Pathogenesis Of Peptic Ulcer Disease Research Articles

The Association Between Genes cagA, vacA and iceA of Helicobacter pylori and Peptic Ulcer Diseases in Thailand

Purpose: Helicobacter pylori (H. pylori) infection causes gastric inflammation and gastritis which increase the risk for peptic ulcer disease (PUD). Several genes of H. pylori such as cagA, vacA and iceA genes may play an important role in pathogenesis of this disease. The aim of this study was to examine the prevalence of genes cagA, vacA and iceA of H. pylori in patients with PUD compared with patients with non-ulcer dyspepsia (NUD) and to determine the association of these genes with PUD. Methods: In this study, 40 H. pylori isolates were obtained from PUD patients and 40 isolates from NUD patients. Genes cagA, vacA and iceA of H. pylori were identified by using polymerase chain reaction (PCR) with specific primers. Results: The result of this study demonstrated that cagA positive, vacA s1, m2 and iceA2 genes were found predominantly in H. pylori in Thailand. The presence of either cagA, allelic variant vacA and iceA alone does not have a predictive value as a risk marker for clinical outcome of H. pylori infection. In addition, high prevalence of mixed iceA isolates (48.75%) was found in Thai patients. All of these isolates contained single vacA genotype which suggests the presence of mixed iceA genotype in one strain. From analysis, vacA s1a, mixed iceA genotype was found to be significantly associated with PUD (P = 0.04, OR = 2.51, 95%CI = 1.05–6.04). Conclusions: Genes vacA s1a and mixed iceA genotype may play important roles in the pathogenesis of peptic ulcer disease and might be regarded as marker for predicting peptic ulcer disease in Thailand.

Functional Properties of the p33 and p55 Domains of the Helicobacter pylori Vacuolating Cytotoxin

Helicobacter pylori secretes an 88-kDa vacuolating cytotoxin (VacA) that may contribute to the pathogenesis of peptic ulcer disease and gastric cancer. VacA cytotoxic activity requires assembly of VacA monomers into oligomeric structures, formation of anion-selective membrane channels, and entry of VacA into host cells. In this study, we analyzed the functional properties of recombinant VacA fragments corresponding to two putative VacA domains (designated p33 and p55). Immunoprecipitation experiments indicated that these two domains can interact with each other to form protein complexes. In comparison to the individual VacA domains, a mixture of the p33 and p55 proteins exhibited markedly enhanced binding to the plasma membrane of mammalian cells. Furthermore, internalization of the VacA domains was detected when cells were incubated with the p33/p55 mixture but not when the p33 and p55 proteins were tested individually. Incubation of cells with the p33/p55 mixture resulted in cell vacuolation, whereas the individual domains lacked detectable cytotoxic activity. Interestingly, sequential addition of p55 followed by p33 resulted in VacA internalization and cell vacuolation, whereas sequential addition in the reverse order was ineffective. These results indicate that both the p33 and p55 domains contribute to the binding and internalization of VacA and that both domains are required for vacuolating cytotoxic activity. Reconstitution of toxin activity from two separate domains, as described here for VacA, has rarely been described for pore-forming bacterial toxins, which suggests that VacA is a pore-forming toxin with unique structural properties.

Clustering and Redistribution of Late Endocytic Compartments in Response toHelicobacter pyloriVacuolating Toxin

