NSAIDs, Helicobacter pylori, and Pandora's Box.
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Anti-Inflammatory Agents, Non-Steroidal↗
Biomedical subjects
David Y Graham
Publications and source records attributed to David Y Graham.
Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events.
BACKGROUND: In spite of the clear evidence of benefit of aspirin in the secondary prevention of cerebrovascular and cardiovascular thrombotic events, its use in patients at high risk due to a previous event remains suboptimal. A possible explanation for this underuse is concern regarding the relative benefit in relation to the potential risk for serious gastrointestinal events. OBJECTIVE: To compare the benefit and gastrointestinal risk of aspirin use for the secondary prevention of thromboembolic events. DESIGN: A meta-analysis was conducted using 6 trials (6300 patients) meeting the inclusion requirement of use of low-dose aspirin (< or =325 mg/d) in approved secondary prevention indications. RESULTS: Aspirin reduced all-cause mortality by 18%. In addition, aspirin use reduced the number of strokes by 20%, myocardial infarctions by 30%, and other "vascular events" by 30%. Alternately, patients who took aspirin were 2.5 times more likely than those in the placebo group to have gastrointestinal tract bleeding. The number needed to treat for aspirin to prevent 1 death from any cause of mortality was 67, while 100 needed to be treated to detect 1 nonfatal gastrointestinal tract bleeding. CONCLUSION: Aspirin use for the secondary prevention of thromboembolic events has a favorable benefit-to-risk profile and should be encouraged in those at high risk.
Aspirin↗
Prevention of complicated ulcer disease among chronic users of nonsteroidal anti-inflammatory drugs: the use of a nomogram in cost-effectiveness analysis.
BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of clinical upper gastrointestinal tract (UGI) events, namely, symptomatic ulcer, perforation, bleeding, and obstruction. Our objective in this study was to compare the cost-effectiveness of several strategies aimed at reducing the risk of clinical UGI events in NSAID users. METHODS: A decision tree model was used for patients requiring long-term treatment with NSAIDs to compare conventional NSAID therapy alone with 7 other treatment strategies to reduce the risk of NSAID-related clinical UGI events (cotherapy with proton-pump inhibitor, cotherapy with misoprostol, cyclooxygenase [COX]-2-selective NSAID therapy, or Helicobacter pylori treatment followed by each of the previous strategies, including conventional NSAID treatment, respectively). The outcome measure is the incremental cost per clinical UGI event prevented compared with conventional NSAID treatment over 1 year. RESULTS: The use of a COX-2-selective NSAID and cotherapy with proton-pump inhibitors were the 2 most cost-effective strategies. However, the incremental cost associated with these strategies was high (>$35 000) in persons with a low risk of clinical UGI event with conventional NSAIDs (eg, 2.5% per year). If the baseline risk of clinical UGI events is moderately high (eg, 6.5%), using a COX-2-selective NSAID becomes the most effective and least costly (dominant) treatment strategy, followed closely by cotherapy with a daily proton-pump inhibitor. Because small changes in costs or assumed efficacy of these drugs could change the conclusions, the incremental cost-effectiveness ratios between any 2 strategies were presented in a nomogram that allows the flexible use of a wide range of values for costs and rates of clinical UGI events. CONCLUSIONS: The risk of clinical UGI events in NSAID users depends on their baseline risk, the added risk associated with the individual NSAID, and the protection conferred by cotherapy. A nomogram can be used to incorporate these factors and derive estimates regarding cost-effectiveness of competing strategies aimed at reducing the risk of clinical UGI events.
Anti-Inflammatory Agents, Non-Steroidal↗
Cross-reactivity of anti-CagA antibodies with vascular wall antigens: possible pathogenic link between Helicobacter pylori infection and atherosclerosis.
BACKGROUND: Helicobacter pylori-CagA positive strains have been shown to be associated with atherosclerosis. However, the pathogenesis is still undetermined. The aim of this study was to determine whether anti-CagA antibodies cross-react with antigens of normal and atherosclerotic arteries. METHODS AND RESULTS: Eight umbilical cord sections, 14 atherosclerotic artery sections, and 10 gastrointestinal tract sections were examined by immunohistochemistry using polyclonal anti-CagA antibodies. Five atherosclerotic and 3 normal artery samples were also lysed in ice-cold lysis buffer containing protease inhibitors and were immunoprecipitated using the same antibodies. Anti-CagA antibodies reacted with cytoplasm and nuclei of smooth muscle cells in umbilical cord and atherosclerotic vessel sections, cytoplasm of fibroblasts-like cells in intimal atherosclerotic plaques, and the cell membranes of endothelial cells. Anti-CagA antibodies also specifically immunoprecipitated 2 high molecular weight antigens of 160 and 180 kDa from both normal and atherosclerotic artery lysates. CONCLUSIONS: Anti-CagA antibodies cross-react with antigens of both normal and atherosclerotic blood vessels. We speculate that the binding of anti-CagA antibodies to those antigens in injured arteries could influence the progression of atherosclerosis in CagA-positive H pylori-infected patients.
