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Skip Antibiotic Prophylaxis for Upper GI Bleeding in Cirrhosis?
Pooled data from 14 randomized controlled trials (RCTs) found a high probability that no or shorter durations of antibiotic prophylaxis are not worse than longer durations in preventing death from any cause in these patients.
The findings suggest that recommendations for routine antibiotic prophylaxis in patients with cirrhosis and upper GI bleeding “should be reassessed,” the authors said.
They acknowledged, however, that the studies were of low-to-moderate quality and higher quality randomized clinical trial data are needed.
The study, with first author Connor Prosty, MD, of McGill University, in Montreal, Quebec, Canada, was published online in JAMA Internal Medicine.
Questionable Benefit?
Antibiotic prophylaxis became standard decades ago, when up to 60% of variceal bleeds were complicated by infections, which were thought to increase the risk for rebleeding and death.
Yet, the evidence to support the recommendation remains limited, and a recent RCT called into question the necessity of prophylaxis. The study showed no statistically significant difference in mortality or infection among patients with Child-Pugh class A cirrhosis randomized to receive no prophylaxis compared to third-generation cephalosporin.
While generally perceived as safe, antibiotics have potential adverse effects and can select for resistant superinfections, Prosty and colleagues pointed out.
They also noted that shorter courses of antibiotics have been proven to be as good, if not better, than longer courses across numerous other infectious indications. Recommendations for primary and secondary antibiotic prophylaxis for spontaneous bacterial peritonitis are being reassessed due to a weak evidence base, lack of mortality benefit, and potential for harm.
To revisit antibiotic prophylaxis for upper GI bleeding in patients with cirrhosis, Prosty and colleagues did a systematic review and meta-analysis of 14 RCTs involving 1322 patients.
Two of the trials compared longer (5-7 days) with shorter (2-3 days) antibiotics, and 12 compared any antibiotic prophylaxis (1-10 days) to none.
The primary outcome was all-cause mortality, with a prespecified noninferiority margin of 5% on the risk difference (RD) scale. Secondary outcomes included early rebleeding and bacterial infections.
Overall, shorter antibiotic durations (including none) had a 97.3% probability of noninferiority to longer durations for all-cause mortality (RD, 0.9%; 95% credible interval [CrI], -2.6% to 4.9%).
Shorter durations had a 73.8% probability of noninferiority for early rebleeding (RD, 2.9%; 95% CrI, -4.2% to 10.0%) but were associated with more study-defined bacterial infections (RD, 15.2%; 95% CrI, 5.0%-25.9%). However, the authors cited methodological concerns about the definitions of these infections in the included studies.
The probabilities of noninferiority of shorter durations for mortality, early rebleeding, and bacterial infections were higher in studies published after 2004.
Change Practice Now?
“Our findings re-open the discussion surrounding the long-standing and firmly held belief that antibiotic prophylaxis has a mortality benefit in patients with cirrhosis presenting with upper gastrointestinal bleeds,” Prosty and colleagues wrote.
They cautioned, however, that the study quality was “low to moderate, bacterial infections were heterogeneously defined, and no studies reported adverse events. Higher-quality RCTs are needed to determine the benefit and optimal duration of antibiotic prophylaxis in the modern era of advanced interventions.”
The authors of a commentary published with the study noted that management of upper GI bleeding in cirrhosis patients has “greatly improved” since the 1990s, when some of the trials included in the analysis were conducted.
Hepatologists Catherine Mezzacappa, MD, MPH, and Guadalupe Garcia-Tsao, MD, both at the Yale School of Medicine, New Haven, Connecticut, agree that it “may be time to revisit whether prophylactic antibiotics continue to provide benefit in patients with cirrhosis and upper GI bleeding, and if so, in which patients.”
They caution, however, that the current level of evidence is “inadequate to answer whether it is time to stop this practice, which has become the standard of care.
New trials for shorter duration and no antibiotic prophylaxis “should be designed in specific patient populations to compare sequelae of antibiotic prophylaxis, including subsequent infections and all-cause mortality,” Mezzacappa and Garcia-Tsao concluded.
The study received no specific funding. The authors and commentary writers had no relevant disclosures.
A version of this article appeared on Medscape.com.
Pooled data from 14 randomized controlled trials (RCTs) found a high probability that no or shorter durations of antibiotic prophylaxis are not worse than longer durations in preventing death from any cause in these patients.
The findings suggest that recommendations for routine antibiotic prophylaxis in patients with cirrhosis and upper GI bleeding “should be reassessed,” the authors said.
They acknowledged, however, that the studies were of low-to-moderate quality and higher quality randomized clinical trial data are needed.
The study, with first author Connor Prosty, MD, of McGill University, in Montreal, Quebec, Canada, was published online in JAMA Internal Medicine.
Questionable Benefit?
Antibiotic prophylaxis became standard decades ago, when up to 60% of variceal bleeds were complicated by infections, which were thought to increase the risk for rebleeding and death.
Yet, the evidence to support the recommendation remains limited, and a recent RCT called into question the necessity of prophylaxis. The study showed no statistically significant difference in mortality or infection among patients with Child-Pugh class A cirrhosis randomized to receive no prophylaxis compared to third-generation cephalosporin.
While generally perceived as safe, antibiotics have potential adverse effects and can select for resistant superinfections, Prosty and colleagues pointed out.
They also noted that shorter courses of antibiotics have been proven to be as good, if not better, than longer courses across numerous other infectious indications. Recommendations for primary and secondary antibiotic prophylaxis for spontaneous bacterial peritonitis are being reassessed due to a weak evidence base, lack of mortality benefit, and potential for harm.
To revisit antibiotic prophylaxis for upper GI bleeding in patients with cirrhosis, Prosty and colleagues did a systematic review and meta-analysis of 14 RCTs involving 1322 patients.
Two of the trials compared longer (5-7 days) with shorter (2-3 days) antibiotics, and 12 compared any antibiotic prophylaxis (1-10 days) to none.
The primary outcome was all-cause mortality, with a prespecified noninferiority margin of 5% on the risk difference (RD) scale. Secondary outcomes included early rebleeding and bacterial infections.
Overall, shorter antibiotic durations (including none) had a 97.3% probability of noninferiority to longer durations for all-cause mortality (RD, 0.9%; 95% credible interval [CrI], -2.6% to 4.9%).
Shorter durations had a 73.8% probability of noninferiority for early rebleeding (RD, 2.9%; 95% CrI, -4.2% to 10.0%) but were associated with more study-defined bacterial infections (RD, 15.2%; 95% CrI, 5.0%-25.9%). However, the authors cited methodological concerns about the definitions of these infections in the included studies.
The probabilities of noninferiority of shorter durations for mortality, early rebleeding, and bacterial infections were higher in studies published after 2004.
Change Practice Now?
“Our findings re-open the discussion surrounding the long-standing and firmly held belief that antibiotic prophylaxis has a mortality benefit in patients with cirrhosis presenting with upper gastrointestinal bleeds,” Prosty and colleagues wrote.
They cautioned, however, that the study quality was “low to moderate, bacterial infections were heterogeneously defined, and no studies reported adverse events. Higher-quality RCTs are needed to determine the benefit and optimal duration of antibiotic prophylaxis in the modern era of advanced interventions.”
The authors of a commentary published with the study noted that management of upper GI bleeding in cirrhosis patients has “greatly improved” since the 1990s, when some of the trials included in the analysis were conducted.
Hepatologists Catherine Mezzacappa, MD, MPH, and Guadalupe Garcia-Tsao, MD, both at the Yale School of Medicine, New Haven, Connecticut, agree that it “may be time to revisit whether prophylactic antibiotics continue to provide benefit in patients with cirrhosis and upper GI bleeding, and if so, in which patients.”
They caution, however, that the current level of evidence is “inadequate to answer whether it is time to stop this practice, which has become the standard of care.
New trials for shorter duration and no antibiotic prophylaxis “should be designed in specific patient populations to compare sequelae of antibiotic prophylaxis, including subsequent infections and all-cause mortality,” Mezzacappa and Garcia-Tsao concluded.
The study received no specific funding. The authors and commentary writers had no relevant disclosures.
A version of this article appeared on Medscape.com.
Pooled data from 14 randomized controlled trials (RCTs) found a high probability that no or shorter durations of antibiotic prophylaxis are not worse than longer durations in preventing death from any cause in these patients.
The findings suggest that recommendations for routine antibiotic prophylaxis in patients with cirrhosis and upper GI bleeding “should be reassessed,” the authors said.
They acknowledged, however, that the studies were of low-to-moderate quality and higher quality randomized clinical trial data are needed.
The study, with first author Connor Prosty, MD, of McGill University, in Montreal, Quebec, Canada, was published online in JAMA Internal Medicine.
Questionable Benefit?
Antibiotic prophylaxis became standard decades ago, when up to 60% of variceal bleeds were complicated by infections, which were thought to increase the risk for rebleeding and death.
Yet, the evidence to support the recommendation remains limited, and a recent RCT called into question the necessity of prophylaxis. The study showed no statistically significant difference in mortality or infection among patients with Child-Pugh class A cirrhosis randomized to receive no prophylaxis compared to third-generation cephalosporin.
While generally perceived as safe, antibiotics have potential adverse effects and can select for resistant superinfections, Prosty and colleagues pointed out.
They also noted that shorter courses of antibiotics have been proven to be as good, if not better, than longer courses across numerous other infectious indications. Recommendations for primary and secondary antibiotic prophylaxis for spontaneous bacterial peritonitis are being reassessed due to a weak evidence base, lack of mortality benefit, and potential for harm.
To revisit antibiotic prophylaxis for upper GI bleeding in patients with cirrhosis, Prosty and colleagues did a systematic review and meta-analysis of 14 RCTs involving 1322 patients.
Two of the trials compared longer (5-7 days) with shorter (2-3 days) antibiotics, and 12 compared any antibiotic prophylaxis (1-10 days) to none.
The primary outcome was all-cause mortality, with a prespecified noninferiority margin of 5% on the risk difference (RD) scale. Secondary outcomes included early rebleeding and bacterial infections.
Overall, shorter antibiotic durations (including none) had a 97.3% probability of noninferiority to longer durations for all-cause mortality (RD, 0.9%; 95% credible interval [CrI], -2.6% to 4.9%).
Shorter durations had a 73.8% probability of noninferiority for early rebleeding (RD, 2.9%; 95% CrI, -4.2% to 10.0%) but were associated with more study-defined bacterial infections (RD, 15.2%; 95% CrI, 5.0%-25.9%). However, the authors cited methodological concerns about the definitions of these infections in the included studies.
The probabilities of noninferiority of shorter durations for mortality, early rebleeding, and bacterial infections were higher in studies published after 2004.
Change Practice Now?
“Our findings re-open the discussion surrounding the long-standing and firmly held belief that antibiotic prophylaxis has a mortality benefit in patients with cirrhosis presenting with upper gastrointestinal bleeds,” Prosty and colleagues wrote.
They cautioned, however, that the study quality was “low to moderate, bacterial infections were heterogeneously defined, and no studies reported adverse events. Higher-quality RCTs are needed to determine the benefit and optimal duration of antibiotic prophylaxis in the modern era of advanced interventions.”
The authors of a commentary published with the study noted that management of upper GI bleeding in cirrhosis patients has “greatly improved” since the 1990s, when some of the trials included in the analysis were conducted.
Hepatologists Catherine Mezzacappa, MD, MPH, and Guadalupe Garcia-Tsao, MD, both at the Yale School of Medicine, New Haven, Connecticut, agree that it “may be time to revisit whether prophylactic antibiotics continue to provide benefit in patients with cirrhosis and upper GI bleeding, and if so, in which patients.”
They caution, however, that the current level of evidence is “inadequate to answer whether it is time to stop this practice, which has become the standard of care.
New trials for shorter duration and no antibiotic prophylaxis “should be designed in specific patient populations to compare sequelae of antibiotic prophylaxis, including subsequent infections and all-cause mortality,” Mezzacappa and Garcia-Tsao concluded.
The study received no specific funding. The authors and commentary writers had no relevant disclosures.
A version of this article appeared on Medscape.com.
New Treatment Guidance Issued for Challenging Overlap of Hypermobility Syndromes and GI Symptoms
to help clinicians comprehend such cases.
“Recognizing and treating GI symptoms in patients with hEDS or hypermobility spectrum disorders and comorbid POTS or MCAS present major challenges for clinicians, who often feel under equipped to address their needs,” AGA reported in the update, published in Clinical Gastroenterology and Hepatology.
Importantly, “the poor understanding of these overlapping syndromes can lead to nonstandardized approaches to diagnostic evaluation and management,” the authors noted.
“Gastroenterology providers should be aware of the features of [these syndromes] to recognize the full complexity of patients presenting with multisystemic symptoms.”
Hypermobility spectrum disorders, which include hEDS, are typically genetic, and patients experience pain along with joint hypermobility, or extreme flexibility of joints beyond the normal range of motion.
With research showing that most of those patients — up to 98% — also experience GI symptoms, gastroenterologists may be encountering them more commonly than realized, Lucinda A. Harris, MD, AGAF, of the Mayo Clinic School of Medicine, in Scottsdale, Arizona, explained to GI & Hepatology News.
“As our knowledge in gastroenterology has progressed, we realize that hypermobility itself predisposes individuals to disorders of brain-gut interaction,” she said. “We may only be seeing the tip of the iceberg when it comes to diagnosing patients with hypermobility.”
Additionally, “many of these patients have POTS, which has also been increasingly diagnosed,” Harris added. “The strong overlap of these conditions prompted us to present this data.”
With a lack of evidence-based understanding of the overlapping syndromes, AGA’s guidance does not carry formal ratings but is drawn from a review of the published literature and expert opinion.
In addition to the key recommendation of being aware of the observed combination of syndromes, their recommendations include:
- Regarding testing: Testing for POTS/MCAS should be targeted to patients presenting with clinical manifestations of the disorders, but universal testing for POTS/MCAS in all patients with hEDS or hypermobility spectrum disorders is not currently supported by the evidence, the guidance advises.
- Gastroenterologists seeing patients with disorders of gut-brain interaction should inquire about joint hypermobility and strongly consider incorporating the Beighton score for assessing joint hypermobility into their practice as a screening tool; if the screen is positive, gastroenterologists may consider applying 2017 diagnostic criteria to diagnose hEDS or offer appropriate referral to a specialist where resources are available, the AGA recommends.
- Medical management: Management of GI symptoms in hEDS or hypermobility spectrum disorders and POTS/MCAS should focus on treating the most prominent GI symptoms and abnormal GI function test results.
- In addition to general disorders of gut-brain interactions and GI motility disorder treatment, management should also include treating any symptoms attributable to POTS and/or MCAS.
Treatment of POTS may include increasing fluid and salt intake, exercise training, and use of compression garments. Special pharmacological treatments for volume expansion, heart rate control, and vasoconstriction with integrated care from multiple specialties (eg, cardiology, neurology) should be considered in patients who do not respond to conservative lifestyle measures.
In patients presenting to gastroenterology providers, testing for mast cell disorders including MCAS should be considered in patients with hEDS or hypermobility spectrum disorders and disorders of gut-brain interaction with episodic symptoms that suggest a more generalized mast cell disorder involving two or more physiological systems. However, current data does not support the use of these tests for routine evaluation of GI symptoms in all patients with hEDS or hypermobility spectrum disorders without clinical or laboratory evidence of a primary or secondary mast cell disorder, the authors noted.
Harris explained that patients presenting with gut-brain disorders are often mistakenly classified as having irritable bowel syndrome or dyspepsia, whereas these conditions may be affecting the GI disorders they have.
“For example, a patient with Ehlers-Danlos syndrome might have problems with constipation, which is impacted by pelvic floor dysfunction,” she said. “Due to their hypermobility, they may experience more pelvic floor descent than usual.”
“If we do not recognize this, the patient risks developing rectal prolapse or not effectively addressing their constipation.”
Regarding patient characteristics, Harris said that those with hEDS and POTS appear to more likely be women and tend to present in younger patients, aged 18-50 years. Of note, there is no genetic test for hEDS.
“The take-home point for clinicians should be to consider POTS and Ehlers-Danlos syndrome when encountering young female patients with symptoms of palpitations, hypermobility, and orthostatic intolerance,” she said.
“Recognizing hypermobility is crucial, not only for GI symptoms but also to prevent joint dislocations, tendon ruptures, and other connective tissue issues.”
Clinicians are further urged to “offer informed counseling, and guide patients away from unreliable sources or fragmented care to foster therapeutic relationships and evidence-based care,” the authors added.
Deciphering Gut-Brain Disorder Challenges
Commenting to GI & Hepatology News, Clair Francomano, MD, a professor of medical and molecular genetics at the Indiana University School of Medicine, in Indianapolis, said the new guidance sheds important light on the syndromes.
“I’m delighted to see this guidance offered through the AGA as it will encourage gastroenterologists to think of EDS, POTS and MCAS when they are evaluating patients with disorders of gut-brain interaction,” Francomano said.
“This should allow patients to receive more accurate and timely diagnoses and appropriate management.”
Francomano noted that the Ehlers-Danlos Society, which provides information for clinicians and patients alike on the syndromes, and where she serves on the medical scientific board, has also been active in raising awareness.
“While co-occurrence of POTS and MCAS with EDS has in fact been recognized for many years, I do think awareness is increasing, in large part due to the advocacy and educational efforts of the Ehlers-Danlos Society,” she said.
The take-home message? “When clinicians see disorders of the gut-brain axis, POTS or MCAS, they should be thinking, ‘Could this be related to joint hypermobility or Ehlers-Danlos syndrome?’” Francomano said.
Harris reported serving as a consultant for AbbVie, Ardelyx, Salix, and Gemelli Biotech and reported receiving research support from Takeda and Anyx. Francomano did not report any relevant disclosures.
A version of this article appeared on Medscape.com.
to help clinicians comprehend such cases.
“Recognizing and treating GI symptoms in patients with hEDS or hypermobility spectrum disorders and comorbid POTS or MCAS present major challenges for clinicians, who often feel under equipped to address their needs,” AGA reported in the update, published in Clinical Gastroenterology and Hepatology.
Importantly, “the poor understanding of these overlapping syndromes can lead to nonstandardized approaches to diagnostic evaluation and management,” the authors noted.
“Gastroenterology providers should be aware of the features of [these syndromes] to recognize the full complexity of patients presenting with multisystemic symptoms.”
Hypermobility spectrum disorders, which include hEDS, are typically genetic, and patients experience pain along with joint hypermobility, or extreme flexibility of joints beyond the normal range of motion.
With research showing that most of those patients — up to 98% — also experience GI symptoms, gastroenterologists may be encountering them more commonly than realized, Lucinda A. Harris, MD, AGAF, of the Mayo Clinic School of Medicine, in Scottsdale, Arizona, explained to GI & Hepatology News.
“As our knowledge in gastroenterology has progressed, we realize that hypermobility itself predisposes individuals to disorders of brain-gut interaction,” she said. “We may only be seeing the tip of the iceberg when it comes to diagnosing patients with hypermobility.”
Additionally, “many of these patients have POTS, which has also been increasingly diagnosed,” Harris added. “The strong overlap of these conditions prompted us to present this data.”
With a lack of evidence-based understanding of the overlapping syndromes, AGA’s guidance does not carry formal ratings but is drawn from a review of the published literature and expert opinion.
In addition to the key recommendation of being aware of the observed combination of syndromes, their recommendations include:
- Regarding testing: Testing for POTS/MCAS should be targeted to patients presenting with clinical manifestations of the disorders, but universal testing for POTS/MCAS in all patients with hEDS or hypermobility spectrum disorders is not currently supported by the evidence, the guidance advises.
- Gastroenterologists seeing patients with disorders of gut-brain interaction should inquire about joint hypermobility and strongly consider incorporating the Beighton score for assessing joint hypermobility into their practice as a screening tool; if the screen is positive, gastroenterologists may consider applying 2017 diagnostic criteria to diagnose hEDS or offer appropriate referral to a specialist where resources are available, the AGA recommends.
- Medical management: Management of GI symptoms in hEDS or hypermobility spectrum disorders and POTS/MCAS should focus on treating the most prominent GI symptoms and abnormal GI function test results.
- In addition to general disorders of gut-brain interactions and GI motility disorder treatment, management should also include treating any symptoms attributable to POTS and/or MCAS.
Treatment of POTS may include increasing fluid and salt intake, exercise training, and use of compression garments. Special pharmacological treatments for volume expansion, heart rate control, and vasoconstriction with integrated care from multiple specialties (eg, cardiology, neurology) should be considered in patients who do not respond to conservative lifestyle measures.
In patients presenting to gastroenterology providers, testing for mast cell disorders including MCAS should be considered in patients with hEDS or hypermobility spectrum disorders and disorders of gut-brain interaction with episodic symptoms that suggest a more generalized mast cell disorder involving two or more physiological systems. However, current data does not support the use of these tests for routine evaluation of GI symptoms in all patients with hEDS or hypermobility spectrum disorders without clinical or laboratory evidence of a primary or secondary mast cell disorder, the authors noted.
Harris explained that patients presenting with gut-brain disorders are often mistakenly classified as having irritable bowel syndrome or dyspepsia, whereas these conditions may be affecting the GI disorders they have.
“For example, a patient with Ehlers-Danlos syndrome might have problems with constipation, which is impacted by pelvic floor dysfunction,” she said. “Due to their hypermobility, they may experience more pelvic floor descent than usual.”
“If we do not recognize this, the patient risks developing rectal prolapse or not effectively addressing their constipation.”
Regarding patient characteristics, Harris said that those with hEDS and POTS appear to more likely be women and tend to present in younger patients, aged 18-50 years. Of note, there is no genetic test for hEDS.
“The take-home point for clinicians should be to consider POTS and Ehlers-Danlos syndrome when encountering young female patients with symptoms of palpitations, hypermobility, and orthostatic intolerance,” she said.
“Recognizing hypermobility is crucial, not only for GI symptoms but also to prevent joint dislocations, tendon ruptures, and other connective tissue issues.”
Clinicians are further urged to “offer informed counseling, and guide patients away from unreliable sources or fragmented care to foster therapeutic relationships and evidence-based care,” the authors added.
Deciphering Gut-Brain Disorder Challenges
Commenting to GI & Hepatology News, Clair Francomano, MD, a professor of medical and molecular genetics at the Indiana University School of Medicine, in Indianapolis, said the new guidance sheds important light on the syndromes.
“I’m delighted to see this guidance offered through the AGA as it will encourage gastroenterologists to think of EDS, POTS and MCAS when they are evaluating patients with disorders of gut-brain interaction,” Francomano said.
“This should allow patients to receive more accurate and timely diagnoses and appropriate management.”
Francomano noted that the Ehlers-Danlos Society, which provides information for clinicians and patients alike on the syndromes, and where she serves on the medical scientific board, has also been active in raising awareness.
“While co-occurrence of POTS and MCAS with EDS has in fact been recognized for many years, I do think awareness is increasing, in large part due to the advocacy and educational efforts of the Ehlers-Danlos Society,” she said.
The take-home message? “When clinicians see disorders of the gut-brain axis, POTS or MCAS, they should be thinking, ‘Could this be related to joint hypermobility or Ehlers-Danlos syndrome?’” Francomano said.
Harris reported serving as a consultant for AbbVie, Ardelyx, Salix, and Gemelli Biotech and reported receiving research support from Takeda and Anyx. Francomano did not report any relevant disclosures.
A version of this article appeared on Medscape.com.
to help clinicians comprehend such cases.
“Recognizing and treating GI symptoms in patients with hEDS or hypermobility spectrum disorders and comorbid POTS or MCAS present major challenges for clinicians, who often feel under equipped to address their needs,” AGA reported in the update, published in Clinical Gastroenterology and Hepatology.
