From the AGA Journals

A single-use duodenoscope may reduce the risk of postendoscopic infections while maintaining a high level of user satisfaction, based on a recent multicenter case series study.

At six tertiary referral centers in the United States, seven expert endoscopists performed more than 70 procedures with disposable scopes, ultimately reporting a median satisfaction score of 9 out of 10, according to lead author Venkataraman Muthusamy, MD, of UCLA Health in Los Angeles, and colleagues.

Writing for Clinical Gastroenterology and Hepatology, the investigators noted that duodenoscope-related infections represent a serious threat to public health, particularly when considered in the context of antibiotic resistance and the high number of endoscopic procedures performed annually.

“Solutions to the duodenoscope contamination problem remain elusive,” the investigators wrote. “Evidence-based interventions are important to guard against labor-intensive measures that are unfeasible, unaffordable, and potentially ineffective.”

According to the investigators, routine culture surveillance and field investigations following suspected duodenoscope-related infections may fail to detect culprit bacteria or shortcomings in equipment reprocessing; and even when performed correctly, standard reprocessing can be insufficient.

“Using current reprocessing techniques, improved compliance with reprocessing guidelines is not a definitive solution because reusable duodenoscope contamination may be present even after high-level disinfection or sterilization,” the investigators wrote, going on to cite Food and Drug Administration–reported contamination rates of 5.4% for high-concern organisms.

To determine if a single-use endoscope could overcome such risks, the investigators first conducted preclinical testing with animal laboratories and simulations, finding that a single-use duodenoscope was comparable with three reusable scope models. The present study, which included 73 patients with normal pancreaticobiliary anatomy, evaluated clinical feasibility, safety, and performance. The single-use duodenoscope was a first-generation device by Boston Scientific named EXALT Model D.

Of the 73 patients, 13 underwent roll-in maneuvers and 60 underwent endoscopic retrograde cholangiopancreatography (ERCP). The most common cause for ERCP was exchange or removal of biliary stent (55.0%), followed by evaluation of biliary defect or stricture (26.7%), then bile duct stone clearance (18.3%). The majority of ERCPs had an American Society for Gastrointestinal Endoscopy (ASGE) procedural complexity grade of 2 (43.3%) or 3 (43.3%), while a minority were graded 1 (11.7%) or, most severe, 4 (1.7%).

Two ERCPs required crossover to a reusable duodenoscope for completion. In the first instance, crossover was needed because dilation of a biliary stricture was unsuccessful, with the endoscopist reporting difficulties maneuvering the disposable scope, possibly because of shaft stiffness. In the second case, crossover was elected because cannulation was unsuccessful with standard access techniques; however, cannulation also was not possible with the reusable scope, necessitating an alternative approach.

According to the investigators, safety signals were comparable with standard practice. No serious, scope-related adverse events were reported. Serious adverse events of any kind were relatively uncommon; three patients developed post-ERCP pancreatitis within 7 days of ERCP, one developed a postsphincterotomy bleed, and one had worsening of a preexisting infection that required hospitalization.

As described above, the endoscopists reported a median overall satisfaction score of 9 out of 10. Specifically, 17 out of 23 scored ERCP maneuvers (73.9%) received a median 5 out of 5 performance rating. Out of 1,289 total ratings, almost all (98.1%) received a performance rating of at least 3 out of 5. Low-scoring performance characteristics (receiving at least one “1” rating), included elevator function; aspects of positioning; visualization; image quality, brightness, or appearance; and ease and ability of passing ancillary devices through the channel of the single-use duodenoscope and into the papilla.

“The new device provides an alternative to reusable duodenoscopes that may harbor residual contamination despite appropriately implemented reprocessing,” the investigators concluded.

They also pointed out that switching to disposable scopes would not completely put an end to postendoscopic infections.

“The single-use duodenoscope is a timely and innovative option to improve exogenous infection control, and must be used with awareness of the continued risk of endogenous infection, with standard infection control precautions and continued diligence in the use of existing reusable devices,” they wrote.

The study was funded by Boston Scientific. The investigators reported additional relationships with Medtronic, Ethicon/Torax, CapsoVision, and others.

SOURCE: Muthusamy V et al. Clin Gastroenterol Hepatol. 2019 Oct 11. doi: 10.1016/j.cgh.2019.10.052.

A single-use duodenoscope may reduce the risk of postendoscopic infections while maintaining a high level of user satisfaction, based on a recent multicenter case series study.

At six tertiary referral centers in the United States, seven expert endoscopists performed more than 70 procedures with disposable scopes, ultimately reporting a median satisfaction score of 9 out of 10, according to lead author Venkataraman Muthusamy, MD, of UCLA Health in Los Angeles, and colleagues.

Writing for Clinical Gastroenterology and Hepatology, the investigators noted that duodenoscope-related infections represent a serious threat to public health, particularly when considered in the context of antibiotic resistance and the high number of endoscopic procedures performed annually.

“Solutions to the duodenoscope contamination problem remain elusive,” the investigators wrote. “Evidence-based interventions are important to guard against labor-intensive measures that are unfeasible, unaffordable, and potentially ineffective.”

According to the investigators, routine culture surveillance and field investigations following suspected duodenoscope-related infections may fail to detect culprit bacteria or shortcomings in equipment reprocessing; and even when performed correctly, standard reprocessing can be insufficient.

“Using current reprocessing techniques, improved compliance with reprocessing guidelines is not a definitive solution because reusable duodenoscope contamination may be present even after high-level disinfection or sterilization,” the investigators wrote, going on to cite Food and Drug Administration–reported contamination rates of 5.4% for high-concern organisms.

To determine if a single-use endoscope could overcome such risks, the investigators first conducted preclinical testing with animal laboratories and simulations, finding that a single-use duodenoscope was comparable with three reusable scope models. The present study, which included 73 patients with normal pancreaticobiliary anatomy, evaluated clinical feasibility, safety, and performance. The single-use duodenoscope was a first-generation device by Boston Scientific named EXALT Model D.

Of the 73 patients, 13 underwent roll-in maneuvers and 60 underwent endoscopic retrograde cholangiopancreatography (ERCP). The most common cause for ERCP was exchange or removal of biliary stent (55.0%), followed by evaluation of biliary defect or stricture (26.7%), then bile duct stone clearance (18.3%). The majority of ERCPs had an American Society for Gastrointestinal Endoscopy (ASGE) procedural complexity grade of 2 (43.3%) or 3 (43.3%), while a minority were graded 1 (11.7%) or, most severe, 4 (1.7%).

Two ERCPs required crossover to a reusable duodenoscope for completion. In the first instance, crossover was needed because dilation of a biliary stricture was unsuccessful, with the endoscopist reporting difficulties maneuvering the disposable scope, possibly because of shaft stiffness. In the second case, crossover was elected because cannulation was unsuccessful with standard access techniques; however, cannulation also was not possible with the reusable scope, necessitating an alternative approach.

According to the investigators, safety signals were comparable with standard practice. No serious, scope-related adverse events were reported. Serious adverse events of any kind were relatively uncommon; three patients developed post-ERCP pancreatitis within 7 days of ERCP, one developed a postsphincterotomy bleed, and one had worsening of a preexisting infection that required hospitalization.

As described above, the endoscopists reported a median overall satisfaction score of 9 out of 10. Specifically, 17 out of 23 scored ERCP maneuvers (73.9%) received a median 5 out of 5 performance rating. Out of 1,289 total ratings, almost all (98.1%) received a performance rating of at least 3 out of 5. Low-scoring performance characteristics (receiving at least one “1” rating), included elevator function; aspects of positioning; visualization; image quality, brightness, or appearance; and ease and ability of passing ancillary devices through the channel of the single-use duodenoscope and into the papilla.

“The new device provides an alternative to reusable duodenoscopes that may harbor residual contamination despite appropriately implemented reprocessing,” the investigators concluded.

They also pointed out that switching to disposable scopes would not completely put an end to postendoscopic infections.

“The single-use duodenoscope is a timely and innovative option to improve exogenous infection control, and must be used with awareness of the continued risk of endogenous infection, with standard infection control precautions and continued diligence in the use of existing reusable devices,” they wrote.

The study was funded by Boston Scientific. The investigators reported additional relationships with Medtronic, Ethicon/Torax, CapsoVision, and others.

SOURCE: Muthusamy V et al. Clin Gastroenterol Hepatol. 2019 Oct 11. doi: 10.1016/j.cgh.2019.10.052.

A single-use duodenoscope may reduce the risk of postendoscopic infections while maintaining a high level of user satisfaction, based on a recent multicenter case series study.

At six tertiary referral centers in the United States, seven expert endoscopists performed more than 70 procedures with disposable scopes, ultimately reporting a median satisfaction score of 9 out of 10, according to lead author Venkataraman Muthusamy, MD, of UCLA Health in Los Angeles, and colleagues.

Writing for Clinical Gastroenterology and Hepatology, the investigators noted that duodenoscope-related infections represent a serious threat to public health, particularly when considered in the context of antibiotic resistance and the high number of endoscopic procedures performed annually.

“Solutions to the duodenoscope contamination problem remain elusive,” the investigators wrote. “Evidence-based interventions are important to guard against labor-intensive measures that are unfeasible, unaffordable, and potentially ineffective.”

According to the investigators, routine culture surveillance and field investigations following suspected duodenoscope-related infections may fail to detect culprit bacteria or shortcomings in equipment reprocessing; and even when performed correctly, standard reprocessing can be insufficient.

“Using current reprocessing techniques, improved compliance with reprocessing guidelines is not a definitive solution because reusable duodenoscope contamination may be present even after high-level disinfection or sterilization,” the investigators wrote, going on to cite Food and Drug Administration–reported contamination rates of 5.4% for high-concern organisms.

To determine if a single-use endoscope could overcome such risks, the investigators first conducted preclinical testing with animal laboratories and simulations, finding that a single-use duodenoscope was comparable with three reusable scope models. The present study, which included 73 patients with normal pancreaticobiliary anatomy, evaluated clinical feasibility, safety, and performance. The single-use duodenoscope was a first-generation device by Boston Scientific named EXALT Model D.

Of the 73 patients, 13 underwent roll-in maneuvers and 60 underwent endoscopic retrograde cholangiopancreatography (ERCP). The most common cause for ERCP was exchange or removal of biliary stent (55.0%), followed by evaluation of biliary defect or stricture (26.7%), then bile duct stone clearance (18.3%). The majority of ERCPs had an American Society for Gastrointestinal Endoscopy (ASGE) procedural complexity grade of 2 (43.3%) or 3 (43.3%), while a minority were graded 1 (11.7%) or, most severe, 4 (1.7%).

Two ERCPs required crossover to a reusable duodenoscope for completion. In the first instance, crossover was needed because dilation of a biliary stricture was unsuccessful, with the endoscopist reporting difficulties maneuvering the disposable scope, possibly because of shaft stiffness. In the second case, crossover was elected because cannulation was unsuccessful with standard access techniques; however, cannulation also was not possible with the reusable scope, necessitating an alternative approach.

According to the investigators, safety signals were comparable with standard practice. No serious, scope-related adverse events were reported. Serious adverse events of any kind were relatively uncommon; three patients developed post-ERCP pancreatitis within 7 days of ERCP, one developed a postsphincterotomy bleed, and one had worsening of a preexisting infection that required hospitalization.

As described above, the endoscopists reported a median overall satisfaction score of 9 out of 10. Specifically, 17 out of 23 scored ERCP maneuvers (73.9%) received a median 5 out of 5 performance rating. Out of 1,289 total ratings, almost all (98.1%) received a performance rating of at least 3 out of 5. Low-scoring performance characteristics (receiving at least one “1” rating), included elevator function; aspects of positioning; visualization; image quality, brightness, or appearance; and ease and ability of passing ancillary devices through the channel of the single-use duodenoscope and into the papilla.

“The new device provides an alternative to reusable duodenoscopes that may harbor residual contamination despite appropriately implemented reprocessing,” the investigators concluded.

They also pointed out that switching to disposable scopes would not completely put an end to postendoscopic infections.

“The single-use duodenoscope is a timely and innovative option to improve exogenous infection control, and must be used with awareness of the continued risk of endogenous infection, with standard infection control precautions and continued diligence in the use of existing reusable devices,” they wrote.

The study was funded by Boston Scientific. The investigators reported additional relationships with Medtronic, Ethicon/Torax, CapsoVision, and others.

SOURCE: Muthusamy V et al. Clin Gastroenterol Hepatol. 2019 Oct 11. doi: 10.1016/j.cgh.2019.10.052.

The American Gastroenterological Association recently issued a clinical practice update for the management of pancreatic necrosis, including 15 recommendations based on a comprehensive literature review and the experiences of leading experts.

Recommendations range from the general, such as the need for a multidisciplinary approach, to the specific, such as the superiority of metal over plastic stents for endoscopic transmural drainage.

The expert review, which was conducted by lead author Todd H. Baron, MD, of the University of North Carolina in Chapel Hill and three other colleagues, was vetted by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board. In addition, the update underwent external peer review prior to publication in Gastroenterology.

In the update, the authors outlined the clinical landscape for pancreatic necrosis, including challenges posed by complex cases and a mortality rate as high as 30%.

“Successful management of these patients requires expert multidisciplinary care by gastroenterologists, surgeons, interventional radiologists, and specialists in critical care medicine, infectious disease, and nutrition,” the investigators wrote.

They went on to explain how management has evolved over the past 10 years.

“Whereby major surgical intervention and debridement was once the mainstay of therapy for patients with symptomatic necrotic collections, a minimally invasive approach focusing on percutaneous drainage and/or endoscopic drainage or debridement is now favored,” they wrote. They added that debridement is still generally agreed to be the best choice for cases of infected necrosis or patients with sterile necrosis “marked by abdominal pain, nausea, vomiting, and nutritional failure or with associated complications including gastrointestinal luminal obstruction, biliary obstruction, recurrent acute pancreatitis, fistulas, or persistent systemic inflammatory response syndrome (SIRS).”

Other elements of care, however, remain debated, the investigators noted, which has led to variations in multiple aspects of care, such as interventional timing, intravenous fluids, antibiotics, and nutrition. Within this framework, the present practice update is aimed at offering “concise best practice advice for the optimal management of patients with this highly morbid condition.”

