From the AGA Journals

Administration of a novel fatty acid–bile acid conjugate safely and significantly reduced liver fat content in patients with nonalcoholic fatty liver disease in a phase II trial.

Administration of resveratrol for 8 weeks, however, failed to improve any features of the disease in a separate placebo-controlled study.

Courtesy of Wikimedia /Nephron / Creative Commons License

In 60 patients aged 18-75 years in a randomized, double-blind, placebo-controlled study of the fatty acid–bile acid conjugate aramchol (Trima Israel Pharmaceutical Products Ltd. Maabarot), 3 months of treatment was associated with a decrease in liver fat content by a mean of 12.57% as measured by magnetic resonance spectroscopy, compared with an increase in liver fat by a mean of 6.39% in patients who received placebo, Dr. Rifaat Safadi of Hadassah University Medical Center, Jerusalem and colleagues reported in the DEcember issue of Clinical Gastroenterology and Hepatology.

The difference between the treatment and placebo groups was significant, even after age, sex, and body mass index were adjusted for.

Liver fat content also decreased in patients who received treatment with a 100-mg dose of aramchol, but the difference compared with placebo was not statistically significant, indicating a dose-response relationship in treated patients, the investigators said (Clin Gastroenterol Hepatol 2014[doi:10.1016/j.cgh.2014.04.038]).

A trend was seen for improvements over time in endothelial function and levels of alanine aminotransferase and adiponectin.

Patients in the study were from 10 centers in Israel, and all had biopsy-confirmed NAFLD (54 patients) or nonalcoholic steatohepatitis (NASH, 6 patients). They were randomized to receive 100 or 300 mg of aramchol or placebo once daily for 3 months.

No serious or drug-related adverse events occurred in the treated patients, the investigators said.

The findings suggest that aramchol is a candidate for the treatment of fatty liver–related diseases, which are “an increasingly relevant public health issue because of their association with the worldwide epidemics of diabetes and obesity,” and for which treatments are lacking, they said, concluding that longer trials in patients with NASH and metabolic complications are warranted to evaluate metabolic and histologic benefits of treatment.

Findings from the resveratrol study were less encouraging.

Eight weeks of treatment at 3,000 mg daily in overweight or obese men with NAFLD who were recruited from clinics in Brisbane from 2011 through 2012 was no better than placebo for improving insulin resistance, hepatic steatosis, or abdominal fat distribution, Dr. Veronique S. Chachay of the University of Queensland, Brisbane, Australia and her colleagues also reported in the December issue of Clinical Gastroenterology and Hepatology.

No changes were observed in plasma lipids or antioxidant activity, and levels of alanine and aspartate aminotransferases increased significantly (from 45 to 63 U/L and from 35 to 45 U/L, respectively) until week 6 in the 10 treated patients, compared with the 10 who received placebo (40 to 48 U/L and 36 to 38 U/L, respectively). Resveratrol did not significantly alter transcription of NQ01, PTP1B, IL6, or H01, the investigators said (Clin Gastroenterol Hepatol 2014[doi:10.106/j.cgh.2014.02.024]).

NAFLD is associated with abdominal obesity, insulin resistance, and inflammation, and while weight loss via calorie restriction is known to reduce features of the disease, there is no pharmacologic therapy available to achieve this end.

The investigators sought to determine if resveratrol – a polyphenol that has been shown to prevent high-energy diet-induced steatosis and insulin resistance in animals – might be beneficial in patients with NAFLD.

“The present study demonstrates that the preventive role of resveratrol observed in diet-induced preclinical models of NAFLD does not translate into a therapeutic role in clinically established NAFLD,” they said, adding that clinical dose-finding studies are “paramount to elucidate the dose-response relationship” and that “the purported calorie-restriction mimicking of resveratrol may require investigation in combination with dietary prescription, standard care, and lifestyle modifications to target adequately the complexity of dysregulation in obesity-related chronic disease.”

The aramchol study was supported by Galmed Medical Research, Ltd. Dr. Safadi reported having no disclosures. The resveratrol study was supported by the Princess Alexandra Research Foundation, the Lions Medical Research Foundation, and the National Health and Medical Research Council of Australia. The authors reported having no disclosures.

Administration of a novel fatty acid–bile acid conjugate safely and significantly reduced liver fat content in patients with nonalcoholic fatty liver disease in a phase II trial.

Administration of resveratrol for 8 weeks, however, failed to improve any features of the disease in a separate placebo-controlled study.

