From the AGA Journals

Use of proton pump inhibitors (PPIs) is not associated with cognitive decline in two prospective, population-based studies of identical twins published in the May issue of Clinical Gastroenterology and Hepatology.

“No stated differences in [mean cognitive] scores between PPI users and nonusers were significant,” wrote Mette Wod, PhD, of the University of Southern Denmark, Odense, with her associates.

Schnoodle/ThinkStock

Past research has yielded mixed findings about whether using PPIs affects the risk of dementia. Preclinical data suggest that exposure to these drugs affects amyloid levels in mice, but “the evidence is equivocal, [and] the results of epidemiologic studies [of humans] have also been inconclusive, with more recent studies pointing toward a null association,” the investigators wrote. Furthermore, there are only “scant” data on whether long-term PPI use affects cognitive function, they noted.

To help clarify the issue, they analyzed prospective data from two studies of twins in Denmark: the Study of Middle-Aged Danish Twins, in which individuals underwent a five-part cognitive battery at baseline and then 10 years later, and the Longitudinal Study of Aging Danish Twins, in which participants underwent the same test at baseline and 2 years later. The cognitive test assessed verbal fluency, forward and backward digit span, and immediate and delayed recall of a 12-item list. Using data from a national prescription registry, the investigators also estimated individuals’ PPI exposure starting 2 years before study enrollment.

In the study of middle-aged twins, participants who used high-dose PPIs before study enrollment had cognitive scores that were slightly lower at baseline, compared with PPI nonusers. Mean baseline scores were 43.1 (standard deviation, 13.1) and 46.8 (SD, 10.2), respectively. However, after researchers adjusted for numerous clinical and demographic variables, the between-group difference in baseline scores narrowed to just 0.69 (95% confidence interval, –4.98 to 3.61), which was not statistically significant.

The longitudinal study of older twins yielded similar results. Individuals who used high doses of PPIs had slightly higher adjusted mean baseline cognitive score than did nonusers, but the difference did not reach statistical significance (0.95; 95% CI, –1.88 to 3.79).

Furthermore, prospective assessments of cognitive decline found no evidence of an effect. In the longitudinal aging study, high-dose PPI users had slightly less cognitive decline (based on a smaller change in test scores over time) than did nonusers, but the adjusted difference in decline between groups was not significant (1.22 points; 95% CI, –3.73 to 1.29). In the middle-aged twin study, individuals with the highest levels of PPI exposure (at least 1,600 daily doses) had slightly less cognitive decline than did nonusers, with an adjusted difference of 0.94 points (95% CI, –1.63 to 3.50) between groups, but this did not reach statistical significance.

“This study is the first to examine the association between long-term PPI use and cognitive decline in a population-based setting,” the researchers concluded. “Cognitive scores of more than 7,800 middle-aged and older Danish twins at baseline did not indicate an association with previous PPI use. Follow-up data on more than 4,000 of these twins did not indicate that use of this class of drugs was correlated to cognitive decline.”

Odense University Hospital provided partial funding. Dr. Wod had no disclosures. Three coinvestigators disclosed ties to AstraZeneca and Bayer AG.

SOURCE: Wod M et al. Clin Gastro Hepatol. 2018 Feb 3. doi: 10.1016/j.cgh.2018.01.034.

Use of proton pump inhibitors (PPIs) is not associated with cognitive decline in two prospective, population-based studies of identical twins published in the May issue of Clinical Gastroenterology and Hepatology.

“No stated differences in [mean cognitive] scores between PPI users and nonusers were significant,” wrote Mette Wod, PhD, of the University of Southern Denmark, Odense, with her associates.

Schnoodle/ThinkStock

Past research has yielded mixed findings about whether using PPIs affects the risk of dementia. Preclinical data suggest that exposure to these drugs affects amyloid levels in mice, but “the evidence is equivocal, [and] the results of epidemiologic studies [of humans] have also been inconclusive, with more recent studies pointing toward a null association,” the investigators wrote. Furthermore, there are only “scant” data on whether long-term PPI use affects cognitive function, they noted.

To help clarify the issue, they analyzed prospective data from two studies of twins in Denmark: the Study of Middle-Aged Danish Twins, in which individuals underwent a five-part cognitive battery at baseline and then 10 years later, and the Longitudinal Study of Aging Danish Twins, in which participants underwent the same test at baseline and 2 years later. The cognitive test assessed verbal fluency, forward and backward digit span, and immediate and delayed recall of a 12-item list. Using data from a national prescription registry, the investigators also estimated individuals’ PPI exposure starting 2 years before study enrollment.

In the study of middle-aged twins, participants who used high-dose PPIs before study enrollment had cognitive scores that were slightly lower at baseline, compared with PPI nonusers. Mean baseline scores were 43.1 (standard deviation, 13.1) and 46.8 (SD, 10.2), respectively. However, after researchers adjusted for numerous clinical and demographic variables, the between-group difference in baseline scores narrowed to just 0.69 (95% confidence interval, –4.98 to 3.61), which was not statistically significant.

The longitudinal study of older twins yielded similar results. Individuals who used high doses of PPIs had slightly higher adjusted mean baseline cognitive score than did nonusers, but the difference did not reach statistical significance (0.95; 95% CI, –1.88 to 3.79).

Furthermore, prospective assessments of cognitive decline found no evidence of an effect. In the longitudinal aging study, high-dose PPI users had slightly less cognitive decline (based on a smaller change in test scores over time) than did nonusers, but the adjusted difference in decline between groups was not significant (1.22 points; 95% CI, –3.73 to 1.29). In the middle-aged twin study, individuals with the highest levels of PPI exposure (at least 1,600 daily doses) had slightly less cognitive decline than did nonusers, with an adjusted difference of 0.94 points (95% CI, –1.63 to 3.50) between groups, but this did not reach statistical significance.

“This study is the first to examine the association between long-term PPI use and cognitive decline in a population-based setting,” the researchers concluded. “Cognitive scores of more than 7,800 middle-aged and older Danish twins at baseline did not indicate an association with previous PPI use. Follow-up data on more than 4,000 of these twins did not indicate that use of this class of drugs was correlated to cognitive decline.”

Odense University Hospital provided partial funding. Dr. Wod had no disclosures. Three coinvestigators disclosed ties to AstraZeneca and Bayer AG.

SOURCE: Wod M et al. Clin Gastro Hepatol. 2018 Feb 3. doi: 10.1016/j.cgh.2018.01.034.

Use of proton pump inhibitors (PPIs) is not associated with cognitive decline in two prospective, population-based studies of identical twins published in the May issue of Clinical Gastroenterology and Hepatology.

“No stated differences in [mean cognitive] scores between PPI users and nonusers were significant,” wrote Mette Wod, PhD, of the University of Southern Denmark, Odense, with her associates.

Schnoodle/ThinkStock

Past research has yielded mixed findings about whether using PPIs affects the risk of dementia. Preclinical data suggest that exposure to these drugs affects amyloid levels in mice, but “the evidence is equivocal, [and] the results of epidemiologic studies [of humans] have also been inconclusive, with more recent studies pointing toward a null association,” the investigators wrote. Furthermore, there are only “scant” data on whether long-term PPI use affects cognitive function, they noted.

To help clarify the issue, they analyzed prospective data from two studies of twins in Denmark: the Study of Middle-Aged Danish Twins, in which individuals underwent a five-part cognitive battery at baseline and then 10 years later, and the Longitudinal Study of Aging Danish Twins, in which participants underwent the same test at baseline and 2 years later. The cognitive test assessed verbal fluency, forward and backward digit span, and immediate and delayed recall of a 12-item list. Using data from a national prescription registry, the investigators also estimated individuals’ PPI exposure starting 2 years before study enrollment.

In the study of middle-aged twins, participants who used high-dose PPIs before study enrollment had cognitive scores that were slightly lower at baseline, compared with PPI nonusers. Mean baseline scores were 43.1 (standard deviation, 13.1) and 46.8 (SD, 10.2), respectively. However, after researchers adjusted for numerous clinical and demographic variables, the between-group difference in baseline scores narrowed to just 0.69 (95% confidence interval, –4.98 to 3.61), which was not statistically significant.

The longitudinal study of older twins yielded similar results. Individuals who used high doses of PPIs had slightly higher adjusted mean baseline cognitive score than did nonusers, but the difference did not reach statistical significance (0.95; 95% CI, –1.88 to 3.79).

Furthermore, prospective assessments of cognitive decline found no evidence of an effect. In the longitudinal aging study, high-dose PPI users had slightly less cognitive decline (based on a smaller change in test scores over time) than did nonusers, but the adjusted difference in decline between groups was not significant (1.22 points; 95% CI, –3.73 to 1.29). In the middle-aged twin study, individuals with the highest levels of PPI exposure (at least 1,600 daily doses) had slightly less cognitive decline than did nonusers, with an adjusted difference of 0.94 points (95% CI, –1.63 to 3.50) between groups, but this did not reach statistical significance.

“This study is the first to examine the association between long-term PPI use and cognitive decline in a population-based setting,” the researchers concluded. “Cognitive scores of more than 7,800 middle-aged and older Danish twins at baseline did not indicate an association with previous PPI use. Follow-up data on more than 4,000 of these twins did not indicate that use of this class of drugs was correlated to cognitive decline.”

Odense University Hospital provided partial funding. Dr. Wod had no disclosures. Three coinvestigators disclosed ties to AstraZeneca and Bayer AG.

SOURCE: Wod M et al. Clin Gastro Hepatol. 2018 Feb 3. doi: 10.1016/j.cgh.2018.01.034.

For patients with cirrhosis, adding serum alpha fetoprotein testing to ultrasound significantly boosted its ability to detect early-stage hepatocellular carcinoma, according to the results of a systematic review and meta-analysis reported in the May issue of Gastroenterology.

Used alone, ultrasound detected only 45% of early-stage hepatocellular carcinomas (95% confidence interval, 30%-62%), reported Kristina Tzartzeva, MD, of the University of Texas, Dallas, with her associates. Adding alpha fetoprotein (AFP) increased this sensitivity to 63% (95% CI, 48%-75%; P = .002). Few studies evaluated alternative surveillance tools, such as CT or MRI.

Diagnosing liver cancer early is key to survival and thus is a central issue in cirrhosis management. However, the best surveillance strategy remains uncertain, hinging as it does on sensitivity, specificity, and cost. The American Association for the Study of Liver Diseases and the European Association for the Study of the Liver recommend that cirrhotic patients undergo twice-yearly ultrasound to screen for hepatocellular carcinoma (HCC), but they disagree about the value of adding serum biomarker AFP testing. Meanwhile, more and more clinics are using CT and MRI because of concerns about the unreliability of ultrasound. “Given few direct comparative studies, we are forced to primarily rely on indirect comparisons across studies,” the reviewers wrote.

To do so, they searched MEDLINE and Scopus and identified 32 studies of HCC surveillance that comprised 13,367 patients, nearly all with baseline cirrhosis. The studies were published from 1990 to August 2016.

Ultrasound detected HCC of any stage with a sensitivity of 84% (95% CI, 76%-92%), but its sensitivity for detecting early-stage disease was less than 50%. In studies that performed direct comparisons, ultrasound alone was significantly less sensitive than ultrasound plus AFP for detecting all stages of HCC (relative risk, 0.80; 95% CI, 0.72-0.88) and early-stage disease (0.78; 0.66-0.92). However, ultrasound alone was more specific than ultrasound plus AFP (RR, 1.08; 95% CI, 1.05-1.09).

Four studies of about 900 patients evaluated cross-sectional imaging with CT or MRI. In one single-center, randomized trial, CT had a sensitivity of 63% for detecting early-stage disease, but the 95% CI for this estimate was very wide (30%-87%) and CT did not significantly outperform ultrasound (Aliment Pharmacol Ther. 2013;38:303-12). In another study, MRI and ultrasound had significantly different sensitivities of 84% and 26% for detecting (usually) early-stage disease (JAMA Oncol. 2017;3[4]:456-63).

SOURCE: Tzartzeva K et al. Gastroenterology. 2018 Feb 6. doi: 10.1053/j.gastro.2018.01.064.

For patients with cirrhosis, adding serum alpha fetoprotein testing to ultrasound significantly boosted its ability to detect early-stage hepatocellular carcinoma, according to the results of a systematic review and meta-analysis reported in the May issue of Gastroenterology.

