Effects of Helicobacter pylori infection on Zollinger-Ellison syndrome

Both Zollinger-Ellison syndrome (ZES) and Helicobacter pylori infection are major etiologic factors for peptic ulcer. The aim of this study was to investigate the effect of H. pylori infection on ZES with special reference to acid secretion. Sixteen patients with ZES were selected (median age, 59 years; range, 39–66 years; M/F, 9/7), and H. pylori status, ulcer location, gastric acid secretion, serum pepsinogen (PG) I and II concentrations, and PG I/II ratio were determined. The seroprevalence of H. pylori infection was 50%, whereas active H. pylori infection was seen in only 25% of the patients. Thirteen patients had duodenal ulcer (DU), 1 had gastric ulcer (GU), and 2 had both GU and DU. DU was seen in both H. pylori-positive and H. pylori-negative patients, whereas GU was found only in H. pylori-positive patients. Both basal and maximal acid outputs were significantly lower in H. pylori-positive patients than in H. pylori-negative patients (P < 0.05). Moreover, both serum PG I and the PG I/II ratio were significantly lower in H. pylori-positive patients than in H. pylori-negative patients. These results indicate that ZES is an independent risk factor for DU, but H. pylori infection may play some role in the development of GU in ZES. In patients with ZES, H. pylori infection may reduce both hypersecretion from parietal cells and PG I secretion from chief cells, and hyperacidity of the stomach in ZES may have eradicated H. pylori in some patients. Received: March 30, 2000 / Accepted: May 26, 2000     

Helicobacter pylori and Zollinger-Ellison syndrome

Helicobacter pylori (previously Campylobacter pylori) is almost invariably associated with chronic duodenal ulcer disease. The relationship between H. pylori infection and duodenal ulcer in Zollinger-Ellison syndrome is unknown. We investigated the frequency of H. pylori infection in Zollinger-Ellison syndrome and also what effect H. pylori infection had on gastric function in patients with Zollinger-Ellison syndrome. H. pylori infection was diagnosed based on a specific serologic (ELISA) assay based on high-molecular-weight cell-associated proteins of H. pylori. We studied 20 patients with Zollinger-Ellison syndrome; 15 men and 5 women ranging in age from 24 to 71 years, median age 51. Six Zollinger-Ellison syndrome patients had H. pylori infection compared to 100 consecutive patients with chronic recurrent duodenal ulcer disease (P less than 0.05). Pretreatment basal acid output in Zollinger-Ellison syndrome patients ranged from 7.9 to 95.0 mmol/hr, median 35.2. Pentagastrin-stimulated maximal acid output ranged from 8.5 to 132 mmol/hr; median 52.7. Acid secretion was lower in the H. pylori-infected patients than the uninfected patients (BAO 24.5 +/- 6.5 vs 45.4 +/- 6.6, and MAO 44.3 +/- 11.8 vs 67.9 +/- 10.7, for H. pylori infected vs uninfected patients, respectively). The difference in BAO was statistically significant (P less than 0.05). The present results indicate that H. pylori is not a major contributing factor in duodenal ulcer associated with Zollinger-Ellison syndrome. The association of a reduced BAO with H. pylori suggests that these findings may be related.     

Oxidative stress in gastric mucosa in Helicobacter pylori infection.

BACKGROUND: Infection with Helicobacter pylori is believed to be associated with generation of reactive oxygen molecules which leads to oxidative stress in the gastric mucosa; but the relation between oxidative stress and gastrointestinal mucosal damage has not been documented. AIM: To look for evidence of oxidative stress and lipid peroxidation in the gastric mucosa in H. pylori-associated peptic ulcer. METHODS: 34 duodenal ulcer (DU) patients with H. pylori infection, 14 DU patients without H. pylori infection and 10 healthy subjects without H. pylori infection were studied. H. pylori infection was diagnosed by histology and rapid urease test on endoscopic biopsies from the gastric body and antrum. Reduced glutathione (GSH) and malondialdehyde (MDA) content were measured in biopsies taken from the gastric antrum. Statistical analysis was done using Student's t test. RESULTS: Tissue levels of GSH were significantly lower (91.7 [35.4] nmole/100 mg versus 147.3 [41.2] nmole/100 mg; p < 0.001) and MDA higher (163.0 [83.4] nmole/100 mg versus 109.2 [51.3] nmole/100 mg; p < 0.01) in patients with DU associated with H. pylori infection as compared to those without H. pylori infection. GSH levels were significantly lower and MDA levels higher in DU patients with or without H. pylori infection as compared to control subjects. Serum MDA levels in DU patients with H. pylori infection were also significantly higher than in patients without H. pylori infection. CONCLUSION: Depletion of gastric mucosal glutathione in H. pylori-infected DU patients may be due to failure of the antioxidant defense system. Failure of the glutathione-dependent defense system results in accumulation of free radicals which can initiate membrane damage by lipid peroxidation.     

