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Increased death rate with platelets for aspirin/clopidogrel GI bleed
Patients with normal platelet counts who have a GI bleed while on antiplatelets were almost six times more likely to die in the hospital if they had a platelet transfusion in a retrospective cohort study from the Yale University in New Haven, Conn.
Ten of the 14 deaths in the 204 transfused patients – versus none of the 3 deaths in the 204 nontransfused patients - were due to bleeding, so it’s possible that the mortality difference was simply because patients with worse bleeding were more likely to get transfused. “On the other hand, the adjusted [odds ratios] for mortality (4.5-6.8 with different sensitivity analyses) [were] large, increasing the likelihood of a cause-and-effect relationship,” said investigators led by gastroenterologist Liam Zakko, MD, now at the Mayo Clinic in Rochester, Minn. (Clin Gastroenterol Hepatol. 2016 Jul 25. doi: 10.1016/j.cgh.2016.07.017).
Current guidelines suggest platelet transfusions are an option for antiplatelet patients with serious GI bleeds, but the Yale team found that they did not reduce rebleeding. “The observation of increased mortality without documentation of clinical benefit suggests a very cautious approach to the use of platelet transfusion. ... We do not support the use of platelet transfusions in patients with GI [bleeds] who are taking antiplatelet agents,” the investigators wrote.
Subjects in the two groups were matched for sex, age, and GI bleed location, and all had platelet counts above 100 × 109/L. Almost everyone was on aspirin for cardiovascular protection, and 30% were on also on clopidogrel.
Just over half in both groups had upper GI bleeds, and about 40% in each group had colonic bleeds. Transfused patients had more-severe bleeding, with overall lower blood pressure and lower hemoglobin; a larger proportion was admitted to the ICU.
On univariate analyses, platelet patients had more cardiovascular events (23% vs. 13%) while in the hospital. They were also more likely to stay in the hospital for more than 4 days (47% vs. 33%) and more likely to die while there (7% vs. 1%). On multivariable analysis, only the greater risk for death during admission remained statistically significant (odds ratio, 5.57; 95% confidence interval, 1.52-27.1). The adjusted odds ratio for recurrent bleeding was not significant.
Four patients in the platelet group died from cardiovascular causes. One patient in the control group had a fatal cardiovascular event.
Although counterintuitive, the authors said that it’s possible that platelet transfusions might actually increase the risk of severe and fatal GI bleeding. “Mechanisms by which platelet transfusion would increase mortality or [GI bleeding]–related mortality are not clear,” but “platelet transfusions are reported to be proinflammatory and alter recipient immunity,” they said.
At least for now, “the most prudent way to manage patients on antiplatelet agents with [GI bleeding] is to follow current evidence-based recommendations,” including early endoscopy, endoscopic hemostatic therapy for high-risk lesions, and intensive proton pump inhibitor therapy in patients with ulcers and high-risk endoscopic features.
“Although not based on high-quality evidence, we believe that hemostatic techniques that do not cause significant tissue damage (e.g., clips rather than thermal devices or sclerosants) should be used in patients on antiplatelet agents, especially if patients are expected to remain on these agents in the future,” they said.
The mean age in the study was 74 years, and about two-thirds of the subjects were men.
The authors had no disclosures.
The management of patients with gastrointestinal bleeding on antithrombotic drugs is a major challenge for gastroenterologists. Unfortunately, the use of aspirin alone has been shown to increase the risk of GI bleed twofold, and the addition of a thienopyridine additionally increases the risk of bleeding twofold. Furthermore, there is no available agent to reverse antiplatelet affects of these drugs, which irreversibly block platelet function for the life of the platelet (8-10 days). Current recommendations for the management of severe GI bleeding in patients receiving antithrombotic therapy include platelet transfusion, including those with a normal platelet count. However, this comes with a price as reversal of platelet function may increase the rate of cardiovascular events.
Zakko et al. performed a retrospective case-control study evaluating the role of platelet transfusion in patients presenting with GI bleeding. Patients were matched by age, sex, and the location of the GI bleed. Most patients included in the study were on low-dose aspirin and almost a third of the patients were taking both aspirin and a thienopyridine. Patients receiving platelet transfusions appeared to have more severe GI bleeding compared with matched controls, as patients receiving transfusion were more likely to have been hypotensive, tachycardic, have a low hemoglobin level, and require treatment in the intensive care unit (72% vs. 28%, P less than .0001). Patients receiving platelet transfusions were also more likely than matched controls to have recurrent GI bleeding as well as major cardiovascular adverse events, including myocardial infarction and inpatient death. After adjusting for patient characteristics, patients receiving platelet transfusions were more likely to have an increased risk of death (adjusted OR, 5.57; 95% CI, 1.52-27.1). The authors conclude that “the use of platelet transfusions in patients with GI bleeding who are taking antiplatelet agents without thrombocytopenia did not reduce rebleeding but was associated with higher mortality.”
Currently, there is no convincing evidence to support platelet transfusion in patients with bleeding on aspirin and/or a thienopyridine. Because the majority of the deaths were due to GI bleeding and not cardiovascular events, the observed increase in adverse events in patients receiving platelet transfusions likely reflects more severe GI bleeding in patients receiving platelet transfusions than in controls. We should avoid platelet transfusions and focus our management on achieving adequate resuscitation, use of proton pump inhibitors for patients with high-risk ulcers, and early endoscopy with endoscopic therapy for high-risk lesions.
John R. Saltzman, MD, AGAF, is director of endoscopy, Brigham and Women’s Hospital, professor of medicine, Harvard Medical School, Boston. He has no conflicts of interest.
The management of patients with gastrointestinal bleeding on antithrombotic drugs is a major challenge for gastroenterologists. Unfortunately, the use of aspirin alone has been shown to increase the risk of GI bleed twofold, and the addition of a thienopyridine additionally increases the risk of bleeding twofold. Furthermore, there is no available agent to reverse antiplatelet affects of these drugs, which irreversibly block platelet function for the life of the platelet (8-10 days). Current recommendations for the management of severe GI bleeding in patients receiving antithrombotic therapy include platelet transfusion, including those with a normal platelet count. However, this comes with a price as reversal of platelet function may increase the rate of cardiovascular events.
Zakko et al. performed a retrospective case-control study evaluating the role of platelet transfusion in patients presenting with GI bleeding. Patients were matched by age, sex, and the location of the GI bleed. Most patients included in the study were on low-dose aspirin and almost a third of the patients were taking both aspirin and a thienopyridine. Patients receiving platelet transfusions appeared to have more severe GI bleeding compared with matched controls, as patients receiving transfusion were more likely to have been hypotensive, tachycardic, have a low hemoglobin level, and require treatment in the intensive care unit (72% vs. 28%, P less than .0001). Patients receiving platelet transfusions were also more likely than matched controls to have recurrent GI bleeding as well as major cardiovascular adverse events, including myocardial infarction and inpatient death. After adjusting for patient characteristics, patients receiving platelet transfusions were more likely to have an increased risk of death (adjusted OR, 5.57; 95% CI, 1.52-27.1). The authors conclude that “the use of platelet transfusions in patients with GI bleeding who are taking antiplatelet agents without thrombocytopenia did not reduce rebleeding but was associated with higher mortality.”
Currently, there is no convincing evidence to support platelet transfusion in patients with bleeding on aspirin and/or a thienopyridine. Because the majority of the deaths were due to GI bleeding and not cardiovascular events, the observed increase in adverse events in patients receiving platelet transfusions likely reflects more severe GI bleeding in patients receiving platelet transfusions than in controls. We should avoid platelet transfusions and focus our management on achieving adequate resuscitation, use of proton pump inhibitors for patients with high-risk ulcers, and early endoscopy with endoscopic therapy for high-risk lesions.
John R. Saltzman, MD, AGAF, is director of endoscopy, Brigham and Women’s Hospital, professor of medicine, Harvard Medical School, Boston. He has no conflicts of interest.
The management of patients with gastrointestinal bleeding on antithrombotic drugs is a major challenge for gastroenterologists. Unfortunately, the use of aspirin alone has been shown to increase the risk of GI bleed twofold, and the addition of a thienopyridine additionally increases the risk of bleeding twofold. Furthermore, there is no available agent to reverse antiplatelet affects of these drugs, which irreversibly block platelet function for the life of the platelet (8-10 days). Current recommendations for the management of severe GI bleeding in patients receiving antithrombotic therapy include platelet transfusion, including those with a normal platelet count. However, this comes with a price as reversal of platelet function may increase the rate of cardiovascular events.
Zakko et al. performed a retrospective case-control study evaluating the role of platelet transfusion in patients presenting with GI bleeding. Patients were matched by age, sex, and the location of the GI bleed. Most patients included in the study were on low-dose aspirin and almost a third of the patients were taking both aspirin and a thienopyridine. Patients receiving platelet transfusions appeared to have more severe GI bleeding compared with matched controls, as patients receiving transfusion were more likely to have been hypotensive, tachycardic, have a low hemoglobin level, and require treatment in the intensive care unit (72% vs. 28%, P less than .0001). Patients receiving platelet transfusions were also more likely than matched controls to have recurrent GI bleeding as well as major cardiovascular adverse events, including myocardial infarction and inpatient death. After adjusting for patient characteristics, patients receiving platelet transfusions were more likely to have an increased risk of death (adjusted OR, 5.57; 95% CI, 1.52-27.1). The authors conclude that “the use of platelet transfusions in patients with GI bleeding who are taking antiplatelet agents without thrombocytopenia did not reduce rebleeding but was associated with higher mortality.”
Currently, there is no convincing evidence to support platelet transfusion in patients with bleeding on aspirin and/or a thienopyridine. Because the majority of the deaths were due to GI bleeding and not cardiovascular events, the observed increase in adverse events in patients receiving platelet transfusions likely reflects more severe GI bleeding in patients receiving platelet transfusions than in controls. We should avoid platelet transfusions and focus our management on achieving adequate resuscitation, use of proton pump inhibitors for patients with high-risk ulcers, and early endoscopy with endoscopic therapy for high-risk lesions.
John R. Saltzman, MD, AGAF, is director of endoscopy, Brigham and Women’s Hospital, professor of medicine, Harvard Medical School, Boston. He has no conflicts of interest.
Patients with normal platelet counts who have a GI bleed while on antiplatelets were almost six times more likely to die in the hospital if they had a platelet transfusion in a retrospective cohort study from the Yale University in New Haven, Conn.
Ten of the 14 deaths in the 204 transfused patients – versus none of the 3 deaths in the 204 nontransfused patients - were due to bleeding, so it’s possible that the mortality difference was simply because patients with worse bleeding were more likely to get transfused. “On the other hand, the adjusted [odds ratios] for mortality (4.5-6.8 with different sensitivity analyses) [were] large, increasing the likelihood of a cause-and-effect relationship,” said investigators led by gastroenterologist Liam Zakko, MD, now at the Mayo Clinic in Rochester, Minn. (Clin Gastroenterol Hepatol. 2016 Jul 25. doi: 10.1016/j.cgh.2016.07.017).
Current guidelines suggest platelet transfusions are an option for antiplatelet patients with serious GI bleeds, but the Yale team found that they did not reduce rebleeding. “The observation of increased mortality without documentation of clinical benefit suggests a very cautious approach to the use of platelet transfusion. ... We do not support the use of platelet transfusions in patients with GI [bleeds] who are taking antiplatelet agents,” the investigators wrote.
Subjects in the two groups were matched for sex, age, and GI bleed location, and all had platelet counts above 100 × 109/L. Almost everyone was on aspirin for cardiovascular protection, and 30% were on also on clopidogrel.
Just over half in both groups had upper GI bleeds, and about 40% in each group had colonic bleeds. Transfused patients had more-severe bleeding, with overall lower blood pressure and lower hemoglobin; a larger proportion was admitted to the ICU.
On univariate analyses, platelet patients had more cardiovascular events (23% vs. 13%) while in the hospital. They were also more likely to stay in the hospital for more than 4 days (47% vs. 33%) and more likely to die while there (7% vs. 1%). On multivariable analysis, only the greater risk for death during admission remained statistically significant (odds ratio, 5.57; 95% confidence interval, 1.52-27.1). The adjusted odds ratio for recurrent bleeding was not significant.
Four patients in the platelet group died from cardiovascular causes. One patient in the control group had a fatal cardiovascular event.
Although counterintuitive, the authors said that it’s possible that platelet transfusions might actually increase the risk of severe and fatal GI bleeding. “Mechanisms by which platelet transfusion would increase mortality or [GI bleeding]–related mortality are not clear,” but “platelet transfusions are reported to be proinflammatory and alter recipient immunity,” they said.
At least for now, “the most prudent way to manage patients on antiplatelet agents with [GI bleeding] is to follow current evidence-based recommendations,” including early endoscopy, endoscopic hemostatic therapy for high-risk lesions, and intensive proton pump inhibitor therapy in patients with ulcers and high-risk endoscopic features.
“Although not based on high-quality evidence, we believe that hemostatic techniques that do not cause significant tissue damage (e.g., clips rather than thermal devices or sclerosants) should be used in patients on antiplatelet agents, especially if patients are expected to remain on these agents in the future,” they said.
The mean age in the study was 74 years, and about two-thirds of the subjects were men.
The authors had no disclosures.
Patients with normal platelet counts who have a GI bleed while on antiplatelets were almost six times more likely to die in the hospital if they had a platelet transfusion in a retrospective cohort study from the Yale University in New Haven, Conn.
Ten of the 14 deaths in the 204 transfused patients – versus none of the 3 deaths in the 204 nontransfused patients - were due to bleeding, so it’s possible that the mortality difference was simply because patients with worse bleeding were more likely to get transfused. “On the other hand, the adjusted [odds ratios] for mortality (4.5-6.8 with different sensitivity analyses) [were] large, increasing the likelihood of a cause-and-effect relationship,” said investigators led by gastroenterologist Liam Zakko, MD, now at the Mayo Clinic in Rochester, Minn. (Clin Gastroenterol Hepatol. 2016 Jul 25. doi: 10.1016/j.cgh.2016.07.017).
Current guidelines suggest platelet transfusions are an option for antiplatelet patients with serious GI bleeds, but the Yale team found that they did not reduce rebleeding. “The observation of increased mortality without documentation of clinical benefit suggests a very cautious approach to the use of platelet transfusion. ... We do not support the use of platelet transfusions in patients with GI [bleeds] who are taking antiplatelet agents,” the investigators wrote.
Subjects in the two groups were matched for sex, age, and GI bleed location, and all had platelet counts above 100 × 109/L. Almost everyone was on aspirin for cardiovascular protection, and 30% were on also on clopidogrel.
Just over half in both groups had upper GI bleeds, and about 40% in each group had colonic bleeds. Transfused patients had more-severe bleeding, with overall lower blood pressure and lower hemoglobin; a larger proportion was admitted to the ICU.
On univariate analyses, platelet patients had more cardiovascular events (23% vs. 13%) while in the hospital. They were also more likely to stay in the hospital for more than 4 days (47% vs. 33%) and more likely to die while there (7% vs. 1%). On multivariable analysis, only the greater risk for death during admission remained statistically significant (odds ratio, 5.57; 95% confidence interval, 1.52-27.1). The adjusted odds ratio for recurrent bleeding was not significant.
