No inverse link found between H. pylori and gastroesophageal reflux disease

Helicobacter pylori was found to have a strong inverse link with Barrett’s esophagus, but not with symptoms of gastroesophageal reflux disease. Erosive esophagitis also was seen to trend toward an inverse association with H. pylori.

Previous reports have attributed a protective effect against gastroesophageal reflux disease (GERD), esophageal adenocarcinoma, and Barrett’s esophagus to H. pylori infection, particularly the cytotoxin-associated gene A (cagA+) strain. Having determined the studies associating H. pylori with GERD either yielded weak support for an inverse relationship, were prone to bias, or were otherwise flawed, a team led by Dr. Joel Rubenstein of the Veterans Affairs Center for Clinical Management Research, Washington, and the University of Michigan Medical School in Ann Arbor analyzed the associations of the three disease outcomes occurring in the same populations with the bacterium.

They constructed a case-control study of men between the ages of 50 and 79 years (n = 533), who had colorectal cancer screening at one of two tertiary medical centers in Michigan between 2008 and 2011, and who were recruited to have upper endoscopy. The study served as a secondary analysis of the Newly Diagnosed Barrett’s Esophagus Study, and included three non–mutually exclusive case groups: Barrett’s esophagus, erosive esophagitis, and GERD symptoms. An additional group of men in the same age group (n = 80) found to have Barrett’s esophagus during clinically indicated upper endoscopy exams was also assessed.

Using logistic regression, the investigators estimated any associations between serum antibodies against H. pylori and cagA+ in the study group, and GERD symptoms, esophagitis, and Barrett’s esophagus. These results were compared with a control group of randomly selected men (n = 177) who did not have any of the three conditions and who were having colorectal screens.

Women were not studied, because of their typically low rates of Barrett’s esophagus. Also excluded were men with any history of upper endoscopy, Barrett’s esophagus, or esophagectomy; diagnostic indication for colonoscopy; inflammatory* bowel disease; known ascites or esophageal varices; any cancers other than melanoma in the previous 5 years; or notable coagulopathy.

The study did include consecutive men between the ages of 50 and 79 years, newly diagnosed at either of the two study sites with Barrett’s esophagus by way of a clinically indicated upper endoscopy.

To determine the presence of GERD, the study group was given a survey that was not formally validated, about their use of proton pump inhibitors (PPI) and histamine₂ receptor agonists (HR₂A) in relation to the frequency they experienced heartburn and regurgitation. Patients who reported weekly heartburn and regurgitation while not using medication were considered to have GERD. A validated survey, the Mayo Clinic’s Gastroesophageal Reflux Questionnaire (GERQ), was applied during the last quarter of the study, although because the GERQ does not address the role of acid-reducing medications, the investigators wrote that there is the chance that patients with GERD managed by medication could have been misclassified by the questionnaire as non-GERD controls.

The study group also underwent colonoscopy, followed by upper endoscopy. If Barrett’s esophagus was suspected, biopsies were obtained. Using the Los Angeles Classification scheme, if class C or D esophagitis was found, patients repeated the endoscopy while taking a PPI before investigators determined if the patient had Barrett’s esophagus. Patients who were not taking any acid-reducing medications at the time of the endoscopy who reported at least weekly symptoms of GERD and had a normal endoscopy without erosive esophagitis or Barrett’s esophagus were considered to have nonerosive reflux symptoms. Patients with Barrett’s esophagus identified on a clinically indicated upper endoscopy were included with the same as those identified among the the people screened for colorectal cancer. Blood samples were drawn from all subjects and assayed for H. pylori.

The results were that 822 of the colorectal cancer patients had upper endoscopy; 328 were randomly selected for descriptive analysis of assays, 22.3% of which were found to have antibodies against H. pylori, with 1.8% equivocal for H. pylori on two assays. Of those positive for H. pylori, nearly half (49.3%) were found to have antibodies against cagA while none of those who were equivocal for H. pylori were found to have antibodies against cagA. Compared with study group members who were seropositive for H. pylori, those who were seronegative were less likely to be smokers and to have higher education and income.