Used alone, ultrasound detected only 45% of early-stage hepatocellular carcinomas (95% confidence interval, 30%-62%), reported Kristina Tzartzeva, MD, of the University of Texas, Dallas, with her associates. Adding alpha fetoprotein (AFP) increased this sensitivity to 63% (95% CI, 48%-75%; P = .002). Few studies evaluated alternative surveillance tools, such as CT or MRI.

Diagnosing liver cancer early is key to survival and thus is a central issue in cirrhosis management. However, the best surveillance strategy remains uncertain, hinging as it does on sensitivity, specificity, and cost. The American Association for the Study of Liver Diseases and the European Association for the Study of the Liver recommend that cirrhotic patients undergo twice-yearly ultrasound to screen for hepatocellular carcinoma (HCC), but they disagree about the value of adding serum biomarker AFP testing. Meanwhile, more and more clinics are using CT and MRI because of concerns about the unreliability of ultrasound. “Given few direct comparative studies, we are forced to primarily rely on indirect comparisons across studies,” the reviewers wrote.

To do so, they searched MEDLINE and Scopus and identified 32 studies of HCC surveillance that comprised 13,367 patients, nearly all with baseline cirrhosis. The studies were published from 1990 to August 2016.

Ultrasound detected HCC of any stage with a sensitivity of 84% (95% CI, 76%-92%), but its sensitivity for detecting early-stage disease was less than 50%. In studies that performed direct comparisons, ultrasound alone was significantly less sensitive than ultrasound plus AFP for detecting all stages of HCC (relative risk, 0.80; 95% CI, 0.72-0.88) and early-stage disease (0.78; 0.66-0.92). However, ultrasound alone was more specific than ultrasound plus AFP (RR, 1.08; 95% CI, 1.05-1.09).

Four studies of about 900 patients evaluated cross-sectional imaging with CT or MRI. In one single-center, randomized trial, CT had a sensitivity of 63% for detecting early-stage disease, but the 95% CI for this estimate was very wide (30%-87%) and CT did not significantly outperform ultrasound (Aliment Pharmacol Ther. 2013;38:303-12). In another study, MRI and ultrasound had significantly different sensitivities of 84% and 26% for detecting (usually) early-stage disease (JAMA Oncol. 2017;3[4]:456-63).

SOURCE: Tzartzeva K et al. Gastroenterology. 2018 Feb 6. doi: 10.1053/j.gastro.2018.01.064.

For patients with cirrhosis, adding serum alpha fetoprotein testing to ultrasound significantly boosted its ability to detect early-stage hepatocellular carcinoma, according to the results of a systematic review and meta-analysis reported in the May issue of Gastroenterology.

Used alone, ultrasound detected only 45% of early-stage hepatocellular carcinomas (95% confidence interval, 30%-62%), reported Kristina Tzartzeva, MD, of the University of Texas, Dallas, with her associates. Adding alpha fetoprotein (AFP) increased this sensitivity to 63% (95% CI, 48%-75%; P = .002). Few studies evaluated alternative surveillance tools, such as CT or MRI.

Diagnosing liver cancer early is key to survival and thus is a central issue in cirrhosis management. However, the best surveillance strategy remains uncertain, hinging as it does on sensitivity, specificity, and cost. The American Association for the Study of Liver Diseases and the European Association for the Study of the Liver recommend that cirrhotic patients undergo twice-yearly ultrasound to screen for hepatocellular carcinoma (HCC), but they disagree about the value of adding serum biomarker AFP testing. Meanwhile, more and more clinics are using CT and MRI because of concerns about the unreliability of ultrasound. “Given few direct comparative studies, we are forced to primarily rely on indirect comparisons across studies,” the reviewers wrote.

To do so, they searched MEDLINE and Scopus and identified 32 studies of HCC surveillance that comprised 13,367 patients, nearly all with baseline cirrhosis. The studies were published from 1990 to August 2016.

Ultrasound detected HCC of any stage with a sensitivity of 84% (95% CI, 76%-92%), but its sensitivity for detecting early-stage disease was less than 50%. In studies that performed direct comparisons, ultrasound alone was significantly less sensitive than ultrasound plus AFP for detecting all stages of HCC (relative risk, 0.80; 95% CI, 0.72-0.88) and early-stage disease (0.78; 0.66-0.92). However, ultrasound alone was more specific than ultrasound plus AFP (RR, 1.08; 95% CI, 1.05-1.09).

Four studies of about 900 patients evaluated cross-sectional imaging with CT or MRI. In one single-center, randomized trial, CT had a sensitivity of 63% for detecting early-stage disease, but the 95% CI for this estimate was very wide (30%-87%) and CT did not significantly outperform ultrasound (Aliment Pharmacol Ther. 2013;38:303-12). In another study, MRI and ultrasound had significantly different sensitivities of 84% and 26% for detecting (usually) early-stage disease (JAMA Oncol. 2017;3[4]:456-63).

SOURCE: Tzartzeva K et al. Gastroenterology. 2018 Feb 6. doi: 10.1053/j.gastro.2018.01.064.

One in seven respondents to a national survey reported a history of fecal incontinence, including one-third within the preceding week, investigators reported.

“Fecal incontinence [FI] is age-related and more prevalent among individuals with inflammatory bowel disease, celiac disease, irritable bowel syndrome, or diabetes than people without these disorders. Proactive screening for FI among these groups is warranted,” Stacy B. Menees, MD, and her associates wrote in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2018.01.062).

Accurately determining the prevalence of FI is difficult because patients are reluctant to disclose symptoms and physicians often do not ask. In one study of HMO enrollees, about a third of patients had a history of FI but fewer than 3% had a medical diagnosis. In other studies, the prevalence of FI has ranged from 2% to 21%. Population aging fuels the need to narrow these estimates because FI becomes more common with age, the investigators noted.

Accordingly, in October 2015, they used a mobile app called MyGIHealth to survey nearly 72,000 individuals about fecal incontinence and other GI symptoms. The survey took about 15 minutes to complete, in return for which respondents could receive cash, shop online, or donate to charity. The investigators assessed FI severity by analyzing responses to the National Institutes of Health FI Patient Reported Outcomes Measurement Information System questionnaire.

Of the 10,033 respondents reporting a history of fecal incontinence (14.4%), 33.3% had experienced at least one episode in the past week. About a third of individuals with FI said it interfered with their daily activities. “Increasing age and concomitant diarrhea and constipation were associated with increased odds [of] FI,” the researchers wrote. Compared with individuals aged 18-24 years, the odds of having ever experienced FI rose by 29% among those aged 25-45 years, by 72% among those aged 45-64 years, and by 118% among persons aged 65 years and older.

Self-reported FI also was significantly more common among individuals with Crohn’s disease (41%), ulcerative colitis (37%), celiac disease (34%), irritable bowel syndrome (13%), or diabetes (13%) than it was among persons without these conditions. Corresponding odds ratios ranged from about 1.5 (diabetes) to 2.8 (celiac disease).

For individuals reporting FI within the past week, greater severity (based on their responses to the NIH FI Patient Reported Outcomes Measurement Information System questionnaire) significantly correlated with being non-Hispanic black (P = .03) or Latino (P = .02) and with having Crohn’s disease (P less than .001), celiac disease (P less than .001), diabetes (P = .04), human immunodeficiency syndrome (P = .001), or chronic idiopathic constipation (P less than .001). “Our study is the first to find differences among racial/ethnic groups regarding FI severity,” the researchers noted. They did not speculate on reasons for the finding, but stressed the importance of screening for FI and screening patients with FI for serious GI diseases.

Ironwood Pharmaceuticals funded the National GI Survey, but the investigators received no funding for this study. Three coinvestigators reported ties to Ironwood Pharmaceuticals and My Total Health.

SOURCE: Menees SB et al. Gastroenterology. 2018 Feb 3. doi: 10.1053/j.gastro.2018.01.062.

One in seven respondents to a national survey reported a history of fecal incontinence, including one-third within the preceding week, investigators reported.

“Fecal incontinence [FI] is age-related and more prevalent among individuals with inflammatory bowel disease, celiac disease, irritable bowel syndrome, or diabetes than people without these disorders. Proactive screening for FI among these groups is warranted,” Stacy B. Menees, MD, and her associates wrote in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2018.01.062).

Accurately determining the prevalence of FI is difficult because patients are reluctant to disclose symptoms and physicians often do not ask. In one study of HMO enrollees, about a third of patients had a history of FI but fewer than 3% had a medical diagnosis. In other studies, the prevalence of FI has ranged from 2% to 21%. Population aging fuels the need to narrow these estimates because FI becomes more common with age, the investigators noted.

Accordingly, in October 2015, they used a mobile app called MyGIHealth to survey nearly 72,000 individuals about fecal incontinence and other GI symptoms. The survey took about 15 minutes to complete, in return for which respondents could receive cash, shop online, or donate to charity. The investigators assessed FI severity by analyzing responses to the National Institutes of Health FI Patient Reported Outcomes Measurement Information System questionnaire.

Of the 10,033 respondents reporting a history of fecal incontinence (14.4%), 33.3% had experienced at least one episode in the past week. About a third of individuals with FI said it interfered with their daily activities. “Increasing age and concomitant diarrhea and constipation were associated with increased odds [of] FI,” the researchers wrote. Compared with individuals aged 18-24 years, the odds of having ever experienced FI rose by 29% among those aged 25-45 years, by 72% among those aged 45-64 years, and by 118% among persons aged 65 years and older.

Self-reported FI also was significantly more common among individuals with Crohn’s disease (41%), ulcerative colitis (37%), celiac disease (34%), irritable bowel syndrome (13%), or diabetes (13%) than it was among persons without these conditions. Corresponding odds ratios ranged from about 1.5 (diabetes) to 2.8 (celiac disease).

For individuals reporting FI within the past week, greater severity (based on their responses to the NIH FI Patient Reported Outcomes Measurement Information System questionnaire) significantly correlated with being non-Hispanic black (P = .03) or Latino (P = .02) and with having Crohn’s disease (P less than .001), celiac disease (P less than .001), diabetes (P = .04), human immunodeficiency syndrome (P = .001), or chronic idiopathic constipation (P less than .001). “Our study is the first to find differences among racial/ethnic groups regarding FI severity,” the researchers noted. They did not speculate on reasons for the finding, but stressed the importance of screening for FI and screening patients with FI for serious GI diseases.

Ironwood Pharmaceuticals funded the National GI Survey, but the investigators received no funding for this study. Three coinvestigators reported ties to Ironwood Pharmaceuticals and My Total Health.

SOURCE: Menees SB et al. Gastroenterology. 2018 Feb 3. doi: 10.1053/j.gastro.2018.01.062.

One in seven respondents to a national survey reported a history of fecal incontinence, including one-third within the preceding week, investigators reported.

“Fecal incontinence [FI] is age-related and more prevalent among individuals with inflammatory bowel disease, celiac disease, irritable bowel syndrome, or diabetes than people without these disorders. Proactive screening for FI among these groups is warranted,” Stacy B. Menees, MD, and her associates wrote in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2018.01.062).

Accurately determining the prevalence of FI is difficult because patients are reluctant to disclose symptoms and physicians often do not ask. In one study of HMO enrollees, about a third of patients had a history of FI but fewer than 3% had a medical diagnosis. In other studies, the prevalence of FI has ranged from 2% to 21%. Population aging fuels the need to narrow these estimates because FI becomes more common with age, the investigators noted.

Accordingly, in October 2015, they used a mobile app called MyGIHealth to survey nearly 72,000 individuals about fecal incontinence and other GI symptoms. The survey took about 15 minutes to complete, in return for which respondents could receive cash, shop online, or donate to charity. The investigators assessed FI severity by analyzing responses to the National Institutes of Health FI Patient Reported Outcomes Measurement Information System questionnaire.

Of the 10,033 respondents reporting a history of fecal incontinence (14.4%), 33.3% had experienced at least one episode in the past week. About a third of individuals with FI said it interfered with their daily activities. “Increasing age and concomitant diarrhea and constipation were associated with increased odds [of] FI,” the researchers wrote. Compared with individuals aged 18-24 years, the odds of having ever experienced FI rose by 29% among those aged 25-45 years, by 72% among those aged 45-64 years, and by 118% among persons aged 65 years and older.

Self-reported FI also was significantly more common among individuals with Crohn’s disease (41%), ulcerative colitis (37%), celiac disease (34%), irritable bowel syndrome (13%), or diabetes (13%) than it was among persons without these conditions. Corresponding odds ratios ranged from about 1.5 (diabetes) to 2.8 (celiac disease).