Courtesy of Wikimedia /Nephron / Creative Commons License

In 60 patients aged 18-75 years in a randomized, double-blind, placebo-controlled study of the fatty acid–bile acid conjugate aramchol (Trima Israel Pharmaceutical Products Ltd. Maabarot), 3 months of treatment was associated with a decrease in liver fat content by a mean of 12.57% as measured by magnetic resonance spectroscopy, compared with an increase in liver fat by a mean of 6.39% in patients who received placebo, Dr. Rifaat Safadi of Hadassah University Medical Center, Jerusalem and colleagues reported in the DEcember issue of Clinical Gastroenterology and Hepatology.

The difference between the treatment and placebo groups was significant, even after age, sex, and body mass index were adjusted for.

Liver fat content also decreased in patients who received treatment with a 100-mg dose of aramchol, but the difference compared with placebo was not statistically significant, indicating a dose-response relationship in treated patients, the investigators said (Clin Gastroenterol Hepatol 2014[doi:10.1016/j.cgh.2014.04.038]).

A trend was seen for improvements over time in endothelial function and levels of alanine aminotransferase and adiponectin.

Patients in the study were from 10 centers in Israel, and all had biopsy-confirmed NAFLD (54 patients) or nonalcoholic steatohepatitis (NASH, 6 patients). They were randomized to receive 100 or 300 mg of aramchol or placebo once daily for 3 months.

No serious or drug-related adverse events occurred in the treated patients, the investigators said.

The findings suggest that aramchol is a candidate for the treatment of fatty liver–related diseases, which are “an increasingly relevant public health issue because of their association with the worldwide epidemics of diabetes and obesity,” and for which treatments are lacking, they said, concluding that longer trials in patients with NASH and metabolic complications are warranted to evaluate metabolic and histologic benefits of treatment.

Findings from the resveratrol study were less encouraging.

Eight weeks of treatment at 3,000 mg daily in overweight or obese men with NAFLD who were recruited from clinics in Brisbane from 2011 through 2012 was no better than placebo for improving insulin resistance, hepatic steatosis, or abdominal fat distribution, Dr. Veronique S. Chachay of the University of Queensland, Brisbane, Australia and her colleagues also reported in the December issue of Clinical Gastroenterology and Hepatology.

No changes were observed in plasma lipids or antioxidant activity, and levels of alanine and aspartate aminotransferases increased significantly (from 45 to 63 U/L and from 35 to 45 U/L, respectively) until week 6 in the 10 treated patients, compared with the 10 who received placebo (40 to 48 U/L and 36 to 38 U/L, respectively). Resveratrol did not significantly alter transcription of NQ01, PTP1B, IL6, or H01, the investigators said (Clin Gastroenterol Hepatol 2014[doi:10.106/j.cgh.2014.02.024]).

NAFLD is associated with abdominal obesity, insulin resistance, and inflammation, and while weight loss via calorie restriction is known to reduce features of the disease, there is no pharmacologic therapy available to achieve this end.

The investigators sought to determine if resveratrol – a polyphenol that has been shown to prevent high-energy diet-induced steatosis and insulin resistance in animals – might be beneficial in patients with NAFLD.

“The present study demonstrates that the preventive role of resveratrol observed in diet-induced preclinical models of NAFLD does not translate into a therapeutic role in clinically established NAFLD,” they said, adding that clinical dose-finding studies are “paramount to elucidate the dose-response relationship” and that “the purported calorie-restriction mimicking of resveratrol may require investigation in combination with dietary prescription, standard care, and lifestyle modifications to target adequately the complexity of dysregulation in obesity-related chronic disease.”

The aramchol study was supported by Galmed Medical Research, Ltd. Dr. Safadi reported having no disclosures. The resveratrol study was supported by the Princess Alexandra Research Foundation, the Lions Medical Research Foundation, and the National Health and Medical Research Council of Australia. The authors reported having no disclosures.

Administration of a novel fatty acid–bile acid conjugate safely and significantly reduced liver fat content in patients with nonalcoholic fatty liver disease in a phase II trial.

Administration of resveratrol for 8 weeks, however, failed to improve any features of the disease in a separate placebo-controlled study.

Courtesy of Wikimedia /Nephron / Creative Commons License

In 60 patients aged 18-75 years in a randomized, double-blind, placebo-controlled study of the fatty acid–bile acid conjugate aramchol (Trima Israel Pharmaceutical Products Ltd. Maabarot), 3 months of treatment was associated with a decrease in liver fat content by a mean of 12.57% as measured by magnetic resonance spectroscopy, compared with an increase in liver fat by a mean of 6.39% in patients who received placebo, Dr. Rifaat Safadi of Hadassah University Medical Center, Jerusalem and colleagues reported in the DEcember issue of Clinical Gastroenterology and Hepatology.