Four patients in the platelet group died from cardiovascular causes. One patient in the control group had a fatal cardiovascular event.
Although counterintuitive, the authors said that it’s possible that platelet transfusions might actually increase the risk of severe and fatal GI bleeding. “Mechanisms by which platelet transfusion would increase mortality or [GI bleeding]–related mortality are not clear,” but “platelet transfusions are reported to be proinflammatory and alter recipient immunity,” they said.
At least for now, “the most prudent way to manage patients on antiplatelet agents with [GI bleeding] is to follow current evidence-based recommendations,” including early endoscopy, endoscopic hemostatic therapy for high-risk lesions, and intensive proton pump inhibitor therapy in patients with ulcers and high-risk endoscopic features.
“Although not based on high-quality evidence, we believe that hemostatic techniques that do not cause significant tissue damage (e.g., clips rather than thermal devices or sclerosants) should be used in patients on antiplatelet agents, especially if patients are expected to remain on these agents in the future,” they said.
The mean age in the study was 74 years, and about two-thirds of the subjects were men.
The authors had no disclosures.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point:
Major finding: Compared with those not transfused, the risk for death during admission remained statistically significant on multivariate analysis (OR, 5.57; 95% CI, 1.52-27.1).
Data source: Retrospective cohort study of 408 GI bleed patients
Disclosures: The authors had no disclosures.
Healthy relatives of IBD patients have intestinal dysbiosis
Healthy first-degree relatives of children and adolescents with inflammatory bowel disease had intestinal dysbiosis and an altered intestinal metabolome that correlated with one another and with the disease state, researchers reported in the November issue of Cellular and Molecular Gastroenterology and Hepatology.
These findings suggest the existence of a “high-risk microbiome/metabolome” that may increase susceptibility to inflammatory bowel disease (IBD), Jonathan Jacobs, MD, of the University of California, Los Angeles, reported with his associates. Among the healthy relatives with dysbiosis, nearly one-third also had elevated levels of fecal calprotectin, a marker of intestinal inflammation that has been previously reported in family members of patients with ulcerative colitis, the researchers noted. “If validated, prospective identification of [high-risk individuals] creates the opportunity to prevent disease development by targeting the dysbiosis and/or its metabolic consequences in the intestine,” they wrote.
Participants in the study fell into one of two “operational taxonomic units” based on their microbial communities, the researchers said. The second taxonomic unit not only was associated with IBD, “but irrespective of disease status, had lower microbial diversity and characteristic shifts in microbial composition, including increased Enterobacteriaceae, consistent with dysbiosis.” Among 21 families in the study, 19 had at least one member in this group. Furthermore, tests of an independent pediatric cohort revealed this same taxonomic group characterized by low microbial diversity and associated with IBD.
Participants also fell into two distinct metabotypes, one of which was associated with IBD and had increased levels of bile acids and amino acid derivatives previously linked to Crohn’s disease, as well as elevated levels of taurine, tryptophan, serinyl tryptophan, and adrenic acid, an omega-6 fatty acid, the researchers said. Taxonomic units and metabolic groups correlated highly with one another among both IBD patients and healthy relatives (P = 3 × 10-8), suggesting a “functional relationship between the microbiome and the metabolome,” the investigators said. Additionally, although most healthy relatives had normal fecal calprotectin levels, those in the second operational taxonomic unit had about sixfold greater odds of elevated calprotectin, compared with those in the first group (P = .05).
“The existence of an IBD-associated operational taxonomic unit type and metabotype in healthy relatives suggests that dysbiosis with its associated metabolic products may be a preexisting trait that precedes the acquisition of [inflammatory bowel] disease,” the investigators concluded. “Validating this interpretation will require prospective longitudinal studies to assess the incidence of IBD in individuals stratified by operational taxonomic type, metabotype, and calprotectin, and to assess the stability of operational taxonomic unit types and metabotypes across time and diet.”
The research was supported by the Helmsley Charitable Trust, the Crohn’s and Colitis Foundation of America, the Fineberg Foundation, the United States Public Health Service, the National Institutes of Health, the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, the European Union, and the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics. The investigators had no conflicts of interest.
Numerous studies have established an association between intestinal dysbiosis and inflammatory bowel disease, and data from mouse models of colitis show that IBD-associated microbiota can exacerbate ongoing inflammation. Still, it is not clear that dysbiosis is either necessary or sufficient to trigger IBD – it could be that the microbiome must first be shaped by an inflammatory state on the host’s side before it can achieve a pathogenic signature and contribute to disease. New findings reported here speak to this question by demonstrating the presence of an IBD-like intestinal microbiome signature in a high-risk population, healthy first-degree relatives of IBD patients. The observation of dysbiosis in at-risk but asymptomatic individuals is an important step toward understanding the sequence of disease onset, raising the provocative possibility that, at least in some cases, dysbiosis is a predisease state, and could potentially be an instigator. The key next step will be longitudinal studies testing the predictive power of these findings. If healthy relatives with the IBD-associated microbiome signatures proceed to develop disease at an increased rate versus relatives with normal gut flora, these signatures would have potential clinical utility either as a screening and risk-assessment tool, or possibly as a target for preventative treatment.
Mark R. Frey, PhD, is assistant professor of pediatrics and biochemistry & molecular medicine at the Saban Research Institute at Children’s Hospital Los Angeles, University of Southern California, Los Angeles. He has no conflicts of interest to disclose.
Numerous studies have established an association between intestinal dysbiosis and inflammatory bowel disease, and data from mouse models of colitis show that IBD-associated microbiota can exacerbate ongoing inflammation. Still, it is not clear that dysbiosis is either necessary or sufficient to trigger IBD – it could be that the microbiome must first be shaped by an inflammatory state on the host’s side before it can achieve a pathogenic signature and contribute to disease. New findings reported here speak to this question by demonstrating the presence of an IBD-like intestinal microbiome signature in a high-risk population, healthy first-degree relatives of IBD patients. The observation of dysbiosis in at-risk but asymptomatic individuals is an important step toward understanding the sequence of disease onset, raising the provocative possibility that, at least in some cases, dysbiosis is a predisease state, and could potentially be an instigator. The key next step will be longitudinal studies testing the predictive power of these findings. If healthy relatives with the IBD-associated microbiome signatures proceed to develop disease at an increased rate versus relatives with normal gut flora, these signatures would have potential clinical utility either as a screening and risk-assessment tool, or possibly as a target for preventative treatment.
Mark R. Frey, PhD, is assistant professor of pediatrics and biochemistry & molecular medicine at the Saban Research Institute at Children’s Hospital Los Angeles, University of Southern California, Los Angeles. He has no conflicts of interest to disclose.
Numerous studies have established an association between intestinal dysbiosis and inflammatory bowel disease, and data from mouse models of colitis show that IBD-associated microbiota can exacerbate ongoing inflammation. Still, it is not clear that dysbiosis is either necessary or sufficient to trigger IBD – it could be that the microbiome must first be shaped by an inflammatory state on the host’s side before it can achieve a pathogenic signature and contribute to disease. New findings reported here speak to this question by demonstrating the presence of an IBD-like intestinal microbiome signature in a high-risk population, healthy first-degree relatives of IBD patients. The observation of dysbiosis in at-risk but asymptomatic individuals is an important step toward understanding the sequence of disease onset, raising the provocative possibility that, at least in some cases, dysbiosis is a predisease state, and could potentially be an instigator. The key next step will be longitudinal studies testing the predictive power of these findings. If healthy relatives with the IBD-associated microbiome signatures proceed to develop disease at an increased rate versus relatives with normal gut flora, these signatures would have potential clinical utility either as a screening and risk-assessment tool, or possibly as a target for preventative treatment.
Mark R. Frey, PhD, is assistant professor of pediatrics and biochemistry & molecular medicine at the Saban Research Institute at Children’s Hospital Los Angeles, University of Southern California, Los Angeles. He has no conflicts of interest to disclose.
Healthy first-degree relatives of children and adolescents with inflammatory bowel disease had intestinal dysbiosis and an altered intestinal metabolome that correlated with one another and with the disease state, researchers reported in the November issue of Cellular and Molecular Gastroenterology and Hepatology.
These findings suggest the existence of a “high-risk microbiome/metabolome” that may increase susceptibility to inflammatory bowel disease (IBD), Jonathan Jacobs, MD, of the University of California, Los Angeles, reported with his associates. Among the healthy relatives with dysbiosis, nearly one-third also had elevated levels of fecal calprotectin, a marker of intestinal inflammation that has been previously reported in family members of patients with ulcerative colitis, the researchers noted. “If validated, prospective identification of [high-risk individuals] creates the opportunity to prevent disease development by targeting the dysbiosis and/or its metabolic consequences in the intestine,” they wrote.
Participants in the study fell into one of two “operational taxonomic units” based on their microbial communities, the researchers said. The second taxonomic unit not only was associated with IBD, “but irrespective of disease status, had lower microbial diversity and characteristic shifts in microbial composition, including increased Enterobacteriaceae, consistent with dysbiosis.” Among 21 families in the study, 19 had at least one member in this group. Furthermore, tests of an independent pediatric cohort revealed this same taxonomic group characterized by low microbial diversity and associated with IBD.
Participants also fell into two distinct metabotypes, one of which was associated with IBD and had increased levels of bile acids and amino acid derivatives previously linked to Crohn’s disease, as well as elevated levels of taurine, tryptophan, serinyl tryptophan, and adrenic acid, an omega-6 fatty acid, the researchers said. Taxonomic units and metabolic groups correlated highly with one another among both IBD patients and healthy relatives (P = 3 × 10-8), suggesting a “functional relationship between the microbiome and the metabolome,” the investigators said. Additionally, although most healthy relatives had normal fecal calprotectin levels, those in the second operational taxonomic unit had about sixfold greater odds of elevated calprotectin, compared with those in the first group (P = .05).
“The existence of an IBD-associated operational taxonomic unit type and metabotype in healthy relatives suggests that dysbiosis with its associated metabolic products may be a preexisting trait that precedes the acquisition of [inflammatory bowel] disease,” the investigators concluded. “Validating this interpretation will require prospective longitudinal studies to assess the incidence of IBD in individuals stratified by operational taxonomic type, metabotype, and calprotectin, and to assess the stability of operational taxonomic unit types and metabotypes across time and diet.”
The research was supported by the Helmsley Charitable Trust, the Crohn’s and Colitis Foundation of America, the Fineberg Foundation, the United States Public Health Service, the National Institutes of Health, the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, the European Union, and the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics. The investigators had no conflicts of interest.
Healthy first-degree relatives of children and adolescents with inflammatory bowel disease had intestinal dysbiosis and an altered intestinal metabolome that correlated with one another and with the disease state, researchers reported in the November issue of Cellular and Molecular Gastroenterology and Hepatology.
These findings suggest the existence of a “high-risk microbiome/metabolome” that may increase susceptibility to inflammatory bowel disease (IBD), Jonathan Jacobs, MD, of the University of California, Los Angeles, reported with his associates. Among the healthy relatives with dysbiosis, nearly one-third also had elevated levels of fecal calprotectin, a marker of intestinal inflammation that has been previously reported in family members of patients with ulcerative colitis, the researchers noted. “If validated, prospective identification of [high-risk individuals] creates the opportunity to prevent disease development by targeting the dysbiosis and/or its metabolic consequences in the intestine,” they wrote.
Participants in the study fell into one of two “operational taxonomic units” based on their microbial communities, the researchers said. The second taxonomic unit not only was associated with IBD, “but irrespective of disease status, had lower microbial diversity and characteristic shifts in microbial composition, including increased Enterobacteriaceae, consistent with dysbiosis.” Among 21 families in the study, 19 had at least one member in this group. Furthermore, tests of an independent pediatric cohort revealed this same taxonomic group characterized by low microbial diversity and associated with IBD.
Participants also fell into two distinct metabotypes, one of which was associated with IBD and had increased levels of bile acids and amino acid derivatives previously linked to Crohn’s disease, as well as elevated levels of taurine, tryptophan, serinyl tryptophan, and adrenic acid, an omega-6 fatty acid, the researchers said. Taxonomic units and metabolic groups correlated highly with one another among both IBD patients and healthy relatives (P = 3 × 10-8), suggesting a “functional relationship between the microbiome and the metabolome,” the investigators said. Additionally, although most healthy relatives had normal fecal calprotectin levels, those in the second operational taxonomic unit had about sixfold greater odds of elevated calprotectin, compared with those in the first group (P = .05).
“The existence of an IBD-associated operational taxonomic unit type and metabotype in healthy relatives suggests that dysbiosis with its associated metabolic products may be a preexisting trait that precedes the acquisition of [inflammatory bowel] disease,” the investigators concluded. “Validating this interpretation will require prospective longitudinal studies to assess the incidence of IBD in individuals stratified by operational taxonomic type, metabotype, and calprotectin, and to assess the stability of operational taxonomic unit types and metabotypes across time and diet.”
The research was supported by the Helmsley Charitable Trust, the Crohn’s and Colitis Foundation of America, the Fineberg Foundation, the United States Public Health Service, the National Institutes of Health, the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, the European Union, and the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics. The investigators had no conflicts of interest.
Key clinical point: Healthy first-degree relatives of patients with remitted inflammatory bowel disease can have intestinal dysbiosis and an altered intestinal metabolome that may signify subclinical inflammation or a “pre-IBD” state.
Major finding: Nineteen of 21 families had at least one member whose microbial taxonomy and metabolome correlated with IBD.
Data source: A cross-sectional study of 21 pediatric and adolescent probands with inflammatory bowel disease, nine parents and six siblings with IBD, and 54 healthy first-degree relatives.
Disclosures: The research was supported by the Helmsley Charitable Trust, the Crohn’s and Colitis Foundation of America, the Fineberg Foundation, the United States Public Health Service, the National Institutes of Health, the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, the European Union, and the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics. The investigators had no conflicts of interest.
Interferon-free HCV treatment can lead to herpesvirus reactivation, experts say
Interferon-free direct-acting antiviral (DAA) regimens for chronic hepatitis C virus (HCV) infection can cause reactivation of herpesvirus, said the authors of a multicenter case series published in the November issue of Clinical Gastroenterology and Hepatology.
Reactivation occurred in 10 of 576 (2%) patients treated at three hospitals in Spain, reported Dr. Christie Perello of Puerta de Hierro University Hospital in Madrid, together with her associates. Clinicians who treat HCV should maintain a high degree of clinical suspicion for latent herpesvirus infection, particularly when patients are older or have undergone liver transplantation, and should consider varicella zoster virus vaccination before beginning DAA therapy in nontransplant patients, they said.