For individuals reporting FI within the past week, greater severity (based on their responses to the NIH FI Patient Reported Outcomes Measurement Information System questionnaire) significantly correlated with being non-Hispanic black (P = .03) or Latino (P = .02) and with having Crohn’s disease (P less than .001), celiac disease (P less than .001), diabetes (P = .04), human immunodeficiency syndrome (P = .001), or chronic idiopathic constipation (P less than .001). “Our study is the first to find differences among racial/ethnic groups regarding FI severity,” the researchers noted. They did not speculate on reasons for the finding, but stressed the importance of screening for FI and screening patients with FI for serious GI diseases.

Ironwood Pharmaceuticals funded the National GI Survey, but the investigators received no funding for this study. Three coinvestigators reported ties to Ironwood Pharmaceuticals and My Total Health.

SOURCE: Menees SB et al. Gastroenterology. 2018 Feb 3. doi: 10.1053/j.gastro.2018.01.062.

Heavy drinking was not associated with higher proportions of liver-related deaths or liver transplantation among patients with drug-induced liver injury (DILI), according to the results of a prospective multicenter cohort study reported in the May issue of Clinical Gastroenterology and Hepatology.

Anabolic steroids were the most common cause of DILI among heavy drinkers, defined as men who averaged more than three drinks a day or women who averaged more than two drinks daily, said Lara Dakhoul, MD, of Indiana University, Indianapolis, and her associates. There also was no evidence that heavy alcohol consumption increased the risk of liver injury attributable to isoniazid exposure, the researchers wrote in.

Although consuming alcohol significantly increases the risk of acetaminophen-induced liver injury, there is much less clarity about the relationship between drinking and hepatotoxicity from drugs such as duloxetine or antituberculosis medications, the researchers noted. In fact, one recent study found that drinking led to less severe liver injury among individuals with DILI. To better elucidate these links, the investigators studied 1,198 individuals with confirmed or probable DILI who enrolled in the DILI Network study (DILIN) between 2004 and 2016. At enrollment, all participants were asked if they consumed alcohol, and those who reported drinking within the past 12 months were offered a shortened version of the Skinner Alcohol Dependence Scale to collect details on alcohol consumption, including type, amount, and frequency.

In all, 601 persons reported consuming at least one alcoholic drink in the preceding year, of whom 348 completed the Skinner questionnaire. A total of 80 individuals reported heavy alcohol consumption. Heavy drinkers were typically in their early 40s, while nondrinkers tended to be nearly 50 years old (P less than .01). Heavy drinkers were also more often men (63%) while nondrinkers were usually women (65%; P less than .01). Heavy drinkers were significantly more likely to have DILI secondary to anabolic steroid exposure (13%) than were nondrinkers (2%; P less than .001). However, latency, pattern of liver injury, peak enzyme levels, and patterns of recovery from steroid hepatotoxicity were similar regardless of alcohol history.

A total of eight patients with DILI died of liver-related causes or underwent liver transplantation, and proportions of patients with these outcomes were similar regardless of alcohol history. These eight patients had no evidence of hepatitis C virus infection, but three appeared to have underlying alcoholic liver disease with superimposed acute-on-chronic liver failure. Heavy drinkers did not have significantly higher DILI severity scores than nondrinkers, but they did have significantly higher peak serum levels of alanine aminotransferase (1,323 U/L vs. 754, respectively; P = .02) and significantly higher levels of bilirubin (16.1 vs. 12.7 mg/dL; P = .03).

The two fatal cases of DILI among heavy drinkers involved a 44-year-old man with underlying alcoholic cirrhosis and steatohepatitis who developed acute-on-chronic liver failure 11 days after starting niacin, and a 76-year-old man with chronic obstructive pulmonary disease and bronchitis flare who developed severe liver injury and skin rash 6 days after starting azithromycin.

The study was not able to assess whether heavy alcohol consumption contributed to liver injury from specific agents, the researchers said. Additionally, a substantial number of drinkers did not complete the Skinner questionnaire, and those who did might have underestimated or underreported their own alcohol consumption. “Counterbalancing these issues are the [study’s] unique strengths, such as prospective design, larger sample size, well-characterized DILI phenotype, and careful, structured adjudication of causality and severity,” the researchers wrote.

SOURCE: Dakhoul L et al. Clin Gastro Hepatol. 2018 Jan 3. doi: 10.1016/j.cgh.2017.12.036.

Heavy drinking was not associated with higher proportions of liver-related deaths or liver transplantation among patients with drug-induced liver injury (DILI), according to the results of a prospective multicenter cohort study reported in the May issue of Clinical Gastroenterology and Hepatology.

Anabolic steroids were the most common cause of DILI among heavy drinkers, defined as men who averaged more than three drinks a day or women who averaged more than two drinks daily, said Lara Dakhoul, MD, of Indiana University, Indianapolis, and her associates. There also was no evidence that heavy alcohol consumption increased the risk of liver injury attributable to isoniazid exposure, the researchers wrote in.

Although consuming alcohol significantly increases the risk of acetaminophen-induced liver injury, there is much less clarity about the relationship between drinking and hepatotoxicity from drugs such as duloxetine or antituberculosis medications, the researchers noted. In fact, one recent study found that drinking led to less severe liver injury among individuals with DILI. To better elucidate these links, the investigators studied 1,198 individuals with confirmed or probable DILI who enrolled in the DILI Network study (DILIN) between 2004 and 2016. At enrollment, all participants were asked if they consumed alcohol, and those who reported drinking within the past 12 months were offered a shortened version of the Skinner Alcohol Dependence Scale to collect details on alcohol consumption, including type, amount, and frequency.

In all, 601 persons reported consuming at least one alcoholic drink in the preceding year, of whom 348 completed the Skinner questionnaire. A total of 80 individuals reported heavy alcohol consumption. Heavy drinkers were typically in their early 40s, while nondrinkers tended to be nearly 50 years old (P less than .01). Heavy drinkers were also more often men (63%) while nondrinkers were usually women (65%; P less than .01). Heavy drinkers were significantly more likely to have DILI secondary to anabolic steroid exposure (13%) than were nondrinkers (2%; P less than .001). However, latency, pattern of liver injury, peak enzyme levels, and patterns of recovery from steroid hepatotoxicity were similar regardless of alcohol history.

A total of eight patients with DILI died of liver-related causes or underwent liver transplantation, and proportions of patients with these outcomes were similar regardless of alcohol history. These eight patients had no evidence of hepatitis C virus infection, but three appeared to have underlying alcoholic liver disease with superimposed acute-on-chronic liver failure. Heavy drinkers did not have significantly higher DILI severity scores than nondrinkers, but they did have significantly higher peak serum levels of alanine aminotransferase (1,323 U/L vs. 754, respectively; P = .02) and significantly higher levels of bilirubin (16.1 vs. 12.7 mg/dL; P = .03).

The two fatal cases of DILI among heavy drinkers involved a 44-year-old man with underlying alcoholic cirrhosis and steatohepatitis who developed acute-on-chronic liver failure 11 days after starting niacin, and a 76-year-old man with chronic obstructive pulmonary disease and bronchitis flare who developed severe liver injury and skin rash 6 days after starting azithromycin.

The study was not able to assess whether heavy alcohol consumption contributed to liver injury from specific agents, the researchers said. Additionally, a substantial number of drinkers did not complete the Skinner questionnaire, and those who did might have underestimated or underreported their own alcohol consumption. “Counterbalancing these issues are the [study’s] unique strengths, such as prospective design, larger sample size, well-characterized DILI phenotype, and careful, structured adjudication of causality and severity,” the researchers wrote.

SOURCE: Dakhoul L et al. Clin Gastro Hepatol. 2018 Jan 3. doi: 10.1016/j.cgh.2017.12.036.

Heavy drinking was not associated with higher proportions of liver-related deaths or liver transplantation among patients with drug-induced liver injury (DILI), according to the results of a prospective multicenter cohort study reported in the May issue of Clinical Gastroenterology and Hepatology.

Anabolic steroids were the most common cause of DILI among heavy drinkers, defined as men who averaged more than three drinks a day or women who averaged more than two drinks daily, said Lara Dakhoul, MD, of Indiana University, Indianapolis, and her associates. There also was no evidence that heavy alcohol consumption increased the risk of liver injury attributable to isoniazid exposure, the researchers wrote in.

Although consuming alcohol significantly increases the risk of acetaminophen-induced liver injury, there is much less clarity about the relationship between drinking and hepatotoxicity from drugs such as duloxetine or antituberculosis medications, the researchers noted. In fact, one recent study found that drinking led to less severe liver injury among individuals with DILI. To better elucidate these links, the investigators studied 1,198 individuals with confirmed or probable DILI who enrolled in the DILI Network study (DILIN) between 2004 and 2016. At enrollment, all participants were asked if they consumed alcohol, and those who reported drinking within the past 12 months were offered a shortened version of the Skinner Alcohol Dependence Scale to collect details on alcohol consumption, including type, amount, and frequency.

In all, 601 persons reported consuming at least one alcoholic drink in the preceding year, of whom 348 completed the Skinner questionnaire. A total of 80 individuals reported heavy alcohol consumption. Heavy drinkers were typically in their early 40s, while nondrinkers tended to be nearly 50 years old (P less than .01). Heavy drinkers were also more often men (63%) while nondrinkers were usually women (65%; P less than .01). Heavy drinkers were significantly more likely to have DILI secondary to anabolic steroid exposure (13%) than were nondrinkers (2%; P less than .001). However, latency, pattern of liver injury, peak enzyme levels, and patterns of recovery from steroid hepatotoxicity were similar regardless of alcohol history.

A total of eight patients with DILI died of liver-related causes or underwent liver transplantation, and proportions of patients with these outcomes were similar regardless of alcohol history. These eight patients had no evidence of hepatitis C virus infection, but three appeared to have underlying alcoholic liver disease with superimposed acute-on-chronic liver failure. Heavy drinkers did not have significantly higher DILI severity scores than nondrinkers, but they did have significantly higher peak serum levels of alanine aminotransferase (1,323 U/L vs. 754, respectively; P = .02) and significantly higher levels of bilirubin (16.1 vs. 12.7 mg/dL; P = .03).

The two fatal cases of DILI among heavy drinkers involved a 44-year-old man with underlying alcoholic cirrhosis and steatohepatitis who developed acute-on-chronic liver failure 11 days after starting niacin, and a 76-year-old man with chronic obstructive pulmonary disease and bronchitis flare who developed severe liver injury and skin rash 6 days after starting azithromycin.

The study was not able to assess whether heavy alcohol consumption contributed to liver injury from specific agents, the researchers said. Additionally, a substantial number of drinkers did not complete the Skinner questionnaire, and those who did might have underestimated or underreported their own alcohol consumption. “Counterbalancing these issues are the [study’s] unique strengths, such as prospective design, larger sample size, well-characterized DILI phenotype, and careful, structured adjudication of causality and severity,” the researchers wrote.

SOURCE: Dakhoul L et al. Clin Gastro Hepatol. 2018 Jan 3. doi: 10.1016/j.cgh.2017.12.036.

A scoring model encompassing just four traits accurately predicted which patients with Barrett’s esophagus were most likely to develop high-grade dysplasia or esophageal adenocarcinoma, researchers reported in the April issue of Gastroenterology (2017 Dec 19. doi: 10.1053/j.gastro.2017.12.009).

Those risk factors included sex, smoking, length of Barrett’s esophagus, and the presence of baseline low-grade dysplasia, said Sravanthi Parasa, MD, of Swedish Medical Center, Seattle, and her associates. For example, a male with a history of smoking found to have a 5-cm, nondysplastic Barrett’s esophagus on histology during his index endoscopy would fall into the model’s intermediate risk category, with a 0.7% annual risk of progression to high-grade dysplasia or esophageal adenocarcinoma, they explained. “This model has the potential to complement molecular biomarker panels currently in development,” they wrote.

Barrett’s esophagus increases the risk of esophageal adenocarcinoma by anywhere from 30 to 125 times, a range that reflects the multifactorial nature of progression and the hypothesis that not all patients with Barrett’s esophagus should undergo the same frequency of endoscopic surveillance, said the researchers. To incorporate predictors of progression into a single model, they analyzed prospective data from nearly 3,000 patients with Barrett’s esophagus who were followed for a median of 6 years at five centers in the United States and one center in the Netherlands. At baseline, patients were an average of 55 years old (standard deviation, 20 years), 84% were men, 88% were white, and the average Barrett’s esophagus length was 3.7 cm (SD, 3.2 cm).