Importantly, “the poor understanding of these overlapping syndromes can lead to nonstandardized approaches to diagnostic evaluation and management,” the authors noted.
“Gastroenterology providers should be aware of the features of [these syndromes] to recognize the full complexity of patients presenting with multisystemic symptoms.”
Hypermobility spectrum disorders, which include hEDS, are typically genetic, and patients experience pain along with joint hypermobility, or extreme flexibility of joints beyond the normal range of motion.
With research showing that most of those patients — up to 98% — also experience GI symptoms, gastroenterologists may be encountering them more commonly than realized, Lucinda A. Harris, MD, AGAF, of the Mayo Clinic School of Medicine, in Scottsdale, Arizona, explained to GI & Hepatology News.
“As our knowledge in gastroenterology has progressed, we realize that hypermobility itself predisposes individuals to disorders of brain-gut interaction,” she said. “We may only be seeing the tip of the iceberg when it comes to diagnosing patients with hypermobility.”
Additionally, “many of these patients have POTS, which has also been increasingly diagnosed,” Harris added. “The strong overlap of these conditions prompted us to present this data.”
With a lack of evidence-based understanding of the overlapping syndromes, AGA’s guidance does not carry formal ratings but is drawn from a review of the published literature and expert opinion.
In addition to the key recommendation of being aware of the observed combination of syndromes, their recommendations include:
- Regarding testing: Testing for POTS/MCAS should be targeted to patients presenting with clinical manifestations of the disorders, but universal testing for POTS/MCAS in all patients with hEDS or hypermobility spectrum disorders is not currently supported by the evidence, the guidance advises.
- Gastroenterologists seeing patients with disorders of gut-brain interaction should inquire about joint hypermobility and strongly consider incorporating the Beighton score for assessing joint hypermobility into their practice as a screening tool; if the screen is positive, gastroenterologists may consider applying 2017 diagnostic criteria to diagnose hEDS or offer appropriate referral to a specialist where resources are available, the AGA recommends.
- Medical management: Management of GI symptoms in hEDS or hypermobility spectrum disorders and POTS/MCAS should focus on treating the most prominent GI symptoms and abnormal GI function test results.
- In addition to general disorders of gut-brain interactions and GI motility disorder treatment, management should also include treating any symptoms attributable to POTS and/or MCAS.
Treatment of POTS may include increasing fluid and salt intake, exercise training, and use of compression garments. Special pharmacological treatments for volume expansion, heart rate control, and vasoconstriction with integrated care from multiple specialties (eg, cardiology, neurology) should be considered in patients who do not respond to conservative lifestyle measures.
In patients presenting to gastroenterology providers, testing for mast cell disorders including MCAS should be considered in patients with hEDS or hypermobility spectrum disorders and disorders of gut-brain interaction with episodic symptoms that suggest a more generalized mast cell disorder involving two or more physiological systems. However, current data does not support the use of these tests for routine evaluation of GI symptoms in all patients with hEDS or hypermobility spectrum disorders without clinical or laboratory evidence of a primary or secondary mast cell disorder, the authors noted.
Harris explained that patients presenting with gut-brain disorders are often mistakenly classified as having irritable bowel syndrome or dyspepsia, whereas these conditions may be affecting the GI disorders they have.
“For example, a patient with Ehlers-Danlos syndrome might have problems with constipation, which is impacted by pelvic floor dysfunction,” she said. “Due to their hypermobility, they may experience more pelvic floor descent than usual.”
“If we do not recognize this, the patient risks developing rectal prolapse or not effectively addressing their constipation.”
Regarding patient characteristics, Harris said that those with hEDS and POTS appear to more likely be women and tend to present in younger patients, aged 18-50 years. Of note, there is no genetic test for hEDS.
“The take-home point for clinicians should be to consider POTS and Ehlers-Danlos syndrome when encountering young female patients with symptoms of palpitations, hypermobility, and orthostatic intolerance,” she said.
“Recognizing hypermobility is crucial, not only for GI symptoms but also to prevent joint dislocations, tendon ruptures, and other connective tissue issues.”
Clinicians are further urged to “offer informed counseling, and guide patients away from unreliable sources or fragmented care to foster therapeutic relationships and evidence-based care,” the authors added.
Deciphering Gut-Brain Disorder Challenges
Commenting to GI & Hepatology News, Clair Francomano, MD, a professor of medical and molecular genetics at the Indiana University School of Medicine, in Indianapolis, said the new guidance sheds important light on the syndromes.
“I’m delighted to see this guidance offered through the AGA as it will encourage gastroenterologists to think of EDS, POTS and MCAS when they are evaluating patients with disorders of gut-brain interaction,” Francomano said.
“This should allow patients to receive more accurate and timely diagnoses and appropriate management.”
Francomano noted that the Ehlers-Danlos Society, which provides information for clinicians and patients alike on the syndromes, and where she serves on the medical scientific board, has also been active in raising awareness.
“While co-occurrence of POTS and MCAS with EDS has in fact been recognized for many years, I do think awareness is increasing, in large part due to the advocacy and educational efforts of the Ehlers-Danlos Society,” she said.
The take-home message? “When clinicians see disorders of the gut-brain axis, POTS or MCAS, they should be thinking, ‘Could this be related to joint hypermobility or Ehlers-Danlos syndrome?’” Francomano said.
Harris reported serving as a consultant for AbbVie, Ardelyx, Salix, and Gemelli Biotech and reported receiving research support from Takeda and Anyx. Francomano did not report any relevant disclosures.
A version of this article appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Journal Highlights: May-July 2025
Esophagus/Motility
Nguyen AD, et al. AGA Clinical Practice Update on Incorporating Functional Lumen Imaging Probe Into Esophageal Clinical Practice: Expert Review. Gastroenterology. 2025 Jul. doi: 10.1053/j.gastro.2025.05.011.
Hartnett DA, et al. Distribution of Esophageal Eosinophilia as a Predictor of Proton Pump Inhibitor Response in Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2025 Jul. doi: 10.1016/j.cgh.2025.06.032.
Gyawali CP, et al. pH Impedance Monitoring on Proton Pump Inhibitor Therapy Impacts Management Decisions in Proven GERD but not in Unproven GERD. Clin Gastroenterol Hepatol. 2025 May. doi: 10.1016/j.cgh.2025.02.032.
Stomach
Wiklund AK, et al. Risk of Gastric Adenocarcinoma After Eradication of Helicobacter pylori. Gastroenterology. 2025 Feb. doi: 10.1053/j.gastro.2025.01.239.
Sonaiya S, et al. Over-the-Scope Clip versus Standard Endoscopic Therapy as First-Line Intervention for Nonvariceal Upper Gastrointestinal Bleeding: A Cost-Effectiveness Analysis. Tech Innov Gastrointest. 2025 Jun. doi: 10.1016/j.tige.2025.250935.
Colon
Hassan C, et al. Colon Cancer Screening, Surveillance, and Treatment: Novel Artificial Intelligence Driving Strategies in the Management of Colon Lesions. Gastroenterology. 2025 Mar. doi: 10.1053/j.gastro.2025.02.021.
Pancreas
Wilcox CM, et al; US Pancreatic Disease Study Group. Management of the Disconnected Pancreatic Duct in Pancreatic Necrosis. Clin Gastroenterol Hepatol. 2025 Jul. doi: 10.1016/j.cgh.2025.05.024.
Ghimire C, et al. The effect of advances in pancreatic cancer treatment in population mortality: A SEER-based study. Gastro Hep Adv. 2025 Jul. doi: 10.1016/j.gastha.2025.100739.
Hepatology
Canivet CM, et al. Validation of the AASLD/EASL Multi-Step Screening Strategies for MASLD. Gastro Hep Adv. 2025 Jul. doi: 10.1016/j.gastha.2025.100747.
Miscellaneous
Chang L, et al. Gut Feelings: The Critical Role of Interoception in Obesity and Disorders of Gut-Brain Interaction. Gastroenterology. 2025 Aug. doi: 10.1053/j.gastro.2025.04.002.
Bashiri K, et al. Advancing Hemostatic Powder Technologies for Management of Gastrointestinal Bleeding: Challenges and Solutions. Tech Innov Gastrointest. 2025 Jul. doi: 10.1016/j.tige.2025.250940.
Dr. Trieu is assistant professor of medicine, interventional endoscopy, in the Division of Gastroenterology at Washington University in St. Louis School of Medicine, Missouri.
Esophagus/Motility
Nguyen AD, et al. AGA Clinical Practice Update on Incorporating Functional Lumen Imaging Probe Into Esophageal Clinical Practice: Expert Review. Gastroenterology. 2025 Jul. doi: 10.1053/j.gastro.2025.05.011.
Hartnett DA, et al. Distribution of Esophageal Eosinophilia as a Predictor of Proton Pump Inhibitor Response in Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2025 Jul. doi: 10.1016/j.cgh.2025.06.032.
Gyawali CP, et al. pH Impedance Monitoring on Proton Pump Inhibitor Therapy Impacts Management Decisions in Proven GERD but not in Unproven GERD. Clin Gastroenterol Hepatol. 2025 May. doi: 10.1016/j.cgh.2025.02.032.
Stomach
Wiklund AK, et al. Risk of Gastric Adenocarcinoma After Eradication of Helicobacter pylori. Gastroenterology. 2025 Feb. doi: 10.1053/j.gastro.2025.01.239.
Sonaiya S, et al. Over-the-Scope Clip versus Standard Endoscopic Therapy as First-Line Intervention for Nonvariceal Upper Gastrointestinal Bleeding: A Cost-Effectiveness Analysis. Tech Innov Gastrointest. 2025 Jun. doi: 10.1016/j.tige.2025.250935.
Colon
Hassan C, et al. Colon Cancer Screening, Surveillance, and Treatment: Novel Artificial Intelligence Driving Strategies in the Management of Colon Lesions. Gastroenterology. 2025 Mar. doi: 10.1053/j.gastro.2025.02.021.
Pancreas
Wilcox CM, et al; US Pancreatic Disease Study Group. Management of the Disconnected Pancreatic Duct in Pancreatic Necrosis. Clin Gastroenterol Hepatol. 2025 Jul. doi: 10.1016/j.cgh.2025.05.024.
Ghimire C, et al. The effect of advances in pancreatic cancer treatment in population mortality: A SEER-based study. Gastro Hep Adv. 2025 Jul. doi: 10.1016/j.gastha.2025.100739.
Hepatology
Canivet CM, et al. Validation of the AASLD/EASL Multi-Step Screening Strategies for MASLD. Gastro Hep Adv. 2025 Jul. doi: 10.1016/j.gastha.2025.100747.
Miscellaneous
Chang L, et al. Gut Feelings: The Critical Role of Interoception in Obesity and Disorders of Gut-Brain Interaction. Gastroenterology. 2025 Aug. doi: 10.1053/j.gastro.2025.04.002.
Bashiri K, et al. Advancing Hemostatic Powder Technologies for Management of Gastrointestinal Bleeding: Challenges and Solutions. Tech Innov Gastrointest. 2025 Jul. doi: 10.1016/j.tige.2025.250940.
Dr. Trieu is assistant professor of medicine, interventional endoscopy, in the Division of Gastroenterology at Washington University in St. Louis School of Medicine, Missouri.
Esophagus/Motility
Nguyen AD, et al. AGA Clinical Practice Update on Incorporating Functional Lumen Imaging Probe Into Esophageal Clinical Practice: Expert Review. Gastroenterology. 2025 Jul. doi: 10.1053/j.gastro.2025.05.011.
Hartnett DA, et al. Distribution of Esophageal Eosinophilia as a Predictor of Proton Pump Inhibitor Response in Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2025 Jul. doi: 10.1016/j.cgh.2025.06.032.
Gyawali CP, et al. pH Impedance Monitoring on Proton Pump Inhibitor Therapy Impacts Management Decisions in Proven GERD but not in Unproven GERD. Clin Gastroenterol Hepatol. 2025 May. doi: 10.1016/j.cgh.2025.02.032.
Stomach
Wiklund AK, et al. Risk of Gastric Adenocarcinoma After Eradication of Helicobacter pylori. Gastroenterology. 2025 Feb. doi: 10.1053/j.gastro.2025.01.239.
Sonaiya S, et al. Over-the-Scope Clip versus Standard Endoscopic Therapy as First-Line Intervention for Nonvariceal Upper Gastrointestinal Bleeding: A Cost-Effectiveness Analysis. Tech Innov Gastrointest. 2025 Jun. doi: 10.1016/j.tige.2025.250935.
Colon
Hassan C, et al. Colon Cancer Screening, Surveillance, and Treatment: Novel Artificial Intelligence Driving Strategies in the Management of Colon Lesions. Gastroenterology. 2025 Mar. doi: 10.1053/j.gastro.2025.02.021.
Pancreas
Wilcox CM, et al; US Pancreatic Disease Study Group. Management of the Disconnected Pancreatic Duct in Pancreatic Necrosis. Clin Gastroenterol Hepatol. 2025 Jul. doi: 10.1016/j.cgh.2025.05.024.
Ghimire C, et al. The effect of advances in pancreatic cancer treatment in population mortality: A SEER-based study. Gastro Hep Adv. 2025 Jul. doi: 10.1016/j.gastha.2025.100739.
Hepatology
Canivet CM, et al. Validation of the AASLD/EASL Multi-Step Screening Strategies for MASLD. Gastro Hep Adv. 2025 Jul. doi: 10.1016/j.gastha.2025.100747.
Miscellaneous
Chang L, et al. Gut Feelings: The Critical Role of Interoception in Obesity and Disorders of Gut-Brain Interaction. Gastroenterology. 2025 Aug. doi: 10.1053/j.gastro.2025.04.002.
Bashiri K, et al. Advancing Hemostatic Powder Technologies for Management of Gastrointestinal Bleeding: Challenges and Solutions. Tech Innov Gastrointest. 2025 Jul. doi: 10.1016/j.tige.2025.250940.
Dr. Trieu is assistant professor of medicine, interventional endoscopy, in the Division of Gastroenterology at Washington University in St. Louis School of Medicine, Missouri.
Most GI Service Chiefs Support POCUS Training, But Uptake Is Slow
, according to a national survey.
Low POCUS uptake may be explained by substantial barriers to implementation, including lack of trained instructors, necessary equipment, and support staff, lead author Keerthi Thallapureddy, MD, of the University of Texas Health San Antonio, and colleagues, reported.
“POCUS is being increasingly used by gastroenterologists due to its portability and real-time diagnostic ability,” the investigators wrote in Gastro Hep Advances, but “there is limited understanding of how gastroenterologists use POCUS.”
To learn more, the investigators conducted a nationwide survey of the VA healthcare system. Separate questionnaires were sent to chiefs of staff (n = 130) and GI service chiefs (n = 117), yielding response rates of 100% and 79%, respectively.
Respondents represented a wide distribution of geographic regions and institutional complexity levels, with 80% of GI groups based at high-complexity centers and 92% in urban locations. A minority (8%) reported the presence of a liver transplant program.
Data collection focused on the prevalence of POCUS use, types of clinical applications, institutional policies and training processes, and perceived or actual barriers to wider adoption. Barriers were sorted into three categories: training, equipment, and infrastructure.
Of the 93 GI service chiefs who participated in the survey, 44% reported that at least 1 gastroenterologist at their facility currently uses POCUS. Most common procedural uses were paracentesis (23%) and liver biopsy (13%), while ascites assessment (19%) and biliary visualization (7%) were the most common diagnostic uses.
Among the same respondents, 69% said they would support sending clinicians to a POCUS training course, and 37% said their teams had expressed an active interest in pursuing such training. Only 17% of facilities had a formal process in place to obtain POCUS training, and an equal proportion had implemented a facility-wide policy to guide its use.
Barriers to implementation were widespread and often multifactorial.
Most challenges related to training: 48% of sites reported a lack of trained providers, 28% cited insufficient funding for training, 24% noted a lack of training opportunities, and 14% reported difficulty securing travel funds.
Equipment limitations were also common, with 41% of sites lacking ultrasound machines and 27% lacking funding to purchase them.
Institutional infrastructure posed further hurdles. Nearly a quarter of GI chiefs (23%) reported lacking a clinician champion to lead implementation, while others cited a lack of support staff, simulation space, privileging criteria, image archiving capabilities, or standardized reporting forms.
“Our findings on current POCUS use, training, barriers, and infrastructure can guide expansion of POCUS use and training among GI groups,” Dr. Thallapureddy and colleagues wrote, noting that early efforts to expand access to GI-specific POCUS training are already underway.
They cited growing interest from national organizations such as the American Gastroenterological Association and the American Association for the Study of Liver Diseases, the latter of which piloted training workshops at the 2024 Liver Meeting. Similarly, the International Bowel Ultrasound Group now offers a 3-part certification program in intestinal ultrasound and is developing additional online and interactive modules to improve training accessibility.
The study was supported by the US Department of Veterans Affairs, Quality Enhancement Research Initiative Partnered Evaluation Initiative Grant, and the VA National Center for Patient Safety. The investigators reported no conflicts of interest.
, according to a national survey.
Low POCUS uptake may be explained by substantial barriers to implementation, including lack of trained instructors, necessary equipment, and support staff, lead author Keerthi Thallapureddy, MD, of the University of Texas Health San Antonio, and colleagues, reported.
“POCUS is being increasingly used by gastroenterologists due to its portability and real-time diagnostic ability,” the investigators wrote in Gastro Hep Advances, but “there is limited understanding of how gastroenterologists use POCUS.”
To learn more, the investigators conducted a nationwide survey of the VA healthcare system. Separate questionnaires were sent to chiefs of staff (n = 130) and GI service chiefs (n = 117), yielding response rates of 100% and 79%, respectively.
Respondents represented a wide distribution of geographic regions and institutional complexity levels, with 80% of GI groups based at high-complexity centers and 92% in urban locations. A minority (8%) reported the presence of a liver transplant program.
Data collection focused on the prevalence of POCUS use, types of clinical applications, institutional policies and training processes, and perceived or actual barriers to wider adoption. Barriers were sorted into three categories: training, equipment, and infrastructure.
Of the 93 GI service chiefs who participated in the survey, 44% reported that at least 1 gastroenterologist at their facility currently uses POCUS. Most common procedural uses were paracentesis (23%) and liver biopsy (13%), while ascites assessment (19%) and biliary visualization (7%) were the most common diagnostic uses.
Among the same respondents, 69% said they would support sending clinicians to a POCUS training course, and 37% said their teams had expressed an active interest in pursuing such training. Only 17% of facilities had a formal process in place to obtain POCUS training, and an equal proportion had implemented a facility-wide policy to guide its use.
Barriers to implementation were widespread and often multifactorial.
Most challenges related to training: 48% of sites reported a lack of trained providers, 28% cited insufficient funding for training, 24% noted a lack of training opportunities, and 14% reported difficulty securing travel funds.
Equipment limitations were also common, with 41% of sites lacking ultrasound machines and 27% lacking funding to purchase them.
Institutional infrastructure posed further hurdles. Nearly a quarter of GI chiefs (23%) reported lacking a clinician champion to lead implementation, while others cited a lack of support staff, simulation space, privileging criteria, image archiving capabilities, or standardized reporting forms.
“Our findings on current POCUS use, training, barriers, and infrastructure can guide expansion of POCUS use and training among GI groups,” Dr. Thallapureddy and colleagues wrote, noting that early efforts to expand access to GI-specific POCUS training are already underway.
They cited growing interest from national organizations such as the American Gastroenterological Association and the American Association for the Study of Liver Diseases, the latter of which piloted training workshops at the 2024 Liver Meeting. Similarly, the International Bowel Ultrasound Group now offers a 3-part certification program in intestinal ultrasound and is developing additional online and interactive modules to improve training accessibility.
The study was supported by the US Department of Veterans Affairs, Quality Enhancement Research Initiative Partnered Evaluation Initiative Grant, and the VA National Center for Patient Safety. The investigators reported no conflicts of interest.
, according to a national survey.
Low POCUS uptake may be explained by substantial barriers to implementation, including lack of trained instructors, necessary equipment, and support staff, lead author Keerthi Thallapureddy, MD, of the University of Texas Health San Antonio, and colleagues, reported.
“POCUS is being increasingly used by gastroenterologists due to its portability and real-time diagnostic ability,” the investigators wrote in Gastro Hep Advances, but “there is limited understanding of how gastroenterologists use POCUS.”
To learn more, the investigators conducted a nationwide survey of the VA healthcare system. Separate questionnaires were sent to chiefs of staff (n = 130) and GI service chiefs (n = 117), yielding response rates of 100% and 79%, respectively.
Respondents represented a wide distribution of geographic regions and institutional complexity levels, with 80% of GI groups based at high-complexity centers and 92% in urban locations. A minority (8%) reported the presence of a liver transplant program.
Data collection focused on the prevalence of POCUS use, types of clinical applications, institutional policies and training processes, and perceived or actual barriers to wider adoption. Barriers were sorted into three categories: training, equipment, and infrastructure.
Of the 93 GI service chiefs who participated in the survey, 44% reported that at least 1 gastroenterologist at their facility currently uses POCUS. Most common procedural uses were paracentesis (23%) and liver biopsy (13%), while ascites assessment (19%) and biliary visualization (7%) were the most common diagnostic uses.
Among the same respondents, 69% said they would support sending clinicians to a POCUS training course, and 37% said their teams had expressed an active interest in pursuing such training. Only 17% of facilities had a formal process in place to obtain POCUS training, and an equal proportion had implemented a facility-wide policy to guide its use.
Barriers to implementation were widespread and often multifactorial.
Most challenges related to training: 48% of sites reported a lack of trained providers, 28% cited insufficient funding for training, 24% noted a lack of training opportunities, and 14% reported difficulty securing travel funds.
Equipment limitations were also common, with 41% of sites lacking ultrasound machines and 27% lacking funding to purchase them.
Institutional infrastructure posed further hurdles. Nearly a quarter of GI chiefs (23%) reported lacking a clinician champion to lead implementation, while others cited a lack of support staff, simulation space, privileging criteria, image archiving capabilities, or standardized reporting forms.
“Our findings on current POCUS use, training, barriers, and infrastructure can guide expansion of POCUS use and training among GI groups,” Dr. Thallapureddy and colleagues wrote, noting that early efforts to expand access to GI-specific POCUS training are already underway.
They cited growing interest from national organizations such as the American Gastroenterological Association and the American Association for the Study of Liver Diseases, the latter of which piloted training workshops at the 2024 Liver Meeting. Similarly, the International Bowel Ultrasound Group now offers a 3-part certification program in intestinal ultrasound and is developing additional online and interactive modules to improve training accessibility.
The study was supported by the US Department of Veterans Affairs, Quality Enhancement Research Initiative Partnered Evaluation Initiative Grant, and the VA National Center for Patient Safety. The investigators reported no conflicts of interest.
FROM GASTRO HEP ADVANCES
Evolving Standards of Practice: Esophageal Varices and Barrett’s Esophagus
Dear colleagues,
In the dynamic field of medicine, long-held practices are being reevaluated in light of new evidence and evolving standards of practice.
Dr. Anahita Rabiee discusses the importance of prioritizing non-selective beta blockers (NSBB) over endoscopic variceal ligation (EVL) in the primary prophylaxis of variceal bleeding in patients with compensated cirrhosis. Drawing on data from the PREDESCI trial and real-world experience, she argues that NSBB address the upstream driver—portal hypertension—more broadly and effectively than EVL. In a complementary piece, Dr. Tarek Sawas explores the nuanced landscape of screening and surveillance in Barrett’s esophagus. From how to manage irregular Z-lines, to rethinking the need for 1-year follow-up endoscopies and interpreting the implications of the BOSS trial, Dr. Sawas advocates for a more personalized, risk-based approach.