Promoter methylation of E-cadherin gene in gastric mucosa associated with Helicobacter pylori infection and in gastric cancer

BACKGROUND:E-cadherin is an adhesion molecule involved in tumour invasion/metastasis. Silencing of E-cadherin by promoter CpG methylation has been shown in both familial and sporadic gastric cancers. Helicobacter pylori is a class I carcinogen in gastric cancer. AIMS: This study was undertaken to investigate the association between methylation of E-cadherin and H pylori in gastric mucosa from dyspeptic patients, and in intestinal metaplasia and primary and metastatic adenocarcinoma from surgical specimens of patients with gastric cancer. METHODS: E-cadherin methylation was studied using methylation specific polymerase chain reaction in microdissected tissue from biopsies or surgical resection specimens. E-cadherin expression was studied by immunohistochemistry. RESULTS: E-cadherin methylation was present in 31% (11/35) of gastric mucosae from dyspeptic patients, and was associated with H pylori infection (p=0.002), but was independent of the age of the patient or presence or absence of gastritis. E-cadherin methylation was present in 0% (0/8) of normal mucosa, 57% (12/21) of intestinal metaplasias, and 58% (15/26) of primary and 65% (21/32) of metastatic cancers. E-cadherin methylation status was concordant in 92% (11/12) of intestinal metaplasias and primary cancers, and in 85% (17/20) of primary and metastatic cancers from the same resected specimen. E-cadherin methylation in gastric cancer was associated with depth of tumour invasion (p=0.02) and regional nodal metastasis (p=0.05). CONCLUSION:E-cadherin methylation is an early event in gastric carcinogenesis, and is initiated by H pylori infection.     

p53 expression in gastric mucosa with Helicobacter pylori infection

Expression of p53 was examined immunohistochemically in the Japanese monkey model with Helicobacter pylori infection of the gastric mucosa to investigate the association between H. pylori infection and gastric carcinogenesis for a period of 4 years. In the course of these observations, from 3 years after H. pylori inoculation, nuclear staining for p53 was seen in the glandular cells of the mucosa infected with H. pylori, especially in the neck region of the glands. There was a gradual increase in the number of immunopositive cases among the infected animals. Three years after inoculation, three out of six cases, and 4 years after inoculation, four out of six cases exhibited positive staining for p53. Before inoculation, and up to 2 years after inoculation, the infected group showed no immunoreaction for p53. The non-infected group likewise displayed no immunostaining for p53 through 4 years of observation. These results suggest that p53 alterations occur in the H. pylori-infected gastric mucosa and that H. pylori infection may play an important role in gastric carcinogenesis.     

幽门螺杆菌感染诱导胃粘膜环氧化酶-2表达

目的 探讨幽门螺杆菌（Hp)感染对胃粘膜环氧化酶－2（COX－2）表达的影响。方法 27例无任何症状健康检查者，经胃镜采取胃窦部粘膜组织，用于Hp检测、病理组织学检查及免疫组织化学检查COX－2的表达。结果 18例Hp感染者胃粘膜上皮细胞和炎症细胞表达COX－2，而9例Hp阴性者胃粘膜均不表达COX－2。结论 Hp感染诱导胃粘膜COX－2表达。     