The researchers created the model by starting with many demographic and clinical candidate variables and then using backward selection to eliminate those that did not predict progression with a P value of .05 or less. This is the same method used in the Framingham Heart Study, they noted. In all, 154 (6%) patients with Barrett’s esophagus developed high-grade dysplasia or esophageal adenocarcinoma, with an annual progression rate of about 1%. The significant predictors of progression included male sex, smoking, length of Barrett’s esophagus, and low-grade dysplasia at baseline. A model that included only these four variables distinguished progressors from nonprogressors with a c statistic of 0.76 (95% confidence interval, 0.72 to 0.80; P less than .001). Using 30% of patients as an internal validation cohort, the model’s calibration slope was 0.99 and its calibration intercept was -0.09 cohort (perfectly calibrated models have a slope of 1.0 and an intercept of 0.0).

Therefore, the model was well calibrated and did an appropriate job of identifying risk groups, the investigators concluded. Considering that the overall risk of Barrett’s esophagus progression is low, using this model could help avoid excess costs and burdens of unnecessary surveillance, they added. “We recognize that there is a key interest in contemporary medical research whether a marker (e.g. molecular, genetic) could add to incremental value of a risk progression score,” they wrote. “This can be an area of future research.”

There were no funding sources. Dr. Parasa had no disclosures. One coinvestigator disclosed ties to Cook Medical, CDx Diagnostics, and Cosmo Pharmaceuticals.

SOURCE: Parasa S et al. Gastroenterology. 2017 Dec 19. doi: 10.1053/j.gastro.2017.12.009.

A scoring model encompassing just four traits accurately predicted which patients with Barrett’s esophagus were most likely to develop high-grade dysplasia or esophageal adenocarcinoma, researchers reported in the April issue of Gastroenterology (2017 Dec 19. doi: 10.1053/j.gastro.2017.12.009).

Those risk factors included sex, smoking, length of Barrett’s esophagus, and the presence of baseline low-grade dysplasia, said Sravanthi Parasa, MD, of Swedish Medical Center, Seattle, and her associates. For example, a male with a history of smoking found to have a 5-cm, nondysplastic Barrett’s esophagus on histology during his index endoscopy would fall into the model’s intermediate risk category, with a 0.7% annual risk of progression to high-grade dysplasia or esophageal adenocarcinoma, they explained. “This model has the potential to complement molecular biomarker panels currently in development,” they wrote.

Barrett’s esophagus increases the risk of esophageal adenocarcinoma by anywhere from 30 to 125 times, a range that reflects the multifactorial nature of progression and the hypothesis that not all patients with Barrett’s esophagus should undergo the same frequency of endoscopic surveillance, said the researchers. To incorporate predictors of progression into a single model, they analyzed prospective data from nearly 3,000 patients with Barrett’s esophagus who were followed for a median of 6 years at five centers in the United States and one center in the Netherlands. At baseline, patients were an average of 55 years old (standard deviation, 20 years), 84% were men, 88% were white, and the average Barrett’s esophagus length was 3.7 cm (SD, 3.2 cm).

The researchers created the model by starting with many demographic and clinical candidate variables and then using backward selection to eliminate those that did not predict progression with a P value of .05 or less. This is the same method used in the Framingham Heart Study, they noted. In all, 154 (6%) patients with Barrett’s esophagus developed high-grade dysplasia or esophageal adenocarcinoma, with an annual progression rate of about 1%. The significant predictors of progression included male sex, smoking, length of Barrett’s esophagus, and low-grade dysplasia at baseline. A model that included only these four variables distinguished progressors from nonprogressors with a c statistic of 0.76 (95% confidence interval, 0.72 to 0.80; P less than .001). Using 30% of patients as an internal validation cohort, the model’s calibration slope was 0.99 and its calibration intercept was -0.09 cohort (perfectly calibrated models have a slope of 1.0 and an intercept of 0.0).

Therefore, the model was well calibrated and did an appropriate job of identifying risk groups, the investigators concluded. Considering that the overall risk of Barrett’s esophagus progression is low, using this model could help avoid excess costs and burdens of unnecessary surveillance, they added. “We recognize that there is a key interest in contemporary medical research whether a marker (e.g. molecular, genetic) could add to incremental value of a risk progression score,” they wrote. “This can be an area of future research.”

There were no funding sources. Dr. Parasa had no disclosures. One coinvestigator disclosed ties to Cook Medical, CDx Diagnostics, and Cosmo Pharmaceuticals.

SOURCE: Parasa S et al. Gastroenterology. 2017 Dec 19. doi: 10.1053/j.gastro.2017.12.009.

A scoring model encompassing just four traits accurately predicted which patients with Barrett’s esophagus were most likely to develop high-grade dysplasia or esophageal adenocarcinoma, researchers reported in the April issue of Gastroenterology (2017 Dec 19. doi: 10.1053/j.gastro.2017.12.009).

Those risk factors included sex, smoking, length of Barrett’s esophagus, and the presence of baseline low-grade dysplasia, said Sravanthi Parasa, MD, of Swedish Medical Center, Seattle, and her associates. For example, a male with a history of smoking found to have a 5-cm, nondysplastic Barrett’s esophagus on histology during his index endoscopy would fall into the model’s intermediate risk category, with a 0.7% annual risk of progression to high-grade dysplasia or esophageal adenocarcinoma, they explained. “This model has the potential to complement molecular biomarker panels currently in development,” they wrote.

Barrett’s esophagus increases the risk of esophageal adenocarcinoma by anywhere from 30 to 125 times, a range that reflects the multifactorial nature of progression and the hypothesis that not all patients with Barrett’s esophagus should undergo the same frequency of endoscopic surveillance, said the researchers. To incorporate predictors of progression into a single model, they analyzed prospective data from nearly 3,000 patients with Barrett’s esophagus who were followed for a median of 6 years at five centers in the United States and one center in the Netherlands. At baseline, patients were an average of 55 years old (standard deviation, 20 years), 84% were men, 88% were white, and the average Barrett’s esophagus length was 3.7 cm (SD, 3.2 cm).

The researchers created the model by starting with many demographic and clinical candidate variables and then using backward selection to eliminate those that did not predict progression with a P value of .05 or less. This is the same method used in the Framingham Heart Study, they noted. In all, 154 (6%) patients with Barrett’s esophagus developed high-grade dysplasia or esophageal adenocarcinoma, with an annual progression rate of about 1%. The significant predictors of progression included male sex, smoking, length of Barrett’s esophagus, and low-grade dysplasia at baseline. A model that included only these four variables distinguished progressors from nonprogressors with a c statistic of 0.76 (95% confidence interval, 0.72 to 0.80; P less than .001). Using 30% of patients as an internal validation cohort, the model’s calibration slope was 0.99 and its calibration intercept was -0.09 cohort (perfectly calibrated models have a slope of 1.0 and an intercept of 0.0).

Therefore, the model was well calibrated and did an appropriate job of identifying risk groups, the investigators concluded. Considering that the overall risk of Barrett’s esophagus progression is low, using this model could help avoid excess costs and burdens of unnecessary surveillance, they added. “We recognize that there is a key interest in contemporary medical research whether a marker (e.g. molecular, genetic) could add to incremental value of a risk progression score,” they wrote. “This can be an area of future research.”

There were no funding sources. Dr. Parasa had no disclosures. One coinvestigator disclosed ties to Cook Medical, CDx Diagnostics, and Cosmo Pharmaceuticals.

SOURCE: Parasa S et al. Gastroenterology. 2017 Dec 19. doi: 10.1053/j.gastro.2017.12.009.

Increased donor liver perfusate levels of an underglycosylated glycoprotein predicted primary transplant nonfunction with 100% accuracy in two prospective cohorts, researchers reported in Gastroenterology.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Glycomic alterations of immunoglobulin G “represent inflammatory disturbances in the liver that [mean it] will fail after transplantation,” wrote Xavier Verhelst, MD, of Ghent (Belgium) University Hospital, and his associates. The new glycomarker “could be a tool to safely select high-risk organs for liver transplantation that otherwise would be discarded from the donor pool based on a conventional clinical assessment,” and also could help prevent engraftment failures. “To our knowledge, not a single biomarker has demonstrated the same accuracy today,” they wrote in the April issue of Gastroenterology.

Chronic shortages of donor livers contribute to morbidity and death worldwide. However, relaxing donor criteria is controversial because of the increased risk of primary nonfunction, which affects some 2%-10% of liver transplantation patients, and early allograft dysfunction, which is even more common. Although no reliable scoring systems or biomarkers have been able to predict these outcomes prior to transplantation, clinical glycomics of serum has proven useful for diagnosing hepatic fibrosis, cirrhosis, and hepatocellular carcinoma, and for distinguishing hepatic steatosis from nonalcoholic steatohepatitis. “Perfusate biomarkers are an attractive alternative [to] liver biopsy or serum markers, because perfusate is believed to represent the condition of the entire liver parenchyma and is easy to collect in large volumes,” the researchers wrote.

Accordingly, they studied 66 patients who underwent liver transplantation at a single center in Belgium and a separate validation cohort of 56 transplantation recipients from two centers. The most common reason for liver transplantation was decompensated cirrhosis secondary to alcoholism, followed by chronic hepatitis C or B virus infection, acute liver failure, and polycystic liver disease. Donor grafts were transported using cold static storage (21° C), and hepatic veins were flushed to collect perfusate before transplantation. Protein-linked N-glycans was isolated from these perfusate samples and analyzed with a multicapillary electrophoresis-based ABI3130 sequencer.

The four patients in the primary study cohort who developed primary nonfunction resembled the others in terms of all clinical and demographic parameters except that they had a markedly increased concentration (P less than .0001) of a single-glycan, agalacto core-alpha-1,6-fucosylated biantennary glycan, dubbed NGA2F. The single patient in the validation cohort who developed primary nonfunction also had a significantly increased concentration of NGA2F (P = .037). There were no false positives in either cohort, and a 13% cutoff for perfusate NGA2F level identified primary nonfunction with 100% accuracy, the researchers said. In a multivariable model of donor risk index and perfusate markers, only NGA2F was prognostic for developing primary nonfunction (P less than .0001).

The researchers found no specific glycomic signature for early allograft dysfunction, perhaps because it is more complex and multifactorial, they wrote. Although electrophoresis testing took 48 hours, work is underway to shorten this to a “clinically acceptable time frame,” they added. They recommended multicenter studies to validate their findings.

Funders included the Research Fund – Flanders and Ghent University. The researchers reported having no conflicts of interest.

SOURCE: Verhelst X et al. Gastroenterology 2018 Jan 6. doi: 10.1053/j.gastro.2017.12.027.

Increased donor liver perfusate levels of an underglycosylated glycoprotein predicted primary transplant nonfunction with 100% accuracy in two prospective cohorts, researchers reported in Gastroenterology.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Glycomic alterations of immunoglobulin G “represent inflammatory disturbances in the liver that [mean it] will fail after transplantation,” wrote Xavier Verhelst, MD, of Ghent (Belgium) University Hospital, and his associates. The new glycomarker “could be a tool to safely select high-risk organs for liver transplantation that otherwise would be discarded from the donor pool based on a conventional clinical assessment,” and also could help prevent engraftment failures. “To our knowledge, not a single biomarker has demonstrated the same accuracy today,” they wrote in the April issue of Gastroenterology.

Chronic shortages of donor livers contribute to morbidity and death worldwide. However, relaxing donor criteria is controversial because of the increased risk of primary nonfunction, which affects some 2%-10% of liver transplantation patients, and early allograft dysfunction, which is even more common. Although no reliable scoring systems or biomarkers have been able to predict these outcomes prior to transplantation, clinical glycomics of serum has proven useful for diagnosing hepatic fibrosis, cirrhosis, and hepatocellular carcinoma, and for distinguishing hepatic steatosis from nonalcoholic steatohepatitis. “Perfusate biomarkers are an attractive alternative [to] liver biopsy or serum markers, because perfusate is believed to represent the condition of the entire liver parenchyma and is easy to collect in large volumes,” the researchers wrote.

Accordingly, they studied 66 patients who underwent liver transplantation at a single center in Belgium and a separate validation cohort of 56 transplantation recipients from two centers. The most common reason for liver transplantation was decompensated cirrhosis secondary to alcoholism, followed by chronic hepatitis C or B virus infection, acute liver failure, and polycystic liver disease. Donor grafts were transported using cold static storage (21° C), and hepatic veins were flushed to collect perfusate before transplantation. Protein-linked N-glycans was isolated from these perfusate samples and analyzed with a multicapillary electrophoresis-based ABI3130 sequencer.