Antibodies, Bacterial↗
Risk Factors Associated with Helicobacter pylori Infection among Children in a Defined Geographic Area.
Factors influencing the pattern of Helicobacter pylori infection among children living in adjacent urban and rural areas of northern Sardinia, Italy, were compared. The seroprevalence of H. pylori infection was 22% (625 of 2810 children) in the study population and was significantly higher among children in rural areas (37%) than in urban areas (13%) (odds ratio [OR], 3.8; 95% confidence interval [CI], 3.2-4.7; P<.005). This difference was consistent within each age group. In rural areas, children who had dogs were at greatest risk for H. pylori infection (OR, 1.8; 95% CI, 1.3-2.6; P<.05). No association was seen between H. pylori seropositivity and a history of breast-feeding. Urban children attending day care centers had a higher prevalence of infection (17%) than did those who never attended (12%) (OR, 1.5; 95% CI, 1.1-2.0; P<.05). The epidemiology of H. pylori infection is complex; even within the same geographic area, different factors influence acquisition of H. pylori infection.
Adolescent↗
Helicobacter pylori in North and South America before Columbus.
We present a molecular epidemiologic study, based on an analysis of vacA, cagA and cag right end junction genotypes from 1042 Helicobacter pylori isolates, suggesting that H. pylori was present in the New World before Columbus. Eight Native Colombian and Alaskan strains possessed novel vacA and/or cagA gene structures and were more closely related to East Asian than to non-Asian H. pylori. Some Native Alaskan strains appear to have originated in Central Asia and to have arrived after strains found in South America suggesting that H. pylori crossed the Bering Strait from Asia to the New World at different times.
Americas↗
Norwalk virus infection and disease is associated with ABO histo-blood group type.
Some people are resistant to Norwalk virus (NV) infection; however, the factor(s) responsible for resistance or susceptibility to NV infection has not been identified. This study investigated the relationship between a person's ABO histo-blood group type and the risk of NV infection and symptomatic disease after clinical challenge. ABO phenotypes were identified by using serum samples from volunteers who participated in an NV challenge study (n=51). Individuals with an O phenotype were more likely to be infected with NV (odds ratio [OR], 11.8; 95% confidence interval [CI], 1.3-103), whereas persons with a B histo-blood group antigen had decreased risk of infection (OR, 0.096; 95% CI, 0.16-0.56) and symptomatic disease (OR, 0; 95% CI, 0-0.999). This is the first report demonstrating an association between a genetic factor and the risk of NV infection and symptomatic disease.
ABO Blood-Group System↗
Age at acquisition of Helicobacter pylori infection: a follow-up study from infancy to adulthood.
BACKGROUND: Helicobacter pylori infection is common worldwide, but the time of acquisition is unclear. We investigated this issue in a cohort of children selected retrospectively from a population followed up for 21 years. METHODS: We monitored 224 children (99 black, 125 white; 110 male, 114 female) from 1975-76 (ages 1-3 years) to 1995-96. H pylori status was assessed by presence of serum IgG antibodies. FINDINGS: 18 (8.0%) children at age 1-3 years had H pylori antibodies (13% black vs 4% white children, p=0.008). By age 18-23 years, the prevalence of the infection was 24.5% (43% black vs 8% white participants, p< 0.0001). Of the 206 children not infected at baseline, 40 (19%) became infected by age 21-23. The crude incidence rate per year was 1.4% for the whole cohort, ranging from 2.1% at 4-5 years and 1.5% at age 7-9 years to 0.3% at 21-23 years. The seroconversion rate was higher among black than among white children (relative risk 3.3, 95% CI 1.8-6.2, p=0.001). The median age for seroconversion was 7.5 years for both races. Nine of the 58 seropositive children cleared the infection during follow-up. The rate of seroreversion per year was 1.1%; it was highest among children at age 4-5 years (2.2% vs 0.2% at ages 18-19). INTERPRETATION: Most newly acquired H pylori infections happened before age 10 years. Treatment and preventive strategies should be aimed at children in this age-group.
Adult↗
Patterns of gastric atrophy in intestinal type gastric carcinoma.
