根除幽门螺杆菌在预防胃癌中的作用

胃癌在全球恶性肿瘤致死亡的原因中位居第二位,幽门螺杆菌（H．pylori）感染是胃癌发生的重要病因。动物研究显示根除H.pylori,特别是在早期阶段,能有效预防胃癌的发生。部分病例通过根除npylori可阻止胃癌前病变的发展并可能使其逆转。最新研究表明根除H．pylori可降低胃癌发生的风险,对无萎缩或肠化生者可能尤其有效。本文就根除H．p）tori在预防胃癌中作用的研究进展作一综述。     

Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer in Japan

This article describes the characteristics of H. pylori infection dynamics in early gastric cancer cases in Japan and the reduced likelihood of metachronous cancer development and growth inhibition by H. pylori eradication based on healing of background gastric mucosa. In the future, these clinical studies and experimental studies in Mongolian gerbils and mice should elucidate the role of H. pylori infection in the development of gastric carcinogenesis to clinical cancer on the genetic level so that gastric cancer prevention by H. pylori eradication is established.     

The effect of Helicobacter pylori eradication on reducing the incidence of gastric cancer

Epidemiologically, the association between chronic Helicobacter pylori infection and development of gastric cancer is well established. Although the possibility of preventing gastric cancer by eradicating H. pylori infection was recently investigated by several research groups, the results remain controversial. The aim of this study was to determine whether the eradication of H. pylori infection would reduce the incidence of gastric cancer. In total, 304 patients with persistent H. pylori infection and 404 patients with H. pylori infection eradicated were examined annually for gastric cancer by endoscopy. Over an average of 3.1 years for the first group and 3.2 years for the second group, 13 and 6 patients, respectively, were diagnosed as having new gastric cancer. The cumulative incidence of gastric cancer was statistically different between the groups (P=0.019; log-rank test). The hazard ratio of H. pylori eradication was 0.335 by Cox proportional hazards model (P=0.047). Differentiated gastric cancer was found in 11 patients in the persistent infection group and 3 patients in the eradicated group. The incidence of differentiated cancer was significantly different (P=0.017) between the groups, but not for undifferentiated cancer (P=0.847). The results of the current study suggest that the eradication of H. pylori infection reduces the incidence of gastric cancer.     

Prevention of gastric cancer by Helicobacter pylori eradication

The evidence supporting the important role of Helicobacter pylori causing gastric cancer is getting stronger. The mechanisms by which H. pylori can influence the progression to severe changes in the gastric mucosa are under investigation. An increased gastric epithelial cell proliferation has been observed in individuals infected with H. pylori. This lifelong increased cell turnover is deemed to be a major risk factor for increased mutational changes and may lead to the development of gastric cancer. Successful eradication of H. pylori infection induces the healing of the gastritis and a significant decrease in gastric epithelial cell proliferation. Nevertheless, it is right now unknown at which time the point of no return, meaning at which time an eradication therapy leads to a benefit for the individual to prevent gastric cancer, has been reached. Therefore the major question that arises is to whom an eradication therapy should be offered to prevent gastric cancer. A general elimination of the infection might be worthwhile, but seems to be unrealistic now because of the high prevalence of the infection and the missing of a vaccine. This review reflects possible mechanisms of gastric cancer development induced by chronic H. pylori infection and recent investigational trials for prevention of gastric cancer by H. pylori eradication therapy will be discussed.     

Causal role of Helicobacter pylori infection in gastric cancer

Gastric cancer is the second most frequent cancer in the world, accounting for a large proportion of all cancer cases in Asia, Latin America, and some countries in Europe. Helicobacter pylori(H pylori) is regarded as playing a specific role in the development of atrophic gastritis, which represents the most recognized pathway in multistep intestinal-type gastric carcinogenesis. Recent studies suggest that a combination of host genetic factors, bacterial virulence factors, and environmental and lifestyle factors determine the severity of gastric damage and the eventual clinical outcome of H pylori infection. The seminal discovery of H pylori as the leading cause of gastric cancer should lead to effective eradication strategies. Prevention of gastric cancer requires better screening strategies to identify candidates for eradication.     

