Helicobacter pylori as a new paradigm in the pathogenesis of upper GI diseases

Discovery of H. pylori from human gastric mucosa have induced an evolution in the concepts of upper GI diseases, especially in those of gastritis, peptic ulcer and gastric cancer. A new classification of gastritis, Sydney system and updated Sydney system, are proposed and commonly used in worldwide. Eradication treatment against H. pylori infection can completely improve the histologic gastritis, which is defined by the infiltration of inflammatory cells. In gastric and duodenal ulceration, the eradication of H. pylori accelerates the ulcer healing without acid suppression, and prevents the ulcer recurrence without any maintenance therapy. These accumulating data suggest that H. pylori could have an etiologic relation to ulcer diseases, because these are a kind of intervention study on etiology. Thus, in ulcer diseases, H. pylori is proven to play an etiologic role. On the basis of these studies, a new treatment strategy is proposed in upper GI diseases. This is a new paradigm on upper GI diseases.     

The treatment of peptic ulcer in elderly CRF patients

It is well known that CRF patients may suffer from various types of upper GI tract lesions such as esophagitis, erosive or atrophic gastritis, gastro-duodenal ulcers and polyps. Above all, acute gastric mucosal lesion with atrophic changes has been complicated with elderly CRF patients in relatively high frequency in recent years. A number of causes for upper GI tract lesions in CRF patients have been raised, which include mental and physical stresses, hypergastrinemia associated with lower renal metabolic clearance rate, secondary hyperparathyroidism, hypoperfusion in gastric mucosal blood flow, malnutrition, and also H. pylori recently. The treatments for these upper GI tract lesions are directed toward both suppression of offensive factors and strengthening of defensive factors in gastro-duodenal mucosae. It is needless to say that special attentions should be always paid for doses, intervals or durations in any drugs prescribed for elderly CRF patients because of lower renal metabolic clearance rates for drugs.     

幽门螺杆菌血清分型与上消化道疾病的关系

目的 探讨幽门螺杆菌(helicobacter pylori,Hp or H.pylori)分型与消化道不同疾病的关系。方法 入选198例Hp阳性的胃镜检查患者，采用免疫印迹法进行Hp的血清学分型，并取胃窦黏膜经HE染色观察胃窦黏膜病理组织学变化。结果 198例患者中检出HpI型菌株173例(87．4％)，Ⅱ型菌株25例(12．6％)。I型较II型Hp感染者胃镜下消化性溃疡、胃癌的比例更高，P=0.012；与胃炎组比较，十二指肠球部溃疡组、胃癌组的I型感染者更高（P值分别为0.026、0.048），而与胃溃疡组无显著差别(P=0.125)。病理组织学改变I型较II型Hp感染者的结果更为严重（P=0.038）。结论 临床上消化道疾病患者Hp感染以I型菌株最为多见。Hp感染的分型诊断有助于对胃、十二指肠疾病类型及病情的判断，I型菌株感染者需要更为积极的治疗。     

Helicobacter pylori infection and eradication

H. pylori infection is associated with various gastroduodenal diseases such as gastritis, peptic ulcer, gastric cancer, gastric MALT lymphoma. H. pylori infection is suggested that it plays a role as protective factor not promoting factor for reflux esophagitis and GERD. Epidemiological studies showed lower prevalence of H. pylori infection in reflux esophagitis and Barrett's esophagus comparing the control. Increased occurrence of reflux esophagitis after curing of H. pylori infection was reported. However, the relationship between H. pylori infection and reflux esophagitis has not been actually made clear. Also the mechanism of reflux esophagitis occurrence after H. pylori eradication is not obscure.     