Among these pieces of advice, the authors emphasized that routine prophylactic antibiotics and/or antifungals to prevent infected necrosis are unsupported by multiple clinical trials. When infection is suspected, the update recommends broad spectrum intravenous antibiotics, noting that, in most cases, it is unnecessary to perform CT-guided fine-needle aspiration for cultures and gram stain.

Regarding nutrition, the update recommends against “pancreatic rest”; instead, it calls for early oral intake and, if this is not possible, then initiation of total enteral nutrition. Although the authors deemed multiple routes of enteral feeding acceptable, they favored nasogastric or nasoduodenal tubes, when appropriate, because of ease of placement and maintenance. For prolonged total enteral nutrition or patients unable to tolerate nasoenteric feeding, the authors recommended endoscopic feeding tube placement with a percutaneous endoscopic gastrostomy tube for those who can tolerate gastric feeding or a percutaneous endoscopic jejunostomy tube for those who cannot or have a high risk of aspiration.

As described above, the update recommends debridement for cases of infected pancreatic necrosis. Ideally, this should be performed at least 4 weeks after onset, and avoided altogether within the first 2 weeks, because of associated risks of morbidity and mortality; instead, during this acute phase, percutaneous drainage may be considered.

For walled-off pancreatic necrosis, the authors recommended transmural drainage via endoscopic therapy because this mitigates risk of pancreatocutaneous fistula. Percutaneous drainage may be considered in addition to, or in absence of, endoscopic drainage, depending on clinical status.

The remainder of the update covers decisions related to stents, other minimally invasive techniques, open operative debridement, and disconnected left pancreatic remnants, along with discussions of key supporting clinical trials.

The investigators disclosed relationships with Cook Endoscopy, Boston Scientific, Olympus, and others.

SOURCE: Baron TH et al. Gastroenterology. 2019 Aug 31. doi: 10.1053/j.gastro.2019.07.064.

Review the Gastroenterology clinical guidelines collection for AGA Institute statements detailing preferred approaches to specific medical problems or issues based on the most current available data at https://www.gastrojournal.org/content/agai. 

The American Gastroenterological Association recently issued a clinical practice update for the management of pancreatic necrosis, including 15 recommendations based on a comprehensive literature review and the experiences of leading experts.

Recommendations range from the general, such as the need for a multidisciplinary approach, to the specific, such as the superiority of metal over plastic stents for endoscopic transmural drainage.

The expert review, which was conducted by lead author Todd H. Baron, MD, of the University of North Carolina in Chapel Hill and three other colleagues, was vetted by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board. In addition, the update underwent external peer review prior to publication in Gastroenterology.

In the update, the authors outlined the clinical landscape for pancreatic necrosis, including challenges posed by complex cases and a mortality rate as high as 30%.

“Successful management of these patients requires expert multidisciplinary care by gastroenterologists, surgeons, interventional radiologists, and specialists in critical care medicine, infectious disease, and nutrition,” the investigators wrote.

They went on to explain how management has evolved over the past 10 years.

“Whereby major surgical intervention and debridement was once the mainstay of therapy for patients with symptomatic necrotic collections, a minimally invasive approach focusing on percutaneous drainage and/or endoscopic drainage or debridement is now favored,” they wrote. They added that debridement is still generally agreed to be the best choice for cases of infected necrosis or patients with sterile necrosis “marked by abdominal pain, nausea, vomiting, and nutritional failure or with associated complications including gastrointestinal luminal obstruction, biliary obstruction, recurrent acute pancreatitis, fistulas, or persistent systemic inflammatory response syndrome (SIRS).”

Other elements of care, however, remain debated, the investigators noted, which has led to variations in multiple aspects of care, such as interventional timing, intravenous fluids, antibiotics, and nutrition. Within this framework, the present practice update is aimed at offering “concise best practice advice for the optimal management of patients with this highly morbid condition.”

Among these pieces of advice, the authors emphasized that routine prophylactic antibiotics and/or antifungals to prevent infected necrosis are unsupported by multiple clinical trials. When infection is suspected, the update recommends broad spectrum intravenous antibiotics, noting that, in most cases, it is unnecessary to perform CT-guided fine-needle aspiration for cultures and gram stain.

Regarding nutrition, the update recommends against “pancreatic rest”; instead, it calls for early oral intake and, if this is not possible, then initiation of total enteral nutrition. Although the authors deemed multiple routes of enteral feeding acceptable, they favored nasogastric or nasoduodenal tubes, when appropriate, because of ease of placement and maintenance. For prolonged total enteral nutrition or patients unable to tolerate nasoenteric feeding, the authors recommended endoscopic feeding tube placement with a percutaneous endoscopic gastrostomy tube for those who can tolerate gastric feeding or a percutaneous endoscopic jejunostomy tube for those who cannot or have a high risk of aspiration.

As described above, the update recommends debridement for cases of infected pancreatic necrosis. Ideally, this should be performed at least 4 weeks after onset, and avoided altogether within the first 2 weeks, because of associated risks of morbidity and mortality; instead, during this acute phase, percutaneous drainage may be considered.

For walled-off pancreatic necrosis, the authors recommended transmural drainage via endoscopic therapy because this mitigates risk of pancreatocutaneous fistula. Percutaneous drainage may be considered in addition to, or in absence of, endoscopic drainage, depending on clinical status.

The remainder of the update covers decisions related to stents, other minimally invasive techniques, open operative debridement, and disconnected left pancreatic remnants, along with discussions of key supporting clinical trials.

The investigators disclosed relationships with Cook Endoscopy, Boston Scientific, Olympus, and others.

SOURCE: Baron TH et al. Gastroenterology. 2019 Aug 31. doi: 10.1053/j.gastro.2019.07.064.

Review the Gastroenterology clinical guidelines collection for AGA Institute statements detailing preferred approaches to specific medical problems or issues based on the most current available data at https://www.gastrojournal.org/content/agai. 

The American Gastroenterological Association recently issued a clinical practice update for the management of pancreatic necrosis, including 15 recommendations based on a comprehensive literature review and the experiences of leading experts.

Recommendations range from the general, such as the need for a multidisciplinary approach, to the specific, such as the superiority of metal over plastic stents for endoscopic transmural drainage.

The expert review, which was conducted by lead author Todd H. Baron, MD, of the University of North Carolina in Chapel Hill and three other colleagues, was vetted by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board. In addition, the update underwent external peer review prior to publication in Gastroenterology.

In the update, the authors outlined the clinical landscape for pancreatic necrosis, including challenges posed by complex cases and a mortality rate as high as 30%.

“Successful management of these patients requires expert multidisciplinary care by gastroenterologists, surgeons, interventional radiologists, and specialists in critical care medicine, infectious disease, and nutrition,” the investigators wrote.

They went on to explain how management has evolved over the past 10 years.

“Whereby major surgical intervention and debridement was once the mainstay of therapy for patients with symptomatic necrotic collections, a minimally invasive approach focusing on percutaneous drainage and/or endoscopic drainage or debridement is now favored,” they wrote. They added that debridement is still generally agreed to be the best choice for cases of infected necrosis or patients with sterile necrosis “marked by abdominal pain, nausea, vomiting, and nutritional failure or with associated complications including gastrointestinal luminal obstruction, biliary obstruction, recurrent acute pancreatitis, fistulas, or persistent systemic inflammatory response syndrome (SIRS).”

Other elements of care, however, remain debated, the investigators noted, which has led to variations in multiple aspects of care, such as interventional timing, intravenous fluids, antibiotics, and nutrition. Within this framework, the present practice update is aimed at offering “concise best practice advice for the optimal management of patients with this highly morbid condition.”

Among these pieces of advice, the authors emphasized that routine prophylactic antibiotics and/or antifungals to prevent infected necrosis are unsupported by multiple clinical trials. When infection is suspected, the update recommends broad spectrum intravenous antibiotics, noting that, in most cases, it is unnecessary to perform CT-guided fine-needle aspiration for cultures and gram stain.

Regarding nutrition, the update recommends against “pancreatic rest”; instead, it calls for early oral intake and, if this is not possible, then initiation of total enteral nutrition. Although the authors deemed multiple routes of enteral feeding acceptable, they favored nasogastric or nasoduodenal tubes, when appropriate, because of ease of placement and maintenance. For prolonged total enteral nutrition or patients unable to tolerate nasoenteric feeding, the authors recommended endoscopic feeding tube placement with a percutaneous endoscopic gastrostomy tube for those who can tolerate gastric feeding or a percutaneous endoscopic jejunostomy tube for those who cannot or have a high risk of aspiration.

As described above, the update recommends debridement for cases of infected pancreatic necrosis. Ideally, this should be performed at least 4 weeks after onset, and avoided altogether within the first 2 weeks, because of associated risks of morbidity and mortality; instead, during this acute phase, percutaneous drainage may be considered.

For walled-off pancreatic necrosis, the authors recommended transmural drainage via endoscopic therapy because this mitigates risk of pancreatocutaneous fistula. Percutaneous drainage may be considered in addition to, or in absence of, endoscopic drainage, depending on clinical status.

The remainder of the update covers decisions related to stents, other minimally invasive techniques, open operative debridement, and disconnected left pancreatic remnants, along with discussions of key supporting clinical trials.

The investigators disclosed relationships with Cook Endoscopy, Boston Scientific, Olympus, and others.

SOURCE: Baron TH et al. Gastroenterology. 2019 Aug 31. doi: 10.1053/j.gastro.2019.07.064.

Review the Gastroenterology clinical guidelines collection for AGA Institute statements detailing preferred approaches to specific medical problems or issues based on the most current available data at https://www.gastrojournal.org/content/agai. 

The Canadian Association of Gastroenterology (CAG) recently co-published a clinical practice guideline for the management of bile acid diarrhea (BAD) in Clinical Gastroenterology and Hepatology and the Journal of the Canadian Association of Gastroenterology.

Given a minimal evidence base, 16 out of the 17 guideline recommendations are conditional, according to lead author Daniel C. Sadowski, MD, of Royal Alexandra Hospital, Edmonton, Alta., and colleagues. Considering the shortage of high-quality evidence, the panel called for more randomized clinical trials to address current knowledge gaps.

“BAD is an understudied, often underappreciated condition, and questions remain regarding its diagnosis and treatment,” the panelists wrote in Clinical Gastroenterology and Hepatology. “There have been guidelines on the management of chronic diarrhea from the American Gastroenterological Association, and the British Society of Gastroenterology, but diagnosis and management of BAD was not assessed extensively in these publications. The British Society of Gastroenterology updated guidelines on the investigation of chronic diarrhea in adults, published after the consensus meeting, addressed some issues related to BAD.”

For the current guideline, using available evidence and clinical experience, expert panelists from Canada, the United States, and the United Kingdom aimed to “provide a reasonable and practical approach to care for specialists.” The guideline was further reviewed by the CAG Practice Affairs and Clinical Affairs Committees and the CAG Board of Directors.

The guideline first puts BAD in clinical context, noting a chronic diarrhea prevalence rate of approximately 5%. According to the guideline, approximately 1 out of 4 of these patients with chronic diarrhea may have BAD and prevalence of BAD is likely higher among those with other conditions, such as terminal ileal disease.

While BAD may be relatively common, it isn’t necessarily easy to diagnose, the panelists noted.

“The diagnosis of BAD continues to be a challenge, although this may be improved in the future with the general availability of screening serologic tests and other diagnostic tests,” the panelists wrote. “Although a treatment trial with bile acid sequestrants therapy (BAST) often is used, this approach has not been studied adequately, and likely is imprecise, and may lead to both undertreatment and overtreatment.”

Instead, the panelists recommended testing for BAD with 75-selenium homocholic acid taurine (SeHCAT) or 7-alpha-hydroxy-4-cholesten-3-one.

After addressing treatable causes of BAD, the guideline recommends initial therapy with cholestyramine or, if this is poorly tolerated, switching to BAST. However, the panelists advised against BAST for patients with resection or ileal Crohn’s disease, for whom other antidiarrheal agents are more suitable. When appropriate, BAST should be given at the lowest effective dose, with periodic trials of on-demand, intermittent administration, the panelists recommended. When BAST is ineffective, the guideline recommends that clinicians review concurrent medications as a possible cause of BAD or reinvestigate.

Concluding the guideline, the panelists emphasized the need for more high-quality research.

“The group recognized that specific, high-certainty evidence was lacking in many areas and recommended further studies that would improve the data available in future methodologic evaluations,” the panelists wrote.

While improving diagnostic accuracy of BAD should be a major goal of such research, progress is currently limited by an integral shortcoming of diagnostic test accuracy (DTA) studies, the panelists wrote.

“The main challenge in conducting DTA studies for BAD is the lack of a widely accepted or universally agreed-upon reference standard because the condition is defined and classified based on pathophysiologic mechanisms and its response to treatment (BAST),” the panelists wrote. “In addition, the index tests (SeHCAT, C4, FGF19, fecal bile acid assay) provide a continuous measure of metabolic function. Hence, DTA studies are not the most appropriate study design.”

“Therefore, one of the research priorities in BAD is for the scientific and clinical communities to agree on a reference standard that best represents BAD (e.g., response to BAST), with full understanding that the reference standard is and likely will be imperfect.”

The guideline was funded by unrestricted grants from Pendopharm and GE Healthcare Canada. The panelists disclosed relationships with AstraZeneca, AbbVie, Merck, Pfizer, and others.

Review the AGA clinical practice guideline on the laboratory evaluation of functional diarrhea and diarrhea-predominan irritable bowel syndrome in adults at https:/www.gastrojournal.org/article/S0016-5085(19)41083-4/fulltext.

SOURCE: Sadowski DC et al. Clin Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.cgh.2019.08.062.

The Canadian Association of Gastroenterology (CAG) recently co-published a clinical practice guideline for the management of bile acid diarrhea (BAD) in Clinical Gastroenterology and Hepatology and the Journal of the Canadian Association of Gastroenterology.

Given a minimal evidence base, 16 out of the 17 guideline recommendations are conditional, according to lead author Daniel C. Sadowski, MD, of Royal Alexandra Hospital, Edmonton, Alta., and colleagues. Considering the shortage of high-quality evidence, the panel called for more randomized clinical trials to address current knowledge gaps.