Helicobacter pylori infection and development of gastric cancer in Korea: long-term follow-up

BACKGROUND AND AIM: Infection of Helicobacter pylori is viewed as a major driver of progression to the precancerous state or to gastric cancer. This study was performed to investigate the effect of H. pylori infection on gastric cancer development and to determine to what extent H. pylori eradication is likely to reduce the prevalence of gastric cancer. METHODS: Gastric cancer development was investigated in 1790 Korean subjects who underwent gastroscopy and H. pylori testing between 1992 and 1998. The effects of H. pylori-positive and eradicated states on gastric cancer development were analyzed. RESULTS: Gastric cancer developed in 5 of the study cohort during a mean follow-up period of 9.4 years. All of these patients were positive for H. pylori infection, and 4 of the 5 had antral intestinal metaplasia (IM) at the time of study enrollment. One of these 5 patients was in an eradicated state when the gastric cancer was diagnosed, and had histologic IM before eradication therapy was performed. Gastric cancer was found to develop 10.9 times more frequently in the presence of IM than in its absence. CONCLUSIONS: The present study shows a close relationship between H. pylori infection and IM, and between IM and the development of gastric cancer. In addition, our finding suggests that chronic H. pylori infection looks like an important risk factor for the development of gastric cancer in Korea, where the prevalence of H. pylori remains high. This study indicates that to prevent gastric cancer H. pylori eradication is best performed before the development of IM.     

Eradication of H pylori for the prevention of gastric cancer

Infection with H pylori is the most important known etiological factor associated with gastric cancer. While colonization of the gastric mucosa with H pylori results in active and chronic gastritis in virtually all individuals infected, the likelihood of developing gastric cancer depends on environmental, bacterial virulence and host specific factors. The majority of all gastric cancer cases are attributable to H pylori infection and therefore theoretically preventable. There is evidence from animal models that eradication of H pylori at an early time point can prevent gastric cancer development. However, randomized clinical trials exploring the prophylactic effect of H pylori eradication on the incidence of gastric cancer in humans remain sparse and have yielded conflicting results. Better markers for the identification of patients at risk for H pylori induced gastric malignancy are needed to allow the development of a more efficient public eradication strategy. Meanwhile, screening and treatment of H pylori in first-degree relatives of gastric cancer patients as well as certain high-risk populations might be beneficial.     

Characteristics and predictors of gastric cancer after Helicobacter pylori eradication

Helicobacter pylori(H. pylori) eradication can reduce gastric cancer. However, gastric cancer still develops after eradication, and cases who received eradication therapy are increasing. In this study, we have reviewed the characteristics and predictors of primary gastric cancer developing after H. pylori eradication. In terms of the characteristics, endoscopic, histologic, and molecular characteristics are reported. Endoscopically, gastric cancer after eradication is often depressedtype and shows a gastritis-like appearance, which sometimes makes the diagnosis difficult. Histologically, most gastric cancer after eradication is intestinal type, and non-neoplastic epithelium, also called epithelium with low-grade atypia, is frequently seen over the tumor, which is presumably the cause of the endoscopic gastritis-like appearance. As for molecular characteristics, some markers, such as Ki67, MUC2, and Wnt5a expression, are lower in cancer from patients in whom H. pylori has been eradicated. In terms of predictors, several Japanese studies have reported that severe endoscopic atrophy at eradication is a risk factor for gastric cancer development. Histologic intestinal metaplasia, especially in the corpus, and long-term use of proton pump inhibitors, are also reported as risk factors for gastric cancer after H. pylori eradication. These studies on the characteristics and predictors of gastric cancer development will become the cornerstone for establishing a novel surveillance program based on the gastric cancer risk stratification specific to H. pylori-eradicated patients.     

The effect of eradicating helicobacter pylori on the development of gastric cancer in patients with peptic ulcer disease

OBJECTIVES: Infection with Helicobacter pylori is a risk factor for the development of gastric cancer. However, it is not known whether eradication therapy can prevent the development of gastric cancer in persons in whom the cancer is not yet established. In the present study, we investigated whether the eradication of H. pylori in patients with peptic ulcer disease reduces the likelihood of their developing gastric cancer. METHODS: Prospective posteradication evaluations were conducted in 1,342 consecutive patients (1,191 men and 151 women; mean age: 50 yr) with peptic ulcer diseases who had received H. pylori eradication therapy. After confirmation of eradication, endoscopy and a urea breath test were performed yearly. RESULTS: A total of 1,120 patients completed more than 1-yr follow-up and were followed for up to 8.6 yr (a mean of 3.4 yr). Gastric cancer developed in 8 of 944 patients cured of infection and 4 of 176 who had persistent infection (p= 0.04; log-rank test). All the gastric cancer developed in patients with gastric ulcer, but none in patients with duodenal ulcer (p= 0.005; Fisher's exact test). In patients with gastric ulcer, persistent infection was identified as a significant factor for the risk of developing gastric cancer (hazard ratio: 3.35; 95% confidence interval: 1.00-11.22; p= 0.04; Cox's proportional-hazards model). CONCLUSION: H. pylori eradication may reduce their risk of developing gastric cancer in patients with gastric ulcer. Large-scale studies in additional populations of this important international public-health issue are warranted.     

