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The first randomized controlled trial of forceps-assisted cannulation during endoscopic retrograde cholangiopancreatography (ERCP) has shown that this technique can significantly improve the success rate of the procedure.

The results emerged from the small, single-center SOCCER trial of 152 patients recruited from March 2022 to October 2024 and are published in The American Journal of Gastroenterology.

Both groups had a slightly higher number of female participants, and the mean ages of the participants were 61.9 years in the forceps group and 68.3 years in the no forceps group.

First author Steven M. Hadley Jr, an MD candidate at Northwestern Feinberg School of Medicine in Chicago, and colleagues reported that forceps assistance in difficult cannulations yielded significantly higher success rates than no forceps assistance (100% vs 83.9%; P < .001).

The investigators noted that difficult cannulations during ERCP have a frequency of 42%. Cannulation failure is associated with increased morbidity — including longer hospitalization, increased ICU admissions, readmissions, and increased financial cost — as well as mortality rates of up to 10%.

SOCCER defined difficult cannulation as a papilla in or on the rim of a diverticulum, five or more attempts, attempts lasting 5 or more minutes, or two or more unintended pancreatic duct wire passages. Other features were redundant tissue overlaying the papilla or a type 2, 3, or 4 papilla.

The study found forceps assistance also had a nonstatistically significant lower rate of difficult cannulations than no forceps (57.1% vs 69.1%; P = .132). The rate of post-ERCP pancreatitis (PEP) was similarly low in both groups: 5.7% with forceps vs 3.7% without forceps (P = .705). The no forceps group had significantly more cannulation attempts after randomization than the forceps group (14 vs 8.3; P = .026).

Patients who crossed over to forceps assistance all had successful cannulations.

The technique has long been used to overcome cannulation difficulties, said Timothy B. Gardner, MD, MS, a gastroenterologist at the Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, and a coauthor of the study. “It was particularly effective for cannulations with redundant tissue limiting access to the papilla,” Gardner told GI & Hepatology News. “We decided to design a randomized trial to determine the extent to which this technique worked. We believed our study would answer an important question that would hopefully lead to an improvement in endoscopy practice.”

While a few case reports and video demos had described the technique, no trials had assessed its effectiveness, Hadley added. “We found the technique to be effective based on our experience, but it was exciting to see that a rigorously designed randomized trial proved that it is indeed a very effective technique to facilitate cannulation.”

Hadley noted the technique does not increase PEP incidence, unlike the commonly used precut sphincterotomy and the double-wire method for difficult cannulations. “As a result, the forceps-assisted technique may be an effective first-line option and may reduce the need for additional, more invasive procedures including surgery and repeat ERCP to obtain the therapeutic intent of the original ERCP.”

The paper outlines the technique’s methodology, he added, “so we believe endoscopists who read the manuscript will be able to start implementing the technique into their practice.”

Commenting on the paper but not involved in it, Christopher J. DiMaio, MD, regional director of Endoscopy for Northwell Health Physician Partners Gastroenterology and a gastroenterologist in Greenlawn, New York, called it potentially helpful but aimed at a niche group of expert practitioners. “The technique appears safe and very effective, which is the number one concern, and I would definitely keep it in my back pocket,” he said. “I expect it will be used more commonly now because of this study.”

He added that although expert endoscopists are familiar with the approach, they use more time-tested and sometimes more aggressive maneuvers to cope with difficult cannulations. “But this is a simple technique using a device that should be available to most high-volume endoscopists.”

DiMaio also noted that he would have liked to see an actual decrease in PEP incidence in the intervention group.

Looking ahead, Hadley said it would be interesting to compare the effectiveness of the double-wire technique against forceps-assisted cannulation in a randomized context. “A study we’re already looking into is seeing whether physician experience with the technique impacts outcomes.”

This study was supported by the American College of Gastroenterology. The authors and DiMaio reported having no relevant competing interests.

A version of this article first appeared on Medscape.com.

The first randomized controlled trial of forceps-assisted cannulation during endoscopic retrograde cholangiopancreatography (ERCP) has shown that this technique can significantly improve the success rate of the procedure.

The results emerged from the small, single-center SOCCER trial of 152 patients recruited from March 2022 to October 2024 and are published in The American Journal of Gastroenterology.

Both groups had a slightly higher number of female participants, and the mean ages of the participants were 61.9 years in the forceps group and 68.3 years in the no forceps group.

First author Steven M. Hadley Jr, an MD candidate at Northwestern Feinberg School of Medicine in Chicago, and colleagues reported that forceps assistance in difficult cannulations yielded significantly higher success rates than no forceps assistance (100% vs 83.9%; P < .001).

The investigators noted that difficult cannulations during ERCP have a frequency of 42%. Cannulation failure is associated with increased morbidity — including longer hospitalization, increased ICU admissions, readmissions, and increased financial cost — as well as mortality rates of up to 10%.

SOCCER defined difficult cannulation as a papilla in or on the rim of a diverticulum, five or more attempts, attempts lasting 5 or more minutes, or two or more unintended pancreatic duct wire passages. Other features were redundant tissue overlaying the papilla or a type 2, 3, or 4 papilla.

The study found forceps assistance also had a nonstatistically significant lower rate of difficult cannulations than no forceps (57.1% vs 69.1%; P = .132). The rate of post-ERCP pancreatitis (PEP) was similarly low in both groups: 5.7% with forceps vs 3.7% without forceps (P = .705). The no forceps group had significantly more cannulation attempts after randomization than the forceps group (14 vs 8.3; P = .026).

Patients who crossed over to forceps assistance all had successful cannulations.

The technique has long been used to overcome cannulation difficulties, said Timothy B. Gardner, MD, MS, a gastroenterologist at the Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, and a coauthor of the study. “It was particularly effective for cannulations with redundant tissue limiting access to the papilla,” Gardner told GI & Hepatology News. “We decided to design a randomized trial to determine the extent to which this technique worked. We believed our study would answer an important question that would hopefully lead to an improvement in endoscopy practice.”

While a few case reports and video demos had described the technique, no trials had assessed its effectiveness, Hadley added. “We found the technique to be effective based on our experience, but it was exciting to see that a rigorously designed randomized trial proved that it is indeed a very effective technique to facilitate cannulation.”

Hadley noted the technique does not increase PEP incidence, unlike the commonly used precut sphincterotomy and the double-wire method for difficult cannulations. “As a result, the forceps-assisted technique may be an effective first-line option and may reduce the need for additional, more invasive procedures including surgery and repeat ERCP to obtain the therapeutic intent of the original ERCP.”

The paper outlines the technique’s methodology, he added, “so we believe endoscopists who read the manuscript will be able to start implementing the technique into their practice.”

Commenting on the paper but not involved in it, Christopher J. DiMaio, MD, regional director of Endoscopy for Northwell Health Physician Partners Gastroenterology and a gastroenterologist in Greenlawn, New York, called it potentially helpful but aimed at a niche group of expert practitioners. “The technique appears safe and very effective, which is the number one concern, and I would definitely keep it in my back pocket,” he said. “I expect it will be used more commonly now because of this study.”

He added that although expert endoscopists are familiar with the approach, they use more time-tested and sometimes more aggressive maneuvers to cope with difficult cannulations. “But this is a simple technique using a device that should be available to most high-volume endoscopists.”

DiMaio also noted that he would have liked to see an actual decrease in PEP incidence in the intervention group.

Looking ahead, Hadley said it would be interesting to compare the effectiveness of the double-wire technique against forceps-assisted cannulation in a randomized context. “A study we’re already looking into is seeing whether physician experience with the technique impacts outcomes.”

This study was supported by the American College of Gastroenterology. The authors and DiMaio reported having no relevant competing interests.

A version of this article first appeared on Medscape.com.

The first randomized controlled trial of forceps-assisted cannulation during endoscopic retrograde cholangiopancreatography (ERCP) has shown that this technique can significantly improve the success rate of the procedure.

The results emerged from the small, single-center SOCCER trial of 152 patients recruited from March 2022 to October 2024 and are published in The American Journal of Gastroenterology.

Both groups had a slightly higher number of female participants, and the mean ages of the participants were 61.9 years in the forceps group and 68.3 years in the no forceps group.