We hope these perspectives spark dialogue and reflection in your own practice. Join the conversation on X at @AGA_GIHN.
Gyanprakash A. Ketwaroo, MD, MSc, is associate professor of medicine, Yale University, New Haven, and chief of endoscopy at West Haven VA Medical Center, both in Connecticut. He is an associate editor for GI & Hepatology News.
Choose NSBBs, Not EVL, in Patients with Compensated Cirrhosis
BY ANAHITA RABIEE, MD, MHS
I strongly favor the use of non selective beta blockers (NSBBs) in patients with compensated cirrhosis, rather than endoscopy and esophageal variceal ligation (EVL) for primary prophylaxis.
Since the results of PREDESCI trial (β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (CSPH)) were published in 2019, there has been much debate on the role of screening endoscopy and EVL for primary prophylaxis. While many argue that a single randomized trial should not overturn long standing practice, several compelling reasons convince me to choose NSBBs, when possible.
Recent guidance from major liver societies now recommends NSBBs as first line therapy for CSPH. Yet, adoption in clinical practice remains inconsistent.
Here is why I believe NSBB represent a better solution:
Treating Upstream, Not Just a Local Treatment
NSBBs such as propranolol and nadolol decrease portal pressure by decreasing portal venous inflow through β1 and β2 adrenergic blockade. Carvedilol is often preferred given its additional α1 adrenergic blocking activity making it the most effective one in decreasing the portal pressure. Therefore, NSBBs address the upstream driver of decompensation by decreasing portal pressures.
EVL, in contrast, is a local fix that only prevents variceal bleeding. Ascites, not variceal bleeding, is the most common initial decompensating event and is associated with high mortality. Preventing all forms of decompensation is clearly preferable to preventing just one.
Broader Eligibility, More Patients Benefit
CSPH is defined as hepatic venous pressure gradient (HVPG)>10 mmHg, the threshold where increased portal venous inflow secondary to splanchnic vasodilation and hyperdynamic circulation drives the increase in portal hypertension. This threshold has been shown to strongly predict decompensation in patients with compensated disease.
While all patients with varices have CSPH, not all patients with CSPH have varices. They can be identified by other non invasive criteria such as cross sectional imaging showing collaterals, or liver stiffness and platelet thresholds that have been previously validated. By restricting intervention to those with large varices and offering only EVL, we miss the opportunity to intervene earlier and to a broader group that would benefit from this treatment.
Comprehensive Protection Without Repeated Endoscopies
Once on an appropriate NSBB dose, patients are protected against variceal bleeding (at least as effectively as EVL). This eliminates the need for repeated surveillance endoscopies to identify and treat large varices in otherwise compensated patients.
Better Tolerated and – In Many Cases – Overlaps With Existing Medication List!
While overtreatment is a concern, regular endoscopies every two years are also burdensome. Many patients already need beta blockers for cardiac conditions such as atrial fibrillation, ischemic heart disease or hypertension. Carvedilol, in particular, offers dual benefit for both hepatologists and cardiologists.
It is important to emphasize that these arguments apply to compensated cirrhosis. In decompensated disease, the approach changes. After a variceal bleed, both NSBBs and EVL are required for secondary prophylaxis. In patients with prior ascites but no variceal bleed, the benefit of NSBBs is less pronounced since decompensation has already occurred. In this setting, NSBBs can still be used selectively, but only if systolic blood pressure remains above 90 mmHg.
The evidence supporting NSBBs over EVL in compensated cirrhosis is not perfect, but few things in medicine are. Given current data, NSBBs should be the first line therapy in compensated cirrhosis with CSPH. Once a patient is on an appropriate and tolerated NSBB dose, routine endoscopic surveillance is unnecessary. Endoscopy should be reserved for those who cannot tolerate NSBBs, in whom EVL is then indicated if large varices are present.
Dr. Rabiee is based at the Yale School of Medicine, New Haven, Connecticut, and the Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut. She has no disclosures in regard to this article.
Rethinking Screening and Surveillance in Barrett’s Esophagus: Navigating Controversies and Nuances
BY TAREK SAWAS, MD, MPH
Barrett’s esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Despite our comprehensive guidelines, many of the day-to-day decisions still rely on clinical judgment and honest conversations with patients. This article explores common scenarios in which management decisions are nuanced and the right answer remains debatable.
Irregular Z-Line/Ultrashort Segment BE: Leave Or Watch It?
Few findings provoke more confusion than irregular Z-line or intestinal metaplasia (IM) < 1 cm at the gastroesophageal junction (GEJ). For years, we have debated whether these subtle changes represent a precursor to EAC or simply a benign variant. We have wrestled with how to handle these cases from whether we should take biopsies to how to perform surveillance.
The American College of Gastroenterology (ACG) guideline suggests that irregular Z-lines should not be routinely biopsied or surveyed. Similarly, the upcoming American Gastroenterology Association (AGA) surveillance guideline suggests against surveillance of IM<1 cm citing the low individual annual risk of progression to high-grade dysplasia (HGD) and EAC of 0.23% per year which is lower than that of non-dysplastic Barrett’s esophagus (NDBE). However, this is not the entire picture.
Despite the low per-patient risk, IM<1cm is highly prevalent with columnar mucosa observed in approximately 15% of patients undergoing upper endoscopy. This paradox is unsettling. While any one patient with IM<1 cm is unlikely to progress to EAC, the group accounts for a meaningful share of the EAC burden. Some experts have argued that this justifies routine biopsy and surveillance in all patients with visible columnar mucosa regardless of length. However, this approach risks overwhelming our surveillance infrastructure.
A recent decision modeling analysis suggested that at the lowest progression rates, either no surveillance or one-time endoscopy can be considered. Based on these data, I do not regularly biopsy ultrashort segments unless the mucosa appears suspicious. In those with IM<1 cm detected during a high-quality endoscopic exam, no follow-up is needed. However, if the exam is suboptimal, I perform a 1-time high-quality repeat exam. If there is no evidence of dysplasia then I do not pursue any further surveillance.
The One-Year Follow-Up Endoscopy: Is It Necessary?
Another controversy is the one-year follow-up endoscopy after an initial diagnosis of NDBE. Proponents of this approach cite the high proportion of post endoscopy esophageal neoplasia and cancer (PEEN/PEEC) detected in the first year after diagnosis (missed HGD/EAC). In fact, PEEN account for about a quarter of all HGD/EAC cases diagnosed during surveillance.
While this approach might mitigate PEEN/PEEC risk, it may not be necessary if the index endoscopy is high quality. To ensure high quality exams, several best practices have been proposed including:
- Use of high-definition white light endoscopy (HD-WLE) with chromoendoscopy (virtual or dye based)
- Appropriate inspection time (1 minute per cm of circumferential BE)
- Accurate documentation using the Prague criteria
- Adherence to the Seattle protocol with additional targeted biopsies
If the index endoscopy meets these quality metrics, I typically do not bring the patient back at one year. However, if the exam quality is in question, then I repeat it at one year to establish a reliable baseline and rule out prevalent neoplasia.
Surveillance In NDBE: After BOSS, Do We Rethink Everything?
The recently published BOSS trial (Barrett’s Oesophagus Surveillance Study) has reignited the debate over the value of endoscopic surveillance in NDBE. In this study, 3,453 patients with NDBE across the UK were randomized to either surveillance endoscopy every two years or endoscopy only as clinically indicated. After a median follow-up of 12.8 years, the trial found no significant difference in all-cause mortality between the two groups.
While these findings are important, they should be interpreted with caution. First, the primary endpoint, all-cause mortality, is not optimal for evaluating surveillance for EAC. Surveillance is not intended to reduce all-cause mortality but rather to reduce EAC–related mortality. Second, a substantial number of patients in the no surveillance group still underwent endoscopy at intervals that were not meaningfully different from those in the surveillance group. If both groups receive similar exposure to endoscopy, the comparison loses power. Lastly, the trial was underpowered due to overestimation of progression risk during its initial design. As we have since learned, the risk of progression of NDBE is lower than originally assumed.
So where do we stand now? For me, the BOSS trial does not negate the value of surveillance. it reminds us that a one-size-fits-all approach is inefficient, and our strategy must be risk based. For low-risk individuals, particularly older adults with short-segment NDBE, surveillance may offer little benefit. But in healthier, younger patients with longer segments or additional risk factors, surveillance remains an essential tool for early neoplasia detection.
When to Stop Surveillance
Perhaps the most under-discussed point is when to stop surveillance. Existing guidelines do not account for competing mortality risks unrelated to EAC or provide specific recommendations regarding cessation of surveillance. The desired benefits of surveillance likely diminish with advanced age and greater comorbidity because of lower life expectancy and ineligibility for definitive therapy for EAC.
A recent modeling study found that the optimal ages for last surveillance were 81, 80, 77, and 73 years for men with no, mild, moderate, and severe comorbidity respectively and 75, 73, 73, and 69 years for women. In my practice, I discuss surveillance cessation in patients older than 75 based on their comorbidities. If the risk of progression is outweighed by the risk of the procedure or by the reality of limited life expectancy, we should not hesitate to consider surveillance cessation.
In summary, high-quality endoscopic exam in appropriately selected patients remains the cornerstone of BE surveillance. A more personalized, risk-based approach is needed taking into account competing comorbidities. Emerging technology through risk stratification tools such as biomarkers and artificial intelligence may refine our approach and help address the current limitations.
Dr. Sawas is based at the University of Texas Southwestern, Dallas, Texas. He has no disclosures in regard to this article.
Dear colleagues,
In the dynamic field of medicine, long-held practices are being reevaluated in light of new evidence and evolving standards of practice.
Dr. Anahita Rabiee discusses the importance of prioritizing non-selective beta blockers (NSBB) over endoscopic variceal ligation (EVL) in the primary prophylaxis of variceal bleeding in patients with compensated cirrhosis. Drawing on data from the PREDESCI trial and real-world experience, she argues that NSBB address the upstream driver—portal hypertension—more broadly and effectively than EVL. In a complementary piece, Dr. Tarek Sawas explores the nuanced landscape of screening and surveillance in Barrett’s esophagus. From how to manage irregular Z-lines, to rethinking the need for 1-year follow-up endoscopies and interpreting the implications of the BOSS trial, Dr. Sawas advocates for a more personalized, risk-based approach.
We hope these perspectives spark dialogue and reflection in your own practice. Join the conversation on X at @AGA_GIHN.
Gyanprakash A. Ketwaroo, MD, MSc, is associate professor of medicine, Yale University, New Haven, and chief of endoscopy at West Haven VA Medical Center, both in Connecticut. He is an associate editor for GI & Hepatology News.
Choose NSBBs, Not EVL, in Patients with Compensated Cirrhosis
BY ANAHITA RABIEE, MD, MHS
I strongly favor the use of non selective beta blockers (NSBBs) in patients with compensated cirrhosis, rather than endoscopy and esophageal variceal ligation (EVL) for primary prophylaxis.
Since the results of PREDESCI trial (β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (CSPH)) were published in 2019, there has been much debate on the role of screening endoscopy and EVL for primary prophylaxis. While many argue that a single randomized trial should not overturn long standing practice, several compelling reasons convince me to choose NSBBs, when possible.
Recent guidance from major liver societies now recommends NSBBs as first line therapy for CSPH. Yet, adoption in clinical practice remains inconsistent.
Here is why I believe NSBB represent a better solution:
Treating Upstream, Not Just a Local Treatment
NSBBs such as propranolol and nadolol decrease portal pressure by decreasing portal venous inflow through β1 and β2 adrenergic blockade. Carvedilol is often preferred given its additional α1 adrenergic blocking activity making it the most effective one in decreasing the portal pressure. Therefore, NSBBs address the upstream driver of decompensation by decreasing portal pressures.
EVL, in contrast, is a local fix that only prevents variceal bleeding. Ascites, not variceal bleeding, is the most common initial decompensating event and is associated with high mortality. Preventing all forms of decompensation is clearly preferable to preventing just one.
Broader Eligibility, More Patients Benefit
CSPH is defined as hepatic venous pressure gradient (HVPG)>10 mmHg, the threshold where increased portal venous inflow secondary to splanchnic vasodilation and hyperdynamic circulation drives the increase in portal hypertension. This threshold has been shown to strongly predict decompensation in patients with compensated disease.
While all patients with varices have CSPH, not all patients with CSPH have varices. They can be identified by other non invasive criteria such as cross sectional imaging showing collaterals, or liver stiffness and platelet thresholds that have been previously validated. By restricting intervention to those with large varices and offering only EVL, we miss the opportunity to intervene earlier and to a broader group that would benefit from this treatment.
Comprehensive Protection Without Repeated Endoscopies
Once on an appropriate NSBB dose, patients are protected against variceal bleeding (at least as effectively as EVL). This eliminates the need for repeated surveillance endoscopies to identify and treat large varices in otherwise compensated patients.
Better Tolerated and – In Many Cases – Overlaps With Existing Medication List!
While overtreatment is a concern, regular endoscopies every two years are also burdensome. Many patients already need beta blockers for cardiac conditions such as atrial fibrillation, ischemic heart disease or hypertension. Carvedilol, in particular, offers dual benefit for both hepatologists and cardiologists.
It is important to emphasize that these arguments apply to compensated cirrhosis. In decompensated disease, the approach changes. After a variceal bleed, both NSBBs and EVL are required for secondary prophylaxis. In patients with prior ascites but no variceal bleed, the benefit of NSBBs is less pronounced since decompensation has already occurred. In this setting, NSBBs can still be used selectively, but only if systolic blood pressure remains above 90 mmHg.
The evidence supporting NSBBs over EVL in compensated cirrhosis is not perfect, but few things in medicine are. Given current data, NSBBs should be the first line therapy in compensated cirrhosis with CSPH. Once a patient is on an appropriate and tolerated NSBB dose, routine endoscopic surveillance is unnecessary. Endoscopy should be reserved for those who cannot tolerate NSBBs, in whom EVL is then indicated if large varices are present.
Dr. Rabiee is based at the Yale School of Medicine, New Haven, Connecticut, and the Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut. She has no disclosures in regard to this article.
Rethinking Screening and Surveillance in Barrett’s Esophagus: Navigating Controversies and Nuances
BY TAREK SAWAS, MD, MPH
Barrett’s esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Despite our comprehensive guidelines, many of the day-to-day decisions still rely on clinical judgment and honest conversations with patients. This article explores common scenarios in which management decisions are nuanced and the right answer remains debatable.
Irregular Z-Line/Ultrashort Segment BE: Leave Or Watch It?
Few findings provoke more confusion than irregular Z-line or intestinal metaplasia (IM) < 1 cm at the gastroesophageal junction (GEJ). For years, we have debated whether these subtle changes represent a precursor to EAC or simply a benign variant. We have wrestled with how to handle these cases from whether we should take biopsies to how to perform surveillance.
The American College of Gastroenterology (ACG) guideline suggests that irregular Z-lines should not be routinely biopsied or surveyed. Similarly, the upcoming American Gastroenterology Association (AGA) surveillance guideline suggests against surveillance of IM<1 cm citing the low individual annual risk of progression to high-grade dysplasia (HGD) and EAC of 0.23% per year which is lower than that of non-dysplastic Barrett’s esophagus (NDBE). However, this is not the entire picture.
Despite the low per-patient risk, IM<1cm is highly prevalent with columnar mucosa observed in approximately 15% of patients undergoing upper endoscopy. This paradox is unsettling. While any one patient with IM<1 cm is unlikely to progress to EAC, the group accounts for a meaningful share of the EAC burden. Some experts have argued that this justifies routine biopsy and surveillance in all patients with visible columnar mucosa regardless of length. However, this approach risks overwhelming our surveillance infrastructure.
A recent decision modeling analysis suggested that at the lowest progression rates, either no surveillance or one-time endoscopy can be considered. Based on these data, I do not regularly biopsy ultrashort segments unless the mucosa appears suspicious. In those with IM<1 cm detected during a high-quality endoscopic exam, no follow-up is needed. However, if the exam is suboptimal, I perform a 1-time high-quality repeat exam. If there is no evidence of dysplasia then I do not pursue any further surveillance.
The One-Year Follow-Up Endoscopy: Is It Necessary?
Another controversy is the one-year follow-up endoscopy after an initial diagnosis of NDBE. Proponents of this approach cite the high proportion of post endoscopy esophageal neoplasia and cancer (PEEN/PEEC) detected in the first year after diagnosis (missed HGD/EAC). In fact, PEEN account for about a quarter of all HGD/EAC cases diagnosed during surveillance.
While this approach might mitigate PEEN/PEEC risk, it may not be necessary if the index endoscopy is high quality. To ensure high quality exams, several best practices have been proposed including:
- Use of high-definition white light endoscopy (HD-WLE) with chromoendoscopy (virtual or dye based)
- Appropriate inspection time (1 minute per cm of circumferential BE)
- Accurate documentation using the Prague criteria
- Adherence to the Seattle protocol with additional targeted biopsies
If the index endoscopy meets these quality metrics, I typically do not bring the patient back at one year. However, if the exam quality is in question, then I repeat it at one year to establish a reliable baseline and rule out prevalent neoplasia.
Surveillance In NDBE: After BOSS, Do We Rethink Everything?
The recently published BOSS trial (Barrett’s Oesophagus Surveillance Study) has reignited the debate over the value of endoscopic surveillance in NDBE. In this study, 3,453 patients with NDBE across the UK were randomized to either surveillance endoscopy every two years or endoscopy only as clinically indicated. After a median follow-up of 12.8 years, the trial found no significant difference in all-cause mortality between the two groups.
While these findings are important, they should be interpreted with caution. First, the primary endpoint, all-cause mortality, is not optimal for evaluating surveillance for EAC. Surveillance is not intended to reduce all-cause mortality but rather to reduce EAC–related mortality. Second, a substantial number of patients in the no surveillance group still underwent endoscopy at intervals that were not meaningfully different from those in the surveillance group. If both groups receive similar exposure to endoscopy, the comparison loses power. Lastly, the trial was underpowered due to overestimation of progression risk during its initial design. As we have since learned, the risk of progression of NDBE is lower than originally assumed.
So where do we stand now? For me, the BOSS trial does not negate the value of surveillance. it reminds us that a one-size-fits-all approach is inefficient, and our strategy must be risk based. For low-risk individuals, particularly older adults with short-segment NDBE, surveillance may offer little benefit. But in healthier, younger patients with longer segments or additional risk factors, surveillance remains an essential tool for early neoplasia detection.
When to Stop Surveillance
Perhaps the most under-discussed point is when to stop surveillance. Existing guidelines do not account for competing mortality risks unrelated to EAC or provide specific recommendations regarding cessation of surveillance. The desired benefits of surveillance likely diminish with advanced age and greater comorbidity because of lower life expectancy and ineligibility for definitive therapy for EAC.
A recent modeling study found that the optimal ages for last surveillance were 81, 80, 77, and 73 years for men with no, mild, moderate, and severe comorbidity respectively and 75, 73, 73, and 69 years for women. In my practice, I discuss surveillance cessation in patients older than 75 based on their comorbidities. If the risk of progression is outweighed by the risk of the procedure or by the reality of limited life expectancy, we should not hesitate to consider surveillance cessation.
In summary, high-quality endoscopic exam in appropriately selected patients remains the cornerstone of BE surveillance. A more personalized, risk-based approach is needed taking into account competing comorbidities. Emerging technology through risk stratification tools such as biomarkers and artificial intelligence may refine our approach and help address the current limitations.
Dr. Sawas is based at the University of Texas Southwestern, Dallas, Texas. He has no disclosures in regard to this article.
Dear colleagues,
In the dynamic field of medicine, long-held practices are being reevaluated in light of new evidence and evolving standards of practice.
Dr. Anahita Rabiee discusses the importance of prioritizing non-selective beta blockers (NSBB) over endoscopic variceal ligation (EVL) in the primary prophylaxis of variceal bleeding in patients with compensated cirrhosis. Drawing on data from the PREDESCI trial and real-world experience, she argues that NSBB address the upstream driver—portal hypertension—more broadly and effectively than EVL. In a complementary piece, Dr. Tarek Sawas explores the nuanced landscape of screening and surveillance in Barrett’s esophagus. From how to manage irregular Z-lines, to rethinking the need for 1-year follow-up endoscopies and interpreting the implications of the BOSS trial, Dr. Sawas advocates for a more personalized, risk-based approach.
We hope these perspectives spark dialogue and reflection in your own practice. Join the conversation on X at @AGA_GIHN.
Gyanprakash A. Ketwaroo, MD, MSc, is associate professor of medicine, Yale University, New Haven, and chief of endoscopy at West Haven VA Medical Center, both in Connecticut. He is an associate editor for GI & Hepatology News.
Choose NSBBs, Not EVL, in Patients with Compensated Cirrhosis
BY ANAHITA RABIEE, MD, MHS
I strongly favor the use of non selective beta blockers (NSBBs) in patients with compensated cirrhosis, rather than endoscopy and esophageal variceal ligation (EVL) for primary prophylaxis.
Since the results of PREDESCI trial (β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (CSPH)) were published in 2019, there has been much debate on the role of screening endoscopy and EVL for primary prophylaxis. While many argue that a single randomized trial should not overturn long standing practice, several compelling reasons convince me to choose NSBBs, when possible.
Recent guidance from major liver societies now recommends NSBBs as first line therapy for CSPH. Yet, adoption in clinical practice remains inconsistent.
Here is why I believe NSBB represent a better solution:
Treating Upstream, Not Just a Local Treatment
NSBBs such as propranolol and nadolol decrease portal pressure by decreasing portal venous inflow through β1 and β2 adrenergic blockade. Carvedilol is often preferred given its additional α1 adrenergic blocking activity making it the most effective one in decreasing the portal pressure. Therefore, NSBBs address the upstream driver of decompensation by decreasing portal pressures.
EVL, in contrast, is a local fix that only prevents variceal bleeding. Ascites, not variceal bleeding, is the most common initial decompensating event and is associated with high mortality. Preventing all forms of decompensation is clearly preferable to preventing just one.
Broader Eligibility, More Patients Benefit
CSPH is defined as hepatic venous pressure gradient (HVPG)>10 mmHg, the threshold where increased portal venous inflow secondary to splanchnic vasodilation and hyperdynamic circulation drives the increase in portal hypertension. This threshold has been shown to strongly predict decompensation in patients with compensated disease.
While all patients with varices have CSPH, not all patients with CSPH have varices. They can be identified by other non invasive criteria such as cross sectional imaging showing collaterals, or liver stiffness and platelet thresholds that have been previously validated. By restricting intervention to those with large varices and offering only EVL, we miss the opportunity to intervene earlier and to a broader group that would benefit from this treatment.
Comprehensive Protection Without Repeated Endoscopies
Once on an appropriate NSBB dose, patients are protected against variceal bleeding (at least as effectively as EVL). This eliminates the need for repeated surveillance endoscopies to identify and treat large varices in otherwise compensated patients.
Better Tolerated and – In Many Cases – Overlaps With Existing Medication List!
While overtreatment is a concern, regular endoscopies every two years are also burdensome. Many patients already need beta blockers for cardiac conditions such as atrial fibrillation, ischemic heart disease or hypertension. Carvedilol, in particular, offers dual benefit for both hepatologists and cardiologists.
It is important to emphasize that these arguments apply to compensated cirrhosis. In decompensated disease, the approach changes. After a variceal bleed, both NSBBs and EVL are required for secondary prophylaxis. In patients with prior ascites but no variceal bleed, the benefit of NSBBs is less pronounced since decompensation has already occurred. In this setting, NSBBs can still be used selectively, but only if systolic blood pressure remains above 90 mmHg.