In all, 2% of patients had herpesvirus reactivations a median of 8 weeks after starting an interferon-free DAA regimen. Seven patients had cirrhosis, three were liver transplant recipients, and all achieved a sustained viral response. Seven patients were receiving sofosbuvir with ledipasvir, either with or without ribavirin; two patients were receiving ombitasvir with paritaprevir and ritonavir plus dasabuvir, with or without ribavirin; and one patient was receiving sofosbuvir with simeprevir plus ribavirin. Median age was 67 years. Seven cases involved cutaneous herpes, two involved ocular herpes, and one was herpes labialis. Two patients developed postherpetic neuralgia requiring gabapentin or pregabalin therapy, and one developed keratouveitis that was treated with valacyclovir (1 g every 8 hours for 7 days). Two other patients also received valacyclovir, three received famciclovir, and the remaining four received acyclovir. When the study was published, one patient, a 68-year-old male with postherpetic neuralgia, had residual symptoms even after undergoing antiviral therapy and nerve ablation. This patient was a liver transplantee and therefore was immunosuppressed, but like the others, he only developed herpesvirus reactivation after starting DAA HCV treatment, the researcher said.
In contrast, there were no reactivations among historical controls during a median of 37 months of follow-up. “Even when a causal relationship is not definitive, based on the temporal association and recent experience we conclude that the incidence of herpesvirus reactivation may be increased among patients on interferon-free regimens,” the researchers concluded. “More research is necessary in this new field because unexpected events might be arising in patients treated with direct-acting antivirals.”
The investigators did not report funding sources. Dr. Perello had no disclosures. Four coinvestigators reported ties to Gilead, Bristol-Myers Squibb, AbbVie, Merck Sharp & Dohme, and Janssen.
Interferon-free direct-acting antiviral (DAA) regimens for chronic hepatitis C virus (HCV) infection can cause reactivation of herpesvirus, said the authors of a multicenter case series published in the November issue of Clinical Gastroenterology and Hepatology.
Reactivation occurred in 10 of 576 (2%) patients treated at three hospitals in Spain, reported Dr. Christie Perello of Puerta de Hierro University Hospital in Madrid, together with her associates. Clinicians who treat HCV should maintain a high degree of clinical suspicion for latent herpesvirus infection, particularly when patients are older or have undergone liver transplantation, and should consider varicella zoster virus vaccination before beginning DAA therapy in nontransplant patients, they said.
In all, 2% of patients had herpesvirus reactivations a median of 8 weeks after starting an interferon-free DAA regimen. Seven patients had cirrhosis, three were liver transplant recipients, and all achieved a sustained viral response. Seven patients were receiving sofosbuvir with ledipasvir, either with or without ribavirin; two patients were receiving ombitasvir with paritaprevir and ritonavir plus dasabuvir, with or without ribavirin; and one patient was receiving sofosbuvir with simeprevir plus ribavirin. Median age was 67 years. Seven cases involved cutaneous herpes, two involved ocular herpes, and one was herpes labialis. Two patients developed postherpetic neuralgia requiring gabapentin or pregabalin therapy, and one developed keratouveitis that was treated with valacyclovir (1 g every 8 hours for 7 days). Two other patients also received valacyclovir, three received famciclovir, and the remaining four received acyclovir. When the study was published, one patient, a 68-year-old male with postherpetic neuralgia, had residual symptoms even after undergoing antiviral therapy and nerve ablation. This patient was a liver transplantee and therefore was immunosuppressed, but like the others, he only developed herpesvirus reactivation after starting DAA HCV treatment, the researcher said.
In contrast, there were no reactivations among historical controls during a median of 37 months of follow-up. “Even when a causal relationship is not definitive, based on the temporal association and recent experience we conclude that the incidence of herpesvirus reactivation may be increased among patients on interferon-free regimens,” the researchers concluded. “More research is necessary in this new field because unexpected events might be arising in patients treated with direct-acting antivirals.”
The investigators did not report funding sources. Dr. Perello had no disclosures. Four coinvestigators reported ties to Gilead, Bristol-Myers Squibb, AbbVie, Merck Sharp & Dohme, and Janssen.
Interferon-free direct-acting antiviral (DAA) regimens for chronic hepatitis C virus (HCV) infection can cause reactivation of herpesvirus, said the authors of a multicenter case series published in the November issue of Clinical Gastroenterology and Hepatology.
Reactivation occurred in 10 of 576 (2%) patients treated at three hospitals in Spain, reported Dr. Christie Perello of Puerta de Hierro University Hospital in Madrid, together with her associates. Clinicians who treat HCV should maintain a high degree of clinical suspicion for latent herpesvirus infection, particularly when patients are older or have undergone liver transplantation, and should consider varicella zoster virus vaccination before beginning DAA therapy in nontransplant patients, they said.
In all, 2% of patients had herpesvirus reactivations a median of 8 weeks after starting an interferon-free DAA regimen. Seven patients had cirrhosis, three were liver transplant recipients, and all achieved a sustained viral response. Seven patients were receiving sofosbuvir with ledipasvir, either with or without ribavirin; two patients were receiving ombitasvir with paritaprevir and ritonavir plus dasabuvir, with or without ribavirin; and one patient was receiving sofosbuvir with simeprevir plus ribavirin. Median age was 67 years. Seven cases involved cutaneous herpes, two involved ocular herpes, and one was herpes labialis. Two patients developed postherpetic neuralgia requiring gabapentin or pregabalin therapy, and one developed keratouveitis that was treated with valacyclovir (1 g every 8 hours for 7 days). Two other patients also received valacyclovir, three received famciclovir, and the remaining four received acyclovir. When the study was published, one patient, a 68-year-old male with postherpetic neuralgia, had residual symptoms even after undergoing antiviral therapy and nerve ablation. This patient was a liver transplantee and therefore was immunosuppressed, but like the others, he only developed herpesvirus reactivation after starting DAA HCV treatment, the researcher said.
In contrast, there were no reactivations among historical controls during a median of 37 months of follow-up. “Even when a causal relationship is not definitive, based on the temporal association and recent experience we conclude that the incidence of herpesvirus reactivation may be increased among patients on interferon-free regimens,” the researchers concluded. “More research is necessary in this new field because unexpected events might be arising in patients treated with direct-acting antivirals.”
The investigators did not report funding sources. Dr. Perello had no disclosures. Four coinvestigators reported ties to Gilead, Bristol-Myers Squibb, AbbVie, Merck Sharp & Dohme, and Janssen.
Key clinical point: Latent herpesvirus infection may reactivate with interferon-free direct-acting antiviral treatment for chronic hepatitis C virus infection.
Major finding: In all, 2% of recipients of these regimens had herpesvirus reactivation a median of 8 weeks after starting treatment. Historical controls had no documented reactivations.
Data source: A multicenter retrospective study of 576 HCV-infected patients treated with interferon-free DAA regimens and 230 historical matched controls.
Disclosures: The investigators did not report funding sources. Dr. Perello had no disclosures. Four coinvestigators reported ties to Gilead, Bristol-Myers Squibb, AbbVie, Merck Sharp & Dohme, and Janssen.
Study reinforces need to properly examine proximal large bowel during colonoscopy
Interval colorectal cancers were proximally located and had DNA mismatch repair deficiency significantly more often than did colorectal cancers in colonoscopy-naive patients, researchers reported in the November issue of Gastroenterology.
The findings underscore the need to effectively visualize the large colon to avoid missing lesions during colonoscopy, said Elena M. Stoffel, MD, MPH, of the University of Michigan Health System, Ann Arbor, and her associates. “Studies consistently show that colonoscopy affords less protection against proximal cancers, and DNA mismatch repair deficiency tumors are more frequent among proximal cancers,” they noted. But the proximal and distal colon also have different embryologic origins and gene expression profiles, “prompting some to suggest that these might be considered as two distinct organs. Whether the precursors of postcolonoscopy colorectal cancers are simply harder to detect or resect endoscopically, or whether their behavior differs on the basis of anatomic location or molecular subtype remains unclear,” they added.
A variety of quality-related factors contribute to the risk of postcolonoscopy or interval colorectal cancer, as do clinical characteristics such as older age at diagnosis, proximal tumor location, family history of colorectal cancer, and previous polypectomy, the investigators noted. To further explore the clinical and molecular correlates of postcolonoscopy tumors, they conducted a cross-sectional study of 10,365 colorectal cancers diagnosed in Denmark between 2007 and 2011 (Gastroenterology. 2016 Jul 18. doi: 10.1053/j.gastro.2016.07.010). A total of 725 (7%) of the colorectal cancers occurred after colonoscopy, the researchers determined. These lesions were significantly more often located in the proximal colon (odds ratio, 2.34; 95% confidence interval, 1.90-2.89) and were more likely to have DNA mismatch repair deficiency (OR, 1.26; 95% CI, 1.00-59) when compared with colorectal cancers diagnosed in patients with no prior colonoscopy. However, they also were significantly less likely to be metastatic at presentation (OR, 0.65; 95% CI, 0.48-0.89). Interval colorectal cancers were particularly likely to be located in the proximal colon and/or to have DNA mismatch repair deficiency when diagnosed 3-6 years after colonoscopy, but the excess burden of these characteristics persisted up to 10 years after colonoscopy, the researchers said.
Molecular analyses of 85 postcolonoscopy colorectal cancers from one hospital indicated that 24% had DNA mismatch repair deficiency. When considering only those tumors diagnosed within 10 years after colonoscopy, 27% had KRAS/NRAS mutations, 19% had BRAF mutations, and 19% had PIK3CA mutations. The 7% of tumors with molecular features of Lynch syndrome all occurred within 10 years after index colonoscopy and accounted for a third of cases of DNA mismatch repair deficiency, reflecting the role of this mutation pathway in Lynch syndrome and its tendency to rapidly progress, the investigators said.
Notably, 38% of colorectal cancers diagnosed within a year after colonoscopy involved an incomplete examination, compared with only 16% of cases diagnosed within 1-10 years after colonoscopy, they also reported. This finding and the clinical and molecular correlates of the interval cancers “supports the popular assumption that many cancers diagnosed soon after colonoscopy result from missed lesions,” they concluded. “However, the heterogeneity in clinical and molecular features of cancers diagnosed at different time intervals suggests postcolonoscopy colorectal cancers are likely multifactorial in their etiology and clinical behavior.”
The study was supported by the Danish Cancer Society, the Lundbeck Foundation, the Novo Nordisk Foundation, the National Institutes of Health, M.D. Anderson Cancer Center, and a University of Texas Frederick Becker Distinguished University Chair in Cancer Research. The investigators had no disclosures.
Interval colorectal cancers were proximally located and had DNA mismatch repair deficiency significantly more often than did colorectal cancers in colonoscopy-naive patients, researchers reported in the November issue of Gastroenterology.
The findings underscore the need to effectively visualize the large colon to avoid missing lesions during colonoscopy, said Elena M. Stoffel, MD, MPH, of the University of Michigan Health System, Ann Arbor, and her associates. “Studies consistently show that colonoscopy affords less protection against proximal cancers, and DNA mismatch repair deficiency tumors are more frequent among proximal cancers,” they noted. But the proximal and distal colon also have different embryologic origins and gene expression profiles, “prompting some to suggest that these might be considered as two distinct organs. Whether the precursors of postcolonoscopy colorectal cancers are simply harder to detect or resect endoscopically, or whether their behavior differs on the basis of anatomic location or molecular subtype remains unclear,” they added.
A variety of quality-related factors contribute to the risk of postcolonoscopy or interval colorectal cancer, as do clinical characteristics such as older age at diagnosis, proximal tumor location, family history of colorectal cancer, and previous polypectomy, the investigators noted. To further explore the clinical and molecular correlates of postcolonoscopy tumors, they conducted a cross-sectional study of 10,365 colorectal cancers diagnosed in Denmark between 2007 and 2011 (Gastroenterology. 2016 Jul 18. doi: 10.1053/j.gastro.2016.07.010). A total of 725 (7%) of the colorectal cancers occurred after colonoscopy, the researchers determined. These lesions were significantly more often located in the proximal colon (odds ratio, 2.34; 95% confidence interval, 1.90-2.89) and were more likely to have DNA mismatch repair deficiency (OR, 1.26; 95% CI, 1.00-59) when compared with colorectal cancers diagnosed in patients with no prior colonoscopy. However, they also were significantly less likely to be metastatic at presentation (OR, 0.65; 95% CI, 0.48-0.89). Interval colorectal cancers were particularly likely to be located in the proximal colon and/or to have DNA mismatch repair deficiency when diagnosed 3-6 years after colonoscopy, but the excess burden of these characteristics persisted up to 10 years after colonoscopy, the researchers said.
Molecular analyses of 85 postcolonoscopy colorectal cancers from one hospital indicated that 24% had DNA mismatch repair deficiency. When considering only those tumors diagnosed within 10 years after colonoscopy, 27% had KRAS/NRAS mutations, 19% had BRAF mutations, and 19% had PIK3CA mutations. The 7% of tumors with molecular features of Lynch syndrome all occurred within 10 years after index colonoscopy and accounted for a third of cases of DNA mismatch repair deficiency, reflecting the role of this mutation pathway in Lynch syndrome and its tendency to rapidly progress, the investigators said.
Notably, 38% of colorectal cancers diagnosed within a year after colonoscopy involved an incomplete examination, compared with only 16% of cases diagnosed within 1-10 years after colonoscopy, they also reported. This finding and the clinical and molecular correlates of the interval cancers “supports the popular assumption that many cancers diagnosed soon after colonoscopy result from missed lesions,” they concluded. “However, the heterogeneity in clinical and molecular features of cancers diagnosed at different time intervals suggests postcolonoscopy colorectal cancers are likely multifactorial in their etiology and clinical behavior.”
The study was supported by the Danish Cancer Society, the Lundbeck Foundation, the Novo Nordisk Foundation, the National Institutes of Health, M.D. Anderson Cancer Center, and a University of Texas Frederick Becker Distinguished University Chair in Cancer Research. The investigators had no disclosures.
Interval colorectal cancers were proximally located and had DNA mismatch repair deficiency significantly more often than did colorectal cancers in colonoscopy-naive patients, researchers reported in the November issue of Gastroenterology.
The findings underscore the need to effectively visualize the large colon to avoid missing lesions during colonoscopy, said Elena M. Stoffel, MD, MPH, of the University of Michigan Health System, Ann Arbor, and her associates. “Studies consistently show that colonoscopy affords less protection against proximal cancers, and DNA mismatch repair deficiency tumors are more frequent among proximal cancers,” they noted. But the proximal and distal colon also have different embryologic origins and gene expression profiles, “prompting some to suggest that these might be considered as two distinct organs. Whether the precursors of postcolonoscopy colorectal cancers are simply harder to detect or resect endoscopically, or whether their behavior differs on the basis of anatomic location or molecular subtype remains unclear,” they added.