First author Steven M. Hadley Jr, an MD candidate at Northwestern Feinberg School of Medicine in Chicago, and colleagues reported that forceps assistance in difficult cannulations yielded significantly higher success rates than no forceps assistance (100% vs 83.9%; P < .001).

The investigators noted that difficult cannulations during ERCP have a frequency of 42%. Cannulation failure is associated with increased morbidity — including longer hospitalization, increased ICU admissions, readmissions, and increased financial cost — as well as mortality rates of up to 10%.

SOCCER defined difficult cannulation as a papilla in or on the rim of a diverticulum, five or more attempts, attempts lasting 5 or more minutes, or two or more unintended pancreatic duct wire passages. Other features were redundant tissue overlaying the papilla or a type 2, 3, or 4 papilla.

The study found forceps assistance also had a nonstatistically significant lower rate of difficult cannulations than no forceps (57.1% vs 69.1%; P = .132). The rate of post-ERCP pancreatitis (PEP) was similarly low in both groups: 5.7% with forceps vs 3.7% without forceps (P = .705). The no forceps group had significantly more cannulation attempts after randomization than the forceps group (14 vs 8.3; P = .026).

Patients who crossed over to forceps assistance all had successful cannulations.

The technique has long been used to overcome cannulation difficulties, said Timothy B. Gardner, MD, MS, a gastroenterologist at the Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, and a coauthor of the study. “It was particularly effective for cannulations with redundant tissue limiting access to the papilla,” Gardner told GI & Hepatology News. “We decided to design a randomized trial to determine the extent to which this technique worked. We believed our study would answer an important question that would hopefully lead to an improvement in endoscopy practice.”

While a few case reports and video demos had described the technique, no trials had assessed its effectiveness, Hadley added. “We found the technique to be effective based on our experience, but it was exciting to see that a rigorously designed randomized trial proved that it is indeed a very effective technique to facilitate cannulation.”

Hadley noted the technique does not increase PEP incidence, unlike the commonly used precut sphincterotomy and the double-wire method for difficult cannulations. “As a result, the forceps-assisted technique may be an effective first-line option and may reduce the need for additional, more invasive procedures including surgery and repeat ERCP to obtain the therapeutic intent of the original ERCP.”

The paper outlines the technique’s methodology, he added, “so we believe endoscopists who read the manuscript will be able to start implementing the technique into their practice.”

Commenting on the paper but not involved in it, Christopher J. DiMaio, MD, regional director of Endoscopy for Northwell Health Physician Partners Gastroenterology and a gastroenterologist in Greenlawn, New York, called it potentially helpful but aimed at a niche group of expert practitioners. “The technique appears safe and very effective, which is the number one concern, and I would definitely keep it in my back pocket,” he said. “I expect it will be used more commonly now because of this study.”

He added that although expert endoscopists are familiar with the approach, they use more time-tested and sometimes more aggressive maneuvers to cope with difficult cannulations. “But this is a simple technique using a device that should be available to most high-volume endoscopists.”

DiMaio also noted that he would have liked to see an actual decrease in PEP incidence in the intervention group.

Looking ahead, Hadley said it would be interesting to compare the effectiveness of the double-wire technique against forceps-assisted cannulation in a randomized context. “A study we’re already looking into is seeing whether physician experience with the technique impacts outcomes.”

This study was supported by the American College of Gastroenterology. The authors and DiMaio reported having no relevant competing interests.

A version of this article first appeared on Medscape.com.

Adults with gastrointestinal (GI) diseases are significantly more likely to experience sleep disturbances than those without GI conditions, a new study involving more than 10,000 individuals has found.

“Emerging evidence suggests a bidirectional relationship between GI diseases and sleep disorders, whereby dysfunction in one domain may exacerbate the other,” wrote Shicheng Ye, PhD, of The Third Clinical Medical College of Guangzhou University of Chinese Medicine, and colleagues. However, previous studies on the association between GI and sleep problems have been small, and the role of depression as a mediator has not been well explored.

In the study, which was published online in BMC Gastroenterology, the researchers reviewed data from the US National Health and Nutrition Examination Survey between 2005 and 2014. The study population included 10,626 adults aged 20 years or older, with a mean age of 45.6 years, 50.8% of whom were women. Of these, 6444 were identified as having GI disease on the basis of a “yes” response to the question of whether they had a stomach or intestinal illness with vomiting or diarrhea within the past 30 days.

Researchers also examined responses to survey questions related to sleep duration, trouble sleeping, and diagnosis of a sleep disorder. Individuals with vs without GI diseases had a significantly higher prevalence of sleep trouble (37.99% vs 24.21%; P < .001) and a greater frequency of diagnosed sleep disorders (14.99% vs 8.08%; P < .001).

An analysis adjusted for demographic, lifestyle, and clinical factors found that individuals with vs without GI diseases were 70% more likely to have sleep trouble. Individuals with vs without GI diseases were also significantly more likely to have a diagnosed sleep disorder and a reduction in sleep duration (adjusted odds ratio, 1.8; adjusted beta, -0.15).

The association between GI diseases and sleep problems remained consistent across individuals of multiple subgroups, including those without hypertension, diabetes, or a history of smoking. It also remained significant among individuals with coronary heart disease and higher scores on the dietary index for gut microbiota. No significant interaction effects related to age, sex, or chronic disease appeared in any subgroup (P > .05).

An additional mediation analysis found that depression partly mediated the associations between GI diseases and sleep issues. Depression accounted for 21.29% of the total effect on sleep problems, 19.23% of the effect on sleep disorders, and 26.68% of the effect on sleep duration.

The mediating role of depression on the association between GI disease and sleep problems may not be exclusive, the researchers wrote. Other potential mechanisms may include systemic inflammation, visceral hypersensitivity, and metabolic dysfunction.

The findings were limited by several factors, including the possibly underpowered sample size for machine-learning models and the reliance on self-reports of GI diseases, sleep outcomes, and coronary heart disease, the researchers noted. Other limitations included the inability to adjust for confounding factors, including obstructive sleep apnea, chronic pain, and hypertension.

However, the results illustrate the need to address both psychological and GI factors in clinical practice to improve sleep health, the researchers wrote. More research is needed to identify causal pathways and develop targeted, multidimensional interventions for this interconnected trio of health problems.

 

Increasing Evidence for Gut-Brain Interaction

Both sleep disorders and disorders of GBI (DGBI) are highly prevalent worldwide, Jatin Roper, MD, gastroenterologist and associate professor of medicine at Duke University, Durham, North Carolina, told GI & Hepatology News.

“A growing body of evidence suggests that DGBI, including irritable bowel syndrome, are caused by imbalances in signaling between the brain and the intestine, which include the vagus nerve, hormonal signals, the gut microbiota, and immune system,” said Roper, who was not involved in the current study.

“Since many sleep disturbances are centrally mediated, it is plausible that sleep and gastrointestinal disorders could be mechanistically linked,” he said. Rigorous analysis of patient databases for a possible association between sleep and GI disorders, as was done in the current study, is an important step.

The current study findings were not unexpected, “particularly the finding that depression may mediate a link between sleep and GI disorders, because depression is well known to be associated to sleep disturbances and DGBI,” Roper said.

However, GI doctors often do not ask patients about problems with sleep, and pulmonary doctors or sleep specialists may not ask patients about GI symptoms, Roper noted. Similarly, patients may not bring up all their symptoms when seeing these specialists.

“The current study underscores the need for comprehensive, multisystem evaluations in specialty clinics for sleep and GI conditions and appropriate referrals to specialists, when necessary,” he said.

The research raised an important question of whether sleep and GI disorders are associated with each other because of other underlying medical conditions, which may be difficult to control for in cross-sectional studies, or whether sleep problems cause GI problems or vice versa, Roper said. Other uncertainties include whether the conditions are biologically linked, possibly through shared changes in the brain-gut axis.

Long-term observational studies would be useful to identify whether sleep disturbances precede DGBI or vice versa, Roper added.

The study received no outside funding. The researchers and Roper had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

Adults with gastrointestinal (GI) diseases are significantly more likely to experience sleep disturbances than those without GI conditions, a new study involving more than 10,000 individuals has found.

“Emerging evidence suggests a bidirectional relationship between GI diseases and sleep disorders, whereby dysfunction in one domain may exacerbate the other,” wrote Shicheng Ye, PhD, of The Third Clinical Medical College of Guangzhou University of Chinese Medicine, and colleagues. However, previous studies on the association between GI and sleep problems have been small, and the role of depression as a mediator has not been well explored.