The difference between the treatment and placebo groups was significant, even after age, sex, and body mass index were adjusted for.

Liver fat content also decreased in patients who received treatment with a 100-mg dose of aramchol, but the difference compared with placebo was not statistically significant, indicating a dose-response relationship in treated patients, the investigators said (Clin Gastroenterol Hepatol 2014[doi:10.1016/j.cgh.2014.04.038]).

A trend was seen for improvements over time in endothelial function and levels of alanine aminotransferase and adiponectin.

Patients in the study were from 10 centers in Israel, and all had biopsy-confirmed NAFLD (54 patients) or nonalcoholic steatohepatitis (NASH, 6 patients). They were randomized to receive 100 or 300 mg of aramchol or placebo once daily for 3 months.

No serious or drug-related adverse events occurred in the treated patients, the investigators said.

The findings suggest that aramchol is a candidate for the treatment of fatty liver–related diseases, which are “an increasingly relevant public health issue because of their association with the worldwide epidemics of diabetes and obesity,” and for which treatments are lacking, they said, concluding that longer trials in patients with NASH and metabolic complications are warranted to evaluate metabolic and histologic benefits of treatment.

Findings from the resveratrol study were less encouraging.

Eight weeks of treatment at 3,000 mg daily in overweight or obese men with NAFLD who were recruited from clinics in Brisbane from 2011 through 2012 was no better than placebo for improving insulin resistance, hepatic steatosis, or abdominal fat distribution, Dr. Veronique S. Chachay of the University of Queensland, Brisbane, Australia and her colleagues also reported in the December issue of Clinical Gastroenterology and Hepatology.

No changes were observed in plasma lipids or antioxidant activity, and levels of alanine and aspartate aminotransferases increased significantly (from 45 to 63 U/L and from 35 to 45 U/L, respectively) until week 6 in the 10 treated patients, compared with the 10 who received placebo (40 to 48 U/L and 36 to 38 U/L, respectively). Resveratrol did not significantly alter transcription of NQ01, PTP1B, IL6, or H01, the investigators said (Clin Gastroenterol Hepatol 2014[doi:10.106/j.cgh.2014.02.024]).

NAFLD is associated with abdominal obesity, insulin resistance, and inflammation, and while weight loss via calorie restriction is known to reduce features of the disease, there is no pharmacologic therapy available to achieve this end.

The investigators sought to determine if resveratrol – a polyphenol that has been shown to prevent high-energy diet-induced steatosis and insulin resistance in animals – might be beneficial in patients with NAFLD.

“The present study demonstrates that the preventive role of resveratrol observed in diet-induced preclinical models of NAFLD does not translate into a therapeutic role in clinically established NAFLD,” they said, adding that clinical dose-finding studies are “paramount to elucidate the dose-response relationship” and that “the purported calorie-restriction mimicking of resveratrol may require investigation in combination with dietary prescription, standard care, and lifestyle modifications to target adequately the complexity of dysregulation in obesity-related chronic disease.”

The aramchol study was supported by Galmed Medical Research, Ltd. Dr. Safadi reported having no disclosures. The resveratrol study was supported by the Princess Alexandra Research Foundation, the Lions Medical Research Foundation, and the National Health and Medical Research Council of Australia. The authors reported having no disclosures.

Higher serum concentrations of infliximab are associated with clinical response, mucosal healing, and clinical remission in adults with moderate to severe ulcerative colitis, according to post hoc analyses of data from the Active Ulcerative Colitis Trials, ACT-1 and ACT-2.

In the 728 patients from the two randomized, controlled phase III pivotal trials, median serum concentrations of infliximab at week 8 were higher among patients with clinical response or mucosal healing during induction than in those who did not achieve these endpoints. For example, the median concentration among those who received 5-mg/kg doses of infliximab was 35.0 mcg/mL in responders, compared with 25.8 mcg/mL in nonresponders, Omoniyi J. Adedokun of Janssen Research and Development, Spring House, Pa., and colleagues reported in the December issue of Gastroenterology [doi:10.1053/j.gastro.2014.08.035].

“Similar results were observed for clinical response and mucosal healing during maintenance at week 30 and week 54,” the investigators wrote, noting that in the 5-mg/kg group, the median trough serum infliximab concentration was several-fold higher in responders than in nonresponders (3.9 vs. 1.2 mcg/mL at week 30 and 5.0 vs. 0.7 mcg/mL at week 54).