Helicobacter pylori-infected animal models are extremely suitable for the investigation of gastric carcinogenesis

Although various animal models have been developed to clarify gastric carcinogenesis, apparent mechanism of gastric cancer was not clarified in recent years. Since the recognition of the pathogenicity of Helicobacter pylori (H pylori), several animal models with H pylori infection have been developed to confirm the association between H pylori and gastric cancer. Nonhuman primate and rodent models were suitable for this study. Japanese monkey model revealed atrophic gastritis and p53 mutation after long-term infection of H pylori. Mongolian gerbil model showed the development of gastric carcinoma with H pylori infection alone, as well as with combination of chemical carcinogens, such as N-methyl-N-nitrosourea and N-methyl-N-nitro-N-nitrosoguanidine. The histopathological changes of these animal models after H pylori inoculation are closely similar to those in human beings with H pylori infection. Eradication therapy attenuated the development of gastric cancer in Hpylori-infected Mongolian gerbil. Although several features of animal models differ from those seen in human beings, these experimental models provide a starting point for further studies to clarify the mechanism of gastric carcinogenesis as a result of H pylori infection and assist the planning of eradication therapy to prevent gastric carcinoma.     

Helicobacter pylori and gastric acid secretion

Helicobacter pylori (H. pylori) infection leads to profound changes in gastric physiology. Several clinical and animal studies have been performed to clarify the influence of H. pylori on gastric acid secretion. Published data, however, are not consistent throughout. Infection of the gastric antrum, which can be observed mainly in duodenal ulcer patients, increases gastrin release and consecutively acid output. The net effect of corpus and antrum gastritis, such as in patients with gastric cancer, is to decrease acid secretion. Chronic H. pylori infection may finally promote gastric atrophy with irreversibly diminished acid secretion but in earlier stages of this infection eradication of H. pylori normalizes gastric secretory activity.     

Faecal calprotectin: factors affecting levels and its potential role as a surrogate marker for risk of development of Crohn’s Disease

Infection with Helicobacter pylori is associated with severe digestive diseases including chronic gastritis, peptic ulcer disease, and gastric cancer. Successful eradication of this common gastric pathogen in individual patients is known to prevent the occurrence of peptic ulcer disease and gastric cancer. With half of the world’s population being infected with H, pylori and only few antibiotics result in an effective eradication, a successful antibiotic driven worldwide eradication program seems unlikely. In addition, H. pylori eradication is not always beneficial as it has been described that eradication can be associated with an increased frequency of other disorders such as pediatric asthma, inflammatory bowel diseases and Barrett’s Esophagus. We have to accept that eradication of this infection is a two-edged sword that is both useful and harmful and we should therefore focus our H. pylori eradication policy toward selectively identify and destroy only the virulent strains. In order to still be able to effectively treat H. pylori infections in the future we need an alternative diagnostic/treatment algorithm. This would involve a shift towards more precise and enhanced disease predicting diagnosis that tries to identify patients with chance of developing severe diseases such as gastric cancer, rather than the current regime that is geared towards find and destroy all H. pylori.     

Helicobacter pylori associated gastric intestinal metaplasia: Treatment and surveillance

Gastric cancer(GC) is one of the leading causes of cancer related death in the world, particularly in East Asia. According to the Correa's cancer cascade, noncardia GC is usually developed through a series of mucosal changes from non-atrophic gastritis to atrophic gastritis(AG), intestinal metaplasia(IM), dysplasia and adenocarcinoma. Atrophic gastritis and IM are therefore generally considered to be pre-neoplastic gastric lesions. Helicobacter pylori(H. pylori) infection is an important initiating and promoting step of this gastric carcinogenesis cascade. Emerging long-term data showed that eradication of H. pylori reduced the risk of subsequent cancer development. It however remains confusing whether eradication of the bacterium in individuals with pre-neoplastic gastric lesions could regress these changes as well as in preventing cancer. Whilst H. pylori eradication could likely regress AG, the presence of IM may be a point of no return in this cascade. Hence, surveillance by endoscopy may be indicated in those with extensive IM or those with incomplete IM, particularly in populations with high GC risk. The optimal interval and the best tool of surveillance endoscopy remains to be determined in future studies.     

