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Alcohol showed no cardiovascular benefits in nonalcoholic fatty liver disease
Alcohol consumption produced no apparent cardiovascular benefits among individuals with nonalcoholic fatty liver disease, according to a study of 570 white and black adults from the Coronary Artery Risk Development in Young Adults (CARDIA) longitudinal cohort.
After researchers controlled for multiple demographic and clinical confounders, alcohol use was not associated with cardiovascular risk factors such as diabetes, hypertension, or hyperlipidemia, nor with homeostatic model assessment of insulin resistance, C-reactive protein level, total cholesterol, systolic or diastolic blood pressure, coronary artery calcification, E/A ratio, or global longitudinal strain among individuals with nonalcoholic fatty liver disease (NAFLD), reported Lisa B. VanWagner, MD, of Northwestern University, Chicago, and her associates. “[A] recommendation of cardiovascular disease risk benefit of alcohol use in persons with NAFLD cannot be made based on the current findings,” they wrote. They advocated for prospective, long-term studies to better understand how various types and doses of alcohol affect hard cardiovascular endpoints in patients with NAFLD. Their study was published in Gastroenterology.
CARDIA enrolled 5,115 black and white adults aged 18-30 years from four cities in the United States, and followed them long term. Participants were asked about alcohol consumption at study entry and again at 15, 20, and 25 years of follow-up. At year 25, participants underwent computed tomography (CT) examinations of the thorax and abdomen and tissue Doppler echocardiography with myocardial strain measured by speckle tracking (Gastroenterology. 2017 Aug 9. doi: 10.1053/j.gastro.2017.08.012).
The 570 participants with NAFLD averaged 50 years of age, 54% were black, 46% were female, and 58% consumed at least one alcoholic drink per week, said the researchers. Compared with nondrinkers, drinkers had attained significantly higher education levels, were significantly more likely to be white and male, and had a significantly lower average body mass index (34.4 kg/m2 vs. 37.3 kg/m2) and C-reactive protein level (4.2 vs. 6.1 mg per L), and a significantly lower prevalence of diabetes (23% vs. 37%), impaired glucose tolerance (42% vs. 49%), obesity (75% vs. 83%) and metabolic syndrome (55% vs. 66%) (P less than .05 for all comparisons). Drinkers and nondrinkers resembled each other in terms of lipid profiles, use of lipid-lowering medications, liver attenuation scores, and systolic and diastolic blood pressures, although significantly more nondrinkers used antihypertensive medications (46% vs.35%; P = .005).
Drinkers had a higher prevalence of coronary artery calcification, defined as Agatston score above 0 (42% vs. 34%), and the difference approached statistical significance (P = .05). However, after they adjusted for multiple potential confounders, the researchers found no link between alcohol consumption and risk factors for cardiovascular disease or between alcohol consumption and measures of subclinical cardiovascular disease. This finding persisted in sensitivity analyses that examined alcohol dose, binge drinking, history of cardiovascular events, and former heavy alcohol use.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Taken together, the findings “challenge the belief that alcohol use may reduce cardiovascular disease risk in persons with nonalcoholic fatty liver disease,” the investigators concluded. Clinical heart failure was too rare to reliably assess, but “we failed to observe an association between alcohol use and multiple markers of subclinical changes in cardiac structure and function that may be precursors of incident heart failure in NAFLD,” they wrote. More longitudinal studies would be needed to clarify how moderate alcohol use in NAFLD affects coronary artery calcification or changes in myocardial structure and function, they cautioned.
The National Institutes of Health supported the work. The investigators reported having no relevant conflicts of interest.
Alcohol consumption produced no apparent cardiovascular benefits among individuals with nonalcoholic fatty liver disease, according to a study of 570 white and black adults from the Coronary Artery Risk Development in Young Adults (CARDIA) longitudinal cohort.
After researchers controlled for multiple demographic and clinical confounders, alcohol use was not associated with cardiovascular risk factors such as diabetes, hypertension, or hyperlipidemia, nor with homeostatic model assessment of insulin resistance, C-reactive protein level, total cholesterol, systolic or diastolic blood pressure, coronary artery calcification, E/A ratio, or global longitudinal strain among individuals with nonalcoholic fatty liver disease (NAFLD), reported Lisa B. VanWagner, MD, of Northwestern University, Chicago, and her associates. “[A] recommendation of cardiovascular disease risk benefit of alcohol use in persons with NAFLD cannot be made based on the current findings,” they wrote. They advocated for prospective, long-term studies to better understand how various types and doses of alcohol affect hard cardiovascular endpoints in patients with NAFLD. Their study was published in Gastroenterology.
CARDIA enrolled 5,115 black and white adults aged 18-30 years from four cities in the United States, and followed them long term. Participants were asked about alcohol consumption at study entry and again at 15, 20, and 25 years of follow-up. At year 25, participants underwent computed tomography (CT) examinations of the thorax and abdomen and tissue Doppler echocardiography with myocardial strain measured by speckle tracking (Gastroenterology. 2017 Aug 9. doi: 10.1053/j.gastro.2017.08.012).
The 570 participants with NAFLD averaged 50 years of age, 54% were black, 46% were female, and 58% consumed at least one alcoholic drink per week, said the researchers. Compared with nondrinkers, drinkers had attained significantly higher education levels, were significantly more likely to be white and male, and had a significantly lower average body mass index (34.4 kg/m2 vs. 37.3 kg/m2) and C-reactive protein level (4.2 vs. 6.1 mg per L), and a significantly lower prevalence of diabetes (23% vs. 37%), impaired glucose tolerance (42% vs. 49%), obesity (75% vs. 83%) and metabolic syndrome (55% vs. 66%) (P less than .05 for all comparisons). Drinkers and nondrinkers resembled each other in terms of lipid profiles, use of lipid-lowering medications, liver attenuation scores, and systolic and diastolic blood pressures, although significantly more nondrinkers used antihypertensive medications (46% vs.35%; P = .005).
Drinkers had a higher prevalence of coronary artery calcification, defined as Agatston score above 0 (42% vs. 34%), and the difference approached statistical significance (P = .05). However, after they adjusted for multiple potential confounders, the researchers found no link between alcohol consumption and risk factors for cardiovascular disease or between alcohol consumption and measures of subclinical cardiovascular disease. This finding persisted in sensitivity analyses that examined alcohol dose, binge drinking, history of cardiovascular events, and former heavy alcohol use.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Taken together, the findings “challenge the belief that alcohol use may reduce cardiovascular disease risk in persons with nonalcoholic fatty liver disease,” the investigators concluded. Clinical heart failure was too rare to reliably assess, but “we failed to observe an association between alcohol use and multiple markers of subclinical changes in cardiac structure and function that may be precursors of incident heart failure in NAFLD,” they wrote. More longitudinal studies would be needed to clarify how moderate alcohol use in NAFLD affects coronary artery calcification or changes in myocardial structure and function, they cautioned.
The National Institutes of Health supported the work. The investigators reported having no relevant conflicts of interest.
Alcohol consumption produced no apparent cardiovascular benefits among individuals with nonalcoholic fatty liver disease, according to a study of 570 white and black adults from the Coronary Artery Risk Development in Young Adults (CARDIA) longitudinal cohort.
After researchers controlled for multiple demographic and clinical confounders, alcohol use was not associated with cardiovascular risk factors such as diabetes, hypertension, or hyperlipidemia, nor with homeostatic model assessment of insulin resistance, C-reactive protein level, total cholesterol, systolic or diastolic blood pressure, coronary artery calcification, E/A ratio, or global longitudinal strain among individuals with nonalcoholic fatty liver disease (NAFLD), reported Lisa B. VanWagner, MD, of Northwestern University, Chicago, and her associates. “[A] recommendation of cardiovascular disease risk benefit of alcohol use in persons with NAFLD cannot be made based on the current findings,” they wrote. They advocated for prospective, long-term studies to better understand how various types and doses of alcohol affect hard cardiovascular endpoints in patients with NAFLD. Their study was published in Gastroenterology.
CARDIA enrolled 5,115 black and white adults aged 18-30 years from four cities in the United States, and followed them long term. Participants were asked about alcohol consumption at study entry and again at 15, 20, and 25 years of follow-up. At year 25, participants underwent computed tomography (CT) examinations of the thorax and abdomen and tissue Doppler echocardiography with myocardial strain measured by speckle tracking (Gastroenterology. 2017 Aug 9. doi: 10.1053/j.gastro.2017.08.012).
The 570 participants with NAFLD averaged 50 years of age, 54% were black, 46% were female, and 58% consumed at least one alcoholic drink per week, said the researchers. Compared with nondrinkers, drinkers had attained significantly higher education levels, were significantly more likely to be white and male, and had a significantly lower average body mass index (34.4 kg/m2 vs. 37.3 kg/m2) and C-reactive protein level (4.2 vs. 6.1 mg per L), and a significantly lower prevalence of diabetes (23% vs. 37%), impaired glucose tolerance (42% vs. 49%), obesity (75% vs. 83%) and metabolic syndrome (55% vs. 66%) (P less than .05 for all comparisons). Drinkers and nondrinkers resembled each other in terms of lipid profiles, use of lipid-lowering medications, liver attenuation scores, and systolic and diastolic blood pressures, although significantly more nondrinkers used antihypertensive medications (46% vs.35%; P = .005).
Drinkers had a higher prevalence of coronary artery calcification, defined as Agatston score above 0 (42% vs. 34%), and the difference approached statistical significance (P = .05). However, after they adjusted for multiple potential confounders, the researchers found no link between alcohol consumption and risk factors for cardiovascular disease or between alcohol consumption and measures of subclinical cardiovascular disease. This finding persisted in sensitivity analyses that examined alcohol dose, binge drinking, history of cardiovascular events, and former heavy alcohol use.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Taken together, the findings “challenge the belief that alcohol use may reduce cardiovascular disease risk in persons with nonalcoholic fatty liver disease,” the investigators concluded. Clinical heart failure was too rare to reliably assess, but “we failed to observe an association between alcohol use and multiple markers of subclinical changes in cardiac structure and function that may be precursors of incident heart failure in NAFLD,” they wrote. More longitudinal studies would be needed to clarify how moderate alcohol use in NAFLD affects coronary artery calcification or changes in myocardial structure and function, they cautioned.
The National Institutes of Health supported the work. The investigators reported having no relevant conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: No cardioprotective effects were shown with alcohol consumption in adults with nonalcoholic fatty liver disease.
Major finding: After researchers adjusted for multiple confounders, alcohol use was not associated with risk factors for cardiovascular disease or with indicators of subclinical cardiovascular disease.
Data source: A longitudinal, population-based study of 570 individuals with nonalcoholic fatty liver disease.
Disclosures: The National Institutes of Health supported the work. The investigators reported having no relevant conflicts of interest.
Biophysical properties of HCV evolve over course of infection
Hepatitis C virus (HCV) particles are of lowest density and most infectious early in the course of infection, based on findings from a study of chimeric mice.
Over time, however, viral density became more heterogeneous and infectivity fell, reported Ursula Andreo, PhD, of Rockefeller University, New York, with her coinvestigators. A diet of 10% sucrose, which in rats induces hepatic secretion of very-low-density lipoprotein (VLDL), caused HCV particles to become slightly lower density and more infectious in the mice, the researchers reported. Although the shift was “minor,” it “correlated with a trend toward enhanced triglyceride and cholesterol levels in the same fractions,” they wrote. They recommended studying high-fat diets to determine whether altering the VLDL secretion pathway affects the biophysical properties of HCV. “A high-fat diet might have a more significant impact on the lipoprotein profile in this humanized mouse model,” they wrote in Cellular and Molecular Gastroenterology and Hepatology (2017 Jul;4[3]:405-17).
Because HCV tends to associate with lipoproteins, it shows a range of buoyant densities in the blood of infected patients. The “entry, replication, and assembly [of the virion] are linked closely to host lipid and lipoprotein metabolism,” wrote Dr. Andreo and her colleagues.
They created an in vivo model to study the buoyant density and infectivity of HCV particles, as well as their interaction with lipoproteins, by grafting human hepatocytes into the livers of immunodeficient mice that were homozygous recessive for fumarylacetoacetate hydrolase. Next, they infected 13 of these chimeric mice with J6-JFH1, an HCV strain that can establish long-term infections in mice that have human liver grafts (Proc Natl Acad Sci USA. 2006;103[10]:3805-9). The human liver xenograft reconstituted the FAH gene, restoring triglycerides to normal levels in the chimeric mice and creating a suitable “humanlike” model of lipoprotein metabolism, the investigators wrote.
Density fractionation of infectious mouse serum revealed higher infectivity in the low-density fractions soon after infection, which also has been observed in a human liver chimeric mouse model of severe combined immunodeficiency disease, they added. In the HCV model, the human liver grafts were conserved 5 weeks after infection, and the mice had a lower proportion of lighter, infectious HCV particles.
The researchers lacked sufficient material to directly study the composition of virions or detect viral proteins in the various density fractions. However, they determined that apolipoprotein C1 was the lightest fraction and that apolipoprotein E was mainly found in the five lightest fractions. Both these apolipoproteins are “essential factors of HCV infectivity,” and neither redistributed over time, they said. They suggested using immunoelectron microscopy or mass spectrometry to study the nature and infectivity of viral particles further.
In humans, ingesting a high-fat milkshake increases detectable HCV RNA in the VLDL fraction, the researchers noted. In rodents, a sucrose diet also has been found to increase VLDL lipidation and secretion, so they gave five of the infected chimeric mice drinking water containing 10% sucrose. After 5 weeks, these mice had increased infectivity and higher levels of triglycerides and cholesterol, but the effect was small and disappeared after the sucrose was withdrawn.
HCV “circulates as a population of particles of light, as well as dense, buoyant densities, and both are infectious,” the researchers concluded. “Changes in diet, as well as conditions such as fasting and feeding, affect the distribution of HCV buoyant density gradients.”
Funders included the National Institutes of Health and the American Association for the Study of Liver Diseases. The investigators disclosed no conflicts.
A hallmark of HCV infection is the association of virus particles with lipoproteins. The HCV virion (lipo-viro particle, LVP) is composed of nucleocapsid and envelope glycoproteins associated with very-low- and low-density lipoproteins, cholesterol, and apolipoproteins. The lipid components determine the size, density, hepatotropism, and infectivity of LVPs and play a role in cell entry, morphogenesis, release, and viral escape mechanisms. LVPs undergo dynamic changes during infection, and dietary triglycerides induce alterations in their biophysical properties and infectivity.
Dr. Andreo and colleagues used humanized Fah–/– mice to analyze the evolution of HCV particles during infection. As previously reported, two viral populations of different densities were detected in mice sera, with higher infectivity observed for the low-density population. The proportions and infectivity of these populations varied during infection, reflecting changes in biochemical features of the virus. Sucrose diet influenced the properties of virus particles; these properties’ changes correlated with a redistribution of triglycerides and cholesterol among lipoproteins.
Changes in biochemical features of the virus during infection represent a fascinating aspect of the structural heterogeneity, which influences HCV infectivity and evolution of the disease. Further studies in experimental models that reproduce the lipoprotein-dependent morphogenesis and release of virus particles, maturation, and intravascular remodeling of HCV-associated lipoproteins would help to develop novel lipid-targeting inhibitors to improve existing therapies.
Agata Budkowska, PhD, is scientific advisor for the department of international affairs at the Institut Pasteur, Paris. She has no conflicts of interest.
A hallmark of HCV infection is the association of virus particles with lipoproteins. The HCV virion (lipo-viro particle, LVP) is composed of nucleocapsid and envelope glycoproteins associated with very-low- and low-density lipoproteins, cholesterol, and apolipoproteins. The lipid components determine the size, density, hepatotropism, and infectivity of LVPs and play a role in cell entry, morphogenesis, release, and viral escape mechanisms. LVPs undergo dynamic changes during infection, and dietary triglycerides induce alterations in their biophysical properties and infectivity.