Helicobacter pylori infection in gastric remnant cancer after gastrectomy

Patients who have undergone distal gastrectomy for peptic ulcer are at higher risk of developing gastric remnant cancer, and chronic bile reflux is believed to increase the risk of cancer in remnant stomach. In remnant stomach, carcinogenesis may be prevented by selecting the anastomosis method with a few reflux of intestinal juice including a bile acid. How Helicobacter pylori(H. pylori) infection participate in stomal gastritis and gastric remnant cancer, same as early gastric cancer in the intact stomach, is attended. H. pylori positive rate of remnant stomach is different by examination method and a report, but its rate is decreased every year after gastrectomy and in particular low in Billroth-II(B-II) anastomosis. B-II anastomosis is followed by a significantly lower rate than B-1. This may reflect the role of bile reflux because bile reflux interferes with colonization by H. pylori. Gastric cancer excision usual increase complicates gastric remnant stomach and H. pylori infection, but while H. pylori infection lasts after gastrectomy for gastric cancer, cell proliferation increase in remnant stomach. In remnant stomach after gastrectomy for gastric cancer, while H. pylori infection continues, H. pylori infection may cause remnant gastritis and a second cancer of remnant stomach. H. pylori infection and bile reflux seem to have a synergistic effect on cell proliferation in remnant stomach and may explain the increased risk of gastric remnant cancer. The cancer-causing dominant role might changed from H. pylori infection predominance to bile reflux every year after gastrectomy. Furthermore, a prophylactic effect to carcinogenesis by H. pylori eradication therapy is expected. Eradication of H. pylori after gastrectomy for gastric cancer has been recommended.     

Esophagitis, gastritis and duodenitis provoked by cure of Helicobacter pylori infection

It has been recently reported that curing Helicobacter pylori (H. pylori) infection may provoke reflux esophagitis. We studied the effect of cure of H. pylori infection on the development of disorders of the upper gastrointestinal (UGI) tract. The estimated incidence of reflux esophagitis, gastric erosions and duodenal erosions after cure of infection was 8.9%, 32.8% and 8.9%. The incidences of reflux esophagitis, gastric erosions and duodenal erosions were 10.0%, 30.0% and 6.7% in patients with gastric ulcer, 2.8%, 36.1% and 27.8% in those with duodenal ulcer and 9.2%, 30.3% and 1.3% in those with atrophic gastritis. Therefore, patients whose H. pylori infection has been cured should carefully be investigated by endoscopy for H. pylori-associated disease.     

Gastric MALT lymphoma in the absence of Helicobacter pylori infection presenting as an upper gastrointestinal hemorrhage

Gastric MALT lymphoma is almost exclusively a sequelae of Helicobacter pylori infection and rarely presents with profuse bleeding. Gastric mucosa is not normally thought to contain lymphoid tissue, yet in the presence of H pylori reactive lymphoid follicles form which are possibly throught to predispose the patient to developing lymphoma. GI bleeding from these tumors is common during treatment as a consequence of tumor regression or necrosis. We present the case of a MALT Lymphoma in a 59 year-old woman manifesting as a brisk upper GI bleed without serologic or microbiologic evidence of an H pylori infection.     

A case of Helicobacter pylori infection complicated with gastric cancer, gastric mucosa-associated lymphoid tissue lymphoma, and idiopathic thrombocytopenic purpura successfully treated with laparoscopy-assisted total gastrectomy and splenectomy

Helicobacter pylori infection plays a key role in the pathogenesis of H. pylori-associated diseases, including gastroduodenal and non-gastroduodenal diseases. A 71-year-old man was evaluated for a positive fecal occult blood test by upper gastrointestinal endoscopy, which revealed H. pylori infection, two adenocarcinomas and two gastric mucosa-associated lymphoid tissue lymphomas. Hematological examination revealed low platelet-count, elevated platelet-associated immunoglobulin G and anti-H. pylori immunoglobulin G antibodies. We diagnosed H. pylori infection complicated by simultaneous occurrence of gastric cancer, gastric mucosa-associated lymphoid tissue lymphoma, and idiopathic thrombocytopenic purpura. These diseases were successfully treated with laparoscopy-assisted total gastrectomy and splenectomy, and there was no evidence of recurrence for about 2 years. This is the first reported case of H. pylori infection complicated by these three diseases and cured with laparoscopic surgery.     