A variety of quality-related factors contribute to the risk of postcolonoscopy or interval colorectal cancer, as do clinical characteristics such as older age at diagnosis, proximal tumor location, family history of colorectal cancer, and previous polypectomy, the investigators noted. To further explore the clinical and molecular correlates of postcolonoscopy tumors, they conducted a cross-sectional study of 10,365 colorectal cancers diagnosed in Denmark between 2007 and 2011 (Gastroenterology. 2016 Jul 18. doi: 10.1053/j.gastro.2016.07.010). A total of 725 (7%) of the colorectal cancers occurred after colonoscopy, the researchers determined. These lesions were significantly more often located in the proximal colon (odds ratio, 2.34; 95% confidence interval, 1.90-2.89) and were more likely to have DNA mismatch repair deficiency (OR, 1.26; 95% CI, 1.00-59) when compared with colorectal cancers diagnosed in patients with no prior colonoscopy. However, they also were significantly less likely to be metastatic at presentation (OR, 0.65; 95% CI, 0.48-0.89). Interval colorectal cancers were particularly likely to be located in the proximal colon and/or to have DNA mismatch repair deficiency when diagnosed 3-6 years after colonoscopy, but the excess burden of these characteristics persisted up to 10 years after colonoscopy, the researchers said.
Molecular analyses of 85 postcolonoscopy colorectal cancers from one hospital indicated that 24% had DNA mismatch repair deficiency. When considering only those tumors diagnosed within 10 years after colonoscopy, 27% had KRAS/NRAS mutations, 19% had BRAF mutations, and 19% had PIK3CA mutations. The 7% of tumors with molecular features of Lynch syndrome all occurred within 10 years after index colonoscopy and accounted for a third of cases of DNA mismatch repair deficiency, reflecting the role of this mutation pathway in Lynch syndrome and its tendency to rapidly progress, the investigators said.
Notably, 38% of colorectal cancers diagnosed within a year after colonoscopy involved an incomplete examination, compared with only 16% of cases diagnosed within 1-10 years after colonoscopy, they also reported. This finding and the clinical and molecular correlates of the interval cancers “supports the popular assumption that many cancers diagnosed soon after colonoscopy result from missed lesions,” they concluded. “However, the heterogeneity in clinical and molecular features of cancers diagnosed at different time intervals suggests postcolonoscopy colorectal cancers are likely multifactorial in their etiology and clinical behavior.”
The study was supported by the Danish Cancer Society, the Lundbeck Foundation, the Novo Nordisk Foundation, the National Institutes of Health, M.D. Anderson Cancer Center, and a University of Texas Frederick Becker Distinguished University Chair in Cancer Research. The investigators had no disclosures.
FROM GASTROENTEROLOGY
Key clinical point: A large population-based study reinforced the need to properly examine the proximal large bowel during colonoscopy.
Major finding: Postcolonoscopy colorectal cancers were significantly more likely to be proximal (OR, 2.34) and to have DNA mismatch repair deficiency (OR, 1.26) compared with colorectal cancers diagnosed in patients with no prior colonoscopy.
Data source: A population-based, cross-sectional study of 10,365 newly diagnosed colorectal cancer cases.
Disclosures: The study was supported by the Danish Cancer Society, the Lundbeck Foundation, the Novo Nordisk Foundation, the National Institutes of Health, M.D. Anderson Cancer Center, and a University of Texas Frederick Becker Distinguished University Chair in Cancer Research. The investigators had no disclosures.
VIDEO: Duodenal bulb sampling barely increased celiac yield in low-probability cohort
Separate sampling of the duodenal bulb increased detection of celiac disease by only 0.1% when endoscopy patients had a low pretest probability of celiac disease, according to research published in the November issue of Clinical Gastroenterology and Hepatology.
Duodenal bulb histology did reveal other abnormal findings, such as chronic peptic duodenitis, gastric heterotopia, and Brunner gland hyperplasia, wrote Samantha Stoven, MD, of Mayo Clinic, Rochester, Minn., and her associates. These findings did not seem to impede the identification of celiac disease, but their clinical implications were unclear, the researchers noted.
Most studies of the diagnostic yield of duodenal bulb specimens have been performed in patients with known celiac disease or positive serology. In past studies of these high-probability cohorts, duodenal bulb sampling increased the diagnostic yield of celiac disease anywhere from 1.8% to 18%, but whether and how that finding translates to low-probability cohorts is unclear, the researchers said. Therefore, they retrospectively analyzed data from 679 endoscopy patients who had both duodenal bulb and small bowel biopsies collected at three Mayo Clinic sites in 2011. These sites are “open access,” meaning that patients can be referred for endoscopy without the approval of a gastroenterologist.
The average age of the patients was 50 years, and 63% were female. They were most commonly referred for duodenal biopsy because of chronic dyspepsia (46% of patients), diarrhea (35%), or nausea (17%). Patients with either known celiac disease or positive serology were excluded from the study (Clin Gastroenterol Hepatol. 2016 Mar 7. doi: 10.1016/j.cgh.2016.02.026). A total of 265 patients (39%) had abnormal duodenal histology, which was most often diagnosed as chronic peptic duodenitis, the researchers said. Histologic abnormalities usually involved the duodenal bulb (36% of cases), not the distal duodenum (15%; P less than .0001). However, among the 16 patients (2%) found to have celiac disease, just one patient had disease only in the duodenal bulb. Thus, duodenal bulb sampling increased the diagnostic yield of celiac disease by only 0.1% when considering the overall cohort. The patient with celiac disease limited to the bulb was a 46-year-old female presenting with diarrhea and anemia who had normal serologies but a permissive human leukocyte antigen test. Her duodenal bulb had villous atrophy and more than 25 intraepithelial lymphocytes per 100 epithelial cells, while her distal duodenum was normal.
Among the 85% of patients who had normal distal duodenums, 28% had abnormal bulb histology, most often chronic peptic duodenitis, active chronic peptic duodenitis, or gastric heterotopia, the researchers said. Among the 59% of patients whose celiac serology before endoscopy was truly unknown, only two (0.5%) had histologic changes consistent with celiac disease, which in both cases were located in the distal duodenum.
SOURCE: American Gastroenterological Association
“Individual sampling of the duodenal bulb in patients with either negative or unknown celiac serologic status can be considered in practices where expert gastrointestinal pathologists are present and there is agreement that both samples can be submitted in the same bottle, or there is not a separate charge for the additional container. Further studies may be needed to assess the diagnostic yield of separate bulb biopsies for celiac detection in all comers.”
An American College of Gastroenterology Junior Faculty Development Award helped support the work. Senior author Joseph A. Murray, MD, disclosed ties to Alba Therapeutics, Alvine Pharmaceuticals, AMAG Pharmaceuticals, and several other corporate entities. The remaining authors had no disclosures.
Histologic diagnosis of celiac disease has traditionally relied upon endoscopic biopsies from the second and third portions of the duodenum. However, several recent studies indicate that duodenal bulb biopsies may show changes of celiac disease, despite normal histology in the more distal duodenum.
In their study, Dr. Stoven and her colleagues evaluated the diagnostic utility of endoscopic duodenal bulb biopsy in patients with a low probability for celiac disease. A new diagnosis of celiac disease was made in 16 of their 679 patients (2.4%). Only one patient showed villous atrophy of the duodenal bulb with normal histology of the more distal duodenum. Although a diagnosis of celiac disease was made, the case was atypical not only because distal duodenal biopsies were normal but also because multiple celiac serology tests were negative, raising the possibility of nonceliac villous atrophy. Thus, the added diagnostic yield of duodenal bulb biopsies in this low-risk population was extremely low (0.15% at most).
Ciaran P. Kelly, MD, AGAF, professor of medicine, Harvard Medical School, director Celiac Center, Beth Israel Deaconess Medical Center, Boston, has acted as a scientific adviser to companies including Celimmune, Cour Pharmaceuticals, ImmunogenX, and Takeda; he also acts as principal investigator on a research grant on celiac disease supported by Aptalis.
Histologic diagnosis of celiac disease has traditionally relied upon endoscopic biopsies from the second and third portions of the duodenum. However, several recent studies indicate that duodenal bulb biopsies may show changes of celiac disease, despite normal histology in the more distal duodenum.
In their study, Dr. Stoven and her colleagues evaluated the diagnostic utility of endoscopic duodenal bulb biopsy in patients with a low probability for celiac disease. A new diagnosis of celiac disease was made in 16 of their 679 patients (2.4%). Only one patient showed villous atrophy of the duodenal bulb with normal histology of the more distal duodenum. Although a diagnosis of celiac disease was made, the case was atypical not only because distal duodenal biopsies were normal but also because multiple celiac serology tests were negative, raising the possibility of nonceliac villous atrophy. Thus, the added diagnostic yield of duodenal bulb biopsies in this low-risk population was extremely low (0.15% at most).
Ciaran P. Kelly, MD, AGAF, professor of medicine, Harvard Medical School, director Celiac Center, Beth Israel Deaconess Medical Center, Boston, has acted as a scientific adviser to companies including Celimmune, Cour Pharmaceuticals, ImmunogenX, and Takeda; he also acts as principal investigator on a research grant on celiac disease supported by Aptalis.
Histologic diagnosis of celiac disease has traditionally relied upon endoscopic biopsies from the second and third portions of the duodenum. However, several recent studies indicate that duodenal bulb biopsies may show changes of celiac disease, despite normal histology in the more distal duodenum.
In their study, Dr. Stoven and her colleagues evaluated the diagnostic utility of endoscopic duodenal bulb biopsy in patients with a low probability for celiac disease. A new diagnosis of celiac disease was made in 16 of their 679 patients (2.4%). Only one patient showed villous atrophy of the duodenal bulb with normal histology of the more distal duodenum. Although a diagnosis of celiac disease was made, the case was atypical not only because distal duodenal biopsies were normal but also because multiple celiac serology tests were negative, raising the possibility of nonceliac villous atrophy. Thus, the added diagnostic yield of duodenal bulb biopsies in this low-risk population was extremely low (0.15% at most).
Ciaran P. Kelly, MD, AGAF, professor of medicine, Harvard Medical School, director Celiac Center, Beth Israel Deaconess Medical Center, Boston, has acted as a scientific adviser to companies including Celimmune, Cour Pharmaceuticals, ImmunogenX, and Takeda; he also acts as principal investigator on a research grant on celiac disease supported by Aptalis.
Separate sampling of the duodenal bulb increased detection of celiac disease by only 0.1% when endoscopy patients had a low pretest probability of celiac disease, according to research published in the November issue of Clinical Gastroenterology and Hepatology.
Duodenal bulb histology did reveal other abnormal findings, such as chronic peptic duodenitis, gastric heterotopia, and Brunner gland hyperplasia, wrote Samantha Stoven, MD, of Mayo Clinic, Rochester, Minn., and her associates. These findings did not seem to impede the identification of celiac disease, but their clinical implications were unclear, the researchers noted.
Most studies of the diagnostic yield of duodenal bulb specimens have been performed in patients with known celiac disease or positive serology. In past studies of these high-probability cohorts, duodenal bulb sampling increased the diagnostic yield of celiac disease anywhere from 1.8% to 18%, but whether and how that finding translates to low-probability cohorts is unclear, the researchers said. Therefore, they retrospectively analyzed data from 679 endoscopy patients who had both duodenal bulb and small bowel biopsies collected at three Mayo Clinic sites in 2011. These sites are “open access,” meaning that patients can be referred for endoscopy without the approval of a gastroenterologist.
The average age of the patients was 50 years, and 63% were female. They were most commonly referred for duodenal biopsy because of chronic dyspepsia (46% of patients), diarrhea (35%), or nausea (17%). Patients with either known celiac disease or positive serology were excluded from the study (Clin Gastroenterol Hepatol. 2016 Mar 7. doi: 10.1016/j.cgh.2016.02.026). A total of 265 patients (39%) had abnormal duodenal histology, which was most often diagnosed as chronic peptic duodenitis, the researchers said. Histologic abnormalities usually involved the duodenal bulb (36% of cases), not the distal duodenum (15%; P less than .0001). However, among the 16 patients (2%) found to have celiac disease, just one patient had disease only in the duodenal bulb. Thus, duodenal bulb sampling increased the diagnostic yield of celiac disease by only 0.1% when considering the overall cohort. The patient with celiac disease limited to the bulb was a 46-year-old female presenting with diarrhea and anemia who had normal serologies but a permissive human leukocyte antigen test. Her duodenal bulb had villous atrophy and more than 25 intraepithelial lymphocytes per 100 epithelial cells, while her distal duodenum was normal.
Among the 85% of patients who had normal distal duodenums, 28% had abnormal bulb histology, most often chronic peptic duodenitis, active chronic peptic duodenitis, or gastric heterotopia, the researchers said. Among the 59% of patients whose celiac serology before endoscopy was truly unknown, only two (0.5%) had histologic changes consistent with celiac disease, which in both cases were located in the distal duodenum.
SOURCE: American Gastroenterological Association
“Individual sampling of the duodenal bulb in patients with either negative or unknown celiac serologic status can be considered in practices where expert gastrointestinal pathologists are present and there is agreement that both samples can be submitted in the same bottle, or there is not a separate charge for the additional container. Further studies may be needed to assess the diagnostic yield of separate bulb biopsies for celiac detection in all comers.”
An American College of Gastroenterology Junior Faculty Development Award helped support the work. Senior author Joseph A. Murray, MD, disclosed ties to Alba Therapeutics, Alvine Pharmaceuticals, AMAG Pharmaceuticals, and several other corporate entities. The remaining authors had no disclosures.
Separate sampling of the duodenal bulb increased detection of celiac disease by only 0.1% when endoscopy patients had a low pretest probability of celiac disease, according to research published in the November issue of Clinical Gastroenterology and Hepatology.
Duodenal bulb histology did reveal other abnormal findings, such as chronic peptic duodenitis, gastric heterotopia, and Brunner gland hyperplasia, wrote Samantha Stoven, MD, of Mayo Clinic, Rochester, Minn., and her associates. These findings did not seem to impede the identification of celiac disease, but their clinical implications were unclear, the researchers noted.
Most studies of the diagnostic yield of duodenal bulb specimens have been performed in patients with known celiac disease or positive serology. In past studies of these high-probability cohorts, duodenal bulb sampling increased the diagnostic yield of celiac disease anywhere from 1.8% to 18%, but whether and how that finding translates to low-probability cohorts is unclear, the researchers said. Therefore, they retrospectively analyzed data from 679 endoscopy patients who had both duodenal bulb and small bowel biopsies collected at three Mayo Clinic sites in 2011. These sites are “open access,” meaning that patients can be referred for endoscopy without the approval of a gastroenterologist.
The average age of the patients was 50 years, and 63% were female. They were most commonly referred for duodenal biopsy because of chronic dyspepsia (46% of patients), diarrhea (35%), or nausea (17%). Patients with either known celiac disease or positive serology were excluded from the study (Clin Gastroenterol Hepatol. 2016 Mar 7. doi: 10.1016/j.cgh.2016.02.026). A total of 265 patients (39%) had abnormal duodenal histology, which was most often diagnosed as chronic peptic duodenitis, the researchers said. Histologic abnormalities usually involved the duodenal bulb (36% of cases), not the distal duodenum (15%; P less than .0001). However, among the 16 patients (2%) found to have celiac disease, just one patient had disease only in the duodenal bulb. Thus, duodenal bulb sampling increased the diagnostic yield of celiac disease by only 0.1% when considering the overall cohort. The patient with celiac disease limited to the bulb was a 46-year-old female presenting with diarrhea and anemia who had normal serologies but a permissive human leukocyte antigen test. Her duodenal bulb had villous atrophy and more than 25 intraepithelial lymphocytes per 100 epithelial cells, while her distal duodenum was normal.