Causal role of Helicobacter pylori infection and eradication therapy in gastric carcinogenesis

Many epidemiological reports indicate that Helicobacterpylori(H pylori)infection plays an important role ingastric carcinogenesis.Several genetic and epigeneticalterations contribute to the initiation,promotion,andprogression of the cancer cells in a multi-step manner.H pylori is known to induce chronic inflammation in thegastric mucosa.Its products,including superoxides,participate in the DNA damage followed by initiation,andthe inflammation-derived cytokines and growth factorscontribute to the promotion of gastric carcinogenesis.By eradicating H pylori,gastric inflammation can becured; the therapy diminishes the levels not onlyof inflammatory cell infiltration,but also atrophy/intestinal metaplasia in part.A randomized controlledtrial revealed that the eradication therapy diminishedthe gastric cancer prevalence in cases without pre-cancerous conditions.In addition,recent epidemiologicalstudies from Japanese groups demonstrated thatthe development of gastric cancer,especially of theintestinal type,was decreased by successful eradicationtherapy,although these were designed in a non-randomized manner.However,it should be mentionedthat endoscopic detection is the only way to evaluate thedegree of gastric carcinogenesis.We have reported thatthe endoscopic and histological morphologies could bemodified by eradication therapy and it might contributeto the prevalence of gastric cancer development.Considering the biological nature of cancer cellproliferation,it is considered that a sufficiently long-termfollow-up would be essential to discuss the anticancereffect of eradication therapy.     

Helicobacter pylori infection and gastric cancer

According to several prospective controlled epidemiologic studies, the positive rate of H. pylori antibody was shown to be higher in the patients with gastric cancer than in the control group. Retrospective studies on the association between gastric cancer and H. pylori have been conducted in a large number of subjects and the results can be classified broadly into two categories, i.e., findings affirming an association and others denying it. Research concerning the association between gastric cancer and H. pylori has achieved great progress over time, leading to the recognition of this relationship by the WHO. One of the greatest concerns is to ascertain whether the final outcome of H. pylori-induced gastritis may lead to gastric cancer. The onset of gastric cancer can be explained as being caused not only by H. pylori infection, but also by a combination of various factors such as food and the environment. However, the possibility that the occurrence of gastric cancer, like the recurrence of peptic ulcer, can be prevented by eradication of H. pylori has also been suggested. Further progress in clinical research is needed to resolve this issue.     

Role of Helicobacter pylori infection in gastric carcinogenesis:Current knowledge and future directions

Helicobacter pylori(H. pylori) plays a role in the patho-genesis of gastric cancer. The outcome of the infection depends on environmental factors and bacterial and host characteristics. Gastric carcinogenesis is a multistep process that is reversible in the early phase of mucosal damage, but the exact point of no return has not been identified. Therefore, two main therapeutic strategies could reduce gastric cancer incidence:(1) eradication of the already present infection; and(2) immunization(prior to or during the course of the infection). The success of a gastric cancer prevention strategy depends on timing because the prevention strategy must be introduced before the point of no return in gastric carcinogenesis. Although the exact point of no return has not been identified, infection should be eradicated before severe atrophy of the gastric mucosa develops. Eradication therapy rates remain suboptimal due to increasing H. pylori resistance to antibiotics and patient noncompliance. Vaccination against H. pylori would reduce the cost of eradication therapies and lower gastric cancer incidence. A vaccine against H. pylori is still a research challenge. An effective vaccine should have an adequate route of delivery, appropriate bacterial antigens and effective and safe adjuvants. Future research should focus on the development of rescue eradication therapy protocols until an efficacious vaccine against the bacterium becomes available.     

Gastro-oesophageal reflux and duodenogastric reflux before and after eradication in Helicobacter pylori gastritis

OBJECTIVE: Helicobacter pylori and duodenogastric reflux (DGR) are both associated with chronic gastritis, peptic ulcer and gastric cancer. The nature of their interrelationship remains unclear. H. pylori eradication has also been reported to result in new or worsening acid gastro-oesophageal reflux (GOR). The aim of this study was to investigate the relationship between GOR, DGR and H. pylori infection. METHOD: 25 patients with H. pylori gastritis underwent ambulatory 24-hour oesophageal and gastric pHmetry and gastric bilirubin monitoring before and 12 weeks after H. pylori eradication, confirmed by 14C urea breath testing (UBT). Ten healthy subjects served as a control group. RESULTS: There were no differences between patient and control groups for gastric alkaline exposure or gastric bilirubin exposure (P> 0.25 in all categories). Oesophageal acid reflux was higher in the study group (P< 0.02). No differences were detected in oesophageal acid reflux, gastric alkaline exposure, or gastric bilirubin exposure (P = 0.35, 0.18 and 0.11, respectively) before and after eradication. CONCLUSIONS: Acid GOR is not increased by H. pylori eradication. DGR in patients with H. pylori gastritis is similar to that in healthy, non-infected subjects. H. pylori eradication produces no change in GOR or DGR. In patients with chronic gastritis, H. pylori infection and DGR appear to be independent of each other.     