Noting that classification errors for GERD might have biased the estimated associations with H. pylori toward the null, the investigators discovered that while there was a strong inverse connection between H. pylori, especially the cagA+ strain, and erosive esophagus (H. pylori adjusted odds ratio, 0.63; 95% confidence interval: 0.37-1.08 and cagA+ OR, 0.47; 95% CI: 0.21-1.03) and Barrett’s esophagus (OR, 0.53; 95% CI: 0.29 -0.97), especially the cagA+ strain (OR, 0.36; 95% CI: 0.14-0.90), they could not make a decisive link between GERD symptoms and H. pylori infection (OR, 0.948; 95% CI: 0.548-1.64 and cagA+ OR, 0.967; 95% CI: 0.461-2.03) (Clin. Gastroenterol. Hepatol. 2013 [doi: 10.1016/j.cgh.2013.08.029]).

Dr. Rubenstein and his colleagues theorized that since the GERD link was not found, the mechanism of H. pylori’s negative association with Barrett’s esophagus might be from the direct impact of the bacteria on the inflammatory or mucosal response; its indirect effects on the production of leptin or ghrelin; or a confounding effect created by genetic regulation of cytokines or prior alterations in the esophageal and gastric microbiota.

The study was underwritten by the National Institutes of Health and by a senior marketing grant from the American Society for Gastrointestinal Endoscopy. Dr. Rubenstein and his associates reported no relevant disclosures.

[email protected]

*Correction, 9/20/2013: An earlier version of this story incorrectly identified inflammatory bowel disease.

Helicobacter pylori was found to have a strong inverse link with Barrett’s esophagus, but not with symptoms of gastroesophageal reflux disease. Erosive esophagitis also was seen to trend toward an inverse association with H. pylori.

Previous reports have attributed a protective effect against gastroesophageal reflux disease (GERD), esophageal adenocarcinoma, and Barrett’s esophagus to H. pylori infection, particularly the cytotoxin-associated gene A (cagA+) strain. Having determined the studies associating H. pylori with GERD either yielded weak support for an inverse relationship, were prone to bias, or were otherwise flawed, a team led by Dr. Joel Rubenstein of the Veterans Affairs Center for Clinical Management Research, Washington, and the University of Michigan Medical School in Ann Arbor analyzed the associations of the three disease outcomes occurring in the same populations with the bacterium.

They constructed a case-control study of men between the ages of 50 and 79 years (n = 533), who had colorectal cancer screening at one of two tertiary medical centers in Michigan between 2008 and 2011, and who were recruited to have upper endoscopy. The study served as a secondary analysis of the Newly Diagnosed Barrett’s Esophagus Study, and included three non–mutually exclusive case groups: Barrett’s esophagus, erosive esophagitis, and GERD symptoms. An additional group of men in the same age group (n = 80) found to have Barrett’s esophagus during clinically indicated upper endoscopy exams was also assessed.

Using logistic regression, the investigators estimated any associations between serum antibodies against H. pylori and cagA+ in the study group, and GERD symptoms, esophagitis, and Barrett’s esophagus. These results were compared with a control group of randomly selected men (n = 177) who did not have any of the three conditions and who were having colorectal screens.

Women were not studied, because of their typically low rates of Barrett’s esophagus. Also excluded were men with any history of upper endoscopy, Barrett’s esophagus, or esophagectomy; diagnostic indication for colonoscopy; inflammatory* bowel disease; known ascites or esophageal varices; any cancers other than melanoma in the previous 5 years; or notable coagulopathy.

The study did include consecutive men between the ages of 50 and 79 years, newly diagnosed at either of the two study sites with Barrett’s esophagus by way of a clinically indicated upper endoscopy.

To determine the presence of GERD, the study group was given a survey that was not formally validated, about their use of proton pump inhibitors (PPI) and histamine₂ receptor agonists (HR₂A) in relation to the frequency they experienced heartburn and regurgitation. Patients who reported weekly heartburn and regurgitation while not using medication were considered to have GERD. A validated survey, the Mayo Clinic’s Gastroesophageal Reflux Questionnaire (GERQ), was applied during the last quarter of the study, although because the GERQ does not address the role of acid-reducing medications, the investigators wrote that there is the chance that patients with GERD managed by medication could have been misclassified by the questionnaire as non-GERD controls.