Among the 85% of patients who had normal distal duodenums, 28% had abnormal bulb histology, most often chronic peptic duodenitis, active chronic peptic duodenitis, or gastric heterotopia, the researchers said. Among the 59% of patients whose celiac serology before endoscopy was truly unknown, only two (0.5%) had histologic changes consistent with celiac disease, which in both cases were located in the distal duodenum.
SOURCE: American Gastroenterological Association
“Individual sampling of the duodenal bulb in patients with either negative or unknown celiac serologic status can be considered in practices where expert gastrointestinal pathologists are present and there is agreement that both samples can be submitted in the same bottle, or there is not a separate charge for the additional container. Further studies may be needed to assess the diagnostic yield of separate bulb biopsies for celiac detection in all comers.”
An American College of Gastroenterology Junior Faculty Development Award helped support the work. Senior author Joseph A. Murray, MD, disclosed ties to Alba Therapeutics, Alvine Pharmaceuticals, AMAG Pharmaceuticals, and several other corporate entities. The remaining authors had no disclosures.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Separate sampling of the duodenal bulb increased detection of celiac disease by only 0.1% when endoscopy patients had a low pretest probability of celiac disease.
Major finding: One (0.1%) patient had celiac disease limited to the duodenal bulb.
Data source: A multicenter retrospective study of 679 patients without celiac disease or positive serology from whom duodenal bulb and small bowel biopsies were collected during endoscopy.
Disclosures: An American College of Gastroenterology Junior Faculty Development Award helped support the work. Senior author Joseph A. Murray, MD, disclosed ties to Alba Therapeutics, Alvine Pharmaceuticals, AMAG Pharmaceuticals, and several other corporate entities. The remaining authors had no disclosures.
Ombitasvir, paritaprevir, ritonavir, and dasabuvir in CKD patients with HCV
Twelve weeks of ombitasvir, paritaprevir, ritonavir, and dasabuvir (Viekira Pak) achieved sustained viral response in 90% of patients with noncirrhotic chronic hepatitis C virus (HCV) genotype 1 infection and comorbid stage 4 or 5 chronic kidney disease, according to a small, single-arm, industry-sponsored trial reported in the November issue of Gastroenterology.
Adverse effects were usually mild or moderate, and serious adverse effects were considered unrelated to treatment, Paul Pockros, MD, at Scripps Clinic and Scripps Translational Science Institute in La Jolla, Calif., and his associates reported in Gastroenterology. No patients stopped direct-acting antivirals because of adverse effects, although nearly half had to interrupt or discontinue ribavirin because of worsening anemia. “The results of this study are important for hepatologists, gastroenterologists, and infectious disease specialists who are accustomed to treating HCV-infected patients with direct-acting antiviral therapy but who may not yet have seen sufficient data to initiate [it] in patients with end-stage renal disease,” the researchers said. “Nephrologists, who may not be accustomed to treating HCV, should also be aware that treatment options may now be available that can help prevent end-stage sequelae of HCV.”
All patients completed treatment, and 18 (90%) achieved sustained viral response (95% confidence interval, 70%-97%). The most common adverse events were anemia (45% of patients), fatigue (35%), diarrhea (25%), and nausea (25%). Among the two patients who did not achieve sustained viral response, one relapsed and the other died. The relapse occurred in a 49-year-old black man on hemodialysis who took about 91% of his medication doses, compared with about 97% for the rest of the cohort, the investigators said. This patient also had to interrupt ribavirin after his hemoglobin level dropped below 10 g/dL. The death occurred in a 60-year-old male hemodialysis patient who had hypertensive nephropathy and developed hypertensive urgency and cardiomyopathy soon after finishing treatment. His death, although considered unrelated to HCV treatment, underscores the need for close monitoring and collaboration between physicians treating HCV and nephrologists, the researchers said.
Most patients in this study were in stage 5 chronic kidney disease. However, the median baseline hemoglobin level was relatively high at 12 g/dL, implying that these patients would tolerate ribavirin better than would those with more pronounced anemia, the researchers noted. Nonetheless, 9 of 13 patients had to interrupt discontinue ribavirin because of worsening anemia. “Therefore, this study does not provide guidance for chronic kidney disease patients with much lower baseline hemoglobin levels, who might not tolerate even a small decrease,” the investigators cautioned.
AbbVie makes Viekira Pak and sponsored the study. Dr. Pockros disclosed ties to AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Merck.
Twelve weeks of ombitasvir, paritaprevir, ritonavir, and dasabuvir (Viekira Pak) achieved sustained viral response in 90% of patients with noncirrhotic chronic hepatitis C virus (HCV) genotype 1 infection and comorbid stage 4 or 5 chronic kidney disease, according to a small, single-arm, industry-sponsored trial reported in the November issue of Gastroenterology.
Adverse effects were usually mild or moderate, and serious adverse effects were considered unrelated to treatment, Paul Pockros, MD, at Scripps Clinic and Scripps Translational Science Institute in La Jolla, Calif., and his associates reported in Gastroenterology. No patients stopped direct-acting antivirals because of adverse effects, although nearly half had to interrupt or discontinue ribavirin because of worsening anemia. “The results of this study are important for hepatologists, gastroenterologists, and infectious disease specialists who are accustomed to treating HCV-infected patients with direct-acting antiviral therapy but who may not yet have seen sufficient data to initiate [it] in patients with end-stage renal disease,” the researchers said. “Nephrologists, who may not be accustomed to treating HCV, should also be aware that treatment options may now be available that can help prevent end-stage sequelae of HCV.”
All patients completed treatment, and 18 (90%) achieved sustained viral response (95% confidence interval, 70%-97%). The most common adverse events were anemia (45% of patients), fatigue (35%), diarrhea (25%), and nausea (25%). Among the two patients who did not achieve sustained viral response, one relapsed and the other died. The relapse occurred in a 49-year-old black man on hemodialysis who took about 91% of his medication doses, compared with about 97% for the rest of the cohort, the investigators said. This patient also had to interrupt ribavirin after his hemoglobin level dropped below 10 g/dL. The death occurred in a 60-year-old male hemodialysis patient who had hypertensive nephropathy and developed hypertensive urgency and cardiomyopathy soon after finishing treatment. His death, although considered unrelated to HCV treatment, underscores the need for close monitoring and collaboration between physicians treating HCV and nephrologists, the researchers said.
Most patients in this study were in stage 5 chronic kidney disease. However, the median baseline hemoglobin level was relatively high at 12 g/dL, implying that these patients would tolerate ribavirin better than would those with more pronounced anemia, the researchers noted. Nonetheless, 9 of 13 patients had to interrupt discontinue ribavirin because of worsening anemia. “Therefore, this study does not provide guidance for chronic kidney disease patients with much lower baseline hemoglobin levels, who might not tolerate even a small decrease,” the investigators cautioned.
AbbVie makes Viekira Pak and sponsored the study. Dr. Pockros disclosed ties to AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Merck.
Twelve weeks of ombitasvir, paritaprevir, ritonavir, and dasabuvir (Viekira Pak) achieved sustained viral response in 90% of patients with noncirrhotic chronic hepatitis C virus (HCV) genotype 1 infection and comorbid stage 4 or 5 chronic kidney disease, according to a small, single-arm, industry-sponsored trial reported in the November issue of Gastroenterology.
Adverse effects were usually mild or moderate, and serious adverse effects were considered unrelated to treatment, Paul Pockros, MD, at Scripps Clinic and Scripps Translational Science Institute in La Jolla, Calif., and his associates reported in Gastroenterology. No patients stopped direct-acting antivirals because of adverse effects, although nearly half had to interrupt or discontinue ribavirin because of worsening anemia. “The results of this study are important for hepatologists, gastroenterologists, and infectious disease specialists who are accustomed to treating HCV-infected patients with direct-acting antiviral therapy but who may not yet have seen sufficient data to initiate [it] in patients with end-stage renal disease,” the researchers said. “Nephrologists, who may not be accustomed to treating HCV, should also be aware that treatment options may now be available that can help prevent end-stage sequelae of HCV.”
All patients completed treatment, and 18 (90%) achieved sustained viral response (95% confidence interval, 70%-97%). The most common adverse events were anemia (45% of patients), fatigue (35%), diarrhea (25%), and nausea (25%). Among the two patients who did not achieve sustained viral response, one relapsed and the other died. The relapse occurred in a 49-year-old black man on hemodialysis who took about 91% of his medication doses, compared with about 97% for the rest of the cohort, the investigators said. This patient also had to interrupt ribavirin after his hemoglobin level dropped below 10 g/dL. The death occurred in a 60-year-old male hemodialysis patient who had hypertensive nephropathy and developed hypertensive urgency and cardiomyopathy soon after finishing treatment. His death, although considered unrelated to HCV treatment, underscores the need for close monitoring and collaboration between physicians treating HCV and nephrologists, the researchers said.
Most patients in this study were in stage 5 chronic kidney disease. However, the median baseline hemoglobin level was relatively high at 12 g/dL, implying that these patients would tolerate ribavirin better than would those with more pronounced anemia, the researchers noted. Nonetheless, 9 of 13 patients had to interrupt discontinue ribavirin because of worsening anemia. “Therefore, this study does not provide guidance for chronic kidney disease patients with much lower baseline hemoglobin levels, who might not tolerate even a small decrease,” the investigators cautioned.
AbbVie makes Viekira Pak and sponsored the study. Dr. Pockros disclosed ties to AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Merck.
FROM GASTROENTEROLOGY
Key clinical point: Twelve weeks of ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin was relatively well tolerated and cured most genotype 1 chronic hepatitis C virus infections in patients with severe or end-stage renal disease.
Major finding: All patients completed treatment and 18 (90%) achieved sustained viral response. The most common adverse effect was anemia (45% of patients).
Data source: A single-arm, multicenter study of 20 treatment-naive, noncirrhotic adults with HCV genotype 1 infection and stage 4 or 5 chronic kidney disease.
Disclosures: AbbVie makes Viekira Pak and sponsored the study. Dr. Pockros disclosed ties to AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Merck.
Analysis yields ‘strong evidence’ for benefit of physical activity in NAFLD
Regular physical exercise significantly improved measures of nonalcoholic fatty liver disease independently of dietary changes, according to a meta-analysis of randomized controlled* trials published in the October issue of Clinical Gastroenterology and Hepatology.
“On the basis of the current findings, physical activity should be recommended not only in combination with dietary changes but also independently as an effective approach to manage NAFLD,” wrote Lorenzo Orci, MD, and his associates at the University of Geneva. “We propose that the level of evidence surrounding the specific role of physical activity in the management of NAFLD is now sufficient to be awarded a grade of Ia.”
Nonalcoholic fatty liver disease, “the hepatic manifestation of metabolic syndrome,” affects at least one in four U.S. adults and 15%-35% of individuals in Europe, the Middle East, China, and Japan, the researchers noted. Dietary changes are the cornerstone of NAFLD management, and there is less evidence for how physical exercise affects liver fat content. Therefore, the researchers searched MEDLINE, Embase, and the Cochrane databases from inception through October 2015 to find randomized trials of the impact of physical activity on markers of liver steatosis and liver inflammation in patients diagnosed with NAFLD, obesity, type 2 diabetes, or metabolic syndrome. This approach yielded 28 trials with data from more than 1,600 patients. Only two trials were multicenter, 13 required participants to have an NAFLD diagnosis, four focused on type 2 diabetes, and most of the rest included sedentary obese patients without requiring a diagnosis of NAFLD, the researchers said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.036).
After researchers accounted for dietary changes, physical activity led to a significant drop in intrahepatic lipid content with a standardized mean difference of –0.69 compared with controls (95% confidence interval, –0.90 to –0.48; P less than .0001). “Because effect sizes such as standard mean difference [SMD] are difficult to interpret, the translation of such a statistical measure into a clinically relevant notion has been the focus of research for more than a decade,” the investigators added. “A commonly used interpretation was proposed by Cohen, who suggested that SMDs of 0.2, 0.5, and 0.8 correspond to small, moderate, and large effect sizes, respectively. By using this rule of thumb, our results indicate that physical activity exerts a moderate-to-large impact on the reduction of intrahepatic lipid content.”
Exercise reduced liver fat content even more in pediatric patients (SMD, –0.75; 95% CI, –0.1 to –0.5; P less than .0001) and in patients who had been specifically diagnosed with NAFLD (SMD, –0.86; 95% CI, –1.26 to –0.46; P less than .0001). Patients with the highest baseline body mass index also seemed to benefit more than patients with lower baseline BMI (P = .04). Indeed, exercise reduced BMI itself by a weighted mean difference of 0.8 (95% CI, –1.22 to 0.38; P less than .001), the researchers noted. Exercise intensity did not seem to affect the likelihood of benefit. There was a trend toward a greater effect of aerobic over resistance training (P = .06), and few studies examined the effects of combining both types of exercise.
The multivariable analysis also linked physical activity to an average 3.30 IU/L drop in alanine aminotransferase levels (95% CI, –5.57 to –1.04) and to a 4.9 IU/L decrease in aspartate aminotransferase levels (95% CI, –8.68 to –1.02). The investigators were unable to assess the long-term effects of physical exercise, nor its effects on hepatic fibrosis or inflammation, they noted. Nonetheless, the moderate to large effect size “provides strong evidence for the recommendation of physical activity as an effective intervention in the treatment of NAFLD,” they concluded. “Physical activity is also associated with an improvement in blood levels of aminotransferases and is particularly beneficial in patients presenting with severe obesity at baseline.”
The work was funded by the Ligue Genevoise contre le Cancer and the Dr Henri Dubois-Ferrière/Dinu Lipatti Foundation and by the Swiss National Science Foundation. The investigators had no disclosures.
*Content was updated on 10/25/2016
There has been tremendous interest in developing pharmacologic treatments for nonalcoholic steatohepatitis, especially in the Western world. There has not been significant enthusiasm for investigating exercise-based lifestyle modification as a primary treatment for NASH. Although the meta-analysis by Orci et al. included 28 studies, there are only 2 studies (combined, fewer than 100 patients) that examined the effect of exercise on liver histology in NASH and they both suggest that lifestyle modification consisting of exercise in addition to dietary modification improves liver histology in NASH. A seminal study was published by Vilar-Gomez et al. (Gastroenterology. 2015;149:367-78) that showed that a lifestyle modification consisting of reduction in caloric intake by 750 kcal/d along with low-intensity exercise (200 minutes of walking each week) led to significant improvement in liver histology, especially in those who lost at least 5% of their body weight.
Naga Chalasani, MD, AGAF, FACG, FAASLD, is the David W. Crabb Professor and director of the division of gastroenterology and hepatology, Indiana University, Purdue. He had no relevant conflicts.