The evidence supporting NSBBs over EVL in compensated cirrhosis is not perfect, but few things in medicine are. Given current data, NSBBs should be the first line therapy in compensated cirrhosis with CSPH. Once a patient is on an appropriate and tolerated NSBB dose, routine endoscopic surveillance is unnecessary. Endoscopy should be reserved for those who cannot tolerate NSBBs, in whom EVL is then indicated if large varices are present.
Dr. Rabiee is based at the Yale School of Medicine, New Haven, Connecticut, and the Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut. She has no disclosures in regard to this article.
Rethinking Screening and Surveillance in Barrett’s Esophagus: Navigating Controversies and Nuances
BY TAREK SAWAS, MD, MPH
Barrett’s esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Despite our comprehensive guidelines, many of the day-to-day decisions still rely on clinical judgment and honest conversations with patients. This article explores common scenarios in which management decisions are nuanced and the right answer remains debatable.
Irregular Z-Line/Ultrashort Segment BE: Leave Or Watch It?
Few findings provoke more confusion than irregular Z-line or intestinal metaplasia (IM) < 1 cm at the gastroesophageal junction (GEJ). For years, we have debated whether these subtle changes represent a precursor to EAC or simply a benign variant. We have wrestled with how to handle these cases from whether we should take biopsies to how to perform surveillance.
The American College of Gastroenterology (ACG) guideline suggests that irregular Z-lines should not be routinely biopsied or surveyed. Similarly, the upcoming American Gastroenterology Association (AGA) surveillance guideline suggests against surveillance of IM<1 cm citing the low individual annual risk of progression to high-grade dysplasia (HGD) and EAC of 0.23% per year which is lower than that of non-dysplastic Barrett’s esophagus (NDBE). However, this is not the entire picture.
Despite the low per-patient risk, IM<1cm is highly prevalent with columnar mucosa observed in approximately 15% of patients undergoing upper endoscopy. This paradox is unsettling. While any one patient with IM<1 cm is unlikely to progress to EAC, the group accounts for a meaningful share of the EAC burden. Some experts have argued that this justifies routine biopsy and surveillance in all patients with visible columnar mucosa regardless of length. However, this approach risks overwhelming our surveillance infrastructure.
A recent decision modeling analysis suggested that at the lowest progression rates, either no surveillance or one-time endoscopy can be considered. Based on these data, I do not regularly biopsy ultrashort segments unless the mucosa appears suspicious. In those with IM<1 cm detected during a high-quality endoscopic exam, no follow-up is needed. However, if the exam is suboptimal, I perform a 1-time high-quality repeat exam. If there is no evidence of dysplasia then I do not pursue any further surveillance.
The One-Year Follow-Up Endoscopy: Is It Necessary?
Another controversy is the one-year follow-up endoscopy after an initial diagnosis of NDBE. Proponents of this approach cite the high proportion of post endoscopy esophageal neoplasia and cancer (PEEN/PEEC) detected in the first year after diagnosis (missed HGD/EAC). In fact, PEEN account for about a quarter of all HGD/EAC cases diagnosed during surveillance.
While this approach might mitigate PEEN/PEEC risk, it may not be necessary if the index endoscopy is high quality. To ensure high quality exams, several best practices have been proposed including:
- Use of high-definition white light endoscopy (HD-WLE) with chromoendoscopy (virtual or dye based)
- Appropriate inspection time (1 minute per cm of circumferential BE)
- Accurate documentation using the Prague criteria
- Adherence to the Seattle protocol with additional targeted biopsies
If the index endoscopy meets these quality metrics, I typically do not bring the patient back at one year. However, if the exam quality is in question, then I repeat it at one year to establish a reliable baseline and rule out prevalent neoplasia.
Surveillance In NDBE: After BOSS, Do We Rethink Everything?
The recently published BOSS trial (Barrett’s Oesophagus Surveillance Study) has reignited the debate over the value of endoscopic surveillance in NDBE. In this study, 3,453 patients with NDBE across the UK were randomized to either surveillance endoscopy every two years or endoscopy only as clinically indicated. After a median follow-up of 12.8 years, the trial found no significant difference in all-cause mortality between the two groups.
While these findings are important, they should be interpreted with caution. First, the primary endpoint, all-cause mortality, is not optimal for evaluating surveillance for EAC. Surveillance is not intended to reduce all-cause mortality but rather to reduce EAC–related mortality. Second, a substantial number of patients in the no surveillance group still underwent endoscopy at intervals that were not meaningfully different from those in the surveillance group. If both groups receive similar exposure to endoscopy, the comparison loses power. Lastly, the trial was underpowered due to overestimation of progression risk during its initial design. As we have since learned, the risk of progression of NDBE is lower than originally assumed.
So where do we stand now? For me, the BOSS trial does not negate the value of surveillance. it reminds us that a one-size-fits-all approach is inefficient, and our strategy must be risk based. For low-risk individuals, particularly older adults with short-segment NDBE, surveillance may offer little benefit. But in healthier, younger patients with longer segments or additional risk factors, surveillance remains an essential tool for early neoplasia detection.
When to Stop Surveillance
Perhaps the most under-discussed point is when to stop surveillance. Existing guidelines do not account for competing mortality risks unrelated to EAC or provide specific recommendations regarding cessation of surveillance. The desired benefits of surveillance likely diminish with advanced age and greater comorbidity because of lower life expectancy and ineligibility for definitive therapy for EAC.
A recent modeling study found that the optimal ages for last surveillance were 81, 80, 77, and 73 years for men with no, mild, moderate, and severe comorbidity respectively and 75, 73, 73, and 69 years for women. In my practice, I discuss surveillance cessation in patients older than 75 based on their comorbidities. If the risk of progression is outweighed by the risk of the procedure or by the reality of limited life expectancy, we should not hesitate to consider surveillance cessation.
In summary, high-quality endoscopic exam in appropriately selected patients remains the cornerstone of BE surveillance. A more personalized, risk-based approach is needed taking into account competing comorbidities. Emerging technology through risk stratification tools such as biomarkers and artificial intelligence may refine our approach and help address the current limitations.
Dr. Sawas is based at the University of Texas Southwestern, Dallas, Texas. He has no disclosures in regard to this article.
GLP-1 Receptor Agonist Use in Gastrointestinal Endoscopy: A Review of Current Evidence and Guidelines
The use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has increased over the past several years and has become a cornerstone in both diabetes and weight loss management, particularly because of its unique combination of glucose control, weight reduction potential, and cardiac and metabolic benefits. However, increased use of these agents presents a dilemma in gastrointestinal endoscopy as it pertains to their safety and management during the periprocedural period.
highlighting gaps and future directions.
Pharmacology and Mechanisms of Action
GLP-1 RAs have several mechanisms of action that make them relevant in gastrointestinal endoscopy. These medications modulate glucose control via enhancement of glucose-dependent insulin secretion and reduction of postprandial glucagon, which promotes satiety and delays gastric emptying. This delay in gastric emptying mediated by vagal pathways has been postulated to increase gastric residuals, posing a risk for aspiration during anesthesia.1
It is important to also consider the pharmacokinetics of GLP-1 RAs, as some have shorter half-lives on the order of several hours, like exenatide, while others, like semaglutide, are dosed weekly. Additionally, common side effects of GLP-1 RAs include nausea, vomiting, bloating, and early satiety, which pose challenges for patients undergoing endoscopic procedures.
Current Guidelines
Various societies have published guidelines on the periprocedural use of GLP-1 RAs. The American Society of Anesthesiologist (ASA) in 2023 presented early recommendations to hold GLP-1 RAs either day of procedure or week prior depending on pharmacokinetics, because of the risk of delayed gastric emptying and increased potential for aspiration.2 Soon thereafter, a multi-gastroenterology society guideline was released stating more data is needed to decide if GLP-1 RAs need to be held prior to endoscopic procedures.3
In early 2024, the American Gastroenterological Association (AGA) published a rapid clinical update that advocated for a more individualized approach, particularly in light of limited overall data for GLP-1 RAs and endoscopic procedures.4 In asymptomatic patients who follow typical fasting protocols for procedures, it is generally safe to proceed with endoscopy without holding GLP-1 RAs. In symptomatic patients (nausea, abdominal distension, etc), the AGA advises additional precautions, including performing transabdominal ultrasound if feasible to assess retained gastric contents. The AGA also suggests placing a patient on a clear liquid diet the day prior to the procedure — rather than holding GLP-1 RAs — as another reasonable strategy.
The guidelines continue to evolve with newer multi-society guidelines establishing best practices. While initially in 2023 the ASA did recommend holding these medications prior to endoscopy, the initial guidance was based on expert opinion with limited evidence. Newer multi-society guidance published jointly by the ASA along with various gastroenterology societies, including the AGA in December 2024, takes a more nuanced approach.5
The newer guidelines include two main recommendations:
1. Periprocedural management of GLP-1 RAs should be a joint decision among the procedural, anesthesia, and prescribing team balancing metabolic needs vs patient risks.
- In a low-risk patient, one that is asymptomatic and on standard dosing, among other factors, the guidance states that GLP-1 RAs can be continued.
- In higher-risk patients, the original guidance of holding a day or a week prior to endoscopic procedures should be followed.
2. Periprocedural management of GLP-1 RAs should attempt to minimize the aspiration risks loosely associated with delayed gastric emptying.
- Consider a 24-hour clear liquid diet a day prior to the procedure and transabdominal ultrasound to check gastric contents.
- It is acknowledged that this guidance is based on limited evidence and will be evolving as new medications and data are released.
Recent Clinical Studies
Although there is very little data to guide clinicians, several recent studies have been published that can direct clinical decision-making as guidelines continue to be refined and updated.
A multicenter trial of approximately 800 patients undergoing upper endoscopy found a significant difference in rates of retained gastric contents between those that underwent endoscopy who did and did not follow the ASA guidance on periprocedural management of GLP-1 RAs (12.7% vs 4.4%; P < .0001). However, there were no significant differences in rates of aborted procedures or unplanned intubations.
Furthermore, a multivariable analysis was performed controlling for GLP-1 RA type and other factors, which found the likelihood of gastric retention increased by 36% for every 1% increase in hemoglobin A1c. This study suggests that a more individualized approach to holding GLP-1 RA would be applicable rather than a universal periprocedural hold.6
More recently, a single-center study of nearly 600 patients undergoing upper endoscopy showed that while there were slightly increased rates of retained gastric contents (OR 3.80; P = .003) and aborted procedures (1.3% vs 0%; P = .02), the rates of adverse anesthesia events (hypoxia, etc) were similar between the groups and no cases of pulmonary aspiration were noted.7
One single-center study of 57 patients evaluated the safety of GLP-1 RAs in those undergoing endoscopic sleeve gastrectomy. GLP-1 RAs were continued on all patients, but all adhered to a liquid only diet for at least 24 hours prior to the procedure. There were no instances of retained gastric solids, aspiration, or hypoxia. This study suggests that with a 24-hour clear liquid diet and routine NPO recommendations prior to endoscopy, it would be safe to continue GLP-1 RAs. This study provides rationale for the AGA recommendation for a clear liquid diet 24 hours prior to endoscopic procedures for those on GLP-1 RAs.8
A study looking at those who underwent emergency surgery and endoscopy with claims data of use of GLP-1 RAs found an overall incidence of postoperative respiratory complications of 3.5% for those with GLP-1 RAs fill history vs 4.0% for those without (P = .12). Approximately 800 of the 24,000 patients identified had undergone endoscopic procedures for GI bleeding or food impaction. The study overall showed that preoperative use of GLP-1 RAs in patients undergoing surgery or endoscopy, evaluated as a combined group, was not associated with an increased risk of pulmonary complications.9
Lastly, a systematic review and meta-analysis that included 15 studies that quantified gastric emptying using various methods, including gastric emptying scintigraphy and acetaminophen absorption test, found that there was a quantifiable delay in gastric emptying of about 36 minutes, compared to placebo (P < .01), in patients using GLP-1 RAs. However, compared to standard periprocedural fasting, this delay is clinically insignificant and standard fasting protocols would still be appropriate for patients on GLP-1 RAs.10
These studies taken together suggest that while GLP-1 RAs can mildly increase the likelihood of retained gastric contents, there is no statistically significant increase in the risk of aspiration or other anesthesia complications. Furthermore, while decreased gastric emptying is a known effect of GLP-1 RAs, this effect may not be clinically significant in the context of standard periprocedural fasting protocols particularly when combined with a 24-hour clear liquid diet. These findings support at a minimum a more patient-specific strategy for periprocedural management of GLP-1 RAs.
Clinical Implications
These most recent studies, as well as prior studies and guidelines by various societies lead to a dilemma among endoscopists on proper patient counseling on GLP-1 RAs use before endoscopic procedures. Clinicians must balance the metabolic benefits of GLP-1 RAs with potential endoscopic complications and risks.
Holding therapy theoretically decreases aspiration risk and pulmonary complications, though evidence remains low to support this. Holding medication, however, affects glycemic control leading to potential rebound hyperglycemia which may impact and delay plans for endoscopy. With growing indications for the use of GLP-1 RAs, a more tailored patient-centered treatment plan may be required, especially with consideration of procedure indication and comorbidities.
Currently, practice patterns at different institutions vary widely, making standardization much more difficult. Some centers have opted to follow ASA guidelines of holding these medications up to 1 week prior to procedures, while others have continued therapy with no pre-procedural adjustments. This leaves endoscopists to deal with the downstream effects of inconvenience to patients, care delays, and financial considerations if procedures are postponed related to GLP-1 RAs use.
Future Directions
Future studies are needed to make further evidence-based recommendations. Studies should focus on stratifying risks and recommendations based on procedure type (EGD, colonoscopy, etc). More widespread implementation of gastric ultrasound can assist in real-time decision-making, albeit this would require expertise and dedicated time within the pre-procedural workflow. Randomized controlled trials comparing outcomes of patients who continue GLP-1 RAs vs those who discontinue stratified by baseline risk will be instrumental for making concrete guidelines that provide clarity on periprocedural management of GLP-1 RAs.
Conclusion
The periprocedural management of GLP-1 RAs remains a controversial topic that presents unique challenges in endoscopy. Several guidelines have been released by various stakeholders including anesthesiologists, gastroenterologists, and other prescribing providers. Clinical data remains limited with no robust evidence available to suggest that gastric emptying delays caused by GLP-1 RAs prior to endoscopic procedures significantly increases risk of aspiration, pulmonary complications, or other comorbidities. Evolving multi-society guidelines will be important to establish more consistent practices with reassessment of the data as new studies emerge. A multidisciplinary, individualized patient approach may be the best strategy for managing GLP-1 RAs for patients undergoing endoscopic procedures.
Dr. Sekar and Dr. Asamoah are based in the department of gastroenterology at MedStar Georgetown University Hospital, Washington, D.C. Dr. Sekar reports no conflicts of interest in regard to this article. Dr. Asamoah serves on the Johnson & Johnson advisory board for inflammatory bowel disease–related therapies.
References
1. Halim MA et al. Glucagon-Like Peptide-1 Inhibits Prandial Gastrointestinal Motility Through Myenteric Neuronal Mechanisms in Humans. J Clin Endocrinol Metab. 2018 Feb. doi: 10.1210/jc.2017-02006.
2. American Society of Anesthesiologists. American Society of Anesthesiologists releases consensus-based guidance on preoperative use of GLP-1 receptor agonists. 2023 Jun 20. www.asahq.org/about-asa/newsroom/news-releases/2023/06/american-society-of-anesthesiologists-consensus-based-guidance-on-preoperative
3. American Gastroenterological Association. GI multi-society statement regarding GLP-1 agonists and endoscopy. 2023 Jul 25. gastro.org/news/gi-multi-society-statement-regarding-glp-1-agonists-and-endoscopy/.
4. Hashash JG et al. AGA Rapid Clinical Practice Update on the Management of Patients Taking GLP-1 Receptor Agonists Prior to Endoscopy: Communication. Clin Gastroenterol Hepatol. 2024 Apr. doi: 10.1016/j.cgh.2023.11.002.
5. Kindel TL et al; American Gastroenterological Association; American Society for Metabolic and Bariatric Surgery; American Society of Anesthesiologists; International Society of Perioperative Care of Patients with Obesity; Society of American Gastrointestinal and Endoscopic Surgeons. Multi-society Clinical Practice Guidance for the Safe Use of Glucagon-like Peptide-1 Receptor Agonists in the Perioperative Period. Clin Gastroenterol Hepatol. 2024 Oct. doi: 10.1016/j.cgh.2024.10.003.
6. Phan J et al. Glucagon-Like Peptide Receptor Agonists Use Before Endoscopy Is Associated With Low Retained Gastric Contents: A Multicenter Cross-Sectional Analysis. Am J Gastroenterol. 2025 Mar. doi: 10.14309/ajg.0000000000002969.
7. Panchal S et al. Endoscopy and Anesthesia Outcomes Associated With Glucagon-like Peptide-1 Receptor Agonist use in Patients Undergoing Outpatient Upper Endoscopy. Gastrointest Endosc. 2025 Aug. doi:10.1016/j.gie.2025.01.004.
8. Maselli DB et al. Safe Continuation of glucagon-like Peptide 1 Receptor Agonists at Endoscopy: A Case Series of 57 Adults Undergoing Endoscopic Sleeve Gastroplasty. Obes Surg. 2024 Jul. doi: 10.1007/s11695-024-07278-2.
9. Dixit AA et al. Preoperative GLP-1 Receptor Agonist Use and Risk of Postoperative Respiratory Complications. JAMA. 2024 Apr. doi: 10.1001/jama.2024.5003.
10. Hiramoto B et al. Quantified Metrics of Gastric Emptying Delay by Glucagon-Like Peptide-1 Agonists: A systematic review and meta-analysis with insights for periprocedural management. Am J Gastroenterol. 2024 Jun. doi: 10.14309/ajg.0000000000002820.
The use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has increased over the past several years and has become a cornerstone in both diabetes and weight loss management, particularly because of its unique combination of glucose control, weight reduction potential, and cardiac and metabolic benefits. However, increased use of these agents presents a dilemma in gastrointestinal endoscopy as it pertains to their safety and management during the periprocedural period.
highlighting gaps and future directions.
Pharmacology and Mechanisms of Action
GLP-1 RAs have several mechanisms of action that make them relevant in gastrointestinal endoscopy. These medications modulate glucose control via enhancement of glucose-dependent insulin secretion and reduction of postprandial glucagon, which promotes satiety and delays gastric emptying. This delay in gastric emptying mediated by vagal pathways has been postulated to increase gastric residuals, posing a risk for aspiration during anesthesia.1
It is important to also consider the pharmacokinetics of GLP-1 RAs, as some have shorter half-lives on the order of several hours, like exenatide, while others, like semaglutide, are dosed weekly. Additionally, common side effects of GLP-1 RAs include nausea, vomiting, bloating, and early satiety, which pose challenges for patients undergoing endoscopic procedures.
Current Guidelines
Various societies have published guidelines on the periprocedural use of GLP-1 RAs. The American Society of Anesthesiologist (ASA) in 2023 presented early recommendations to hold GLP-1 RAs either day of procedure or week prior depending on pharmacokinetics, because of the risk of delayed gastric emptying and increased potential for aspiration.2 Soon thereafter, a multi-gastroenterology society guideline was released stating more data is needed to decide if GLP-1 RAs need to be held prior to endoscopic procedures.3
In early 2024, the American Gastroenterological Association (AGA) published a rapid clinical update that advocated for a more individualized approach, particularly in light of limited overall data for GLP-1 RAs and endoscopic procedures.4 In asymptomatic patients who follow typical fasting protocols for procedures, it is generally safe to proceed with endoscopy without holding GLP-1 RAs. In symptomatic patients (nausea, abdominal distension, etc), the AGA advises additional precautions, including performing transabdominal ultrasound if feasible to assess retained gastric contents. The AGA also suggests placing a patient on a clear liquid diet the day prior to the procedure — rather than holding GLP-1 RAs — as another reasonable strategy.
The guidelines continue to evolve with newer multi-society guidelines establishing best practices. While initially in 2023 the ASA did recommend holding these medications prior to endoscopy, the initial guidance was based on expert opinion with limited evidence. Newer multi-society guidance published jointly by the ASA along with various gastroenterology societies, including the AGA in December 2024, takes a more nuanced approach.5
The newer guidelines include two main recommendations:
1. Periprocedural management of GLP-1 RAs should be a joint decision among the procedural, anesthesia, and prescribing team balancing metabolic needs vs patient risks.
- In a low-risk patient, one that is asymptomatic and on standard dosing, among other factors, the guidance states that GLP-1 RAs can be continued.
- In higher-risk patients, the original guidance of holding a day or a week prior to endoscopic procedures should be followed.
2. Periprocedural management of GLP-1 RAs should attempt to minimize the aspiration risks loosely associated with delayed gastric emptying.
- Consider a 24-hour clear liquid diet a day prior to the procedure and transabdominal ultrasound to check gastric contents.
- It is acknowledged that this guidance is based on limited evidence and will be evolving as new medications and data are released.
Recent Clinical Studies
Although there is very little data to guide clinicians, several recent studies have been published that can direct clinical decision-making as guidelines continue to be refined and updated.
A multicenter trial of approximately 800 patients undergoing upper endoscopy found a significant difference in rates of retained gastric contents between those that underwent endoscopy who did and did not follow the ASA guidance on periprocedural management of GLP-1 RAs (12.7% vs 4.4%; P < .0001). However, there were no significant differences in rates of aborted procedures or unplanned intubations.
Furthermore, a multivariable analysis was performed controlling for GLP-1 RA type and other factors, which found the likelihood of gastric retention increased by 36% for every 1% increase in hemoglobin A1c. This study suggests that a more individualized approach to holding GLP-1 RA would be applicable rather than a universal periprocedural hold.6
More recently, a single-center study of nearly 600 patients undergoing upper endoscopy showed that while there were slightly increased rates of retained gastric contents (OR 3.80; P = .003) and aborted procedures (1.3% vs 0%; P = .02), the rates of adverse anesthesia events (hypoxia, etc) were similar between the groups and no cases of pulmonary aspiration were noted.7
One single-center study of 57 patients evaluated the safety of GLP-1 RAs in those undergoing endoscopic sleeve gastrectomy. GLP-1 RAs were continued on all patients, but all adhered to a liquid only diet for at least 24 hours prior to the procedure. There were no instances of retained gastric solids, aspiration, or hypoxia. This study suggests that with a 24-hour clear liquid diet and routine NPO recommendations prior to endoscopy, it would be safe to continue GLP-1 RAs. This study provides rationale for the AGA recommendation for a clear liquid diet 24 hours prior to endoscopic procedures for those on GLP-1 RAs.8
A study looking at those who underwent emergency surgery and endoscopy with claims data of use of GLP-1 RAs found an overall incidence of postoperative respiratory complications of 3.5% for those with GLP-1 RAs fill history vs 4.0% for those without (P = .12). Approximately 800 of the 24,000 patients identified had undergone endoscopic procedures for GI bleeding or food impaction. The study overall showed that preoperative use of GLP-1 RAs in patients undergoing surgery or endoscopy, evaluated as a combined group, was not associated with an increased risk of pulmonary complications.9
Lastly, a systematic review and meta-analysis that included 15 studies that quantified gastric emptying using various methods, including gastric emptying scintigraphy and acetaminophen absorption test, found that there was a quantifiable delay in gastric emptying of about 36 minutes, compared to placebo (P < .01), in patients using GLP-1 RAs. However, compared to standard periprocedural fasting, this delay is clinically insignificant and standard fasting protocols would still be appropriate for patients on GLP-1 RAs.10
These studies taken together suggest that while GLP-1 RAs can mildly increase the likelihood of retained gastric contents, there is no statistically significant increase in the risk of aspiration or other anesthesia complications. Furthermore, while decreased gastric emptying is a known effect of GLP-1 RAs, this effect may not be clinically significant in the context of standard periprocedural fasting protocols particularly when combined with a 24-hour clear liquid diet. These findings support at a minimum a more patient-specific strategy for periprocedural management of GLP-1 RAs.