“BAD is an understudied, often underappreciated condition, and questions remain regarding its diagnosis and treatment,” the panelists wrote in Clinical Gastroenterology and Hepatology. “There have been guidelines on the management of chronic diarrhea from the American Gastroenterological Association, and the British Society of Gastroenterology, but diagnosis and management of BAD was not assessed extensively in these publications. The British Society of Gastroenterology updated guidelines on the investigation of chronic diarrhea in adults, published after the consensus meeting, addressed some issues related to BAD.”

For the current guideline, using available evidence and clinical experience, expert panelists from Canada, the United States, and the United Kingdom aimed to “provide a reasonable and practical approach to care for specialists.” The guideline was further reviewed by the CAG Practice Affairs and Clinical Affairs Committees and the CAG Board of Directors.

The guideline first puts BAD in clinical context, noting a chronic diarrhea prevalence rate of approximately 5%. According to the guideline, approximately 1 out of 4 of these patients with chronic diarrhea may have BAD and prevalence of BAD is likely higher among those with other conditions, such as terminal ileal disease.

While BAD may be relatively common, it isn’t necessarily easy to diagnose, the panelists noted.

“The diagnosis of BAD continues to be a challenge, although this may be improved in the future with the general availability of screening serologic tests and other diagnostic tests,” the panelists wrote. “Although a treatment trial with bile acid sequestrants therapy (BAST) often is used, this approach has not been studied adequately, and likely is imprecise, and may lead to both undertreatment and overtreatment.”

Instead, the panelists recommended testing for BAD with 75-selenium homocholic acid taurine (SeHCAT) or 7-alpha-hydroxy-4-cholesten-3-one.

After addressing treatable causes of BAD, the guideline recommends initial therapy with cholestyramine or, if this is poorly tolerated, switching to BAST. However, the panelists advised against BAST for patients with resection or ileal Crohn’s disease, for whom other antidiarrheal agents are more suitable. When appropriate, BAST should be given at the lowest effective dose, with periodic trials of on-demand, intermittent administration, the panelists recommended. When BAST is ineffective, the guideline recommends that clinicians review concurrent medications as a possible cause of BAD or reinvestigate.

Concluding the guideline, the panelists emphasized the need for more high-quality research.

“The group recognized that specific, high-certainty evidence was lacking in many areas and recommended further studies that would improve the data available in future methodologic evaluations,” the panelists wrote.

While improving diagnostic accuracy of BAD should be a major goal of such research, progress is currently limited by an integral shortcoming of diagnostic test accuracy (DTA) studies, the panelists wrote.

“The main challenge in conducting DTA studies for BAD is the lack of a widely accepted or universally agreed-upon reference standard because the condition is defined and classified based on pathophysiologic mechanisms and its response to treatment (BAST),” the panelists wrote. “In addition, the index tests (SeHCAT, C4, FGF19, fecal bile acid assay) provide a continuous measure of metabolic function. Hence, DTA studies are not the most appropriate study design.”

“Therefore, one of the research priorities in BAD is for the scientific and clinical communities to agree on a reference standard that best represents BAD (e.g., response to BAST), with full understanding that the reference standard is and likely will be imperfect.”

The guideline was funded by unrestricted grants from Pendopharm and GE Healthcare Canada. The panelists disclosed relationships with AstraZeneca, AbbVie, Merck, Pfizer, and others.

Review the AGA clinical practice guideline on the laboratory evaluation of functional diarrhea and diarrhea-predominan irritable bowel syndrome in adults at https:/www.gastrojournal.org/article/S0016-5085(19)41083-4/fulltext.

SOURCE: Sadowski DC et al. Clin Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.cgh.2019.08.062.

The Canadian Association of Gastroenterology (CAG) recently co-published a clinical practice guideline for the management of bile acid diarrhea (BAD) in Clinical Gastroenterology and Hepatology and the Journal of the Canadian Association of Gastroenterology.

Given a minimal evidence base, 16 out of the 17 guideline recommendations are conditional, according to lead author Daniel C. Sadowski, MD, of Royal Alexandra Hospital, Edmonton, Alta., and colleagues. Considering the shortage of high-quality evidence, the panel called for more randomized clinical trials to address current knowledge gaps.

“BAD is an understudied, often underappreciated condition, and questions remain regarding its diagnosis and treatment,” the panelists wrote in Clinical Gastroenterology and Hepatology. “There have been guidelines on the management of chronic diarrhea from the American Gastroenterological Association, and the British Society of Gastroenterology, but diagnosis and management of BAD was not assessed extensively in these publications. The British Society of Gastroenterology updated guidelines on the investigation of chronic diarrhea in adults, published after the consensus meeting, addressed some issues related to BAD.”

For the current guideline, using available evidence and clinical experience, expert panelists from Canada, the United States, and the United Kingdom aimed to “provide a reasonable and practical approach to care for specialists.” The guideline was further reviewed by the CAG Practice Affairs and Clinical Affairs Committees and the CAG Board of Directors.

The guideline first puts BAD in clinical context, noting a chronic diarrhea prevalence rate of approximately 5%. According to the guideline, approximately 1 out of 4 of these patients with chronic diarrhea may have BAD and prevalence of BAD is likely higher among those with other conditions, such as terminal ileal disease.

While BAD may be relatively common, it isn’t necessarily easy to diagnose, the panelists noted.

“The diagnosis of BAD continues to be a challenge, although this may be improved in the future with the general availability of screening serologic tests and other diagnostic tests,” the panelists wrote. “Although a treatment trial with bile acid sequestrants therapy (BAST) often is used, this approach has not been studied adequately, and likely is imprecise, and may lead to both undertreatment and overtreatment.”

Instead, the panelists recommended testing for BAD with 75-selenium homocholic acid taurine (SeHCAT) or 7-alpha-hydroxy-4-cholesten-3-one.

After addressing treatable causes of BAD, the guideline recommends initial therapy with cholestyramine or, if this is poorly tolerated, switching to BAST. However, the panelists advised against BAST for patients with resection or ileal Crohn’s disease, for whom other antidiarrheal agents are more suitable. When appropriate, BAST should be given at the lowest effective dose, with periodic trials of on-demand, intermittent administration, the panelists recommended. When BAST is ineffective, the guideline recommends that clinicians review concurrent medications as a possible cause of BAD or reinvestigate.

Concluding the guideline, the panelists emphasized the need for more high-quality research.

“The group recognized that specific, high-certainty evidence was lacking in many areas and recommended further studies that would improve the data available in future methodologic evaluations,” the panelists wrote.

While improving diagnostic accuracy of BAD should be a major goal of such research, progress is currently limited by an integral shortcoming of diagnostic test accuracy (DTA) studies, the panelists wrote.

“The main challenge in conducting DTA studies for BAD is the lack of a widely accepted or universally agreed-upon reference standard because the condition is defined and classified based on pathophysiologic mechanisms and its response to treatment (BAST),” the panelists wrote. “In addition, the index tests (SeHCAT, C4, FGF19, fecal bile acid assay) provide a continuous measure of metabolic function. Hence, DTA studies are not the most appropriate study design.”

“Therefore, one of the research priorities in BAD is for the scientific and clinical communities to agree on a reference standard that best represents BAD (e.g., response to BAST), with full understanding that the reference standard is and likely will be imperfect.”

The guideline was funded by unrestricted grants from Pendopharm and GE Healthcare Canada. The panelists disclosed relationships with AstraZeneca, AbbVie, Merck, Pfizer, and others.

Review the AGA clinical practice guideline on the laboratory evaluation of functional diarrhea and diarrhea-predominan irritable bowel syndrome in adults at https:/www.gastrojournal.org/article/S0016-5085(19)41083-4/fulltext.

SOURCE: Sadowski DC et al. Clin Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.cgh.2019.08.062.

Postcolonoscopy colorectal cancers were more likely to arise in the proximal colon and to show microsatellite instability, according to the results of a retrospective population-based study of 168 adults with incident colorectal cancers.

In all, 64% of postcolonoscopy colorectal cancers were located in the proximal colon, compared with 44% of detected colorectal cancers (P = .016), reported Niloy Jewel Samadder, MD, of the University of Utah in Salt Lake City, together with his associates. Furthermore, microsatellite instability (MSI) was detected in 32% of postcolonoscopy colorectal cancers, versus 13% of detected colorectal cancers (P = .005). These findings may point to differences in the underlying biology of postcolonoscopy colorectal cancers and detected colorectal cancers, they said. Studies are needed “to determine if postcolonoscopy cancers arise through a specific genetic pathway that may accelerate neoplastic progression,” they wrote in Clinical Gastroenterology and Hepatology.

Postcolonoscopy colorectal cancers are a “small but clinically important subset of colorectal cancers” that are diagnosed after the patient has a colonoscopy in which no cancer is detected, the researchers noted. These cancers have an estimated global prevalence ranging from 3% to 9% and an estimated pooled prevalence of 3.7% (Am J Gastroenterol. 2014;109:1375-89). Risk factors for postcolonoscopy colorectal cancers include low adenoma detection rates, rural facilities, and care by physicians who are not gastroenterologists. However, tumor-specific and patient-specific factors, including location within the colon and superior survival, compared with detected cancers, raises the possibility of underlying molecular differences related to tumorigenesis, the researchers said.

To investigate this idea, they retrospectively analyzed data from residents of Utah between 50 and 80 years old who had a colonoscopy between, Feb. 15, 1995, and Jan. 31, 2009, at one of two large clinical facilities in Utah (Intermountain Healthcare or the University of Utah Health Sciences). Using a state population-based database, they merged medical information from these patients with cancer histories from the Utah Cancer Registry. This enabled them to compare all 84 postcolonoscopy colorectal cancers (defined as those detected within 6-60 months of colonoscopy) with tissue available for analysis with 84 detected colorectal cancers (detected within 6 months of a colonoscopy).

In the multivariable analysis, MSI was the only molecular feature that was significantly more frequent in postcolonoscopy versus detected colorectal cancers (odds ratio, 4.20; 95% confidence interval, 1.58-11.14). However, postcolonoscopy colorectal cancers were significantly more likely to be early stage (86% versus 69% for detected colorectal cancers; P = .040). Five-year survival did not significantly differ between the groups.

“The molecular signatures of postcolonoscopy colorectal cancers in our study overlap with those of sporadic MSI and serrated pathways, suggesting these mechanisms play a disproportionate role in postcolonoscopy colorectal cancers.” the researchers said. “Additional studies are needed to determine whether these postcolonoscopy colorectal cancers arise through a familial cancer pathway and/or serrated neoplastic pathway of sporadic lesions.

Funders included the American College of Gastroenterology, the National Cancer Institute, the Huntsman Cancer Foundation, the University of Utah, and the Utah Department of Health. Dr. Samadder reported consulting relationships with Cancer Prevention Pharmaceuticals and Janssen Research and Development. The other researchers reported having no conflicts of interest.
 

SOURCE: Samadder NJ et al. Clin Gastroenterol Hepatol. 2019 Mar 28. doi: 10.1016/j.cgh.2019.02.040.

Postcolonoscopy colorectal cancers were more likely to arise in the proximal colon and to show microsatellite instability, according to the results of a retrospective population-based study of 168 adults with incident colorectal cancers.

In all, 64% of postcolonoscopy colorectal cancers were located in the proximal colon, compared with 44% of detected colorectal cancers (P = .016), reported Niloy Jewel Samadder, MD, of the University of Utah in Salt Lake City, together with his associates. Furthermore, microsatellite instability (MSI) was detected in 32% of postcolonoscopy colorectal cancers, versus 13% of detected colorectal cancers (P = .005). These findings may point to differences in the underlying biology of postcolonoscopy colorectal cancers and detected colorectal cancers, they said. Studies are needed “to determine if postcolonoscopy cancers arise through a specific genetic pathway that may accelerate neoplastic progression,” they wrote in Clinical Gastroenterology and Hepatology.

Postcolonoscopy colorectal cancers are a “small but clinically important subset of colorectal cancers” that are diagnosed after the patient has a colonoscopy in which no cancer is detected, the researchers noted. These cancers have an estimated global prevalence ranging from 3% to 9% and an estimated pooled prevalence of 3.7% (Am J Gastroenterol. 2014;109:1375-89). Risk factors for postcolonoscopy colorectal cancers include low adenoma detection rates, rural facilities, and care by physicians who are not gastroenterologists. However, tumor-specific and patient-specific factors, including location within the colon and superior survival, compared with detected cancers, raises the possibility of underlying molecular differences related to tumorigenesis, the researchers said.

To investigate this idea, they retrospectively analyzed data from residents of Utah between 50 and 80 years old who had a colonoscopy between, Feb. 15, 1995, and Jan. 31, 2009, at one of two large clinical facilities in Utah (Intermountain Healthcare or the University of Utah Health Sciences). Using a state population-based database, they merged medical information from these patients with cancer histories from the Utah Cancer Registry. This enabled them to compare all 84 postcolonoscopy colorectal cancers (defined as those detected within 6-60 months of colonoscopy) with tissue available for analysis with 84 detected colorectal cancers (detected within 6 months of a colonoscopy).

In the multivariable analysis, MSI was the only molecular feature that was significantly more frequent in postcolonoscopy versus detected colorectal cancers (odds ratio, 4.20; 95% confidence interval, 1.58-11.14). However, postcolonoscopy colorectal cancers were significantly more likely to be early stage (86% versus 69% for detected colorectal cancers; P = .040). Five-year survival did not significantly differ between the groups.

“The molecular signatures of postcolonoscopy colorectal cancers in our study overlap with those of sporadic MSI and serrated pathways, suggesting these mechanisms play a disproportionate role in postcolonoscopy colorectal cancers.” the researchers said. “Additional studies are needed to determine whether these postcolonoscopy colorectal cancers arise through a familial cancer pathway and/or serrated neoplastic pathway of sporadic lesions.

Funders included the American College of Gastroenterology, the National Cancer Institute, the Huntsman Cancer Foundation, the University of Utah, and the Utah Department of Health. Dr. Samadder reported consulting relationships with Cancer Prevention Pharmaceuticals and Janssen Research and Development. The other researchers reported having no conflicts of interest.
 