There has been tremendous interest in developing pharmacologic treatments for nonalcoholic steatohepatitis, especially in the Western world. There has not been significant enthusiasm for investigating exercise-based lifestyle modification as a primary treatment for NASH. Although the meta-analysis by Orci et al. included 28 studies, there are only 2 studies (combined, fewer than 100 patients) that examined the effect of exercise on liver histology in NASH and they both suggest that lifestyle modification consisting of exercise in addition to dietary modification improves liver histology in NASH. A seminal study was published by Vilar-Gomez et al. (Gastroenterology. 2015;149:367-78) that showed that a lifestyle modification consisting of reduction in caloric intake by 750 kcal/d along with low-intensity exercise (200 minutes of walking each week) led to significant improvement in liver histology, especially in those who lost at least 5% of their body weight.
Naga Chalasani, MD, AGAF, FACG, FAASLD, is the David W. Crabb Professor and director of the division of gastroenterology and hepatology, Indiana University, Purdue. He had no relevant conflicts.
There has been tremendous interest in developing pharmacologic treatments for nonalcoholic steatohepatitis, especially in the Western world. There has not been significant enthusiasm for investigating exercise-based lifestyle modification as a primary treatment for NASH. Although the meta-analysis by Orci et al. included 28 studies, there are only 2 studies (combined, fewer than 100 patients) that examined the effect of exercise on liver histology in NASH and they both suggest that lifestyle modification consisting of exercise in addition to dietary modification improves liver histology in NASH. A seminal study was published by Vilar-Gomez et al. (Gastroenterology. 2015;149:367-78) that showed that a lifestyle modification consisting of reduction in caloric intake by 750 kcal/d along with low-intensity exercise (200 minutes of walking each week) led to significant improvement in liver histology, especially in those who lost at least 5% of their body weight.
Naga Chalasani, MD, AGAF, FACG, FAASLD, is the David W. Crabb Professor and director of the division of gastroenterology and hepatology, Indiana University, Purdue. He had no relevant conflicts.
Regular physical exercise significantly improved measures of nonalcoholic fatty liver disease independently of dietary changes, according to a meta-analysis of randomized controlled* trials published in the October issue of Clinical Gastroenterology and Hepatology.
“On the basis of the current findings, physical activity should be recommended not only in combination with dietary changes but also independently as an effective approach to manage NAFLD,” wrote Lorenzo Orci, MD, and his associates at the University of Geneva. “We propose that the level of evidence surrounding the specific role of physical activity in the management of NAFLD is now sufficient to be awarded a grade of Ia.”
Nonalcoholic fatty liver disease, “the hepatic manifestation of metabolic syndrome,” affects at least one in four U.S. adults and 15%-35% of individuals in Europe, the Middle East, China, and Japan, the researchers noted. Dietary changes are the cornerstone of NAFLD management, and there is less evidence for how physical exercise affects liver fat content. Therefore, the researchers searched MEDLINE, Embase, and the Cochrane databases from inception through October 2015 to find randomized trials of the impact of physical activity on markers of liver steatosis and liver inflammation in patients diagnosed with NAFLD, obesity, type 2 diabetes, or metabolic syndrome. This approach yielded 28 trials with data from more than 1,600 patients. Only two trials were multicenter, 13 required participants to have an NAFLD diagnosis, four focused on type 2 diabetes, and most of the rest included sedentary obese patients without requiring a diagnosis of NAFLD, the researchers said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.036).
After researchers accounted for dietary changes, physical activity led to a significant drop in intrahepatic lipid content with a standardized mean difference of –0.69 compared with controls (95% confidence interval, –0.90 to –0.48; P less than .0001). “Because effect sizes such as standard mean difference [SMD] are difficult to interpret, the translation of such a statistical measure into a clinically relevant notion has been the focus of research for more than a decade,” the investigators added. “A commonly used interpretation was proposed by Cohen, who suggested that SMDs of 0.2, 0.5, and 0.8 correspond to small, moderate, and large effect sizes, respectively. By using this rule of thumb, our results indicate that physical activity exerts a moderate-to-large impact on the reduction of intrahepatic lipid content.”
Exercise reduced liver fat content even more in pediatric patients (SMD, –0.75; 95% CI, –0.1 to –0.5; P less than .0001) and in patients who had been specifically diagnosed with NAFLD (SMD, –0.86; 95% CI, –1.26 to –0.46; P less than .0001). Patients with the highest baseline body mass index also seemed to benefit more than patients with lower baseline BMI (P = .04). Indeed, exercise reduced BMI itself by a weighted mean difference of 0.8 (95% CI, –1.22 to 0.38; P less than .001), the researchers noted. Exercise intensity did not seem to affect the likelihood of benefit. There was a trend toward a greater effect of aerobic over resistance training (P = .06), and few studies examined the effects of combining both types of exercise.
The multivariable analysis also linked physical activity to an average 3.30 IU/L drop in alanine aminotransferase levels (95% CI, –5.57 to –1.04) and to a 4.9 IU/L decrease in aspartate aminotransferase levels (95% CI, –8.68 to –1.02). The investigators were unable to assess the long-term effects of physical exercise, nor its effects on hepatic fibrosis or inflammation, they noted. Nonetheless, the moderate to large effect size “provides strong evidence for the recommendation of physical activity as an effective intervention in the treatment of NAFLD,” they concluded. “Physical activity is also associated with an improvement in blood levels of aminotransferases and is particularly beneficial in patients presenting with severe obesity at baseline.”
The work was funded by the Ligue Genevoise contre le Cancer and the Dr Henri Dubois-Ferrière/Dinu Lipatti Foundation and by the Swiss National Science Foundation. The investigators had no disclosures.
*Content was updated on 10/25/2016
Regular physical exercise significantly improved measures of nonalcoholic fatty liver disease independently of dietary changes, according to a meta-analysis of randomized controlled* trials published in the October issue of Clinical Gastroenterology and Hepatology.
“On the basis of the current findings, physical activity should be recommended not only in combination with dietary changes but also independently as an effective approach to manage NAFLD,” wrote Lorenzo Orci, MD, and his associates at the University of Geneva. “We propose that the level of evidence surrounding the specific role of physical activity in the management of NAFLD is now sufficient to be awarded a grade of Ia.”
Nonalcoholic fatty liver disease, “the hepatic manifestation of metabolic syndrome,” affects at least one in four U.S. adults and 15%-35% of individuals in Europe, the Middle East, China, and Japan, the researchers noted. Dietary changes are the cornerstone of NAFLD management, and there is less evidence for how physical exercise affects liver fat content. Therefore, the researchers searched MEDLINE, Embase, and the Cochrane databases from inception through October 2015 to find randomized trials of the impact of physical activity on markers of liver steatosis and liver inflammation in patients diagnosed with NAFLD, obesity, type 2 diabetes, or metabolic syndrome. This approach yielded 28 trials with data from more than 1,600 patients. Only two trials were multicenter, 13 required participants to have an NAFLD diagnosis, four focused on type 2 diabetes, and most of the rest included sedentary obese patients without requiring a diagnosis of NAFLD, the researchers said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.036).
After researchers accounted for dietary changes, physical activity led to a significant drop in intrahepatic lipid content with a standardized mean difference of –0.69 compared with controls (95% confidence interval, –0.90 to –0.48; P less than .0001). “Because effect sizes such as standard mean difference [SMD] are difficult to interpret, the translation of such a statistical measure into a clinically relevant notion has been the focus of research for more than a decade,” the investigators added. “A commonly used interpretation was proposed by Cohen, who suggested that SMDs of 0.2, 0.5, and 0.8 correspond to small, moderate, and large effect sizes, respectively. By using this rule of thumb, our results indicate that physical activity exerts a moderate-to-large impact on the reduction of intrahepatic lipid content.”
Exercise reduced liver fat content even more in pediatric patients (SMD, –0.75; 95% CI, –0.1 to –0.5; P less than .0001) and in patients who had been specifically diagnosed with NAFLD (SMD, –0.86; 95% CI, –1.26 to –0.46; P less than .0001). Patients with the highest baseline body mass index also seemed to benefit more than patients with lower baseline BMI (P = .04). Indeed, exercise reduced BMI itself by a weighted mean difference of 0.8 (95% CI, –1.22 to 0.38; P less than .001), the researchers noted. Exercise intensity did not seem to affect the likelihood of benefit. There was a trend toward a greater effect of aerobic over resistance training (P = .06), and few studies examined the effects of combining both types of exercise.
The multivariable analysis also linked physical activity to an average 3.30 IU/L drop in alanine aminotransferase levels (95% CI, –5.57 to –1.04) and to a 4.9 IU/L decrease in aspartate aminotransferase levels (95% CI, –8.68 to –1.02). The investigators were unable to assess the long-term effects of physical exercise, nor its effects on hepatic fibrosis or inflammation, they noted. Nonetheless, the moderate to large effect size “provides strong evidence for the recommendation of physical activity as an effective intervention in the treatment of NAFLD,” they concluded. “Physical activity is also associated with an improvement in blood levels of aminotransferases and is particularly beneficial in patients presenting with severe obesity at baseline.”
The work was funded by the Ligue Genevoise contre le Cancer and the Dr Henri Dubois-Ferrière/Dinu Lipatti Foundation and by the Swiss National Science Foundation. The investigators had no disclosures.
*Content was updated on 10/25/2016
Key clinical point: Physical activity benefits measures of nonalcoholic fatty liver disease independently of diet.
Major finding: After researchers accounted for dietary changes, physical activity led to a significant drop in intrahepatic lipid content with a standardized mean difference of –0.69 compared with controls (95% confidence interval, –0.90 to –0.48; P less than .0001).
Data source: A systematic review and meta-analysis of 28 randomized controlled trials comprising more than 16,000 patients.
Disclosures: The work was funded by the Ligue Genevoise contre le Cancer and the Dr Henri Dubois-Ferrière/Dinu Lipatti Foundation and by the Swiss National Science Foundation. The researchers had no disclosures.
VIDEO: Transcriptomics link gastric cancer to RNA misediting
Changes in the sequence of RNA – also known as RNA editing – might contribute to the pathogenesis and prognosis of gastric cancer, investigators reported in the October issue of Gastroenterology.
By performing high-throughput transcriptome sequencing (or RNA-Seq) of gastric tumor tissue and cell lines, they identified “a clear RNA misediting phenotype” characterized by an imbalance in enzymes called adenosine deaminases that act on RNA, or ADAR, Tim Hon Man Chan, MD, of the National University of Singapore and his associates said. Normal gastric tissue did not show these changes, and they were associated with tumor progression and a poor prognosis, the investigators added.
Gastric cancer is the third most lethal malignancy worldwide. RNA editing in humans usually involves the conversion of adenosine-to-inosine (A-to-I), which is catalyzed by the ADAR1 and ADAR2 enzymes and has been linked to liver and esophageal cancer. To explore the role of A-to-I RNA editing in gastric cancer, the researchers performed next-generation sequencing transcriptomics of 14 tissue specimens from primary gastric tumors and 14 matched samples from noncancerous gastric tissue. They also sequenced gastric cancer cell lines and analyzed single nucleotide polymorphism array and RNA-Seq data from the gastric cancer datasets of The Cancer Genome Atlas (Gastroenterology. 2016 Jun 30. doi: 10.1053/j.gastro.2016.06.043).
Compared with normal tissue specimens, almost all the samples of gastric cancers showed clear evidence of ADAR dysregulation – specifically, the gain of the ADAR1 gene and the loss of the ADAR2 gene, the researchers said. Furthermore, both the in vivo and in vitro studies indicated that RNA editing enabled ADAR1 to function as an oncogene in gastric cancer, while ADAR2 functioned as a tumor suppressor gene. In The Cancer Genome Atlas, about 36% of gastric cancer patients had gained ADAR1, while 44% of patients had lost ADAR2. Not only did these changes lead to a significant rise in ADAR1 mRNA expression and a significant decrease in ADAR2 mRNA expression, but patients with the most developed gastric tumors had the highest levels of ADAR1/ADAR2 dysregulation and the worst clinical prognosis, the investigators said.
SOURCE: American Gastroenterological Association
Additional tests of a model target gene called PODXL (podocalyxin-like) showed that ADAR2 regulates the editing of codon 241 such that histidine is replaced with arginine, which then neutralizes the normal tumorigenic ability of unedited or wild-type PODXL, the researchers reported. “Our data suggest that dysregulation of RNA editing is pervasive in gastric cancer, approaching levels reported for other types of epigenetic dysregulation including DNA methylation and histone modification,” they added. Taken together, the findings “highlight RNA editing as an important pathogenic mechanism in gastric carcinogenesis, and ADAR enzymes as potential gastric cancer therapeutic targets.”
These findings are especially important because the identification of DNA mutations in gastric cancer has not led to viable therapies except for traztuzumab in ERBB2-positive gastric cancer and ramucirumab in advanced gastric cancer, the investigators said. “Our study demonstrates that differentially expressed ADARs in gastric tumors with consequent A-to-I RNA editing dysregulation may serve as a second layer of ‘somatic mutations’ and a novel contributor to gastric cancer,” they concluded.
The work was funded by the National Research Foundation Singapore, the Singapore Ministry of Education, and several other noncorporate entities. The researchers had no disclosures.
Changes in the sequence of RNA – also known as RNA editing – might contribute to the pathogenesis and prognosis of gastric cancer, investigators reported in the October issue of Gastroenterology.
By performing high-throughput transcriptome sequencing (or RNA-Seq) of gastric tumor tissue and cell lines, they identified “a clear RNA misediting phenotype” characterized by an imbalance in enzymes called adenosine deaminases that act on RNA, or ADAR, Tim Hon Man Chan, MD, of the National University of Singapore and his associates said. Normal gastric tissue did not show these changes, and they were associated with tumor progression and a poor prognosis, the investigators added.
Gastric cancer is the third most lethal malignancy worldwide. RNA editing in humans usually involves the conversion of adenosine-to-inosine (A-to-I), which is catalyzed by the ADAR1 and ADAR2 enzymes and has been linked to liver and esophageal cancer. To explore the role of A-to-I RNA editing in gastric cancer, the researchers performed next-generation sequencing transcriptomics of 14 tissue specimens from primary gastric tumors and 14 matched samples from noncancerous gastric tissue. They also sequenced gastric cancer cell lines and analyzed single nucleotide polymorphism array and RNA-Seq data from the gastric cancer datasets of The Cancer Genome Atlas (Gastroenterology. 2016 Jun 30. doi: 10.1053/j.gastro.2016.06.043).
Compared with normal tissue specimens, almost all the samples of gastric cancers showed clear evidence of ADAR dysregulation – specifically, the gain of the ADAR1 gene and the loss of the ADAR2 gene, the researchers said. Furthermore, both the in vivo and in vitro studies indicated that RNA editing enabled ADAR1 to function as an oncogene in gastric cancer, while ADAR2 functioned as a tumor suppressor gene. In The Cancer Genome Atlas, about 36% of gastric cancer patients had gained ADAR1, while 44% of patients had lost ADAR2. Not only did these changes lead to a significant rise in ADAR1 mRNA expression and a significant decrease in ADAR2 mRNA expression, but patients with the most developed gastric tumors had the highest levels of ADAR1/ADAR2 dysregulation and the worst clinical prognosis, the investigators said.