Dr. Andreo and colleagues used humanized Fah–/– mice to analyze the evolution of HCV particles during infection. As previously reported, two viral populations of different densities were detected in mice sera, with higher infectivity observed for the low-density population. The proportions and infectivity of these populations varied during infection, reflecting changes in biochemical features of the virus. Sucrose diet influenced the properties of virus particles; these properties’ changes correlated with a redistribution of triglycerides and cholesterol among lipoproteins.
Changes in biochemical features of the virus during infection represent a fascinating aspect of the structural heterogeneity, which influences HCV infectivity and evolution of the disease. Further studies in experimental models that reproduce the lipoprotein-dependent morphogenesis and release of virus particles, maturation, and intravascular remodeling of HCV-associated lipoproteins would help to develop novel lipid-targeting inhibitors to improve existing therapies.
Agata Budkowska, PhD, is scientific advisor for the department of international affairs at the Institut Pasteur, Paris. She has no conflicts of interest.
A hallmark of HCV infection is the association of virus particles with lipoproteins. The HCV virion (lipo-viro particle, LVP) is composed of nucleocapsid and envelope glycoproteins associated with very-low- and low-density lipoproteins, cholesterol, and apolipoproteins. The lipid components determine the size, density, hepatotropism, and infectivity of LVPs and play a role in cell entry, morphogenesis, release, and viral escape mechanisms. LVPs undergo dynamic changes during infection, and dietary triglycerides induce alterations in their biophysical properties and infectivity.
Dr. Andreo and colleagues used humanized Fah–/– mice to analyze the evolution of HCV particles during infection. As previously reported, two viral populations of different densities were detected in mice sera, with higher infectivity observed for the low-density population. The proportions and infectivity of these populations varied during infection, reflecting changes in biochemical features of the virus. Sucrose diet influenced the properties of virus particles; these properties’ changes correlated with a redistribution of triglycerides and cholesterol among lipoproteins.
Changes in biochemical features of the virus during infection represent a fascinating aspect of the structural heterogeneity, which influences HCV infectivity and evolution of the disease. Further studies in experimental models that reproduce the lipoprotein-dependent morphogenesis and release of virus particles, maturation, and intravascular remodeling of HCV-associated lipoproteins would help to develop novel lipid-targeting inhibitors to improve existing therapies.
Agata Budkowska, PhD, is scientific advisor for the department of international affairs at the Institut Pasteur, Paris. She has no conflicts of interest.
Hepatitis C virus (HCV) particles are of lowest density and most infectious early in the course of infection, based on findings from a study of chimeric mice.
Over time, however, viral density became more heterogeneous and infectivity fell, reported Ursula Andreo, PhD, of Rockefeller University, New York, with her coinvestigators. A diet of 10% sucrose, which in rats induces hepatic secretion of very-low-density lipoprotein (VLDL), caused HCV particles to become slightly lower density and more infectious in the mice, the researchers reported. Although the shift was “minor,” it “correlated with a trend toward enhanced triglyceride and cholesterol levels in the same fractions,” they wrote. They recommended studying high-fat diets to determine whether altering the VLDL secretion pathway affects the biophysical properties of HCV. “A high-fat diet might have a more significant impact on the lipoprotein profile in this humanized mouse model,” they wrote in Cellular and Molecular Gastroenterology and Hepatology (2017 Jul;4[3]:405-17).
Because HCV tends to associate with lipoproteins, it shows a range of buoyant densities in the blood of infected patients. The “entry, replication, and assembly [of the virion] are linked closely to host lipid and lipoprotein metabolism,” wrote Dr. Andreo and her colleagues.
They created an in vivo model to study the buoyant density and infectivity of HCV particles, as well as their interaction with lipoproteins, by grafting human hepatocytes into the livers of immunodeficient mice that were homozygous recessive for fumarylacetoacetate hydrolase. Next, they infected 13 of these chimeric mice with J6-JFH1, an HCV strain that can establish long-term infections in mice that have human liver grafts (Proc Natl Acad Sci USA. 2006;103[10]:3805-9). The human liver xenograft reconstituted the FAH gene, restoring triglycerides to normal levels in the chimeric mice and creating a suitable “humanlike” model of lipoprotein metabolism, the investigators wrote.
Density fractionation of infectious mouse serum revealed higher infectivity in the low-density fractions soon after infection, which also has been observed in a human liver chimeric mouse model of severe combined immunodeficiency disease, they added. In the HCV model, the human liver grafts were conserved 5 weeks after infection, and the mice had a lower proportion of lighter, infectious HCV particles.
The researchers lacked sufficient material to directly study the composition of virions or detect viral proteins in the various density fractions. However, they determined that apolipoprotein C1 was the lightest fraction and that apolipoprotein E was mainly found in the five lightest fractions. Both these apolipoproteins are “essential factors of HCV infectivity,” and neither redistributed over time, they said. They suggested using immunoelectron microscopy or mass spectrometry to study the nature and infectivity of viral particles further.
In humans, ingesting a high-fat milkshake increases detectable HCV RNA in the VLDL fraction, the researchers noted. In rodents, a sucrose diet also has been found to increase VLDL lipidation and secretion, so they gave five of the infected chimeric mice drinking water containing 10% sucrose. After 5 weeks, these mice had increased infectivity and higher levels of triglycerides and cholesterol, but the effect was small and disappeared after the sucrose was withdrawn.
HCV “circulates as a population of particles of light, as well as dense, buoyant densities, and both are infectious,” the researchers concluded. “Changes in diet, as well as conditions such as fasting and feeding, affect the distribution of HCV buoyant density gradients.”
Funders included the National Institutes of Health and the American Association for the Study of Liver Diseases. The investigators disclosed no conflicts.
Hepatitis C virus (HCV) particles are of lowest density and most infectious early in the course of infection, based on findings from a study of chimeric mice.
Over time, however, viral density became more heterogeneous and infectivity fell, reported Ursula Andreo, PhD, of Rockefeller University, New York, with her coinvestigators. A diet of 10% sucrose, which in rats induces hepatic secretion of very-low-density lipoprotein (VLDL), caused HCV particles to become slightly lower density and more infectious in the mice, the researchers reported. Although the shift was “minor,” it “correlated with a trend toward enhanced triglyceride and cholesterol levels in the same fractions,” they wrote. They recommended studying high-fat diets to determine whether altering the VLDL secretion pathway affects the biophysical properties of HCV. “A high-fat diet might have a more significant impact on the lipoprotein profile in this humanized mouse model,” they wrote in Cellular and Molecular Gastroenterology and Hepatology (2017 Jul;4[3]:405-17).
Because HCV tends to associate with lipoproteins, it shows a range of buoyant densities in the blood of infected patients. The “entry, replication, and assembly [of the virion] are linked closely to host lipid and lipoprotein metabolism,” wrote Dr. Andreo and her colleagues.
They created an in vivo model to study the buoyant density and infectivity of HCV particles, as well as their interaction with lipoproteins, by grafting human hepatocytes into the livers of immunodeficient mice that were homozygous recessive for fumarylacetoacetate hydrolase. Next, they infected 13 of these chimeric mice with J6-JFH1, an HCV strain that can establish long-term infections in mice that have human liver grafts (Proc Natl Acad Sci USA. 2006;103[10]:3805-9). The human liver xenograft reconstituted the FAH gene, restoring triglycerides to normal levels in the chimeric mice and creating a suitable “humanlike” model of lipoprotein metabolism, the investigators wrote.
Density fractionation of infectious mouse serum revealed higher infectivity in the low-density fractions soon after infection, which also has been observed in a human liver chimeric mouse model of severe combined immunodeficiency disease, they added. In the HCV model, the human liver grafts were conserved 5 weeks after infection, and the mice had a lower proportion of lighter, infectious HCV particles.
The researchers lacked sufficient material to directly study the composition of virions or detect viral proteins in the various density fractions. However, they determined that apolipoprotein C1 was the lightest fraction and that apolipoprotein E was mainly found in the five lightest fractions. Both these apolipoproteins are “essential factors of HCV infectivity,” and neither redistributed over time, they said. They suggested using immunoelectron microscopy or mass spectrometry to study the nature and infectivity of viral particles further.
In humans, ingesting a high-fat milkshake increases detectable HCV RNA in the VLDL fraction, the researchers noted. In rodents, a sucrose diet also has been found to increase VLDL lipidation and secretion, so they gave five of the infected chimeric mice drinking water containing 10% sucrose. After 5 weeks, these mice had increased infectivity and higher levels of triglycerides and cholesterol, but the effect was small and disappeared after the sucrose was withdrawn.
HCV “circulates as a population of particles of light, as well as dense, buoyant densities, and both are infectious,” the researchers concluded. “Changes in diet, as well as conditions such as fasting and feeding, affect the distribution of HCV buoyant density gradients.”
Funders included the National Institutes of Health and the American Association for the Study of Liver Diseases. The investigators disclosed no conflicts.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: The biophysical properties of the hepatitis C virus evolve during the course of infection and shift with dietary changes.
Major finding: Density fractionation of infectious mouse serum showed higher infectivity in the low-density fractions soon after infection, but heterogeneity subsequently increased while infectivity decreased. A 5-week diet of 10% sucrose produced a minor shift toward infectivity that correlated with redistribution of triglycerides and cholesterol.
Data source: A study of 13 human liver chimeric mice.
Disclosures: Funders included the National Institutes of Health and the American Association for the Study of Liver Diseases. The investigators disclosed no conflicts.
POEM found safe, effective for treating achalasia after failed Heller myotomy
Peroral endoscopic myotomy (POEM) safely and effectively treated achalasia in patients with persistent symptoms after Heller myotomy, according to the results of a retrospective study of 180 patients treated at 13 centers worldwide.
Rates of clinical success were 81% among patients who had previously undergone Heller myotomy and 94% among those who had not (P = .01), reported Saowanee Ngamruengphong, MD, of Johns Hopkins Medical Center, Baltimore, with her associates. The groups did not significantly differ in terms of rates of adverse events (8% and 13%, respectively), postprocedural symptomatic reflux (30% and 32%), or reflux esophagitis (44% and 52%). “Although the rate of clinical success in patients with prior Heller myotomy is lower than in those without [it], the safety profile of POEM is comparable,” they wrote in the October issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.01.031).
Heller myotomy achieves a long-term symptomatic response in about 90% of patients with achalasia and has a complication rate of only about 5%, according to Dr. Ngamruengphong and her associates. When this surgery does not successfully resolve symptoms, patients historically have chosen between repeating it or undergoing pneumatic dilation. However, POEM posted high success rates in several small, single-center case series. Thus, the researchers analyzed data on 180 adults with achalasia whose Eckardt scores were at least 3 and who underwent POEM at 13 tertiary care centers in Australia, France, Hong Kong, India, Italy, Japan, the United Kingdom, and the United States during 2009-2015.
POEM was a technical success for 98% for the group of patients who previously had undergone Heller myotomy and for 100% for those who had not, the researchers reported. In the univariate analysis, predictors of clinical failure included prior Heller myotomy (odds ratio, 3.6; 95% confidence interval, 1.3-10.4; P = .02) and prior pneumatic dilation (OR, 2.9; 95% CI, 1.2-7.4; P = .02). In the multivariable analysis, prior Heller myotomy significantly increased the chances of clinical failure (adjusted OR, 3.0; 95% confidence interval, 1.0-8.9; P = .04) after accounting for prior pneumatic dilation and baseline Eckardt score. Prior pneumatic dilation reached borderline significance (adjusted OR, 2.6; 95% CI, 0.99-7.0; P = .05). Clinical failure was not associated with age, sex, achalasia subtypes, previous therapy, baseline Eckardt score, length of myotomy, orientation of myotomy, or extent of lower esophageal sphincter myotomy.
“Previous studies have reported that the success rates of pneumatic dilation in patients who failed prior Heller myotomy ranged between 50% and 89%,” the researchers said. However, success is often short-lived, with up to 45% of patients needing another procedure within 2 years, putting them at risk of “potentially serious adverse events, such as esophageal perforation or aspiration,” they added.
Repeat surgical myotomy is reportedly successful in 73%-89% of cases; however, itis technically challenging because of adhesions and fibrosis from the previous surgery and is associated with a high risk of gastrointestinal perforation.
Clinicians should carefully investigate the reasons a Heller myotomy failed in order to elect a course of action, the researchers emphasized. “For instance, for patients with symptom relapse or failure to respond to surgical myotomy as a result of incomplete myotomy or myotomy fibrosis, POEM is likely to be effective,” they said. “On the other hand, when the cause of persistent symptoms after surgical myotomy is tight fundoplication, a redo fundoplication should be recommended.”
Dr. Ngamruengphong had no disclosures. Three coinvestigators disclosed consulting relationships with Boston Scientific, Medtronic, Sandhill Scientific, Erbe, and Cosmo Pharmaceuticals.
Peroral endoscopic myotomy (POEM) safely and effectively treated achalasia in patients with persistent symptoms after Heller myotomy, according to the results of a retrospective study of 180 patients treated at 13 centers worldwide.
Rates of clinical success were 81% among patients who had previously undergone Heller myotomy and 94% among those who had not (P = .01), reported Saowanee Ngamruengphong, MD, of Johns Hopkins Medical Center, Baltimore, with her associates. The groups did not significantly differ in terms of rates of adverse events (8% and 13%, respectively), postprocedural symptomatic reflux (30% and 32%), or reflux esophagitis (44% and 52%). “Although the rate of clinical success in patients with prior Heller myotomy is lower than in those without [it], the safety profile of POEM is comparable,” they wrote in the October issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.01.031).
Heller myotomy achieves a long-term symptomatic response in about 90% of patients with achalasia and has a complication rate of only about 5%, according to Dr. Ngamruengphong and her associates. When this surgery does not successfully resolve symptoms, patients historically have chosen between repeating it or undergoing pneumatic dilation. However, POEM posted high success rates in several small, single-center case series. Thus, the researchers analyzed data on 180 adults with achalasia whose Eckardt scores were at least 3 and who underwent POEM at 13 tertiary care centers in Australia, France, Hong Kong, India, Italy, Japan, the United Kingdom, and the United States during 2009-2015.
POEM was a technical success for 98% for the group of patients who previously had undergone Heller myotomy and for 100% for those who had not, the researchers reported. In the univariate analysis, predictors of clinical failure included prior Heller myotomy (odds ratio, 3.6; 95% confidence interval, 1.3-10.4; P = .02) and prior pneumatic dilation (OR, 2.9; 95% CI, 1.2-7.4; P = .02). In the multivariable analysis, prior Heller myotomy significantly increased the chances of clinical failure (adjusted OR, 3.0; 95% confidence interval, 1.0-8.9; P = .04) after accounting for prior pneumatic dilation and baseline Eckardt score. Prior pneumatic dilation reached borderline significance (adjusted OR, 2.6; 95% CI, 0.99-7.0; P = .05). Clinical failure was not associated with age, sex, achalasia subtypes, previous therapy, baseline Eckardt score, length of myotomy, orientation of myotomy, or extent of lower esophageal sphincter myotomy.
“Previous studies have reported that the success rates of pneumatic dilation in patients who failed prior Heller myotomy ranged between 50% and 89%,” the researchers said. However, success is often short-lived, with up to 45% of patients needing another procedure within 2 years, putting them at risk of “potentially serious adverse events, such as esophageal perforation or aspiration,” they added.
Repeat surgical myotomy is reportedly successful in 73%-89% of cases; however, itis technically challenging because of adhesions and fibrosis from the previous surgery and is associated with a high risk of gastrointestinal perforation.
Clinicians should carefully investigate the reasons a Heller myotomy failed in order to elect a course of action, the researchers emphasized. “For instance, for patients with symptom relapse or failure to respond to surgical myotomy as a result of incomplete myotomy or myotomy fibrosis, POEM is likely to be effective,” they said. “On the other hand, when the cause of persistent symptoms after surgical myotomy is tight fundoplication, a redo fundoplication should be recommended.”
Dr. Ngamruengphong had no disclosures. Three coinvestigators disclosed consulting relationships with Boston Scientific, Medtronic, Sandhill Scientific, Erbe, and Cosmo Pharmaceuticals.
Peroral endoscopic myotomy (POEM) safely and effectively treated achalasia in patients with persistent symptoms after Heller myotomy, according to the results of a retrospective study of 180 patients treated at 13 centers worldwide.