In the study, which was published online in BMC Gastroenterology, the researchers reviewed data from the US National Health and Nutrition Examination Survey between 2005 and 2014. The study population included 10,626 adults aged 20 years or older, with a mean age of 45.6 years, 50.8% of whom were women. Of these, 6444 were identified as having GI disease on the basis of a “yes” response to the question of whether they had a stomach or intestinal illness with vomiting or diarrhea within the past 30 days.

Researchers also examined responses to survey questions related to sleep duration, trouble sleeping, and diagnosis of a sleep disorder. Individuals with vs without GI diseases had a significantly higher prevalence of sleep trouble (37.99% vs 24.21%; P < .001) and a greater frequency of diagnosed sleep disorders (14.99% vs 8.08%; P < .001).

An analysis adjusted for demographic, lifestyle, and clinical factors found that individuals with vs without GI diseases were 70% more likely to have sleep trouble. Individuals with vs without GI diseases were also significantly more likely to have a diagnosed sleep disorder and a reduction in sleep duration (adjusted odds ratio, 1.8; adjusted beta, -0.15).

The association between GI diseases and sleep problems remained consistent across individuals of multiple subgroups, including those without hypertension, diabetes, or a history of smoking. It also remained significant among individuals with coronary heart disease and higher scores on the dietary index for gut microbiota. No significant interaction effects related to age, sex, or chronic disease appeared in any subgroup (P > .05).

An additional mediation analysis found that depression partly mediated the associations between GI diseases and sleep issues. Depression accounted for 21.29% of the total effect on sleep problems, 19.23% of the effect on sleep disorders, and 26.68% of the effect on sleep duration.

The mediating role of depression on the association between GI disease and sleep problems may not be exclusive, the researchers wrote. Other potential mechanisms may include systemic inflammation, visceral hypersensitivity, and metabolic dysfunction.

The findings were limited by several factors, including the possibly underpowered sample size for machine-learning models and the reliance on self-reports of GI diseases, sleep outcomes, and coronary heart disease, the researchers noted. Other limitations included the inability to adjust for confounding factors, including obstructive sleep apnea, chronic pain, and hypertension.

However, the results illustrate the need to address both psychological and GI factors in clinical practice to improve sleep health, the researchers wrote. More research is needed to identify causal pathways and develop targeted, multidimensional interventions for this interconnected trio of health problems.

 

Increasing Evidence for Gut-Brain Interaction

Both sleep disorders and disorders of GBI (DGBI) are highly prevalent worldwide, Jatin Roper, MD, gastroenterologist and associate professor of medicine at Duke University, Durham, North Carolina, told GI & Hepatology News.

“A growing body of evidence suggests that DGBI, including irritable bowel syndrome, are caused by imbalances in signaling between the brain and the intestine, which include the vagus nerve, hormonal signals, the gut microbiota, and immune system,” said Roper, who was not involved in the current study.

“Since many sleep disturbances are centrally mediated, it is plausible that sleep and gastrointestinal disorders could be mechanistically linked,” he said. Rigorous analysis of patient databases for a possible association between sleep and GI disorders, as was done in the current study, is an important step.

The current study findings were not unexpected, “particularly the finding that depression may mediate a link between sleep and GI disorders, because depression is well known to be associated to sleep disturbances and DGBI,” Roper said.

However, GI doctors often do not ask patients about problems with sleep, and pulmonary doctors or sleep specialists may not ask patients about GI symptoms, Roper noted. Similarly, patients may not bring up all their symptoms when seeing these specialists.

“The current study underscores the need for comprehensive, multisystem evaluations in specialty clinics for sleep and GI conditions and appropriate referrals to specialists, when necessary,” he said.

The research raised an important question of whether sleep and GI disorders are associated with each other because of other underlying medical conditions, which may be difficult to control for in cross-sectional studies, or whether sleep problems cause GI problems or vice versa, Roper said. Other uncertainties include whether the conditions are biologically linked, possibly through shared changes in the brain-gut axis.

Long-term observational studies would be useful to identify whether sleep disturbances precede DGBI or vice versa, Roper added.

The study received no outside funding. The researchers and Roper had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

Adults with gastrointestinal (GI) diseases are significantly more likely to experience sleep disturbances than those without GI conditions, a new study involving more than 10,000 individuals has found.

“Emerging evidence suggests a bidirectional relationship between GI diseases and sleep disorders, whereby dysfunction in one domain may exacerbate the other,” wrote Shicheng Ye, PhD, of The Third Clinical Medical College of Guangzhou University of Chinese Medicine, and colleagues. However, previous studies on the association between GI and sleep problems have been small, and the role of depression as a mediator has not been well explored.

In the study, which was published online in BMC Gastroenterology, the researchers reviewed data from the US National Health and Nutrition Examination Survey between 2005 and 2014. The study population included 10,626 adults aged 20 years or older, with a mean age of 45.6 years, 50.8% of whom were women. Of these, 6444 were identified as having GI disease on the basis of a “yes” response to the question of whether they had a stomach or intestinal illness with vomiting or diarrhea within the past 30 days.

Researchers also examined responses to survey questions related to sleep duration, trouble sleeping, and diagnosis of a sleep disorder. Individuals with vs without GI diseases had a significantly higher prevalence of sleep trouble (37.99% vs 24.21%; P < .001) and a greater frequency of diagnosed sleep disorders (14.99% vs 8.08%; P < .001).

An analysis adjusted for demographic, lifestyle, and clinical factors found that individuals with vs without GI diseases were 70% more likely to have sleep trouble. Individuals with vs without GI diseases were also significantly more likely to have a diagnosed sleep disorder and a reduction in sleep duration (adjusted odds ratio, 1.8; adjusted beta, -0.15).

The association between GI diseases and sleep problems remained consistent across individuals of multiple subgroups, including those without hypertension, diabetes, or a history of smoking. It also remained significant among individuals with coronary heart disease and higher scores on the dietary index for gut microbiota. No significant interaction effects related to age, sex, or chronic disease appeared in any subgroup (P > .05).

An additional mediation analysis found that depression partly mediated the associations between GI diseases and sleep issues. Depression accounted for 21.29% of the total effect on sleep problems, 19.23% of the effect on sleep disorders, and 26.68% of the effect on sleep duration.

The mediating role of depression on the association between GI disease and sleep problems may not be exclusive, the researchers wrote. Other potential mechanisms may include systemic inflammation, visceral hypersensitivity, and metabolic dysfunction.

The findings were limited by several factors, including the possibly underpowered sample size for machine-learning models and the reliance on self-reports of GI diseases, sleep outcomes, and coronary heart disease, the researchers noted. Other limitations included the inability to adjust for confounding factors, including obstructive sleep apnea, chronic pain, and hypertension.

However, the results illustrate the need to address both psychological and GI factors in clinical practice to improve sleep health, the researchers wrote. More research is needed to identify causal pathways and develop targeted, multidimensional interventions for this interconnected trio of health problems.

 

Increasing Evidence for Gut-Brain Interaction

Both sleep disorders and disorders of GBI (DGBI) are highly prevalent worldwide, Jatin Roper, MD, gastroenterologist and associate professor of medicine at Duke University, Durham, North Carolina, told GI & Hepatology News.

“A growing body of evidence suggests that DGBI, including irritable bowel syndrome, are caused by imbalances in signaling between the brain and the intestine, which include the vagus nerve, hormonal signals, the gut microbiota, and immune system,” said Roper, who was not involved in the current study.

“Since many sleep disturbances are centrally mediated, it is plausible that sleep and gastrointestinal disorders could be mechanistically linked,” he said. Rigorous analysis of patient databases for a possible association between sleep and GI disorders, as was done in the current study, is an important step.

The current study findings were not unexpected, “particularly the finding that depression may mediate a link between sleep and GI disorders, because depression is well known to be associated to sleep disturbances and DGBI,” Roper said.

However, GI doctors often do not ask patients about problems with sleep, and pulmonary doctors or sleep specialists may not ask patients about GI symptoms, Roper noted. Similarly, patients may not bring up all their symptoms when seeing these specialists.