SOURCE: American Gastroenterological Association
Additional tests of a model target gene called PODXL (podocalyxin-like) showed that ADAR2 regulates the editing of codon 241 such that histidine is replaced with arginine, which then neutralizes the normal tumorigenic ability of unedited or wild-type PODXL, the researchers reported. “Our data suggest that dysregulation of RNA editing is pervasive in gastric cancer, approaching levels reported for other types of epigenetic dysregulation including DNA methylation and histone modification,” they added. Taken together, the findings “highlight RNA editing as an important pathogenic mechanism in gastric carcinogenesis, and ADAR enzymes as potential gastric cancer therapeutic targets.”
These findings are especially important because the identification of DNA mutations in gastric cancer has not led to viable therapies except for traztuzumab in ERBB2-positive gastric cancer and ramucirumab in advanced gastric cancer, the investigators said. “Our study demonstrates that differentially expressed ADARs in gastric tumors with consequent A-to-I RNA editing dysregulation may serve as a second layer of ‘somatic mutations’ and a novel contributor to gastric cancer,” they concluded.
The work was funded by the National Research Foundation Singapore, the Singapore Ministry of Education, and several other noncorporate entities. The researchers had no disclosures.
Changes in the sequence of RNA – also known as RNA editing – might contribute to the pathogenesis and prognosis of gastric cancer, investigators reported in the October issue of Gastroenterology.
By performing high-throughput transcriptome sequencing (or RNA-Seq) of gastric tumor tissue and cell lines, they identified “a clear RNA misediting phenotype” characterized by an imbalance in enzymes called adenosine deaminases that act on RNA, or ADAR, Tim Hon Man Chan, MD, of the National University of Singapore and his associates said. Normal gastric tissue did not show these changes, and they were associated with tumor progression and a poor prognosis, the investigators added.
Gastric cancer is the third most lethal malignancy worldwide. RNA editing in humans usually involves the conversion of adenosine-to-inosine (A-to-I), which is catalyzed by the ADAR1 and ADAR2 enzymes and has been linked to liver and esophageal cancer. To explore the role of A-to-I RNA editing in gastric cancer, the researchers performed next-generation sequencing transcriptomics of 14 tissue specimens from primary gastric tumors and 14 matched samples from noncancerous gastric tissue. They also sequenced gastric cancer cell lines and analyzed single nucleotide polymorphism array and RNA-Seq data from the gastric cancer datasets of The Cancer Genome Atlas (Gastroenterology. 2016 Jun 30. doi: 10.1053/j.gastro.2016.06.043).
Compared with normal tissue specimens, almost all the samples of gastric cancers showed clear evidence of ADAR dysregulation – specifically, the gain of the ADAR1 gene and the loss of the ADAR2 gene, the researchers said. Furthermore, both the in vivo and in vitro studies indicated that RNA editing enabled ADAR1 to function as an oncogene in gastric cancer, while ADAR2 functioned as a tumor suppressor gene. In The Cancer Genome Atlas, about 36% of gastric cancer patients had gained ADAR1, while 44% of patients had lost ADAR2. Not only did these changes lead to a significant rise in ADAR1 mRNA expression and a significant decrease in ADAR2 mRNA expression, but patients with the most developed gastric tumors had the highest levels of ADAR1/ADAR2 dysregulation and the worst clinical prognosis, the investigators said.
SOURCE: American Gastroenterological Association
Additional tests of a model target gene called PODXL (podocalyxin-like) showed that ADAR2 regulates the editing of codon 241 such that histidine is replaced with arginine, which then neutralizes the normal tumorigenic ability of unedited or wild-type PODXL, the researchers reported. “Our data suggest that dysregulation of RNA editing is pervasive in gastric cancer, approaching levels reported for other types of epigenetic dysregulation including DNA methylation and histone modification,” they added. Taken together, the findings “highlight RNA editing as an important pathogenic mechanism in gastric carcinogenesis, and ADAR enzymes as potential gastric cancer therapeutic targets.”
These findings are especially important because the identification of DNA mutations in gastric cancer has not led to viable therapies except for traztuzumab in ERBB2-positive gastric cancer and ramucirumab in advanced gastric cancer, the investigators said. “Our study demonstrates that differentially expressed ADARs in gastric tumors with consequent A-to-I RNA editing dysregulation may serve as a second layer of ‘somatic mutations’ and a novel contributor to gastric cancer,” they concluded.
The work was funded by the National Research Foundation Singapore, the Singapore Ministry of Education, and several other noncorporate entities. The researchers had no disclosures.
FROM GASTROENTEROLOGY
Key clinical point: Sequence alterations at the RNA level may contribute to the pathology and prognosis of gastric cancer.
Major finding: Compared with normal gastric tissue, almost all gastric cancer specimens exhibited an RNA misediting phenotype characterized by the respective gain and loss of the ADAR1 and ADAR2 genes.
Data source: High-throughput transcriptome sequencing (RNA-Seq) of gastric cancer and normal tissue, sequencing of gastric cancer cell lines, and analyses of The Cancer Genome Atlas.
Disclosures: The work was funded by the National Research Foundation Singapore, the Singapore Ministry of Education, and several other noncorporate entities. The investigators had no disclosures.
CSF2RB mutation, common in Ashkenazim, linked to Crohn’s
A frameshift mutation in the CSF2RB gene that is common in Ashkenazi Jews has been linked to Crohn’s disease, according to a report in Gastroenterology.
The Ashkenazi Jewish population has a four- to sevenfold higher prevalence of Crohn’s disease than does the general population. To identify possible genetic mutations associated with the disease, researchers performed exome sequencing of samples from 1,477 Ashkenazi Jewish patients with Crohn’s disease and 2,614 Ashkenazi Jewish control subjects who didn’t have the disorder. All the study participants were enrolled at medical centers throughout North America, Europe, and Israel, noted Ling-Shiang Chuang, PhD, a postdoctoral fellow in genetics and genomic sciences, Mount Sinai Medical Center, New York, and his associates.
They genotyped 224 frameshift mutations and identified one in the colony-stimulating factor 2–receptor beta common subunit (CSF2RB) gene that was significantly associated with Crohn’s disease. They validated this association in a replication cohort of 1,515 Ashkenazi Jewish patients with Crohn’s disease and 7,052 health Ashkenazi control subjects, observing nearly identical allele frequencies and odds ratios as in the discovery cohort.
Since the CSF2RB gene encodes for the receptor for GM-CSF (granulocyte-macrophage colony-stimulating factor) cytokines, the mutation would be expected to reduce GM-CSF signaling in monocytes obtained from carriers. The investigators found this was true when they examined monocytes taken from intestinal-tissue samples and peripheral-blood samples from affected patients.
“The present findings of a loss-of-function frameshift variant in the CSF2RB gene argue for a primary pathogenic role of decreased GM-CSF signaling in driving a subset of Crohn’s disease cases. As many as 30% of cases have increased levels of anti-GM-CSF antibodies, which can neutralize GM-CSF activity, indicating that impaired GM-CSF signaling plays a major role in Crohn’s disease,” Dr. Chuang and his associates wrote (Gastroenterol. 2016;151:710-23.e2. doi: 10.1053/j.gastro.2016.06.045).
Future research may identify subgroups of Crohn’s patients in which treatments that target GM-CSF signaling may be effective, and it may also point the way to novel therapies for the broader population of patients with Crohn’s disease, they added.
This study was supported by the National Institutes of Health, the Inflammatory Bowel Disease Genetics Consortium, the Genetic Research Center at Mount Sinai Medical Center, New York’s Crohn’s Foundation, and several others. Dr. Chuang and his associates reported having no relevant financial disclosures.
Genome-wide association studies (GWASs) have identified over 200 DNA mutations (mainly single nucleotide polymorphisms, SNPs) contributing to inflammatory bowel disease. However, their causality in IBD remains unknown. In the post-GWAS era, functional characterization and mechanistic elucidation of these SNPs is a major challenge. SNPs impacting the protein-coding genes can drastically alter protein function and play an important role in molecular pathogenesis. However, most SNPs are in noncoding genes and their impact on gene regulation and disease outcome remains largely unknown. This study reveals a frameshift mutation in the CSF2RB gene associated with Crohn’s disease in an Ashkenazi Jewish population. A frameshift mutation results in the deletion or insertion in a DNA sequence that shifts the way the sequence is transcribed into RNA. The most well described frameshift mutation in Crohn’s disease with clinical relevance is in the NOD2 gene, which results in impaired immune response to microbial stimuli. Because GWASs show association not causality, the biological consequence of the CSF2RB frameshift mutation in intestinal macrophages leads to a decrease in its response to granulocyte-monocyte stimulating factor (GM-CSF) providing a potential mechanistic role for the mutation in Crohn’s disease pathogenesis in a disease-relevant cell and site. This study will pave the way for future important studies that reveal the impact of SNPs on Crohn’s disease development, prognosis, and eventually response to therapy.
Shehzad Z. Sheikh MD, PhD, assistant professor of medicine, department of medicine, division of gastroenterology and hepatology, University of North Carolina, Chapel Hill.
Genome-wide association studies (GWASs) have identified over 200 DNA mutations (mainly single nucleotide polymorphisms, SNPs) contributing to inflammatory bowel disease. However, their causality in IBD remains unknown. In the post-GWAS era, functional characterization and mechanistic elucidation of these SNPs is a major challenge. SNPs impacting the protein-coding genes can drastically alter protein function and play an important role in molecular pathogenesis. However, most SNPs are in noncoding genes and their impact on gene regulation and disease outcome remains largely unknown. This study reveals a frameshift mutation in the CSF2RB gene associated with Crohn’s disease in an Ashkenazi Jewish population. A frameshift mutation results in the deletion or insertion in a DNA sequence that shifts the way the sequence is transcribed into RNA. The most well described frameshift mutation in Crohn’s disease with clinical relevance is in the NOD2 gene, which results in impaired immune response to microbial stimuli. Because GWASs show association not causality, the biological consequence of the CSF2RB frameshift mutation in intestinal macrophages leads to a decrease in its response to granulocyte-monocyte stimulating factor (GM-CSF) providing a potential mechanistic role for the mutation in Crohn’s disease pathogenesis in a disease-relevant cell and site. This study will pave the way for future important studies that reveal the impact of SNPs on Crohn’s disease development, prognosis, and eventually response to therapy.
Shehzad Z. Sheikh MD, PhD, assistant professor of medicine, department of medicine, division of gastroenterology and hepatology, University of North Carolina, Chapel Hill.
Genome-wide association studies (GWASs) have identified over 200 DNA mutations (mainly single nucleotide polymorphisms, SNPs) contributing to inflammatory bowel disease. However, their causality in IBD remains unknown. In the post-GWAS era, functional characterization and mechanistic elucidation of these SNPs is a major challenge. SNPs impacting the protein-coding genes can drastically alter protein function and play an important role in molecular pathogenesis. However, most SNPs are in noncoding genes and their impact on gene regulation and disease outcome remains largely unknown. This study reveals a frameshift mutation in the CSF2RB gene associated with Crohn’s disease in an Ashkenazi Jewish population. A frameshift mutation results in the deletion or insertion in a DNA sequence that shifts the way the sequence is transcribed into RNA. The most well described frameshift mutation in Crohn’s disease with clinical relevance is in the NOD2 gene, which results in impaired immune response to microbial stimuli. Because GWASs show association not causality, the biological consequence of the CSF2RB frameshift mutation in intestinal macrophages leads to a decrease in its response to granulocyte-monocyte stimulating factor (GM-CSF) providing a potential mechanistic role for the mutation in Crohn’s disease pathogenesis in a disease-relevant cell and site. This study will pave the way for future important studies that reveal the impact of SNPs on Crohn’s disease development, prognosis, and eventually response to therapy.
Shehzad Z. Sheikh MD, PhD, assistant professor of medicine, department of medicine, division of gastroenterology and hepatology, University of North Carolina, Chapel Hill.
A frameshift mutation in the CSF2RB gene that is common in Ashkenazi Jews has been linked to Crohn’s disease, according to a report in Gastroenterology.
The Ashkenazi Jewish population has a four- to sevenfold higher prevalence of Crohn’s disease than does the general population. To identify possible genetic mutations associated with the disease, researchers performed exome sequencing of samples from 1,477 Ashkenazi Jewish patients with Crohn’s disease and 2,614 Ashkenazi Jewish control subjects who didn’t have the disorder. All the study participants were enrolled at medical centers throughout North America, Europe, and Israel, noted Ling-Shiang Chuang, PhD, a postdoctoral fellow in genetics and genomic sciences, Mount Sinai Medical Center, New York, and his associates.
They genotyped 224 frameshift mutations and identified one in the colony-stimulating factor 2–receptor beta common subunit (CSF2RB) gene that was significantly associated with Crohn’s disease. They validated this association in a replication cohort of 1,515 Ashkenazi Jewish patients with Crohn’s disease and 7,052 health Ashkenazi control subjects, observing nearly identical allele frequencies and odds ratios as in the discovery cohort.
Since the CSF2RB gene encodes for the receptor for GM-CSF (granulocyte-macrophage colony-stimulating factor) cytokines, the mutation would be expected to reduce GM-CSF signaling in monocytes obtained from carriers. The investigators found this was true when they examined monocytes taken from intestinal-tissue samples and peripheral-blood samples from affected patients.
“The present findings of a loss-of-function frameshift variant in the CSF2RB gene argue for a primary pathogenic role of decreased GM-CSF signaling in driving a subset of Crohn’s disease cases. As many as 30% of cases have increased levels of anti-GM-CSF antibodies, which can neutralize GM-CSF activity, indicating that impaired GM-CSF signaling plays a major role in Crohn’s disease,” Dr. Chuang and his associates wrote (Gastroenterol. 2016;151:710-23.e2. doi: 10.1053/j.gastro.2016.06.045).
Future research may identify subgroups of Crohn’s patients in which treatments that target GM-CSF signaling may be effective, and it may also point the way to novel therapies for the broader population of patients with Crohn’s disease, they added.
This study was supported by the National Institutes of Health, the Inflammatory Bowel Disease Genetics Consortium, the Genetic Research Center at Mount Sinai Medical Center, New York’s Crohn’s Foundation, and several others. Dr. Chuang and his associates reported having no relevant financial disclosures.
A frameshift mutation in the CSF2RB gene that is common in Ashkenazi Jews has been linked to Crohn’s disease, according to a report in Gastroenterology.
The Ashkenazi Jewish population has a four- to sevenfold higher prevalence of Crohn’s disease than does the general population. To identify possible genetic mutations associated with the disease, researchers performed exome sequencing of samples from 1,477 Ashkenazi Jewish patients with Crohn’s disease and 2,614 Ashkenazi Jewish control subjects who didn’t have the disorder. All the study participants were enrolled at medical centers throughout North America, Europe, and Israel, noted Ling-Shiang Chuang, PhD, a postdoctoral fellow in genetics and genomic sciences, Mount Sinai Medical Center, New York, and his associates.