胃黏膜相关淋巴样组织瘤与幽门螺杆菌感染的相关性研究

目的 回顾分析胃黏膜相关淋巴组织（MALT）瘤与幽门螺杆菌（Hp)感染的相关性。方法 收集手术和病理理诊的消化道原发性非霍奇金淋巴瘤35例，行常规病理和免疫组化染色（CD3，CD5，CD10，CD20，CD23，CD45RO，Kappa,Lamda,Cyclinl,Ki67,TUNEL)重新作出病理学评价。同时观察Hp感染情况。结果 （1）MALT瘤共21例，其中胃MALT瘤16例，小肠1例，结肠4例。（2）胃MALT瘤中，除3例因切片均为癌组织无法判定有无Hp感染以外，余13例Hp均为阳性。（3）胃MALT瘤中，Ⅰ1期2例，Ⅱ1期5例，ⅡE期9例，（4）内镜误判为胃癌者3例，误判为巨大肥厚性胃炎者1例，误判为萎缩性胃炎者1例，诊断为慢性胃炎者5例，6例患者系胃镜活检确诊。（5）1例经3个疗程抗Hp治疗，病变完全消退，Hp转阴，经内镜及病理检查随访3年未见复发。结论 （1）胃MALT瘤与Hp感染关系密切，（2）抗Hp治疗可治愈早期MALT瘤。     

Helicobacter pylori infection induces antibodies cross-reacting with human gastric mucosa

The authors' previous observation that many of the monoclonal antibodies against Helicobacter pylori cross-react with the cells of the human gastric mucosa prompted them to investigate the possibility that gastric self-antigens cross-reacting with H. pylori could be involved in the immune response against this organism. It was found that three antibodies against H. pylori, CB-4, CB-10, and CB-14, that cross-react with the human gastric mucosa also intensely cross-reacted with murine gastric epithelial cells. A strong reaction against autologous mucosa was also evident in the sera of mice immunized with H. pylori but not with other bacteria. A serological study performed in a group of 82 patients undergoing gastroscopy showed that the presence of seropositivity against H. pylori was strongly correlated with the presence of autoantibodies against human antral gastric mucosa. This activity was neutralized after absorption of the sera with H. pylori but not with other gram-negative bacteria. The antibodies in the mouse and in the human did not react with other segments of the gastrointestinal tract or with most of the other organs. Mice bearing hybridomas secreting a cross-reacting antibody (CB-4) had histopathologic abnormalities in their stomachs. These lesions were absent in the stomachs of mice bearing hybridomas secreting a non-cross-reacting antibody (CB-26). It was concluded that H. pylori infection can stimulate antibodies cross-reacting with gastric autoantigens and that this immunologic mechanism may represent a pathogenic link between H. pylori and gastritis.     

Global analysis of Helicobacter pylori gene expression in human gastric mucosa

BACKGROUND & AIMS: Helicobacter pylori inhabits a highly restricted ecological niche in the human gastric mucosa. Microbial gene expression in the context of persistent infection remains largely uncharacterized. METHODS: An RNA analysis method, selective capture of transcribed sequences, was used in conjunction with genomic array hybridization to characterize H. pylori complementary DNAs (cDNAs) obtained from both human and experimentally infected gerbil gastric tissue specimens. RESULTS: Bacterial cDNAs obtained by selective capture of transcribed sequences from tissues hybridized to arrayed DNA fragments representing approximately 70% of open reading frames in the H. pylori genome. RNAs for most of these open reading frames were also detected by array hybridization analyses of total RNA prepared from the isolated H. pylori strains cultured in vitro. However, a subset of H. pylori RNAs detected in gastric tissue specimens was consistently undetectable in bacteria grown in vitro. The majority of these RNAs encode factors unique to H. pylori that are potentially produced in response to interactions with mammalian gastric mucosa. CONCLUSIONS: The combination of selective capture of transcribed sequences with array hybridization has allowed a global analysis of bacterial gene expression occurring in human tissues during a natural infection.     

幽门螺杆菌感染对胃粘膜超微结构的影响

目的研究幽门螺杆菌（Ｈｐ）感染及其根除前后胃粘膜超微结构的变化．方法Ｈｐ感染患者１０例经三联疗法２８ｄ．Ｈｐ阴转７例于停药１月后及治疗前内镜下取胃窦粘膜，经切片染色后分别行透射电镜及扫描电镜观察．结果透射电镜显示，Ｈｐ聚集处上皮细胞微绒毛变短、减少或消失，细胞呈毛刺状或外突形成分枝状，细胞膜内侧粘液颗粒聚集，细胞破裂，释放粘液颗粒．扫描电镜下Ｈｐ横卧于微绒毛表面或垂直镶嵌在微绒毛里．应用三联疗法（德诺１２０ｍｇ＋四环素０２５ｇ＋呋喃唑酮１０ｍｇ，４次／ｄ）治疗２８ｄ，停药１月后７例Ｈｐ根除．电镜显示Ｈｐ消失，粘膜细胞变性逆转，上皮细胞及微绒毛结构恢复正常．结论Ｈｐ引起的胃粘膜超微结构损害在根除Ｈｐ后有改善及恢复     