“The current study underscores the need for comprehensive, multisystem evaluations in specialty clinics for sleep and GI conditions and appropriate referrals to specialists, when necessary,” he said.

The research raised an important question of whether sleep and GI disorders are associated with each other because of other underlying medical conditions, which may be difficult to control for in cross-sectional studies, or whether sleep problems cause GI problems or vice versa, Roper said. Other uncertainties include whether the conditions are biologically linked, possibly through shared changes in the brain-gut axis.

Long-term observational studies would be useful to identify whether sleep disturbances precede DGBI or vice versa, Roper added.

The study received no outside funding. The researchers and Roper had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

Did you know you can honor a family member, friend, or colleague whose life has been touched by GI research through a gift to the AGA Research Foundation? Your gift will honor a loved one or yourself and support the AGA Research Awards Program, while giving you a tax benefit.

Named award. An AGA pilot award can be renamed after you or a loved one, and targeted for a specific gastrointestinal research area. A new pilot research award can be established with a pledge of $40,000+ or through an estate gift. Gifts of cash or appreciated securities may be used to establish a named award. 

Your next step. A named award gift is a wonderful way to acknowledge a loved one’s vision for the future. To learn more about ways to recognize your honoree, contact us at [email protected].

A lack of funding can prevent talented individuals from pursuing a research career, thereby denying them the opportunity to conduct work that will ultimately benefit patients with critical needs. A named award donation to the AGA Research Foundation will help support and fund investigators with a research grant in the field of gastroenterology and hepatology.

Did you know you can honor a family member, friend, or colleague whose life has been touched by GI research through a gift to the AGA Research Foundation? Your gift will honor a loved one or yourself and support the AGA Research Awards Program, while giving you a tax benefit.

Named award. An AGA pilot award can be renamed after you or a loved one, and targeted for a specific gastrointestinal research area. A new pilot research award can be established with a pledge of $40,000+ or through an estate gift. Gifts of cash or appreciated securities may be used to establish a named award. 

Your next step. A named award gift is a wonderful way to acknowledge a loved one’s vision for the future. To learn more about ways to recognize your honoree, contact us at [email protected].

A lack of funding can prevent talented individuals from pursuing a research career, thereby denying them the opportunity to conduct work that will ultimately benefit patients with critical needs. A named award donation to the AGA Research Foundation will help support and fund investigators with a research grant in the field of gastroenterology and hepatology.

Did you know you can honor a family member, friend, or colleague whose life has been touched by GI research through a gift to the AGA Research Foundation? Your gift will honor a loved one or yourself and support the AGA Research Awards Program, while giving you a tax benefit.

Named award. An AGA pilot award can be renamed after you or a loved one, and targeted for a specific gastrointestinal research area. A new pilot research award can be established with a pledge of $40,000+ or through an estate gift. Gifts of cash or appreciated securities may be used to establish a named award. 

Your next step. A named award gift is a wonderful way to acknowledge a loved one’s vision for the future. To learn more about ways to recognize your honoree, contact us at [email protected].

A lack of funding can prevent talented individuals from pursuing a research career, thereby denying them the opportunity to conduct work that will ultimately benefit patients with critical needs. A named award donation to the AGA Research Foundation will help support and fund investigators with a research grant in the field of gastroenterology and hepatology.

Patients with intestinal methanogen overgrowth (IMO) have a higher rate and severity of constipation but a lower rate and severity of diarrhea, according to a systematic review and meta-analysis published in Clinical Gastroenterology and Hepatology.

“The distinct phenotype of patients with IMO should be incorporated in patient-reported outcome measures and further correlated with mechanistic microbiome studies,” wrote investigators led by gastroenterologist Ali Rezaie, MD, MSc, medical director of the GI Motility Program at Cedars-Sinai Medical Center and director of biotechnology in the center’s Medically Associated Science and Technology (MAST) Program. Recognizing specific GI symptom profiles can improve diagnosis and treatment strategies, facilitating further clinical trials and targeted microbiome studies to optimize patient care. 

Excessive luminal loads of methanogenic archaea – archaea being bacteria-like prokaryotes and one of the main three domains of the tree of life – have been implicated in the pathophysiology of various diseases, including constipation. 

 

The Study

To elucidate the phenotypical presentation of IMO in patients, Rezaie’s group compared the prevalence and severity of gastrointestinal (GI) symptoms in individuals who had IMO with those who did not have IMO. IMO was based on excess levels of this gaseous GI byproduct in exhaled breath tests.

Searching electronic databases from inception to September 2023, the researchers identified 19 eligible studies from diverse geographical regions with 1293 IMO patients and 3208 controls. Eleven studies were performed in the United States; the other studies were conducted in France (n = 2), India (n = 2), New Zealand (n = 1), South Korea (n = 1), Italy (n = 1), and the United Kingdom (n = 1). Thirteen studies were of high quality, as defined by a Newcastle-Ottawa Assessment Scale score of 6. 

Patients with IMO were found to exhibit a range of GI symptoms, including bloating (78%), constipation (51%), diarrhea (33%), abdominal pain (65%), nausea (30%), and flatulence (56%).

In other findings:

• Patients with IMO had a significantly higher prevalence of constipation vs controls: 47% vs 38% (odds ratio [OR], 2.04, 95% confidence interval [CI], 1.48-2.83, P < .0001).
• They had a lower prevalence of diarrhea: 37% vs 52% (OR .58, 95% CI, .37-.90, P = .01); and nausea: 32% vs 45%; (OR, .75; 95% CI, .60-.94, P = .01).
• Patients with IMO had more severe constipation: standard mean deviation [SMD], .77 (95% CI, .11-1.43, P = .02) and a lower severity of diarrhea: SMD, –.71 (95% CI, –1.39 to –.03, P = .04). Significant heterogeneity of effect, however, was detected.
• Constipation was more prevalent in IMO diagnosed with the lactulose breath test and the glucose breath test and constipation was particularly prevalent in Europe and the United States.

Mechanism of Action

The findings on constipation and diarrhea corroborate methane’s slowing physiologic effects on motility, the authors noted. It has been consistently found to delay gut transit, both small bowel and colonic transit.

Mechanistically, methane reduces small intestinal peristaltic velocity while augmenting non-propagating contraction amplitude, suggesting that reduction of intestinal transit time is mediated through promotion of non-propulsive contractions.

“This study further consolidates methane’s causal role in constipation and paves the way to establish validated disease-specific patient-reported outcomes,” Rezaie and associates wrote, calling for longitudinal and mechanistic studies assessing the archaeome in order to advance understanding of IMO.

This study was funded in part by Nancy Stark and Stanley Lezman in support of the MAST Program’s Innovation Project at Cedars-Sinai.

Rezaie serves as a consultant/speaker for Bausch Health. Cedars-Sinai Medical Center has a licensing agreement with Gemelli Biotech, in which Rezaie and coauthor Pimentel have equity. They also hold equity in Good LIFE. Pimentel consults for and has received grant support from Bausch Health.

Patients with intestinal methanogen overgrowth (IMO) have a higher rate and severity of constipation but a lower rate and severity of diarrhea, according to a systematic review and meta-analysis published in Clinical Gastroenterology and Hepatology.

“The distinct phenotype of patients with IMO should be incorporated in patient-reported outcome measures and further correlated with mechanistic microbiome studies,” wrote investigators led by gastroenterologist Ali Rezaie, MD, MSc, medical director of the GI Motility Program at Cedars-Sinai Medical Center and director of biotechnology in the center’s Medically Associated Science and Technology (MAST) Program. Recognizing specific GI symptom profiles can improve diagnosis and treatment strategies, facilitating further clinical trials and targeted microbiome studies to optimize patient care. 

Excessive luminal loads of methanogenic archaea – archaea being bacteria-like prokaryotes and one of the main three domains of the tree of life – have been implicated in the pathophysiology of various diseases, including constipation. 

 

The Study

To elucidate the phenotypical presentation of IMO in patients, Rezaie’s group compared the prevalence and severity of gastrointestinal (GI) symptoms in individuals who had IMO with those who did not have IMO. IMO was based on excess levels of this gaseous GI byproduct in exhaled breath tests.