They genotyped 224 frameshift mutations and identified one in the colony-stimulating factor 2–receptor beta common subunit (CSF2RB) gene that was significantly associated with Crohn’s disease. They validated this association in a replication cohort of 1,515 Ashkenazi Jewish patients with Crohn’s disease and 7,052 health Ashkenazi control subjects, observing nearly identical allele frequencies and odds ratios as in the discovery cohort.
Since the CSF2RB gene encodes for the receptor for GM-CSF (granulocyte-macrophage colony-stimulating factor) cytokines, the mutation would be expected to reduce GM-CSF signaling in monocytes obtained from carriers. The investigators found this was true when they examined monocytes taken from intestinal-tissue samples and peripheral-blood samples from affected patients.
“The present findings of a loss-of-function frameshift variant in the CSF2RB gene argue for a primary pathogenic role of decreased GM-CSF signaling in driving a subset of Crohn’s disease cases. As many as 30% of cases have increased levels of anti-GM-CSF antibodies, which can neutralize GM-CSF activity, indicating that impaired GM-CSF signaling plays a major role in Crohn’s disease,” Dr. Chuang and his associates wrote (Gastroenterol. 2016;151:710-23.e2. doi: 10.1053/j.gastro.2016.06.045).
Future research may identify subgroups of Crohn’s patients in which treatments that target GM-CSF signaling may be effective, and it may also point the way to novel therapies for the broader population of patients with Crohn’s disease, they added.
This study was supported by the National Institutes of Health, the Inflammatory Bowel Disease Genetics Consortium, the Genetic Research Center at Mount Sinai Medical Center, New York’s Crohn’s Foundation, and several others. Dr. Chuang and his associates reported having no relevant financial disclosures.
FROM GASTROENTEROLOGY
Key clinical point: A frameshift mutation in the CSF2RB gene that is common in Ashkenazi Jews has been linked to Crohn’s disease.
Major finding: Genotyping of 224 frameshift mutations identified one in the colony-stimulating factor 2–receptor common subunit (CSF2RB) gene that was significantly associated with Crohn’s disease.
Data source: Exome sequencing and genotype analyses of samples from 1,477 Ashkenazi Jewish people with Crohn’s disease and 2,614 without it.
Disclosures: This study was supported by the National Institutes of Health, the Inflammatory Bowel Disease Genetics Consortium, the Genetic Research Center at Mount Sinai Medical Center, New York’s Crohn’s Foundation, and several others. Dr. Chuang and his associates reported having no relevant financial disclosures.
Real-world study: 8 weeks of two-drug combo highly effective against HCV
Eight weeks of a two-drug combination led to sustained viral response (SVR) in 94% of noncirrhotic, treatment-naive, genotype 1 hepatitis C virus–infected patients, based on a retrospective study of Veterans Affairs health system data presented in the September issue of Gastroenterology.
But VA clinicians prescribed the 8-week regimen to less than half of eligible patients, said George Ioannou, MD, of the Veterans Affairs Puget Sound Health Care System in Seattle. Increasing its use, when appropriate, “could save on costs,” although the currently available interferon-free regimens “leave substantial room for improvement in SVRs among persons with cirrhosis and genotype 2 or 3 infections,” he and his associates wrote.
The two-drug regimen contained sofosbuvir and ledipasvir. Clinical trials of sofosbuvir, ledipasvir/sofosbuvir, and paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD) have reported SVR rates well above 90%, “with the exception of certain subgroups, such as patients with Child’s B or C cirrhosis and those infected with genotype 3 HCV,” the researchers noted. However, older interferon-based regimens did not perform as well in the real world as in trials, and “it is unclear if this is the case for current interferon-free regimens, or whether the relative ease of administration of these regimens has narrowed the SVR gap between clinical trials and clinical practice.” Questions also persist about how effective the interferon-free regimens are in various HCV genotypes and subgroups, they added (Gastroenterology 2016 Jul 18. doi: 10.1053/j.gastro.2016.05.049). To help answer these questions, they analyzed data from more than 17,000 HCV patients in the VA health care system who received sofosbuvir, ledipasvir/sofosbuvir, or paritaprevir/ritonavir/ombitasvir and dasabuvir between January 2014 and June 2015. The cohort included about 14,000 patients with genotype 1 infections, about 2,100 patients with genotype 2 infections, about 1,200 patients with genotype 3 infections, and 135 patients with genotype 4 infections. Patients averaged 62 years of age, about half were non-Hispanic white, 29% were non-Hispanic black, and nearly a third had been diagnosed with cirrhosis, including 10% with decompensated cirrhosis.
The VA guidelines recommended 8 weeks instead of 12 weeks of ledipasvir/sofosbuvir for treatment-naive, noncirrhotic, genotype 1 patients with a viral load under 6 million IU/mL, although that recommendation was not FDA approved and was based only on a post hoc analysis of the ION-3 trial, the investigators noted. These concerns seemed to affect practice – of 4,066 eligible patients, only 1,975 (49%) received the 8-week regimen. Notably, however, their rate of SVR 12 weeks after treatment (SVR12) was 95.1% (95% confidence interval, 94% to 96%) – nearly identical to that of patients with the same characteristics who received 12 weeks of treatment (95.8%; 94.7% to 96.8%; P = .6).
Rates of SVR12 did not significantly differ between ledipasvir/sofosbuvir and PrOD regimens, including in multivariable and propensity score–adjusted analyses, the researchers reported. Rates of SVR12 also exceeded 90% in subgroups of treatment-experienced and cirrhotic genotype 1 patients, they added. However, rates of SVR12 were lower for nongenotype 1 infections, as has been observed in trials. Specifically, rates of SVR12 were 90% for genotype 4 patients, 86% for genotype 2 patients who received sofosbuvir and ribavirin, and 75% for genotype 3 patients (including 78% for patients given ledipasvir/sofosbuvir plus ribavirin, 87% for patients given sofosbuvir and pegylated interferon plus ribavirin, and 71% for patients given sofosbuvir monotherapy). For cirrhotic patients, rates of SVR12 were 91% for genotype 1, 77% for genotype 2, 66% for genotype 3, and 84% for genotype 4.
The findings confirm that the new interferon-free regimens “can achieve remarkably high SVR rates in real-world clinical practice, especially in genotype 1–infected patients,” the researchers wrote. The cost of these regimens is “the main obstacle to curing HCV” in as many patients as possible, but is expected to “decline dramatically” as the FDA approves new regimens, they noted. “In fact, costs decreased dramatically within the VA after the completion of our study and after the FDA approved elbasvir/grazoprevir in January 2016.”
The study was funded by the Department of Veterans Affairs. The investigators had no disclosures.
Eight weeks of a two-drug combination led to sustained viral response (SVR) in 94% of noncirrhotic, treatment-naive, genotype 1 hepatitis C virus–infected patients, based on a retrospective study of Veterans Affairs health system data presented in the September issue of Gastroenterology.
But VA clinicians prescribed the 8-week regimen to less than half of eligible patients, said George Ioannou, MD, of the Veterans Affairs Puget Sound Health Care System in Seattle. Increasing its use, when appropriate, “could save on costs,” although the currently available interferon-free regimens “leave substantial room for improvement in SVRs among persons with cirrhosis and genotype 2 or 3 infections,” he and his associates wrote.
The two-drug regimen contained sofosbuvir and ledipasvir. Clinical trials of sofosbuvir, ledipasvir/sofosbuvir, and paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD) have reported SVR rates well above 90%, “with the exception of certain subgroups, such as patients with Child’s B or C cirrhosis and those infected with genotype 3 HCV,” the researchers noted. However, older interferon-based regimens did not perform as well in the real world as in trials, and “it is unclear if this is the case for current interferon-free regimens, or whether the relative ease of administration of these regimens has narrowed the SVR gap between clinical trials and clinical practice.” Questions also persist about how effective the interferon-free regimens are in various HCV genotypes and subgroups, they added (Gastroenterology 2016 Jul 18. doi: 10.1053/j.gastro.2016.05.049). To help answer these questions, they analyzed data from more than 17,000 HCV patients in the VA health care system who received sofosbuvir, ledipasvir/sofosbuvir, or paritaprevir/ritonavir/ombitasvir and dasabuvir between January 2014 and June 2015. The cohort included about 14,000 patients with genotype 1 infections, about 2,100 patients with genotype 2 infections, about 1,200 patients with genotype 3 infections, and 135 patients with genotype 4 infections. Patients averaged 62 years of age, about half were non-Hispanic white, 29% were non-Hispanic black, and nearly a third had been diagnosed with cirrhosis, including 10% with decompensated cirrhosis.
The VA guidelines recommended 8 weeks instead of 12 weeks of ledipasvir/sofosbuvir for treatment-naive, noncirrhotic, genotype 1 patients with a viral load under 6 million IU/mL, although that recommendation was not FDA approved and was based only on a post hoc analysis of the ION-3 trial, the investigators noted. These concerns seemed to affect practice – of 4,066 eligible patients, only 1,975 (49%) received the 8-week regimen. Notably, however, their rate of SVR 12 weeks after treatment (SVR12) was 95.1% (95% confidence interval, 94% to 96%) – nearly identical to that of patients with the same characteristics who received 12 weeks of treatment (95.8%; 94.7% to 96.8%; P = .6).
Rates of SVR12 did not significantly differ between ledipasvir/sofosbuvir and PrOD regimens, including in multivariable and propensity score–adjusted analyses, the researchers reported. Rates of SVR12 also exceeded 90% in subgroups of treatment-experienced and cirrhotic genotype 1 patients, they added. However, rates of SVR12 were lower for nongenotype 1 infections, as has been observed in trials. Specifically, rates of SVR12 were 90% for genotype 4 patients, 86% for genotype 2 patients who received sofosbuvir and ribavirin, and 75% for genotype 3 patients (including 78% for patients given ledipasvir/sofosbuvir plus ribavirin, 87% for patients given sofosbuvir and pegylated interferon plus ribavirin, and 71% for patients given sofosbuvir monotherapy). For cirrhotic patients, rates of SVR12 were 91% for genotype 1, 77% for genotype 2, 66% for genotype 3, and 84% for genotype 4.
The findings confirm that the new interferon-free regimens “can achieve remarkably high SVR rates in real-world clinical practice, especially in genotype 1–infected patients,” the researchers wrote. The cost of these regimens is “the main obstacle to curing HCV” in as many patients as possible, but is expected to “decline dramatically” as the FDA approves new regimens, they noted. “In fact, costs decreased dramatically within the VA after the completion of our study and after the FDA approved elbasvir/grazoprevir in January 2016.”
The study was funded by the Department of Veterans Affairs. The investigators had no disclosures.
Eight weeks of a two-drug combination led to sustained viral response (SVR) in 94% of noncirrhotic, treatment-naive, genotype 1 hepatitis C virus–infected patients, based on a retrospective study of Veterans Affairs health system data presented in the September issue of Gastroenterology.
But VA clinicians prescribed the 8-week regimen to less than half of eligible patients, said George Ioannou, MD, of the Veterans Affairs Puget Sound Health Care System in Seattle. Increasing its use, when appropriate, “could save on costs,” although the currently available interferon-free regimens “leave substantial room for improvement in SVRs among persons with cirrhosis and genotype 2 or 3 infections,” he and his associates wrote.
The two-drug regimen contained sofosbuvir and ledipasvir. Clinical trials of sofosbuvir, ledipasvir/sofosbuvir, and paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD) have reported SVR rates well above 90%, “with the exception of certain subgroups, such as patients with Child’s B or C cirrhosis and those infected with genotype 3 HCV,” the researchers noted. However, older interferon-based regimens did not perform as well in the real world as in trials, and “it is unclear if this is the case for current interferon-free regimens, or whether the relative ease of administration of these regimens has narrowed the SVR gap between clinical trials and clinical practice.” Questions also persist about how effective the interferon-free regimens are in various HCV genotypes and subgroups, they added (Gastroenterology 2016 Jul 18. doi: 10.1053/j.gastro.2016.05.049). To help answer these questions, they analyzed data from more than 17,000 HCV patients in the VA health care system who received sofosbuvir, ledipasvir/sofosbuvir, or paritaprevir/ritonavir/ombitasvir and dasabuvir between January 2014 and June 2015. The cohort included about 14,000 patients with genotype 1 infections, about 2,100 patients with genotype 2 infections, about 1,200 patients with genotype 3 infections, and 135 patients with genotype 4 infections. Patients averaged 62 years of age, about half were non-Hispanic white, 29% were non-Hispanic black, and nearly a third had been diagnosed with cirrhosis, including 10% with decompensated cirrhosis.
The VA guidelines recommended 8 weeks instead of 12 weeks of ledipasvir/sofosbuvir for treatment-naive, noncirrhotic, genotype 1 patients with a viral load under 6 million IU/mL, although that recommendation was not FDA approved and was based only on a post hoc analysis of the ION-3 trial, the investigators noted. These concerns seemed to affect practice – of 4,066 eligible patients, only 1,975 (49%) received the 8-week regimen. Notably, however, their rate of SVR 12 weeks after treatment (SVR12) was 95.1% (95% confidence interval, 94% to 96%) – nearly identical to that of patients with the same characteristics who received 12 weeks of treatment (95.8%; 94.7% to 96.8%; P = .6).
Rates of SVR12 did not significantly differ between ledipasvir/sofosbuvir and PrOD regimens, including in multivariable and propensity score–adjusted analyses, the researchers reported. Rates of SVR12 also exceeded 90% in subgroups of treatment-experienced and cirrhotic genotype 1 patients, they added. However, rates of SVR12 were lower for nongenotype 1 infections, as has been observed in trials. Specifically, rates of SVR12 were 90% for genotype 4 patients, 86% for genotype 2 patients who received sofosbuvir and ribavirin, and 75% for genotype 3 patients (including 78% for patients given ledipasvir/sofosbuvir plus ribavirin, 87% for patients given sofosbuvir and pegylated interferon plus ribavirin, and 71% for patients given sofosbuvir monotherapy). For cirrhotic patients, rates of SVR12 were 91% for genotype 1, 77% for genotype 2, 66% for genotype 3, and 84% for genotype 4.
The findings confirm that the new interferon-free regimens “can achieve remarkably high SVR rates in real-world clinical practice, especially in genotype 1–infected patients,” the researchers wrote. The cost of these regimens is “the main obstacle to curing HCV” in as many patients as possible, but is expected to “decline dramatically” as the FDA approves new regimens, they noted. “In fact, costs decreased dramatically within the VA after the completion of our study and after the FDA approved elbasvir/grazoprevir in January 2016.”
The study was funded by the Department of Veterans Affairs. The investigators had no disclosures.
FROM GASTROENTEROLOGY
Key clinical point: Eight-week and 12-week regimens of ledipasvir/sofosbuvir achieved similarly high rates of sustained viral response (SVR) among noncirrhotic, treatment-naive, genotype 1 hepatitis C virus–infected patients with viral loads under 6 million IU/mL.
Major finding: Twelve weeks after treatment, rates of SVR were 95.1% for the 8-week regimen and 95.8% for the 12-week regimen (P = .6).
Data source: A retrospective analysis of data from 17,487 patients with HCV infection.
Disclosures: The study was funded by the Department of Veterans Affairs. The investigators had no disclosures.