Clinical Implications
These most recent studies, as well as prior studies and guidelines by various societies lead to a dilemma among endoscopists on proper patient counseling on GLP-1 RAs use before endoscopic procedures. Clinicians must balance the metabolic benefits of GLP-1 RAs with potential endoscopic complications and risks.
Holding therapy theoretically decreases aspiration risk and pulmonary complications, though evidence remains low to support this. Holding medication, however, affects glycemic control leading to potential rebound hyperglycemia which may impact and delay plans for endoscopy. With growing indications for the use of GLP-1 RAs, a more tailored patient-centered treatment plan may be required, especially with consideration of procedure indication and comorbidities.
Currently, practice patterns at different institutions vary widely, making standardization much more difficult. Some centers have opted to follow ASA guidelines of holding these medications up to 1 week prior to procedures, while others have continued therapy with no pre-procedural adjustments. This leaves endoscopists to deal with the downstream effects of inconvenience to patients, care delays, and financial considerations if procedures are postponed related to GLP-1 RAs use.
Future Directions
Future studies are needed to make further evidence-based recommendations. Studies should focus on stratifying risks and recommendations based on procedure type (EGD, colonoscopy, etc). More widespread implementation of gastric ultrasound can assist in real-time decision-making, albeit this would require expertise and dedicated time within the pre-procedural workflow. Randomized controlled trials comparing outcomes of patients who continue GLP-1 RAs vs those who discontinue stratified by baseline risk will be instrumental for making concrete guidelines that provide clarity on periprocedural management of GLP-1 RAs.
Conclusion
The periprocedural management of GLP-1 RAs remains a controversial topic that presents unique challenges in endoscopy. Several guidelines have been released by various stakeholders including anesthesiologists, gastroenterologists, and other prescribing providers. Clinical data remains limited with no robust evidence available to suggest that gastric emptying delays caused by GLP-1 RAs prior to endoscopic procedures significantly increases risk of aspiration, pulmonary complications, or other comorbidities. Evolving multi-society guidelines will be important to establish more consistent practices with reassessment of the data as new studies emerge. A multidisciplinary, individualized patient approach may be the best strategy for managing GLP-1 RAs for patients undergoing endoscopic procedures.
Dr. Sekar and Dr. Asamoah are based in the department of gastroenterology at MedStar Georgetown University Hospital, Washington, D.C. Dr. Sekar reports no conflicts of interest in regard to this article. Dr. Asamoah serves on the Johnson & Johnson advisory board for inflammatory bowel disease–related therapies.
References
1. Halim MA et al. Glucagon-Like Peptide-1 Inhibits Prandial Gastrointestinal Motility Through Myenteric Neuronal Mechanisms in Humans. J Clin Endocrinol Metab. 2018 Feb. doi: 10.1210/jc.2017-02006.
2. American Society of Anesthesiologists. American Society of Anesthesiologists releases consensus-based guidance on preoperative use of GLP-1 receptor agonists. 2023 Jun 20. www.asahq.org/about-asa/newsroom/news-releases/2023/06/american-society-of-anesthesiologists-consensus-based-guidance-on-preoperative
3. American Gastroenterological Association. GI multi-society statement regarding GLP-1 agonists and endoscopy. 2023 Jul 25. gastro.org/news/gi-multi-society-statement-regarding-glp-1-agonists-and-endoscopy/.
4. Hashash JG et al. AGA Rapid Clinical Practice Update on the Management of Patients Taking GLP-1 Receptor Agonists Prior to Endoscopy: Communication. Clin Gastroenterol Hepatol. 2024 Apr. doi: 10.1016/j.cgh.2023.11.002.
5. Kindel TL et al; American Gastroenterological Association; American Society for Metabolic and Bariatric Surgery; American Society of Anesthesiologists; International Society of Perioperative Care of Patients with Obesity; Society of American Gastrointestinal and Endoscopic Surgeons. Multi-society Clinical Practice Guidance for the Safe Use of Glucagon-like Peptide-1 Receptor Agonists in the Perioperative Period. Clin Gastroenterol Hepatol. 2024 Oct. doi: 10.1016/j.cgh.2024.10.003.
6. Phan J et al. Glucagon-Like Peptide Receptor Agonists Use Before Endoscopy Is Associated With Low Retained Gastric Contents: A Multicenter Cross-Sectional Analysis. Am J Gastroenterol. 2025 Mar. doi: 10.14309/ajg.0000000000002969.
7. Panchal S et al. Endoscopy and Anesthesia Outcomes Associated With Glucagon-like Peptide-1 Receptor Agonist use in Patients Undergoing Outpatient Upper Endoscopy. Gastrointest Endosc. 2025 Aug. doi:10.1016/j.gie.2025.01.004.
8. Maselli DB et al. Safe Continuation of glucagon-like Peptide 1 Receptor Agonists at Endoscopy: A Case Series of 57 Adults Undergoing Endoscopic Sleeve Gastroplasty. Obes Surg. 2024 Jul. doi: 10.1007/s11695-024-07278-2.
9. Dixit AA et al. Preoperative GLP-1 Receptor Agonist Use and Risk of Postoperative Respiratory Complications. JAMA. 2024 Apr. doi: 10.1001/jama.2024.5003.
10. Hiramoto B et al. Quantified Metrics of Gastric Emptying Delay by Glucagon-Like Peptide-1 Agonists: A systematic review and meta-analysis with insights for periprocedural management. Am J Gastroenterol. 2024 Jun. doi: 10.14309/ajg.0000000000002820.
The use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has increased over the past several years and has become a cornerstone in both diabetes and weight loss management, particularly because of its unique combination of glucose control, weight reduction potential, and cardiac and metabolic benefits. However, increased use of these agents presents a dilemma in gastrointestinal endoscopy as it pertains to their safety and management during the periprocedural period.
highlighting gaps and future directions.
Pharmacology and Mechanisms of Action
GLP-1 RAs have several mechanisms of action that make them relevant in gastrointestinal endoscopy. These medications modulate glucose control via enhancement of glucose-dependent insulin secretion and reduction of postprandial glucagon, which promotes satiety and delays gastric emptying. This delay in gastric emptying mediated by vagal pathways has been postulated to increase gastric residuals, posing a risk for aspiration during anesthesia.1
It is important to also consider the pharmacokinetics of GLP-1 RAs, as some have shorter half-lives on the order of several hours, like exenatide, while others, like semaglutide, are dosed weekly. Additionally, common side effects of GLP-1 RAs include nausea, vomiting, bloating, and early satiety, which pose challenges for patients undergoing endoscopic procedures.
Current Guidelines
Various societies have published guidelines on the periprocedural use of GLP-1 RAs. The American Society of Anesthesiologist (ASA) in 2023 presented early recommendations to hold GLP-1 RAs either day of procedure or week prior depending on pharmacokinetics, because of the risk of delayed gastric emptying and increased potential for aspiration.2 Soon thereafter, a multi-gastroenterology society guideline was released stating more data is needed to decide if GLP-1 RAs need to be held prior to endoscopic procedures.3
In early 2024, the American Gastroenterological Association (AGA) published a rapid clinical update that advocated for a more individualized approach, particularly in light of limited overall data for GLP-1 RAs and endoscopic procedures.4 In asymptomatic patients who follow typical fasting protocols for procedures, it is generally safe to proceed with endoscopy without holding GLP-1 RAs. In symptomatic patients (nausea, abdominal distension, etc), the AGA advises additional precautions, including performing transabdominal ultrasound if feasible to assess retained gastric contents. The AGA also suggests placing a patient on a clear liquid diet the day prior to the procedure — rather than holding GLP-1 RAs — as another reasonable strategy.
The guidelines continue to evolve with newer multi-society guidelines establishing best practices. While initially in 2023 the ASA did recommend holding these medications prior to endoscopy, the initial guidance was based on expert opinion with limited evidence. Newer multi-society guidance published jointly by the ASA along with various gastroenterology societies, including the AGA in December 2024, takes a more nuanced approach.5
The newer guidelines include two main recommendations:
1. Periprocedural management of GLP-1 RAs should be a joint decision among the procedural, anesthesia, and prescribing team balancing metabolic needs vs patient risks.
- In a low-risk patient, one that is asymptomatic and on standard dosing, among other factors, the guidance states that GLP-1 RAs can be continued.
- In higher-risk patients, the original guidance of holding a day or a week prior to endoscopic procedures should be followed.
2. Periprocedural management of GLP-1 RAs should attempt to minimize the aspiration risks loosely associated with delayed gastric emptying.
- Consider a 24-hour clear liquid diet a day prior to the procedure and transabdominal ultrasound to check gastric contents.
- It is acknowledged that this guidance is based on limited evidence and will be evolving as new medications and data are released.
Recent Clinical Studies
Although there is very little data to guide clinicians, several recent studies have been published that can direct clinical decision-making as guidelines continue to be refined and updated.
A multicenter trial of approximately 800 patients undergoing upper endoscopy found a significant difference in rates of retained gastric contents between those that underwent endoscopy who did and did not follow the ASA guidance on periprocedural management of GLP-1 RAs (12.7% vs 4.4%; P < .0001). However, there were no significant differences in rates of aborted procedures or unplanned intubations.
Furthermore, a multivariable analysis was performed controlling for GLP-1 RA type and other factors, which found the likelihood of gastric retention increased by 36% for every 1% increase in hemoglobin A1c. This study suggests that a more individualized approach to holding GLP-1 RA would be applicable rather than a universal periprocedural hold.6
More recently, a single-center study of nearly 600 patients undergoing upper endoscopy showed that while there were slightly increased rates of retained gastric contents (OR 3.80; P = .003) and aborted procedures (1.3% vs 0%; P = .02), the rates of adverse anesthesia events (hypoxia, etc) were similar between the groups and no cases of pulmonary aspiration were noted.7
One single-center study of 57 patients evaluated the safety of GLP-1 RAs in those undergoing endoscopic sleeve gastrectomy. GLP-1 RAs were continued on all patients, but all adhered to a liquid only diet for at least 24 hours prior to the procedure. There were no instances of retained gastric solids, aspiration, or hypoxia. This study suggests that with a 24-hour clear liquid diet and routine NPO recommendations prior to endoscopy, it would be safe to continue GLP-1 RAs. This study provides rationale for the AGA recommendation for a clear liquid diet 24 hours prior to endoscopic procedures for those on GLP-1 RAs.8
A study looking at those who underwent emergency surgery and endoscopy with claims data of use of GLP-1 RAs found an overall incidence of postoperative respiratory complications of 3.5% for those with GLP-1 RAs fill history vs 4.0% for those without (P = .12). Approximately 800 of the 24,000 patients identified had undergone endoscopic procedures for GI bleeding or food impaction. The study overall showed that preoperative use of GLP-1 RAs in patients undergoing surgery or endoscopy, evaluated as a combined group, was not associated with an increased risk of pulmonary complications.9
Lastly, a systematic review and meta-analysis that included 15 studies that quantified gastric emptying using various methods, including gastric emptying scintigraphy and acetaminophen absorption test, found that there was a quantifiable delay in gastric emptying of about 36 minutes, compared to placebo (P < .01), in patients using GLP-1 RAs. However, compared to standard periprocedural fasting, this delay is clinically insignificant and standard fasting protocols would still be appropriate for patients on GLP-1 RAs.10
These studies taken together suggest that while GLP-1 RAs can mildly increase the likelihood of retained gastric contents, there is no statistically significant increase in the risk of aspiration or other anesthesia complications. Furthermore, while decreased gastric emptying is a known effect of GLP-1 RAs, this effect may not be clinically significant in the context of standard periprocedural fasting protocols particularly when combined with a 24-hour clear liquid diet. These findings support at a minimum a more patient-specific strategy for periprocedural management of GLP-1 RAs.
Clinical Implications
These most recent studies, as well as prior studies and guidelines by various societies lead to a dilemma among endoscopists on proper patient counseling on GLP-1 RAs use before endoscopic procedures. Clinicians must balance the metabolic benefits of GLP-1 RAs with potential endoscopic complications and risks.
Holding therapy theoretically decreases aspiration risk and pulmonary complications, though evidence remains low to support this. Holding medication, however, affects glycemic control leading to potential rebound hyperglycemia which may impact and delay plans for endoscopy. With growing indications for the use of GLP-1 RAs, a more tailored patient-centered treatment plan may be required, especially with consideration of procedure indication and comorbidities.
Currently, practice patterns at different institutions vary widely, making standardization much more difficult. Some centers have opted to follow ASA guidelines of holding these medications up to 1 week prior to procedures, while others have continued therapy with no pre-procedural adjustments. This leaves endoscopists to deal with the downstream effects of inconvenience to patients, care delays, and financial considerations if procedures are postponed related to GLP-1 RAs use.
Future Directions
Future studies are needed to make further evidence-based recommendations. Studies should focus on stratifying risks and recommendations based on procedure type (EGD, colonoscopy, etc). More widespread implementation of gastric ultrasound can assist in real-time decision-making, albeit this would require expertise and dedicated time within the pre-procedural workflow. Randomized controlled trials comparing outcomes of patients who continue GLP-1 RAs vs those who discontinue stratified by baseline risk will be instrumental for making concrete guidelines that provide clarity on periprocedural management of GLP-1 RAs.
Conclusion
The periprocedural management of GLP-1 RAs remains a controversial topic that presents unique challenges in endoscopy. Several guidelines have been released by various stakeholders including anesthesiologists, gastroenterologists, and other prescribing providers. Clinical data remains limited with no robust evidence available to suggest that gastric emptying delays caused by GLP-1 RAs prior to endoscopic procedures significantly increases risk of aspiration, pulmonary complications, or other comorbidities. Evolving multi-society guidelines will be important to establish more consistent practices with reassessment of the data as new studies emerge. A multidisciplinary, individualized patient approach may be the best strategy for managing GLP-1 RAs for patients undergoing endoscopic procedures.
Dr. Sekar and Dr. Asamoah are based in the department of gastroenterology at MedStar Georgetown University Hospital, Washington, D.C. Dr. Sekar reports no conflicts of interest in regard to this article. Dr. Asamoah serves on the Johnson & Johnson advisory board for inflammatory bowel disease–related therapies.
References
1. Halim MA et al. Glucagon-Like Peptide-1 Inhibits Prandial Gastrointestinal Motility Through Myenteric Neuronal Mechanisms in Humans. J Clin Endocrinol Metab. 2018 Feb. doi: 10.1210/jc.2017-02006.
2. American Society of Anesthesiologists. American Society of Anesthesiologists releases consensus-based guidance on preoperative use of GLP-1 receptor agonists. 2023 Jun 20. www.asahq.org/about-asa/newsroom/news-releases/2023/06/american-society-of-anesthesiologists-consensus-based-guidance-on-preoperative
3. American Gastroenterological Association. GI multi-society statement regarding GLP-1 agonists and endoscopy. 2023 Jul 25. gastro.org/news/gi-multi-society-statement-regarding-glp-1-agonists-and-endoscopy/.
4. Hashash JG et al. AGA Rapid Clinical Practice Update on the Management of Patients Taking GLP-1 Receptor Agonists Prior to Endoscopy: Communication. Clin Gastroenterol Hepatol. 2024 Apr. doi: 10.1016/j.cgh.2023.11.002.
5. Kindel TL et al; American Gastroenterological Association; American Society for Metabolic and Bariatric Surgery; American Society of Anesthesiologists; International Society of Perioperative Care of Patients with Obesity; Society of American Gastrointestinal and Endoscopic Surgeons. Multi-society Clinical Practice Guidance for the Safe Use of Glucagon-like Peptide-1 Receptor Agonists in the Perioperative Period. Clin Gastroenterol Hepatol. 2024 Oct. doi: 10.1016/j.cgh.2024.10.003.
6. Phan J et al. Glucagon-Like Peptide Receptor Agonists Use Before Endoscopy Is Associated With Low Retained Gastric Contents: A Multicenter Cross-Sectional Analysis. Am J Gastroenterol. 2025 Mar. doi: 10.14309/ajg.0000000000002969.
7. Panchal S et al. Endoscopy and Anesthesia Outcomes Associated With Glucagon-like Peptide-1 Receptor Agonist use in Patients Undergoing Outpatient Upper Endoscopy. Gastrointest Endosc. 2025 Aug. doi:10.1016/j.gie.2025.01.004.
8. Maselli DB et al. Safe Continuation of glucagon-like Peptide 1 Receptor Agonists at Endoscopy: A Case Series of 57 Adults Undergoing Endoscopic Sleeve Gastroplasty. Obes Surg. 2024 Jul. doi: 10.1007/s11695-024-07278-2.
9. Dixit AA et al. Preoperative GLP-1 Receptor Agonist Use and Risk of Postoperative Respiratory Complications. JAMA. 2024 Apr. doi: 10.1001/jama.2024.5003.
10. Hiramoto B et al. Quantified Metrics of Gastric Emptying Delay by Glucagon-Like Peptide-1 Agonists: A systematic review and meta-analysis with insights for periprocedural management. Am J Gastroenterol. 2024 Jun. doi: 10.14309/ajg.0000000000002820.
Less Invasive Sponge Test Stratifies Risk in Patients With Barrett’s Esophagus
The biomarker risk panel collected by the panesophageal Cytosponge-on-a-string in more than 900 UK patients helped identify those at highest risk for dysplasia or cancer and needing endoscopy. It was found safe for following low-risk patients who did not need endoscopy.
Endoscopic surveillance is the clinical standard for BE, but its effectiveness is inconsistent, wrote Rebecca C. Fitzgerald, MD, AGAF, professor in the Early Cancer Institute at the University of Cambridge in Cambridge, England, and colleagues in The Lancet.
“It is often performed by nonspecialists, and recent trials show that around 10% of cases of dysplasia and cancer are missed, which means some patients re-present within a year of their surveillance procedure with a symptomatic cancer that should have been diagnosed earlier,” Fitzgerald told GI & Hepatology News.
Moreover, repeated endoscopy monitoring is stressful. “A simple nonendoscopic capsule sponge test done nearer to home is less scary and could be less operator-dependent. By reducing the burden of endoscopy in patients at very low risk we can focus more on the patients at higher risk,” she said.
In 2022, her research group had reported that the capsule sponge test, coupled with a centralized lab test for p53 and atypia, can risk-stratify patients into low-, moderate-, and high-risk groups. “In the current study, we wanted to check this risk stratification capsule sponge test in the real world. Our main aim was to see if we could conform the 2022 results with the hypothesis that the low-risk patients — more than 50% of patients in surveillance — would have a risk of high-grade dysplasia or cancer that was sufficiently low — that is, less than from 3% — and could therefore have follow-up with the capsule sponge without requiring endoscopy.”
The investigators hypothesized that the 15% at high risk would have a significant chance of dysplasia warranting endoscopy in a specialist center.
“Our results showed that in the low-risk group the risk of high-grade dysplasia or cancer was 0.4%, suggesting these patients could be offered follow-up with the capsule sponge test,” Fitzgerald said.
The high-risk group with a double biomarker positive (p53 and atypia) had an 85% risk for dysplasia or cancer. “We call this a tier 1 or ultra-high risk, and this suggests these cases merit a specialist endoscopy in a center that could treat the dysplasia/cancer,” she said.
Study Details
Adult participants (n = 910) were recruited from August 2020 to December 2024 in two multicenter, prospective, pragmatic implementation studies from 13 hospitals. Patients with nondysplastic BE on last endoscopy had a capsule sponge test.
Patient risk was assigned as low (clinical and capsule sponge biomarkers negative), moderate (negative for capsule sponge biomarkers, positive clinical biomarkers: age, sex, and segment length), or high risk (p53 abnormality, glandular atypia regardless of clinical biomarkers, or both). The primary outcome was a diagnosis of high-grade dysplasia or cancer necessitating treatment, according to the risk group.
In the cohort, 138 (15%) were classified as having high risk, 283 (31%) had moderate risk, and 489 (54%) had low risk.
The positive predictive value for any dysplasia or worse in the high-risk group was 37.7% (95% CI, 29.7-46.4). Patients with both atypia and aberrant p53 had the highest risk for high-grade dysplasia or cancer with a relative risk of 135.8 (95% CI, 32.7-564.0) vs the low-risk group.
The prevalence of high-grade dysplasia or cancer in the low-risk group was, as mentioned, just 0.4% (95% CI, 0.1-1.6), while the negative predictive value for any dysplasia or cancer was 97.8% (95% CI, 95.9-98.8). Applying a machine learning algorithm reduced the proportion needing p53 pathology review to 32% without missing any positive cases.
Offering a US perspective on the study, Nicholas J. Shaheen, MD, MPH, AGAF, professor of medicine and director of the NC Translational & Clinical Sciences Institute at the University of North Carolina School of Medicine in Chapel Hill, called the findings “very provocative.”
“We have known for some time that nonendoscopic techniques could be used to screen for Barrett’s esophagus and esophageal cancer, allowing us to screen larger groups of patients in a more cost-effective manner compared to traditional upper endoscopy,” he told GI & Hepatology News. “This study suggests that, in addition to case-finding for Barrett’s [esophagus], a nonendoscopic sponge-based technique can also help us stratify risk, finding cases that either already harbor cancer or are at high risk to do so.”
Shaheen said these cases deserve immediate attention since they are most likely to benefit from timely endoscopic intervention. “The study also suggests that a nonendoscopic result could someday be used to decide subsequent follow-up, with low-risk patients undergoing further nonendoscopic surveillance, while higher-risk patients would move on to endoscopy. Such a paradigm could unburden our endoscopy units from low-risk patients unlikely to benefit from endoscopy as well as increase the numbers of patients who are able to be screened.”
Fitzgerald added, “The GI community is realizing that we need a better approach to managing patients with Barrett’s [esophagus]. In the UK this evidence is being considered by our guideline committee, and it would influence the upcoming guidelines in 2025 with a requirement to continue to audit the results. Outside of the UK we hope this will pave the way for nonendoscopic approaches to Barrett’s [esophagus] surveillance.”
One ongoing goal is to optimize the biomarkers, Fitzgerald said. “For patients with longer segments we would like to add additional genomic biomarkers to refine the risk predictions,” she said. “We need a more operator-independent, consistent method for monitoring Barrett’s [esophagus]. This large real-world study is highly encouraging for a more personalized and patient-friendly approach to Barrett’s [esophagus] surveillance.”
This study was funded by Innovate UK, Cancer Research UK, National Health Service England Cancer Alliance. Cytosponge technology is licensed by the Medical Research Council to Medtronic. Fitzgerald declared holding patents related to this test. Fitzgerald reported being a shareholder in Cyted Health.
Shaheen reported receiving research funding from Lucid Diagnostics and Cyted Health, both of which are manufacturers of nonendoscopic screening devices for BE.
A version of this article appeared on Medscape.com.
The biomarker risk panel collected by the panesophageal Cytosponge-on-a-string in more than 900 UK patients helped identify those at highest risk for dysplasia or cancer and needing endoscopy. It was found safe for following low-risk patients who did not need endoscopy.
Endoscopic surveillance is the clinical standard for BE, but its effectiveness is inconsistent, wrote Rebecca C. Fitzgerald, MD, AGAF, professor in the Early Cancer Institute at the University of Cambridge in Cambridge, England, and colleagues in The Lancet.
“It is often performed by nonspecialists, and recent trials show that around 10% of cases of dysplasia and cancer are missed, which means some patients re-present within a year of their surveillance procedure with a symptomatic cancer that should have been diagnosed earlier,” Fitzgerald told GI & Hepatology News.
