e.g., India) with poorer health, lower living standards, and the enormous cost of universal treatment. However, with further understanding of Hp-associated disease mechanisms, a breakthrough in the development of Hp vaccines is expected.
II. Hp-associated gastric cancer
Atrophic gastritis, a precancerous disease of gastric cancer, can cause a decrease or absence of gastric acid secretion, which in turn leads to changes in the microbiome of the stomach. Since the degree of damage to the gastric mucosa varies, the clinical manifestations of Hp infection in individuals are diverse. However, clearance of Hp may stop the progression of atrophy and may partially reverse the lesions, thereby reducing the risk of gastric cancer.
Nevertheless, when precancerous disease progresses to a certain stage, there is still a high risk of cancer formation. Thus, secondary prevention may be an effective way to reduce mortality from gastric cancer. In addition to endoscopic surveillance, secondary prevention includes the detection of serum pepsinogen levels, which can be associated with the risk of gastric cancer and avoid repeated endoscopy; the potential risk of patients can also be specifically determined through a pathological staging system.
The preventive effect of Hp eradication on gastric cancer depends on the patient’s cancer risk at the time. For example, cancer can be completely or almost completely prevented in patients with non-atrophic gastritis. Patients with irreversible changes in the gastric mucosa are at high risk, but Hp eradication ensures that their risk is no longer increased. Risk stratification also identifies patients who would benefit from a secondary prevention program after Hp eradication.
Hp eradication is beneficial for patients with cancers at high risk of death, such as patients with early gastric cancer (gastric adenocarcinoma confined to the mucosa and submucosa of the stomach with or without regional lymph node metastasis). In patients treated endoscopically for early gastric cancer, the chance of developing gastric cancer again in the presence of Hp infection increases from 1% to more than 4% per year. Hp eradication reduces this risk to about 1/3.
Studies have shown that Hp causes persistent acute and chronic inflammation of the gastric epithelium, leading to genetic instability, genetic and epigenetic changes in the associated cells, and progression to gastric cancer. During tumor progression, gastric cancer cells may also acquire the ability to evade immune killing, suppress immune responses and metastasize distantly. interaction between Hp and other gastric microorganisms (endogenous and exogenous factors, etc.) can also produce carcinogens. Environmental factors (especially diet), are also important risk factors for gastric cancer.
Hp-induced inflammation can cause transformation of gastric epithelial cells and lead to alterations in the intragastric microenvironment, increasing the chances of DNA damage and somatic mutations. hp can also induce methylation of CpG islands, especially the loci encoding oncogenes, such as E-cadherin. hp can also stimulate cytidine deaminase activation, which can cause nucleotide alterations. In addition, Hp infection can lead to DNA double-strand breaks, increased miRNA expression, and increased genetic instability. Most Hp-associated events can be reversed upon Hp clearance.
More virulent Hp strains (e.g., CagA-positive strains) will increase the risk of gastric cancer. However, the relationship between specific virulence factors and disease is not yet clear. The virulence of strains is closely related to the degree of inflammatory response and can be used as a marker to assess the severity of inflammation. All Hp strains can cause gastritis, and the difference in risk of gastric cancer between the most and least virulent strains is less than 3-fold. Therefore, some opinions suggest that all Hp strains should be removed regardless of bacterial virulence.
Clinical studies of Hp clearance
Hp clearance can eliminate harmful irritation and promote the regression of inflammation. However, the regression of inflammation is also the result of coordination between anti-inflammatory factors, so it is not clear whether Hp-associated inflammation subsides due to bactericidal effects. There is evidence that atrophic gastritis or gastric lining atrophy can be partially reversed, as shown in some studies prior to the discovery of Hp, where corticosteroid therapy partially reversed gastric lining cells and principal cells in atrophic gastritis. However, the observations related to patients carrying out Hp clearance therapy have not been clarified.
Clinical studies and animal studies have demonstrated that tamoxifen causes partial reversal of intestinal heterotypic hyperplasia, while ADP ribosylation inhibitors (such as Olaparib and prostaglandin E2) cause the same results. These interesting studies suggest that reversal of atrophic gastritis is feasible.