Searching electronic databases from inception to September 2023, the researchers identified 19 eligible studies from diverse geographical regions with 1293 IMO patients and 3208 controls. Eleven studies were performed in the United States; the other studies were conducted in France (n = 2), India (n = 2), New Zealand (n = 1), South Korea (n = 1), Italy (n = 1), and the United Kingdom (n = 1). Thirteen studies were of high quality, as defined by a Newcastle-Ottawa Assessment Scale score of 6. 

Patients with IMO were found to exhibit a range of GI symptoms, including bloating (78%), constipation (51%), diarrhea (33%), abdominal pain (65%), nausea (30%), and flatulence (56%).

In other findings:

• Patients with IMO had a significantly higher prevalence of constipation vs controls: 47% vs 38% (odds ratio [OR], 2.04, 95% confidence interval [CI], 1.48-2.83, P < .0001).
• They had a lower prevalence of diarrhea: 37% vs 52% (OR .58, 95% CI, .37-.90, P = .01); and nausea: 32% vs 45%; (OR, .75; 95% CI, .60-.94, P = .01).
• Patients with IMO had more severe constipation: standard mean deviation [SMD], .77 (95% CI, .11-1.43, P = .02) and a lower severity of diarrhea: SMD, –.71 (95% CI, –1.39 to –.03, P = .04). Significant heterogeneity of effect, however, was detected.
• Constipation was more prevalent in IMO diagnosed with the lactulose breath test and the glucose breath test and constipation was particularly prevalent in Europe and the United States.

Mechanism of Action

The findings on constipation and diarrhea corroborate methane’s slowing physiologic effects on motility, the authors noted. It has been consistently found to delay gut transit, both small bowel and colonic transit.

Mechanistically, methane reduces small intestinal peristaltic velocity while augmenting non-propagating contraction amplitude, suggesting that reduction of intestinal transit time is mediated through promotion of non-propulsive contractions.

“This study further consolidates methane’s causal role in constipation and paves the way to establish validated disease-specific patient-reported outcomes,” Rezaie and associates wrote, calling for longitudinal and mechanistic studies assessing the archaeome in order to advance understanding of IMO.

This study was funded in part by Nancy Stark and Stanley Lezman in support of the MAST Program’s Innovation Project at Cedars-Sinai.

Rezaie serves as a consultant/speaker for Bausch Health. Cedars-Sinai Medical Center has a licensing agreement with Gemelli Biotech, in which Rezaie and coauthor Pimentel have equity. They also hold equity in Good LIFE. Pimentel consults for and has received grant support from Bausch Health.

Patients with intestinal methanogen overgrowth (IMO) have a higher rate and severity of constipation but a lower rate and severity of diarrhea, according to a systematic review and meta-analysis published in Clinical Gastroenterology and Hepatology.

“The distinct phenotype of patients with IMO should be incorporated in patient-reported outcome measures and further correlated with mechanistic microbiome studies,” wrote investigators led by gastroenterologist Ali Rezaie, MD, MSc, medical director of the GI Motility Program at Cedars-Sinai Medical Center and director of biotechnology in the center’s Medically Associated Science and Technology (MAST) Program. Recognizing specific GI symptom profiles can improve diagnosis and treatment strategies, facilitating further clinical trials and targeted microbiome studies to optimize patient care. 

Excessive luminal loads of methanogenic archaea – archaea being bacteria-like prokaryotes and one of the main three domains of the tree of life – have been implicated in the pathophysiology of various diseases, including constipation. 

 

The Study

To elucidate the phenotypical presentation of IMO in patients, Rezaie’s group compared the prevalence and severity of gastrointestinal (GI) symptoms in individuals who had IMO with those who did not have IMO. IMO was based on excess levels of this gaseous GI byproduct in exhaled breath tests.

Searching electronic databases from inception to September 2023, the researchers identified 19 eligible studies from diverse geographical regions with 1293 IMO patients and 3208 controls. Eleven studies were performed in the United States; the other studies were conducted in France (n = 2), India (n = 2), New Zealand (n = 1), South Korea (n = 1), Italy (n = 1), and the United Kingdom (n = 1). Thirteen studies were of high quality, as defined by a Newcastle-Ottawa Assessment Scale score of 6. 

Patients with IMO were found to exhibit a range of GI symptoms, including bloating (78%), constipation (51%), diarrhea (33%), abdominal pain (65%), nausea (30%), and flatulence (56%).

In other findings:

• Patients with IMO had a significantly higher prevalence of constipation vs controls: 47% vs 38% (odds ratio [OR], 2.04, 95% confidence interval [CI], 1.48-2.83, P < .0001).
• They had a lower prevalence of diarrhea: 37% vs 52% (OR .58, 95% CI, .37-.90, P = .01); and nausea: 32% vs 45%; (OR, .75; 95% CI, .60-.94, P = .01).
• Patients with IMO had more severe constipation: standard mean deviation [SMD], .77 (95% CI, .11-1.43, P = .02) and a lower severity of diarrhea: SMD, –.71 (95% CI, –1.39 to –.03, P = .04). Significant heterogeneity of effect, however, was detected.
• Constipation was more prevalent in IMO diagnosed with the lactulose breath test and the glucose breath test and constipation was particularly prevalent in Europe and the United States.

Mechanism of Action

The findings on constipation and diarrhea corroborate methane’s slowing physiologic effects on motility, the authors noted. It has been consistently found to delay gut transit, both small bowel and colonic transit.

Mechanistically, methane reduces small intestinal peristaltic velocity while augmenting non-propagating contraction amplitude, suggesting that reduction of intestinal transit time is mediated through promotion of non-propulsive contractions.

“This study further consolidates methane’s causal role in constipation and paves the way to establish validated disease-specific patient-reported outcomes,” Rezaie and associates wrote, calling for longitudinal and mechanistic studies assessing the archaeome in order to advance understanding of IMO.

This study was funded in part by Nancy Stark and Stanley Lezman in support of the MAST Program’s Innovation Project at Cedars-Sinai.

Rezaie serves as a consultant/speaker for Bausch Health. Cedars-Sinai Medical Center has a licensing agreement with Gemelli Biotech, in which Rezaie and coauthor Pimentel have equity. They also hold equity in Good LIFE. Pimentel consults for and has received grant support from Bausch Health.

No evidence of a causal relationship between previously suspected pharmacologic triggers and increased risk of microscopic colitis (MC) emerged from a nationwide longitudinal study of older Swedish individuals in a national database.

“Sensitivity analyses suggest that previously reported associations and persistent association with SSRI [selective serotonin reuptake inhibitor] initiation may be due to surveillance bias,” wrote gastroenterologist Hamed Khalili, MD, MPH, of Massachusetts General Hospital, Boston, and colleagues in Annals of Internal Medicine, advising clinicians to carefully balance the benefits of these medication classes against the very low likelihood of a causal relationship with MC.

While two smaller studies had challenged the belief that these medications can cause MC, Khalili told GI & Hepatology News, “the quality of the data that supported or refuted this hypothesis were low. Nevertheless, most in the field consider MC to be largely related to medications so we thought it was important to systematically answer this question.”

While most medications thought to trigger MC were found not to be causally linked, he added, “we did observe a marginal association with SSRIs but could not rule out the possibility that the association is related to residual bias.”

The authors noted that the incidence of MC in older persons is rising rapidly and is thought to account for more than 30% of chronic diarrhea cases in this group.

Despite weak evidence in the literature, the treatment guidelines of several societies, including the American Gastroenterological Association, recommend discontinuing potential pharmacologic triggers as first-line prevention or as an adjunct therapy, particularly in recurrent or refractory MC. But this approach may be ineffective in patients with established disease and could lead to inappropriate discontinuation of medication such as antihypertensives, the authors argued.

As to proposed mechanisms of action, said Khalili, “for PPIs [proton-pump inhibitors,] people thought it was related to changes in the gut microbiome. For NSAIDs [nonsteroidal anti-inflammatory drugs], people thought it could be related to changes in the gut barrier function. But overall, not a single mechanism would have explained all the prior associations that were observed.”

While medications such as PPIs and SSRIs can cause diarrhea in a small subset of users, Khalili added, “most patients generally catch these side effects very quickly and realize that stopping these medications will improve their diarrhea. This is very different than most patients we as gastroenterologists see with a new diagnosis of MC. Many of them may have been on these medications for a long time. We believe that stopping medications in these patients is unnecessary.” 