SOURCE: Samadder NJ et al. Clin Gastroenterol Hepatol. 2019 Mar 28. doi: 10.1016/j.cgh.2019.02.040.

Postcolonoscopy colorectal cancers were more likely to arise in the proximal colon and to show microsatellite instability, according to the results of a retrospective population-based study of 168 adults with incident colorectal cancers.

In all, 64% of postcolonoscopy colorectal cancers were located in the proximal colon, compared with 44% of detected colorectal cancers (P = .016), reported Niloy Jewel Samadder, MD, of the University of Utah in Salt Lake City, together with his associates. Furthermore, microsatellite instability (MSI) was detected in 32% of postcolonoscopy colorectal cancers, versus 13% of detected colorectal cancers (P = .005). These findings may point to differences in the underlying biology of postcolonoscopy colorectal cancers and detected colorectal cancers, they said. Studies are needed “to determine if postcolonoscopy cancers arise through a specific genetic pathway that may accelerate neoplastic progression,” they wrote in Clinical Gastroenterology and Hepatology.

Postcolonoscopy colorectal cancers are a “small but clinically important subset of colorectal cancers” that are diagnosed after the patient has a colonoscopy in which no cancer is detected, the researchers noted. These cancers have an estimated global prevalence ranging from 3% to 9% and an estimated pooled prevalence of 3.7% (Am J Gastroenterol. 2014;109:1375-89). Risk factors for postcolonoscopy colorectal cancers include low adenoma detection rates, rural facilities, and care by physicians who are not gastroenterologists. However, tumor-specific and patient-specific factors, including location within the colon and superior survival, compared with detected cancers, raises the possibility of underlying molecular differences related to tumorigenesis, the researchers said.

To investigate this idea, they retrospectively analyzed data from residents of Utah between 50 and 80 years old who had a colonoscopy between, Feb. 15, 1995, and Jan. 31, 2009, at one of two large clinical facilities in Utah (Intermountain Healthcare or the University of Utah Health Sciences). Using a state population-based database, they merged medical information from these patients with cancer histories from the Utah Cancer Registry. This enabled them to compare all 84 postcolonoscopy colorectal cancers (defined as those detected within 6-60 months of colonoscopy) with tissue available for analysis with 84 detected colorectal cancers (detected within 6 months of a colonoscopy).

In the multivariable analysis, MSI was the only molecular feature that was significantly more frequent in postcolonoscopy versus detected colorectal cancers (odds ratio, 4.20; 95% confidence interval, 1.58-11.14). However, postcolonoscopy colorectal cancers were significantly more likely to be early stage (86% versus 69% for detected colorectal cancers; P = .040). Five-year survival did not significantly differ between the groups.

“The molecular signatures of postcolonoscopy colorectal cancers in our study overlap with those of sporadic MSI and serrated pathways, suggesting these mechanisms play a disproportionate role in postcolonoscopy colorectal cancers.” the researchers said. “Additional studies are needed to determine whether these postcolonoscopy colorectal cancers arise through a familial cancer pathway and/or serrated neoplastic pathway of sporadic lesions.

Funders included the American College of Gastroenterology, the National Cancer Institute, the Huntsman Cancer Foundation, the University of Utah, and the Utah Department of Health. Dr. Samadder reported consulting relationships with Cancer Prevention Pharmaceuticals and Janssen Research and Development. The other researchers reported having no conflicts of interest.
 

SOURCE: Samadder NJ et al. Clin Gastroenterol Hepatol. 2019 Mar 28. doi: 10.1016/j.cgh.2019.02.040.

A high level of hepatitis B core–related antigen (HBcrAg) was a complementary risk factor for hepatocellular carcinoma, according to the results of a retrospective cohort study of more than 2,600 noncirrhotic adults with untreated hepatitis B virus (HBV) infection with a median of 16 years of follow-up.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

“Patients with an intermediate viral load and high levels of HBcrAg had a risk for hepatocellular carcinoma that did not differ significantly from that of patients with a high viral load. [An] HBcrAg of 10 KU/mL may serve as a novel biomarker for the management of patients with intermediate viral load in our clinical practice,” wrote Tai-Chung Tseng, MD, PhD, of National Taiwan University Hospital in Taipei and associates in Gastroenterology.

Deciding whether to start antiviral therapy is controversial for some patients with HBV infection. Typically, monitoring without treatment is recommended for patients who have both low hepatitis B surface antigen levels (less than 1,000 IU/mL) and low levels of HBV DNA (less than 2,000 IU/mL), and early antiviral therapy is recommended for patients who have high levels of HBV DNA (20,000 IU/mL or more). However, there is no clear evidence that early antiviral therapy benefits patients who have intermediate levels of HBV DNA (2,000-19,999 IU/mL) and are negative for hepatitis B e antigen. Biomarkers for risk-stratifying these patients also are lacking, the researchers noted.

Therefore, they studied a cohort of 2,666 adults who had tested positive for hepatitis B surface antigen and were followed at National Taiwan University Hospital from 1985 through 2000. No patient had cirrhosis at baseline. In all, 209 patients developed hepatocellular carcinoma, yielding an incidence rate of 4.91 cases per 1,000 person-years.

Hepatitis B core–related antigen level remained an independent risk factor for hepatocellular carcinoma after accounting for age, sex, serum alanine aminotransferase (ALT) level, FIB-4 index, hepatitis B e antigen status, hepatitis B genotype (B, C, or undetermined), and HBV DNA level. Compared with patients whose HBcrAg level was less than 10 KU, a level of 10-99 KU/mL was associated with a nearly threefold increase in risk for hepatocellular carcinoma (HR, 2.93; 95% CI, 1.67-4.80), and this risk rose even further as HBcrAg levels increased.

In the subgroup of patients who tested negative for hepatitis B e antigen, had an intermediate HBV DNA load (2,000-19,999 IU/mL), and had a normal baseline ALT level (less than 40 U/L), a high HBcrAg level (10 KU/mL or more) was tied to a nearly fivefold greater risk for hepatocellular carcinoma (HR, 4.89; 95% CI, 2.18-10.93). This approximated the risk that is observed with high viral load (20,000 IU/mL), the researchers noted. In contrast, a low HBcrAg level was associated with a risk similar to that of minimal risk carriers (annual incidence rate, 0.10%; 95% CI, 0.04%-0.24%).

“To the best of our knowledge, this is the first study to report HBcrAg level as an independent viral biomarker to stratify hepatocellular risks in a large number of patients with intermediate viral load,” the researchers commented. Among the study limitations, 412 patients received antiviral therapy during follow-up. “This is a retrospective cohort study including Asian HBV patients with genotype B or C infection,” the investigators added. “It is unclear whether this finding could be extrapolated to populations with other HBV genotype infections. Nonetheless, we had a sound cohort, as several HBsAg-related clinical findings based on our cohort have already been validated by other prospective cohort studies, implying that our data were unlikely to be biased by the study design.”

Funders included National Taiwan University Hospital, the Ministry of Science and Technology, Executive Yuan in Taiwan, and National Health Research Institutes. The researchers reported having no conflicts of interest.

SOURCE: Tseng T-C et al. Gastroenterology. 2019 Aug 27. doi: 10.1053/j.gastro.2019.08.028.

A high level of hepatitis B core–related antigen (HBcrAg) was a complementary risk factor for hepatocellular carcinoma, according to the results of a retrospective cohort study of more than 2,600 noncirrhotic adults with untreated hepatitis B virus (HBV) infection with a median of 16 years of follow-up.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

“Patients with an intermediate viral load and high levels of HBcrAg had a risk for hepatocellular carcinoma that did not differ significantly from that of patients with a high viral load. [An] HBcrAg of 10 KU/mL may serve as a novel biomarker for the management of patients with intermediate viral load in our clinical practice,” wrote Tai-Chung Tseng, MD, PhD, of National Taiwan University Hospital in Taipei and associates in Gastroenterology.

Deciding whether to start antiviral therapy is controversial for some patients with HBV infection. Typically, monitoring without treatment is recommended for patients who have both low hepatitis B surface antigen levels (less than 1,000 IU/mL) and low levels of HBV DNA (less than 2,000 IU/mL), and early antiviral therapy is recommended for patients who have high levels of HBV DNA (20,000 IU/mL or more). However, there is no clear evidence that early antiviral therapy benefits patients who have intermediate levels of HBV DNA (2,000-19,999 IU/mL) and are negative for hepatitis B e antigen. Biomarkers for risk-stratifying these patients also are lacking, the researchers noted.

Therefore, they studied a cohort of 2,666 adults who had tested positive for hepatitis B surface antigen and were followed at National Taiwan University Hospital from 1985 through 2000. No patient had cirrhosis at baseline. In all, 209 patients developed hepatocellular carcinoma, yielding an incidence rate of 4.91 cases per 1,000 person-years.

Hepatitis B core–related antigen level remained an independent risk factor for hepatocellular carcinoma after accounting for age, sex, serum alanine aminotransferase (ALT) level, FIB-4 index, hepatitis B e antigen status, hepatitis B genotype (B, C, or undetermined), and HBV DNA level. Compared with patients whose HBcrAg level was less than 10 KU, a level of 10-99 KU/mL was associated with a nearly threefold increase in risk for hepatocellular carcinoma (HR, 2.93; 95% CI, 1.67-4.80), and this risk rose even further as HBcrAg levels increased.

In the subgroup of patients who tested negative for hepatitis B e antigen, had an intermediate HBV DNA load (2,000-19,999 IU/mL), and had a normal baseline ALT level (less than 40 U/L), a high HBcrAg level (10 KU/mL or more) was tied to a nearly fivefold greater risk for hepatocellular carcinoma (HR, 4.89; 95% CI, 2.18-10.93). This approximated the risk that is observed with high viral load (20,000 IU/mL), the researchers noted. In contrast, a low HBcrAg level was associated with a risk similar to that of minimal risk carriers (annual incidence rate, 0.10%; 95% CI, 0.04%-0.24%).

“To the best of our knowledge, this is the first study to report HBcrAg level as an independent viral biomarker to stratify hepatocellular risks in a large number of patients with intermediate viral load,” the researchers commented. Among the study limitations, 412 patients received antiviral therapy during follow-up. “This is a retrospective cohort study including Asian HBV patients with genotype B or C infection,” the investigators added. “It is unclear whether this finding could be extrapolated to populations with other HBV genotype infections. Nonetheless, we had a sound cohort, as several HBsAg-related clinical findings based on our cohort have already been validated by other prospective cohort studies, implying that our data were unlikely to be biased by the study design.”

Funders included National Taiwan University Hospital, the Ministry of Science and Technology, Executive Yuan in Taiwan, and National Health Research Institutes. The researchers reported having no conflicts of interest.

SOURCE: Tseng T-C et al. Gastroenterology. 2019 Aug 27. doi: 10.1053/j.gastro.2019.08.028.

A high level of hepatitis B core–related antigen (HBcrAg) was a complementary risk factor for hepatocellular carcinoma, according to the results of a retrospective cohort study of more than 2,600 noncirrhotic adults with untreated hepatitis B virus (HBV) infection with a median of 16 years of follow-up.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

“Patients with an intermediate viral load and high levels of HBcrAg had a risk for hepatocellular carcinoma that did not differ significantly from that of patients with a high viral load. [An] HBcrAg of 10 KU/mL may serve as a novel biomarker for the management of patients with intermediate viral load in our clinical practice,” wrote Tai-Chung Tseng, MD, PhD, of National Taiwan University Hospital in Taipei and associates in Gastroenterology.

Deciding whether to start antiviral therapy is controversial for some patients with HBV infection. Typically, monitoring without treatment is recommended for patients who have both low hepatitis B surface antigen levels (less than 1,000 IU/mL) and low levels of HBV DNA (less than 2,000 IU/mL), and early antiviral therapy is recommended for patients who have high levels of HBV DNA (20,000 IU/mL or more). However, there is no clear evidence that early antiviral therapy benefits patients who have intermediate levels of HBV DNA (2,000-19,999 IU/mL) and are negative for hepatitis B e antigen. Biomarkers for risk-stratifying these patients also are lacking, the researchers noted.

Therefore, they studied a cohort of 2,666 adults who had tested positive for hepatitis B surface antigen and were followed at National Taiwan University Hospital from 1985 through 2000. No patient had cirrhosis at baseline. In all, 209 patients developed hepatocellular carcinoma, yielding an incidence rate of 4.91 cases per 1,000 person-years.

Hepatitis B core–related antigen level remained an independent risk factor for hepatocellular carcinoma after accounting for age, sex, serum alanine aminotransferase (ALT) level, FIB-4 index, hepatitis B e antigen status, hepatitis B genotype (B, C, or undetermined), and HBV DNA level. Compared with patients whose HBcrAg level was less than 10 KU, a level of 10-99 KU/mL was associated with a nearly threefold increase in risk for hepatocellular carcinoma (HR, 2.93; 95% CI, 1.67-4.80), and this risk rose even further as HBcrAg levels increased.

In the subgroup of patients who tested negative for hepatitis B e antigen, had an intermediate HBV DNA load (2,000-19,999 IU/mL), and had a normal baseline ALT level (less than 40 U/L), a high HBcrAg level (10 KU/mL or more) was tied to a nearly fivefold greater risk for hepatocellular carcinoma (HR, 4.89; 95% CI, 2.18-10.93). This approximated the risk that is observed with high viral load (20,000 IU/mL), the researchers noted. In contrast, a low HBcrAg level was associated with a risk similar to that of minimal risk carriers (annual incidence rate, 0.10%; 95% CI, 0.04%-0.24%).

“To the best of our knowledge, this is the first study to report HBcrAg level as an independent viral biomarker to stratify hepatocellular risks in a large number of patients with intermediate viral load,” the researchers commented. Among the study limitations, 412 patients received antiviral therapy during follow-up. “This is a retrospective cohort study including Asian HBV patients with genotype B or C infection,” the investigators added. “It is unclear whether this finding could be extrapolated to populations with other HBV genotype infections. Nonetheless, we had a sound cohort, as several HBsAg-related clinical findings based on our cohort have already been validated by other prospective cohort studies, implying that our data were unlikely to be biased by the study design.”