Rates of clinical success were 81% among patients who had previously undergone Heller myotomy and 94% among those who had not (P = .01), reported Saowanee Ngamruengphong, MD, of Johns Hopkins Medical Center, Baltimore, with her associates. The groups did not significantly differ in terms of rates of adverse events (8% and 13%, respectively), postprocedural symptomatic reflux (30% and 32%), or reflux esophagitis (44% and 52%). “Although the rate of clinical success in patients with prior Heller myotomy is lower than in those without [it], the safety profile of POEM is comparable,” they wrote in the October issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.01.031).
Heller myotomy achieves a long-term symptomatic response in about 90% of patients with achalasia and has a complication rate of only about 5%, according to Dr. Ngamruengphong and her associates. When this surgery does not successfully resolve symptoms, patients historically have chosen between repeating it or undergoing pneumatic dilation. However, POEM posted high success rates in several small, single-center case series. Thus, the researchers analyzed data on 180 adults with achalasia whose Eckardt scores were at least 3 and who underwent POEM at 13 tertiary care centers in Australia, France, Hong Kong, India, Italy, Japan, the United Kingdom, and the United States during 2009-2015.
POEM was a technical success for 98% for the group of patients who previously had undergone Heller myotomy and for 100% for those who had not, the researchers reported. In the univariate analysis, predictors of clinical failure included prior Heller myotomy (odds ratio, 3.6; 95% confidence interval, 1.3-10.4; P = .02) and prior pneumatic dilation (OR, 2.9; 95% CI, 1.2-7.4; P = .02). In the multivariable analysis, prior Heller myotomy significantly increased the chances of clinical failure (adjusted OR, 3.0; 95% confidence interval, 1.0-8.9; P = .04) after accounting for prior pneumatic dilation and baseline Eckardt score. Prior pneumatic dilation reached borderline significance (adjusted OR, 2.6; 95% CI, 0.99-7.0; P = .05). Clinical failure was not associated with age, sex, achalasia subtypes, previous therapy, baseline Eckardt score, length of myotomy, orientation of myotomy, or extent of lower esophageal sphincter myotomy.
“Previous studies have reported that the success rates of pneumatic dilation in patients who failed prior Heller myotomy ranged between 50% and 89%,” the researchers said. However, success is often short-lived, with up to 45% of patients needing another procedure within 2 years, putting them at risk of “potentially serious adverse events, such as esophageal perforation or aspiration,” they added.
Repeat surgical myotomy is reportedly successful in 73%-89% of cases; however, itis technically challenging because of adhesions and fibrosis from the previous surgery and is associated with a high risk of gastrointestinal perforation.
Clinicians should carefully investigate the reasons a Heller myotomy failed in order to elect a course of action, the researchers emphasized. “For instance, for patients with symptom relapse or failure to respond to surgical myotomy as a result of incomplete myotomy or myotomy fibrosis, POEM is likely to be effective,” they said. “On the other hand, when the cause of persistent symptoms after surgical myotomy is tight fundoplication, a redo fundoplication should be recommended.”
Dr. Ngamruengphong had no disclosures. Three coinvestigators disclosed consulting relationships with Boston Scientific, Medtronic, Sandhill Scientific, Erbe, and Cosmo Pharmaceuticals.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point:
Major finding: Rates of clinical success were 81% when patients had previously undergone Heller myotomy and 94% when they had not (P = .01). Rates of adverse events (8% and 13%, respectively), as well as rates of postprocedural symptomatic reflux (30% and 32%) and reflux esophagitis (44% and 52%), were similar between groups.
Data source: A multicenter retrospective study of 180 patients with achalasia, half of whom had symptoms despite prior Heller myotomy.
Disclosures: Dr. Ngamruengphong had no disclosures. Three coinvestigators disclosed consulting relationships with Boston Scientific, Medtronic, Sandhill Scientific, Erbe, and Cosmo Pharmaceuticals.
Study linked H2 receptor antagonists, but not PPIs, to dementia
A large prospective study of middle-aged and older women found no convincing evidence that using proton pump inhibitors increased their risk of dementia, investigators reported.
However, using H2 receptor antagonists for at least 9 years was associated with a slight decrease in scores of learning and working memory (mean decrease, –0.2; 95% confidence interval, –0.3 to –0.08; P less than .001), Paul Lochhead, MBChB, PhD, and his associates wrote in the October issue of Gastroenterology (doi: 10.1053/j.gastro.2017.06.061). “Since our primary hypothesis related to PPI [proton pump inhibitor] use, our findings for [H2 receptor antagonists] should be interpreted with caution,” they said.
Source: American Gastroenterological Association
In a recent German study of a medical claims database, use of PPIs was associated with a 44% increase in the likelihood of incident dementia (JAMA Neurol. 2016;73:410-6). “The existence of a causal mechanism linking PPI use to dementia is suggested by observations from cellular and animal models of Alzheimer’s disease, where PPI exposure appears to influence amyloid-beta metabolism,” Dr. Lochhead and his associates wrote. “However, other preclinical data on PPIs and Alzheimer’s disease are conflicting.” Noting that cognitive function predicts dementia later in life, they analyzed prospective data on medications and other potential risk factors from 13,864 participants in the Nurses’ Health Study II who had completed Cogstate, a computerized, self-administered neuropsychological battery.
Study participants averaged 61 years old when they underwent cognitive testing, ranging in age from 50 to 70 years. Users of PPIs tended to be older, had more comorbidities, were less physically active, had higher body mass indexes, had less education, and ate a lower-quality diet than women who did not use PPIs. After adjusting for such confounders, using PPIs for 9-14 years was associated with a modest decrease in scores for psychomotor speed and attention (mean score difference, compared with never users, –0.06; 95% CI, –0.11 to 0.00; P = .03). “For comparison, in multivariable models, a 1-year increase in age was associated with mean score decreases of 0.03 for psychomotor speed and attention, 0.02 for learning and working memory, and 0.03 for overall cognition,” the researchers wrote.
Next, they examined links between use of H2 receptor antagonists and cognitive scores among 10,778 study participants who had used PPIs for 2 years or less. Use of H2 receptor antagonists for 9-14 years predicted poorer scores on learning, working memory, and overall cognition, even after controlling for potential confounders (P less than or equal to .002). “The magnitudes of mean score differences were larger than those observed in the analysis of PPI use, particularly for learning and working memory,” the researchers noted. Additionally, PPI use did not predict lower cognitive scores among individuals who had never used H2 receptor antagonists.
On the other hand, using PPIs for 9-14 years was associated with the equivalent of about 2 years of age-related cognitive decline, and controlling for exposure to H2 receptor antagonists weakened even this modest effect, the investigators said. Users and nonusers of PPIs tend to differ on many measures, and analyses of claims data, such as the German study above, are less able to account for these potential confounders, they noted. “Nonjudicious PPI prescribing is especially frequent among the elderly and those with cognitive impairment,” they added. “Therefore, elderly individuals who have frequent contact with health providers are at increased risk of both PPI prescription and dementia diagnosis. This bias may not be completely mitigated by adjustment for comorbidities or polypharmacy.”
The findings regarding H2 receptor antagonists reflect those of three smaller cohort studies, and these medications are known to cause central nervous system effects in the elderly, including delirium, the researchers said. Ranitidine and cimetidine have anticholinergic effects that also could “pose a risk for adverse cognitive effects with long-term use.”
Dr. Lochhead reported having no conflicts. Two coinvestigators disclosed ties to Bayer Healthcare, Pfizer, Aralez Pharmaceuticals, AbbVie, Samsung Bioepis, and Takeda.
Numerous possible PPI-related adverse events have been reported within the past few years; some resultant media attention has caused anxiety for patients. Dementia is a dreaded diagnosis. Therefore, initial reports that PPI treatment might be associated with an increased risk of dementia attracted considerable media attention, much of which was unbalanced and uninformed. There is no obvious biological rationale for such an association, and the risks reported initially were of small magnitude (for example, hazard ratios of approximately 1.4). However, patients cannot reliably assess levels of risk from media coverage that often veers toward sensationalism.
The study by Lochhead et al. is a welcome contribution to the topic of PPI safety. Using the Nurses’ Health Study II database, the investigators measured cognitive function in a large group of female PPI users and nonusers. Unsurprisingly, PPI users were older and sicker than nonusers. There were quantitatively small changes in some measures of cognitive function among PPI users. However, learning and working memory scores, which are more predictive of Alzheimer’s-type cognitive decline, were unaffected by PPI use.
For those prescribers with residual concerns about any association between PPIs and dementia, these prospectively collected data on cognitive function should provide further reassurance. It is appropriate that this study should have been highlighted in GI & Hepatology News, but since it lacks the potential sensationalism of studies that report a putative association, we should not expect it to be discussed on the TV evening news anytime soon!
Colin W. Howden, MD, AGAF, is chief of gastroenterology at University of Tennessee Health Science Center, Memphis. He has been a consultant, investigator, and/or speaker for all PPI manufacturers at some time. He is currently a consultant for Takeda, Aralez, and Pfizer Consumer Health.
Numerous possible PPI-related adverse events have been reported within the past few years; some resultant media attention has caused anxiety for patients. Dementia is a dreaded diagnosis. Therefore, initial reports that PPI treatment might be associated with an increased risk of dementia attracted considerable media attention, much of which was unbalanced and uninformed. There is no obvious biological rationale for such an association, and the risks reported initially were of small magnitude (for example, hazard ratios of approximately 1.4). However, patients cannot reliably assess levels of risk from media coverage that often veers toward sensationalism.
The study by Lochhead et al. is a welcome contribution to the topic of PPI safety. Using the Nurses’ Health Study II database, the investigators measured cognitive function in a large group of female PPI users and nonusers. Unsurprisingly, PPI users were older and sicker than nonusers. There were quantitatively small changes in some measures of cognitive function among PPI users. However, learning and working memory scores, which are more predictive of Alzheimer’s-type cognitive decline, were unaffected by PPI use.
For those prescribers with residual concerns about any association between PPIs and dementia, these prospectively collected data on cognitive function should provide further reassurance. It is appropriate that this study should have been highlighted in GI & Hepatology News, but since it lacks the potential sensationalism of studies that report a putative association, we should not expect it to be discussed on the TV evening news anytime soon!
Colin W. Howden, MD, AGAF, is chief of gastroenterology at University of Tennessee Health Science Center, Memphis. He has been a consultant, investigator, and/or speaker for all PPI manufacturers at some time. He is currently a consultant for Takeda, Aralez, and Pfizer Consumer Health.
Numerous possible PPI-related adverse events have been reported within the past few years; some resultant media attention has caused anxiety for patients. Dementia is a dreaded diagnosis. Therefore, initial reports that PPI treatment might be associated with an increased risk of dementia attracted considerable media attention, much of which was unbalanced and uninformed. There is no obvious biological rationale for such an association, and the risks reported initially were of small magnitude (for example, hazard ratios of approximately 1.4). However, patients cannot reliably assess levels of risk from media coverage that often veers toward sensationalism.
The study by Lochhead et al. is a welcome contribution to the topic of PPI safety. Using the Nurses’ Health Study II database, the investigators measured cognitive function in a large group of female PPI users and nonusers. Unsurprisingly, PPI users were older and sicker than nonusers. There were quantitatively small changes in some measures of cognitive function among PPI users. However, learning and working memory scores, which are more predictive of Alzheimer’s-type cognitive decline, were unaffected by PPI use.
For those prescribers with residual concerns about any association between PPIs and dementia, these prospectively collected data on cognitive function should provide further reassurance. It is appropriate that this study should have been highlighted in GI & Hepatology News, but since it lacks the potential sensationalism of studies that report a putative association, we should not expect it to be discussed on the TV evening news anytime soon!
Colin W. Howden, MD, AGAF, is chief of gastroenterology at University of Tennessee Health Science Center, Memphis. He has been a consultant, investigator, and/or speaker for all PPI manufacturers at some time. He is currently a consultant for Takeda, Aralez, and Pfizer Consumer Health.
A large prospective study of middle-aged and older women found no convincing evidence that using proton pump inhibitors increased their risk of dementia, investigators reported.
However, using H2 receptor antagonists for at least 9 years was associated with a slight decrease in scores of learning and working memory (mean decrease, –0.2; 95% confidence interval, –0.3 to –0.08; P less than .001), Paul Lochhead, MBChB, PhD, and his associates wrote in the October issue of Gastroenterology (doi: 10.1053/j.gastro.2017.06.061). “Since our primary hypothesis related to PPI [proton pump inhibitor] use, our findings for [H2 receptor antagonists] should be interpreted with caution,” they said.
Source: American Gastroenterological Association
In a recent German study of a medical claims database, use of PPIs was associated with a 44% increase in the likelihood of incident dementia (JAMA Neurol. 2016;73:410-6). “The existence of a causal mechanism linking PPI use to dementia is suggested by observations from cellular and animal models of Alzheimer’s disease, where PPI exposure appears to influence amyloid-beta metabolism,” Dr. Lochhead and his associates wrote. “However, other preclinical data on PPIs and Alzheimer’s disease are conflicting.” Noting that cognitive function predicts dementia later in life, they analyzed prospective data on medications and other potential risk factors from 13,864 participants in the Nurses’ Health Study II who had completed Cogstate, a computerized, self-administered neuropsychological battery.
Study participants averaged 61 years old when they underwent cognitive testing, ranging in age from 50 to 70 years. Users of PPIs tended to be older, had more comorbidities, were less physically active, had higher body mass indexes, had less education, and ate a lower-quality diet than women who did not use PPIs. After adjusting for such confounders, using PPIs for 9-14 years was associated with a modest decrease in scores for psychomotor speed and attention (mean score difference, compared with never users, –0.06; 95% CI, –0.11 to 0.00; P = .03). “For comparison, in multivariable models, a 1-year increase in age was associated with mean score decreases of 0.03 for psychomotor speed and attention, 0.02 for learning and working memory, and 0.03 for overall cognition,” the researchers wrote.
Next, they examined links between use of H2 receptor antagonists and cognitive scores among 10,778 study participants who had used PPIs for 2 years or less. Use of H2 receptor antagonists for 9-14 years predicted poorer scores on learning, working memory, and overall cognition, even after controlling for potential confounders (P less than or equal to .002). “The magnitudes of mean score differences were larger than those observed in the analysis of PPI use, particularly for learning and working memory,” the researchers noted. Additionally, PPI use did not predict lower cognitive scores among individuals who had never used H2 receptor antagonists.
On the other hand, using PPIs for 9-14 years was associated with the equivalent of about 2 years of age-related cognitive decline, and controlling for exposure to H2 receptor antagonists weakened even this modest effect, the investigators said. Users and nonusers of PPIs tend to differ on many measures, and analyses of claims data, such as the German study above, are less able to account for these potential confounders, they noted. “Nonjudicious PPI prescribing is especially frequent among the elderly and those with cognitive impairment,” they added. “Therefore, elderly individuals who have frequent contact with health providers are at increased risk of both PPI prescription and dementia diagnosis. This bias may not be completely mitigated by adjustment for comorbidities or polypharmacy.”
The findings regarding H2 receptor antagonists reflect those of three smaller cohort studies, and these medications are known to cause central nervous system effects in the elderly, including delirium, the researchers said. Ranitidine and cimetidine have anticholinergic effects that also could “pose a risk for adverse cognitive effects with long-term use.”
Dr. Lochhead reported having no conflicts. Two coinvestigators disclosed ties to Bayer Healthcare, Pfizer, Aralez Pharmaceuticals, AbbVie, Samsung Bioepis, and Takeda.
A large prospective study of middle-aged and older women found no convincing evidence that using proton pump inhibitors increased their risk of dementia, investigators reported.
However, using H2 receptor antagonists for at least 9 years was associated with a slight decrease in scores of learning and working memory (mean decrease, –0.2; 95% confidence interval, –0.3 to –0.08; P less than .001), Paul Lochhead, MBChB, PhD, and his associates wrote in the October issue of Gastroenterology (doi: 10.1053/j.gastro.2017.06.061). “Since our primary hypothesis related to PPI [proton pump inhibitor] use, our findings for [H2 receptor antagonists] should be interpreted with caution,” they said.