The four patients in the primary study cohort who developed primary nonfunction resembled the others in terms of all clinical and demographic parameters except that they had a markedly increased concentration (P less than .0001) of a single-glycan, agalacto core-alpha-1,6-fucosylated biantennary glycan, dubbed NGA2F. The single patient in the validation cohort who developed primary nonfunction also had a significantly increased concentration of NGA2F (P = .037). There were no false positives in either cohort, and a 13% cutoff for perfusate NGA2F level identified primary nonfunction with 100% accuracy, the researchers said. In a multivariable model of donor risk index and perfusate markers, only NGA2F was prognostic for developing primary nonfunction (P less than .0001).

The researchers found no specific glycomic signature for early allograft dysfunction, perhaps because it is more complex and multifactorial, they wrote. Although electrophoresis testing took 48 hours, work is underway to shorten this to a “clinically acceptable time frame,” they added. They recommended multicenter studies to validate their findings.

Funders included the Research Fund – Flanders and Ghent University. The researchers reported having no conflicts of interest.

SOURCE: Verhelst X et al. Gastroenterology 2018 Jan 6. doi: 10.1053/j.gastro.2017.12.027.

Increased donor liver perfusate levels of an underglycosylated glycoprotein predicted primary transplant nonfunction with 100% accuracy in two prospective cohorts, researchers reported in Gastroenterology.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Glycomic alterations of immunoglobulin G “represent inflammatory disturbances in the liver that [mean it] will fail after transplantation,” wrote Xavier Verhelst, MD, of Ghent (Belgium) University Hospital, and his associates. The new glycomarker “could be a tool to safely select high-risk organs for liver transplantation that otherwise would be discarded from the donor pool based on a conventional clinical assessment,” and also could help prevent engraftment failures. “To our knowledge, not a single biomarker has demonstrated the same accuracy today,” they wrote in the April issue of Gastroenterology.

Chronic shortages of donor livers contribute to morbidity and death worldwide. However, relaxing donor criteria is controversial because of the increased risk of primary nonfunction, which affects some 2%-10% of liver transplantation patients, and early allograft dysfunction, which is even more common. Although no reliable scoring systems or biomarkers have been able to predict these outcomes prior to transplantation, clinical glycomics of serum has proven useful for diagnosing hepatic fibrosis, cirrhosis, and hepatocellular carcinoma, and for distinguishing hepatic steatosis from nonalcoholic steatohepatitis. “Perfusate biomarkers are an attractive alternative [to] liver biopsy or serum markers, because perfusate is believed to represent the condition of the entire liver parenchyma and is easy to collect in large volumes,” the researchers wrote.

Accordingly, they studied 66 patients who underwent liver transplantation at a single center in Belgium and a separate validation cohort of 56 transplantation recipients from two centers. The most common reason for liver transplantation was decompensated cirrhosis secondary to alcoholism, followed by chronic hepatitis C or B virus infection, acute liver failure, and polycystic liver disease. Donor grafts were transported using cold static storage (21° C), and hepatic veins were flushed to collect perfusate before transplantation. Protein-linked N-glycans was isolated from these perfusate samples and analyzed with a multicapillary electrophoresis-based ABI3130 sequencer.

The four patients in the primary study cohort who developed primary nonfunction resembled the others in terms of all clinical and demographic parameters except that they had a markedly increased concentration (P less than .0001) of a single-glycan, agalacto core-alpha-1,6-fucosylated biantennary glycan, dubbed NGA2F. The single patient in the validation cohort who developed primary nonfunction also had a significantly increased concentration of NGA2F (P = .037). There were no false positives in either cohort, and a 13% cutoff for perfusate NGA2F level identified primary nonfunction with 100% accuracy, the researchers said. In a multivariable model of donor risk index and perfusate markers, only NGA2F was prognostic for developing primary nonfunction (P less than .0001).

The researchers found no specific glycomic signature for early allograft dysfunction, perhaps because it is more complex and multifactorial, they wrote. Although electrophoresis testing took 48 hours, work is underway to shorten this to a “clinically acceptable time frame,” they added. They recommended multicenter studies to validate their findings.

Funders included the Research Fund – Flanders and Ghent University. The researchers reported having no conflicts of interest.

SOURCE: Verhelst X et al. Gastroenterology 2018 Jan 6. doi: 10.1053/j.gastro.2017.12.027.

Pioglitazone therapy given for 18 months benefited patients with nonalcoholic steatohepatitis (NASH) similarly regardless of whether they had type 2 diabetes mellitus or prediabetes, according to the results of a randomized prospective trial.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

The primary outcome, at least a 2-point reduction in nonalcoholic fatty liver disease activity score compared with placebo, without worsening fibrosis, was met by 48% of NASH patients with T2DM and by 46% of those with prediabetes, reported Fernando Bril, MD, of the division of endocrinology, diabetes, and metabolism at the University of Florida, Gainesville, and his associates. The report was published in Clinical Gastroenterology and Hepatology.
 

NASH resolved completely in 44% with T2DM and 26% of patients without it, respectively, perhaps indicating that pioglitazone acts slightly differently when patients with NASH have T2DM, according to the investigators. “Although the effects on fibrosis appear to be similar in both groups, pioglitazone may contribute to halting [its] rapid progression [in T2DM],” they wrote. “These differences will deserve further exploration in larger clinical trials.”

The trial (NCT00994682) enrolled 101 patients with biopsy-confirmed NASH, of whom 52 had T2DM and 49 had prediabetes based on clinical history, baseline fasting plasma glucose, hemoglobin A_1c, and an oral glucose tolerance test, as per American Diabetes Association guidelines. After a 4-week run-in period, patients were randomly assigned to receive either pioglitazone (45 mg per day) or placebo for 18 months. All patients received lifestyle counseling and a hypocaloric (500-kcal reduced) diet.

Compared with placebo, pioglitazone improved most secondary outcomes similarly regardless of whether patients were T2DM or prediabetes. The two exceptions were fibrosis and insulin sensitivity of adipose tissue. Patients with T2DM only experienced improved fibrosis in the setting of pioglitazone therapy (P = .035 vs. baseline). In prediabetic patients, fibrosis lessened moderately over time, regardless of whether they received pioglitazone or placebo. Insulin sensitivity of adipose tissue improved much more markedly with treatment in patients with T2DM (P less than .001 vs. baseline) than in those with prediabetes (P = .002 for T2DM vs. prediabetes).

Compared with placebo, pioglitazone improved hepatic and skeletal muscle insulin sensitivity similarly, regardless of diabetes status. Likewise, intrahepatic triglyceride content, as measured by proton magnetic resonance spectroscopy, fell by 11% in pioglitazone recipients with T2DM and by 9% of those with prediabetes, a nonsignificant difference. Pioglitazone also led to a statistically similar decrease in plasma alanine aminotransferase level regardless of whether patients had T2DM (50 U/L) or were prediabetic (36 U/L).

This trial’s key takeaway is that pioglitazone improves liver histology in NASH whether or not patients are diabetic, said the researchers. “We believed that it was essential to compare its efficacy in patients with [and] without T2DM because of the vast number of patients with prediabetes and NASH and given the significant metabolic and cardioprotective effects of pioglitazone among patients without T2DM,” they wrote. The natural history of NASH is worse in the presence of T2DM, which might explain pioglitazone’s superior effects on fibrosis and insulin sensitivity of adipose tissue in this population, they added.

The Burroughs Wellcome Fund, the American Diabetes Association, and the Veteran’s Affairs Merit Award supported the work. Senior author Kenneth Cusi, MD, disclosed nonfinancial support from Takeda Pharmaceuticals, grants from Novartis and Janssen Research and Development, and consulting relationships with Eli Lilly, Tobira Therapeutics, and Pfizer. The other authors had no conflicts.

Source: Bril F, et al. Clin Gastroenterol Hepatol. 2018 Feb 24. doi: 10.1016/j.cgh.2017.12.001.

Pioglitazone therapy given for 18 months benefited patients with nonalcoholic steatohepatitis (NASH) similarly regardless of whether they had type 2 diabetes mellitus or prediabetes, according to the results of a randomized prospective trial.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

The primary outcome, at least a 2-point reduction in nonalcoholic fatty liver disease activity score compared with placebo, without worsening fibrosis, was met by 48% of NASH patients with T2DM and by 46% of those with prediabetes, reported Fernando Bril, MD, of the division of endocrinology, diabetes, and metabolism at the University of Florida, Gainesville, and his associates. The report was published in Clinical Gastroenterology and Hepatology.
 

NASH resolved completely in 44% with T2DM and 26% of patients without it, respectively, perhaps indicating that pioglitazone acts slightly differently when patients with NASH have T2DM, according to the investigators. “Although the effects on fibrosis appear to be similar in both groups, pioglitazone may contribute to halting [its] rapid progression [in T2DM],” they wrote. “These differences will deserve further exploration in larger clinical trials.”

The trial (NCT00994682) enrolled 101 patients with biopsy-confirmed NASH, of whom 52 had T2DM and 49 had prediabetes based on clinical history, baseline fasting plasma glucose, hemoglobin A_1c, and an oral glucose tolerance test, as per American Diabetes Association guidelines. After a 4-week run-in period, patients were randomly assigned to receive either pioglitazone (45 mg per day) or placebo for 18 months. All patients received lifestyle counseling and a hypocaloric (500-kcal reduced) diet.

Compared with placebo, pioglitazone improved most secondary outcomes similarly regardless of whether patients were T2DM or prediabetes. The two exceptions were fibrosis and insulin sensitivity of adipose tissue. Patients with T2DM only experienced improved fibrosis in the setting of pioglitazone therapy (P = .035 vs. baseline). In prediabetic patients, fibrosis lessened moderately over time, regardless of whether they received pioglitazone or placebo. Insulin sensitivity of adipose tissue improved much more markedly with treatment in patients with T2DM (P less than .001 vs. baseline) than in those with prediabetes (P = .002 for T2DM vs. prediabetes).

Compared with placebo, pioglitazone improved hepatic and skeletal muscle insulin sensitivity similarly, regardless of diabetes status. Likewise, intrahepatic triglyceride content, as measured by proton magnetic resonance spectroscopy, fell by 11% in pioglitazone recipients with T2DM and by 9% of those with prediabetes, a nonsignificant difference. Pioglitazone also led to a statistically similar decrease in plasma alanine aminotransferase level regardless of whether patients had T2DM (50 U/L) or were prediabetic (36 U/L).

This trial’s key takeaway is that pioglitazone improves liver histology in NASH whether or not patients are diabetic, said the researchers. “We believed that it was essential to compare its efficacy in patients with [and] without T2DM because of the vast number of patients with prediabetes and NASH and given the significant metabolic and cardioprotective effects of pioglitazone among patients without T2DM,” they wrote. The natural history of NASH is worse in the presence of T2DM, which might explain pioglitazone’s superior effects on fibrosis and insulin sensitivity of adipose tissue in this population, they added.

The Burroughs Wellcome Fund, the American Diabetes Association, and the Veteran’s Affairs Merit Award supported the work. Senior author Kenneth Cusi, MD, disclosed nonfinancial support from Takeda Pharmaceuticals, grants from Novartis and Janssen Research and Development, and consulting relationships with Eli Lilly, Tobira Therapeutics, and Pfizer. The other authors had no conflicts.

Source: Bril F, et al. Clin Gastroenterol Hepatol. 2018 Feb 24. doi: 10.1016/j.cgh.2017.12.001.

Pioglitazone therapy given for 18 months benefited patients with nonalcoholic steatohepatitis (NASH) similarly regardless of whether they had type 2 diabetes mellitus or prediabetes, according to the results of a randomized prospective trial.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

The primary outcome, at least a 2-point reduction in nonalcoholic fatty liver disease activity score compared with placebo, without worsening fibrosis, was met by 48% of NASH patients with T2DM and by 46% of those with prediabetes, reported Fernando Bril, MD, of the division of endocrinology, diabetes, and metabolism at the University of Florida, Gainesville, and his associates. The report was published in Clinical Gastroenterology and Hepatology.
 