 

Study Details

The investigators looked at eligible residents in Sweden age 65 years or older in the years 2006 to 2017 (n = 191,482 to 2,634,777). Participants had no history of inflammatory bowel disease and different cohorts were examined for various common medications from calcium channel blockers to statins.

With a primary outcome of biopsy-verified MC, dates of diagnosis were obtained from Sweden’s national histopathology cohort ESPRESSO (Epidemiology Strengthened by Histopathology Reports in Sweden). Among the findings:

• The 12- and 24-month cumulative incidences of MC were less than 0.05% under all treatment strategies.
• Estimated 12-month risk differences were close to null under angiotensin-converting enzyme vs calcium-channel blocker (CCB) initiation, angiotensin-receptor blocker vs CCB initiation, NSAID initiation vs noninitiation, PPI inhibitor initiation vs noninitiation, and statin initiation vs noninitiation.
• The estimated 12-month risk difference was 0.04% (95% CI, 0.03%-0.05%) for SSRIs vs mirtazapine.
• Results were similar for 24-month risk differences. Several medications such as SSRIs were also associated with increased risk for undergoing colonoscopy with a normal colorectal mucosa biopsy result.

“We think it’s unlikely that stopping these medications will improve symptoms of MC,” Khalili said. 

Commenting on the paper but not involved in it, Jordan E. Axelrad, MD, MPH, codirector of the Inflammatory Bowel Disease Center at NYU Langone Health in New York City, said, “This study strengthens the argument that MC is an immune-mediated disease, not primarily driven by drug exposures. But future studies in diverse cohorts are required to validate these findings.” He said the study nevertheless provides reassurance that previously reported associations may have been overstated or confounded by factors such as reverse causation and increased healthcare utilization preceding the MC diagnosis.

In the meantime, Axelrad added, the findings “may reduce the inclination to promptly discontinue medications historically associated with MC in newly diagnosed cases. Also, these data help shift the clinical focus away from medication cessation alone and toward a needed and broader MC management strategy. US-based validation would likely highlight these changes in our patients.”

Despite concerns about the study’s unmeasured confounding because of differential healthcare utilization or surveillance, the modest association observed between SSRI and MC is supported by literature linking catecholamine and serotonin to gut innate immunity and microbiota, Khalili’s group wrote. “However, this finding may also be confounded by other factors including persisting surveillance and protopathic bias, especially since an association was also seen for risk for receipt of a colonoscopy with normal mucosa.”

Khalili believes the Swedish results are applicable even to the more diverse US population. He noted that lack of primary care data limited measurement of and adjustment for symptoms and medical diagnoses that increase risk. But according to Axelrad, MC is more prevalent in White, older patients, who are well-represented in Swedish cohorts but to a lesser extent in US populations. “Additionally, environmental factors and medication use patterns differ between Sweden and the US, particularly in regard to over-the-counter medication access.”

The findings have implications for future research in pharmacoepidemiologic studies of gastrointestinal-related outcomes. Since many routinely prescribed medications such as SSRIs were associated with an apparent increased risk for colonoscopies with normal colorectal biopsy results, future studies that examine gastrointestinal-specific adverse events should carefully consider potential surveillance bias.

In the meantime, Khalili stressed, it’s important to highlight that while some of these medications cause diarrhea in a small subset of patients, stopping medications in these patients is unnecessary.

This study was supported by the National Institutes of Health (NIH) and the Swedish Research Council. Khalili disclosed grants from the Crohn’s & Coiltis Foundation, the NIH and the Helmsley CharitableTrust, as well as stock ownership in Cylinder Health. One coauthor is employed by Massachusetts General Hospital. Axelrad had no relevant competing interests.







 

No evidence of a causal relationship between previously suspected pharmacologic triggers and increased risk of microscopic colitis (MC) emerged from a nationwide longitudinal study of older Swedish individuals in a national database.

“Sensitivity analyses suggest that previously reported associations and persistent association with SSRI [selective serotonin reuptake inhibitor] initiation may be due to surveillance bias,” wrote gastroenterologist Hamed Khalili, MD, MPH, of Massachusetts General Hospital, Boston, and colleagues in Annals of Internal Medicine, advising clinicians to carefully balance the benefits of these medication classes against the very low likelihood of a causal relationship with MC.

While two smaller studies had challenged the belief that these medications can cause MC, Khalili told GI & Hepatology News, “the quality of the data that supported or refuted this hypothesis were low. Nevertheless, most in the field consider MC to be largely related to medications so we thought it was important to systematically answer this question.”

While most medications thought to trigger MC were found not to be causally linked, he added, “we did observe a marginal association with SSRIs but could not rule out the possibility that the association is related to residual bias.”

The authors noted that the incidence of MC in older persons is rising rapidly and is thought to account for more than 30% of chronic diarrhea cases in this group.

Despite weak evidence in the literature, the treatment guidelines of several societies, including the American Gastroenterological Association, recommend discontinuing potential pharmacologic triggers as first-line prevention or as an adjunct therapy, particularly in recurrent or refractory MC. But this approach may be ineffective in patients with established disease and could lead to inappropriate discontinuation of medication such as antihypertensives, the authors argued.

As to proposed mechanisms of action, said Khalili, “for PPIs [proton-pump inhibitors,] people thought it was related to changes in the gut microbiome. For NSAIDs [nonsteroidal anti-inflammatory drugs], people thought it could be related to changes in the gut barrier function. But overall, not a single mechanism would have explained all the prior associations that were observed.”

While medications such as PPIs and SSRIs can cause diarrhea in a small subset of users, Khalili added, “most patients generally catch these side effects very quickly and realize that stopping these medications will improve their diarrhea. This is very different than most patients we as gastroenterologists see with a new diagnosis of MC. Many of them may have been on these medications for a long time. We believe that stopping medications in these patients is unnecessary.” 

 

Study Details

The investigators looked at eligible residents in Sweden age 65 years or older in the years 2006 to 2017 (n = 191,482 to 2,634,777). Participants had no history of inflammatory bowel disease and different cohorts were examined for various common medications from calcium channel blockers to statins.

With a primary outcome of biopsy-verified MC, dates of diagnosis were obtained from Sweden’s national histopathology cohort ESPRESSO (Epidemiology Strengthened by Histopathology Reports in Sweden). Among the findings:

• The 12- and 24-month cumulative incidences of MC were less than 0.05% under all treatment strategies.
• Estimated 12-month risk differences were close to null under angiotensin-converting enzyme vs calcium-channel blocker (CCB) initiation, angiotensin-receptor blocker vs CCB initiation, NSAID initiation vs noninitiation, PPI inhibitor initiation vs noninitiation, and statin initiation vs noninitiation.
• The estimated 12-month risk difference was 0.04% (95% CI, 0.03%-0.05%) for SSRIs vs mirtazapine.
• Results were similar for 24-month risk differences. Several medications such as SSRIs were also associated with increased risk for undergoing colonoscopy with a normal colorectal mucosa biopsy result.

“We think it’s unlikely that stopping these medications will improve symptoms of MC,” Khalili said. 

Commenting on the paper but not involved in it, Jordan E. Axelrad, MD, MPH, codirector of the Inflammatory Bowel Disease Center at NYU Langone Health in New York City, said, “This study strengthens the argument that MC is an immune-mediated disease, not primarily driven by drug exposures. But future studies in diverse cohorts are required to validate these findings.” He said the study nevertheless provides reassurance that previously reported associations may have been overstated or confounded by factors such as reverse causation and increased healthcare utilization preceding the MC diagnosis.

In the meantime, Axelrad added, the findings “may reduce the inclination to promptly discontinue medications historically associated with MC in newly diagnosed cases. Also, these data help shift the clinical focus away from medication cessation alone and toward a needed and broader MC management strategy. US-based validation would likely highlight these changes in our patients.”

Despite concerns about the study’s unmeasured confounding because of differential healthcare utilization or surveillance, the modest association observed between SSRI and MC is supported by literature linking catecholamine and serotonin to gut innate immunity and microbiota, Khalili’s group wrote. “However, this finding may also be confounded by other factors including persisting surveillance and protopathic bias, especially since an association was also seen for risk for receipt of a colonoscopy with normal mucosa.”