Source: American Gastroenterological Association
In a recent German study of a medical claims database, use of PPIs was associated with a 44% increase in the likelihood of incident dementia (JAMA Neurol. 2016;73:410-6). “The existence of a causal mechanism linking PPI use to dementia is suggested by observations from cellular and animal models of Alzheimer’s disease, where PPI exposure appears to influence amyloid-beta metabolism,” Dr. Lochhead and his associates wrote. “However, other preclinical data on PPIs and Alzheimer’s disease are conflicting.” Noting that cognitive function predicts dementia later in life, they analyzed prospective data on medications and other potential risk factors from 13,864 participants in the Nurses’ Health Study II who had completed Cogstate, a computerized, self-administered neuropsychological battery.
Study participants averaged 61 years old when they underwent cognitive testing, ranging in age from 50 to 70 years. Users of PPIs tended to be older, had more comorbidities, were less physically active, had higher body mass indexes, had less education, and ate a lower-quality diet than women who did not use PPIs. After adjusting for such confounders, using PPIs for 9-14 years was associated with a modest decrease in scores for psychomotor speed and attention (mean score difference, compared with never users, –0.06; 95% CI, –0.11 to 0.00; P = .03). “For comparison, in multivariable models, a 1-year increase in age was associated with mean score decreases of 0.03 for psychomotor speed and attention, 0.02 for learning and working memory, and 0.03 for overall cognition,” the researchers wrote.
Next, they examined links between use of H2 receptor antagonists and cognitive scores among 10,778 study participants who had used PPIs for 2 years or less. Use of H2 receptor antagonists for 9-14 years predicted poorer scores on learning, working memory, and overall cognition, even after controlling for potential confounders (P less than or equal to .002). “The magnitudes of mean score differences were larger than those observed in the analysis of PPI use, particularly for learning and working memory,” the researchers noted. Additionally, PPI use did not predict lower cognitive scores among individuals who had never used H2 receptor antagonists.
On the other hand, using PPIs for 9-14 years was associated with the equivalent of about 2 years of age-related cognitive decline, and controlling for exposure to H2 receptor antagonists weakened even this modest effect, the investigators said. Users and nonusers of PPIs tend to differ on many measures, and analyses of claims data, such as the German study above, are less able to account for these potential confounders, they noted. “Nonjudicious PPI prescribing is especially frequent among the elderly and those with cognitive impairment,” they added. “Therefore, elderly individuals who have frequent contact with health providers are at increased risk of both PPI prescription and dementia diagnosis. This bias may not be completely mitigated by adjustment for comorbidities or polypharmacy.”
The findings regarding H2 receptor antagonists reflect those of three smaller cohort studies, and these medications are known to cause central nervous system effects in the elderly, including delirium, the researchers said. Ranitidine and cimetidine have anticholinergic effects that also could “pose a risk for adverse cognitive effects with long-term use.”
Dr. Lochhead reported having no conflicts. Two coinvestigators disclosed ties to Bayer Healthcare, Pfizer, Aralez Pharmaceuticals, AbbVie, Samsung Bioepis, and Takeda.
FROM GASTROENTEROLOGY
Key clinical point: A large prospective cohort study linked long-term use of H2 receptor antagonists, but not PPIs, to dementia.
Major finding: Use of PPIs did not significantly predict incident dementia in the adjusted analysis. However, using H2 receptor antagonists for at least 9 years was associated with a slight decrease in scores of learning and working memory (mean decrease, –0.2; P less than .001).
Data source: A population-based cohort study of 13,864 middle-aged and older women.
Disclosures: Dr. Lochhead reported having no conflicts. Two coinvestigators disclosed ties to Bayer Healthcare, Pfizer, Aralez Pharmaceuticals, AbbVie, Samsung Bioepis, and Takeda.
Statin use cuts risks in compensated cirrhosis
For patients with compensated cirrhosis, statin therapy was associated with about a 46% decrease in the risk of hepatic decompensation and mortality and with a 27% drop in the risk of portal hypertension and variceal bleeding, according to moderate-quality evidence from a systematic review and meta-analysis of 13 studies.
Low-quality data also suggested that statins might help protect against the progression of noncirrhotic chronic liver disease, said Rebecca G. Kim of the University of California at San Diego and her associates. “Large, pragmatic randomized controlled trials in patients with compensated cirrhosis are required to confirm these observations,” they wrote in the October issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.04.039).
Prior studies have reported mixed findings on how statin therapy affects chronic liver disease. For their review, Ms. Kim and her associates searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Cochrane Database and Systematic Reviews, Scopus, Web of Science, and PubMed for randomized controlled trials or cohort studies published through March 25, 2017. They identified 10 cohort studies and three randomized controlled trials of adults with fibrosis without cirrhosis, compensated cirrhosis, or decompensated cirrhosis that evaluated statin exposure and reported associations between exposure and outcomes related to cirrhosis. They excluded case-control studies, cross-sectional studies, and studies that focused only on the relationship between statin use and the risk of hepatocellular carcinoma.
The resulting data set included 121,058 patients with chronic liver diseases, of whom 85% had chronic hepatitis C virus infection. A total of 46% of patients were exposed to statins, which appeared to reduce their risk of hepatic decompensation, variceal bleeding, and mortality. Among 87 such patients in five studies, statin use was associated with a 46% decrease in the risk of hepatic decompensation and death, with risk ratios of 0.54 (95% confidence intervals, 0.46-0.62 and 0.47-0.61, respectively). Statin use also was associated with a 27% lower risk of variceal bleeding or progression of portal hypertension, based on an analysis of 110 events in 236 patients from three trials (RR, 0.73; 95% CI, 0.59-0.91). Finally, statin use also was associated with a 58% lower risk of fibrosis progression or cirrhosis in patients with noncirrhotic chronic liver disease, but the 95% CIs for the risk estimate did not reach statistical significance (0.16-1.11).
Source: American Gastroenterological Association
Most studies lacked data on dose and duration of statin exposure, the researchers said. However, four cohort studies reported dose-dependent effects that were most pronounced after more than a year of treatment. “Similarly, several different types of statins were studied, and observed effects were assumed to be class-specific effects,” the reviewers wrote. “However, it is possible that lipophilic and lipophobic statins may have differential efficacy in decreasing fibrosis progression.”
Together, these findings support prior studies suggesting that statin therapy is safe and can potentially reduce the risk of hepatocellular carcinoma in this patient population, they concluded. Statins “may potentially improve patient-relevant outcomes in patients with chronic liver diseases and improve survival without significant additional costs.”
The reviewers acknowledged the American Gastroenterological Association Foundation, a T. Franklin Williams Scholarship Award, the National Institutes of Health, and the National Library of Medicine. They reported having no relevant conflicts of interest.
This story was updated on 9/13/2017.
The main mechanism in the development of cirrhosis in patients with chronic liver disease (CLD) is increased hepatic fibrogenesis. The initial consequence of cirrhosis is portal hypertension, which is the main driver of decompensation (defined as the presence of ascites, variceal hemorrhage, or encephalopathy).
Statins are widely used for reducing cholesterol levels and cardiovascular risk. However, statins ameliorate endothelial dysfunction and have additional antifibrotic, anti-inflammatory, and antithrombotic properties, all of them of potential benefit in preventing progression of CLD/cirrhosis. In fact, statins have been shown to reduce portal pressure in cirrhosis.
In a meta-analysis of 13 studies, Kim et al. demonstrated that statin use is associated with a 58% lower risk of developing cirrhosis/fibrosis progression in patients with CLD (not statistically significant), while in patients with compensated cirrhosis of any etiology, statin use was associated with a statistically significant 46% lower risk of developing decompensation and death.
Most studies in the meta-analysis were observational/retrospective. Although the authors jointly analyzed three randomized controlled trials, only one of the trials looked at clinical outcomes. This important double-blind, placebo-controlled study in patients with recent variceal hemorrhage showed a significantly lower mortality in patients randomized to simvastatin.
Therefore, although the evidence is not yet sufficient to recommend the widespread use of statins in patients with CLD/cirrhosis, providers should not avoid using statins in patients with CLD/cirrhosis who otherwise need them. In fact, they should actively look for indications that would justify their use.
Guadalupe Garcia-Tsao, MD, is professor of medicine at Yale University, chief of digestive diseases at the VA-CT Healthcare System, and director of the clinical core of the Yale Liver Center, New Haven, Conn. She had no conflicts of interest.
The main mechanism in the development of cirrhosis in patients with chronic liver disease (CLD) is increased hepatic fibrogenesis. The initial consequence of cirrhosis is portal hypertension, which is the main driver of decompensation (defined as the presence of ascites, variceal hemorrhage, or encephalopathy).
Statins are widely used for reducing cholesterol levels and cardiovascular risk. However, statins ameliorate endothelial dysfunction and have additional antifibrotic, anti-inflammatory, and antithrombotic properties, all of them of potential benefit in preventing progression of CLD/cirrhosis. In fact, statins have been shown to reduce portal pressure in cirrhosis.
In a meta-analysis of 13 studies, Kim et al. demonstrated that statin use is associated with a 58% lower risk of developing cirrhosis/fibrosis progression in patients with CLD (not statistically significant), while in patients with compensated cirrhosis of any etiology, statin use was associated with a statistically significant 46% lower risk of developing decompensation and death.
Most studies in the meta-analysis were observational/retrospective. Although the authors jointly analyzed three randomized controlled trials, only one of the trials looked at clinical outcomes. This important double-blind, placebo-controlled study in patients with recent variceal hemorrhage showed a significantly lower mortality in patients randomized to simvastatin.
Therefore, although the evidence is not yet sufficient to recommend the widespread use of statins in patients with CLD/cirrhosis, providers should not avoid using statins in patients with CLD/cirrhosis who otherwise need them. In fact, they should actively look for indications that would justify their use.
Guadalupe Garcia-Tsao, MD, is professor of medicine at Yale University, chief of digestive diseases at the VA-CT Healthcare System, and director of the clinical core of the Yale Liver Center, New Haven, Conn. She had no conflicts of interest.
The main mechanism in the development of cirrhosis in patients with chronic liver disease (CLD) is increased hepatic fibrogenesis. The initial consequence of cirrhosis is portal hypertension, which is the main driver of decompensation (defined as the presence of ascites, variceal hemorrhage, or encephalopathy).
Statins are widely used for reducing cholesterol levels and cardiovascular risk. However, statins ameliorate endothelial dysfunction and have additional antifibrotic, anti-inflammatory, and antithrombotic properties, all of them of potential benefit in preventing progression of CLD/cirrhosis. In fact, statins have been shown to reduce portal pressure in cirrhosis.
In a meta-analysis of 13 studies, Kim et al. demonstrated that statin use is associated with a 58% lower risk of developing cirrhosis/fibrosis progression in patients with CLD (not statistically significant), while in patients with compensated cirrhosis of any etiology, statin use was associated with a statistically significant 46% lower risk of developing decompensation and death.
Most studies in the meta-analysis were observational/retrospective. Although the authors jointly analyzed three randomized controlled trials, only one of the trials looked at clinical outcomes. This important double-blind, placebo-controlled study in patients with recent variceal hemorrhage showed a significantly lower mortality in patients randomized to simvastatin.
Therefore, although the evidence is not yet sufficient to recommend the widespread use of statins in patients with CLD/cirrhosis, providers should not avoid using statins in patients with CLD/cirrhosis who otherwise need them. In fact, they should actively look for indications that would justify their use.
Guadalupe Garcia-Tsao, MD, is professor of medicine at Yale University, chief of digestive diseases at the VA-CT Healthcare System, and director of the clinical core of the Yale Liver Center, New Haven, Conn. She had no conflicts of interest.
For patients with compensated cirrhosis, statin therapy was associated with about a 46% decrease in the risk of hepatic decompensation and mortality and with a 27% drop in the risk of portal hypertension and variceal bleeding, according to moderate-quality evidence from a systematic review and meta-analysis of 13 studies.
Low-quality data also suggested that statins might help protect against the progression of noncirrhotic chronic liver disease, said Rebecca G. Kim of the University of California at San Diego and her associates. “Large, pragmatic randomized controlled trials in patients with compensated cirrhosis are required to confirm these observations,” they wrote in the October issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.04.039).
Prior studies have reported mixed findings on how statin therapy affects chronic liver disease. For their review, Ms. Kim and her associates searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Cochrane Database and Systematic Reviews, Scopus, Web of Science, and PubMed for randomized controlled trials or cohort studies published through March 25, 2017. They identified 10 cohort studies and three randomized controlled trials of adults with fibrosis without cirrhosis, compensated cirrhosis, or decompensated cirrhosis that evaluated statin exposure and reported associations between exposure and outcomes related to cirrhosis. They excluded case-control studies, cross-sectional studies, and studies that focused only on the relationship between statin use and the risk of hepatocellular carcinoma.
The resulting data set included 121,058 patients with chronic liver diseases, of whom 85% had chronic hepatitis C virus infection. A total of 46% of patients were exposed to statins, which appeared to reduce their risk of hepatic decompensation, variceal bleeding, and mortality. Among 87 such patients in five studies, statin use was associated with a 46% decrease in the risk of hepatic decompensation and death, with risk ratios of 0.54 (95% confidence intervals, 0.46-0.62 and 0.47-0.61, respectively). Statin use also was associated with a 27% lower risk of variceal bleeding or progression of portal hypertension, based on an analysis of 110 events in 236 patients from three trials (RR, 0.73; 95% CI, 0.59-0.91). Finally, statin use also was associated with a 58% lower risk of fibrosis progression or cirrhosis in patients with noncirrhotic chronic liver disease, but the 95% CIs for the risk estimate did not reach statistical significance (0.16-1.11).
Source: American Gastroenterological Association
Most studies lacked data on dose and duration of statin exposure, the researchers said. However, four cohort studies reported dose-dependent effects that were most pronounced after more than a year of treatment. “Similarly, several different types of statins were studied, and observed effects were assumed to be class-specific effects,” the reviewers wrote. “However, it is possible that lipophilic and lipophobic statins may have differential efficacy in decreasing fibrosis progression.”
Together, these findings support prior studies suggesting that statin therapy is safe and can potentially reduce the risk of hepatocellular carcinoma in this patient population, they concluded. Statins “may potentially improve patient-relevant outcomes in patients with chronic liver diseases and improve survival without significant additional costs.”
The reviewers acknowledged the American Gastroenterological Association Foundation, a T. Franklin Williams Scholarship Award, the National Institutes of Health, and the National Library of Medicine. They reported having no relevant conflicts of interest.
This story was updated on 9/13/2017.
For patients with compensated cirrhosis, statin therapy was associated with about a 46% decrease in the risk of hepatic decompensation and mortality and with a 27% drop in the risk of portal hypertension and variceal bleeding, according to moderate-quality evidence from a systematic review and meta-analysis of 13 studies.
Low-quality data also suggested that statins might help protect against the progression of noncirrhotic chronic liver disease, said Rebecca G. Kim of the University of California at San Diego and her associates. “Large, pragmatic randomized controlled trials in patients with compensated cirrhosis are required to confirm these observations,” they wrote in the October issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.04.039).
Prior studies have reported mixed findings on how statin therapy affects chronic liver disease. For their review, Ms. Kim and her associates searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Cochrane Database and Systematic Reviews, Scopus, Web of Science, and PubMed for randomized controlled trials or cohort studies published through March 25, 2017. They identified 10 cohort studies and three randomized controlled trials of adults with fibrosis without cirrhosis, compensated cirrhosis, or decompensated cirrhosis that evaluated statin exposure and reported associations between exposure and outcomes related to cirrhosis. They excluded case-control studies, cross-sectional studies, and studies that focused only on the relationship between statin use and the risk of hepatocellular carcinoma.