The study group also underwent colonoscopy, followed by upper endoscopy. If Barrett’s esophagus was suspected, biopsies were obtained. Using the Los Angeles Classification scheme, if class C or D esophagitis was found, patients repeated the endoscopy while taking a PPI before investigators determined if the patient had Barrett’s esophagus. Patients who were not taking any acid-reducing medications at the time of the endoscopy who reported at least weekly symptoms of GERD and had a normal endoscopy without erosive esophagitis or Barrett’s esophagus were considered to have nonerosive reflux symptoms. Patients with Barrett’s esophagus identified on a clinically indicated upper endoscopy were included with the same as those identified among the the people screened for colorectal cancer. Blood samples were drawn from all subjects and assayed for H. pylori.

The results were that 822 of the colorectal cancer patients had upper endoscopy; 328 were randomly selected for descriptive analysis of assays, 22.3% of which were found to have antibodies against H. pylori, with 1.8% equivocal for H. pylori on two assays. Of those positive for H. pylori, nearly half (49.3%) were found to have antibodies against cagA while none of those who were equivocal for H. pylori were found to have antibodies against cagA. Compared with study group members who were seropositive for H. pylori, those who were seronegative were less likely to be smokers and to have higher education and income.

Noting that classification errors for GERD might have biased the estimated associations with H. pylori toward the null, the investigators discovered that while there was a strong inverse connection between H. pylori, especially the cagA+ strain, and erosive esophagus (H. pylori adjusted odds ratio, 0.63; 95% confidence interval: 0.37-1.08 and cagA+ OR, 0.47; 95% CI: 0.21-1.03) and Barrett’s esophagus (OR, 0.53; 95% CI: 0.29 -0.97), especially the cagA+ strain (OR, 0.36; 95% CI: 0.14-0.90), they could not make a decisive link between GERD symptoms and H. pylori infection (OR, 0.948; 95% CI: 0.548-1.64 and cagA+ OR, 0.967; 95% CI: 0.461-2.03) (Clin. Gastroenterol. Hepatol. 2013 [doi: 10.1016/j.cgh.2013.08.029]).

Dr. Rubenstein and his colleagues theorized that since the GERD link was not found, the mechanism of H. pylori’s negative association with Barrett’s esophagus might be from the direct impact of the bacteria on the inflammatory or mucosal response; its indirect effects on the production of leptin or ghrelin; or a confounding effect created by genetic regulation of cytokines or prior alterations in the esophageal and gastric microbiota.

The study was underwritten by the National Institutes of Health and by a senior marketing grant from the American Society for Gastrointestinal Endoscopy. Dr. Rubenstein and his associates reported no relevant disclosures.

[email protected]

*Correction, 9/20/2013: An earlier version of this story incorrectly identified inflammatory bowel disease.

Helicobacter pylori was found to have a strong inverse link with Barrett’s esophagus, but not with symptoms of gastroesophageal reflux disease. Erosive esophagitis also was seen to trend toward an inverse association with H. pylori.

Previous reports have attributed a protective effect against gastroesophageal reflux disease (GERD), esophageal adenocarcinoma, and Barrett’s esophagus to H. pylori infection, particularly the cytotoxin-associated gene A (cagA+) strain. Having determined the studies associating H. pylori with GERD either yielded weak support for an inverse relationship, were prone to bias, or were otherwise flawed, a team led by Dr. Joel Rubenstein of the Veterans Affairs Center for Clinical Management Research, Washington, and the University of Michigan Medical School in Ann Arbor analyzed the associations of the three disease outcomes occurring in the same populations with the bacterium.

They constructed a case-control study of men between the ages of 50 and 79 years (n = 533), who had colorectal cancer screening at one of two tertiary medical centers in Michigan between 2008 and 2011, and who were recruited to have upper endoscopy. The study served as a secondary analysis of the Newly Diagnosed Barrett’s Esophagus Study, and included three non–mutually exclusive case groups: Barrett’s esophagus, erosive esophagitis, and GERD symptoms. An additional group of men in the same age group (n = 80) found to have Barrett’s esophagus during clinically indicated upper endoscopy exams was also assessed.