Khalili believes the Swedish results are applicable even to the more diverse US population. He noted that lack of primary care data limited measurement of and adjustment for symptoms and medical diagnoses that increase risk. But according to Axelrad, MC is more prevalent in White, older patients, who are well-represented in Swedish cohorts but to a lesser extent in US populations. “Additionally, environmental factors and medication use patterns differ between Sweden and the US, particularly in regard to over-the-counter medication access.”

The findings have implications for future research in pharmacoepidemiologic studies of gastrointestinal-related outcomes. Since many routinely prescribed medications such as SSRIs were associated with an apparent increased risk for colonoscopies with normal colorectal biopsy results, future studies that examine gastrointestinal-specific adverse events should carefully consider potential surveillance bias.

In the meantime, Khalili stressed, it’s important to highlight that while some of these medications cause diarrhea in a small subset of patients, stopping medications in these patients is unnecessary.

This study was supported by the National Institutes of Health (NIH) and the Swedish Research Council. Khalili disclosed grants from the Crohn’s & Coiltis Foundation, the NIH and the Helmsley CharitableTrust, as well as stock ownership in Cylinder Health. One coauthor is employed by Massachusetts General Hospital. Axelrad had no relevant competing interests.







 

No evidence of a causal relationship between previously suspected pharmacologic triggers and increased risk of microscopic colitis (MC) emerged from a nationwide longitudinal study of older Swedish individuals in a national database.

“Sensitivity analyses suggest that previously reported associations and persistent association with SSRI [selective serotonin reuptake inhibitor] initiation may be due to surveillance bias,” wrote gastroenterologist Hamed Khalili, MD, MPH, of Massachusetts General Hospital, Boston, and colleagues in Annals of Internal Medicine, advising clinicians to carefully balance the benefits of these medication classes against the very low likelihood of a causal relationship with MC.

While two smaller studies had challenged the belief that these medications can cause MC, Khalili told GI & Hepatology News, “the quality of the data that supported or refuted this hypothesis were low. Nevertheless, most in the field consider MC to be largely related to medications so we thought it was important to systematically answer this question.”

While most medications thought to trigger MC were found not to be causally linked, he added, “we did observe a marginal association with SSRIs but could not rule out the possibility that the association is related to residual bias.”

The authors noted that the incidence of MC in older persons is rising rapidly and is thought to account for more than 30% of chronic diarrhea cases in this group.

Despite weak evidence in the literature, the treatment guidelines of several societies, including the American Gastroenterological Association, recommend discontinuing potential pharmacologic triggers as first-line prevention or as an adjunct therapy, particularly in recurrent or refractory MC. But this approach may be ineffective in patients with established disease and could lead to inappropriate discontinuation of medication such as antihypertensives, the authors argued.

As to proposed mechanisms of action, said Khalili, “for PPIs [proton-pump inhibitors,] people thought it was related to changes in the gut microbiome. For NSAIDs [nonsteroidal anti-inflammatory drugs], people thought it could be related to changes in the gut barrier function. But overall, not a single mechanism would have explained all the prior associations that were observed.”

While medications such as PPIs and SSRIs can cause diarrhea in a small subset of users, Khalili added, “most patients generally catch these side effects very quickly and realize that stopping these medications will improve their diarrhea. This is very different than most patients we as gastroenterologists see with a new diagnosis of MC. Many of them may have been on these medications for a long time. We believe that stopping medications in these patients is unnecessary.” 

 

Study Details

The investigators looked at eligible residents in Sweden age 65 years or older in the years 2006 to 2017 (n = 191,482 to 2,634,777). Participants had no history of inflammatory bowel disease and different cohorts were examined for various common medications from calcium channel blockers to statins.

With a primary outcome of biopsy-verified MC, dates of diagnosis were obtained from Sweden’s national histopathology cohort ESPRESSO (Epidemiology Strengthened by Histopathology Reports in Sweden). Among the findings:

• The 12- and 24-month cumulative incidences of MC were less than 0.05% under all treatment strategies.
• Estimated 12-month risk differences were close to null under angiotensin-converting enzyme vs calcium-channel blocker (CCB) initiation, angiotensin-receptor blocker vs CCB initiation, NSAID initiation vs noninitiation, PPI inhibitor initiation vs noninitiation, and statin initiation vs noninitiation.
• The estimated 12-month risk difference was 0.04% (95% CI, 0.03%-0.05%) for SSRIs vs mirtazapine.
• Results were similar for 24-month risk differences. Several medications such as SSRIs were also associated with increased risk for undergoing colonoscopy with a normal colorectal mucosa biopsy result.

“We think it’s unlikely that stopping these medications will improve symptoms of MC,” Khalili said. 

Commenting on the paper but not involved in it, Jordan E. Axelrad, MD, MPH, codirector of the Inflammatory Bowel Disease Center at NYU Langone Health in New York City, said, “This study strengthens the argument that MC is an immune-mediated disease, not primarily driven by drug exposures. But future studies in diverse cohorts are required to validate these findings.” He said the study nevertheless provides reassurance that previously reported associations may have been overstated or confounded by factors such as reverse causation and increased healthcare utilization preceding the MC diagnosis.

In the meantime, Axelrad added, the findings “may reduce the inclination to promptly discontinue medications historically associated with MC in newly diagnosed cases. Also, these data help shift the clinical focus away from medication cessation alone and toward a needed and broader MC management strategy. US-based validation would likely highlight these changes in our patients.”

Despite concerns about the study’s unmeasured confounding because of differential healthcare utilization or surveillance, the modest association observed between SSRI and MC is supported by literature linking catecholamine and serotonin to gut innate immunity and microbiota, Khalili’s group wrote. “However, this finding may also be confounded by other factors including persisting surveillance and protopathic bias, especially since an association was also seen for risk for receipt of a colonoscopy with normal mucosa.”

Khalili believes the Swedish results are applicable even to the more diverse US population. He noted that lack of primary care data limited measurement of and adjustment for symptoms and medical diagnoses that increase risk. But according to Axelrad, MC is more prevalent in White, older patients, who are well-represented in Swedish cohorts but to a lesser extent in US populations. “Additionally, environmental factors and medication use patterns differ between Sweden and the US, particularly in regard to over-the-counter medication access.”

The findings have implications for future research in pharmacoepidemiologic studies of gastrointestinal-related outcomes. Since many routinely prescribed medications such as SSRIs were associated with an apparent increased risk for colonoscopies with normal colorectal biopsy results, future studies that examine gastrointestinal-specific adverse events should carefully consider potential surveillance bias.

In the meantime, Khalili stressed, it’s important to highlight that while some of these medications cause diarrhea in a small subset of patients, stopping medications in these patients is unnecessary.

This study was supported by the National Institutes of Health (NIH) and the Swedish Research Council. Khalili disclosed grants from the Crohn’s & Coiltis Foundation, the NIH and the Helmsley CharitableTrust, as well as stock ownership in Cylinder Health. One coauthor is employed by Massachusetts General Hospital. Axelrad had no relevant competing interests.







 

TOPLINE: A large-scale case-control study using the Million Veteran Program (MVP) found The study found independent associations of both genetic predisposition and Agent Orange (AO) exposure for several lymphoid malignant neoplasm subtypes.

METHODOLOGY:

• A case-control study included 255,155 US veterans enrolled in the MVP with available genotype, Agent Orange exposure information, and lymphoid malignant neoplasm diagnosis from January 1, 1965, through June T1, 2024.

• Analysis focused on non-Hispanic White veterans (median age 67 years; 92.5% male) due to ancestry distribution requirements for genome-wide association studies data availability.

• Researchers excluded 628 samples across all lymphoid malignant neoplasm groups and 61,343 control samples due to unavailability of AO exposure information.

• Investigators analyzed risk for chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and multiple myeloma as primary outcomes.

TAKEAWAY:

• Agent Orange exposure was associated with increased risk for chronic lymphocytic leukemia (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.40-1.84), diffuse large B-cell lymphoma (OR, 1.26; 95% CI, 1.03-1.53), follicular lymphoma (OR, 1.71; 95% CI, 1.39-2.11), and multiple myeloma (OR, 1.58; 95% CI, 1.35-1.86).