The resulting data set included 121,058 patients with chronic liver diseases, of whom 85% had chronic hepatitis C virus infection. A total of 46% of patients were exposed to statins, which appeared to reduce their risk of hepatic decompensation, variceal bleeding, and mortality. Among 87 such patients in five studies, statin use was associated with a 46% decrease in the risk of hepatic decompensation and death, with risk ratios of 0.54 (95% confidence intervals, 0.46-0.62 and 0.47-0.61, respectively). Statin use also was associated with a 27% lower risk of variceal bleeding or progression of portal hypertension, based on an analysis of 110 events in 236 patients from three trials (RR, 0.73; 95% CI, 0.59-0.91). Finally, statin use also was associated with a 58% lower risk of fibrosis progression or cirrhosis in patients with noncirrhotic chronic liver disease, but the 95% CIs for the risk estimate did not reach statistical significance (0.16-1.11).
Source: American Gastroenterological Association
Most studies lacked data on dose and duration of statin exposure, the researchers said. However, four cohort studies reported dose-dependent effects that were most pronounced after more than a year of treatment. “Similarly, several different types of statins were studied, and observed effects were assumed to be class-specific effects,” the reviewers wrote. “However, it is possible that lipophilic and lipophobic statins may have differential efficacy in decreasing fibrosis progression.”
Together, these findings support prior studies suggesting that statin therapy is safe and can potentially reduce the risk of hepatocellular carcinoma in this patient population, they concluded. Statins “may potentially improve patient-relevant outcomes in patients with chronic liver diseases and improve survival without significant additional costs.”
The reviewers acknowledged the American Gastroenterological Association Foundation, a T. Franklin Williams Scholarship Award, the National Institutes of Health, and the National Library of Medicine. They reported having no relevant conflicts of interest.
This story was updated on 9/13/2017.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Statin therapy was associated with a significantly lower risk of hepatic decompensation and death in patients with compensated cirrhosis.
Major finding: Statin therapy was associated with a 46% decrease in the risk of both hepatic decompensation and mortality (risk ratios, 0.54) and with a 27% drop in the risk of portal hypertension and variceal bleeding (RR, 0.73).
Data source: A systematic review and meta-analysis of 10 cohort studies and three randomized controlled trials (121,058 patients).
Disclosures: The reviewers acknowledged the American Gastroenterological Association Foundation, a T. Franklin Williams Scholarship Award, the National Institutes of Health, and the National Library of Medicine. They reported having no relevant conflicts of interest.
Enhanced disinfection of duodenoscopes did not reduce contamination
Duodenoscopes had similar rates of contamination after double high-level disinfection, standard high-level disinfection, or standard high-level disinfection followed by ethylene oxide gas sterilization, a randomized, prospective study of 516 bacterial cultures of 18 duodenoscopes showed.
“Our results do not support the routine use of double high-level disinfection or ethylene oxide sterilization for duodenoscope reprocessing,” wrote Graham M. Snyder, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, and his associates. They stopped the study after 3 months because none of the duodenoscopes cultured multidrug-resistant organisms, the primary endpoint. “[We] found that in the nonoutbreak setting, duodenoscope contamination by multidrug-resistant organisms is extremely uncommon,” they wrote in the October issue of Gastroenterology (doi: 10.1053/j.gastro.2017.06.052). However, 16% of duodenoscopes cultured at least one colony-forming unit (CFU) after either standard high-level or double high-level disinfection, and 23% of duodenoscopes produced at least one CFU despite standard high-level disinfection followed by ethylene gas sterilization (P = .2), the investigators reported.
Outbreaks of carbapenem-resistant Enterobacteriaceae infections have been traced to duodenoscopes, even though they were reprocessed according to manufacturer instructions. In 2015, the Food and Drug Administration responded by warning that the design of duodenoscopes might preclude effective cleaning. Reasons for residual contamination remain uncertain, but biofilms, which are notoriously resistant to standard disinfection methods, might be a culprit, Dr. Snyder and his associates noted. Accordingly, some experts have suggested repeating the reprocessing cycle or adding ethylene oxide sterilization, but these measures are costly, time intensive, and not widely available. Furthermore, their efficacy “has never been systematically studied in a nonoutbreak setting,” the researchers wrote.
In response, they studied 516 cultures of elevator mechanisms and working channels from 18 reprocessed duodenoscopes (Olympus, model TJF-Q180). Immediately after use, each duodenoscope was manually wiped with enzymatic solution (EmPower), and then was manually reprocessed within an hour before undergoing automated reprocessing (System 83 Plus 9) with ortho-phthalaldehyde disinfectant (MetriCide OPA Plus) followed by ethanol flush. One-third of the duodenoscopes were randomly assigned to undergo double high-level disinfection with two automated reprocessing cycles, and another third underwent standard high-level disinfection followed by ethylene oxide gas sterilization (Steri-Vac sterilizer/aerator). All instruments were stored by hanging them vertically in an unventilated cabinet.
Multidrug-resistant organisms were cultured from 3% of rectal swabs and duodenal aspirates, but not from any of the cultures of duodenoscopes. Therefore, the study was stopped for futility. The enhanced disinfection methods failed to prevent contamination, compared with standard high-level disinfection, the researchers noted. Ten or more CFUs grew in 2% of duodenoscopes that underwent standard high-level disinfection, 4% of those that underwent double high-level disinfection, and 4% of those that underwent high-level disinfection followed by ethylene oxide sterilization (P = .4).
“There is no consensus on what parts of the standard high-level disinfection process should be repeated,” the investigators wrote. “It is uncertain if the addition of a second cycle of manual reprocessing might have improved the effectiveness of double high-level disinfection.”
Funders included the American Society for Gastrointestinal Endoscopy and Beth Israel Deaconess Medical Center. The investigators reported having no conflicts of interest.
Duodenoscopes had similar rates of contamination after double high-level disinfection, standard high-level disinfection, or standard high-level disinfection followed by ethylene oxide gas sterilization, a randomized, prospective study of 516 bacterial cultures of 18 duodenoscopes showed.
“Our results do not support the routine use of double high-level disinfection or ethylene oxide sterilization for duodenoscope reprocessing,” wrote Graham M. Snyder, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, and his associates. They stopped the study after 3 months because none of the duodenoscopes cultured multidrug-resistant organisms, the primary endpoint. “[We] found that in the nonoutbreak setting, duodenoscope contamination by multidrug-resistant organisms is extremely uncommon,” they wrote in the October issue of Gastroenterology (doi: 10.1053/j.gastro.2017.06.052). However, 16% of duodenoscopes cultured at least one colony-forming unit (CFU) after either standard high-level or double high-level disinfection, and 23% of duodenoscopes produced at least one CFU despite standard high-level disinfection followed by ethylene gas sterilization (P = .2), the investigators reported.
Outbreaks of carbapenem-resistant Enterobacteriaceae infections have been traced to duodenoscopes, even though they were reprocessed according to manufacturer instructions. In 2015, the Food and Drug Administration responded by warning that the design of duodenoscopes might preclude effective cleaning. Reasons for residual contamination remain uncertain, but biofilms, which are notoriously resistant to standard disinfection methods, might be a culprit, Dr. Snyder and his associates noted. Accordingly, some experts have suggested repeating the reprocessing cycle or adding ethylene oxide sterilization, but these measures are costly, time intensive, and not widely available. Furthermore, their efficacy “has never been systematically studied in a nonoutbreak setting,” the researchers wrote.
In response, they studied 516 cultures of elevator mechanisms and working channels from 18 reprocessed duodenoscopes (Olympus, model TJF-Q180). Immediately after use, each duodenoscope was manually wiped with enzymatic solution (EmPower), and then was manually reprocessed within an hour before undergoing automated reprocessing (System 83 Plus 9) with ortho-phthalaldehyde disinfectant (MetriCide OPA Plus) followed by ethanol flush. One-third of the duodenoscopes were randomly assigned to undergo double high-level disinfection with two automated reprocessing cycles, and another third underwent standard high-level disinfection followed by ethylene oxide gas sterilization (Steri-Vac sterilizer/aerator). All instruments were stored by hanging them vertically in an unventilated cabinet.
Multidrug-resistant organisms were cultured from 3% of rectal swabs and duodenal aspirates, but not from any of the cultures of duodenoscopes. Therefore, the study was stopped for futility. The enhanced disinfection methods failed to prevent contamination, compared with standard high-level disinfection, the researchers noted. Ten or more CFUs grew in 2% of duodenoscopes that underwent standard high-level disinfection, 4% of those that underwent double high-level disinfection, and 4% of those that underwent high-level disinfection followed by ethylene oxide sterilization (P = .4).
“There is no consensus on what parts of the standard high-level disinfection process should be repeated,” the investigators wrote. “It is uncertain if the addition of a second cycle of manual reprocessing might have improved the effectiveness of double high-level disinfection.”
Funders included the American Society for Gastrointestinal Endoscopy and Beth Israel Deaconess Medical Center. The investigators reported having no conflicts of interest.
Duodenoscopes had similar rates of contamination after double high-level disinfection, standard high-level disinfection, or standard high-level disinfection followed by ethylene oxide gas sterilization, a randomized, prospective study of 516 bacterial cultures of 18 duodenoscopes showed.
“Our results do not support the routine use of double high-level disinfection or ethylene oxide sterilization for duodenoscope reprocessing,” wrote Graham M. Snyder, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, and his associates. They stopped the study after 3 months because none of the duodenoscopes cultured multidrug-resistant organisms, the primary endpoint. “[We] found that in the nonoutbreak setting, duodenoscope contamination by multidrug-resistant organisms is extremely uncommon,” they wrote in the October issue of Gastroenterology (doi: 10.1053/j.gastro.2017.06.052). However, 16% of duodenoscopes cultured at least one colony-forming unit (CFU) after either standard high-level or double high-level disinfection, and 23% of duodenoscopes produced at least one CFU despite standard high-level disinfection followed by ethylene gas sterilization (P = .2), the investigators reported.
Outbreaks of carbapenem-resistant Enterobacteriaceae infections have been traced to duodenoscopes, even though they were reprocessed according to manufacturer instructions. In 2015, the Food and Drug Administration responded by warning that the design of duodenoscopes might preclude effective cleaning. Reasons for residual contamination remain uncertain, but biofilms, which are notoriously resistant to standard disinfection methods, might be a culprit, Dr. Snyder and his associates noted. Accordingly, some experts have suggested repeating the reprocessing cycle or adding ethylene oxide sterilization, but these measures are costly, time intensive, and not widely available. Furthermore, their efficacy “has never been systematically studied in a nonoutbreak setting,” the researchers wrote.
In response, they studied 516 cultures of elevator mechanisms and working channels from 18 reprocessed duodenoscopes (Olympus, model TJF-Q180). Immediately after use, each duodenoscope was manually wiped with enzymatic solution (EmPower), and then was manually reprocessed within an hour before undergoing automated reprocessing (System 83 Plus 9) with ortho-phthalaldehyde disinfectant (MetriCide OPA Plus) followed by ethanol flush. One-third of the duodenoscopes were randomly assigned to undergo double high-level disinfection with two automated reprocessing cycles, and another third underwent standard high-level disinfection followed by ethylene oxide gas sterilization (Steri-Vac sterilizer/aerator). All instruments were stored by hanging them vertically in an unventilated cabinet.
Multidrug-resistant organisms were cultured from 3% of rectal swabs and duodenal aspirates, but not from any of the cultures of duodenoscopes. Therefore, the study was stopped for futility. The enhanced disinfection methods failed to prevent contamination, compared with standard high-level disinfection, the researchers noted. Ten or more CFUs grew in 2% of duodenoscopes that underwent standard high-level disinfection, 4% of those that underwent double high-level disinfection, and 4% of those that underwent high-level disinfection followed by ethylene oxide sterilization (P = .4).
“There is no consensus on what parts of the standard high-level disinfection process should be repeated,” the investigators wrote. “It is uncertain if the addition of a second cycle of manual reprocessing might have improved the effectiveness of double high-level disinfection.”
Funders included the American Society for Gastrointestinal Endoscopy and Beth Israel Deaconess Medical Center. The investigators reported having no conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: Enhanced disinfection of duodenoscopes did not provide additional protection against contamination.
Major finding: No cultures were positive for multidrug-resistant organisms, but 16% of duodenoscopes had at least one colony-forming unit despite standard high-level disinfection or double high-level disinfection. Standard high-level disinfection followed by ethylene oxide gas failed to sterilize 23% of duodenoscopes (P = .2).
Data source: A single-center, prospective randomized study of 516 cultures of 18 duodenoscopes.
Disclosures: Funders included the American Society for Gastrointestinal Endoscopy and Beth Israel Deaconess Medical Center. The investigators reported having no conflicts of interest.
AGA Guideline: Therapeutic drug monitoring in IBD
Physicians should perform reactive therapeutic drug monitoring to guide changes in anti–tumor necrosis factor (TNF) therapy in patients with active inflammatory bowel disease and should consider target trough concentrations of at least 5 mcg/mL for infliximab, at least 7.5 mcg/mL for adalimumab, and at least 20 mcg/mL for certolizumab pegol, according to a guideline from the AGA Institute, published in the September 2017 issue of Gastroenterology (Gastroenterology. doi: 10.1053/j.gastro.2017.07.032).
Therapeutic drug monitoring can help guide whether to ramp up a dose (if the trough level is below the threshold) or switch therapy (if the trough level is above the threshold) when patients are not responding adequately to maintenance treatment. A nonresponder with optimal trough concentrations might need to switch drug classes, the guideline noted. A patient with low trough levels and no antidrug antibodies is probably experiencing rapid drug clearance in the setting of high inflammation. A patient with low or undetectable trough levels and high antidrug antibody titers has developed neutralizing antidrug antibodies. However, trough concentrations can vary for many other reasons, ranging from disease severity and inflammation to body mass index and sex. Therefore, target levels also vary and can be challenging to set.
The AGA makes no recommendation about routine, proactive TDM in patients with quiescent IBD who are on anti-TNF agents. While proactive TDM can shed light on endoscopic response and drug clearance, it might also trigger a premature switch of therapies; this is particularly likely because physicians have sparse data on either target trough levels for asymptomatic patients or the clinical significance of “low-titer” antidrug antibodies. The optimal frequency of proactive TDM also remains unclear.
Pending better data, the AGA recommended checking infliximab or adalimumab trough levels as close to the next dose as possible – that is, within 24 hours. Drug trough levels are consistent across commercial assays, but antidrug antibody titers are not, and there are no uniform thresholds for clinically relevant antidrug antibody titers. “Therefore, it may be beneficial to utilize the same assay when checking for trough concentration and antidrug antibodies,” the guideline stated.
For patients on a thiopurine, routine testing of thiopurine methyltransferase (TPMT) enzyme or genotype is recommended to guide dosing. In three pooled studies comprising 1,145 patients, only two patients were homozygous; further, rates of hematologic adverse events, clinical remission, and treatment discontinuation did not differ based on TPMT testing itself. However, using TPMT testing to guide dosing was associated with an 89% decrease in the risk of hematologic adverse events among patients who had a homozygous genotype or had low or absent TPMT enzymatic activity. “While this risk may be mitigated by routine laboratory CBC checking, adherence to regular monitoring in clinical practice is suboptimal,” the guideline stated. “It is important to continue to perform routine lab monitoring [of] CBC and liver enzymes after starting a thiopurine, regardless of the TPMT testing results.”
The AGA also conditionally supported reactive monitoring of thiopurine metabolites to guide treatment changes if patients develop breakthrough symptoms or treatment-related adverse effects. For active IBD symptoms in spite of thiopurine monotherapy, a target 6-thioguanine (6-TGN) cutoff between 230 and 450 pmol per 8 x 108 RBC is recommended. Again, supporting evidence is of “very low quality” – in a retrospective, observational study, patients who received treatment according to a TDM algorithm were five times more likely to respond to a change in therapy (relative risk, 5.2). The guideline recommended against monitoring thiopurine metabolites in quiescent IBD. Studies did not support this practice, compared with standard dosing, although no study of thiopurine metabolites included patients on thiopurine/anti-TNF combination therapy, the guideline’s authors noted.