Funders included National Taiwan University Hospital, the Ministry of Science and Technology, Executive Yuan in Taiwan, and National Health Research Institutes. The researchers reported having no conflicts of interest.

SOURCE: Tseng T-C et al. Gastroenterology. 2019 Aug 27. doi: 10.1053/j.gastro.2019.08.028.

Taking daily aspirin may help keep nonalcoholic fatty liver disease (NAFLD) from progressing to liver fibrosis and nonalcoholic steatohepatitis (NASH), suggest the results of a prospective study of 361 adults.

Previously, preclinical evidence had linked aspirin to fibrogenesis prevention in fatty liver disease, but this is the first report of a prospective study to do so. Daily aspirin use “was associated with less severe histologic features of NAFLD (nonalcoholic fatty liver disease) at study enrollment and with significantly lower risk for advanced fibrosis over time in a duration-dependent manner,” wrote Tracey G. Simon, MD, MPH, and her associates. Their report is in Clinical Gastroenterology and Hepatology.

The study comprised 361 adults with biopsy-confirmed NAFLD who were enrolled in the Massachusetts General Hospital NAFLD Repository between 2006 and 2015. At baseline, 151 individuals were already on daily aspirin, usually to reduce the primary (54%) or secondary (30%) risk of cardiovascular disease. Median duration of aspirin use was 2.5 years. After a median 7.4 years of follow-up (which was similar between aspirin users and nonusers), daily aspirin use was associated with significantly lower odds of NASH (adjusted odds ratio, 0.68; 95% confidence interval, 0.37-0.89) and fibrosis (aOR, 0.54; 95% CI, 0.31-0.82).

The researchers did not find a similar protective effect for nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin (adjusted hazard ratio for advanced fibrosis, 0.93; 95% CI, 0.81–1.05). This might be because of differences between how aspirin and nonaspirin NSAIDs affect COX isoforms – aspirin does so irreversibly, while other NSAIDs have a reversible effect, they added. “Nonaspirin NSAIDs also disrupt the intestinal barrier, increasing delivery of proinflammatory cytokines to the liver,” they wrote. “Finally, aspirin uniquely modulates bioactive lipids by stimulating the biosynthesis of pro-resolving mediators and inhibiting proinflammatory lipids, which in turn may prevent progressive liver damage.”

In this study, a single blinded hepatopathologist interpreted baseline liver biopsy specimens, and patients were followed every 3-6 months with clinical examinations and serial calculations of FIB-4, NFS, and APRI scores. All patients were followed for at least a year. Patients were classified as users of nonaspirin NSAIDs if they reported using an NSAID besides aspirin at least twice weekly, or if they had been prescribed drugs such as ibuprofen, naproxen, ketoprofen, diclofenac, or indomethacin.

In a longitudinal analysis of the 317 patients who had early-stage (F0-2) fibrosis at baseline, 86 developed new-onset advanced fibrosis over a median of 3,692 person-years, the researchers said. In all, 26 individuals developed hepatic decompensation and 18 patients died, including eight from liver-related causes. Importantly, the link between aspirin and decreased risk of fibrosis progression seemed to depend on duration of use (adjusted P trend = .026), with the greatest benefit seen with 4 years or more of use (aHR, 0.50; 95% CI, 0.35-0.73). Although subgroup analyses were limited by lack of power, daily aspirin use was associated with a 36% lower odds of incident advanced fibrosis among the 72 study participants who had paired biopsy samples, even after accounting for the effect of age, sex, baseline fibrosis stage, and time between biopsies (aOR, 0.64; 95% CI, 0.50-0.80).

“Our findings add to the growing literature supporting the potential hepatoprotective effects of aspirin in NAFLD,” the researchers concluded. “Research to uncover the mechanisms by which aspirin might prevent fibrogenesis could help develop urgently needed antifibrotic therapies for NAFLD.”

Funders included the National Institutes of Health and the AASLD Foundation. The investigators reported having no conflicts of interest.

SOURCE: Simon TG et al. Clin Gastroenterol Hepatol. 2019 May 8.

Taking daily aspirin may help keep nonalcoholic fatty liver disease (NAFLD) from progressing to liver fibrosis and nonalcoholic steatohepatitis (NASH), suggest the results of a prospective study of 361 adults.

Previously, preclinical evidence had linked aspirin to fibrogenesis prevention in fatty liver disease, but this is the first report of a prospective study to do so. Daily aspirin use “was associated with less severe histologic features of NAFLD (nonalcoholic fatty liver disease) at study enrollment and with significantly lower risk for advanced fibrosis over time in a duration-dependent manner,” wrote Tracey G. Simon, MD, MPH, and her associates. Their report is in Clinical Gastroenterology and Hepatology.

The study comprised 361 adults with biopsy-confirmed NAFLD who were enrolled in the Massachusetts General Hospital NAFLD Repository between 2006 and 2015. At baseline, 151 individuals were already on daily aspirin, usually to reduce the primary (54%) or secondary (30%) risk of cardiovascular disease. Median duration of aspirin use was 2.5 years. After a median 7.4 years of follow-up (which was similar between aspirin users and nonusers), daily aspirin use was associated with significantly lower odds of NASH (adjusted odds ratio, 0.68; 95% confidence interval, 0.37-0.89) and fibrosis (aOR, 0.54; 95% CI, 0.31-0.82).

The researchers did not find a similar protective effect for nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin (adjusted hazard ratio for advanced fibrosis, 0.93; 95% CI, 0.81–1.05). This might be because of differences between how aspirin and nonaspirin NSAIDs affect COX isoforms – aspirin does so irreversibly, while other NSAIDs have a reversible effect, they added. “Nonaspirin NSAIDs also disrupt the intestinal barrier, increasing delivery of proinflammatory cytokines to the liver,” they wrote. “Finally, aspirin uniquely modulates bioactive lipids by stimulating the biosynthesis of pro-resolving mediators and inhibiting proinflammatory lipids, which in turn may prevent progressive liver damage.”

In this study, a single blinded hepatopathologist interpreted baseline liver biopsy specimens, and patients were followed every 3-6 months with clinical examinations and serial calculations of FIB-4, NFS, and APRI scores. All patients were followed for at least a year. Patients were classified as users of nonaspirin NSAIDs if they reported using an NSAID besides aspirin at least twice weekly, or if they had been prescribed drugs such as ibuprofen, naproxen, ketoprofen, diclofenac, or indomethacin.

In a longitudinal analysis of the 317 patients who had early-stage (F0-2) fibrosis at baseline, 86 developed new-onset advanced fibrosis over a median of 3,692 person-years, the researchers said. In all, 26 individuals developed hepatic decompensation and 18 patients died, including eight from liver-related causes. Importantly, the link between aspirin and decreased risk of fibrosis progression seemed to depend on duration of use (adjusted P trend = .026), with the greatest benefit seen with 4 years or more of use (aHR, 0.50; 95% CI, 0.35-0.73). Although subgroup analyses were limited by lack of power, daily aspirin use was associated with a 36% lower odds of incident advanced fibrosis among the 72 study participants who had paired biopsy samples, even after accounting for the effect of age, sex, baseline fibrosis stage, and time between biopsies (aOR, 0.64; 95% CI, 0.50-0.80).

“Our findings add to the growing literature supporting the potential hepatoprotective effects of aspirin in NAFLD,” the researchers concluded. “Research to uncover the mechanisms by which aspirin might prevent fibrogenesis could help develop urgently needed antifibrotic therapies for NAFLD.”

Funders included the National Institutes of Health and the AASLD Foundation. The investigators reported having no conflicts of interest.

SOURCE: Simon TG et al. Clin Gastroenterol Hepatol. 2019 May 8.

Taking daily aspirin may help keep nonalcoholic fatty liver disease (NAFLD) from progressing to liver fibrosis and nonalcoholic steatohepatitis (NASH), suggest the results of a prospective study of 361 adults.

Previously, preclinical evidence had linked aspirin to fibrogenesis prevention in fatty liver disease, but this is the first report of a prospective study to do so. Daily aspirin use “was associated with less severe histologic features of NAFLD (nonalcoholic fatty liver disease) at study enrollment and with significantly lower risk for advanced fibrosis over time in a duration-dependent manner,” wrote Tracey G. Simon, MD, MPH, and her associates. Their report is in Clinical Gastroenterology and Hepatology.

The study comprised 361 adults with biopsy-confirmed NAFLD who were enrolled in the Massachusetts General Hospital NAFLD Repository between 2006 and 2015. At baseline, 151 individuals were already on daily aspirin, usually to reduce the primary (54%) or secondary (30%) risk of cardiovascular disease. Median duration of aspirin use was 2.5 years. After a median 7.4 years of follow-up (which was similar between aspirin users and nonusers), daily aspirin use was associated with significantly lower odds of NASH (adjusted odds ratio, 0.68; 95% confidence interval, 0.37-0.89) and fibrosis (aOR, 0.54; 95% CI, 0.31-0.82).

The researchers did not find a similar protective effect for nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin (adjusted hazard ratio for advanced fibrosis, 0.93; 95% CI, 0.81–1.05). This might be because of differences between how aspirin and nonaspirin NSAIDs affect COX isoforms – aspirin does so irreversibly, while other NSAIDs have a reversible effect, they added. “Nonaspirin NSAIDs also disrupt the intestinal barrier, increasing delivery of proinflammatory cytokines to the liver,” they wrote. “Finally, aspirin uniquely modulates bioactive lipids by stimulating the biosynthesis of pro-resolving mediators and inhibiting proinflammatory lipids, which in turn may prevent progressive liver damage.”

In this study, a single blinded hepatopathologist interpreted baseline liver biopsy specimens, and patients were followed every 3-6 months with clinical examinations and serial calculations of FIB-4, NFS, and APRI scores. All patients were followed for at least a year. Patients were classified as users of nonaspirin NSAIDs if they reported using an NSAID besides aspirin at least twice weekly, or if they had been prescribed drugs such as ibuprofen, naproxen, ketoprofen, diclofenac, or indomethacin.

In a longitudinal analysis of the 317 patients who had early-stage (F0-2) fibrosis at baseline, 86 developed new-onset advanced fibrosis over a median of 3,692 person-years, the researchers said. In all, 26 individuals developed hepatic decompensation and 18 patients died, including eight from liver-related causes. Importantly, the link between aspirin and decreased risk of fibrosis progression seemed to depend on duration of use (adjusted P trend = .026), with the greatest benefit seen with 4 years or more of use (aHR, 0.50; 95% CI, 0.35-0.73). Although subgroup analyses were limited by lack of power, daily aspirin use was associated with a 36% lower odds of incident advanced fibrosis among the 72 study participants who had paired biopsy samples, even after accounting for the effect of age, sex, baseline fibrosis stage, and time between biopsies (aOR, 0.64; 95% CI, 0.50-0.80).

“Our findings add to the growing literature supporting the potential hepatoprotective effects of aspirin in NAFLD,” the researchers concluded. “Research to uncover the mechanisms by which aspirin might prevent fibrogenesis could help develop urgently needed antifibrotic therapies for NAFLD.”

Funders included the National Institutes of Health and the AASLD Foundation. The investigators reported having no conflicts of interest.

SOURCE: Simon TG et al. Clin Gastroenterol Hepatol. 2019 May 8.

A toll-like receptor 9 (TLR9) antagonist may eventually be used to combat brain edema in acute liver failure, according to investigators.

This prediction is based on results of a recent study involving mouse models, which showed that ODN2088, a TLR9 antagonist, could stop ammonia-induced colocalization of DNA with TLR9 in innate immune cells, thereby blocking cytokine production and ensuant brain edema, reported lead author Godhev Kumar Manakkat Vijay of King’s College London and colleagues.

“Ammonia plays a pivotal role in the development of hepatic encephalopathy and brain edema in acute liver failure,” the investigators explained in Cellular and Molecular Gastroenterology and Hepatology. “A robust systemic inflammatory response and susceptibility to developing infection are common in acute liver failure, exacerbate the development of ammonia-induced brain edema and are major prognosticators. Experimental models have unequivocally associated ammonia exposure with astrocyte swelling and brain edema, potentiated by proinflammatory cytokines.”

The investigators added that, “although the evidence base supporting the relationship between ammonia, inflammation, and brain edema is robust in acute liver failure, there is a paucity of data characterizing the specific pathogenic mechanisms entailed.” Previous research suggested that TLR9 plays a key role in acetaminophen-induced liver inflammation, they noted, and that ammonia, in combination with DNA, triggers TLR9 expression in neutrophils, which brought TLR9 into focus for the present study.

Along with wild-type mice, the investigators relied upon two knockout models: TLR9–/– mice, in which TLR9 is entirely absent, and LysM-Cre TLR9fl/fl mice, in which TLR9 is absent from lysozyme-expressing cells (predominantly neutrophils and macrophages). Comparing against controls, the investigators assessed cytokine production and brain edema in each type of mouse when intraperitoneally injected with ammonium acetate (4 mmol/kg). Specifically, 6 hours after injection, they measured intracellular cytokines in splenic macrophages, CD8+ T cells, and CD4+ T cells. In addition, they recorded total plasma DNA and brain water, a measure of brain edema.

Following ammonium acetate injection, wild-type mice developed brain edema and liver enlargement, while TLR9–/– mice and control-injected mice did not. After injection, total plasma DNA levels rose by comparable magnitudes in both wild-type mice and TLR9–/– mice, but did not change in control-injected mice, suggesting that ammonium-acetate injection was causing a release of DNA, which was binding with TLR9, resulting in activation of the innate immune system.

This hypothesis was supported by measurements of cytokines in T cells and splenic macrophages, which showed that wild-type mice had elevations of cytokines, whereas knockout mice did not. Further experiments showed that LysM-Cre TLR9fl/fl mice had similar outcomes as TLR9–/– mice, highlighting that macrophages and neutrophils are the key immune cells linking TLR9 activation with cytokine release, and therefore brain edema.

To ensure that brain edema was not directly caused by the acetate component of ammonium acetate, or acetate’s potential to increase pH, a different set of wild-type mice were injected with sodium acetate adjusted to the same pH as ammonium acetate. This had no impact on cytokine production, brain-water content, or liver-to-body weight ratio, confirming that acetate was not responsible for brain edema while providing further support for the role of TLR9.