Helicobacter pylori VacA is a secreted protein toxin that may contribute to the pathogenesis of peptic ulcer disease and gastric adenocarcinoma. When added to cultured mammalian cells in the presence of weak bases (e.g., ammonium chloride), VacA induces the formation of large cytoplasmic vacuoles. Here, we report a previously unrecognized capacity of VacA to induce clustering and perinuclear redistribution of late endocytic compartments. In contrast to VacA-induced cell vacuolation, VacA-induced clustering and redistribution of late endocytic compartments are not dependent on the presence of weak bases and are not inhibited by bafilomycin A1. VacA mutant toxins defective in the capacity to form anion-selective membrane channels fail to cause clustering and redistribution. VacA-induced clusters of late endocytic compartments undergo transformation into vacuoles after the addition of ammonium chloride. VacA-induced clustering and redistribution of late endocytic compartments occur in cells expressing wild-type or constitutively active Rab7, but not in cells expressing dominant-negative mutant Rab7. In VacA-treated cells containing clustered late endocytic compartments, overexpression of dominant-negative Rab7 causes reversion to a nonclustered distribution. Redistribution of late endocytic compartments to the perinuclear region requires a functional microtubule cytoskeleton, whereas clustering of these compartments and vacuole formation do not. These data provide evidence that clustering of late endocytic compartments is a critical mechanistic step in the process of VacA-induced cell vacuolation. We speculate that VacA-induced alterations in late endocytic membrane traffic contribute to the capacity of H. pylori to persistently colonize the human gastric mucosa.

Interactions between p-33 and p-55 Domains of the Helicobacter pylori Vacuolating Cytotoxin (VacA)

The VacA toxin secreted by Helicobacter pylori is considered to be an important virulence factor in the pathogenesis of peptic ulcer disease and gastric cancer. VacA monomers self-assemble into water-soluble oligomeric structures and can form anion-selective membrane channels. The goal of this study was to characterize VacA-VacA interactions that may mediate assembly of VacA monomers into higher order structures. We investigated potential interactions between two domains of VacA (termed p-33 and p-55) by using a yeast two-hybrid system. p-33/p-55 interactions were detected in this system, whereas p-33/p-33 and p-55/p-55 interactions were not detected. Several p-33 proteins containing internal deletion mutations were unable to interact with wild-type p-55 in the yeast two-hybrid system. Introduction of these same deletion mutations into the H. pylori vacA gene resulted in secretion of mutant VacA proteins that failed to assemble into large oligomeric structures and that lacked vacuolating toxic activity for HeLa cells. Additional mapping studies in the yeast two-hybrid system indicated that only the N-terminal portion of the p-55 domain is required for p-33/p-55 interactions. To characterize further p-33/p-55 interactions, we engineered an H. pylori strain that produced a VacA toxin containing an enterokinase cleavage site located between the p-33 and p-55 domains. Enterokinase treatment resulted in complete proteolysis of VacA into p-33 and p-55 domains, which remained physically associated within oligomeric structures and retained vacuolating cytotoxin activity. These results provide evidence that interactions between p-33 and p-55 domains play an important role in VacA assembly into oligomeric structures.

Cellular localization of cholecystokinin receptors as the molecular basis of the periperal regulation of acid secretion.

Gastrin stimulates gastric acid secretion through direct activation of CCK-B/gastrin receptors on parietal cells and indirectly through release of histamine from ECL cells. Cholecystokinin (CCK) is structurally closely related to gastrin and shares high affinity for CCK-B/gastrin receptors. In contrast to gastrin, CCK also recognizes CCK-A receptors. While CCK appears to be a negative regulator of gastric acid secretion and postprandial release of gastrin in the normal human gastrointestinal tract, its impact on the pathogenesis of acid hypersecretion in Helicobacter pylori-infected individuals remains uncertain. This article will review the endocrine and paracrine regulatory pathways which are activated by CCK/gastrin peptides and which appear relevant in the pathogenesis of peptic ulcer disease in man.

The prevalence of H. pylori is still substantial in rheumatic patients

The separate contribution of NSAIDs and H. pylori in the pathogenesis of peptic ulcer disease has not been fully elucidated. The aim of this study was to investigate the seroprevalence of H. pylori in patients with rheumatic diseases and chronic NSAID treatment. Patients with a rheumatic disease, age 40-80 years, and regular use of NSAIDs (at least 3 times a week) were included (n = 1214). IgG-antibodies to H. pylori were found in 39% and increased gradually with age: from 25% in patients in the 40-50 years age group to 48% in patients aged 70-80 years (p < 0.0001). No difference was observed between men and women, or between the three centres. In our population of rheumatic patients treated with NSAIDs the seroprevalence of H. pylori is substantial (39%), but seems to be lower than in previous reports, which may be due to a cohort effect.

Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis

The relation between H pylori infection and use of non-steroidal anti-inflammatory drugs (NSAIDs) in the pathogenesis of peptic-ulcer disease is controversial. We undertook a meta-analysis to address this issue. By computer and manually we sought observational studies on the prevalence of peptic-ulcer disease in adult NSAID takers or the prevalence of H pylori infection and NSAID use in patients with peptic-ulcer bleeding. Summary odds ratios were calculated from the raw data. Tests for homogeneity were done. Of 463 citations identified, 25 studies met inclusion criteria. In 16 studies of 1625 NSAID takers, uncomplicated peptic-ulcer disease was significantly more common in patients positive than in those negative for H pylori (341/817 [41.7%] vs 209/808 [25.9%]; odds ratio 2.12 [95% CI 1.68-2.67]). In five controlled studies, peptic-ulcer disease was significantly more common in NSAID takers (138/385 [35.8%]) than in controls (23/276 [8.3%]), irrespective of H pylori infection. Compared with H pylori negative individuals not taking NSAIDs, the risk of ulcer in H pylori infected NSAID takers was 61.1 (9.98-373). H pylori infection increased the risk of peptic-ulcer disease in NSAID takers 3.53-fold in addition to the risk associated with NSAID use (odds ratio 19.4). Similarly, in the presence of risk of peptic-ulcer disease associated with H pylori infection (18.1), use of NSAIDs increased the risk of peptic-ulcer disease 3.55-fold. H pylori infection and NSAID use increased the risk of ulcer bleeding 1.79-fold and 4.85-fold, respectively. However, the risk of ulcer bleeding increased to 6.13 when both factors were present. Both H pylori infection and NSAID use independently and significantly increase the risk of peptic ulcer and ulcer bleeding. There is synergism for the development of peptic ulcer and ulcer bleeding between H pylori infection and NSAID use. Peptic-ulcer disease is rare in H pylori negative non-NSAID takers.

In search of the Helicobacter pylori VacA mechanism of action

Helicobacter pylori secretes an ~88 kDa VacA toxin that is considered to be an important virulence factor in the pathogenesis of peptic ulcer disease. Over the past decade, research on the molecular mechanisms and biological functions of VacA has generated a complex and often puzzling scenario. VacA is secreted into the extracellular space and also is partially retained on the bacterial cell surface, exists in monomeric and oligomeric forms, and binds to multiple eukaryotic cell-surface receptors. The cellular effects induced by VacA include vacuolation, alteration of endo-lysosomal function, pore formation in the plasma membrane, apoptosis, and epithelial monolayer permeabilisation. VacA has been reported to target several different cell components, including endocytic vesicles, mitochondria, the cytoskeleton, and epithelial cell–cell junctions. It remains unclear whether VacA should be classified as an A/B type toxin, a channel-forming toxin, or both. This review is intended to summarise our current knowledge about VacA, and to orient the reader to this fascinating and challenging research area.

Role of herpes simplex virus type 1 (HSV-1) in the pathogenesis of peptic ulcer disease

Role of herpes simplex virus type 1 (HSV-1) in the pathogenesis of peptic ulcer disease

Role of herpes simplex virus type 1 (HSV-1) in the pathogenesis of peptic ulcer disease

Role of herpes simplex virus type 1 (HSV-1) in the pathogenesis of peptic ulcer disease

Smoking and peptic ulcer in the Helicobacter pylori era.