NASH resolved completely in 44% with T2DM and 26% of patients without it, respectively, perhaps indicating that pioglitazone acts slightly differently when patients with NASH have T2DM, according to the investigators. “Although the effects on fibrosis appear to be similar in both groups, pioglitazone may contribute to halting [its] rapid progression [in T2DM],” they wrote. “These differences will deserve further exploration in larger clinical trials.”

The trial (NCT00994682) enrolled 101 patients with biopsy-confirmed NASH, of whom 52 had T2DM and 49 had prediabetes based on clinical history, baseline fasting plasma glucose, hemoglobin A_1c, and an oral glucose tolerance test, as per American Diabetes Association guidelines. After a 4-week run-in period, patients were randomly assigned to receive either pioglitazone (45 mg per day) or placebo for 18 months. All patients received lifestyle counseling and a hypocaloric (500-kcal reduced) diet.

Compared with placebo, pioglitazone improved most secondary outcomes similarly regardless of whether patients were T2DM or prediabetes. The two exceptions were fibrosis and insulin sensitivity of adipose tissue. Patients with T2DM only experienced improved fibrosis in the setting of pioglitazone therapy (P = .035 vs. baseline). In prediabetic patients, fibrosis lessened moderately over time, regardless of whether they received pioglitazone or placebo. Insulin sensitivity of adipose tissue improved much more markedly with treatment in patients with T2DM (P less than .001 vs. baseline) than in those with prediabetes (P = .002 for T2DM vs. prediabetes).

Compared with placebo, pioglitazone improved hepatic and skeletal muscle insulin sensitivity similarly, regardless of diabetes status. Likewise, intrahepatic triglyceride content, as measured by proton magnetic resonance spectroscopy, fell by 11% in pioglitazone recipients with T2DM and by 9% of those with prediabetes, a nonsignificant difference. Pioglitazone also led to a statistically similar decrease in plasma alanine aminotransferase level regardless of whether patients had T2DM (50 U/L) or were prediabetic (36 U/L).

This trial’s key takeaway is that pioglitazone improves liver histology in NASH whether or not patients are diabetic, said the researchers. “We believed that it was essential to compare its efficacy in patients with [and] without T2DM because of the vast number of patients with prediabetes and NASH and given the significant metabolic and cardioprotective effects of pioglitazone among patients without T2DM,” they wrote. The natural history of NASH is worse in the presence of T2DM, which might explain pioglitazone’s superior effects on fibrosis and insulin sensitivity of adipose tissue in this population, they added.

The Burroughs Wellcome Fund, the American Diabetes Association, and the Veteran’s Affairs Merit Award supported the work. Senior author Kenneth Cusi, MD, disclosed nonfinancial support from Takeda Pharmaceuticals, grants from Novartis and Janssen Research and Development, and consulting relationships with Eli Lilly, Tobira Therapeutics, and Pfizer. The other authors had no conflicts.

Source: Bril F, et al. Clin Gastroenterol Hepatol. 2018 Feb 24. doi: 10.1016/j.cgh.2017.12.001.

Psychogastroenterology is the science of applying psychological principles and techniques to alleviate the burden of chronic digestive diseases. This burden includes digestive symptoms and disease severity, as well as patients’ ability to cope with them. Chronic digestive diseases, such as irritable bowel syndrome, gastroesophageal reflux disease, and inflammatory bowel diseases, cannot be disentangled from their psychosocial context. In this regard, the role of gastroenterologists in promoting best practices for the assessment and referral of patients across the spectrum of disease to brain-gut psychotherapies is crucial.

A review by Laurie Keefer, PhD, AGAF, and her coauthors, published in the April issue of Gastroenterology, provided a clinical update on the structure and efficacy of two major classes of psychogastroenterology – cognitive-behavioral therapy (CBT) and gut-directed hypnotherapy (HYP). The review discussed the effects of these therapies on GI symptoms and the patients’ ability to improve coping, resilience, and self-regulation. The review also provided a framework to understand the scientific rationale and best practices associated with incorporating brain-gut psychotherapies into routine GI care. Furthermore, it presented recommendations on how to address psychological issues and make effective referrals in routine practice.

Previous studies had highlighted that the burden of chronic digestive diseases is amplified by psychosocial factors, including poor coping, depression, and poor social support. Mental health professionals specializing in psychogastroenterology integrate the use of brain-gut psychotherapies into GI practice settings, which may help reduce health care utilization and symptom burden.

The article contains best practice advice based on a review of the literature, including existing systematic reviews and expert opinions. These best practices include the following:

• Gastroenterologists routinely should assess health-related quality of life, symptom-specific anxieties, early-life adversity, and functional impairment related to a patient’s digestive complaints.
• Gastroenterologists should master patient-friendly language to help explain the brain-gut pathway and how this pathway can become dysregulated by any number of factors, the psychosocial risks perpetuating and maintaining factors of GI diseases, and why the gastroenterologist is referring a patient to a mental health provider.
• Gastroenterologists should know the structure and core features of the most effective brain-gut psychotherapies.
• Gastroenterologists should establish a direct referral and ongoing communication pathway with one or two qualified mental health providers and assure patients that he/she will remain a part of the care team.
• Gastroenterologists should familiarize themselves with one or two neuromodulators that can be used to augment behavioral therapies when necessary.

Patient education about the referral to a mental health provider is difficult and requires attention to detail and fostering a good physician-patient relationship. It is important to help patients understand why they are being referred to a psychologist for a gastrointestinal complaint and that their physical symptoms are not being discounted. Failure to properly explain the reason for referral may lead to poor follow-through and even lead the patient to seek care with another provider.

In order to foster widespread integration of these services, research and clinical gaps need to be addressed. Research gaps include the lack of prospective trials that compare the relative effectiveness of brain-gut psychotherapies with each other and/or with that of psychotropic medications. Other promising brain-gut therapies, such as mindfulness meditation or acceptance-based approaches, lack sufficient research to be included in clinical practice. Limited evidence supports the effect of psychotherapies have in accelerating or enhancing the efficacy of pharmacologic therapies and on improving disease course or inflammation in conditions such as Crohn’s and ulcerative colitis.

SOURCE: Keefer L et al. Gastroenterology. doi: 10.1053/j.gastro.2018.01.045.

Psychogastroenterology is the science of applying psychological principles and techniques to alleviate the burden of chronic digestive diseases. This burden includes digestive symptoms and disease severity, as well as patients’ ability to cope with them. Chronic digestive diseases, such as irritable bowel syndrome, gastroesophageal reflux disease, and inflammatory bowel diseases, cannot be disentangled from their psychosocial context. In this regard, the role of gastroenterologists in promoting best practices for the assessment and referral of patients across the spectrum of disease to brain-gut psychotherapies is crucial.

A review by Laurie Keefer, PhD, AGAF, and her coauthors, published in the April issue of Gastroenterology, provided a clinical update on the structure and efficacy of two major classes of psychogastroenterology – cognitive-behavioral therapy (CBT) and gut-directed hypnotherapy (HYP). The review discussed the effects of these therapies on GI symptoms and the patients’ ability to improve coping, resilience, and self-regulation. The review also provided a framework to understand the scientific rationale and best practices associated with incorporating brain-gut psychotherapies into routine GI care. Furthermore, it presented recommendations on how to address psychological issues and make effective referrals in routine practice.

Previous studies had highlighted that the burden of chronic digestive diseases is amplified by psychosocial factors, including poor coping, depression, and poor social support. Mental health professionals specializing in psychogastroenterology integrate the use of brain-gut psychotherapies into GI practice settings, which may help reduce health care utilization and symptom burden.

The article contains best practice advice based on a review of the literature, including existing systematic reviews and expert opinions. These best practices include the following:

• Gastroenterologists routinely should assess health-related quality of life, symptom-specific anxieties, early-life adversity, and functional impairment related to a patient’s digestive complaints.
• Gastroenterologists should master patient-friendly language to help explain the brain-gut pathway and how this pathway can become dysregulated by any number of factors, the psychosocial risks perpetuating and maintaining factors of GI diseases, and why the gastroenterologist is referring a patient to a mental health provider.
• Gastroenterologists should know the structure and core features of the most effective brain-gut psychotherapies.
• Gastroenterologists should establish a direct referral and ongoing communication pathway with one or two qualified mental health providers and assure patients that he/she will remain a part of the care team.
• Gastroenterologists should familiarize themselves with one or two neuromodulators that can be used to augment behavioral therapies when necessary.

Patient education about the referral to a mental health provider is difficult and requires attention to detail and fostering a good physician-patient relationship. It is important to help patients understand why they are being referred to a psychologist for a gastrointestinal complaint and that their physical symptoms are not being discounted. Failure to properly explain the reason for referral may lead to poor follow-through and even lead the patient to seek care with another provider.

In order to foster widespread integration of these services, research and clinical gaps need to be addressed. Research gaps include the lack of prospective trials that compare the relative effectiveness of brain-gut psychotherapies with each other and/or with that of psychotropic medications. Other promising brain-gut therapies, such as mindfulness meditation or acceptance-based approaches, lack sufficient research to be included in clinical practice. Limited evidence supports the effect of psychotherapies have in accelerating or enhancing the efficacy of pharmacologic therapies and on improving disease course or inflammation in conditions such as Crohn’s and ulcerative colitis.

SOURCE: Keefer L et al. Gastroenterology. doi: 10.1053/j.gastro.2018.01.045.

Psychogastroenterology is the science of applying psychological principles and techniques to alleviate the burden of chronic digestive diseases. This burden includes digestive symptoms and disease severity, as well as patients’ ability to cope with them. Chronic digestive diseases, such as irritable bowel syndrome, gastroesophageal reflux disease, and inflammatory bowel diseases, cannot be disentangled from their psychosocial context. In this regard, the role of gastroenterologists in promoting best practices for the assessment and referral of patients across the spectrum of disease to brain-gut psychotherapies is crucial.

A review by Laurie Keefer, PhD, AGAF, and her coauthors, published in the April issue of Gastroenterology, provided a clinical update on the structure and efficacy of two major classes of psychogastroenterology – cognitive-behavioral therapy (CBT) and gut-directed hypnotherapy (HYP). The review discussed the effects of these therapies on GI symptoms and the patients’ ability to improve coping, resilience, and self-regulation. The review also provided a framework to understand the scientific rationale and best practices associated with incorporating brain-gut psychotherapies into routine GI care. Furthermore, it presented recommendations on how to address psychological issues and make effective referrals in routine practice.

Previous studies had highlighted that the burden of chronic digestive diseases is amplified by psychosocial factors, including poor coping, depression, and poor social support. Mental health professionals specializing in psychogastroenterology integrate the use of brain-gut psychotherapies into GI practice settings, which may help reduce health care utilization and symptom burden.

The article contains best practice advice based on a review of the literature, including existing systematic reviews and expert opinions. These best practices include the following:

• Gastroenterologists routinely should assess health-related quality of life, symptom-specific anxieties, early-life adversity, and functional impairment related to a patient’s digestive complaints.
• Gastroenterologists should master patient-friendly language to help explain the brain-gut pathway and how this pathway can become dysregulated by any number of factors, the psychosocial risks perpetuating and maintaining factors of GI diseases, and why the gastroenterologist is referring a patient to a mental health provider.
• Gastroenterologists should know the structure and core features of the most effective brain-gut psychotherapies.
• Gastroenterologists should establish a direct referral and ongoing communication pathway with one or two qualified mental health providers and assure patients that he/she will remain a part of the care team.
• Gastroenterologists should familiarize themselves with one or two neuromodulators that can be used to augment behavioral therapies when necessary.

Patient education about the referral to a mental health provider is difficult and requires attention to detail and fostering a good physician-patient relationship. It is important to help patients understand why they are being referred to a psychologist for a gastrointestinal complaint and that their physical symptoms are not being discounted. Failure to properly explain the reason for referral may lead to poor follow-through and even lead the patient to seek care with another provider.

In order to foster widespread integration of these services, research and clinical gaps need to be addressed. Research gaps include the lack of prospective trials that compare the relative effectiveness of brain-gut psychotherapies with each other and/or with that of psychotropic medications. Other promising brain-gut therapies, such as mindfulness meditation or acceptance-based approaches, lack sufficient research to be included in clinical practice. Limited evidence supports the effect of psychotherapies have in accelerating or enhancing the efficacy of pharmacologic therapies and on improving disease course or inflammation in conditions such as Crohn’s and ulcerative colitis.

SOURCE: Keefer L et al. Gastroenterology. doi: 10.1053/j.gastro.2018.01.045.