Moreover, repeated endoscopy monitoring is stressful. “A simple nonendoscopic capsule sponge test done nearer to home is less scary and could be less operator-dependent. By reducing the burden of endoscopy in patients at very low risk we can focus more on the patients at higher risk,” she said.
In 2022, her research group had reported that the capsule sponge test, coupled with a centralized lab test for p53 and atypia, can risk-stratify patients into low-, moderate-, and high-risk groups. “In the current study, we wanted to check this risk stratification capsule sponge test in the real world. Our main aim was to see if we could conform the 2022 results with the hypothesis that the low-risk patients — more than 50% of patients in surveillance — would have a risk of high-grade dysplasia or cancer that was sufficiently low — that is, less than from 3% — and could therefore have follow-up with the capsule sponge without requiring endoscopy.”
The investigators hypothesized that the 15% at high risk would have a significant chance of dysplasia warranting endoscopy in a specialist center.
“Our results showed that in the low-risk group the risk of high-grade dysplasia or cancer was 0.4%, suggesting these patients could be offered follow-up with the capsule sponge test,” Fitzgerald said.
The high-risk group with a double biomarker positive (p53 and atypia) had an 85% risk for dysplasia or cancer. “We call this a tier 1 or ultra-high risk, and this suggests these cases merit a specialist endoscopy in a center that could treat the dysplasia/cancer,” she said.
Study Details
Adult participants (n = 910) were recruited from August 2020 to December 2024 in two multicenter, prospective, pragmatic implementation studies from 13 hospitals. Patients with nondysplastic BE on last endoscopy had a capsule sponge test.
Patient risk was assigned as low (clinical and capsule sponge biomarkers negative), moderate (negative for capsule sponge biomarkers, positive clinical biomarkers: age, sex, and segment length), or high risk (p53 abnormality, glandular atypia regardless of clinical biomarkers, or both). The primary outcome was a diagnosis of high-grade dysplasia or cancer necessitating treatment, according to the risk group.
In the cohort, 138 (15%) were classified as having high risk, 283 (31%) had moderate risk, and 489 (54%) had low risk.
The positive predictive value for any dysplasia or worse in the high-risk group was 37.7% (95% CI, 29.7-46.4). Patients with both atypia and aberrant p53 had the highest risk for high-grade dysplasia or cancer with a relative risk of 135.8 (95% CI, 32.7-564.0) vs the low-risk group.
The prevalence of high-grade dysplasia or cancer in the low-risk group was, as mentioned, just 0.4% (95% CI, 0.1-1.6), while the negative predictive value for any dysplasia or cancer was 97.8% (95% CI, 95.9-98.8). Applying a machine learning algorithm reduced the proportion needing p53 pathology review to 32% without missing any positive cases.
Offering a US perspective on the study, Nicholas J. Shaheen, MD, MPH, AGAF, professor of medicine and director of the NC Translational & Clinical Sciences Institute at the University of North Carolina School of Medicine in Chapel Hill, called the findings “very provocative.”
“We have known for some time that nonendoscopic techniques could be used to screen for Barrett’s esophagus and esophageal cancer, allowing us to screen larger groups of patients in a more cost-effective manner compared to traditional upper endoscopy,” he told GI & Hepatology News. “This study suggests that, in addition to case-finding for Barrett’s [esophagus], a nonendoscopic sponge-based technique can also help us stratify risk, finding cases that either already harbor cancer or are at high risk to do so.”
Shaheen said these cases deserve immediate attention since they are most likely to benefit from timely endoscopic intervention. “The study also suggests that a nonendoscopic result could someday be used to decide subsequent follow-up, with low-risk patients undergoing further nonendoscopic surveillance, while higher-risk patients would move on to endoscopy. Such a paradigm could unburden our endoscopy units from low-risk patients unlikely to benefit from endoscopy as well as increase the numbers of patients who are able to be screened.”
Fitzgerald added, “The GI community is realizing that we need a better approach to managing patients with Barrett’s [esophagus]. In the UK this evidence is being considered by our guideline committee, and it would influence the upcoming guidelines in 2025 with a requirement to continue to audit the results. Outside of the UK we hope this will pave the way for nonendoscopic approaches to Barrett’s [esophagus] surveillance.”
One ongoing goal is to optimize the biomarkers, Fitzgerald said. “For patients with longer segments we would like to add additional genomic biomarkers to refine the risk predictions,” she said. “We need a more operator-independent, consistent method for monitoring Barrett’s [esophagus]. This large real-world study is highly encouraging for a more personalized and patient-friendly approach to Barrett’s [esophagus] surveillance.”
This study was funded by Innovate UK, Cancer Research UK, National Health Service England Cancer Alliance. Cytosponge technology is licensed by the Medical Research Council to Medtronic. Fitzgerald declared holding patents related to this test. Fitzgerald reported being a shareholder in Cyted Health.
Shaheen reported receiving research funding from Lucid Diagnostics and Cyted Health, both of which are manufacturers of nonendoscopic screening devices for BE.
A version of this article appeared on Medscape.com.
The biomarker risk panel collected by the panesophageal Cytosponge-on-a-string in more than 900 UK patients helped identify those at highest risk for dysplasia or cancer and needing endoscopy. It was found safe for following low-risk patients who did not need endoscopy.
Endoscopic surveillance is the clinical standard for BE, but its effectiveness is inconsistent, wrote Rebecca C. Fitzgerald, MD, AGAF, professor in the Early Cancer Institute at the University of Cambridge in Cambridge, England, and colleagues in The Lancet.
“It is often performed by nonspecialists, and recent trials show that around 10% of cases of dysplasia and cancer are missed, which means some patients re-present within a year of their surveillance procedure with a symptomatic cancer that should have been diagnosed earlier,” Fitzgerald told GI & Hepatology News.
Moreover, repeated endoscopy monitoring is stressful. “A simple nonendoscopic capsule sponge test done nearer to home is less scary and could be less operator-dependent. By reducing the burden of endoscopy in patients at very low risk we can focus more on the patients at higher risk,” she said.
In 2022, her research group had reported that the capsule sponge test, coupled with a centralized lab test for p53 and atypia, can risk-stratify patients into low-, moderate-, and high-risk groups. “In the current study, we wanted to check this risk stratification capsule sponge test in the real world. Our main aim was to see if we could conform the 2022 results with the hypothesis that the low-risk patients — more than 50% of patients in surveillance — would have a risk of high-grade dysplasia or cancer that was sufficiently low — that is, less than from 3% — and could therefore have follow-up with the capsule sponge without requiring endoscopy.”
The investigators hypothesized that the 15% at high risk would have a significant chance of dysplasia warranting endoscopy in a specialist center.
“Our results showed that in the low-risk group the risk of high-grade dysplasia or cancer was 0.4%, suggesting these patients could be offered follow-up with the capsule sponge test,” Fitzgerald said.
The high-risk group with a double biomarker positive (p53 and atypia) had an 85% risk for dysplasia or cancer. “We call this a tier 1 or ultra-high risk, and this suggests these cases merit a specialist endoscopy in a center that could treat the dysplasia/cancer,” she said.
Study Details
Adult participants (n = 910) were recruited from August 2020 to December 2024 in two multicenter, prospective, pragmatic implementation studies from 13 hospitals. Patients with nondysplastic BE on last endoscopy had a capsule sponge test.
Patient risk was assigned as low (clinical and capsule sponge biomarkers negative), moderate (negative for capsule sponge biomarkers, positive clinical biomarkers: age, sex, and segment length), or high risk (p53 abnormality, glandular atypia regardless of clinical biomarkers, or both). The primary outcome was a diagnosis of high-grade dysplasia or cancer necessitating treatment, according to the risk group.
In the cohort, 138 (15%) were classified as having high risk, 283 (31%) had moderate risk, and 489 (54%) had low risk.
The positive predictive value for any dysplasia or worse in the high-risk group was 37.7% (95% CI, 29.7-46.4). Patients with both atypia and aberrant p53 had the highest risk for high-grade dysplasia or cancer with a relative risk of 135.8 (95% CI, 32.7-564.0) vs the low-risk group.
The prevalence of high-grade dysplasia or cancer in the low-risk group was, as mentioned, just 0.4% (95% CI, 0.1-1.6), while the negative predictive value for any dysplasia or cancer was 97.8% (95% CI, 95.9-98.8). Applying a machine learning algorithm reduced the proportion needing p53 pathology review to 32% without missing any positive cases.
Offering a US perspective on the study, Nicholas J. Shaheen, MD, MPH, AGAF, professor of medicine and director of the NC Translational & Clinical Sciences Institute at the University of North Carolina School of Medicine in Chapel Hill, called the findings “very provocative.”
“We have known for some time that nonendoscopic techniques could be used to screen for Barrett’s esophagus and esophageal cancer, allowing us to screen larger groups of patients in a more cost-effective manner compared to traditional upper endoscopy,” he told GI & Hepatology News. “This study suggests that, in addition to case-finding for Barrett’s [esophagus], a nonendoscopic sponge-based technique can also help us stratify risk, finding cases that either already harbor cancer or are at high risk to do so.”
Shaheen said these cases deserve immediate attention since they are most likely to benefit from timely endoscopic intervention. “The study also suggests that a nonendoscopic result could someday be used to decide subsequent follow-up, with low-risk patients undergoing further nonendoscopic surveillance, while higher-risk patients would move on to endoscopy. Such a paradigm could unburden our endoscopy units from low-risk patients unlikely to benefit from endoscopy as well as increase the numbers of patients who are able to be screened.”
Fitzgerald added, “The GI community is realizing that we need a better approach to managing patients with Barrett’s [esophagus]. In the UK this evidence is being considered by our guideline committee, and it would influence the upcoming guidelines in 2025 with a requirement to continue to audit the results. Outside of the UK we hope this will pave the way for nonendoscopic approaches to Barrett’s [esophagus] surveillance.”
One ongoing goal is to optimize the biomarkers, Fitzgerald said. “For patients with longer segments we would like to add additional genomic biomarkers to refine the risk predictions,” she said. “We need a more operator-independent, consistent method for monitoring Barrett’s [esophagus]. This large real-world study is highly encouraging for a more personalized and patient-friendly approach to Barrett’s [esophagus] surveillance.”
This study was funded by Innovate UK, Cancer Research UK, National Health Service England Cancer Alliance. Cytosponge technology is licensed by the Medical Research Council to Medtronic. Fitzgerald declared holding patents related to this test. Fitzgerald reported being a shareholder in Cyted Health.
Shaheen reported receiving research funding from Lucid Diagnostics and Cyted Health, both of which are manufacturers of nonendoscopic screening devices for BE.
A version of this article appeared on Medscape.com.
Hypothyroidism Linked to Gut Microbiome Disturbances
, according to results of a study.
“[The research] supports the idea that improving gut health could have far-reaching effects beyond digestion, possibly even helping to prevent autoimmune diseases, such as Hashimoto thyroiditis,” said senior author Ruchi Mathur, MD, director of the Diabetes Outpatient Treatment and Education Center and director of Clinical Operations of Medically Associated Science and Technology, at Cedars-Sinai in Los Angeles, in a press statement for the study, which was presented at ENDO 2025: The Endocrine Society Annual Meeting.
“These findings open the door to new screening and prevention strategies,” Mathur added. “For example, doctors may begin to monitor thyroid health more closely in patients with SIBO, and vice versa.”
With some small studies previously suggesting an association between the gut microbiome and hypothyroidism, Mathur and colleagues further explored the relationship in two analyses.
Assessing the Role of the Small Bowel
For the first, they evaluated data on 49 patients with Hashimoto thyroiditis (HT) and 323 controls without the condition from their REIMAGINE trial, which included small bowel fluid samples from upper endoscopies and DNA sequencing.
In the study, all patients with HT were treated with thyroid replacement (levothyroxine), hence, there were notably no significant differences between the two groups in terms of thyroid stimulating hormone (TSH) levels.
Despite the lack of those differences, patients with HT had a prevalence of SIBO more than twice that of the control group, independent of gender (33% vs 15%; odds ratio, 2.71; P = .005).
When the two groups were further subdivided into two groups each — those with and without SIBO — significant further variations of microbial diversity were observed between those with and without HT, Mathur told GI & Hepatology News.
“Interestingly, we saw the small bowel microbiome was not only different in SIBO-positive patients, including higher gram negatives, which is to be expected, but that the presence or absence of hypothyroidism itself was associated with specific patterns of these gram-negative bacteria,” she explained.
“In addition, when we looked at hypothyroidism without SIBO present, there were also changes between groups, such as higher Neisseria in the hypothyroid group.”
“All these findings are novel as this is the first paper to look specifically at the small bowel,” she added, noting that previous smaller studies have focused more on evaluation of stool samples.
“We believe the small bowel is the most metabolically active area of the intestine and plays an important role in metabolism,” Mathur noted. “Thus, the microbial changes here are likely more physiologically significant than the patterns seen in stool.”
Further Findings from a Large Population
In a separate analysis, the team evaluated data from the TriNetX database on the 10-year incidence of developing SIBO among 1.1 million subjects with hypothyroidism in the US compared with 1 million controls.
They found that people with hypothyroidism were approximately twice as likely to develop SIBO compared with those without hypothyroidism (relative risk [RR], 2.20).
Furthermore, those with HT, in particular, had an even higher risk, at 2.4 times the controls (RR, 2.40).
Treatment with levothyroxine decreased the risk of developing SIBO in hypothyroidism (RR, 0.33) and HT (RR, 0.78) vs those who did not receive treatment.
Mechanisms?
However, the fact that differences in SIBO were observed even between people who were treated for HT and those without the condition in the first analysis, and hence had similar TSH levels, was notable, Mathur said.
“This suggests that perhaps there are other factors aside from TSH levels and free T4 that are at play here,” she said. “Some people have theorized that perhaps delayed gut motility in hypothyroidism promotes the development of SIBO; however, there are many other factors within this complex interplay between the microbiome and the thyroid that could also be playing a role.”
“For example, SIBO leads to inflammation and weakening of the gut barrier,” Mathur explained.
Furthermore, “levothyroxine absorption and cycling of the thyroid hormone occurs predominantly in the small bowel, [while the] microbiome plays a key role in the absorption of iron, selenium, iodine, and zinc, which are critical for thyroid function.”
Overall, “further research is needed to understand how the mechanisms are affected during the development of SIBO and hypothyroidism,” Mathur said.
Assessment of Changes Over Time Anticipated
Commenting on the research, Gregory A. Brent, MD, senior executive academic vice-chair of the Department of Medicine and professor of medicine and physiology at the David Geffen School of Medicine at University of California Los Angeles said the study is indeed novel.
“This, to my knowledge, is the first investigation to link characteristics of the small bowel microbiome with hypothyroidism,” Brent told GI & Hepatology News.
While any clinical significance has yet to be determined, “the association of these small bowel microbiome changes with hypothyroidism may have implications for contributing to the onset of autoimmune hypothyroidism in susceptible populations as well as influences on levothyroxine absorption in hypothyroid patients on levothyroxine therapy,” Brent said.
With the SIBO differences observed even among treated patients with vs without HT, “it seems less likely that the microbiome changes are the result of reduced thyroid hormone signaling,” Brent noted.
Furthermore, a key piece of the puzzle will be to observe the microbiome changes over time, he added.
“These studies were at a single time point [and] longitudinal studies will be especially important to see how the association changes over time and are influenced by the treatment of hypothyroidism and of SIBO,” Brent said.
The authors and Brent had no disclosures to report.
A version of this article appeared on Medscape.com.
, according to results of a study.
“[The research] supports the idea that improving gut health could have far-reaching effects beyond digestion, possibly even helping to prevent autoimmune diseases, such as Hashimoto thyroiditis,” said senior author Ruchi Mathur, MD, director of the Diabetes Outpatient Treatment and Education Center and director of Clinical Operations of Medically Associated Science and Technology, at Cedars-Sinai in Los Angeles, in a press statement for the study, which was presented at ENDO 2025: The Endocrine Society Annual Meeting.
“These findings open the door to new screening and prevention strategies,” Mathur added. “For example, doctors may begin to monitor thyroid health more closely in patients with SIBO, and vice versa.”
With some small studies previously suggesting an association between the gut microbiome and hypothyroidism, Mathur and colleagues further explored the relationship in two analyses.
Assessing the Role of the Small Bowel
For the first, they evaluated data on 49 patients with Hashimoto thyroiditis (HT) and 323 controls without the condition from their REIMAGINE trial, which included small bowel fluid samples from upper endoscopies and DNA sequencing.
In the study, all patients with HT were treated with thyroid replacement (levothyroxine), hence, there were notably no significant differences between the two groups in terms of thyroid stimulating hormone (TSH) levels.
Despite the lack of those differences, patients with HT had a prevalence of SIBO more than twice that of the control group, independent of gender (33% vs 15%; odds ratio, 2.71; P = .005).
When the two groups were further subdivided into two groups each — those with and without SIBO — significant further variations of microbial diversity were observed between those with and without HT, Mathur told GI & Hepatology News.
“Interestingly, we saw the small bowel microbiome was not only different in SIBO-positive patients, including higher gram negatives, which is to be expected, but that the presence or absence of hypothyroidism itself was associated with specific patterns of these gram-negative bacteria,” she explained.
“In addition, when we looked at hypothyroidism without SIBO present, there were also changes between groups, such as higher Neisseria in the hypothyroid group.”
“All these findings are novel as this is the first paper to look specifically at the small bowel,” she added, noting that previous smaller studies have focused more on evaluation of stool samples.
“We believe the small bowel is the most metabolically active area of the intestine and plays an important role in metabolism,” Mathur noted. “Thus, the microbial changes here are likely more physiologically significant than the patterns seen in stool.”
Further Findings from a Large Population
In a separate analysis, the team evaluated data from the TriNetX database on the 10-year incidence of developing SIBO among 1.1 million subjects with hypothyroidism in the US compared with 1 million controls.
They found that people with hypothyroidism were approximately twice as likely to develop SIBO compared with those without hypothyroidism (relative risk [RR], 2.20).
Furthermore, those with HT, in particular, had an even higher risk, at 2.4 times the controls (RR, 2.40).
Treatment with levothyroxine decreased the risk of developing SIBO in hypothyroidism (RR, 0.33) and HT (RR, 0.78) vs those who did not receive treatment.
Mechanisms?
However, the fact that differences in SIBO were observed even between people who were treated for HT and those without the condition in the first analysis, and hence had similar TSH levels, was notable, Mathur said.
“This suggests that perhaps there are other factors aside from TSH levels and free T4 that are at play here,” she said. “Some people have theorized that perhaps delayed gut motility in hypothyroidism promotes the development of SIBO; however, there are many other factors within this complex interplay between the microbiome and the thyroid that could also be playing a role.”
“For example, SIBO leads to inflammation and weakening of the gut barrier,” Mathur explained.
Furthermore, “levothyroxine absorption and cycling of the thyroid hormone occurs predominantly in the small bowel, [while the] microbiome plays a key role in the absorption of iron, selenium, iodine, and zinc, which are critical for thyroid function.”
Overall, “further research is needed to understand how the mechanisms are affected during the development of SIBO and hypothyroidism,” Mathur said.
Assessment of Changes Over Time Anticipated
Commenting on the research, Gregory A. Brent, MD, senior executive academic vice-chair of the Department of Medicine and professor of medicine and physiology at the David Geffen School of Medicine at University of California Los Angeles said the study is indeed novel.
“This, to my knowledge, is the first investigation to link characteristics of the small bowel microbiome with hypothyroidism,” Brent told GI & Hepatology News.
While any clinical significance has yet to be determined, “the association of these small bowel microbiome changes with hypothyroidism may have implications for contributing to the onset of autoimmune hypothyroidism in susceptible populations as well as influences on levothyroxine absorption in hypothyroid patients on levothyroxine therapy,” Brent said.
With the SIBO differences observed even among treated patients with vs without HT, “it seems less likely that the microbiome changes are the result of reduced thyroid hormone signaling,” Brent noted.
Furthermore, a key piece of the puzzle will be to observe the microbiome changes over time, he added.
“These studies were at a single time point [and] longitudinal studies will be especially important to see how the association changes over time and are influenced by the treatment of hypothyroidism and of SIBO,” Brent said.
The authors and Brent had no disclosures to report.
A version of this article appeared on Medscape.com.
, according to results of a study.
“[The research] supports the idea that improving gut health could have far-reaching effects beyond digestion, possibly even helping to prevent autoimmune diseases, such as Hashimoto thyroiditis,” said senior author Ruchi Mathur, MD, director of the Diabetes Outpatient Treatment and Education Center and director of Clinical Operations of Medically Associated Science and Technology, at Cedars-Sinai in Los Angeles, in a press statement for the study, which was presented at ENDO 2025: The Endocrine Society Annual Meeting.
“These findings open the door to new screening and prevention strategies,” Mathur added. “For example, doctors may begin to monitor thyroid health more closely in patients with SIBO, and vice versa.”
With some small studies previously suggesting an association between the gut microbiome and hypothyroidism, Mathur and colleagues further explored the relationship in two analyses.
Assessing the Role of the Small Bowel
For the first, they evaluated data on 49 patients with Hashimoto thyroiditis (HT) and 323 controls without the condition from their REIMAGINE trial, which included small bowel fluid samples from upper endoscopies and DNA sequencing.
In the study, all patients with HT were treated with thyroid replacement (levothyroxine), hence, there were notably no significant differences between the two groups in terms of thyroid stimulating hormone (TSH) levels.
Despite the lack of those differences, patients with HT had a prevalence of SIBO more than twice that of the control group, independent of gender (33% vs 15%; odds ratio, 2.71; P = .005).
When the two groups were further subdivided into two groups each — those with and without SIBO — significant further variations of microbial diversity were observed between those with and without HT, Mathur told GI & Hepatology News.
“Interestingly, we saw the small bowel microbiome was not only different in SIBO-positive patients, including higher gram negatives, which is to be expected, but that the presence or absence of hypothyroidism itself was associated with specific patterns of these gram-negative bacteria,” she explained.
“In addition, when we looked at hypothyroidism without SIBO present, there were also changes between groups, such as higher Neisseria in the hypothyroid group.”
“All these findings are novel as this is the first paper to look specifically at the small bowel,” she added, noting that previous smaller studies have focused more on evaluation of stool samples.
“We believe the small bowel is the most metabolically active area of the intestine and plays an important role in metabolism,” Mathur noted. “Thus, the microbial changes here are likely more physiologically significant than the patterns seen in stool.”
Further Findings from a Large Population
In a separate analysis, the team evaluated data from the TriNetX database on the 10-year incidence of developing SIBO among 1.1 million subjects with hypothyroidism in the US compared with 1 million controls.
They found that people with hypothyroidism were approximately twice as likely to develop SIBO compared with those without hypothyroidism (relative risk [RR], 2.20).
Furthermore, those with HT, in particular, had an even higher risk, at 2.4 times the controls (RR, 2.40).
Treatment with levothyroxine decreased the risk of developing SIBO in hypothyroidism (RR, 0.33) and HT (RR, 0.78) vs those who did not receive treatment.
Mechanisms?
However, the fact that differences in SIBO were observed even between people who were treated for HT and those without the condition in the first analysis, and hence had similar TSH levels, was notable, Mathur said.
“This suggests that perhaps there are other factors aside from TSH levels and free T4 that are at play here,” she said. “Some people have theorized that perhaps delayed gut motility in hypothyroidism promotes the development of SIBO; however, there are many other factors within this complex interplay between the microbiome and the thyroid that could also be playing a role.”
“For example, SIBO leads to inflammation and weakening of the gut barrier,” Mathur explained.
Furthermore, “levothyroxine absorption and cycling of the thyroid hormone occurs predominantly in the small bowel, [while the] microbiome plays a key role in the absorption of iron, selenium, iodine, and zinc, which are critical for thyroid function.”