Before the recent understanding of the central importance of Helicobacter pylori in the pathogenesis of peptic ulcer disease, smoking had been regarded as an important contributor to the cause and perpetuation of the disease. In this review, we find that (1) clinical observations indicate that smokers are more likely to develop ulcers, ulcers in smokers are more difficult to heal, and relapse of ulcer disease is more likely in smokers, (2) smoking adversely affects the gastroduodenal mucosal protective mechanisms, thus predisposing to ulcer disease, (3) smoking adversely affects gastroduodenal motility, allowing reflux of harmful duodenal contents into the stomach, (4) smokers appear to be at higher risk of becoming infected with H. pylori and this increased risk may be due to the adverse effects of smoking on antioxidants or the immune system that may interfere with the normal protection against H. pylori, and (5) once H. pylori is eradicated in smokers, they appear to be at no greater risk of peptic ulcer disease. We conclude that smoking in itself appears not to be an independent ulcerogen, but may act by augmenting the harmful effects of H. pylori, both by adversely affecting upper gastrointestinal mucosal protection and physiology and by increasing the risk of H. pylori infection. Thus, we recommend that appropriate advice to ulcer patients who smoke continues to be: stop smoking.

Modes of adherence of Helicobacter pylori to gastric surface epithelium in gastroduodenal disease: a possible sequence of events leading to internalisation.

We have investigated various modes of adherence of Helicobacter pylori to the human gastric epithelium, using transmission electron microscopy, in biopsies from nine patients with peptic ulcer disease and from four patients with chronic active gastritis. H. pylori was demonstrated in abundance in all cases within the surface mucous layer. In all ulcer- and in one out of four gastritis patients H. pylori was shown in close proximity to the gastric epithelium, with concurrent alterations in the configuration of microvilli and the apical cytoplasmic region of gastric cells. Previously described modes of H. pylori adherence were confirmed, such as loose attachment with fibrillar-like strands, firm attachment with pedestal formation, invasion in the intercellular spaces, and invagination with "cup" formation. Moreover, in many cases a fusion between the bacterial outer layer and gastric cell membranes was evident. In four cases (31%; three with active and one with past ulcer disease) viable H. pylori was found in the cytoplasm of gastric mucous cells. Our results support the hypothesis that the different modes of adherence of H. pylori represent a stepwise, possibly sequential, process which in a significant number of cases leads to internalisation of the organism. The invariable occurrence of adhesion and more frequent internalisation of H. pylori in ulcer patients may suggest a link with the pathogenesis of peptic ulcer disease.

Test and treat strategies for Helicobacter pylori in uninvestigated dyspepsia: a Canadian economic analysis.

Recognition of the pivotal role of Helicobacter pylori in the pathogenesis of peptic ulcer disease has revolutionized primary care approaches to dyspepsia. Decision analysis was used to compare the cost effectiveness of empirical ranitidine with a test and treat strategy using either H pylori serology or the 13carbon-urea breath test (13C-UBT). A cohort of patients under age 50 years presenting with uninvestigated dyspepsia was evaluated. Three initial strategies were compared with respect to direct medical costs and effectiveness in curing H pylori-related ulcers - empirical ranitidine, H pylori serology and UBT. A one-year time horizon and third-party payer perspective were adopted in a Canadian health care setting. UBT was more costly than either serology or ranitidine but was the most effective strategy and required the fewest endoscopies. No strategy demonstrated dominance over another in the base case. The incremental cost effectiveness ratio (ICER) of serology versus ranitidine was $118/cure, and sensitivity analysis induced dominance of serology in several plausible scenarios. The baseline ICER of UBT versus serology was $885/cure but showed substantial variation in sensitivity analysis. Each ICER was highly sensitive to variation in the cost of the tests themselves. At a serology cost of $25, UBT became dominant when its cost fell to $39. In low risk patients with uninvestigated dyspepsia, testing for H pylori using serology appears to be economically attractive. 13C-UBT may be a cost effective alternative to serology if local conditions closely approximate the model parameters. Future changes in the costs of serology and 13C-UBT may determine the optimal approach.

Altered gastrin regulation in mice infected with Helicobacter felis.