Among patients with inflammatory bowel disease (IBD), opioid prescriptions tripled during a recent 20-year period, and heavy use of strong opioids was a significant predictor of all-cause mortality, according to a large cohort study reported in the April issue of Clinical Gastroenterology and Hepatology.

Because this study was retrospective, it could not establish causality, said Nicholas E. Burr, MD, of the University of Leeds (England) and his associates. But “[de]signing and conducting a large-scale randomized controlled trial may not be feasible,” they wrote. “Despite the limitations of observational data, population data sets may be the best method to investigate a potential effect.”

Liderina/Thinkstock

The gastrointestinal side effects of many analgesics complicate pain management for patients with IBD, who not only live with chronic abdominal pain but also can develop arthropathy-related musculoskeletal pain, chronic widespread pain, and fibromyalgia. In addition to the risk of narcotic bowel associated with opioid use in IBD, opioids can mask flares in IBD or can cause toxic dilatation if administered during acute flares, the researchers noted. Because few studies had examined opioid use in IBD, the investigators retrospectively studied 3,517 individuals with Crohn’s disease and 5,349 patients with ulcerative colitis from ResearchOne, a primary care electronic health records database that covers about 10% of patients in England. The data set excluded patients with indeterminate colitis or who underwent colectomy for ulcerative colitis.

From 1990 through 1993, only 10% of patients with IBD were prescribed opioids, vs. 30% from 2010 through 2013 (P less than .005). After the investigators controlled for numerous demographic and clinical variables, being prescribed a strong opioid (morphine, oxycodone, fentanyl, buprenorphine, methadone, hydromorphone, or pethidine) more than three times per year significantly correlated with all-cause mortality in both Crohn’s disease (hazard ratio, 2.2; 95% confidence interval, 1.2-4.0) and ulcerative colitis (HR, 3.3; 95% CI, 1.8-6.2), the researchers reported.Among patients with ulcerative colitis, more moderate use of strong opioids (one to three prescriptions annually) also significantly correlated with all-cause mortality (HR, 2.4; 95% CI, 1.2-5.2), as did heavy use of codeine (HR, 1.8; 95% CI, 1.1-3.1), but these associations did not reach statistical significance among patients with Crohn’s disease. Tramadol was not linked to mortality in either IBD subtype when used alone or in combination with codeine.

Dr. Burr and his associates said they could not control for several important potential confounders, including fistulating disease, quality of life, mental illness, substance abuse, and history of abuse, all of which have been linked to opioid use in IBD. Nonetheless, they found dose-dependent correlations with mortality that highlight a need for pharmacovigilance of opioids in IBD, particularly given dramatic increases in prescriptions, they said. These were primary care data, which tend to accurately reflect long-term medication use, they noted.

Crohn’s and Colitis U.K. and the Leeds Teaching Hospitals NHS Trust Charitable Foundation provided funding. The investigators reported having no conflicts of interest.

SOURCE: Burr NE et al. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.10.022.

Among patients with inflammatory bowel disease (IBD), opioid prescriptions tripled during a recent 20-year period, and heavy use of strong opioids was a significant predictor of all-cause mortality, according to a large cohort study reported in the April issue of Clinical Gastroenterology and Hepatology.

Because this study was retrospective, it could not establish causality, said Nicholas E. Burr, MD, of the University of Leeds (England) and his associates. But “[de]signing and conducting a large-scale randomized controlled trial may not be feasible,” they wrote. “Despite the limitations of observational data, population data sets may be the best method to investigate a potential effect.”

Liderina/Thinkstock

The gastrointestinal side effects of many analgesics complicate pain management for patients with IBD, who not only live with chronic abdominal pain but also can develop arthropathy-related musculoskeletal pain, chronic widespread pain, and fibromyalgia. In addition to the risk of narcotic bowel associated with opioid use in IBD, opioids can mask flares in IBD or can cause toxic dilatation if administered during acute flares, the researchers noted. Because few studies had examined opioid use in IBD, the investigators retrospectively studied 3,517 individuals with Crohn’s disease and 5,349 patients with ulcerative colitis from ResearchOne, a primary care electronic health records database that covers about 10% of patients in England. The data set excluded patients with indeterminate colitis or who underwent colectomy for ulcerative colitis.

From 1990 through 1993, only 10% of patients with IBD were prescribed opioids, vs. 30% from 2010 through 2013 (P less than .005). After the investigators controlled for numerous demographic and clinical variables, being prescribed a strong opioid (morphine, oxycodone, fentanyl, buprenorphine, methadone, hydromorphone, or pethidine) more than three times per year significantly correlated with all-cause mortality in both Crohn’s disease (hazard ratio, 2.2; 95% confidence interval, 1.2-4.0) and ulcerative colitis (HR, 3.3; 95% CI, 1.8-6.2), the researchers reported.Among patients with ulcerative colitis, more moderate use of strong opioids (one to three prescriptions annually) also significantly correlated with all-cause mortality (HR, 2.4; 95% CI, 1.2-5.2), as did heavy use of codeine (HR, 1.8; 95% CI, 1.1-3.1), but these associations did not reach statistical significance among patients with Crohn’s disease. Tramadol was not linked to mortality in either IBD subtype when used alone or in combination with codeine.

Dr. Burr and his associates said they could not control for several important potential confounders, including fistulating disease, quality of life, mental illness, substance abuse, and history of abuse, all of which have been linked to opioid use in IBD. Nonetheless, they found dose-dependent correlations with mortality that highlight a need for pharmacovigilance of opioids in IBD, particularly given dramatic increases in prescriptions, they said. These were primary care data, which tend to accurately reflect long-term medication use, they noted.

Crohn’s and Colitis U.K. and the Leeds Teaching Hospitals NHS Trust Charitable Foundation provided funding. The investigators reported having no conflicts of interest.

SOURCE: Burr NE et al. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.10.022.

Among patients with inflammatory bowel disease (IBD), opioid prescriptions tripled during a recent 20-year period, and heavy use of strong opioids was a significant predictor of all-cause mortality, according to a large cohort study reported in the April issue of Clinical Gastroenterology and Hepatology.

Because this study was retrospective, it could not establish causality, said Nicholas E. Burr, MD, of the University of Leeds (England) and his associates. But “[de]signing and conducting a large-scale randomized controlled trial may not be feasible,” they wrote. “Despite the limitations of observational data, population data sets may be the best method to investigate a potential effect.”

Liderina/Thinkstock

The gastrointestinal side effects of many analgesics complicate pain management for patients with IBD, who not only live with chronic abdominal pain but also can develop arthropathy-related musculoskeletal pain, chronic widespread pain, and fibromyalgia. In addition to the risk of narcotic bowel associated with opioid use in IBD, opioids can mask flares in IBD or can cause toxic dilatation if administered during acute flares, the researchers noted. Because few studies had examined opioid use in IBD, the investigators retrospectively studied 3,517 individuals with Crohn’s disease and 5,349 patients with ulcerative colitis from ResearchOne, a primary care electronic health records database that covers about 10% of patients in England. The data set excluded patients with indeterminate colitis or who underwent colectomy for ulcerative colitis.

From 1990 through 1993, only 10% of patients with IBD were prescribed opioids, vs. 30% from 2010 through 2013 (P less than .005). After the investigators controlled for numerous demographic and clinical variables, being prescribed a strong opioid (morphine, oxycodone, fentanyl, buprenorphine, methadone, hydromorphone, or pethidine) more than three times per year significantly correlated with all-cause mortality in both Crohn’s disease (hazard ratio, 2.2; 95% confidence interval, 1.2-4.0) and ulcerative colitis (HR, 3.3; 95% CI, 1.8-6.2), the researchers reported.Among patients with ulcerative colitis, more moderate use of strong opioids (one to three prescriptions annually) also significantly correlated with all-cause mortality (HR, 2.4; 95% CI, 1.2-5.2), as did heavy use of codeine (HR, 1.8; 95% CI, 1.1-3.1), but these associations did not reach statistical significance among patients with Crohn’s disease. Tramadol was not linked to mortality in either IBD subtype when used alone or in combination with codeine.

Dr. Burr and his associates said they could not control for several important potential confounders, including fistulating disease, quality of life, mental illness, substance abuse, and history of abuse, all of which have been linked to opioid use in IBD. Nonetheless, they found dose-dependent correlations with mortality that highlight a need for pharmacovigilance of opioids in IBD, particularly given dramatic increases in prescriptions, they said. These were primary care data, which tend to accurately reflect long-term medication use, they noted.

Crohn’s and Colitis U.K. and the Leeds Teaching Hospitals NHS Trust Charitable Foundation provided funding. The investigators reported having no conflicts of interest.

SOURCE: Burr NE et al. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.10.022.

Bioengineered liver models have enabled recapitulation of liver architecture with precise control over cellular microenvironments, resulting in stabilized liver functions for several weeks in vitro. Studies have focused on using these models to investigate cell responses to drugs and other stimuli (for example, viruses and cell differentiation cues) to predict clinical outcomes. Gregory H. Underhill, PhD, from the department of bioengineering at the University of Illinois at Urbana-Champaign and Salman R. Khetani, PhD, from the department of bioengineering at the University of Illinois in Chicago presented a comprehensive review of the these advances in bioengineered liver models in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.11.012).

Drug-induced liver injury (DILI) is a leading cause of drug attrition in the United States, with some marketed drugs causing cell necrosis, hepatitis, cholestasis, fibrosis, or a mixture of injury types. Although the Food and Drug Administration requires preclinical drug testing in animal models, differences in species-specific drug metabolism pathways and human genetics may result in inadequate identification of potential for human DILI. Some bioengineered liver models for in vitro studies are based on tissue engineering using high-throughput microarrays, protein micropatterning, microfluidics, specialized plates, biomaterial scaffolds, and bioprinting.

High-throughput cell microarrays enable systematic analysis of a large number of drugs or compounds at a relatively low cost. Several culture platforms have been developed using multiple sources of liver cells, including cancerous and immortalized cell lines. These platforms show enhanced capabilities to evaluate combinatorial effects of multiple signals with independent control of biochemical and biomechanical cues. For instance, a microchip platform for transducing 3-D liver cell cultures with genes for drug metabolism enzymes featuring 532 reaction vessels (micropillars and corresponding microwells) was able to provide information about certain enzyme combinations that led to drug toxicity in cells. The high-throughput cell microarrays are, however, primarily dependent on imaging-based readouts and have a limited ability to investigate cell responses to gradients of microenvironmental signals.

Liver development, physiology, and pathophysiology are dependent on homotypic and heterotypic interactions between parenchymal and nonparenchymal cells (NPCs). Cocultures with both liver- and nonliver-derived NPC types, in vitro, can induce liver functions transiently and have proven useful for investigating host responses to sepsis, mutagenesis, xenobiotic metabolism and toxicity, response to oxidative stress, lipid metabolism, and induction of the acute-phase response. Micropatterned cocultures (MPCCs) are designed to allow the use of different NPC types without significantly altering hepatocyte homotypic interactions. Cell-cell interactions can be precisely controlled to allow for stable functions for up to 4-6 weeks, whereas more randomly distributed cocultures have limited stability. Unlike randomly distributed cocultures, MPCCs can be infected with HBV, HCV, and malaria. Potential limitations of MPCCs include the requirement for specialized equipment and devices for patterning collagen for hepatocyte attachment.

Randomly distributed spheroids or organoids enable 3-D establishment of homotypic cell-cell interactions surrounded by an extracellular matrix. The spheroids can be further cocultured with NPCs that facilitate heterotypic cell-cell interactions and allow the evaluation of outcomes resulting from drugs and other stimuli. Hepatic spheroids maintain major liver functions for several weeks and have proven to be compatible with multiple applications within the drug development pipeline.

These spheroids showed greater sensitivity in identifying known hepatotoxic drugs than did short-term primary human hepatocyte (PHH) monolayers. PHHs secreted liver proteins, such as albumin, transferrin, and fibrinogen, and showed cytochrome-P450 activities for 77-90 days when cultured on a nylon scaffold containing a mixture of liver NPCs and PHHs.

Nanopillar plates can be used to create induced pluripotent stem cell–derived human hepatocyte-like cell (iHep) spheroids; although these spheroids showed some potential for initial drug toxicity screening, they had lower overall sensitivity than conventional PHH monolayers, which suggests that further maturation of iHeps is likely required.