Finally, the investigators treated wild-type mice immediately after ammonium acetate injection with the TLR9 antagonist ODN2088 (50 mcg/mouse). This treatment halted cytokine production, inflammation, and brain edema, strongly supporting the link between these ammonia-induced processes and TLR9 activation.

“These data are well supported by the findings of Imaeda et al. (J Clin Invest. 2009 Feb 2. doi: 10.1172/JCI35958), who in an acetaminophen-induced hepatotoxicity model established that inhibition of TLR9 using ODN2088 and IRS954, a TLR7/9 antagonist, down-regulated proinflammatory cytokine release and reduced mortality,” the investigators wrote. “The amelioration of brain edema and cytokine production by ODN2088 supports exploration of TLR9 antagonism as a therapeutic modality in early acute liver failure to prevent the development of brain edema and intracranial hypertension.”

The study was funded by the U.K. Institute of Liver Studies Charitable Fund and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Vijay GKM et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 8. doi: 10.1016/j.jcmgh.2019.08.002.

A toll-like receptor 9 (TLR9) antagonist may eventually be used to combat brain edema in acute liver failure, according to investigators.

This prediction is based on results of a recent study involving mouse models, which showed that ODN2088, a TLR9 antagonist, could stop ammonia-induced colocalization of DNA with TLR9 in innate immune cells, thereby blocking cytokine production and ensuant brain edema, reported lead author Godhev Kumar Manakkat Vijay of King’s College London and colleagues.

“Ammonia plays a pivotal role in the development of hepatic encephalopathy and brain edema in acute liver failure,” the investigators explained in Cellular and Molecular Gastroenterology and Hepatology. “A robust systemic inflammatory response and susceptibility to developing infection are common in acute liver failure, exacerbate the development of ammonia-induced brain edema and are major prognosticators. Experimental models have unequivocally associated ammonia exposure with astrocyte swelling and brain edema, potentiated by proinflammatory cytokines.”

The investigators added that, “although the evidence base supporting the relationship between ammonia, inflammation, and brain edema is robust in acute liver failure, there is a paucity of data characterizing the specific pathogenic mechanisms entailed.” Previous research suggested that TLR9 plays a key role in acetaminophen-induced liver inflammation, they noted, and that ammonia, in combination with DNA, triggers TLR9 expression in neutrophils, which brought TLR9 into focus for the present study.

Along with wild-type mice, the investigators relied upon two knockout models: TLR9–/– mice, in which TLR9 is entirely absent, and LysM-Cre TLR9fl/fl mice, in which TLR9 is absent from lysozyme-expressing cells (predominantly neutrophils and macrophages). Comparing against controls, the investigators assessed cytokine production and brain edema in each type of mouse when intraperitoneally injected with ammonium acetate (4 mmol/kg). Specifically, 6 hours after injection, they measured intracellular cytokines in splenic macrophages, CD8+ T cells, and CD4+ T cells. In addition, they recorded total plasma DNA and brain water, a measure of brain edema.

Following ammonium acetate injection, wild-type mice developed brain edema and liver enlargement, while TLR9–/– mice and control-injected mice did not. After injection, total plasma DNA levels rose by comparable magnitudes in both wild-type mice and TLR9–/– mice, but did not change in control-injected mice, suggesting that ammonium-acetate injection was causing a release of DNA, which was binding with TLR9, resulting in activation of the innate immune system.

This hypothesis was supported by measurements of cytokines in T cells and splenic macrophages, which showed that wild-type mice had elevations of cytokines, whereas knockout mice did not. Further experiments showed that LysM-Cre TLR9fl/fl mice had similar outcomes as TLR9–/– mice, highlighting that macrophages and neutrophils are the key immune cells linking TLR9 activation with cytokine release, and therefore brain edema.

To ensure that brain edema was not directly caused by the acetate component of ammonium acetate, or acetate’s potential to increase pH, a different set of wild-type mice were injected with sodium acetate adjusted to the same pH as ammonium acetate. This had no impact on cytokine production, brain-water content, or liver-to-body weight ratio, confirming that acetate was not responsible for brain edema while providing further support for the role of TLR9.

Finally, the investigators treated wild-type mice immediately after ammonium acetate injection with the TLR9 antagonist ODN2088 (50 mcg/mouse). This treatment halted cytokine production, inflammation, and brain edema, strongly supporting the link between these ammonia-induced processes and TLR9 activation.

“These data are well supported by the findings of Imaeda et al. (J Clin Invest. 2009 Feb 2. doi: 10.1172/JCI35958), who in an acetaminophen-induced hepatotoxicity model established that inhibition of TLR9 using ODN2088 and IRS954, a TLR7/9 antagonist, down-regulated proinflammatory cytokine release and reduced mortality,” the investigators wrote. “The amelioration of brain edema and cytokine production by ODN2088 supports exploration of TLR9 antagonism as a therapeutic modality in early acute liver failure to prevent the development of brain edema and intracranial hypertension.”

The study was funded by the U.K. Institute of Liver Studies Charitable Fund and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Vijay GKM et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 8. doi: 10.1016/j.jcmgh.2019.08.002.

A toll-like receptor 9 (TLR9) antagonist may eventually be used to combat brain edema in acute liver failure, according to investigators.

This prediction is based on results of a recent study involving mouse models, which showed that ODN2088, a TLR9 antagonist, could stop ammonia-induced colocalization of DNA with TLR9 in innate immune cells, thereby blocking cytokine production and ensuant brain edema, reported lead author Godhev Kumar Manakkat Vijay of King’s College London and colleagues.

“Ammonia plays a pivotal role in the development of hepatic encephalopathy and brain edema in acute liver failure,” the investigators explained in Cellular and Molecular Gastroenterology and Hepatology. “A robust systemic inflammatory response and susceptibility to developing infection are common in acute liver failure, exacerbate the development of ammonia-induced brain edema and are major prognosticators. Experimental models have unequivocally associated ammonia exposure with astrocyte swelling and brain edema, potentiated by proinflammatory cytokines.”

The investigators added that, “although the evidence base supporting the relationship between ammonia, inflammation, and brain edema is robust in acute liver failure, there is a paucity of data characterizing the specific pathogenic mechanisms entailed.” Previous research suggested that TLR9 plays a key role in acetaminophen-induced liver inflammation, they noted, and that ammonia, in combination with DNA, triggers TLR9 expression in neutrophils, which brought TLR9 into focus for the present study.

Along with wild-type mice, the investigators relied upon two knockout models: TLR9–/– mice, in which TLR9 is entirely absent, and LysM-Cre TLR9fl/fl mice, in which TLR9 is absent from lysozyme-expressing cells (predominantly neutrophils and macrophages). Comparing against controls, the investigators assessed cytokine production and brain edema in each type of mouse when intraperitoneally injected with ammonium acetate (4 mmol/kg). Specifically, 6 hours after injection, they measured intracellular cytokines in splenic macrophages, CD8+ T cells, and CD4+ T cells. In addition, they recorded total plasma DNA and brain water, a measure of brain edema.

Following ammonium acetate injection, wild-type mice developed brain edema and liver enlargement, while TLR9–/– mice and control-injected mice did not. After injection, total plasma DNA levels rose by comparable magnitudes in both wild-type mice and TLR9–/– mice, but did not change in control-injected mice, suggesting that ammonium-acetate injection was causing a release of DNA, which was binding with TLR9, resulting in activation of the innate immune system.

This hypothesis was supported by measurements of cytokines in T cells and splenic macrophages, which showed that wild-type mice had elevations of cytokines, whereas knockout mice did not. Further experiments showed that LysM-Cre TLR9fl/fl mice had similar outcomes as TLR9–/– mice, highlighting that macrophages and neutrophils are the key immune cells linking TLR9 activation with cytokine release, and therefore brain edema.

To ensure that brain edema was not directly caused by the acetate component of ammonium acetate, or acetate’s potential to increase pH, a different set of wild-type mice were injected with sodium acetate adjusted to the same pH as ammonium acetate. This had no impact on cytokine production, brain-water content, or liver-to-body weight ratio, confirming that acetate was not responsible for brain edema while providing further support for the role of TLR9.

Finally, the investigators treated wild-type mice immediately after ammonium acetate injection with the TLR9 antagonist ODN2088 (50 mcg/mouse). This treatment halted cytokine production, inflammation, and brain edema, strongly supporting the link between these ammonia-induced processes and TLR9 activation.

“These data are well supported by the findings of Imaeda et al. (J Clin Invest. 2009 Feb 2. doi: 10.1172/JCI35958), who in an acetaminophen-induced hepatotoxicity model established that inhibition of TLR9 using ODN2088 and IRS954, a TLR7/9 antagonist, down-regulated proinflammatory cytokine release and reduced mortality,” the investigators wrote. “The amelioration of brain edema and cytokine production by ODN2088 supports exploration of TLR9 antagonism as a therapeutic modality in early acute liver failure to prevent the development of brain edema and intracranial hypertension.”

The study was funded by the U.K. Institute of Liver Studies Charitable Fund and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Vijay GKM et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 8. doi: 10.1016/j.jcmgh.2019.08.002.

All adult patients with primary sclerosing cholangitis should be screened at least annually for cholangiocarcinoma and gallbladder cancer, particularly in the first year after their diagnosis, according to a clinical practice update published in Clinical Gastroenterology and Hepatology.

Individuals with primary sclerosing cholangitis have a 400-fold higher risk of cholangiocarcinoma, compared with the general population, and around one-third of cancers are detected within 1 year of the cholangitis diagnosis, Christopher L. Bowlus, MD, of the University of California, Davis, and coauthors wrote.

The clinical practice update from the American Gastroenterological Association was in response to the observation that, while there is significant evidence for an increasing incidence of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplant listing among patients with primary sclerosing cholangitis, there is a lack of good evidence to guide cholangiocarcinoma surveillance in these patients.

“The low prevalence and long duration of PSC [primary sclerosing cholangitis] present substantial barriers to better understanding risk stratification, developing biomarkers, and measuring the impact surveillance has on clinical outcomes,” they wrote.

The first recommendation was that surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with primary sclerosing cholangitis, regardless of their disease stage. The authors especially emphasized the importance of surveillance in the first year after a diagnosis of primary sclerosing cholangitis, in patients who also have ulcerative colitis, and in those diagnosed at an older age.

They cited one study that found regular surveillance of patients with primary sclerosing cholangitis was associated with significantly higher 5-year survival rates, compared with those no regular screening (68% vs. 20%; P less than .0061).

In terms of surveillance modalities, the update suggested 6- to 12-monthly imaging of the biliary tree with ultrasound computed tomography, computed tomography, or magnetic resonance imaging – with or without serum carbohydrate antigen 19-9. However the authors wrote that MRI was often preferred to CT because of its superior sensitivity.

They advised against endoscopic retrograde cholangiopancreatography with brush cytology for routine surveillance because of procedural risks. On the other hand, they suggested this procedure, with or without fluorescence in situ hybridization analysis and/or cholangioscopy, could be used for investigation.

“In addition to ERCP [endoscopic retrograde cholangiopancreatography] with brushings, endoscopic ultrasound, intraductal ultrasonography, and cholangioscopy may be used to direct biopsy sampling,” they wrote. Symptoms such as increasing cholestatic biochemistry values, jaundice, fever, right upper quadrant pain, or pruritus should trigger evaluation for cholangiocarcinoma.

However the authors advised “great caution” with the use of fine-needle aspiration of perihilar biliary strictures in liver transplant candidates because of the risk of tumor seeding if the lesion turned out to be cholangiocarcinoma.

On the question of cholangiocarcinoma surveillance in pediatric patients and those with small-duct primary sclerosing cholangitis, the authors wrote that cholangiocarcinoma was so rare in these patients that routine cholangiocarcinoma surveillance was not required.

The clinical update also looked at the prevalence and risk factors for gallbladder cancer, which affects around 2% of individuals with primary sclerosing cholangitis. Two studies found gallbladder polyps in 10%-17% of patients, but the authors noted that “the optimal modality for diagnosis of gallbladder polyps in PSC remains unknown”.

“Because of the high risk of malignancy in gallbladder mass lesions and a 5-year survival rate of 5% to 10% for gallbladder cancer, patients should undergo annual US [ultrasound] screening,” they wrote.

They said the question of whether to perform a cholecystectomy in patients with gallbladder polyps should be guided by the size and growth of the polyps because there is an increased risk of gallbladder cancer in polyps larger than 8 mm and by the clinical status of the patient.

Finally, the update examined the issue of hepatocellular carcinoma in patients with primary sclerosing cholangitis, which – while rare – may increase with the presence of cirrhosis.

The authors advised that patients with primary sclerosing cholangitis and cirrhosis should undergo surveillance for hepatocellular carcinoma every 6 months with ultrasound, CT, or MRI.

“We anticipate that with the development of large patient cohorts, advances in uncovering genetic and other risk factors for cholangiocarcinoma, and development of effective treatments for PSC, further refinement of this practice update will be required.”

Two authors declared consultancies, grants and research contracts with the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Bowlus C et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi 10.1016/j.cgh.2019.07.011.

All adult patients with primary sclerosing cholangitis should be screened at least annually for cholangiocarcinoma and gallbladder cancer, particularly in the first year after their diagnosis, according to a clinical practice update published in Clinical Gastroenterology and Hepatology.

Individuals with primary sclerosing cholangitis have a 400-fold higher risk of cholangiocarcinoma, compared with the general population, and around one-third of cancers are detected within 1 year of the cholangitis diagnosis, Christopher L. Bowlus, MD, of the University of California, Davis, and coauthors wrote.

The clinical practice update from the American Gastroenterological Association was in response to the observation that, while there is significant evidence for an increasing incidence of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplant listing among patients with primary sclerosing cholangitis, there is a lack of good evidence to guide cholangiocarcinoma surveillance in these patients.

“The low prevalence and long duration of PSC [primary sclerosing cholangitis] present substantial barriers to better understanding risk stratification, developing biomarkers, and measuring the impact surveillance has on clinical outcomes,” they wrote.

The first recommendation was that surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with primary sclerosing cholangitis, regardless of their disease stage. The authors especially emphasized the importance of surveillance in the first year after a diagnosis of primary sclerosing cholangitis, in patients who also have ulcerative colitis, and in those diagnosed at an older age.