BACKGROUND: Multifocal atrophic gastritis (MAG) is currently considered a precancerous lesion leading to intestinal type gastric carcinoma. The current study aimed to describe the topography of atrophy in stomachs with early gastric carcinoma. METHODS: Resected stomachs from patients with intestinal type gastric carcinoma were routinely processed, sectioned (an average of 108 sections/stomach), and stained with a triple stain. Sections were scored on a visual analog scale for Helicobacter pylori and intestinal metaplasia. The type of epithelium (antral, oxyntic, transitional) was recorded. Atrophy was defined as the loss of normal glandular components and included intestinal metaplasia and/or pseudo-pyloric metaplasia of the corpus. Pseudo-pyloric metaplasia was identified by the presence of pepsinogen I in mucosa that was topographically corpus but phenotypically antrum. RESULTS: Sixteen stomachs with intestinal type gastric carcinoma were examined. In none of the specimens examined was MAG (independent foci of atrophy) identified. In the majority (88%), atrophy was present as a continuous sheet. Islands of intestinal metaplasia (multifocal intestinal metaplasia) were present within a sheet of pseudo-pyloric metaplasia. A few specimens (12%) had a non-atrophic corpus with almost total replacement of antral epithelium with intestinal metaplasia. Multifocal dysplasia distant from the original tumor was found both in areas with and without intestinal metaplasia. CONCLUSIONS: Contrary to popular belief, atrophy in intestinal type gastric carcinoma is not present as independent foci, but rather as a continuous sheet. Previous studies failed to identify pseudo-pylori metaplasia as a marker for atrophy.
Aged↗
Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo-controlled study of misoprostol vs lansoprazole.
BACKGROUND: Studies that report prevention of ulcer recurrence among long-term users of nonsteroidal anti-inflammatory drugs (NSAIDs) that do not stratify for Helicobacter pylori status may not be generalizable to the large population of individuals without H pylori. METHODS: This was a prospective, double-blind, multicenter, active- and placebo-controlled study among 537 patients without H pylori who were long-term users of NSAIDs and who had a history of endoscopically documented gastric ulcer. Patients were randomized to receive placebo, 200 microg of misoprostol 4 times a day, or 15 or 30 mg of lansoprazole once daily for 12 weeks. Ulcer status was determined by endoscopy at 4, 8, and 12 weeks. RESULTS: Patients receiving lansoprazole (15 or 30 mg) remained free from gastric ulcer longer than those who received placebo (P<.001) but for a shorter time than those who received misoprostol. By week 12, the percentages of gastric ulcer-free patients were as follows: placebo, 51% (95% confidence interval [CI], 41.1%-61.3%); misoprostol, 93% (95% CI, 87.2%-97.9%); 15-mg lansoprazole, 80% (95% CI, 72.5%-87.3%); and 30-mg lansoprazole, 82% (95% CI, 75.0%-89.6%). A significantly higher proportion of patients in the misoprostol group reported treatment-related adverse events and early withdrawal from the study. When the impact of withdrawals on ulcer development was considered (as failures), therapy was successful for 69% for each of the active treatment groups and 35% for the placebo group. CONCLUSIONS: Proton pump inhibitors such as lansoprazole are superior to placebo for the prevention of NSAID-induced gastric ulcers but not superior to misoprostol, 800 microg/d. When the poor compliance and potential adverse effects associated with misoprostol are considered, proton pump inhibitors and full-dose misoprostol are clinically equivalent.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Pathogenesis and therapy of gastric and duodenal ulcer disease.
Despite the decreasing frequency of Helicobacter pylori-induced peptic ulcers, peptic ulcer disease remains a major clinical problem partly because nonsteroidal anti-inflammatory drug ulcers have increased in frequency. The reduction in nonsteroidal anti-inflammatory drug ulcers by use of selective cyclooxygenase-2 inhibitors will not eliminate the problem because of increased use of aspirin for cardiovascular prophylaxis. This article reviews current concepts of peptic ulcer pathogenesis and therapy according to ulcer etiology; discusses potential interactions between etiologies; and considers the therapy for H pylori infection including the effects of antimicrobial resistance, and the role of bismuth quadruple therapy or furazolidone salvage therapy.
Anti-Inflammatory Agents, Non-Steroidal↗
Role of Helicobacter pylori in gastric carcinogenesis.