However, the impact of reversal of intestinal heterotypic hyperplasia on gastric carcinogenesis is not yet clear, due to the genetic instability of the mucosa that develops during the transformation process. Therefore, the risk of gastric cancer development needs to be assessed when conducting studies related to the reversal of atrophic gastritis lesions.
Currently, whole genome sequencing has validated the factors associated with the promotion of gastric carcinogenesis, and therefore a hierarchical molecular classification system has been developed to classify the different etiologies (such as Hp or Epstein Barr virus) and genetics of gastric cancer.
IV. Hp clearance therapy
Hp eradication and prevention of infection are needed if the clinical problems associated with gastric cancer and cancer-induced death are to be resolved. In theory, it is relatively simple to fight Hp infection, and the organism has been sensitive to a variety of antibiotics. There have been improvements in the dose, duration, and combination of regimens for clearance therapy, but little need to consider bacterial resistance.
Currently, the reduced clinical effectiveness of clarithromycin regimens has created some distress for treatment, as this regimen is the only treatment available at some local institutions. Some studies have shown that sequential therapy with new drug combinations has better clinical outcomes. However, in the absence of clarithromycin resistance, four-drug combination regimens containing clarithromycin and metronidazole (sequential, sequential, or mixed regimens) have similar efficacy.
Newer regimens (such as sequential regimens) include a third antibiotic (metronidazole or tinidazole), so this regimen is superior to triple regimens only in the presence of clarithromycin resistance and low resistance to metronidazole. Studies in the Italian population have repeatedly confirmed the superiority of sequential therapy over triple therapy, so one study validated it in a highly metronidazole-resistant population and showed that it was not optimal. Thus, sequential therapy is not superior to conventional triple therapy in certain populations.
Current investigators recognize that data on resistance to various antimicrobial agents (individually and in combination) should be collected before studying clinical outcomes in patients to ensure that the results are generalizable rather than specific.
In many comparative studies, the results are entirely dependent on the resistance patterns of the population. In a population with low resistance to clarithromycin 14-day treatment, 10-day sequential therapy was equivalent or slightly superior to triple therapy. Thus, sequential therapy was considered superior to other treatments in Italy and ineffective in Korea. Therefore many, if not most, of the comparative studies are not applicable to other populations, unless resistance is assessed in the study.
When analyzing the effect of any antimicrobial drug studied, the effect of resistance on the effect should be taken into account. In general, subjects are considered effective when they have a cure rate of about 95%. And to ensure clinical effectiveness, it should be ensured that at least 90% of the subjects are sensitive to the drug. In the past, the so-called superiority studies of new combination therapies were often compared with drugs with very low clinical cure rates (e.g., drugs that have developed resistance), so the credibility of these results deserves further validation.
V. Individualized treatment
Hp clearance therapy is relatively simple, and medical personnel should consider the effectiveness, tolerability (e.g., whether there are allergies or side effects), cost, and resistance patterns of the drugs, and then give drug therapy based on existing experience. When circumstances permit, only regimens with efficiencies above 90% or even 95% should be used clinically. In addition, the patient’s resistance or sensitivity to each drug should be taken into account. However, although rapid molecular assays for clarithromycin resistance are feasible and commercially available, pretreatment tests are not currently widely used.
For some areas where drug susceptibility testing is not yet widely available, the best recommendation is to adopt a previously effective regimen and follow up regularly to ensure complete clearance of the strain. A number of regimens are currently available to achieve 95% and higher bactericidal rates, including clarithromycin 14-day regimens or metronidazole triple therapy, sequential therapy, combination therapy, and levofloxacin triple therapy. For most of the US population, resistance to the combination of clarithromycin and metronidazole is rare, making this regimen the treatment of choice. If the patient’s outcome is poor, the application of bismuth quadruple therapy is then considered.