Altered gastrin expression associated with Helicobacter pylori infection may contribute to the pathogenesis of peptic ulcer disease or gastric cancer in man, but gastrin has not been investigated in a murine model of Helicobacter infection. C57BL/6 mice were inoculated with Helicobacter felis and examined after 4-21 weeks for G and D cell numbers, antral gastrin and somatostatin mRNA, and luminal pH. In H. felis-infected mice, gastrin mRNA declined at four and six weeks after infection to 57% and 23%, respectively, of uninfected control values. Concurrently, somatostatin mRNA showed no change at four weeks and a modest 25% decrease at six weeks after infection. Similar reductions were noted in G and D cell numbers, resulting in a decrease in the G/D cell ratio after mice were infected with H. felis. Infected animals also showed a loss of parietal and chief cells, and an increased gastric pH. H. felis infection in C57BL/6 mice leads to an early suppression of G cell number and gastrin mRNA. These changes precede an alteration in somatostatin cell number and mRNA and, coupled with reductions in parietal and chief cells, may contribute both to severe impairment of gastric acid output and the potential for carcinogenic processes.

PACAP upsets stomach theory.

PACAP upsets stomach theory.

Long-term follow-up of duodenal ulcer in children before and after eradication of Helicobacter pylori.

Helicobacter pylori is a well-known cause of chronic antral gastritis and plays an important role in the pathogenesis of peptic ulcer disease in adults. However, because of the relatively low incidence of duodenal ulcer in childhood, few studies have been directed specifically at the relation between the treatment of H. pylori infection and duodenal ulcer in children. An evaluation in a larger patient population is necessary to draw a conclusion. Twenty-six children with duodenal ulcer and H. pylori antral gastritis received triple therapy (amoxicillin, bismuth, and metronidazole) to investigate whether eradication of the organisms can promote healing and prevent relapse of the ulcers in children. Endoscopic examinations were performed before, 2 months, and 12 months after the beginning of treatment. H. pylori infection was eradicated in 25 (96%) of the 26 patients who underwent upper endoscopic follow-up. Clinical improvement and ulcer healing were achieved in 24 (92%) of 26 children. During a mean follow-up of nearly 2 years, the annual ulcer relapse rate was estimated to be 9%. Triple therapy is the treatment of choice for endoscopically proven duodenal ulcer and histologically proven H. pylori antral gastritis in children. It strongly supports a causal relation between H. pylori and duodenal ulcer disease in children.

Dyspepsia and Helicobacter Pylori Infection: Analysis of 200 Kuwaiti Patients Referred for Endoscopy

Dyspepsia is a very common symptom, and is the reason for most referrals for esophagogastroduodenoscopy (EGD). Peptic ulcer disease (PUD), gastroesophageal reflux and gastric cancer account for a minority of such patients. However, the majority have no significant endoscopic abnormalities (non-ulcer dyspepsia). Recently, infection with Helicobacter pylori (HP) has been implicated in the pathogenesis of PUD and gastric cancer. Since HP can be diagnosed by noninvasive techniques, it has been suggested that endoscopy should be restricted to HP-positive patients who do not respond to empirical therapy with antimicrobials. The aim of this study was to establish the prevalence of HP among Kuwaiti dyspeptic patients referred for endoscopy and to determine whether demographic and clinical screening, or the presence of HP, can help distinguish groups of patients with significant gastroduodenal pathology from those with non-ulcer dyspepsia. Two hundred randomly selected Kuwaiti patients referred for endoscopy were evaluated prospectively. A detailed personal interview was conducted to establish the demographic and clinical profile of each patient and a diagnostic EGD was performed after the interview. Finally, antral mucosal biopsies were taken to determine the presence of HP. The pre-coded data were analyzed. The main endoscopic findings were normal (32%), non-erosive antral gastritis (26%), duodenitis (17.5%), duodenal ulcer (11.5%), deformed bulb (4%), esophagitis (7%), and erosive gastritis (2%). The demographic and clinical characteristics of patients did not correlate with endoscopic findings. The overall prevalence of HP infection was 88.5%. There were no statistically significant differences in the prevalence of HP among patients with various endoscopic findings. HP infection is common in Kuwaiti dyspeptic patients referred for endoscopy, irrespective of their demographic and clinical features or the underlying cause of dyspepsia. Noninvasive methods to detect HP are not valid alternatives to endoscopy in the work-up of dyspeptic patients.