Peptic ulcers and gastric malignancies are the two major complication of the course of Helicobacter pylori-associated chronic gastritis. Both gastric adenocarcinomas and MALT lymphomas occur in association with H. pylori infection, and studies support an etiological association. This article discusses the natural history of H. pylori-related gastric carcinogenesis and criteria to identify people susceptible to H. pylori infection-associated gastric cancer. It then reviews the molecular and genetic mechanisms underlying the malignant transformation of the gastric mucosa associated with H. pylori.
Adenocarcinoma↗
NSAID gastric ulceration: predictive value of gastric pH, mucosal density of polymorphonuclear leukocytes, or levels of IL-8 or nitrite.
NSAID use and Helicobacter pylori both cause damage to the gastric mucosa and can cause peptic ulcers. Our aim was to test the relationship between gastric mucosal polymorphonuclear leukocyte (PMN) infiltration and the severity of NSAID-induced gastric injury. H. pylori density, mucosal interleukin-8 (IL-8), and nitrite levels were assessed after receiving placebo and again after receiving 1000 mg of naproxen daily for three days. Histology was graded using a visual analog scale (0-5). IL-8 levels were assayed by ELISA and nitrite levels by Griess reaction. Eleven healthy volunteers with H. pylori infection entered. All had normal-appearing gastric mucosa after placebo. Postnaproxen gastric damage included three with none, one with mild, three with moderate, two with severe, and three were very severe mucosal injury (including one with an ulcer >5 mm). There was an inverse correlation between endoscopic score and the pH of the gastric juice post-therapy (R = -0.77, P = 0.004). There was no significant change in histologic or biochemical parameters from pretreatment levels. And none of the parameters (eg, PMN density) predicted endoscopic outcome. In conclusion, there was no relation between mucosal PMN density and endoscopic mucosa injury. PMN infiltration, while not predictive, may be a surrogate for an H. pylori infection-related increased risk of NSAID ulcers.
Adult↗
Helicobacter infection in patients with HCV-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma.
Chronic hepatitis may progress to cirrhosis and hepatocellular carcinoma (HCC). HCC represents one of the most common human cancers. Incidence rates for this tumor vary widely on a worldwide, suggesting that environmental factors such as infectious microorganisms, carcinogens, or nutrition play a role in its pathogenesis. Several Helicobacter spp. colonize the liver of animals and induce hepatitis. The aim of this study was to determine whether Helicobacter infection was associated with HCV-related liver diseases in humans. Liver tissue samples, including biopsy and surgically excised tissues, were collected from patients positive for hepatitis C viruses (HCV) RNA in the serum. Genomic DNA was extracted from sections of formalin-fixed paraffin-embedded tissues by using the QIAamp Tissue Kit and subjected to polymerase chain reaction (PCR) analysis using two sets of Helicobacter-specific 16S ribosomal RNA primers. To identify positive samples for H. pylori, a set of primers specific for a conserved region in the H. pylori vacA gene were also used. The patients' H. pylori status was determined by ELISA. Forty-one patients (mean age 54.9, range 19-78 years; 24 men) were studied. Thirty patients had chronic viral hepatitis (CH) without (N = 18) or with (N = 12) cirrhosis (CIR), and 11 patients had HCC. Anti-H. pylori IgG was detected in 54%. The expected 422- and 210-bp fragments of Helicobacter 16S rRNA were amplified from 27% of liver samples, including 17% of CH-CIR and 55% of HCC (P = 0.004). The vacA sequence was amplified in 10 of 41(24%) samples (27% of those with HCC). These data confirm the presence of H. pylori DNA sequences in human liver and suggest an association of Helicobacter spp. with HCV-related chronic liver diseases. Further studies are needed to ascertain whether Helicobacter spp. infection plays a role in the development of HCC.
Adult↗
What the gastroenterologist should know about the gastrointestinal safety profiles of bisphosphonates.
Bisphosphonates are widely prescribed to treat Paget's disease of the bone and to prevent and treat osteoporosis. Soon after the release of alendronate, esophagitis and esophageal strictures were encountered, resulting in labeling changes. Subsequent endoscopic studies in normal subjects showed that alendronate also caused gastric erosions and ulcers. Although the clinical significance of these is still uncertain, the anatomic distribution of both the gastric ulcers and esophageal damage is consistent with a topical irritant effect. Recent data also suggest a synergistic ulcerogenic potential of concurrent alendronate and NSAID use. A 70-mg once-weekly dosage form of alendronate has recently been approved and clinical experience with its gastrointestinal tolerability is ongoing. Risedronate, a third-generation bisphosphonate, appears to have less ulcerogenic potential than alendronate, and esophageal stricture has not been reported. Experience with the bisphosphonates provide a paradigm for the critical role of endoscopists in evaluating the gastrointestinal profile of new drugs. As bisphosphonates are more widely prescribed and more types of bisphosphonates are developed, the role of the gastroenterologist is likely to assume even more importance.