The guideline includes clinical-decision support tools on when to perform TDM and how to interpret results when patients are taking an anti-TNF agent or a thiopurine. The guideline does not cover vedolizumab or ustekinumab because data are sparse. Other knowledge gaps include when best to measure trough concentrations; whether empiric dose escalation or TDM is preferred if response to induction is suboptimal; how target trough concentrations vary based on disease phenotype, disease state, or treatment goals; which levels and durations of antidrug antibody titers are clinically significant; and whether to suppress antidrug antibodies before changing therapy. Future studies should compare routine proactive and reactive TDM, investigate how often to perform proactive TDM, and characterize TDM of newly approved biologic agents, the guideline concluded.
The authors of the guideline document disclosed no conflicts related to the guideline topic.
Physicians should perform reactive therapeutic drug monitoring to guide changes in anti–tumor necrosis factor (TNF) therapy in patients with active inflammatory bowel disease and should consider target trough concentrations of at least 5 mcg/mL for infliximab, at least 7.5 mcg/mL for adalimumab, and at least 20 mcg/mL for certolizumab pegol, according to a guideline from the AGA Institute, published in the September 2017 issue of Gastroenterology (Gastroenterology. doi: 10.1053/j.gastro.2017.07.032).
Therapeutic drug monitoring can help guide whether to ramp up a dose (if the trough level is below the threshold) or switch therapy (if the trough level is above the threshold) when patients are not responding adequately to maintenance treatment. A nonresponder with optimal trough concentrations might need to switch drug classes, the guideline noted. A patient with low trough levels and no antidrug antibodies is probably experiencing rapid drug clearance in the setting of high inflammation. A patient with low or undetectable trough levels and high antidrug antibody titers has developed neutralizing antidrug antibodies. However, trough concentrations can vary for many other reasons, ranging from disease severity and inflammation to body mass index and sex. Therefore, target levels also vary and can be challenging to set.
The AGA makes no recommendation about routine, proactive TDM in patients with quiescent IBD who are on anti-TNF agents. While proactive TDM can shed light on endoscopic response and drug clearance, it might also trigger a premature switch of therapies; this is particularly likely because physicians have sparse data on either target trough levels for asymptomatic patients or the clinical significance of “low-titer” antidrug antibodies. The optimal frequency of proactive TDM also remains unclear.
Pending better data, the AGA recommended checking infliximab or adalimumab trough levels as close to the next dose as possible – that is, within 24 hours. Drug trough levels are consistent across commercial assays, but antidrug antibody titers are not, and there are no uniform thresholds for clinically relevant antidrug antibody titers. “Therefore, it may be beneficial to utilize the same assay when checking for trough concentration and antidrug antibodies,” the guideline stated.
For patients on a thiopurine, routine testing of thiopurine methyltransferase (TPMT) enzyme or genotype is recommended to guide dosing. In three pooled studies comprising 1,145 patients, only two patients were homozygous; further, rates of hematologic adverse events, clinical remission, and treatment discontinuation did not differ based on TPMT testing itself. However, using TPMT testing to guide dosing was associated with an 89% decrease in the risk of hematologic adverse events among patients who had a homozygous genotype or had low or absent TPMT enzymatic activity. “While this risk may be mitigated by routine laboratory CBC checking, adherence to regular monitoring in clinical practice is suboptimal,” the guideline stated. “It is important to continue to perform routine lab monitoring [of] CBC and liver enzymes after starting a thiopurine, regardless of the TPMT testing results.”
The AGA also conditionally supported reactive monitoring of thiopurine metabolites to guide treatment changes if patients develop breakthrough symptoms or treatment-related adverse effects. For active IBD symptoms in spite of thiopurine monotherapy, a target 6-thioguanine (6-TGN) cutoff between 230 and 450 pmol per 8 x 108 RBC is recommended. Again, supporting evidence is of “very low quality” – in a retrospective, observational study, patients who received treatment according to a TDM algorithm were five times more likely to respond to a change in therapy (relative risk, 5.2). The guideline recommended against monitoring thiopurine metabolites in quiescent IBD. Studies did not support this practice, compared with standard dosing, although no study of thiopurine metabolites included patients on thiopurine/anti-TNF combination therapy, the guideline’s authors noted.
The guideline includes clinical-decision support tools on when to perform TDM and how to interpret results when patients are taking an anti-TNF agent or a thiopurine. The guideline does not cover vedolizumab or ustekinumab because data are sparse. Other knowledge gaps include when best to measure trough concentrations; whether empiric dose escalation or TDM is preferred if response to induction is suboptimal; how target trough concentrations vary based on disease phenotype, disease state, or treatment goals; which levels and durations of antidrug antibody titers are clinically significant; and whether to suppress antidrug antibodies before changing therapy. Future studies should compare routine proactive and reactive TDM, investigate how often to perform proactive TDM, and characterize TDM of newly approved biologic agents, the guideline concluded.
The authors of the guideline document disclosed no conflicts related to the guideline topic.
Physicians should perform reactive therapeutic drug monitoring to guide changes in anti–tumor necrosis factor (TNF) therapy in patients with active inflammatory bowel disease and should consider target trough concentrations of at least 5 mcg/mL for infliximab, at least 7.5 mcg/mL for adalimumab, and at least 20 mcg/mL for certolizumab pegol, according to a guideline from the AGA Institute, published in the September 2017 issue of Gastroenterology (Gastroenterology. doi: 10.1053/j.gastro.2017.07.032).
Therapeutic drug monitoring can help guide whether to ramp up a dose (if the trough level is below the threshold) or switch therapy (if the trough level is above the threshold) when patients are not responding adequately to maintenance treatment. A nonresponder with optimal trough concentrations might need to switch drug classes, the guideline noted. A patient with low trough levels and no antidrug antibodies is probably experiencing rapid drug clearance in the setting of high inflammation. A patient with low or undetectable trough levels and high antidrug antibody titers has developed neutralizing antidrug antibodies. However, trough concentrations can vary for many other reasons, ranging from disease severity and inflammation to body mass index and sex. Therefore, target levels also vary and can be challenging to set.
The AGA makes no recommendation about routine, proactive TDM in patients with quiescent IBD who are on anti-TNF agents. While proactive TDM can shed light on endoscopic response and drug clearance, it might also trigger a premature switch of therapies; this is particularly likely because physicians have sparse data on either target trough levels for asymptomatic patients or the clinical significance of “low-titer” antidrug antibodies. The optimal frequency of proactive TDM also remains unclear.
Pending better data, the AGA recommended checking infliximab or adalimumab trough levels as close to the next dose as possible – that is, within 24 hours. Drug trough levels are consistent across commercial assays, but antidrug antibody titers are not, and there are no uniform thresholds for clinically relevant antidrug antibody titers. “Therefore, it may be beneficial to utilize the same assay when checking for trough concentration and antidrug antibodies,” the guideline stated.
For patients on a thiopurine, routine testing of thiopurine methyltransferase (TPMT) enzyme or genotype is recommended to guide dosing. In three pooled studies comprising 1,145 patients, only two patients were homozygous; further, rates of hematologic adverse events, clinical remission, and treatment discontinuation did not differ based on TPMT testing itself. However, using TPMT testing to guide dosing was associated with an 89% decrease in the risk of hematologic adverse events among patients who had a homozygous genotype or had low or absent TPMT enzymatic activity. “While this risk may be mitigated by routine laboratory CBC checking, adherence to regular monitoring in clinical practice is suboptimal,” the guideline stated. “It is important to continue to perform routine lab monitoring [of] CBC and liver enzymes after starting a thiopurine, regardless of the TPMT testing results.”
The AGA also conditionally supported reactive monitoring of thiopurine metabolites to guide treatment changes if patients develop breakthrough symptoms or treatment-related adverse effects. For active IBD symptoms in spite of thiopurine monotherapy, a target 6-thioguanine (6-TGN) cutoff between 230 and 450 pmol per 8 x 108 RBC is recommended. Again, supporting evidence is of “very low quality” – in a retrospective, observational study, patients who received treatment according to a TDM algorithm were five times more likely to respond to a change in therapy (relative risk, 5.2). The guideline recommended against monitoring thiopurine metabolites in quiescent IBD. Studies did not support this practice, compared with standard dosing, although no study of thiopurine metabolites included patients on thiopurine/anti-TNF combination therapy, the guideline’s authors noted.
The guideline includes clinical-decision support tools on when to perform TDM and how to interpret results when patients are taking an anti-TNF agent or a thiopurine. The guideline does not cover vedolizumab or ustekinumab because data are sparse. Other knowledge gaps include when best to measure trough concentrations; whether empiric dose escalation or TDM is preferred if response to induction is suboptimal; how target trough concentrations vary based on disease phenotype, disease state, or treatment goals; which levels and durations of antidrug antibody titers are clinically significant; and whether to suppress antidrug antibodies before changing therapy. Future studies should compare routine proactive and reactive TDM, investigate how often to perform proactive TDM, and characterize TDM of newly approved biologic agents, the guideline concluded.
The authors of the guideline document disclosed no conflicts related to the guideline topic.
FROM GASTROENTEROLOGY
AGA Clinical Practice Update: Opioids in gastroenterology
Physicians should consistently rule out opioid therapy as the cause of gastrointestinal symptoms, states a new clinical practice update published in the September 2017 issue of Clinical Gastroenterology and Hepatology (Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.05.014).
About 4% of Americans receive long-term opioid therapy, primarily for musculoskeletal, postsurgical, or vascular pain, as well as nonsurgical abdominal pain, writes Michael Camilleri, MD, AGAF, of Mayo Clinic in Rochester, Minn., and his associates. Because opioid receptors thickly populate the gastrointestinal tract, exogenous opioids can trigger a variety of gastrointestinal symptoms. Examples include achalasia, gastroparesis, nausea, postsurgical ileus, constipation, and narcotic bowel syndrome.
In the stomach, opioid use can cause gastroparesis, early satiety, and postprandial nausea and emesis, especially in the postoperative setting. Even novel opioid agents that are less likely to cause constipation can retard gastric emptying. For example, tapentadol, a mu-opioid agonist and norepinephrine reuptake inhibitor, delays emptying to the same extent as oxycodone. Tramadol also appears to slow overall orocecal transit. Although gastroparesis itself can cause nausea and emesis, opioids also directly stimulate the chemoreceptor trigger zone in the area postrema in the floor of the fourth ventricle. Options for preventive therapy include using a prokinetic, such as metoclopramide, prochlorperazine, or a 5-hydroxytryptamine3 antagonist, especially if patients are receiving opioids for postoperative pain control.
Exogenous opioids also can cause ileus, especially after abdominal surgery. These patients are already at risk of ileus because of surgical stress from bowel handling, secretion of inflammatory mediators and endogenous opioids, and fluctuating hormone and electrolyte levels. Postoperative analgesia with mu-opioids adds to the risk of ileus by increasing fluid absorption and inhibiting colonic motility.
Both postsurgical and nonsurgical opioid use also can trigger opioid-induced constipation (OIC), in which patients have less than three spontaneous bowel movements a week, harder stools, increased straining, and a feeling of incomplete evacuation. Patients may also report nausea, emesis, and gastroesophageal reflux. Even low-dose and short-term opioid therapy can lead to OIC. Symptoms and treatment response can be assessed with the bowel function index, in which patients rate ease of defecation, completeness of bowel evacuation, and severity of constipation over the past week on a scale of 0-100. Scores of 0-29 suggest no OIC. Patients who score above 30 despite over-the-counter laxatives are candidates for stepped-up treatments, including prolonged-release naloxone and oxycodone, the intestinal secretagogue lubiprostone, or peripherally acting mu-opioid receptor antagonists (PAMORAs), such as methylnaltrexone (12 mg subcutaneously) and naloxegol (12.5 mg or 25 mg per day orally). Additionally, tapentadol controls pain at lower doses than oxycodone and is less likely to cause constipation.
Narcotic bowel syndrome typically presents as moderate to severe daily abdominal pain lasting more than 3 months in patients on long-term opioids equating to a dosage of more than 100 mg morphine daily. Typically, patients report generalized, persistent, colicky abdominal pain that does not respond to dose escalation and worsens with dose tapering. Work-up is negative for differentials such as kidney stones or bowel obstruction. One epidemiological study estimated that 4% of patients on long-term opiates develop narcotic bowel syndrome, but the true prevalence may be higher according to the experts who authored this update. Mechanisms remain unclear but may include neuroplastic changes that favor the facilitation of pain signals rather than their inhibition, inflammation of spinal glial cells through activation of toll-like receptors, abnormal function of the N-methyl-D aspartate receptor at the level of the spinal cord, and central nociceptive abnormalities related to certain psychological traits or a history of trauma.
Treating narcotic bowel syndrome requires detoxification with appropriate nonopioid therapies for pain, anxiety, and withdrawal symptoms, including the use of clonidine. “This is best handled through specialists or centers with expertise in opiate dependence,” the experts stated. Patients who are able to stay off narcotics report improvements in pain, but the recidivism rate is about 50%.
The practice update also covers opioid therapy for gastrointestinal disorders. The PAMORA alvimopan shortens time to first postoperative stool without counteracting opioid analgesia during recovery. Alvimopan also has been found to hasten recovery of gastrointestinal function in patients with postoperative ileus after bowel resection. There is no evidence for using mu-opioid agonists for pain associated with irritable bowel syndrome (IBS), but the synthetic peripheral mu-opioid receptor agonist loperamide can improve stool consistency and urgency. A typical dose is 2 mg after each loose bowel movement or 2-4 mg before eating in cases of postprandial diarrhea. The mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist eluxadoline also can potentially improve stool consistency and urgency, global IBS symptoms, IBS symptom severity score, and quality of life. However, the FDA warns against using eluxadoline in patients who do not have a gallbladder because of the risk of severe outcomes – including death – related to sphincter of Oddi spasm and pancreatitis. Eluxadoline has been linked to at least two such fatalities in cholecystectomized patients. In each case, symptoms began after a single dose.
Dr. Camilleri is funded by the National Institutes of Health. He disclosed ties to AstraZeneca and Shionogi. The two coauthors disclosed ties to Forest Research Labs, Ironwood Pharmaceuticals, Prometheus, and Salix.
Physicians should consistently rule out opioid therapy as the cause of gastrointestinal symptoms, states a new clinical practice update published in the September 2017 issue of Clinical Gastroenterology and Hepatology (Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.05.014).
About 4% of Americans receive long-term opioid therapy, primarily for musculoskeletal, postsurgical, or vascular pain, as well as nonsurgical abdominal pain, writes Michael Camilleri, MD, AGAF, of Mayo Clinic in Rochester, Minn., and his associates. Because opioid receptors thickly populate the gastrointestinal tract, exogenous opioids can trigger a variety of gastrointestinal symptoms. Examples include achalasia, gastroparesis, nausea, postsurgical ileus, constipation, and narcotic bowel syndrome.
In the stomach, opioid use can cause gastroparesis, early satiety, and postprandial nausea and emesis, especially in the postoperative setting. Even novel opioid agents that are less likely to cause constipation can retard gastric emptying. For example, tapentadol, a mu-opioid agonist and norepinephrine reuptake inhibitor, delays emptying to the same extent as oxycodone. Tramadol also appears to slow overall orocecal transit. Although gastroparesis itself can cause nausea and emesis, opioids also directly stimulate the chemoreceptor trigger zone in the area postrema in the floor of the fourth ventricle. Options for preventive therapy include using a prokinetic, such as metoclopramide, prochlorperazine, or a 5-hydroxytryptamine3 antagonist, especially if patients are receiving opioids for postoperative pain control.
Exogenous opioids also can cause ileus, especially after abdominal surgery. These patients are already at risk of ileus because of surgical stress from bowel handling, secretion of inflammatory mediators and endogenous opioids, and fluctuating hormone and electrolyte levels. Postoperative analgesia with mu-opioids adds to the risk of ileus by increasing fluid absorption and inhibiting colonic motility.