Eradication of Helicobacter pylori in Japan]

Twenty five years has passed since the re-discovery of Helicobacter pylori. Many people have studied on this organism since that time. Some mechanisms about gastric mucosal inflammation have been clarified, and pathogenesis of peptic ulcer formation and gastric cancer have been solved. H. pylori infection is related to chronic gastritis, peptic ulcer, gastric carcinoma, and MALToma. In 1998, it was reported that gastric cancer occurred in H. pylori infected mongolian gerbils. In Japan, the prevalence of peptic ulcer and gastric cancer is very high. Therefore, the treatment for H. pylori infection is necessary to prevent occurrence of these diseases. To treat H. pylori infection, various regimen have been tried. Triple therapy with PPI and two antibiotics is recommended for cure of H. pylori infection in European and US guidelines. Some guidelines for management of H. pylori infection and regimen were shown in this part.     

Molecular markers in Helicobacter pylori-associated gastric carcinogenesis

Helicobacter pylori infection is a known risk factor of gastric carcino-genesis. This article presents early molecular alterations associated with H. pylori chronic gastritis and advances in the molecular characterization of preneoplastic intestinal metaplasia (IM) and premalignant gastric mucosal lesions. H. pylori infection induces changes in gene expression, genomic instability and accumulation of gene mutations in the stomach epithelium. Mutations, including LOH and microsatellite instability, and gene hypermethylation are seen not only in gastric cancer, but are already detectable in IM and gastric dysplasia/adenoma. Recent reports using microarray expression analysis identified several gastric epithelial genes that are regulated by H. pylori. Among the many genes showing altered epithelial expression in response to H. pylori, some might be useful as markers to assess gastric cancer risk. Profiles of mutagenesis and gene expression in IM and dysplasia/adenoma have been characterized and represent potential markers of preneoplastic and premalignant lesions during gastric carcinogenesis.     

Ulcers and gastritis

This article reviews recently published literature regarding ulcers and gastritis. Although endoscopy is the most useful procedure for diagnosis in the upper gastrointestinal tract, complications do occur, and procedure-related costs are significant. The appropriate indication for endoscopy has recently been debated. Helicobacter pylori is known to be an important pathogen involved in gastric and duodenal inflammation. Peptic ulcer disease and severe gastric mucosal injury are caused by virulent strains, and many reports have focused on CagA. Follow-up studies on surveillance endoscopy in patients with peptic ulcer or gastritis report that patients with atrophic gastritis and intestinal metaplasia are at significantly higher risk for gastric cancer. H. pylori eradication sometimes causes gastroduodenal erosion and reflux esophagitis, and the mechanisms involved have been revealed. Proton-pump inhibitors are useful in the treatment of ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs), reflux esophagitis, and for preventing rebleeding after endoscopic hemostasis, but the effect of long-term acid suppression on the gastric mucosa is still a matter of debate. H. pylori infection and NSAID intake are both risk factors for peptic ulcer disease, and are important aspects in this field.     

Ulcers and gastritis

This article reviews recently published reports on ulcers and gastritis. Helicobacter pylori is known to be an important pathogen involved in gastroduodenal inflammation and peptic ulcers. Conventional endoscopy is of limited usefulness in the evaluation of gastritis, but magnifying endoscopy is evidently helpful in the diagnosis of chronic atrophic gastritis, intestinal metaplasia, and H. pylori infection. A significant reduction in the incidence of refractory ulcers and the prevalence of H. pylori infection in patients with peptic ulcer disease followed the introduction of H. pylori eradication treatment. Chronic H. pylori infection is associated with gastric cancer, and the effect of H. pylori eradication on the prevention of gastric cancer is an important issue that is still a matter of controversy. Endoscopic hemostasis and intravenous proton-pump inhibitor (PPI) infusion represent a widely accepted approach to the treatment of peptic ulcer bleeding. In clinical practice, it is important to prevent recurrent bleeding and to treat patients who do not respond to endoscopic therapy or PPI treatment. Laparoscopic repair for peptic ulcer perforations, with postoperative eradication treatment, has gradually met with acceptance in patients with H. pylori infection. H. pylori infection and its treatment continue to be interesting problems in this field.     