They cited one study that found regular surveillance of patients with primary sclerosing cholangitis was associated with significantly higher 5-year survival rates, compared with those no regular screening (68% vs. 20%; P less than .0061).

In terms of surveillance modalities, the update suggested 6- to 12-monthly imaging of the biliary tree with ultrasound computed tomography, computed tomography, or magnetic resonance imaging – with or without serum carbohydrate antigen 19-9. However the authors wrote that MRI was often preferred to CT because of its superior sensitivity.

They advised against endoscopic retrograde cholangiopancreatography with brush cytology for routine surveillance because of procedural risks. On the other hand, they suggested this procedure, with or without fluorescence in situ hybridization analysis and/or cholangioscopy, could be used for investigation.

“In addition to ERCP [endoscopic retrograde cholangiopancreatography] with brushings, endoscopic ultrasound, intraductal ultrasonography, and cholangioscopy may be used to direct biopsy sampling,” they wrote. Symptoms such as increasing cholestatic biochemistry values, jaundice, fever, right upper quadrant pain, or pruritus should trigger evaluation for cholangiocarcinoma.

However the authors advised “great caution” with the use of fine-needle aspiration of perihilar biliary strictures in liver transplant candidates because of the risk of tumor seeding if the lesion turned out to be cholangiocarcinoma.

On the question of cholangiocarcinoma surveillance in pediatric patients and those with small-duct primary sclerosing cholangitis, the authors wrote that cholangiocarcinoma was so rare in these patients that routine cholangiocarcinoma surveillance was not required.

The clinical update also looked at the prevalence and risk factors for gallbladder cancer, which affects around 2% of individuals with primary sclerosing cholangitis. Two studies found gallbladder polyps in 10%-17% of patients, but the authors noted that “the optimal modality for diagnosis of gallbladder polyps in PSC remains unknown”.

“Because of the high risk of malignancy in gallbladder mass lesions and a 5-year survival rate of 5% to 10% for gallbladder cancer, patients should undergo annual US [ultrasound] screening,” they wrote.

They said the question of whether to perform a cholecystectomy in patients with gallbladder polyps should be guided by the size and growth of the polyps because there is an increased risk of gallbladder cancer in polyps larger than 8 mm and by the clinical status of the patient.

Finally, the update examined the issue of hepatocellular carcinoma in patients with primary sclerosing cholangitis, which – while rare – may increase with the presence of cirrhosis.

The authors advised that patients with primary sclerosing cholangitis and cirrhosis should undergo surveillance for hepatocellular carcinoma every 6 months with ultrasound, CT, or MRI.

“We anticipate that with the development of large patient cohorts, advances in uncovering genetic and other risk factors for cholangiocarcinoma, and development of effective treatments for PSC, further refinement of this practice update will be required.”

Two authors declared consultancies, grants and research contracts with the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Bowlus C et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi 10.1016/j.cgh.2019.07.011.

All adult patients with primary sclerosing cholangitis should be screened at least annually for cholangiocarcinoma and gallbladder cancer, particularly in the first year after their diagnosis, according to a clinical practice update published in Clinical Gastroenterology and Hepatology.

Individuals with primary sclerosing cholangitis have a 400-fold higher risk of cholangiocarcinoma, compared with the general population, and around one-third of cancers are detected within 1 year of the cholangitis diagnosis, Christopher L. Bowlus, MD, of the University of California, Davis, and coauthors wrote.

The clinical practice update from the American Gastroenterological Association was in response to the observation that, while there is significant evidence for an increasing incidence of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplant listing among patients with primary sclerosing cholangitis, there is a lack of good evidence to guide cholangiocarcinoma surveillance in these patients.

“The low prevalence and long duration of PSC [primary sclerosing cholangitis] present substantial barriers to better understanding risk stratification, developing biomarkers, and measuring the impact surveillance has on clinical outcomes,” they wrote.

The first recommendation was that surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with primary sclerosing cholangitis, regardless of their disease stage. The authors especially emphasized the importance of surveillance in the first year after a diagnosis of primary sclerosing cholangitis, in patients who also have ulcerative colitis, and in those diagnosed at an older age.

They cited one study that found regular surveillance of patients with primary sclerosing cholangitis was associated with significantly higher 5-year survival rates, compared with those no regular screening (68% vs. 20%; P less than .0061).

In terms of surveillance modalities, the update suggested 6- to 12-monthly imaging of the biliary tree with ultrasound computed tomography, computed tomography, or magnetic resonance imaging – with or without serum carbohydrate antigen 19-9. However the authors wrote that MRI was often preferred to CT because of its superior sensitivity.

They advised against endoscopic retrograde cholangiopancreatography with brush cytology for routine surveillance because of procedural risks. On the other hand, they suggested this procedure, with or without fluorescence in situ hybridization analysis and/or cholangioscopy, could be used for investigation.

“In addition to ERCP [endoscopic retrograde cholangiopancreatography] with brushings, endoscopic ultrasound, intraductal ultrasonography, and cholangioscopy may be used to direct biopsy sampling,” they wrote. Symptoms such as increasing cholestatic biochemistry values, jaundice, fever, right upper quadrant pain, or pruritus should trigger evaluation for cholangiocarcinoma.

However the authors advised “great caution” with the use of fine-needle aspiration of perihilar biliary strictures in liver transplant candidates because of the risk of tumor seeding if the lesion turned out to be cholangiocarcinoma.

On the question of cholangiocarcinoma surveillance in pediatric patients and those with small-duct primary sclerosing cholangitis, the authors wrote that cholangiocarcinoma was so rare in these patients that routine cholangiocarcinoma surveillance was not required.

The clinical update also looked at the prevalence and risk factors for gallbladder cancer, which affects around 2% of individuals with primary sclerosing cholangitis. Two studies found gallbladder polyps in 10%-17% of patients, but the authors noted that “the optimal modality for diagnosis of gallbladder polyps in PSC remains unknown”.

“Because of the high risk of malignancy in gallbladder mass lesions and a 5-year survival rate of 5% to 10% for gallbladder cancer, patients should undergo annual US [ultrasound] screening,” they wrote.

They said the question of whether to perform a cholecystectomy in patients with gallbladder polyps should be guided by the size and growth of the polyps because there is an increased risk of gallbladder cancer in polyps larger than 8 mm and by the clinical status of the patient.

Finally, the update examined the issue of hepatocellular carcinoma in patients with primary sclerosing cholangitis, which – while rare – may increase with the presence of cirrhosis.

The authors advised that patients with primary sclerosing cholangitis and cirrhosis should undergo surveillance for hepatocellular carcinoma every 6 months with ultrasound, CT, or MRI.

“We anticipate that with the development of large patient cohorts, advances in uncovering genetic and other risk factors for cholangiocarcinoma, and development of effective treatments for PSC, further refinement of this practice update will be required.”

Two authors declared consultancies, grants and research contracts with the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Bowlus C et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi 10.1016/j.cgh.2019.07.011.

Molecular pathways linked with CD44 variant 9 (CD44v9), a cell surface glycoprotein tied to aggressive gastric cancer after Helicobacter pylori infection, may open doors to stop cancer before it starts, according to two recent studies.

Findings from the first study suggest that persistent inflammation after eradication therapy may continue to drive cancer risk after infection, while the second study revealed a potential therapeutic target related to preneoplastic changes.

The first study, conducted by lead author Hitoshi Tsugawa, PhD, of Keio University, Tokyo, and colleagues, aimed to determine the origin of CD44v9-positive cancer stem-like cells.

“These cells strongly contribute to the development and recurrence of gastric cancer,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology. “However, the origin of CD44v9-positive cells is uncertain.”

The association between H. pylori infection and gastric cancer has been documented, along with a high risk of cancer when gastric epithelial cells overexpress capping actin protein of muscle Z-line alpha subunit 1 (CAPZA1), the researchers noted. Although it has also been shown that CAPZA1 overexpression leads to intracellular accumulations of the H. pylori–derived oncoprotein cytotoxin-associated gene A (CagA), just how these phenomena were connected remained unknown.

Through in vitro analyses of human cells, and in vitro and in vivo experiments involving Mongolian gerbils, the investigators uncovered a chain of events between H. pylori infection and CD44v9 expression. First, the investigators showed that expression levels of CD44v9 and CAPZA1 were directly correlated in five human cases of gastric cancer. Next, several experiments revealed that H. pylori–related oxidative stress drives overexpression of CAPZA1, which, in combination with high levels of beta-catenin, ESRP1, and CagA, promotes expression of CD44v9.

Most directly relevant to future therapies, the investigators compared levels of CAPZA1 between five active cases of H. pylori infection versus five cases successfully treated with eradication therapy. After eradication therapy, CAPZA1 overexpression decreased, but not to a significant degree.

“Our findings suggest that CAPZA1-overexpressing cells remaining in the gastric mucosa after eradication therapy increase the risk of metachronous gastric cancer and that reduction of CAPZA1 expression by amelioration of chronic inflammation after eradication therapy is important to prevent the development of gastric cancer,” the investigators concluded.

The second study, by lead author Anne R. Meyer, a graduate student at Vanderbilt University, Nashville, Tenn., and colleagues, evaluated how zymogenic chief cells are reprogrammed into spasmolytic polypeptide-expressing metaplasia (SPEM), a precursor to dysplasia and gastric cancer.

It had been previously shown that reprogramming to SPEM is promoted and maintained by epithelial cell damage, such as that caused by H. pylori infection, but underlying processes remained unclear, until recent studies suggested a link between SPEM transition and upregulation of CD44v9. Knowing that CD44v9 stabilizes the cystine/glutamate antiporter xCT, the investigators homed in on xCT for a closer look, questioning what role it had in chief cell reprogramming. Again, oxidative stress was identified as the inciting pathophysiologic driver.

“The oxidative stress response, including upregulation of nutrient transporters, plays an important role in many biological processes and the pathogenesis of a variety of diseases,” the investigators wrote in their report, published in Cellular and Molecular Gastroenterology and Hepatology. “Perturbations to the CD44v9-xCT system often result in redox imbalance.”

Using a combination of mouse and human cell lines, and a mouse model, the investigators demonstrated that xCT was upregulated during the initial stages of chief cell programming. Blocking xCT with sulfasalazine after acute gastric injury limited SPEM transition by more than 80%, an effect that was further supported by xCT siRNA knockdown and observations in xCT knockout mice. Reduction in chief cell reprogramming was not observed in the presence of sulfasalazine metabolites, suggesting that the anti-inflammatory properties of sulfasalazine were not responsible for downregulation of reprogramming.

“Targeting xCT may prove an effective tool for arresting metaplasia development in the stomach as well as mucous metaplasia in other epithelial tissues for the analysis of cellular plasticity and oxidative stress response,” the investigators concluded.

The study by Tsugawa and colleagues was funded by Grants-in-Aid for Scientific Research; the Yakult Bio-Science Foundation; the Ministry of Education, Culture, Sports, Science and Technology (MEXT)-supported program for the Strategic Research Foundation at Private Universities; and Keio Gijuku Academic Development Funds. Dr. Suzuki disclosed relationships with Daiichi-Sankyo Co, EA Pharma Co, Otsuka Pharmaceutical Co Ltd, and others. The study by Meyer and colleagues was funded by the National Institutes of Health, the American Association of Cancer Research, the Department of Defense, and others, with no relevant conflicts of interest.

SOURCES: Meyer et al. CMGH. 2019 May 6. doi: 10.1016/j.jcmgh.2019.04.015; Tsugawa et al. CMGH. 2019 May 27. doi: 10.1016/j.jcmgh.2019.05.008.

Molecular pathways linked with CD44 variant 9 (CD44v9), a cell surface glycoprotein tied to aggressive gastric cancer after Helicobacter pylori infection, may open doors to stop cancer before it starts, according to two recent studies.

Findings from the first study suggest that persistent inflammation after eradication therapy may continue to drive cancer risk after infection, while the second study revealed a potential therapeutic target related to preneoplastic changes.

The first study, conducted by lead author Hitoshi Tsugawa, PhD, of Keio University, Tokyo, and colleagues, aimed to determine the origin of CD44v9-positive cancer stem-like cells.

“These cells strongly contribute to the development and recurrence of gastric cancer,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology. “However, the origin of CD44v9-positive cells is uncertain.”

The association between H. pylori infection and gastric cancer has been documented, along with a high risk of cancer when gastric epithelial cells overexpress capping actin protein of muscle Z-line alpha subunit 1 (CAPZA1), the researchers noted. Although it has also been shown that CAPZA1 overexpression leads to intracellular accumulations of the H. pylori–derived oncoprotein cytotoxin-associated gene A (CagA), just how these phenomena were connected remained unknown.

Through in vitro analyses of human cells, and in vitro and in vivo experiments involving Mongolian gerbils, the investigators uncovered a chain of events between H. pylori infection and CD44v9 expression. First, the investigators showed that expression levels of CD44v9 and CAPZA1 were directly correlated in five human cases of gastric cancer. Next, several experiments revealed that H. pylori–related oxidative stress drives overexpression of CAPZA1, which, in combination with high levels of beta-catenin, ESRP1, and CagA, promotes expression of CD44v9.

Most directly relevant to future therapies, the investigators compared levels of CAPZA1 between five active cases of H. pylori infection versus five cases successfully treated with eradication therapy. After eradication therapy, CAPZA1 overexpression decreased, but not to a significant degree.

“Our findings suggest that CAPZA1-overexpressing cells remaining in the gastric mucosa after eradication therapy increase the risk of metachronous gastric cancer and that reduction of CAPZA1 expression by amelioration of chronic inflammation after eradication therapy is important to prevent the development of gastric cancer,” the investigators concluded.

The second study, by lead author Anne R. Meyer, a graduate student at Vanderbilt University, Nashville, Tenn., and colleagues, evaluated how zymogenic chief cells are reprogrammed into spasmolytic polypeptide-expressing metaplasia (SPEM), a precursor to dysplasia and gastric cancer.