Both postsurgical and nonsurgical opioid use also can trigger opioid-induced constipation (OIC), in which patients have less than three spontaneous bowel movements a week, harder stools, increased straining, and a feeling of incomplete evacuation. Patients may also report nausea, emesis, and gastroesophageal reflux. Even low-dose and short-term opioid therapy can lead to OIC. Symptoms and treatment response can be assessed with the bowel function index, in which patients rate ease of defecation, completeness of bowel evacuation, and severity of constipation over the past week on a scale of 0-100. Scores of 0-29 suggest no OIC. Patients who score above 30 despite over-the-counter laxatives are candidates for stepped-up treatments, including prolonged-release naloxone and oxycodone, the intestinal secretagogue lubiprostone, or peripherally acting mu-opioid receptor antagonists (PAMORAs), such as methylnaltrexone (12 mg subcutaneously) and naloxegol (12.5 mg or 25 mg per day orally). Additionally, tapentadol controls pain at lower doses than oxycodone and is less likely to cause constipation.
Narcotic bowel syndrome typically presents as moderate to severe daily abdominal pain lasting more than 3 months in patients on long-term opioids equating to a dosage of more than 100 mg morphine daily. Typically, patients report generalized, persistent, colicky abdominal pain that does not respond to dose escalation and worsens with dose tapering. Work-up is negative for differentials such as kidney stones or bowel obstruction. One epidemiological study estimated that 4% of patients on long-term opiates develop narcotic bowel syndrome, but the true prevalence may be higher according to the experts who authored this update. Mechanisms remain unclear but may include neuroplastic changes that favor the facilitation of pain signals rather than their inhibition, inflammation of spinal glial cells through activation of toll-like receptors, abnormal function of the N-methyl-D aspartate receptor at the level of the spinal cord, and central nociceptive abnormalities related to certain psychological traits or a history of trauma.
Treating narcotic bowel syndrome requires detoxification with appropriate nonopioid therapies for pain, anxiety, and withdrawal symptoms, including the use of clonidine. “This is best handled through specialists or centers with expertise in opiate dependence,” the experts stated. Patients who are able to stay off narcotics report improvements in pain, but the recidivism rate is about 50%.
The practice update also covers opioid therapy for gastrointestinal disorders. The PAMORA alvimopan shortens time to first postoperative stool without counteracting opioid analgesia during recovery. Alvimopan also has been found to hasten recovery of gastrointestinal function in patients with postoperative ileus after bowel resection. There is no evidence for using mu-opioid agonists for pain associated with irritable bowel syndrome (IBS), but the synthetic peripheral mu-opioid receptor agonist loperamide can improve stool consistency and urgency. A typical dose is 2 mg after each loose bowel movement or 2-4 mg before eating in cases of postprandial diarrhea. The mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist eluxadoline also can potentially improve stool consistency and urgency, global IBS symptoms, IBS symptom severity score, and quality of life. However, the FDA warns against using eluxadoline in patients who do not have a gallbladder because of the risk of severe outcomes – including death – related to sphincter of Oddi spasm and pancreatitis. Eluxadoline has been linked to at least two such fatalities in cholecystectomized patients. In each case, symptoms began after a single dose.
Dr. Camilleri is funded by the National Institutes of Health. He disclosed ties to AstraZeneca and Shionogi. The two coauthors disclosed ties to Forest Research Labs, Ironwood Pharmaceuticals, Prometheus, and Salix.
Physicians should consistently rule out opioid therapy as the cause of gastrointestinal symptoms, states a new clinical practice update published in the September 2017 issue of Clinical Gastroenterology and Hepatology (Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.05.014).
About 4% of Americans receive long-term opioid therapy, primarily for musculoskeletal, postsurgical, or vascular pain, as well as nonsurgical abdominal pain, writes Michael Camilleri, MD, AGAF, of Mayo Clinic in Rochester, Minn., and his associates. Because opioid receptors thickly populate the gastrointestinal tract, exogenous opioids can trigger a variety of gastrointestinal symptoms. Examples include achalasia, gastroparesis, nausea, postsurgical ileus, constipation, and narcotic bowel syndrome.
In the stomach, opioid use can cause gastroparesis, early satiety, and postprandial nausea and emesis, especially in the postoperative setting. Even novel opioid agents that are less likely to cause constipation can retard gastric emptying. For example, tapentadol, a mu-opioid agonist and norepinephrine reuptake inhibitor, delays emptying to the same extent as oxycodone. Tramadol also appears to slow overall orocecal transit. Although gastroparesis itself can cause nausea and emesis, opioids also directly stimulate the chemoreceptor trigger zone in the area postrema in the floor of the fourth ventricle. Options for preventive therapy include using a prokinetic, such as metoclopramide, prochlorperazine, or a 5-hydroxytryptamine3 antagonist, especially if patients are receiving opioids for postoperative pain control.
Exogenous opioids also can cause ileus, especially after abdominal surgery. These patients are already at risk of ileus because of surgical stress from bowel handling, secretion of inflammatory mediators and endogenous opioids, and fluctuating hormone and electrolyte levels. Postoperative analgesia with mu-opioids adds to the risk of ileus by increasing fluid absorption and inhibiting colonic motility.
Both postsurgical and nonsurgical opioid use also can trigger opioid-induced constipation (OIC), in which patients have less than three spontaneous bowel movements a week, harder stools, increased straining, and a feeling of incomplete evacuation. Patients may also report nausea, emesis, and gastroesophageal reflux. Even low-dose and short-term opioid therapy can lead to OIC. Symptoms and treatment response can be assessed with the bowel function index, in which patients rate ease of defecation, completeness of bowel evacuation, and severity of constipation over the past week on a scale of 0-100. Scores of 0-29 suggest no OIC. Patients who score above 30 despite over-the-counter laxatives are candidates for stepped-up treatments, including prolonged-release naloxone and oxycodone, the intestinal secretagogue lubiprostone, or peripherally acting mu-opioid receptor antagonists (PAMORAs), such as methylnaltrexone (12 mg subcutaneously) and naloxegol (12.5 mg or 25 mg per day orally). Additionally, tapentadol controls pain at lower doses than oxycodone and is less likely to cause constipation.
Narcotic bowel syndrome typically presents as moderate to severe daily abdominal pain lasting more than 3 months in patients on long-term opioids equating to a dosage of more than 100 mg morphine daily. Typically, patients report generalized, persistent, colicky abdominal pain that does not respond to dose escalation and worsens with dose tapering. Work-up is negative for differentials such as kidney stones or bowel obstruction. One epidemiological study estimated that 4% of patients on long-term opiates develop narcotic bowel syndrome, but the true prevalence may be higher according to the experts who authored this update. Mechanisms remain unclear but may include neuroplastic changes that favor the facilitation of pain signals rather than their inhibition, inflammation of spinal glial cells through activation of toll-like receptors, abnormal function of the N-methyl-D aspartate receptor at the level of the spinal cord, and central nociceptive abnormalities related to certain psychological traits or a history of trauma.
Treating narcotic bowel syndrome requires detoxification with appropriate nonopioid therapies for pain, anxiety, and withdrawal symptoms, including the use of clonidine. “This is best handled through specialists or centers with expertise in opiate dependence,” the experts stated. Patients who are able to stay off narcotics report improvements in pain, but the recidivism rate is about 50%.
The practice update also covers opioid therapy for gastrointestinal disorders. The PAMORA alvimopan shortens time to first postoperative stool without counteracting opioid analgesia during recovery. Alvimopan also has been found to hasten recovery of gastrointestinal function in patients with postoperative ileus after bowel resection. There is no evidence for using mu-opioid agonists for pain associated with irritable bowel syndrome (IBS), but the synthetic peripheral mu-opioid receptor agonist loperamide can improve stool consistency and urgency. A typical dose is 2 mg after each loose bowel movement or 2-4 mg before eating in cases of postprandial diarrhea. The mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist eluxadoline also can potentially improve stool consistency and urgency, global IBS symptoms, IBS symptom severity score, and quality of life. However, the FDA warns against using eluxadoline in patients who do not have a gallbladder because of the risk of severe outcomes – including death – related to sphincter of Oddi spasm and pancreatitis. Eluxadoline has been linked to at least two such fatalities in cholecystectomized patients. In each case, symptoms began after a single dose.
Dr. Camilleri is funded by the National Institutes of Health. He disclosed ties to AstraZeneca and Shionogi. The two coauthors disclosed ties to Forest Research Labs, Ironwood Pharmaceuticals, Prometheus, and Salix.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Colonic microbiota encroachment linked to diabetes
Bacterial infiltration into the colonic mucosa was associated with type 2 diabetes mellitus in humans, confirming prior findings in mice, investigators said.
Unlike in mice, however, microbiota encroachment did not correlate with human adiposity per se, reported Benoit Chassaing, PhD, of Georgia State University, Atlanta, and his associates. Their mouse models all have involved low-grade inflammation, which might impair insulin/leptin signaling and thereby promote both adiposity and dysglycemia, they said. In contrast, “we presume that humans can become obese for other reasons not involving the microbiota,” they added. The findings were published in the September issue of Cellular and Molecular Gastroenterology and Hepatology (2017;2[4]:205-21. doi: 10.1016/j.jcmgh.2017.04.001).
For the study, the investigators analyzed colonic mucosal biopsies from 42 middle-aged diabetic adults who underwent screening colonoscopies at a single Veteran’s Affairs hospital. All but one of the patients were men, 86% were overweight, 45% were obese, and 33% (14 patients) had diabetes. The researchers measured the shortest distance between bacteria and the epithelium using confocal microscopy and fluorescent in situ hybridization.
Nonobese, nondiabetic patients had residual bacteria “almost exclusively” in outer regions of the mucus layer, while obese diabetic patients had bacteria in the dense inner mucus near the epithelium, said the investigators. Unlike in mice, bacterial-epithelial distances did not correlate with adiposity per se among individuals without diabetes (P = .4). Conversely, patients with diabetes had bacterial-epithelial distances that were about one-third of those in euglycemic individuals (P less than .0001), even when they were not obese (P less than .001).
“We conclude that microbiota encroachment is a feature of insulin resistance–associated dysglycemia in humans,” Dr. Chassaing and his associates wrote. Microbiota encroachment did not correlate with ethnicity, use of antibiotics or diabetes treatments, or low-density lipoprotein levels, but it did correlate with a rise in CD19+ cells, probably mucosal B cells, they said. Defining connections among microbiota encroachment, B-cell responses, and metabolic disease might clarify the pathophysiology and treatment of metabolic syndrome, they concluded.
The investigators also induced hyperglycemia in wild-type mice by giving them water with 10% sucrose and intraperitoneal streptozotocin injections. Ten days after the last injection, they measured fasting blood glucose, fecal glucose, and colonic bacterial-epithelial distances. Even though fecal glucose rose as expected, they found no evidence of microbiota encroachment. They concluded that short-term (2-week) hyperglycemia was not enough to cause encroachment. Thus, microbiota encroachment is a characteristic of type 2 diabetes, not of adiposity per se, correlates with disease severity, and might stem from chronic inflammatory processes that drive insulin resistance, they concluded.
Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.
Dr. Chassaing and his colleagues examined the possible importance of the bacteria-free layer adjacent to the colonic epithelium in metabolic syndrome. A shrinking of this layer, termed “bacterial encroachment,” has been associated with human inflammatory bowel disease as well as mouse models of both colitis and metabolic syndrome, but the current study represents its first clear demonstration in human diabetes. In a cohort of 42 patients, the authors found that the epithelial-bacterial distance was inversely correlated with body mass index, fasting glucose, and hemoglobin A1c levels.
Interestingly, the primary predictor of encroachment in these patients was dysglycemia, not body mass index. This could not have been tested in standard mouse models where, because of the nature of the experimental insult, obesity and dysglycemia are essentially linked. Comparing obese human patients with and without dysglycemia, on the other hand, showed that encroachment is only clearly correlated with failed glucose regulation. This, however, is not the end of the story: In coordinated experiments with a short-term murine dysglycemia model, high glucose levels were not sufficient to elicit encroachment, suggesting a more complex metabolic circuit as the driver.
Mark R. Frey, PhD, is associate professor of pediatrics and biochemistry and molecular medicine at the Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California.
Dr. Chassaing and his colleagues examined the possible importance of the bacteria-free layer adjacent to the colonic epithelium in metabolic syndrome. A shrinking of this layer, termed “bacterial encroachment,” has been associated with human inflammatory bowel disease as well as mouse models of both colitis and metabolic syndrome, but the current study represents its first clear demonstration in human diabetes. In a cohort of 42 patients, the authors found that the epithelial-bacterial distance was inversely correlated with body mass index, fasting glucose, and hemoglobin A1c levels.
Interestingly, the primary predictor of encroachment in these patients was dysglycemia, not body mass index. This could not have been tested in standard mouse models where, because of the nature of the experimental insult, obesity and dysglycemia are essentially linked. Comparing obese human patients with and without dysglycemia, on the other hand, showed that encroachment is only clearly correlated with failed glucose regulation. This, however, is not the end of the story: In coordinated experiments with a short-term murine dysglycemia model, high glucose levels were not sufficient to elicit encroachment, suggesting a more complex metabolic circuit as the driver.
Mark R. Frey, PhD, is associate professor of pediatrics and biochemistry and molecular medicine at the Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California.
Dr. Chassaing and his colleagues examined the possible importance of the bacteria-free layer adjacent to the colonic epithelium in metabolic syndrome. A shrinking of this layer, termed “bacterial encroachment,” has been associated with human inflammatory bowel disease as well as mouse models of both colitis and metabolic syndrome, but the current study represents its first clear demonstration in human diabetes. In a cohort of 42 patients, the authors found that the epithelial-bacterial distance was inversely correlated with body mass index, fasting glucose, and hemoglobin A1c levels.
Interestingly, the primary predictor of encroachment in these patients was dysglycemia, not body mass index. This could not have been tested in standard mouse models where, because of the nature of the experimental insult, obesity and dysglycemia are essentially linked. Comparing obese human patients with and without dysglycemia, on the other hand, showed that encroachment is only clearly correlated with failed glucose regulation. This, however, is not the end of the story: In coordinated experiments with a short-term murine dysglycemia model, high glucose levels were not sufficient to elicit encroachment, suggesting a more complex metabolic circuit as the driver.
Mark R. Frey, PhD, is associate professor of pediatrics and biochemistry and molecular medicine at the Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California.
Bacterial infiltration into the colonic mucosa was associated with type 2 diabetes mellitus in humans, confirming prior findings in mice, investigators said.
Unlike in mice, however, microbiota encroachment did not correlate with human adiposity per se, reported Benoit Chassaing, PhD, of Georgia State University, Atlanta, and his associates. Their mouse models all have involved low-grade inflammation, which might impair insulin/leptin signaling and thereby promote both adiposity and dysglycemia, they said. In contrast, “we presume that humans can become obese for other reasons not involving the microbiota,” they added. The findings were published in the September issue of Cellular and Molecular Gastroenterology and Hepatology (2017;2[4]:205-21. doi: 10.1016/j.jcmgh.2017.04.001).
For the study, the investigators analyzed colonic mucosal biopsies from 42 middle-aged diabetic adults who underwent screening colonoscopies at a single Veteran’s Affairs hospital. All but one of the patients were men, 86% were overweight, 45% were obese, and 33% (14 patients) had diabetes. The researchers measured the shortest distance between bacteria and the epithelium using confocal microscopy and fluorescent in situ hybridization.
Nonobese, nondiabetic patients had residual bacteria “almost exclusively” in outer regions of the mucus layer, while obese diabetic patients had bacteria in the dense inner mucus near the epithelium, said the investigators. Unlike in mice, bacterial-epithelial distances did not correlate with adiposity per se among individuals without diabetes (P = .4). Conversely, patients with diabetes had bacterial-epithelial distances that were about one-third of those in euglycemic individuals (P less than .0001), even when they were not obese (P less than .001).
“We conclude that microbiota encroachment is a feature of insulin resistance–associated dysglycemia in humans,” Dr. Chassaing and his associates wrote. Microbiota encroachment did not correlate with ethnicity, use of antibiotics or diabetes treatments, or low-density lipoprotein levels, but it did correlate with a rise in CD19+ cells, probably mucosal B cells, they said. Defining connections among microbiota encroachment, B-cell responses, and metabolic disease might clarify the pathophysiology and treatment of metabolic syndrome, they concluded.