中国幽门螺杆菌感染的现状

我国是幽门螺杆菌（HP）高感染地区，HP感染相关疾病负担（尤其是胃癌）较重，国内学术界应尽快统一认识，重视HP感染的危害，建立有效的胃癌一、二级预防体系；同时，随着近年来抗生素耐药率的不断上升，传统方案根除率逐年下降，临床医师应参照最新共识，规范HP感染的诊治，重视提高初次HP根除率。     

Helicobacter pylori eradication and associated changes in the gastric mucosa

Persistent Helicobacter pylori infection contributes towards the development of chronic gastritis. To clarify the changes in chronic gastritis as a precursor of gastric cancer secondary to H. pylori eradication is an important issue, as it has significant implications for reducing the risk of gastric cancer. Studies published to date, however, are far from consistent with regard to the morphologic changes reported following H. pylori eradication. Of these, some papers reported improvement in gastric atrophy or intestinal metaplasia, versus others reporting no improvement, with the majority of papers published after 2000 reporting improvement in these end points. The inconsistent results concerning the impact of H. pylori eradication on gastric atrophy could be due to the inconsistency of the diagnostic criteria employed for evaluation of the morphology, confounded by the difficulties involved in evaluating atrophic changes in the gastric mucosa. While adherence to the Updated Sydney System available for evaluation of gastritis is primarily required worldwide to ensure consistency in evaluating gastritis, long-term research into the morphologic changes associated with H. pylori eradication is also required to explore strategies for the prevention of gastric cancer with H. pylori eradication.     

Current management of Helicobacter pylori infections in the elderly

Helicobacter pylori infection is a chronic gastric gram-negative infection that increases with age worldwide. However, the percentage age of H. pylori-positive elderly patients who are tested and treated for their infection remains very low. It is now demonstrated that H. pylori infection induces a whole cascade of events leading to gastric pathologies, such as peptic ulcer diseases, gastric precancerous lesions and gastric cancer. Recent data also demonstrated that H. pylori chronic infection can play a role in gastric aging, appetite regulation and extradigestive diseases, such as Alzheimer's disease, in the elderly. The diagnosis of H. pylori infection remains difficult to realize in the very old population, and the urea breath test obtains the best performance in this population. 1-week proton pump inhibitor-based triple therapy regimens are highly effective and well tolerated in elderly patients, and antibiotic resistance remains very low. Low compliance is the main factor related to treatment failure in this population.     

端粒酶表达与幽门螺杆菌感染关系的临床观察

目的　探讨端粒酶表达与幽门螺杆菌 (HP)感染在胃癌发生发展过程中的关系及临床意义。方法　用PCR- EL ISA法、病理组织学方法及快速尿素酶试验检测 111例各种胃病变的胃粘膜活检标本中端粒酶活性和 HP感染情况。结果　胃癌组织中端粒酶表达阳性率为 85 % ,明显高于癌前病变 (2 1.2 % ) ,癌周正常组织 (10 % )及浅表性胃炎(0 ) ,差异非常显著 (P<0 .0 1)。 HP感染率在胃癌组为 5 5 % ,癌前病变组为 6 3.5 %。胃癌及癌前病变端粒酶阳性率在 HP阳性组 (90 .9%、2 4.2 % )高于 HP阴性组 (77.8%、15 .8% ) ,但统计学处理无显著性差异 (P>0 .0 5 )。结论　本研究结果显示 ,检测端粒酶活性有助于胃癌的早期诊断。胃癌及癌前病变组织端粒酶表达与幽门螺杆菌感染无关。     

Indication of H. pylori eradication therapy--who should be treated?