Nutrition status and Helicobacter pylori infection in patients receiving hemodialysis

Chronic kidney disease(CKD) patients receiving hemodialysis(HD) often develop gastrointestinal abnormalities over their long treatment period. In general, prognosis in such patients is poor due to the development of protein-energy wasting(PEW). Therefore, it is important to clarify the etiology of PEW and to establish better strategies to deal with this condition. Chronic Helicobacter pylori(H. pylori) infection in the gastric mucosa has a close association with not only the development of peptic ulcer disease and gastric cancer, but is also associated with abnormal plasma and gastric mucosal ghrelin levels that are seen in malnutrition. It is unclear whether H. pylori infection of the gastric mucosa is directly associated with prognosis in HD patients by affecting ghrelin levels. Recent studies show that the prevalence of H. pylori infection in HD patients is significantly lower than in subjects with normal renal function. In the natural history of H. pylori infection in HD patients, the prevalence of infection decreases as the length of time on HD increases. The severity of gastric mucosal atrophy has been suggested as the major determinant of ghrelin levels in these patients, and eradication therapy of H. pylori improves nutritional status by increasing serum cholinesterase and cholesterol levels, especially in patients with mildto-moderate gastric mucosal atrophy. Prompt H. pylori eradication to inhibit the progress of gastric atrophy may be required to prevent this decrease in ghrelin levels and subsequent PEW and improve the prognosis of HD patients by improving their nutritional status.     

Increased prevalence of precancerous changes in relatives of gastric cancer patients: critical role of H. pylori

BACKGROUND & AIMS: Helicobacter pylori is believed to predispose to gastric cancer by inducing gastric atrophy and hypochlorhydria. First-degree relatives of patients with gastric cancer have an increased risk of developing gastric cancer. The aim of this study was to determine the prevalence of atrophy and hypochlorhydria and their association with H. pylori infection in first-degree relatives of patients with gastric cancer. METHODS: H. pylori status, gastric secretory function, and gastric histology were studied in 100 first-degree relatives of patients with noncardia gastric cancer and compared with those of controls with no family history of this cancer. RESULTS: Compared with healthy controls, relatives of patients with gastric cancer had a higher prevalence of hypochlorhydria (27% vs. 3%) but a similar prevalence of H. pylori infection (63% vs. 64%). Relatives of cancer patients also had a higher prevalence of atrophy (34%) than patients with nonulcer dyspepsia (5%) matched for H. pylori prevalence. Among the relatives of cancer patients, the prevalence of atrophy and hypochlorhydria was increased only in those with evidence of H. pylori infection, was greater in relatives of patients with familial cancer than in relatives of sporadic cancer index patients, and increased with age. Eradication of H. pylori infection produced resolution of the gastric inflammation in each subject and resolution of hypochlorhydria and atrophy in 50% of the subjects. CONCLUSIONS: Relatives of patients with gastric cancer have an increased prevalence of precancerous gastric abnormalities, but this increase is confined to those with H. pylori infection. Consequently, prophylactic eradication of the infection should be offered to such subjects.     

Can gastric cancer be prevented by Helicobacter pylori eradication?

Helicobacter pylori infection always causes chronic gastritis and triggers several gastroduodenal pathologies ranging from peptic ulcer disease to gastric cancer. It is well established that H. pylori eradication decreases the incidence of gastroduodenal ulcer and its recurrence. However, despite being accepted as the critical risk factor for gastric cancer, there is no conclusive evidence that H. pylori eradication decreases the incidence of gastric cancer. Bacterial virulence characteristics, as well as genetic predisposition of the host in conjunction with certain environmental conditions, are the major factors which influence the development of gastric cancer. Preclinical and clinical data suggest that reversibility of precancerous lesions (atrophic gastritis and intestinal metaplasia) is possible in some patients after H. pylori eradication. Since neoplastic lesions do not progress - or even regress in some cases - after H. pylori eradication, eradication therapy should be considered even in patients with precancerous lesions. Nonetheless, progression of atrophic gastritis and intestinal metaplasia into cancer has been also demonstrated in patients after H. pylori eradication, suggesting that there might be a point of no return where genetic changes have already happened and are irreversible despite elimination of the triggering carcinogen (H. pylori). At the present time the clinical decision to treat a patient is based on established risk profiles. A general screen-and-treat policy, although desirable, currently awaits a less complex treatment regimen.