The investigators also induced hyperglycemia in wild-type mice by giving them water with 10% sucrose and intraperitoneal streptozotocin injections. Ten days after the last injection, they measured fasting blood glucose, fecal glucose, and colonic bacterial-epithelial distances. Even though fecal glucose rose as expected, they found no evidence of microbiota encroachment. They concluded that short-term (2-week) hyperglycemia was not enough to cause encroachment. Thus, microbiota encroachment is a characteristic of type 2 diabetes, not of adiposity per se, correlates with disease severity, and might stem from chronic inflammatory processes that drive insulin resistance, they concluded.
Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.
Bacterial infiltration into the colonic mucosa was associated with type 2 diabetes mellitus in humans, confirming prior findings in mice, investigators said.
Unlike in mice, however, microbiota encroachment did not correlate with human adiposity per se, reported Benoit Chassaing, PhD, of Georgia State University, Atlanta, and his associates. Their mouse models all have involved low-grade inflammation, which might impair insulin/leptin signaling and thereby promote both adiposity and dysglycemia, they said. In contrast, “we presume that humans can become obese for other reasons not involving the microbiota,” they added. The findings were published in the September issue of Cellular and Molecular Gastroenterology and Hepatology (2017;2[4]:205-21. doi: 10.1016/j.jcmgh.2017.04.001).
For the study, the investigators analyzed colonic mucosal biopsies from 42 middle-aged diabetic adults who underwent screening colonoscopies at a single Veteran’s Affairs hospital. All but one of the patients were men, 86% were overweight, 45% were obese, and 33% (14 patients) had diabetes. The researchers measured the shortest distance between bacteria and the epithelium using confocal microscopy and fluorescent in situ hybridization.
Nonobese, nondiabetic patients had residual bacteria “almost exclusively” in outer regions of the mucus layer, while obese diabetic patients had bacteria in the dense inner mucus near the epithelium, said the investigators. Unlike in mice, bacterial-epithelial distances did not correlate with adiposity per se among individuals without diabetes (P = .4). Conversely, patients with diabetes had bacterial-epithelial distances that were about one-third of those in euglycemic individuals (P less than .0001), even when they were not obese (P less than .001).
“We conclude that microbiota encroachment is a feature of insulin resistance–associated dysglycemia in humans,” Dr. Chassaing and his associates wrote. Microbiota encroachment did not correlate with ethnicity, use of antibiotics or diabetes treatments, or low-density lipoprotein levels, but it did correlate with a rise in CD19+ cells, probably mucosal B cells, they said. Defining connections among microbiota encroachment, B-cell responses, and metabolic disease might clarify the pathophysiology and treatment of metabolic syndrome, they concluded.
The investigators also induced hyperglycemia in wild-type mice by giving them water with 10% sucrose and intraperitoneal streptozotocin injections. Ten days after the last injection, they measured fasting blood glucose, fecal glucose, and colonic bacterial-epithelial distances. Even though fecal glucose rose as expected, they found no evidence of microbiota encroachment. They concluded that short-term (2-week) hyperglycemia was not enough to cause encroachment. Thus, microbiota encroachment is a characteristic of type 2 diabetes, not of adiposity per se, correlates with disease severity, and might stem from chronic inflammatory processes that drive insulin resistance, they concluded.
Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Microbiota encroachment into colonic mucosa characterizes type 2 diabetes in humans.
Major finding: Regardless of whether they were obese or normal weight, patients with diabetes had bacterial-epithelial colonic distances that were one-third of those in euglycemic individuals (P less than .001).
Data source: A study of 42 Veterans Affairs patients with and without type 2 diabetes mellitus.
Disclosures: Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.
VIDEO: Study highlights risks of postponing cholecystectomy
Almost half of patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) did not undergo cholecystectomy (CCY) within the next 60 days according to the results of a large, retrospective cohort study reported in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2017.05.048).
“Although early and delayed CCY equally reduce the risk of subsequent recurrent biliary events, patients are at 10-fold higher risk of a recurrent biliary event while waiting for a delayed CCY, compared with patients who underwent early CCY,” wrote Robert J. Huang, MD, and his associates of Stanford (Calif.) University Medical Center. Delayed CCY is cost effective, but that benefit must be weighed against the risk of loss to follow-up, especially if patients have “little or no health insurance,” they said.
Source: American Gastroenterological Association
Gallstone disease affects up to 15% of adults in developed societies, including about 20-25 million Americans. Yearly costs of treatment tally at more than $6.2 billion and have risen by more than 20% in 3 decades, according to multiple studies. Approximately 20% of patients with gallstone disease have choledocholithiasis, mainly because gallstones can pass from the gallbladder into the common bile duct. After undergoing ERCP, such patients are typically referred for CCY, but there are no “societal guidelines” on timing the referral, the researchers said. Practice patterns remain “largely institution based and may be subject to the vagaries of surgeon availability and other institutional resource constraints.” One prior study linked a median 7-week wait time for CCY with a 20% rate of recurrent biliary events. To evaluate large-scale practice patterns, the researchers studied 4,516 patients who had undergone ERCP for choledocholithiasis in California (during 2009-2011), New York (during 2011-2013), and Florida (during 2012-2014) and calculated timing and rates of subsequent CCY, recurrent biliary events, and deaths. Patients were followed for up to 365 days after ERCP.
Of the 4,516 patients studied, 1,859 (41.2%) patients underwent CCY during their index hospital admission (early CCY). Of the 2,657 (58.8%) patients who were discharged without CCY, only 491 (18%) had a planned CCY within 60 days (delayed CCY), 350 (71.3%) of which were done in an outpatient setting. Of the patients in the study, 2,168 (48.0%) did not have a CCY (no CCY) during their index visit or within 60 days. Over 365 days of follow-up, 10% of patients who did not have a CCY had recurrent biliary events, compared with 1.3% of patients who underwent early or delayed CCY. The risk of recurrent biliary events for patients who underwent early or delayed CCY was about 88% lower than if they had had no CCY within 60 days of ERCP (P less than .001 for each comparison). Performing CCY during index admission cut the risk of recurrent biliary events occurring within 60 days by 92%, compared with delayed or no CCY (P less than .001).
In all, 15 (0.7%) patients who did not undergo CCY died after subsequent hospitalization for a recurrent biliary event, compared with 1 patient who underwent early CCY (0.1%; P less than .001). There were no deaths associated with recurrent biliary events in the delayed-CCY group. Rates of all-cause mortality over 365 days were 3.1% in the no-CCY group, 0.6% in the early-CCY group, and 0% in the delayed-CCY group. Thus, cumulative death rates were about seven times higher among patients who did not undergo CCY compared with those who did (P less than .001).
Patients who did not undergo CCY tended to be older than delayed- and early-CCY patients (mean ages 66 years, 58 years, and 52 years, respectively). No-CCY patients also tended to have more comorbidities. Nonetheless, having an early CCY retained a “robust” protective effect against recurrent biliary events after accounting for age, sex, comorbidities, stent placement, facility volume, and state of residence. Even after researchers adjusted for those factors, the protective effect of early CCY dropped by less than 5% (from 92% to about 87%), the investigators said.
They also noted that the overall cohort averaged 60 years of age and that 64% were female, which is consistent with the epidemiology of biliary stone disease. Just over half were non-Hispanic whites. Medicare was the single largest primary payer (46%), followed by private insurance (28%) and Medicaid (16%).
“A strategy of delayed CCY performed on an outpatient basis was least costly,” the researchers said. “Performance of early CCY was inversely associated with low facility volume. Hispanic race, Asian race, Medicaid insurance, and no insurance associated inversely with performance of delayed CCY.”
Funders included a seed grant from the Stanford division of gastroenterology and hepatology and the National Institutes of Health. The investigators had no conflicts of interest.
Almost half of patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) did not undergo cholecystectomy (CCY) within the next 60 days according to the results of a large, retrospective cohort study reported in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2017.05.048).
“Although early and delayed CCY equally reduce the risk of subsequent recurrent biliary events, patients are at 10-fold higher risk of a recurrent biliary event while waiting for a delayed CCY, compared with patients who underwent early CCY,” wrote Robert J. Huang, MD, and his associates of Stanford (Calif.) University Medical Center. Delayed CCY is cost effective, but that benefit must be weighed against the risk of loss to follow-up, especially if patients have “little or no health insurance,” they said.
Source: American Gastroenterological Association
Gallstone disease affects up to 15% of adults in developed societies, including about 20-25 million Americans. Yearly costs of treatment tally at more than $6.2 billion and have risen by more than 20% in 3 decades, according to multiple studies. Approximately 20% of patients with gallstone disease have choledocholithiasis, mainly because gallstones can pass from the gallbladder into the common bile duct. After undergoing ERCP, such patients are typically referred for CCY, but there are no “societal guidelines” on timing the referral, the researchers said. Practice patterns remain “largely institution based and may be subject to the vagaries of surgeon availability and other institutional resource constraints.” One prior study linked a median 7-week wait time for CCY with a 20% rate of recurrent biliary events. To evaluate large-scale practice patterns, the researchers studied 4,516 patients who had undergone ERCP for choledocholithiasis in California (during 2009-2011), New York (during 2011-2013), and Florida (during 2012-2014) and calculated timing and rates of subsequent CCY, recurrent biliary events, and deaths. Patients were followed for up to 365 days after ERCP.
Of the 4,516 patients studied, 1,859 (41.2%) patients underwent CCY during their index hospital admission (early CCY). Of the 2,657 (58.8%) patients who were discharged without CCY, only 491 (18%) had a planned CCY within 60 days (delayed CCY), 350 (71.3%) of which were done in an outpatient setting. Of the patients in the study, 2,168 (48.0%) did not have a CCY (no CCY) during their index visit or within 60 days. Over 365 days of follow-up, 10% of patients who did not have a CCY had recurrent biliary events, compared with 1.3% of patients who underwent early or delayed CCY. The risk of recurrent biliary events for patients who underwent early or delayed CCY was about 88% lower than if they had had no CCY within 60 days of ERCP (P less than .001 for each comparison). Performing CCY during index admission cut the risk of recurrent biliary events occurring within 60 days by 92%, compared with delayed or no CCY (P less than .001).
In all, 15 (0.7%) patients who did not undergo CCY died after subsequent hospitalization for a recurrent biliary event, compared with 1 patient who underwent early CCY (0.1%; P less than .001). There were no deaths associated with recurrent biliary events in the delayed-CCY group. Rates of all-cause mortality over 365 days were 3.1% in the no-CCY group, 0.6% in the early-CCY group, and 0% in the delayed-CCY group. Thus, cumulative death rates were about seven times higher among patients who did not undergo CCY compared with those who did (P less than .001).
Patients who did not undergo CCY tended to be older than delayed- and early-CCY patients (mean ages 66 years, 58 years, and 52 years, respectively). No-CCY patients also tended to have more comorbidities. Nonetheless, having an early CCY retained a “robust” protective effect against recurrent biliary events after accounting for age, sex, comorbidities, stent placement, facility volume, and state of residence. Even after researchers adjusted for those factors, the protective effect of early CCY dropped by less than 5% (from 92% to about 87%), the investigators said.
They also noted that the overall cohort averaged 60 years of age and that 64% were female, which is consistent with the epidemiology of biliary stone disease. Just over half were non-Hispanic whites. Medicare was the single largest primary payer (46%), followed by private insurance (28%) and Medicaid (16%).
“A strategy of delayed CCY performed on an outpatient basis was least costly,” the researchers said. “Performance of early CCY was inversely associated with low facility volume. Hispanic race, Asian race, Medicaid insurance, and no insurance associated inversely with performance of delayed CCY.”
Funders included a seed grant from the Stanford division of gastroenterology and hepatology and the National Institutes of Health. The investigators had no conflicts of interest.
Almost half of patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) did not undergo cholecystectomy (CCY) within the next 60 days according to the results of a large, retrospective cohort study reported in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2017.05.048).
“Although early and delayed CCY equally reduce the risk of subsequent recurrent biliary events, patients are at 10-fold higher risk of a recurrent biliary event while waiting for a delayed CCY, compared with patients who underwent early CCY,” wrote Robert J. Huang, MD, and his associates of Stanford (Calif.) University Medical Center. Delayed CCY is cost effective, but that benefit must be weighed against the risk of loss to follow-up, especially if patients have “little or no health insurance,” they said.
Source: American Gastroenterological Association
Gallstone disease affects up to 15% of adults in developed societies, including about 20-25 million Americans. Yearly costs of treatment tally at more than $6.2 billion and have risen by more than 20% in 3 decades, according to multiple studies. Approximately 20% of patients with gallstone disease have choledocholithiasis, mainly because gallstones can pass from the gallbladder into the common bile duct. After undergoing ERCP, such patients are typically referred for CCY, but there are no “societal guidelines” on timing the referral, the researchers said. Practice patterns remain “largely institution based and may be subject to the vagaries of surgeon availability and other institutional resource constraints.” One prior study linked a median 7-week wait time for CCY with a 20% rate of recurrent biliary events. To evaluate large-scale practice patterns, the researchers studied 4,516 patients who had undergone ERCP for choledocholithiasis in California (during 2009-2011), New York (during 2011-2013), and Florida (during 2012-2014) and calculated timing and rates of subsequent CCY, recurrent biliary events, and deaths. Patients were followed for up to 365 days after ERCP.
Of the 4,516 patients studied, 1,859 (41.2%) patients underwent CCY during their index hospital admission (early CCY). Of the 2,657 (58.8%) patients who were discharged without CCY, only 491 (18%) had a planned CCY within 60 days (delayed CCY), 350 (71.3%) of which were done in an outpatient setting. Of the patients in the study, 2,168 (48.0%) did not have a CCY (no CCY) during their index visit or within 60 days. Over 365 days of follow-up, 10% of patients who did not have a CCY had recurrent biliary events, compared with 1.3% of patients who underwent early or delayed CCY. The risk of recurrent biliary events for patients who underwent early or delayed CCY was about 88% lower than if they had had no CCY within 60 days of ERCP (P less than .001 for each comparison). Performing CCY during index admission cut the risk of recurrent biliary events occurring within 60 days by 92%, compared with delayed or no CCY (P less than .001).
In all, 15 (0.7%) patients who did not undergo CCY died after subsequent hospitalization for a recurrent biliary event, compared with 1 patient who underwent early CCY (0.1%; P less than .001). There were no deaths associated with recurrent biliary events in the delayed-CCY group. Rates of all-cause mortality over 365 days were 3.1% in the no-CCY group, 0.6% in the early-CCY group, and 0% in the delayed-CCY group. Thus, cumulative death rates were about seven times higher among patients who did not undergo CCY compared with those who did (P less than .001).
Patients who did not undergo CCY tended to be older than delayed- and early-CCY patients (mean ages 66 years, 58 years, and 52 years, respectively). No-CCY patients also tended to have more comorbidities. Nonetheless, having an early CCY retained a “robust” protective effect against recurrent biliary events after accounting for age, sex, comorbidities, stent placement, facility volume, and state of residence. Even after researchers adjusted for those factors, the protective effect of early CCY dropped by less than 5% (from 92% to about 87%), the investigators said.
They also noted that the overall cohort averaged 60 years of age and that 64% were female, which is consistent with the epidemiology of biliary stone disease. Just over half were non-Hispanic whites. Medicare was the single largest primary payer (46%), followed by private insurance (28%) and Medicaid (16%).
“A strategy of delayed CCY performed on an outpatient basis was least costly,” the researchers said. “Performance of early CCY was inversely associated with low facility volume. Hispanic race, Asian race, Medicaid insurance, and no insurance associated inversely with performance of delayed CCY.”
Funders included a seed grant from the Stanford division of gastroenterology and hepatology and the National Institutes of Health. The investigators had no conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: Almost half of patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) did not undergo cholecystectomy within 60 days.
Major finding: A total of 48% had no cholecystectomy within 60 days. Performing cholecystectomy during index admission cut the risk of recurrent biliary events within 60 days by 92%, compared with delayed or no cholecystectomy (P less than .001).
Data source: A multistate, retrospective study of 4,516 patients hospitalized with choledocholithiasis.
Disclosures: Funders included a Stanford division of gastroenterology and hepatology divisional seed grant and the National Institutes of Health. The investigators had no conflicts of interest.