VI. Possible reasons for treatment failure
The 13C urea breath test is a commonly used method for detecting Hp. However, some studies have shown that the test can give false-positive results and often occurs when the result is close to a critical value. The problem is most common in patients with atrophic gastritis and may be due to the presence of non-Hp-associated urease in the organism. False-positive results can produce erroneous conclusions about the failure of antimicrobial therapy and are particularly prevalent in people who have tried multiple treatment options. Further studies are needed to confirm whether adjuvant therapy with citric or malic acid can reduce false positives.
Future treatment regimens should be more individualized, and the application of new molecular biology methods, such as drug sensitivity testing of stool or biopsy tissue, may allow for appropriate adjustments to treatment regimens. The investigators also tried dual therapy with amoxicillin and high-dose proton pump inhibitors, and the results showed that the regimen was successful in Asia, but the results were not satisfactory for Western populations.
Future directions also include better control of intragastric pH and further understanding of amoxicillin kinetics. Tetracycline is still difficult to obtain in many countries; confirmation is needed that it can be replaced by doxycycline. In addition, the effectiveness of new drugs (e.g., solithromycin) will be further confirmed.
VII. Is Hp infection really beneficial
Any study claiming that a major human pathogen may still be beneficial to health and suggesting that its clearance should be done with caution is intended to raise concern. hp is no exception, and some studies have reported an association between hp clearance and increased prevalence of esophageal adenocarcinoma, childhood asthma, and obesity. However, studies have also only shown a negative association between the two in epidemiological studies, and do not imply a causal relationship.
Of course, with increased understanding, some positive effects related to Hp clearance may be identified, and Hp has been shown to be associated with a variety of diseases through direct interference with metabolism or indirect chronic inflammatory effects. And in a review, Julie
Parsonnet analyzed studies on whether Hp may reduce the risk of immune disorders (e.g., asthma, esophageal cancer, Barrett’s esophagus, gastroesophageal disease, inflammatory bowel disease), infectious diseases (e.g., tuberculosis, gastroenteritis) and obesity. Overall, the article is skeptical of the evidence, concluding that the benefits of Hp infection are negligible.
1. Esophageal disease
The role of Hp in esophageal adenocarcinoma, Barrett’s esophagus and gastroesophageal reflux disease is discussed in the recent Maastricht Consensus. These esophageal diseases are all acid reflux related diseases. hp infection both promotes and inhibits gastric acid reflux; gastric sinus gastritis is associated with increased risk of acid secretion and reflux esophagitis, whereas hp-induced gastric body gastritis reduces gastric acid secretion and thus gastric acid reflux. It is thus clear that bacteria can have multiple effects on gastric acid secretion, depending on the type and degree of gastritis involved.
2. Non-esophageal diseases
(1) Asthma
The initial studies on the rate of Hp infection and asthma were based on the fact that the incidence of asthma was increasing, whereas recent studies have shown that the incidence of asthma has peaked or tended to decrease. A long-term study of a large sample in the United Kingdom showed that the prevalence of Hp infection decreased across all social classes and was most pronounced in the under-5 age group. A study also found a decrease in the incidence of asthma in children. However, these data do not support the idea that Hp infection is a protective factor for childhood asthma.
An animal study suggests that Hp may prevent asthma by promoting immune tolerance, with two Hp antigens (Υ-glutamyl transpeptidase and toxin) inducing the production of regulatory T cells in the gastric mucosa of mice, leading to enhanced tolerance and reduced allergy. In another animal model (dog), it was concluded that asthma prevention may be “based on multiple pathways and multiple bacterial products of colonized flora”. In conclusion, these studies do not support a correlation between increased asthma prevalence and Hp clearance.
(2) Obesity
Obesity is a very complex metabolic problem, and some studies suggest that the increase in the global obese population may be associated with physiological alterations in the stomach. Obesity is caused by an imbalance between energy intake and expenditure, so Hp deficiency may increase appetite. However, it is not clear whether Hp deficiency reduces energy expenditure. However, only weak indirect evidence exists regarding the correlation between obesity and Hp infection. It is possible that there is no pathogenically significant correlation between Hp and obesity.