It had been previously shown that reprogramming to SPEM is promoted and maintained by epithelial cell damage, such as that caused by H. pylori infection, but underlying processes remained unclear, until recent studies suggested a link between SPEM transition and upregulation of CD44v9. Knowing that CD44v9 stabilizes the cystine/glutamate antiporter xCT, the investigators homed in on xCT for a closer look, questioning what role it had in chief cell reprogramming. Again, oxidative stress was identified as the inciting pathophysiologic driver.

“The oxidative stress response, including upregulation of nutrient transporters, plays an important role in many biological processes and the pathogenesis of a variety of diseases,” the investigators wrote in their report, published in Cellular and Molecular Gastroenterology and Hepatology. “Perturbations to the CD44v9-xCT system often result in redox imbalance.”

Using a combination of mouse and human cell lines, and a mouse model, the investigators demonstrated that xCT was upregulated during the initial stages of chief cell programming. Blocking xCT with sulfasalazine after acute gastric injury limited SPEM transition by more than 80%, an effect that was further supported by xCT siRNA knockdown and observations in xCT knockout mice. Reduction in chief cell reprogramming was not observed in the presence of sulfasalazine metabolites, suggesting that the anti-inflammatory properties of sulfasalazine were not responsible for downregulation of reprogramming.

“Targeting xCT may prove an effective tool for arresting metaplasia development in the stomach as well as mucous metaplasia in other epithelial tissues for the analysis of cellular plasticity and oxidative stress response,” the investigators concluded.

The study by Tsugawa and colleagues was funded by Grants-in-Aid for Scientific Research; the Yakult Bio-Science Foundation; the Ministry of Education, Culture, Sports, Science and Technology (MEXT)-supported program for the Strategic Research Foundation at Private Universities; and Keio Gijuku Academic Development Funds. Dr. Suzuki disclosed relationships with Daiichi-Sankyo Co, EA Pharma Co, Otsuka Pharmaceutical Co Ltd, and others. The study by Meyer and colleagues was funded by the National Institutes of Health, the American Association of Cancer Research, the Department of Defense, and others, with no relevant conflicts of interest.

SOURCES: Meyer et al. CMGH. 2019 May 6. doi: 10.1016/j.jcmgh.2019.04.015; Tsugawa et al. CMGH. 2019 May 27. doi: 10.1016/j.jcmgh.2019.05.008.

Molecular pathways linked with CD44 variant 9 (CD44v9), a cell surface glycoprotein tied to aggressive gastric cancer after Helicobacter pylori infection, may open doors to stop cancer before it starts, according to two recent studies.

Findings from the first study suggest that persistent inflammation after eradication therapy may continue to drive cancer risk after infection, while the second study revealed a potential therapeutic target related to preneoplastic changes.

The first study, conducted by lead author Hitoshi Tsugawa, PhD, of Keio University, Tokyo, and colleagues, aimed to determine the origin of CD44v9-positive cancer stem-like cells.

“These cells strongly contribute to the development and recurrence of gastric cancer,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology. “However, the origin of CD44v9-positive cells is uncertain.”

The association between H. pylori infection and gastric cancer has been documented, along with a high risk of cancer when gastric epithelial cells overexpress capping actin protein of muscle Z-line alpha subunit 1 (CAPZA1), the researchers noted. Although it has also been shown that CAPZA1 overexpression leads to intracellular accumulations of the H. pylori–derived oncoprotein cytotoxin-associated gene A (CagA), just how these phenomena were connected remained unknown.

Through in vitro analyses of human cells, and in vitro and in vivo experiments involving Mongolian gerbils, the investigators uncovered a chain of events between H. pylori infection and CD44v9 expression. First, the investigators showed that expression levels of CD44v9 and CAPZA1 were directly correlated in five human cases of gastric cancer. Next, several experiments revealed that H. pylori–related oxidative stress drives overexpression of CAPZA1, which, in combination with high levels of beta-catenin, ESRP1, and CagA, promotes expression of CD44v9.

Most directly relevant to future therapies, the investigators compared levels of CAPZA1 between five active cases of H. pylori infection versus five cases successfully treated with eradication therapy. After eradication therapy, CAPZA1 overexpression decreased, but not to a significant degree.

“Our findings suggest that CAPZA1-overexpressing cells remaining in the gastric mucosa after eradication therapy increase the risk of metachronous gastric cancer and that reduction of CAPZA1 expression by amelioration of chronic inflammation after eradication therapy is important to prevent the development of gastric cancer,” the investigators concluded.

The second study, by lead author Anne R. Meyer, a graduate student at Vanderbilt University, Nashville, Tenn., and colleagues, evaluated how zymogenic chief cells are reprogrammed into spasmolytic polypeptide-expressing metaplasia (SPEM), a precursor to dysplasia and gastric cancer.

It had been previously shown that reprogramming to SPEM is promoted and maintained by epithelial cell damage, such as that caused by H. pylori infection, but underlying processes remained unclear, until recent studies suggested a link between SPEM transition and upregulation of CD44v9. Knowing that CD44v9 stabilizes the cystine/glutamate antiporter xCT, the investigators homed in on xCT for a closer look, questioning what role it had in chief cell reprogramming. Again, oxidative stress was identified as the inciting pathophysiologic driver.

“The oxidative stress response, including upregulation of nutrient transporters, plays an important role in many biological processes and the pathogenesis of a variety of diseases,” the investigators wrote in their report, published in Cellular and Molecular Gastroenterology and Hepatology. “Perturbations to the CD44v9-xCT system often result in redox imbalance.”

Using a combination of mouse and human cell lines, and a mouse model, the investigators demonstrated that xCT was upregulated during the initial stages of chief cell programming. Blocking xCT with sulfasalazine after acute gastric injury limited SPEM transition by more than 80%, an effect that was further supported by xCT siRNA knockdown and observations in xCT knockout mice. Reduction in chief cell reprogramming was not observed in the presence of sulfasalazine metabolites, suggesting that the anti-inflammatory properties of sulfasalazine were not responsible for downregulation of reprogramming.

“Targeting xCT may prove an effective tool for arresting metaplasia development in the stomach as well as mucous metaplasia in other epithelial tissues for the analysis of cellular plasticity and oxidative stress response,” the investigators concluded.

The study by Tsugawa and colleagues was funded by Grants-in-Aid for Scientific Research; the Yakult Bio-Science Foundation; the Ministry of Education, Culture, Sports, Science and Technology (MEXT)-supported program for the Strategic Research Foundation at Private Universities; and Keio Gijuku Academic Development Funds. Dr. Suzuki disclosed relationships with Daiichi-Sankyo Co, EA Pharma Co, Otsuka Pharmaceutical Co Ltd, and others. The study by Meyer and colleagues was funded by the National Institutes of Health, the American Association of Cancer Research, the Department of Defense, and others, with no relevant conflicts of interest.

SOURCES: Meyer et al. CMGH. 2019 May 6. doi: 10.1016/j.jcmgh.2019.04.015; Tsugawa et al. CMGH. 2019 May 27. doi: 10.1016/j.jcmgh.2019.05.008.

At least 50% of patients with irritable bowel syndrome (IBS) described their condition as “extremely bothersome” based on survey data from 3,254 individuals. However, differences in the nature of other symptoms among IBS subtypes, namely IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C), have not been well studied, wrote Sarah Ballou, PhD, of Beth Israel Deaconess Medical Center, Boston, and colleagues.

Source: American Gastroenterological Association

In a study published in Clinical Gastroenterology and Hepatology, the researchers reviewed survey results from 1,587 individuals with IBS-D and 1,667 with IBS-C. The average age of the patients was 47 years, 81% were female, and 90% were white.

Approximately 84% of patients with IBS-C and 93% of those with IBS-D reported abdominal pain, the most common symptom in both groups. Overall, 36% of the 1,885 patients employed or in school reported decreased productivity in those settings.

IBS-C patients were significantly more likely to report that their symptoms caused them to avoid sex, feel self-conscious about their bodies, have trouble concentrating, and feel “not like myself,” compared with IBS-D patients (P less than .004 for all).

IBS-D patients were significantly more likely to report that their symptoms caused them to avoid traveling in general, avoid places without bathrooms, avoid leaving the house, and have trouble making plans, compared with IBS-C patients (P less than .004 for all).

The survey also asked respondents what they would give up for 1 month in exchange for 1 month of relief from IBS symptoms. Overall, approximately 60% said they would give up alcohol, 55% said they would give up caffeine, 40% would give up sex, 24.5% would give up their cell phones, and 21.5% would give up the internet, the researchers wrote.

The study findings were limited by several factors, including the absence of survey respondents with mixed-type IBS, the reliance on self-reports, and the potential for recall bias. Also, the study was not designed to assess the impact of other comorbidities and did not include non-IBS controls, the researchers noted.

However, the results suggest that patients with different IBS subtypes struggle differently in areas of daily function, which has implications for treatment, they wrote.

“This study highlights important differences between IBS-C and IBS-D, which could impact the development and refinement of mind-body therapies for IBS, with tailored treatment goals for each IBS subtype. For example, treatment tailored specifically for IBS-D may be more behaviorally focused (e.g., exposure to specific situations outside the home) while treatment for IBS-C may be more cognitively focused (e.g., evaluating self-esteem and beliefs about self and others) in addition to targeting the bowel dysfunction and pain,” they concluded.

The researchers had no financial conflicts to disclose.

SOURCE: Ballou S et al. Clin Gastroenterol Hepatol. 2019 Aug 13. doi: 10.1016/j.cgh.2019.08.016.

At least 50% of patients with irritable bowel syndrome (IBS) described their condition as “extremely bothersome” based on survey data from 3,254 individuals. However, differences in the nature of other symptoms among IBS subtypes, namely IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C), have not been well studied, wrote Sarah Ballou, PhD, of Beth Israel Deaconess Medical Center, Boston, and colleagues.

Source: American Gastroenterological Association

In a study published in Clinical Gastroenterology and Hepatology, the researchers reviewed survey results from 1,587 individuals with IBS-D and 1,667 with IBS-C. The average age of the patients was 47 years, 81% were female, and 90% were white.

Approximately 84% of patients with IBS-C and 93% of those with IBS-D reported abdominal pain, the most common symptom in both groups. Overall, 36% of the 1,885 patients employed or in school reported decreased productivity in those settings.

IBS-C patients were significantly more likely to report that their symptoms caused them to avoid sex, feel self-conscious about their bodies, have trouble concentrating, and feel “not like myself,” compared with IBS-D patients (P less than .004 for all).

IBS-D patients were significantly more likely to report that their symptoms caused them to avoid traveling in general, avoid places without bathrooms, avoid leaving the house, and have trouble making plans, compared with IBS-C patients (P less than .004 for all).

The survey also asked respondents what they would give up for 1 month in exchange for 1 month of relief from IBS symptoms. Overall, approximately 60% said they would give up alcohol, 55% said they would give up caffeine, 40% would give up sex, 24.5% would give up their cell phones, and 21.5% would give up the internet, the researchers wrote.

The study findings were limited by several factors, including the absence of survey respondents with mixed-type IBS, the reliance on self-reports, and the potential for recall bias. Also, the study was not designed to assess the impact of other comorbidities and did not include non-IBS controls, the researchers noted.

However, the results suggest that patients with different IBS subtypes struggle differently in areas of daily function, which has implications for treatment, they wrote.

“This study highlights important differences between IBS-C and IBS-D, which could impact the development and refinement of mind-body therapies for IBS, with tailored treatment goals for each IBS subtype. For example, treatment tailored specifically for IBS-D may be more behaviorally focused (e.g., exposure to specific situations outside the home) while treatment for IBS-C may be more cognitively focused (e.g., evaluating self-esteem and beliefs about self and others) in addition to targeting the bowel dysfunction and pain,” they concluded.

The researchers had no financial conflicts to disclose.

SOURCE: Ballou S et al. Clin Gastroenterol Hepatol. 2019 Aug 13. doi: 10.1016/j.cgh.2019.08.016.

At least 50% of patients with irritable bowel syndrome (IBS) described their condition as “extremely bothersome” based on survey data from 3,254 individuals. However, differences in the nature of other symptoms among IBS subtypes, namely IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C), have not been well studied, wrote Sarah Ballou, PhD, of Beth Israel Deaconess Medical Center, Boston, and colleagues.

Source: American Gastroenterological Association

In a study published in Clinical Gastroenterology and Hepatology, the researchers reviewed survey results from 1,587 individuals with IBS-D and 1,667 with IBS-C. The average age of the patients was 47 years, 81% were female, and 90% were white.

Approximately 84% of patients with IBS-C and 93% of those with IBS-D reported abdominal pain, the most common symptom in both groups. Overall, 36% of the 1,885 patients employed or in school reported decreased productivity in those settings.

IBS-C patients were significantly more likely to report that their symptoms caused them to avoid sex, feel self-conscious about their bodies, have trouble concentrating, and feel “not like myself,” compared with IBS-D patients (P less than .004 for all).

IBS-D patients were significantly more likely to report that their symptoms caused them to avoid traveling in general, avoid places without bathrooms, avoid leaving the house, and have trouble making plans, compared with IBS-C patients (P less than .004 for all).

The survey also asked respondents what they would give up for 1 month in exchange for 1 month of relief from IBS symptoms. Overall, approximately 60% said they would give up alcohol, 55% said they would give up caffeine, 40% would give up sex, 24.5% would give up their cell phones, and 21.5% would give up the internet, the researchers wrote.

The study findings were limited by several factors, including the absence of survey respondents with mixed-type IBS, the reliance on self-reports, and the potential for recall bias. Also, the study was not designed to assess the impact of other comorbidities and did not include non-IBS controls, the researchers noted.

However, the results suggest that patients with different IBS subtypes struggle differently in areas of daily function, which has implications for treatment, they wrote.

“This study highlights important differences between IBS-C and IBS-D, which could impact the development and refinement of mind-body therapies for IBS, with tailored treatment goals for each IBS subtype. For example, treatment tailored specifically for IBS-D may be more behaviorally focused (e.g., exposure to specific situations outside the home) while treatment for IBS-C may be more cognitively focused (e.g., evaluating self-esteem and beliefs about self and others) in addition to targeting the bowel dysfunction and pain,” they concluded.

The researchers had no financial conflicts to disclose.

SOURCE: Ballou S et al. Clin Gastroenterol Hepatol. 2019 Aug 13. doi: 10.1016/j.cgh.2019.08.016.