Effect of Helicobacter pylori infection on ghrelin expression in human gastric mucosa

OBJECTIVES: One of the counter-effects of Helicobacter pylori eradication therapy is subsequent obesity. Ghrelin is a recently discovered growth hormone releasing peptide. This endogenous secretagogue increases appetite and facilitates fat storage. The majority of circulating ghrelin is produced in the gastric mucosa. Therefore, we aimed at investigating changes in ghrelin immunoreactivity in gastric mucosa tissues of patients infected with H. pylori. METHODS: Sixty-one patients with H. pylori infection (25 cases each of duodenal and gastric ulcer, and 11 cases of gastritis) and 22 healthy controls without H. pylori infection were included in the study. H. pylori-infected patients received standard proton pump-based triple therapy followed by histological examination and (13)C-urea breath test to confirm H. pylori eradication. H. pylori was eradicated in 50 out of 61 patients. Biopsy specimens were obtained from antrum and corpus before and 3 months following eradication. Ghrelin expression was evaluated immunohistochemically with an anti-ghrelin antibody, and the number of ghrelin-positive cells determined per 1 mm(2) of the lamina propria mucosa. RESULTS: There was no relationship between ghrelin immunoreactivity and body weight or body mass index for healthy controls. The number of ghrelin-positive cells was significantly lower for H. pylori-infected patients than for healthy controls. However, the ghrelin-positive cell number increased significantly following H. pylori eradication without significant change in severity of atrophy. CONCLUSIONS: These data indicated that H. pylori infection affected ghrelin expression. After H. pylori eradication, gastric tissue ghrelin concentration increased significantly. This could lead to the increased appetite and weight gain seen following H. pylori eradication.     

Helicobacter pylori infection affects Toll-like receptor 4 expression in human gastric mucosa

BACKGROUND/AIMS: Toll-like receptor 4 (TLR4), which requires a helper molecule, MD-2, is a main receptor for lipopolysaccharide (LPS) from gram-negative bacteria. The expression of TLR4 in H. pylori infection in human gastric mucosa, however, is unclear. The aim of this study was to determine the effect of H. pylori infection on the TLR4 and MD-2 expression in human gastric mucosa. METHODOLOGY: Biopsy samples from the antrum and corpus were obtained from 45 patients (25 patients without H. pylori infection including 5 patients with successful eradication of H. pylori, and 20 patients with H. pylori infection). These samples were used for TLR4, MD-2 mRNA expression study and immunohistochemical study. RESULTS: In patients without H. pylori infection, the expressions of TLR4 and MD-2 were bigger in the corpus mucosa than in the antral mucosa. In patients with H. pylori infection, the expressions of TLR4 and MD-2 significantly increased in the antral and corpus mucosa. Immunohistochemical study revealed similar results as the TLR4 mRNA expression. After the eradication of H. pylori, the expressions of TLR4 and MD-2 were the same levels in both sites as those in patients without H. pylori infection. CONCLUSIONS: The results indicated that H. pylori infection significantly increased TLR4 and MD-2 expressions in the antral and corpus mucosa.     

Expression of TFF2 and Helicobacter pylori infection in carcinogenesis of gastric mucosa