• Polygenic risk scores showed significant associations with all subtypes: chronic lymphocytic leukemia (OR, 1.81; 95% CI, 1.70-1.93), diffuse large B-cell lymphoma (OR, 1.12; 95% CI, 1.02-1.21), follicular lymphoma (OR, 1.33; 95% CI, 1.21-1.47), marginal zone lymphoma (OR, 1.17; 95% CI, 1.04-1.32), and multiple myeloma (OR, 1.41; 95% CI, 1.31-1.52).

• No significant polygenic risk score and AO exposure interactions were observed in the development of any lymphoid malignant neoplasm subtypes.

• The researchers found independent associations of both genetic predisposition and Agent Orange exposure on several lymphoid malignant neoplasm subtypes.

IN PRACTICE:

"Our study addressed the public health concerns surrounding AO exposure and lymphoid malignant neoplasms, finding that both AO exposure and polygenic risk are independently associated with disease, suggesting potentially distinct and additive pathways that merit further investigation,” the authors wrote.

SOURCE: The study was led by Xueyi Teng, PhD, Department of Biological Chemistry, School of Medicine, University of California in Irvine, and Helen Ma, MD, Tibor Rubin Veterans Affairs Medical Center in Long Beach. It was published online in JAMA Network Open.

LIMITATIONS: According to the authors, while this represents the largest study of Agent Orange exposure and genetic risk in lymphoid malignant neoplasm development, the power to find interaction associations in specific subtypes might be limited. Self-reported AO exposure may have introduced survival bias, especially in aggressive subtypes, as patients with aggressive tumors might have died before joining the MVP. Additionally, approximately half of the patients were diagnosed with lymphoid malignant neoplasm before self-reporting AO exposure in the survey, potentially introducing recall bias.

DISCLOSURES: Xueyi Teng, PhD, reported receiving grants from the George E. Hewitt Foundation for Medical Research Postdoc Fellowship during the conduct of the study. The research was supported by grant MVPOOO and Veterans Affairs Career Development Award 1IK2CX002437-O1A1. No other disclosures were reported.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE: A large-scale case-control study using the Million Veteran Program (MVP) found The study found independent associations of both genetic predisposition and Agent Orange (AO) exposure for several lymphoid malignant neoplasm subtypes.

METHODOLOGY:

• A case-control study included 255,155 US veterans enrolled in the MVP with available genotype, Agent Orange exposure information, and lymphoid malignant neoplasm diagnosis from January 1, 1965, through June T1, 2024.

• Analysis focused on non-Hispanic White veterans (median age 67 years; 92.5% male) due to ancestry distribution requirements for genome-wide association studies data availability.

• Researchers excluded 628 samples across all lymphoid malignant neoplasm groups and 61,343 control samples due to unavailability of AO exposure information.

• Investigators analyzed risk for chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and multiple myeloma as primary outcomes.

TAKEAWAY:

• Agent Orange exposure was associated with increased risk for chronic lymphocytic leukemia (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.40-1.84), diffuse large B-cell lymphoma (OR, 1.26; 95% CI, 1.03-1.53), follicular lymphoma (OR, 1.71; 95% CI, 1.39-2.11), and multiple myeloma (OR, 1.58; 95% CI, 1.35-1.86).

• Polygenic risk scores showed significant associations with all subtypes: chronic lymphocytic leukemia (OR, 1.81; 95% CI, 1.70-1.93), diffuse large B-cell lymphoma (OR, 1.12; 95% CI, 1.02-1.21), follicular lymphoma (OR, 1.33; 95% CI, 1.21-1.47), marginal zone lymphoma (OR, 1.17; 95% CI, 1.04-1.32), and multiple myeloma (OR, 1.41; 95% CI, 1.31-1.52).

• No significant polygenic risk score and AO exposure interactions were observed in the development of any lymphoid malignant neoplasm subtypes.

• The researchers found independent associations of both genetic predisposition and Agent Orange exposure on several lymphoid malignant neoplasm subtypes.

IN PRACTICE:

"Our study addressed the public health concerns surrounding AO exposure and lymphoid malignant neoplasms, finding that both AO exposure and polygenic risk are independently associated with disease, suggesting potentially distinct and additive pathways that merit further investigation,” the authors wrote.

SOURCE: The study was led by Xueyi Teng, PhD, Department of Biological Chemistry, School of Medicine, University of California in Irvine, and Helen Ma, MD, Tibor Rubin Veterans Affairs Medical Center in Long Beach. It was published online in JAMA Network Open.

LIMITATIONS: According to the authors, while this represents the largest study of Agent Orange exposure and genetic risk in lymphoid malignant neoplasm development, the power to find interaction associations in specific subtypes might be limited. Self-reported AO exposure may have introduced survival bias, especially in aggressive subtypes, as patients with aggressive tumors might have died before joining the MVP. Additionally, approximately half of the patients were diagnosed with lymphoid malignant neoplasm before self-reporting AO exposure in the survey, potentially introducing recall bias.

DISCLOSURES: Xueyi Teng, PhD, reported receiving grants from the George E. Hewitt Foundation for Medical Research Postdoc Fellowship during the conduct of the study. The research was supported by grant MVPOOO and Veterans Affairs Career Development Award 1IK2CX002437-O1A1. No other disclosures were reported.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE: A large-scale case-control study using the Million Veteran Program (MVP) found The study found independent associations of both genetic predisposition and Agent Orange (AO) exposure for several lymphoid malignant neoplasm subtypes.

METHODOLOGY:

• A case-control study included 255,155 US veterans enrolled in the MVP with available genotype, Agent Orange exposure information, and lymphoid malignant neoplasm diagnosis from January 1, 1965, through June T1, 2024.

• Analysis focused on non-Hispanic White veterans (median age 67 years; 92.5% male) due to ancestry distribution requirements for genome-wide association studies data availability.

• Researchers excluded 628 samples across all lymphoid malignant neoplasm groups and 61,343 control samples due to unavailability of AO exposure information.

• Investigators analyzed risk for chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and multiple myeloma as primary outcomes.

TAKEAWAY:

• Agent Orange exposure was associated with increased risk for chronic lymphocytic leukemia (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.40-1.84), diffuse large B-cell lymphoma (OR, 1.26; 95% CI, 1.03-1.53), follicular lymphoma (OR, 1.71; 95% CI, 1.39-2.11), and multiple myeloma (OR, 1.58; 95% CI, 1.35-1.86).

• Polygenic risk scores showed significant associations with all subtypes: chronic lymphocytic leukemia (OR, 1.81; 95% CI, 1.70-1.93), diffuse large B-cell lymphoma (OR, 1.12; 95% CI, 1.02-1.21), follicular lymphoma (OR, 1.33; 95% CI, 1.21-1.47), marginal zone lymphoma (OR, 1.17; 95% CI, 1.04-1.32), and multiple myeloma (OR, 1.41; 95% CI, 1.31-1.52).

• No significant polygenic risk score and AO exposure interactions were observed in the development of any lymphoid malignant neoplasm subtypes.

• The researchers found independent associations of both genetic predisposition and Agent Orange exposure on several lymphoid malignant neoplasm subtypes.

IN PRACTICE:

"Our study addressed the public health concerns surrounding AO exposure and lymphoid malignant neoplasms, finding that both AO exposure and polygenic risk are independently associated with disease, suggesting potentially distinct and additive pathways that merit further investigation,” the authors wrote.

SOURCE: The study was led by Xueyi Teng, PhD, Department of Biological Chemistry, School of Medicine, University of California in Irvine, and Helen Ma, MD, Tibor Rubin Veterans Affairs Medical Center in Long Beach. It was published online in JAMA Network Open.

LIMITATIONS: According to the authors, while this represents the largest study of Agent Orange exposure and genetic risk in lymphoid malignant neoplasm development, the power to find interaction associations in specific subtypes might be limited. Self-reported AO exposure may have introduced survival bias, especially in aggressive subtypes, as patients with aggressive tumors might have died before joining the MVP. Additionally, approximately half of the patients were diagnosed with lymphoid malignant neoplasm before self-reporting AO exposure in the survey, potentially introducing recall bias.

DISCLOSURES: Xueyi Teng, PhD, reported receiving grants from the George E. Hewitt Foundation for Medical Research Postdoc Fellowship during the conduct of the study. The research was supported by grant MVPOOO and Veterans Affairs Career Development Award 1IK2CX002437-O1A1. No other disclosures were reported.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.