Histamine-induced gastric acid secretion in horses

Abstract Objective To determine gastric secretory responses in horses treated with histamine and to determine the dose of histamine needed to elicit maximal gastric secretion. Animals 6 adult horses with an indwelling gastric cannula. Procedure Gastric contents were collected in 15-minute periods, and volume, pH, hydrogen ion concentration, hydrogen ion output, sodium concentration, and sodium output were determined. Values were determined without any treatment (baseline), after administration of pyrilamine maleate (1 mg/kg of body weight, IV, given during a 15-minute period), and during 1-hour infusions of histamine at 3 rates (7.5, 15, and 30 μg/kg/h, IV). Results Volume and hydrogen ion concentration of gastric contents and hydrogen ion output were significantly increased, compared with baseline values, during histamine infusion. Mean hydrogen ion concentration and hydrogen ion output were significantly greater during infusion of histamine at a rate of 15 or 30 μg/kg/h than at a rate of 7.5 μg/kg/h. Sodium concentration was significantly decreased, compared with baseline value, during histamine infusion, but sodium output was unchanged. Conclusions Histamine at doses of 15 and 30 μg/kg/h, IV stimulated maximal gastric secretion in horses. Histamine appeared to induce only parietal secretion. Clinical Relevance This study provides additional information related to equine gastric physiology, which may benefit further understanding of the pathogenesis of peptic ulcer disease. (Am J Vet Res 1998;59:1303–1306)

The relationship between helicobacter infection and peptic ulcer disease

Helicobacter pylori infection of gastric mucosa is widespread, causing asymptomatic superficial gastritis; however, symptomatic disease in the form of duodenal and gastric ulcers is present only in a small proportion of infected individuals. H pylori causes most of the peptic ulcer disease that is not associated with nonsteroidal anti-inflammatory drug use or gastrinoma. The best evidence for H pylori causing peptic ulcer disease is the reduction of recurrence of this disease with eradication of the organism. The pathogenesis of peptic ulcer disease from initial H pylori infection is not yet completely understood. Diagnosis of H pylori infection in peptic ulcer disease can be made with invasive (endoscopic) and noninvasive (serologic or breath test) testing. Treatment for patients with peptic ulcers due to H pylori is recommended after the diagnosis is established. Triple antimicrobial therapy for two weeks is the best investigated regimen, but two drug therapies that combine a proton pump inhibitor and an antibiotic or antibiotics are available as alternatives.

Managing dyspepsia: what do we know and what do we need to know?

Objective: The conceptual revolution concerning the role of Helicobacter pylori in the pathogenesis of peptic ulcer disease has raised the larger question of how to integrate this new information into the management of patients with dyspepsia. The aim of this research was to critically evaluate current knowledge about dyspepsia and its management. Methods: Relevant articles on dyspepsia were identified from MEDLINE searches and from the bibliographies of identified articles. Studies that contained information on the prevalence of dyspepsia, endoscopic findings, and evaluations of alternative management strategies were reviewed. Results: By coupling H. pylori serological testing with clinical factors such as age and nonsteroidal antiinflammatory drug use, strategies have been developed that identify patients with organic disease. Although the use of these strategies can reduce the volume of endoscopies, their effects on dyspepsia symptoms are unknown. Computerized decision analysis models have been used to evaluate the cost-effectiveness of alternative strategies. The indirect evidence obtained from these models suggests that empiric therapy, guided by H. pylori testing, may be the preferred approach. However, the models have been hampered by the lack of information concerning dyspepsia symptoms, the primary health outcome of the majority of patients seen in primary practice settings. Conclusions: Currently, the knowledge needed to integrate H. pylori tests and antimicrobial therapies into the management of patients with dyspepsia in primary practice settings has not been developed. A pressing need exists for a randomized controlled trial to evaluate alternative management strategies. In conducting such a trial, valid, reliable instruments for measuring dyspepsia will be needed.