Using logistic regression, the investigators estimated any associations between serum antibodies against H. pylori and cagA+ in the study group, and GERD symptoms, esophagitis, and Barrett’s esophagus. These results were compared with a control group of randomly selected men (n = 177) who did not have any of the three conditions and who were having colorectal screens.

Women were not studied, because of their typically low rates of Barrett’s esophagus. Also excluded were men with any history of upper endoscopy, Barrett’s esophagus, or esophagectomy; diagnostic indication for colonoscopy; inflammatory* bowel disease; known ascites or esophageal varices; any cancers other than melanoma in the previous 5 years; or notable coagulopathy.

The study did include consecutive men between the ages of 50 and 79 years, newly diagnosed at either of the two study sites with Barrett’s esophagus by way of a clinically indicated upper endoscopy.

To determine the presence of GERD, the study group was given a survey that was not formally validated, about their use of proton pump inhibitors (PPI) and histamine₂ receptor agonists (HR₂A) in relation to the frequency they experienced heartburn and regurgitation. Patients who reported weekly heartburn and regurgitation while not using medication were considered to have GERD. A validated survey, the Mayo Clinic’s Gastroesophageal Reflux Questionnaire (GERQ), was applied during the last quarter of the study, although because the GERQ does not address the role of acid-reducing medications, the investigators wrote that there is the chance that patients with GERD managed by medication could have been misclassified by the questionnaire as non-GERD controls.

The study group also underwent colonoscopy, followed by upper endoscopy. If Barrett’s esophagus was suspected, biopsies were obtained. Using the Los Angeles Classification scheme, if class C or D esophagitis was found, patients repeated the endoscopy while taking a PPI before investigators determined if the patient had Barrett’s esophagus. Patients who were not taking any acid-reducing medications at the time of the endoscopy who reported at least weekly symptoms of GERD and had a normal endoscopy without erosive esophagitis or Barrett’s esophagus were considered to have nonerosive reflux symptoms. Patients with Barrett’s esophagus identified on a clinically indicated upper endoscopy were included with the same as those identified among the the people screened for colorectal cancer. Blood samples were drawn from all subjects and assayed for H. pylori.

The results were that 822 of the colorectal cancer patients had upper endoscopy; 328 were randomly selected for descriptive analysis of assays, 22.3% of which were found to have antibodies against H. pylori, with 1.8% equivocal for H. pylori on two assays. Of those positive for H. pylori, nearly half (49.3%) were found to have antibodies against cagA while none of those who were equivocal for H. pylori were found to have antibodies against cagA. Compared with study group members who were seropositive for H. pylori, those who were seronegative were less likely to be smokers and to have higher education and income.

Noting that classification errors for GERD might have biased the estimated associations with H. pylori toward the null, the investigators discovered that while there was a strong inverse connection between H. pylori, especially the cagA+ strain, and erosive esophagus (H. pylori adjusted odds ratio, 0.63; 95% confidence interval: 0.37-1.08 and cagA+ OR, 0.47; 95% CI: 0.21-1.03) and Barrett’s esophagus (OR, 0.53; 95% CI: 0.29 -0.97), especially the cagA+ strain (OR, 0.36; 95% CI: 0.14-0.90), they could not make a decisive link between GERD symptoms and H. pylori infection (OR, 0.948; 95% CI: 0.548-1.64 and cagA+ OR, 0.967; 95% CI: 0.461-2.03) (Clin. Gastroenterol. Hepatol. 2013 [doi: 10.1016/j.cgh.2013.08.029]).

Dr. Rubenstein and his colleagues theorized that since the GERD link was not found, the mechanism of H. pylori’s negative association with Barrett’s esophagus might be from the direct impact of the bacteria on the inflammatory or mucosal response; its indirect effects on the production of leptin or ghrelin; or a confounding effect created by genetic regulation of cytokines or prior alterations in the esophageal and gastric microbiota.

The study was underwritten by the National Institutes of Health and by a senior marketing grant from the American Society for Gastrointestinal Endoscopy. Dr. Rubenstein and his associates reported no relevant disclosures.

[email protected]

*Correction, 9/20/2013: An earlier version of this story incorrectly identified inflammatory bowel disease.