With increased evidence of H. pylori infection being deeply related with various gastric diseases, its curative therapy will be approved by social security foundation soon also in Japan. Japanese Society of Helicobacter reported a guideline for H. pylori diagnosis and treatment in July 2000. In the guideline, only peptic ulcers and low grade MALT lymphomas are recommended as an indication of H. pylori eradication and other diseases such as atrophic gastritis, post EMR state for early gastric cancer and post-operated stomach due to gastric cancer, hyperplastic polyps and non-ulcer dyspepsia, were not included. It is speculated that while benefit of eradication therapy for peptic ulcers and low grade MALT lymphomas has been supported by much clinical evidence, that for other diseases was judged not to be enough. Especially as to atrophic gastritis, eradication therapy might be considered in aspect of decreasing gastric cancer risk in Japan. Since accumulated epidemiological and experimental data strongly support its positive correlation with cancer risk, patients in high risk group for gastric cancer could be included for a target eradication therapy. In present, indication of the therapy should be clinically and socially decided according to individual patient.     

Helicobacter pylori induces beta3GnT5 in human gastric cell lines, modulating expression of the SabA ligand sialyl-Lewis x

Chronic Helicobacter pylori infection is recognized as a cause of gastric cancer. H. pylori adhesion to gastric cells is mediated by bacterial adhesins such as sialic acid-binding adhesin (SabA), which binds the carbohydrate structure sialyl-Lewis x. Sialyl-Lewis x expression in the gastric epithelium is induced during persistent H. pylori infection, suggesting that H. pylori modulates host cell glycosylation patterns for enhanced adhesion. Here, we evaluate changes in the glycosylation-related gene expression profile of a human gastric carcinoma cell line following H. pylori infection. We observed that H. pylori significantly altered expression of 168 of the 1,031 human genes tested by microarray, and the extent of these alterations was associated with the pathogenicity of the H. pylori strain. A highly pathogenic strain altered expression of several genes involved in glycan biosynthesis, in particular that encoding beta3 GlcNAc T5 (beta3GnT5), a GlcNAc transferase essential for the biosynthesis of Lewis antigens. beta3GnT5 induction was specific to infection with highly pathogenic strains of H. pylori carrying a cluster of genes known as the cag pathogenicity island, and was dependent on CagA and CagE. Further, beta3GnT5 overexpression in human gastric carcinoma cell lines led to increased sialyl-Lewis x expression and H. pylori adhesion. This study identifies what we believe to be a novel mechanism by which H. pylori modulates the biosynthesis of the SabA ligand in gastric cells, thereby strengthening the epithelial attachment necessary to achieve successful colonization.     

Incidence of Gastric Metaplasia and Helicobacter pylori Infection in Duodenal Bulb - With Specific Reference to Patients With Duodenal Ulcers

We determined the incidence of gastric metaplasia in the duodenal bulb of duodenal ulcer patients and the Helicobacter pylori (H. pylori) infection rate at sites with gastric metaplasia. Biopsy of the duodenal bulb showed the presence of gastric metaplasia in 61 of 86 patients (71%) overall and in 18 of 47 patients (38.3%) who had gastrectomy at an early gastric cancer. The histological diagnosis of H. pylori infection showed good agreement (83.3%) with the result of the rapid urease test, indicating that H. pylori occurs in regions with gastric metaplasia. This finding suggests that H. pylori infects gastric metaplasia in the duodenal bulb, causing mucosal injury, which is then transformed into duodenal ulcers. The exact mechanism by which gastric metaplasia is caused is unknown, but it is believed to occur in the transitional zone in the duodenal mucosa.     

The prospects of vaccination against H. pylori infection

H. pylori causes numerous gastroduodenal diseases including malignancies. Although eradication of H. pylori using antibiotics is clinically performed, it is sometimes unsuccessful because of resistant bacteria and patient non-compliance with treatment. Therefore prophylactic and therapeutic vaccination against H. pylori infection is necessary for clinical use but it is still under study. H. pylori is widely believed to be transmitted in childhood. If long and chronic H. pylori infection causes gastric cancer, vaccination should be targeted at children for the prophylaxis of cancer. Systemic immunization with aluminum hydroxide which has been already proved to be safe for human child, deserve attention.