Potential limitations of randomly distributed spheroids include necrosis of cells in the center of larger spheroids and the requirement for expensive confocal microscopy for high-content imaging of entire spheroid cultures. To overcome the limitation of disorganized cell type interactions over time within the randomly distributed spheroids/organoids, bioprinted human liver organoids are designed to allow precise control of cell placement.

Yet another bioengineered liver model is based on perfusion systems or bioreactors that enable dynamic fluid flow for nutrient and waste exchange. These so called liver-on-a-chip devices contain hepatocyte aggregates adhered to collagen-coated microchannel walls; these are then perfused at optimal flow rates both to meet the oxygen demands of the hepatocytes and deliver low shear stress to the cells that’s similar to what would be the case in vivo. Layered architectures can be created with single-chamber or multichamber, microfluidic device designs that can sustain cell functionality for 2-4 weeks.

Some of the limitations of perfusion systems include the potential binding of drugs to tubing and materials used, large dead volume requiring higher quantities of novel compounds for the treatment of cell cultures, low throughput, and washing away of built-up beneficial molecules with perfusion.

The ongoing development of more sophisticated engineering tools for manipulating cells in culture will lead to continued advances in bioengineered livers that will show improving sensitivity for the prediction of clinically relevant drug and disease outcomes.

This work was funded by National Institutes of Health grants. The author Dr. Khetani disclosed a conflict of interest with Ascendance Biotechnology, which has licensed the micropatterned coculture and related systems from Massachusetts Institute of Technology, Cambridge, and Colorado State University, Fort Collins, for commercial distribution. Dr. Underhill disclosed no conflicts.

SOURCE: Underhill GH and Khetani SR. Cell Molec Gastro Hepatol. 2017. doi: org/10.1016/j.jcmgh.2017.11.012.

Bioengineered liver models have enabled recapitulation of liver architecture with precise control over cellular microenvironments, resulting in stabilized liver functions for several weeks in vitro. Studies have focused on using these models to investigate cell responses to drugs and other stimuli (for example, viruses and cell differentiation cues) to predict clinical outcomes. Gregory H. Underhill, PhD, from the department of bioengineering at the University of Illinois at Urbana-Champaign and Salman R. Khetani, PhD, from the department of bioengineering at the University of Illinois in Chicago presented a comprehensive review of the these advances in bioengineered liver models in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.11.012).

Drug-induced liver injury (DILI) is a leading cause of drug attrition in the United States, with some marketed drugs causing cell necrosis, hepatitis, cholestasis, fibrosis, or a mixture of injury types. Although the Food and Drug Administration requires preclinical drug testing in animal models, differences in species-specific drug metabolism pathways and human genetics may result in inadequate identification of potential for human DILI. Some bioengineered liver models for in vitro studies are based on tissue engineering using high-throughput microarrays, protein micropatterning, microfluidics, specialized plates, biomaterial scaffolds, and bioprinting.

High-throughput cell microarrays enable systematic analysis of a large number of drugs or compounds at a relatively low cost. Several culture platforms have been developed using multiple sources of liver cells, including cancerous and immortalized cell lines. These platforms show enhanced capabilities to evaluate combinatorial effects of multiple signals with independent control of biochemical and biomechanical cues. For instance, a microchip platform for transducing 3-D liver cell cultures with genes for drug metabolism enzymes featuring 532 reaction vessels (micropillars and corresponding microwells) was able to provide information about certain enzyme combinations that led to drug toxicity in cells. The high-throughput cell microarrays are, however, primarily dependent on imaging-based readouts and have a limited ability to investigate cell responses to gradients of microenvironmental signals.

Liver development, physiology, and pathophysiology are dependent on homotypic and heterotypic interactions between parenchymal and nonparenchymal cells (NPCs). Cocultures with both liver- and nonliver-derived NPC types, in vitro, can induce liver functions transiently and have proven useful for investigating host responses to sepsis, mutagenesis, xenobiotic metabolism and toxicity, response to oxidative stress, lipid metabolism, and induction of the acute-phase response. Micropatterned cocultures (MPCCs) are designed to allow the use of different NPC types without significantly altering hepatocyte homotypic interactions. Cell-cell interactions can be precisely controlled to allow for stable functions for up to 4-6 weeks, whereas more randomly distributed cocultures have limited stability. Unlike randomly distributed cocultures, MPCCs can be infected with HBV, HCV, and malaria. Potential limitations of MPCCs include the requirement for specialized equipment and devices for patterning collagen for hepatocyte attachment.

Randomly distributed spheroids or organoids enable 3-D establishment of homotypic cell-cell interactions surrounded by an extracellular matrix. The spheroids can be further cocultured with NPCs that facilitate heterotypic cell-cell interactions and allow the evaluation of outcomes resulting from drugs and other stimuli. Hepatic spheroids maintain major liver functions for several weeks and have proven to be compatible with multiple applications within the drug development pipeline.

These spheroids showed greater sensitivity in identifying known hepatotoxic drugs than did short-term primary human hepatocyte (PHH) monolayers. PHHs secreted liver proteins, such as albumin, transferrin, and fibrinogen, and showed cytochrome-P450 activities for 77-90 days when cultured on a nylon scaffold containing a mixture of liver NPCs and PHHs.

Nanopillar plates can be used to create induced pluripotent stem cell–derived human hepatocyte-like cell (iHep) spheroids; although these spheroids showed some potential for initial drug toxicity screening, they had lower overall sensitivity than conventional PHH monolayers, which suggests that further maturation of iHeps is likely required.

Potential limitations of randomly distributed spheroids include necrosis of cells in the center of larger spheroids and the requirement for expensive confocal microscopy for high-content imaging of entire spheroid cultures. To overcome the limitation of disorganized cell type interactions over time within the randomly distributed spheroids/organoids, bioprinted human liver organoids are designed to allow precise control of cell placement.

Yet another bioengineered liver model is based on perfusion systems or bioreactors that enable dynamic fluid flow for nutrient and waste exchange. These so called liver-on-a-chip devices contain hepatocyte aggregates adhered to collagen-coated microchannel walls; these are then perfused at optimal flow rates both to meet the oxygen demands of the hepatocytes and deliver low shear stress to the cells that’s similar to what would be the case in vivo. Layered architectures can be created with single-chamber or multichamber, microfluidic device designs that can sustain cell functionality for 2-4 weeks.

Some of the limitations of perfusion systems include the potential binding of drugs to tubing and materials used, large dead volume requiring higher quantities of novel compounds for the treatment of cell cultures, low throughput, and washing away of built-up beneficial molecules with perfusion.

The ongoing development of more sophisticated engineering tools for manipulating cells in culture will lead to continued advances in bioengineered livers that will show improving sensitivity for the prediction of clinically relevant drug and disease outcomes.

This work was funded by National Institutes of Health grants. The author Dr. Khetani disclosed a conflict of interest with Ascendance Biotechnology, which has licensed the micropatterned coculture and related systems from Massachusetts Institute of Technology, Cambridge, and Colorado State University, Fort Collins, for commercial distribution. Dr. Underhill disclosed no conflicts.

SOURCE: Underhill GH and Khetani SR. Cell Molec Gastro Hepatol. 2017. doi: org/10.1016/j.jcmgh.2017.11.012.

Bioengineered liver models have enabled recapitulation of liver architecture with precise control over cellular microenvironments, resulting in stabilized liver functions for several weeks in vitro. Studies have focused on using these models to investigate cell responses to drugs and other stimuli (for example, viruses and cell differentiation cues) to predict clinical outcomes. Gregory H. Underhill, PhD, from the department of bioengineering at the University of Illinois at Urbana-Champaign and Salman R. Khetani, PhD, from the department of bioengineering at the University of Illinois in Chicago presented a comprehensive review of the these advances in bioengineered liver models in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.11.012).

Drug-induced liver injury (DILI) is a leading cause of drug attrition in the United States, with some marketed drugs causing cell necrosis, hepatitis, cholestasis, fibrosis, or a mixture of injury types. Although the Food and Drug Administration requires preclinical drug testing in animal models, differences in species-specific drug metabolism pathways and human genetics may result in inadequate identification of potential for human DILI. Some bioengineered liver models for in vitro studies are based on tissue engineering using high-throughput microarrays, protein micropatterning, microfluidics, specialized plates, biomaterial scaffolds, and bioprinting.

High-throughput cell microarrays enable systematic analysis of a large number of drugs or compounds at a relatively low cost. Several culture platforms have been developed using multiple sources of liver cells, including cancerous and immortalized cell lines. These platforms show enhanced capabilities to evaluate combinatorial effects of multiple signals with independent control of biochemical and biomechanical cues. For instance, a microchip platform for transducing 3-D liver cell cultures with genes for drug metabolism enzymes featuring 532 reaction vessels (micropillars and corresponding microwells) was able to provide information about certain enzyme combinations that led to drug toxicity in cells. The high-throughput cell microarrays are, however, primarily dependent on imaging-based readouts and have a limited ability to investigate cell responses to gradients of microenvironmental signals.

Liver development, physiology, and pathophysiology are dependent on homotypic and heterotypic interactions between parenchymal and nonparenchymal cells (NPCs). Cocultures with both liver- and nonliver-derived NPC types, in vitro, can induce liver functions transiently and have proven useful for investigating host responses to sepsis, mutagenesis, xenobiotic metabolism and toxicity, response to oxidative stress, lipid metabolism, and induction of the acute-phase response. Micropatterned cocultures (MPCCs) are designed to allow the use of different NPC types without significantly altering hepatocyte homotypic interactions. Cell-cell interactions can be precisely controlled to allow for stable functions for up to 4-6 weeks, whereas more randomly distributed cocultures have limited stability. Unlike randomly distributed cocultures, MPCCs can be infected with HBV, HCV, and malaria. Potential limitations of MPCCs include the requirement for specialized equipment and devices for patterning collagen for hepatocyte attachment.

Randomly distributed spheroids or organoids enable 3-D establishment of homotypic cell-cell interactions surrounded by an extracellular matrix. The spheroids can be further cocultured with NPCs that facilitate heterotypic cell-cell interactions and allow the evaluation of outcomes resulting from drugs and other stimuli. Hepatic spheroids maintain major liver functions for several weeks and have proven to be compatible with multiple applications within the drug development pipeline.

These spheroids showed greater sensitivity in identifying known hepatotoxic drugs than did short-term primary human hepatocyte (PHH) monolayers. PHHs secreted liver proteins, such as albumin, transferrin, and fibrinogen, and showed cytochrome-P450 activities for 77-90 days when cultured on a nylon scaffold containing a mixture of liver NPCs and PHHs.

Nanopillar plates can be used to create induced pluripotent stem cell–derived human hepatocyte-like cell (iHep) spheroids; although these spheroids showed some potential for initial drug toxicity screening, they had lower overall sensitivity than conventional PHH monolayers, which suggests that further maturation of iHeps is likely required.

Potential limitations of randomly distributed spheroids include necrosis of cells in the center of larger spheroids and the requirement for expensive confocal microscopy for high-content imaging of entire spheroid cultures. To overcome the limitation of disorganized cell type interactions over time within the randomly distributed spheroids/organoids, bioprinted human liver organoids are designed to allow precise control of cell placement.

Yet another bioengineered liver model is based on perfusion systems or bioreactors that enable dynamic fluid flow for nutrient and waste exchange. These so called liver-on-a-chip devices contain hepatocyte aggregates adhered to collagen-coated microchannel walls; these are then perfused at optimal flow rates both to meet the oxygen demands of the hepatocytes and deliver low shear stress to the cells that’s similar to what would be the case in vivo. Layered architectures can be created with single-chamber or multichamber, microfluidic device designs that can sustain cell functionality for 2-4 weeks.

Some of the limitations of perfusion systems include the potential binding of drugs to tubing and materials used, large dead volume requiring higher quantities of novel compounds for the treatment of cell cultures, low throughput, and washing away of built-up beneficial molecules with perfusion.

The ongoing development of more sophisticated engineering tools for manipulating cells in culture will lead to continued advances in bioengineered livers that will show improving sensitivity for the prediction of clinically relevant drug and disease outcomes.

This work was funded by National Institutes of Health grants. The author Dr. Khetani disclosed a conflict of interest with Ascendance Biotechnology, which has licensed the micropatterned coculture and related systems from Massachusetts Institute of Technology, Cambridge, and Colorado State University, Fort Collins, for commercial distribution. Dr. Underhill disclosed no conflicts.

SOURCE: Underhill GH and Khetani SR. Cell Molec Gastro Hepatol. 2017. doi: org/10.1016/j.jcmgh.2017.11.012.