Overall, “further research is needed to understand how the mechanisms are affected during the development of SIBO and hypothyroidism,” Mathur said.
Assessment of Changes Over Time Anticipated
Commenting on the research, Gregory A. Brent, MD, senior executive academic vice-chair of the Department of Medicine and professor of medicine and physiology at the David Geffen School of Medicine at University of California Los Angeles said the study is indeed novel.
“This, to my knowledge, is the first investigation to link characteristics of the small bowel microbiome with hypothyroidism,” Brent told GI & Hepatology News.
While any clinical significance has yet to be determined, “the association of these small bowel microbiome changes with hypothyroidism may have implications for contributing to the onset of autoimmune hypothyroidism in susceptible populations as well as influences on levothyroxine absorption in hypothyroid patients on levothyroxine therapy,” Brent said.
With the SIBO differences observed even among treated patients with vs without HT, “it seems less likely that the microbiome changes are the result of reduced thyroid hormone signaling,” Brent noted.
Furthermore, a key piece of the puzzle will be to observe the microbiome changes over time, he added.
“These studies were at a single time point [and] longitudinal studies will be especially important to see how the association changes over time and are influenced by the treatment of hypothyroidism and of SIBO,” Brent said.
The authors and Brent had no disclosures to report.
A version of this article appeared on Medscape.com.
More Evidence Supports ‘Individualized Approach’ to Pre-Endoscopy GLP-1 RAs
in The American Journal of Gastroenterology. Moreover, most instances occurred in patients using the drugs for type 2 diabetes (T2D) rather than for weight loss alone.
The findings suggest adopting an individualized approach rather than universal preoperative withholding of GLP-1 RAs before endoscopy, concluded Jennifer Phan, MD, medical director of the Hoag Advanced Endoscopy Center in Newport Beach, California, and colleagues. These agents are associated with slowed gastric emptying, possibly raising the risk for pulmonary aspiration. The study identified comorbid uncontrolled T2D as a risk factor for retained gastric contents.
Recommendations from gastroenterological societies and the American Society of Anesthesiologists (ASA) differ regarding pre-endoscopic holding of these ubiquitous agents used for obesity and T2D. “Many patients undergo routine endoscopic procedures, and there was concern from the anesthesia safety perspective for retained gastric contents,” Phan told GI & Hepatology News. “At first these events were seen in a handful of cases; however, out of precaution this resulted in a statement from the ASA recommending that patients hold their GLP-1 medications for at least 1 week prior to a routine endoscopic procedure.”
That guidance resulted in protocol changes within endoscopy units, cancelled procedures, and potential delays in patient care. “We wanted to study whether this concern was clinically valid and to help identify which subgroup of patients are at highest risk in order to best inform anesthesia and endoscopy practices,” Phan added.
The ASA updated its guidance in 2023.
The current study aligns with other research showing that rates of clinically relevant retained gastric contents are < 10%, Phan said. For instance, the American Gastroenterological Association (AGA) published a rapid clinical practice update in November 2023 that found insufficient evidence to support patients stopping the medications before endoscopic procedures. AGA guidance suggests an individual approach for each patient on a GLP-1 RA rather than a blanket statement on how to manage all patients taking the medications.
“Our initial hypothesis was that the rates of clinically relevant retained gastric contents in patients on GLP-1 RA medications would be low,” Phan noted. “This was born out of anecdotal experience of the limited number of aborted procedures we experienced before the ASA statement.”
Her group also hypothesized that the indication for which the GLP-1 RA was prescribed would be important, with patients taking GLP-1 RA medications for diabetes potentially having a higher likelihood of retained contents given the concomitant propensity for delayed gastric motility related to uncontrolled hyperglycemia.
The Study
The investigators identified 815 patients on confirmed GLP-1 RA medications of various types receiving endoscopy from 2021 to 2023 at four centers. Demographics, prescribing practices, and procedure outcomes were captured. GLP-1 RA management of preoperative holding was retroactively classified per ASA guidance.
Of the 815 patients (mean age, 67.7 years; 57.7% women; 53.9% White individuals), 70 (8.7%) exhibited retained gastric contents on endoscopy. Of these 65 (93%) had T2D with a median A1c of 6.5%. Among those with retained contents, most had a minimal (10, 14.3%) or moderate (31, 44.3%) amount of food retained, although 29 (41.4%) had a large quantity. Only one patient required unplanned intubation because of a large quantity of residual content, and none had aspiration events.
In multivariate analysis, the odds ratio of retention in those with diabetes was 4.1. “Given the predominance of diabetes in those with retained gastric contents, we highlight the potential to risk-stratify patients who require further preprocedural consideration,” the authors wrote.
Those with GLP-1 RA held per ASA guidance (406, 49.8%) were less likely to have retained contents (4.4% vs 12.7%; P < .001), but no significant differences for intubation (0% vs 2%; P = .53) or aborting procedure rates (28% vs 18%; P = .40) due to gastric retention were observed.
On multivariable analysis, the likelihood of food retention increased by 36% (95% CI, 1.15-1.60) for every 1% increase in glycosylated hemoglobin after adjusting for GLP-1 RA type and preoperative medication hold.
“Our study can help to differentiate which patients can be at largest risk for retained gastric contents,” Phan said, noting the impact of increasing percentages of A1C. “There’s a 36% increased likelihood of food retention in patients on GLP-1 medications, so a blanket policy to hold GLP-1s in patients who are nondiabetic and taking the medication for obesity may not be the best approach. But if patients have uncontrolled hyperglycemia, then an approach of caution is clinically valid.” In that context, holding the GLP-1 RA injection or lengthening the preoperative clear-liquid diet policy should be considered.
She noted that the study results are generalizable because the study was conducted across multiple types of hospital systems, both university and county, and included all types of GLP-1 RA.
Offering an anesthesiologist’s perspective on the study, Paul Potnuru, MD, an assistant professor in the Department of Anesthesiology, Critical Care, and Pain Medicine at UTHealth Houston and not involved in the study, called the findings “somewhat reassuring” but said the risk for aspiration was still a consideration.
A recent review, however, reported that the risk for GLP-1 RA-associated pulmonary aspiration was low.
Potnuru acknowledged that the original ASA guidance on preoperative GLP-1 RA cessation led to some confusion. “There were not a lot of data on the issue, but some studies found that even with stopping GLP-1s 2 weeks preoperatively some patients still retained gastric content,” he told GI & Hepatology News.
A study at his center recently reported that 56% of GLP-1 RA users had increased pre-anesthesia residual gastric content compared with 19% of nonusers.
From the anesthesiologist’s clinical vantage point, the margin of safety is an issue even if aspiration risk is low. “If there’s a 1 in 1000 chance or even a 1 in 3000 chance, that can be considered too high,” Potnuru said.
He further noted that the current study included only 815 patients, not nearly enough for definitive data. In addition, a retrospective study based on medical records can’t really capture all the real-world procedural changes made in the operating room. “It’s common for anesthesiologists not to document all cases of intubation, for example,” he said.
While the ideal is a completely empty stomach, he agreed that a practical alternative to stopping GLP-1 RA therapy, especially that prescribed for diabetes, would be a 24-hour liquid diet, which would clear the stomach quickly. “If you stop these drugs in patients taking them for diabetes, you get a worsening of their glycemic control,” he said.
He noted that patients have different risk tolerances, with some willing to go ahead even if ultrasound shows gastric retention, while some opt to cancel.
Prospective studies are needed, Potnuru added, “because you find more if you know what you’re looking for.” His center is starting a clinical trial in 150 patients to assess the impact of a 24-hour, liquids-only diet on gastric retention.
According to Phan, other research is following GLP-1 RA users undergoing colonoscopy. “Future studies can look at the added value of point-of-care abdominal ultrasound to see if it increases precision preoperative management in these patients on GLP-1 medications.”
Other groups are examining the safety of these agents in the general context of sedation. “It’s worth noting that the studies are being done on currently available medications and may not apply to future medications such as triple agonists or anti-amylins that may come on the market in the near future,” Phan said.
This study received no financial support. Neither the study authors nor Potnuru had any conflicts of interest.
A version of this article appeared on Medscape.com.
in The American Journal of Gastroenterology. Moreover, most instances occurred in patients using the drugs for type 2 diabetes (T2D) rather than for weight loss alone.
The findings suggest adopting an individualized approach rather than universal preoperative withholding of GLP-1 RAs before endoscopy, concluded Jennifer Phan, MD, medical director of the Hoag Advanced Endoscopy Center in Newport Beach, California, and colleagues. These agents are associated with slowed gastric emptying, possibly raising the risk for pulmonary aspiration. The study identified comorbid uncontrolled T2D as a risk factor for retained gastric contents.
Recommendations from gastroenterological societies and the American Society of Anesthesiologists (ASA) differ regarding pre-endoscopic holding of these ubiquitous agents used for obesity and T2D. “Many patients undergo routine endoscopic procedures, and there was concern from the anesthesia safety perspective for retained gastric contents,” Phan told GI & Hepatology News. “At first these events were seen in a handful of cases; however, out of precaution this resulted in a statement from the ASA recommending that patients hold their GLP-1 medications for at least 1 week prior to a routine endoscopic procedure.”
That guidance resulted in protocol changes within endoscopy units, cancelled procedures, and potential delays in patient care. “We wanted to study whether this concern was clinically valid and to help identify which subgroup of patients are at highest risk in order to best inform anesthesia and endoscopy practices,” Phan added.
The ASA updated its guidance in 2023.
The current study aligns with other research showing that rates of clinically relevant retained gastric contents are < 10%, Phan said. For instance, the American Gastroenterological Association (AGA) published a rapid clinical practice update in November 2023 that found insufficient evidence to support patients stopping the medications before endoscopic procedures. AGA guidance suggests an individual approach for each patient on a GLP-1 RA rather than a blanket statement on how to manage all patients taking the medications.
“Our initial hypothesis was that the rates of clinically relevant retained gastric contents in patients on GLP-1 RA medications would be low,” Phan noted. “This was born out of anecdotal experience of the limited number of aborted procedures we experienced before the ASA statement.”
Her group also hypothesized that the indication for which the GLP-1 RA was prescribed would be important, with patients taking GLP-1 RA medications for diabetes potentially having a higher likelihood of retained contents given the concomitant propensity for delayed gastric motility related to uncontrolled hyperglycemia.
The Study
The investigators identified 815 patients on confirmed GLP-1 RA medications of various types receiving endoscopy from 2021 to 2023 at four centers. Demographics, prescribing practices, and procedure outcomes were captured. GLP-1 RA management of preoperative holding was retroactively classified per ASA guidance.
Of the 815 patients (mean age, 67.7 years; 57.7% women; 53.9% White individuals), 70 (8.7%) exhibited retained gastric contents on endoscopy. Of these 65 (93%) had T2D with a median A1c of 6.5%. Among those with retained contents, most had a minimal (10, 14.3%) or moderate (31, 44.3%) amount of food retained, although 29 (41.4%) had a large quantity. Only one patient required unplanned intubation because of a large quantity of residual content, and none had aspiration events.
In multivariate analysis, the odds ratio of retention in those with diabetes was 4.1. “Given the predominance of diabetes in those with retained gastric contents, we highlight the potential to risk-stratify patients who require further preprocedural consideration,” the authors wrote.
Those with GLP-1 RA held per ASA guidance (406, 49.8%) were less likely to have retained contents (4.4% vs 12.7%; P < .001), but no significant differences for intubation (0% vs 2%; P = .53) or aborting procedure rates (28% vs 18%; P = .40) due to gastric retention were observed.
On multivariable analysis, the likelihood of food retention increased by 36% (95% CI, 1.15-1.60) for every 1% increase in glycosylated hemoglobin after adjusting for GLP-1 RA type and preoperative medication hold.
“Our study can help to differentiate which patients can be at largest risk for retained gastric contents,” Phan said, noting the impact of increasing percentages of A1C. “There’s a 36% increased likelihood of food retention in patients on GLP-1 medications, so a blanket policy to hold GLP-1s in patients who are nondiabetic and taking the medication for obesity may not be the best approach. But if patients have uncontrolled hyperglycemia, then an approach of caution is clinically valid.” In that context, holding the GLP-1 RA injection or lengthening the preoperative clear-liquid diet policy should be considered.
She noted that the study results are generalizable because the study was conducted across multiple types of hospital systems, both university and county, and included all types of GLP-1 RA.
Offering an anesthesiologist’s perspective on the study, Paul Potnuru, MD, an assistant professor in the Department of Anesthesiology, Critical Care, and Pain Medicine at UTHealth Houston and not involved in the study, called the findings “somewhat reassuring” but said the risk for aspiration was still a consideration.
A recent review, however, reported that the risk for GLP-1 RA-associated pulmonary aspiration was low.
Potnuru acknowledged that the original ASA guidance on preoperative GLP-1 RA cessation led to some confusion. “There were not a lot of data on the issue, but some studies found that even with stopping GLP-1s 2 weeks preoperatively some patients still retained gastric content,” he told GI & Hepatology News.
A study at his center recently reported that 56% of GLP-1 RA users had increased pre-anesthesia residual gastric content compared with 19% of nonusers.
From the anesthesiologist’s clinical vantage point, the margin of safety is an issue even if aspiration risk is low. “If there’s a 1 in 1000 chance or even a 1 in 3000 chance, that can be considered too high,” Potnuru said.
He further noted that the current study included only 815 patients, not nearly enough for definitive data. In addition, a retrospective study based on medical records can’t really capture all the real-world procedural changes made in the operating room. “It’s common for anesthesiologists not to document all cases of intubation, for example,” he said.
While the ideal is a completely empty stomach, he agreed that a practical alternative to stopping GLP-1 RA therapy, especially that prescribed for diabetes, would be a 24-hour liquid diet, which would clear the stomach quickly. “If you stop these drugs in patients taking them for diabetes, you get a worsening of their glycemic control,” he said.
He noted that patients have different risk tolerances, with some willing to go ahead even if ultrasound shows gastric retention, while some opt to cancel.
Prospective studies are needed, Potnuru added, “because you find more if you know what you’re looking for.” His center is starting a clinical trial in 150 patients to assess the impact of a 24-hour, liquids-only diet on gastric retention.
According to Phan, other research is following GLP-1 RA users undergoing colonoscopy. “Future studies can look at the added value of point-of-care abdominal ultrasound to see if it increases precision preoperative management in these patients on GLP-1 medications.”
Other groups are examining the safety of these agents in the general context of sedation. “It’s worth noting that the studies are being done on currently available medications and may not apply to future medications such as triple agonists or anti-amylins that may come on the market in the near future,” Phan said.
This study received no financial support. Neither the study authors nor Potnuru had any conflicts of interest.
A version of this article appeared on Medscape.com.
in The American Journal of Gastroenterology. Moreover, most instances occurred in patients using the drugs for type 2 diabetes (T2D) rather than for weight loss alone.
The findings suggest adopting an individualized approach rather than universal preoperative withholding of GLP-1 RAs before endoscopy, concluded Jennifer Phan, MD, medical director of the Hoag Advanced Endoscopy Center in Newport Beach, California, and colleagues. These agents are associated with slowed gastric emptying, possibly raising the risk for pulmonary aspiration. The study identified comorbid uncontrolled T2D as a risk factor for retained gastric contents.
Recommendations from gastroenterological societies and the American Society of Anesthesiologists (ASA) differ regarding pre-endoscopic holding of these ubiquitous agents used for obesity and T2D. “Many patients undergo routine endoscopic procedures, and there was concern from the anesthesia safety perspective for retained gastric contents,” Phan told GI & Hepatology News. “At first these events were seen in a handful of cases; however, out of precaution this resulted in a statement from the ASA recommending that patients hold their GLP-1 medications for at least 1 week prior to a routine endoscopic procedure.”
That guidance resulted in protocol changes within endoscopy units, cancelled procedures, and potential delays in patient care. “We wanted to study whether this concern was clinically valid and to help identify which subgroup of patients are at highest risk in order to best inform anesthesia and endoscopy practices,” Phan added.
The ASA updated its guidance in 2023.
The current study aligns with other research showing that rates of clinically relevant retained gastric contents are < 10%, Phan said. For instance, the American Gastroenterological Association (AGA) published a rapid clinical practice update in November 2023 that found insufficient evidence to support patients stopping the medications before endoscopic procedures. AGA guidance suggests an individual approach for each patient on a GLP-1 RA rather than a blanket statement on how to manage all patients taking the medications.
“Our initial hypothesis was that the rates of clinically relevant retained gastric contents in patients on GLP-1 RA medications would be low,” Phan noted. “This was born out of anecdotal experience of the limited number of aborted procedures we experienced before the ASA statement.”
Her group also hypothesized that the indication for which the GLP-1 RA was prescribed would be important, with patients taking GLP-1 RA medications for diabetes potentially having a higher likelihood of retained contents given the concomitant propensity for delayed gastric motility related to uncontrolled hyperglycemia.
The Study
The investigators identified 815 patients on confirmed GLP-1 RA medications of various types receiving endoscopy from 2021 to 2023 at four centers. Demographics, prescribing practices, and procedure outcomes were captured. GLP-1 RA management of preoperative holding was retroactively classified per ASA guidance.
Of the 815 patients (mean age, 67.7 years; 57.7% women; 53.9% White individuals), 70 (8.7%) exhibited retained gastric contents on endoscopy. Of these 65 (93%) had T2D with a median A1c of 6.5%. Among those with retained contents, most had a minimal (10, 14.3%) or moderate (31, 44.3%) amount of food retained, although 29 (41.4%) had a large quantity. Only one patient required unplanned intubation because of a large quantity of residual content, and none had aspiration events.
In multivariate analysis, the odds ratio of retention in those with diabetes was 4.1. “Given the predominance of diabetes in those with retained gastric contents, we highlight the potential to risk-stratify patients who require further preprocedural consideration,” the authors wrote.
Those with GLP-1 RA held per ASA guidance (406, 49.8%) were less likely to have retained contents (4.4% vs 12.7%; P < .001), but no significant differences for intubation (0% vs 2%; P = .53) or aborting procedure rates (28% vs 18%; P = .40) due to gastric retention were observed.
On multivariable analysis, the likelihood of food retention increased by 36% (95% CI, 1.15-1.60) for every 1% increase in glycosylated hemoglobin after adjusting for GLP-1 RA type and preoperative medication hold.
“Our study can help to differentiate which patients can be at largest risk for retained gastric contents,” Phan said, noting the impact of increasing percentages of A1C. “There’s a 36% increased likelihood of food retention in patients on GLP-1 medications, so a blanket policy to hold GLP-1s in patients who are nondiabetic and taking the medication for obesity may not be the best approach. But if patients have uncontrolled hyperglycemia, then an approach of caution is clinically valid.” In that context, holding the GLP-1 RA injection or lengthening the preoperative clear-liquid diet policy should be considered.
She noted that the study results are generalizable because the study was conducted across multiple types of hospital systems, both university and county, and included all types of GLP-1 RA.
Offering an anesthesiologist’s perspective on the study, Paul Potnuru, MD, an assistant professor in the Department of Anesthesiology, Critical Care, and Pain Medicine at UTHealth Houston and not involved in the study, called the findings “somewhat reassuring” but said the risk for aspiration was still a consideration.
A recent review, however, reported that the risk for GLP-1 RA-associated pulmonary aspiration was low.
Potnuru acknowledged that the original ASA guidance on preoperative GLP-1 RA cessation led to some confusion. “There were not a lot of data on the issue, but some studies found that even with stopping GLP-1s 2 weeks preoperatively some patients still retained gastric content,” he told GI & Hepatology News.
A study at his center recently reported that 56% of GLP-1 RA users had increased pre-anesthesia residual gastric content compared with 19% of nonusers.
From the anesthesiologist’s clinical vantage point, the margin of safety is an issue even if aspiration risk is low. “If there’s a 1 in 1000 chance or even a 1 in 3000 chance, that can be considered too high,” Potnuru said.
He further noted that the current study included only 815 patients, not nearly enough for definitive data. In addition, a retrospective study based on medical records can’t really capture all the real-world procedural changes made in the operating room. “It’s common for anesthesiologists not to document all cases of intubation, for example,” he said.
While the ideal is a completely empty stomach, he agreed that a practical alternative to stopping GLP-1 RA therapy, especially that prescribed for diabetes, would be a 24-hour liquid diet, which would clear the stomach quickly. “If you stop these drugs in patients taking them for diabetes, you get a worsening of their glycemic control,” he said.
He noted that patients have different risk tolerances, with some willing to go ahead even if ultrasound shows gastric retention, while some opt to cancel.
Prospective studies are needed, Potnuru added, “because you find more if you know what you’re looking for.” His center is starting a clinical trial in 150 patients to assess the impact of a 24-hour, liquids-only diet on gastric retention.
According to Phan, other research is following GLP-1 RA users undergoing colonoscopy. “Future studies can look at the added value of point-of-care abdominal ultrasound to see if it increases precision preoperative management in these patients on GLP-1 medications.”
Other groups are examining the safety of these agents in the general context of sedation. “It’s worth noting that the studies are being done on currently available medications and may not apply to future medications such as triple agonists or anti-amylins that may come on the market in the near future,” Phan said.
This study received no financial support. Neither the study authors nor Potnuru had any conflicts of interest.
A version of this article appeared on Medscape.com.
You Are When You Eat: Microbiome Rhythm and Metabolic Health
Similar to circadian rhythms that help regulate when we naturally fall asleep and wake up, microbial rhythms in our gut are naturally active at certain times of the day to help regulate our digestion.
Investigators from the University of California, San Diego sought out to track these microbial rhythms to determine whether aligning the times we eat to when our gut microbes are most active – time-restricted feeding (TRF) – can bolster our metabolic health. Their research was published recently in Cell Host & Microbe.
“Microbial rhythms are daily fluctuations in the composition and function of microbes living in our gut. Much like how our bodies follow an internal clock (circadian rhythm), gut microbes also have their own rhythms, adjusting their activities based on the time of day and when we eat,” said Amir Zarrinpar, MD, PhD, a gastroenterologist at UC San Diego School of Medicine, and senior author of the study.
Zarrinpar and his team were particularly interested in observing whether adopting the TRF approach counteracted the harmful metabolic effects often associated with consuming a high-fat diet.
The study is also notable for the team’s use of technology able to observe real-time microbial changes in the gut — something not previously attainable with existing metagenomics.
How the Study Evolved With New Tech
Researchers separated three groups of mice to analyze their microbiome activity: one on a high-fat diet with unrestricted access, another on the same high-fat diet within a TRF window of 8 hours per day, and a control group on a normal chow diet with unrestricted access.
“In mice, [their] microbial rhythms are well-aligned with their nocturnal lifestyle. For example, during their active (nighttime) period, certain beneficial microbial activities increase, helping digest food, absorb nutrients, and regulate metabolism,” said Zarrinpar. As a result, the team made sure the mice’s TRF window was at night or when they would normally be awake.
“We chose an 8-hour feeding window based on earlier research showing this time period allows mice to consume the same total calories as those with unlimited food access,” said Zarrinpar. “By controlling [the] calories in this way, we ensure any metabolic or microbial benefits we observe are specifically due to the timing of eating, rather than differences in total food intake.”
But before any observations could be made, the team first needed a way to see real-time changes in the animals’ gut microbiomes.
Zarrinpar and his team were able to uncover this, thanks to metatranscriptomics, a technique used to capture real-time microbial activity by profiling RNA transcripts. Compared with the more traditional technique of metagenomics, which could only be used to identify which genes were present, metatranscriptomics provided more in-depth temporal and activity-related context, allowing the team to observe dynamic microbial changes.