Alendronate↗
Genomic fingerprinting and genotyping of Helicobacter pylori strains from patients with duodenal ulcer or gastric cancer from different geographic regions.
Continuing attempts have been made to classify pathogenic strains within bacterial populations based on DNA fingerprints and to identify virulence factors in H. pylori. We studied 287 H. pylori isolates from patients with duodenal ulcer or gastric cancer from three different geographic regions. DNA fingerprints were generated using REP-PCR and analyzed by cluster analysis. The status of three candidate virulence factors-vacA polymorphism, cagA and iceA,-were examined by PCR amplification. Cluster analysis of the REP-PCR fingerprints showed clustering by geographic region but not by disease presentation. cagA was detected in 91.3% of the isolates. Differences in vacA subtypes were observed among the three geographic regions. There was no association between iceA subtypes and clinical outcome. We conclude that geographic differences among the H. pylori strains exist in single gene allelic variants as well as in the conserved noncoding regions such as REP sequences throughout the entire bacterial genome. We did not detect any association between disease presentation and H. pylori genotypes using either DNA fingerprinting or candidate single gene virulence factors.
Antigens, Bacterial↗
Critical effect of Helicobacter pylori infection on the effectiveness of omeprazole for prevention of gastric or duodenal ulcers among chronic NSAID users.
BACKGROUND: The recently reported OMNIUM and ASTRONAUT NSAID ulcer prevention trials using omeprazole to prevent endoscopic ulcer recurrence among chronic NSAID users suggested superiority over misoprostol or ranitidine. AIM: To test the hypothesis the results from the OMNIUM and ASTRONAUT studies would not be generalizible as ulcer healing and ulcer recurrence would differ in relation to Helicobacter pylori status. METHODS: The data regarding H. pylori status were made available by AstraZenca allowing separate analysis of the outcome of those with NSAID ulcers (i.e. without H. pylori infection) and those NSAID use was complicated with the presence of an active H. pylori infection. RESULTS: Reanalysis confirmed that omeprazole was superior to placebo for the prevention of ulcer recurrence in chronic NSAID users. However, overall omeprazole was not significantly better than the subtherapeutic dose (400 microg/day) of misoprostol (14.5% vs. 19.6%, respectively, p =.93); 400 microg of misoprostol was actually superior to omeprazole for the prevention of gastric ulcers among those NSAID ulcers (8.2% vs. 16.6% for misoprostol and omeprazole, respectively; p <.05). Omeprazole was also not statistically different from misoprostol for gastric ulcer prevention in those whose NSAID use was complicated by an active H. pylori infection. Omeprazole was not significantly different from 300 mg of ranitidine for the prevention of NSAID gastric ulcers (14.6% vs. 11.6%, respectively, p =.56). Duodenal ulcers were over represented among H. pylori infected NSAID users and duodenal ulcer prevention was more sensitive to acid suppression than gastric ulcer. CONCLUSION: The OMNIUM and ASTRONAUT trials may have provided an unrealistic sense of security regarding the effectiveness of omeprazole for protection against ulcer recurrence in chronic NSAID users.
Anti-Inflammatory Agents, Non-Steroidal↗
Helicobacter pylori strain and the pattern of gastritis among first-degree relatives of patients with gastric carcinoma.
BACKGROUND: Relatives of gastric cancer patients have an increased risk of gastric cancer, possibly related to genetically-related strains of Helicobacter pylori or a common environment. METHODS: The pattern of gastritis and H. pylori from gastric cancer patients and their first-degree relatives were compared using detailed DNA fingerprints and vacA, cagA, and iceA genotyping. RESULTS: Sixteen index cases from Korea, the US, or Colombia and their 38 first-degree relatives (brothers, sisters, sons and daughters) were studied. No definite, or consistent, relationship between the pattern of gastritis and the relatedness of the H. pylori strain was observed (i.e. relatives could have an identical or a totally different pattern of gastritis regardless if they were infected with identical or highly similar organisms). For example, three elderly siblings of an index case with atrophic pangastritis had identical H. pylori isolates and environments in childhood and yet two had antral predominant nonatrophic gastritis, which is typically associated with duodenal ulcer instead of gastric cancer. CONCLUSIONS: The results of this study are not consistent with the hypothesis that specific virulence factors or similar H. pylori strains correlate with a specific histologic pattern or outcome even among those sharing the same environment in childhood.
Adult↗