AIM: To investigate the expression of TFF2 and Helicobacter pyloriinfection in carcinogenesis of gastric mucosa.METHODS: The expression of TFF2 was immunohistochemically analyzed in paraffin-embedded samples from 119 patients with endoscopic biopsy and subtotal gastrectomy specimens of gastric mucosal lesions, including 16 cases of chronic superficial gastritis (CSG), 20 chronic atrophic gastritis (CAG),35 intestinal metaplasia (IN), 23 gastric epithelial dysplasia (GED) and 25 gastric carcinoma (CA), and Helicobacter pylori infection was detected by Warthin-Starry staining.RESULTS: 1:TFF2 was located in the cytoplasm of gastrk mucous neck cell. The expression of TFF2 was 100 %,100 %, 0, 56.5 % and 0 in CSGs, CAGs, INs, GEDs and CAs, respectively. 2: The value of TFF2 positive cell density in CSG with Helicobacter pyloriinfection was higher than that without Helicobacter pyloriinfection. (52.89±7.27vs46.49±13.04, P＞0.05); But the value of TFF2 positive cell density in CAG and GED with Helicobacter pyloriinfection was significantly lower than that without Helicobacter pylori infection (18.17±4.09 vs 37.93±13.80, P＜0.01 and 14.44±9.32 vs 24.84±10.22, P＜0.05).CONCLUSION: Increase of TFF2 expression in CSG is perhaps associated with the protective mechanism after gastric mucosal injury. Decrease of TFF2 expression in CAG possibly attributes to the decrease in the number of gastric gland cell expressing TFF2. Re-expression of TFF2 in gastric epithelial dysplasia implies that TFF2 possibly contributes to the initiation of gastric carcinoma. The effect of Helicobacter pylori on the expression of TFF2 depends on the status of gastric mucosa.     

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.     

Gastric mucosa in Mongolian and Japanese patients with gastric cancer and Helicobacter pylori infection

AIM: To investigate the characteristics of gastric cancer and gastric mucosa in a Mongolian populationby comparison with a Japanese population.METHODS: A total of 484 Mongolian patients with gastric cancer were enrolled to study gastric cancer characteristics in Mongolians. In addition, a total of 208 Mongolian and 3205 Japanese consecutive outpatients who underwent endoscopy, had abdominal complaints, no history of gastric operation or Helicobacter pylori eradication treatment, and no use of gastric secretion inhibitors such as histamine H2-receptor antagonists or proton pump inhibitors were enrolled. This study was conducted with the approval of the ethics committees of all hospitals. The triple-site biopsy method was used for the histologic diagnosis of gastritis and H. pylori infection in all Mongolian and Japanese cases. The infection rate of H. pylori and the status of gastric mucosa in H. pylori-infected patients were compared between Mongolian and Japanese subjects. Age(± 5 years), sex, and endoscopic diagnosis were matched between the two countries.RESULTS: Approximately 70% of Mongolian patients with gastric cancer were 50-79 years of age, and approximately half of the cancers were located in the upper part of the stomach. Histologically, 65.7% of early cancers exhibited differentiated adenocarcinoma, where as 73.9 % of advanced can cersdisplayed undifferentiated adenocarcinoma. The infection rate of H. pylori was higher in Mongolian than Japanese patients(75.9% vs 4 8. 3 %, P0.0001). When stratified by age, the prevalence was highest among young patients, and tended to decrease in patients aged 50 years or older. The anti-East-Asian Cag Aspecific antibody was negative in 99.4% of H. pyloripositive Mongolian patients. Chronic inflammation, neutrophil activity, glandular atrophy, and intestinal metaplasia scores were significantly lower in Mongolian compared to Japanese H. pylori-positive patients(P 0.0001), with the exception of the intestinal metaplasia score of specimen from the greater curvature of the upper body. The type of gastritis changed from antrumpredominant gastritis to corpus-predominant gastritis with age in both populations.CONCLUSION: Gastric cancer was located in the upper part of the stomach in half of the Mongolian patients; Mongolian patients were infected with non-East-Asiantype H. pylori.     

Helicobacter pylori infection and gastric cancer

Gastric cancer remains a major health burden on many societies claiming hundreds of thousands of lives every year. The discovery of Helicobacter pylori has no doubt revolutionised our understanding of this malignancy, which is now regarded as a paradigm for infection-induced chronic inflammation-mediated cancer. In this paper, we discuss the evidence for the association between H. pylori and gastric adenocarcinoma and MALT lymphoma. We also discuss the pathogenesis of these two forms of cancer and the factors that determine their outcome. There is no doubt that the knowledge accumulated over the past two decades will be translated into eventual victory over this killer cancer, largely because we now appreciate that the best way to prevent the cancer is by preventing acquisition of the infection in the first place, or by eradicating the infection in infected subjects. Defining the optimal timing of intervention is going to be the challenge facing us over the next two decades.