“[Metatranscriptomics] helps us understand not just which microbes are present, but specifically what they are doing at any given moment,” said Zarrinpar. “In contrast, metagenomics looks only at microbial DNA, which provides information about what microbes are potentially capable of doing, but doesn’t tell us if those genes are actively expressed. By comparing microbial gene expression (using metatranscriptomics) and microbial gene abundance (using metagenomics) across different diet and feeding conditions in [light and dark] phases, we aimed to identify how feeding timing might influence microbial activity.”
Because metagenomics focuses on stable genetic material, this technique cannot capture the real-time microbial responses to dietary timing presented in rapidly changing, short-lived RNA. At the same time, the instability of the RNA makes it difficult to test hypotheses experimentally and explains why researchers haven’t more widely relied on metatranscriptomics.
To overcome this difficulty, Zarrinpar and his team had to wait to take advantage of improved bioinformatics tools to simplify their analysis of complex datasets. “It took several years for us to analyze this dataset because robust computational tools for metatranscriptomic analysis were not widely available when we initially collected our samples. Additionally, sequencing costs were very high. To clearly identify microbial activity, we needed deep sequencing coverage to distinguish species-level differences in gene expression, especially for genes that are common across multiple types of microbes,” said Zarrinpar.
What They Found
After monitoring these groups of mice for 8 weeks, the results were revealed.
As predicted, “When mice have free access to a high-fat diet, their normal eating behavior changes significantly. Instead of limiting their activity and feeding to their active nighttime period, these mice begin to stay awake and eat during the day, which is their typical rest phase,” Zarrinpar explained.
“This unusual daytime activity interferes with important physiological processes. Consequently, the animals experience circadian misalignment, a condition similar to what human shift workers experience when their sleep-wake and eating cycles don’t match their internal biological clocks,” he continued. “This misalignment can negatively affect metabolism, immunity, and overall health, potentially leading to metabolic diseases.”
For the mice that consumed a high-fat diet within a TRF window, metabolic phenotyping demonstrated that their specific diet regimen had protected them from harmful high-fat induced effects including adiposity, inflammation, and insulin resistance.
Even more promising, the mice not only were protected from metabolic disruption but also experienced physiological improvements including glucose homeostasis and the partial restoration of the daily microbial rhythms absent in the mice with unrestricted access to a high-fat diet.
While the TRF approach did not fully restore the normal, healthy rhythmicity seen in the control mice, the researchers noted distinct shifts in microbial patterns that indicated time-dependent enrichment in genes attributed to lipid and carbohydrate metabolism.
Better Metabolic Health — and Better Tools for Researching It
Thankfully, the latest advancements in sequencing technology, including long-read sequencing methods, are making metatranscriptomics easier for research. “These newer platforms offer greater resolution at a lower cost, making metatranscriptomics increasingly accessible,” said Zarrinpar. With these emerging technologies, he believes metatranscriptomics will become a more standard, widely used method for researchers to better understand the influence of microbial activity on our health.
These tools, for example, enabled Zarrinpar and the team to delve deeper and focus on the transcription of a particular enzyme they identified as a pivotal influence in observable metabolic improvements: bile salt hydrolase (BSH), known to regulate lipid and glucose metabolism. The TRF approach notably enhanced the expression of the BSH gene during the daytime in the gut microbe Dubosiella newyorkensis, which has a functional human equivalent.
To determine why this happened, the team leveraged genetic engineering to insert several active BSH gene variants into a benign strain of gut bacteria to administer to the mice. The only variant to produce metabolic improvements was the one derived from Dubosiella newyorkensis; the mice who were given this BSH-expressing engineered native bacteria (ENB) had increased lean muscle mass, less body fat, lower insulin levels, enhanced insulin sensitivity, and better blood glucose regulation.
“It is still early to know the full clinical potential of this new BSH-expressing engineered native bacterium,” said Zarrinpar. “However, our long-term goal is to develop a therapeutic that can be administered as a single dose, stably colonize the gut, and provide long-lasting metabolic benefits.” Testing the engineered bacteria in obese and diabetic mice on a high-fat diet would be a next step to determine whether its potential indeed holds up. If proven successful, it could then be used to develop future targeted therapies and interventions to treat common metabolic disorders.
With this engineered bacteria, Zarrinpar and his team are hopeful that it alone can replicate the microbial benefits associated with following a TRF dietary schedule. “In our study, the engineered bacterium continuously expressed the enzyme DnBSH1, independently of dietary or environmental factors. As a result, the bacterium provided metabolic benefits similar to those seen with TRF, even without requiring the mice to strictly adhere to a TRF schedule,” said Zarrinpar.
“This suggests the exciting possibility that this engineered microbe might serve either as a replacement for TRF or as a way to enhance its beneficial effects,” he continued. “Further studies will help determine whether combining this ENB with TRF could provide additional or synergistic improvements in metabolic health.”
Looking Ahead
“As the pioneer of the single anastomosis duodenal switch which separates bile from food until halfway down the GI tract, I agree that bile is very important in controlling metabolism and glucose,” said Mitchell Roslin, MD, chief director of bariatric and metabolic surgery at Lenox Hill Hospital, and the Donald and Barbara Zucker School of Medicine, Hempstead, New York, who was not involved in the study. “Using enzymes or medications that work in the GI tract without absorption into the body is very interesting and has great potential. It is an early but exciting prospect.”
However, Roslin expressed some reservations. “I think we are still trying to understand whether the difference in microbiomes is the cause or effect/association. Is the microbiome the difference or is a different microbiome representative of a diet that has more fiber and less processed foods? Thus, while I find this academically fascinating, I think that there are very basic questions that need better answers, before we look at the transcription of bacteria.”
Furthermore, translating the metabolic results observed in mice to humans might not be as straightforward. “Small animal research is mandatory, but how the findings convert to humans is highly speculative,” said Roslin. “Mice that are studied are usually bred for medical research, with reduced genetic variation. Many animal models are more sensitive to time-restricted eating and caloric restriction than humans.”
While it requires further research and validation, this UC San Diego study nevertheless contributes to our overall understanding of host-microbe interactions. “We demonstrate that host circadian rhythms significantly influence microbial function, and conversely, these microbial functions can directly impact host metabolism,” said Zarrinpar. “Importantly, we now have a method to test how specific microbial activities affect host physiology by engineering native gut bacteria.”
Roslin similarly emphasized the importance of continued investment in exploring the microbial ecosystem inside us all. “There is wider evidence that bacteria and microbes are not just passengers using us for a ride but perhaps manipulating every action we take.”
A version of this article appeared on Medscape.com.
Similar to circadian rhythms that help regulate when we naturally fall asleep and wake up, microbial rhythms in our gut are naturally active at certain times of the day to help regulate our digestion.
Investigators from the University of California, San Diego sought out to track these microbial rhythms to determine whether aligning the times we eat to when our gut microbes are most active – time-restricted feeding (TRF) – can bolster our metabolic health. Their research was published recently in Cell Host & Microbe.
“Microbial rhythms are daily fluctuations in the composition and function of microbes living in our gut. Much like how our bodies follow an internal clock (circadian rhythm), gut microbes also have their own rhythms, adjusting their activities based on the time of day and when we eat,” said Amir Zarrinpar, MD, PhD, a gastroenterologist at UC San Diego School of Medicine, and senior author of the study.
Zarrinpar and his team were particularly interested in observing whether adopting the TRF approach counteracted the harmful metabolic effects often associated with consuming a high-fat diet.
The study is also notable for the team’s use of technology able to observe real-time microbial changes in the gut — something not previously attainable with existing metagenomics.
How the Study Evolved With New Tech
Researchers separated three groups of mice to analyze their microbiome activity: one on a high-fat diet with unrestricted access, another on the same high-fat diet within a TRF window of 8 hours per day, and a control group on a normal chow diet with unrestricted access.
“In mice, [their] microbial rhythms are well-aligned with their nocturnal lifestyle. For example, during their active (nighttime) period, certain beneficial microbial activities increase, helping digest food, absorb nutrients, and regulate metabolism,” said Zarrinpar. As a result, the team made sure the mice’s TRF window was at night or when they would normally be awake.
“We chose an 8-hour feeding window based on earlier research showing this time period allows mice to consume the same total calories as those with unlimited food access,” said Zarrinpar. “By controlling [the] calories in this way, we ensure any metabolic or microbial benefits we observe are specifically due to the timing of eating, rather than differences in total food intake.”
But before any observations could be made, the team first needed a way to see real-time changes in the animals’ gut microbiomes.
Zarrinpar and his team were able to uncover this, thanks to metatranscriptomics, a technique used to capture real-time microbial activity by profiling RNA transcripts. Compared with the more traditional technique of metagenomics, which could only be used to identify which genes were present, metatranscriptomics provided more in-depth temporal and activity-related context, allowing the team to observe dynamic microbial changes.
“[Metatranscriptomics] helps us understand not just which microbes are present, but specifically what they are doing at any given moment,” said Zarrinpar. “In contrast, metagenomics looks only at microbial DNA, which provides information about what microbes are potentially capable of doing, but doesn’t tell us if those genes are actively expressed. By comparing microbial gene expression (using metatranscriptomics) and microbial gene abundance (using metagenomics) across different diet and feeding conditions in [light and dark] phases, we aimed to identify how feeding timing might influence microbial activity.”
Because metagenomics focuses on stable genetic material, this technique cannot capture the real-time microbial responses to dietary timing presented in rapidly changing, short-lived RNA. At the same time, the instability of the RNA makes it difficult to test hypotheses experimentally and explains why researchers haven’t more widely relied on metatranscriptomics.
To overcome this difficulty, Zarrinpar and his team had to wait to take advantage of improved bioinformatics tools to simplify their analysis of complex datasets. “It took several years for us to analyze this dataset because robust computational tools for metatranscriptomic analysis were not widely available when we initially collected our samples. Additionally, sequencing costs were very high. To clearly identify microbial activity, we needed deep sequencing coverage to distinguish species-level differences in gene expression, especially for genes that are common across multiple types of microbes,” said Zarrinpar.
What They Found
After monitoring these groups of mice for 8 weeks, the results were revealed.
As predicted, “When mice have free access to a high-fat diet, their normal eating behavior changes significantly. Instead of limiting their activity and feeding to their active nighttime period, these mice begin to stay awake and eat during the day, which is their typical rest phase,” Zarrinpar explained.
“This unusual daytime activity interferes with important physiological processes. Consequently, the animals experience circadian misalignment, a condition similar to what human shift workers experience when their sleep-wake and eating cycles don’t match their internal biological clocks,” he continued. “This misalignment can negatively affect metabolism, immunity, and overall health, potentially leading to metabolic diseases.”
For the mice that consumed a high-fat diet within a TRF window, metabolic phenotyping demonstrated that their specific diet regimen had protected them from harmful high-fat induced effects including adiposity, inflammation, and insulin resistance.
Even more promising, the mice not only were protected from metabolic disruption but also experienced physiological improvements including glucose homeostasis and the partial restoration of the daily microbial rhythms absent in the mice with unrestricted access to a high-fat diet.
While the TRF approach did not fully restore the normal, healthy rhythmicity seen in the control mice, the researchers noted distinct shifts in microbial patterns that indicated time-dependent enrichment in genes attributed to lipid and carbohydrate metabolism.
Better Metabolic Health — and Better Tools for Researching It
Thankfully, the latest advancements in sequencing technology, including long-read sequencing methods, are making metatranscriptomics easier for research. “These newer platforms offer greater resolution at a lower cost, making metatranscriptomics increasingly accessible,” said Zarrinpar. With these emerging technologies, he believes metatranscriptomics will become a more standard, widely used method for researchers to better understand the influence of microbial activity on our health.
These tools, for example, enabled Zarrinpar and the team to delve deeper and focus on the transcription of a particular enzyme they identified as a pivotal influence in observable metabolic improvements: bile salt hydrolase (BSH), known to regulate lipid and glucose metabolism. The TRF approach notably enhanced the expression of the BSH gene during the daytime in the gut microbe Dubosiella newyorkensis, which has a functional human equivalent.
To determine why this happened, the team leveraged genetic engineering to insert several active BSH gene variants into a benign strain of gut bacteria to administer to the mice. The only variant to produce metabolic improvements was the one derived from Dubosiella newyorkensis; the mice who were given this BSH-expressing engineered native bacteria (ENB) had increased lean muscle mass, less body fat, lower insulin levels, enhanced insulin sensitivity, and better blood glucose regulation.
“It is still early to know the full clinical potential of this new BSH-expressing engineered native bacterium,” said Zarrinpar. “However, our long-term goal is to develop a therapeutic that can be administered as a single dose, stably colonize the gut, and provide long-lasting metabolic benefits.” Testing the engineered bacteria in obese and diabetic mice on a high-fat diet would be a next step to determine whether its potential indeed holds up. If proven successful, it could then be used to develop future targeted therapies and interventions to treat common metabolic disorders.
With this engineered bacteria, Zarrinpar and his team are hopeful that it alone can replicate the microbial benefits associated with following a TRF dietary schedule. “In our study, the engineered bacterium continuously expressed the enzyme DnBSH1, independently of dietary or environmental factors. As a result, the bacterium provided metabolic benefits similar to those seen with TRF, even without requiring the mice to strictly adhere to a TRF schedule,” said Zarrinpar.
“This suggests the exciting possibility that this engineered microbe might serve either as a replacement for TRF or as a way to enhance its beneficial effects,” he continued. “Further studies will help determine whether combining this ENB with TRF could provide additional or synergistic improvements in metabolic health.”
Looking Ahead
“As the pioneer of the single anastomosis duodenal switch which separates bile from food until halfway down the GI tract, I agree that bile is very important in controlling metabolism and glucose,” said Mitchell Roslin, MD, chief director of bariatric and metabolic surgery at Lenox Hill Hospital, and the Donald and Barbara Zucker School of Medicine, Hempstead, New York, who was not involved in the study. “Using enzymes or medications that work in the GI tract without absorption into the body is very interesting and has great potential. It is an early but exciting prospect.”
However, Roslin expressed some reservations. “I think we are still trying to understand whether the difference in microbiomes is the cause or effect/association. Is the microbiome the difference or is a different microbiome representative of a diet that has more fiber and less processed foods? Thus, while I find this academically fascinating, I think that there are very basic questions that need better answers, before we look at the transcription of bacteria.”
Furthermore, translating the metabolic results observed in mice to humans might not be as straightforward. “Small animal research is mandatory, but how the findings convert to humans is highly speculative,” said Roslin. “Mice that are studied are usually bred for medical research, with reduced genetic variation. Many animal models are more sensitive to time-restricted eating and caloric restriction than humans.”
While it requires further research and validation, this UC San Diego study nevertheless contributes to our overall understanding of host-microbe interactions. “We demonstrate that host circadian rhythms significantly influence microbial function, and conversely, these microbial functions can directly impact host metabolism,” said Zarrinpar. “Importantly, we now have a method to test how specific microbial activities affect host physiology by engineering native gut bacteria.”
Roslin similarly emphasized the importance of continued investment in exploring the microbial ecosystem inside us all. “There is wider evidence that bacteria and microbes are not just passengers using us for a ride but perhaps manipulating every action we take.”
A version of this article appeared on Medscape.com.
Similar to circadian rhythms that help regulate when we naturally fall asleep and wake up, microbial rhythms in our gut are naturally active at certain times of the day to help regulate our digestion.
Investigators from the University of California, San Diego sought out to track these microbial rhythms to determine whether aligning the times we eat to when our gut microbes are most active – time-restricted feeding (TRF) – can bolster our metabolic health. Their research was published recently in Cell Host & Microbe.
“Microbial rhythms are daily fluctuations in the composition and function of microbes living in our gut. Much like how our bodies follow an internal clock (circadian rhythm), gut microbes also have their own rhythms, adjusting their activities based on the time of day and when we eat,” said Amir Zarrinpar, MD, PhD, a gastroenterologist at UC San Diego School of Medicine, and senior author of the study.
Zarrinpar and his team were particularly interested in observing whether adopting the TRF approach counteracted the harmful metabolic effects often associated with consuming a high-fat diet.
The study is also notable for the team’s use of technology able to observe real-time microbial changes in the gut — something not previously attainable with existing metagenomics.
How the Study Evolved With New Tech
Researchers separated three groups of mice to analyze their microbiome activity: one on a high-fat diet with unrestricted access, another on the same high-fat diet within a TRF window of 8 hours per day, and a control group on a normal chow diet with unrestricted access.
“In mice, [their] microbial rhythms are well-aligned with their nocturnal lifestyle. For example, during their active (nighttime) period, certain beneficial microbial activities increase, helping digest food, absorb nutrients, and regulate metabolism,” said Zarrinpar. As a result, the team made sure the mice’s TRF window was at night or when they would normally be awake.
“We chose an 8-hour feeding window based on earlier research showing this time period allows mice to consume the same total calories as those with unlimited food access,” said Zarrinpar. “By controlling [the] calories in this way, we ensure any metabolic or microbial benefits we observe are specifically due to the timing of eating, rather than differences in total food intake.”
But before any observations could be made, the team first needed a way to see real-time changes in the animals’ gut microbiomes.
Zarrinpar and his team were able to uncover this, thanks to metatranscriptomics, a technique used to capture real-time microbial activity by profiling RNA transcripts. Compared with the more traditional technique of metagenomics, which could only be used to identify which genes were present, metatranscriptomics provided more in-depth temporal and activity-related context, allowing the team to observe dynamic microbial changes.
“[Metatranscriptomics] helps us understand not just which microbes are present, but specifically what they are doing at any given moment,” said Zarrinpar. “In contrast, metagenomics looks only at microbial DNA, which provides information about what microbes are potentially capable of doing, but doesn’t tell us if those genes are actively expressed. By comparing microbial gene expression (using metatranscriptomics) and microbial gene abundance (using metagenomics) across different diet and feeding conditions in [light and dark] phases, we aimed to identify how feeding timing might influence microbial activity.”
Because metagenomics focuses on stable genetic material, this technique cannot capture the real-time microbial responses to dietary timing presented in rapidly changing, short-lived RNA. At the same time, the instability of the RNA makes it difficult to test hypotheses experimentally and explains why researchers haven’t more widely relied on metatranscriptomics.
To overcome this difficulty, Zarrinpar and his team had to wait to take advantage of improved bioinformatics tools to simplify their analysis of complex datasets. “It took several years for us to analyze this dataset because robust computational tools for metatranscriptomic analysis were not widely available when we initially collected our samples. Additionally, sequencing costs were very high. To clearly identify microbial activity, we needed deep sequencing coverage to distinguish species-level differences in gene expression, especially for genes that are common across multiple types of microbes,” said Zarrinpar.
What They Found
After monitoring these groups of mice for 8 weeks, the results were revealed.
As predicted, “When mice have free access to a high-fat diet, their normal eating behavior changes significantly. Instead of limiting their activity and feeding to their active nighttime period, these mice begin to stay awake and eat during the day, which is their typical rest phase,” Zarrinpar explained.
“This unusual daytime activity interferes with important physiological processes. Consequently, the animals experience circadian misalignment, a condition similar to what human shift workers experience when their sleep-wake and eating cycles don’t match their internal biological clocks,” he continued. “This misalignment can negatively affect metabolism, immunity, and overall health, potentially leading to metabolic diseases.”
For the mice that consumed a high-fat diet within a TRF window, metabolic phenotyping demonstrated that their specific diet regimen had protected them from harmful high-fat induced effects including adiposity, inflammation, and insulin resistance.
Even more promising, the mice not only were protected from metabolic disruption but also experienced physiological improvements including glucose homeostasis and the partial restoration of the daily microbial rhythms absent in the mice with unrestricted access to a high-fat diet.
While the TRF approach did not fully restore the normal, healthy rhythmicity seen in the control mice, the researchers noted distinct shifts in microbial patterns that indicated time-dependent enrichment in genes attributed to lipid and carbohydrate metabolism.
Better Metabolic Health — and Better Tools for Researching It
Thankfully, the latest advancements in sequencing technology, including long-read sequencing methods, are making metatranscriptomics easier for research. “These newer platforms offer greater resolution at a lower cost, making metatranscriptomics increasingly accessible,” said Zarrinpar. With these emerging technologies, he believes metatranscriptomics will become a more standard, widely used method for researchers to better understand the influence of microbial activity on our health.
These tools, for example, enabled Zarrinpar and the team to delve deeper and focus on the transcription of a particular enzyme they identified as a pivotal influence in observable metabolic improvements: bile salt hydrolase (BSH), known to regulate lipid and glucose metabolism. The TRF approach notably enhanced the expression of the BSH gene during the daytime in the gut microbe Dubosiella newyorkensis, which has a functional human equivalent.
To determine why this happened, the team leveraged genetic engineering to insert several active BSH gene variants into a benign strain of gut bacteria to administer to the mice. The only variant to produce metabolic improvements was the one derived from Dubosiella newyorkensis; the mice who were given this BSH-expressing engineered native bacteria (ENB) had increased lean muscle mass, less body fat, lower insulin levels, enhanced insulin sensitivity, and better blood glucose regulation.
“It is still early to know the full clinical potential of this new BSH-expressing engineered native bacterium,” said Zarrinpar. “However, our long-term goal is to develop a therapeutic that can be administered as a single dose, stably colonize the gut, and provide long-lasting metabolic benefits.” Testing the engineered bacteria in obese and diabetic mice on a high-fat diet would be a next step to determine whether its potential indeed holds up. If proven successful, it could then be used to develop future targeted therapies and interventions to treat common metabolic disorders.
With this engineered bacteria, Zarrinpar and his team are hopeful that it alone can replicate the microbial benefits associated with following a TRF dietary schedule. “In our study, the engineered bacterium continuously expressed the enzyme DnBSH1, independently of dietary or environmental factors. As a result, the bacterium provided metabolic benefits similar to those seen with TRF, even without requiring the mice to strictly adhere to a TRF schedule,” said Zarrinpar.
“This suggests the exciting possibility that this engineered microbe might serve either as a replacement for TRF or as a way to enhance its beneficial effects,” he continued. “Further studies will help determine whether combining this ENB with TRF could provide additional or synergistic improvements in metabolic health.”
Looking Ahead
“As the pioneer of the single anastomosis duodenal switch which separates bile from food until halfway down the GI tract, I agree that bile is very important in controlling metabolism and glucose,” said Mitchell Roslin, MD, chief director of bariatric and metabolic surgery at Lenox Hill Hospital, and the Donald and Barbara Zucker School of Medicine, Hempstead, New York, who was not involved in the study. “Using enzymes or medications that work in the GI tract without absorption into the body is very interesting and has great potential. It is an early but exciting prospect.”
However, Roslin expressed some reservations. “I think we are still trying to understand whether the difference in microbiomes is the cause or effect/association. Is the microbiome the difference or is a different microbiome representative of a diet that has more fiber and less processed foods? Thus, while I find this academically fascinating, I think that there are very basic questions that need better answers, before we look at the transcription of bacteria.”
Furthermore, translating the metabolic results observed in mice to humans might not be as straightforward. “Small animal research is mandatory, but how the findings convert to humans is highly speculative,” said Roslin. “Mice that are studied are usually bred for medical research, with reduced genetic variation. Many animal models are more sensitive to time-restricted eating and caloric restriction than humans.”
While it requires further research and validation, this UC San Diego study nevertheless contributes to our overall understanding of host-microbe interactions. “We demonstrate that host circadian rhythms significantly influence microbial function, and conversely, these microbial functions can directly impact host metabolism,” said Zarrinpar. “Importantly, we now have a method to test how specific microbial activities affect host physiology by engineering native gut bacteria.”
Roslin similarly emphasized the importance of continued investment in exploring the microbial ecosystem inside us all. “There is wider evidence that bacteria and microbes are not just passengers using us for a ride but perhaps manipulating every action we take.”
A version of this article appeared on Medscape.com.