Concentrations did not differ significantly at 8 weeks in remitters and nonremitters in the 5-mg/kg group, but they did in patients who received 10 mg/kg and in patients in both dose groups at weeks 30 and 54, the investigators reported.

When assessed by infliximab concentration quartiles, treatment efficacy – defined by clinical response, mucosal healing, and/or clinical remission – generally improved with increasing concentrations in patients in both the 5- and 10-mg/kg groups; those with concentrations in the lowest quartile consistently were less likely to show clinical response, clinical remission, or mucosal healing, and had rates of success approaching those observed in the placebo groups.

Optimal infliximab concentration target thresholds associated with clinical improvement in ulcerative colitis patients in these analyses were 41 mcg/mL at week 8 (sensitivity, specificity, and positive predictive values of 63%, 62%, and 80%, respectively) and 3.7 mcg/mL at week 30 for maintenance of clinical response (sensitivity, specificity, and positive predictive values of 65%, 71%, and 82%, respectively). The data at week 54 suggested a range for serum infliximab concentrations of similar sensitivity, specificity, and positive predictive value, but those data represented only a subset of patients assessed, the investigators said.

Patients who achieved an efficacy outcome, but who failed to maintain that outcome, had lower serum infliximab concentrations earlier in the course of therapy than did those who maintained the outcome, the investigators said.

“In general, the lower the infliximab concentration at a given time point, the more likely the patients were to fail to maintain remission,” they wrote.

The findings demonstrate a strong association between serum infliximab concentration and efficacy outcomes in patients with ulcerative colitis, and highlight the possibility of infliximab dose optimization – particularly in patients who are likely to lose efficacy while receiving a standard dose of infliximab, the investigators said.

Target threshold concentrations identified by this analysis could help clinicians understand why an individual patient fails to achieve the expected efficacy, but a prospective study designed to confirm the importance of optimizing infliximab concentrations is needed before it can be determined whether these results can be exploited to achieve better outcomes for patients with ulcerative colitis, Mr. Adedokun and coinvestigators said.

The ACT trials were funded by Janssen Research and Development, which also employs Mr. Adedokun.

Higher serum concentrations of infliximab are associated with clinical response, mucosal healing, and clinical remission in adults with moderate to severe ulcerative colitis, according to post hoc analyses of data from the Active Ulcerative Colitis Trials, ACT-1 and ACT-2.

In the 728 patients from the two randomized, controlled phase III pivotal trials, median serum concentrations of infliximab at week 8 were higher among patients with clinical response or mucosal healing during induction than in those who did not achieve these endpoints. For example, the median concentration among those who received 5-mg/kg doses of infliximab was 35.0 mcg/mL in responders, compared with 25.8 mcg/mL in nonresponders, Omoniyi J. Adedokun of Janssen Research and Development, Spring House, Pa., and colleagues reported in the December issue of Gastroenterology [doi:10.1053/j.gastro.2014.08.035].

“Similar results were observed for clinical response and mucosal healing during maintenance at week 30 and week 54,” the investigators wrote, noting that in the 5-mg/kg group, the median trough serum infliximab concentration was several-fold higher in responders than in nonresponders (3.9 vs. 1.2 mcg/mL at week 30 and 5.0 vs. 0.7 mcg/mL at week 54).

Concentrations did not differ significantly at 8 weeks in remitters and nonremitters in the 5-mg/kg group, but they did in patients who received 10 mg/kg and in patients in both dose groups at weeks 30 and 54, the investigators reported.

When assessed by infliximab concentration quartiles, treatment efficacy – defined by clinical response, mucosal healing, and/or clinical remission – generally improved with increasing concentrations in patients in both the 5- and 10-mg/kg groups; those with concentrations in the lowest quartile consistently were less likely to show clinical response, clinical remission, or mucosal healing, and had rates of success approaching those observed in the placebo groups.

Optimal infliximab concentration target thresholds associated with clinical improvement in ulcerative colitis patients in these analyses were 41 mcg/mL at week 8 (sensitivity, specificity, and positive predictive values of 63%, 62%, and 80%, respectively) and 3.7 mcg/mL at week 30 for maintenance of clinical response (sensitivity, specificity, and positive predictive values of 65%, 71%, and 82%, respectively). The data at week 54 suggested a range for serum infliximab concentrations of similar sensitivity, specificity, and positive predictive value, but those data represented only a subset of patients assessed, the investigators said.

Patients who achieved an efficacy outcome, but who failed to maintain that outcome, had lower serum infliximab concentrations earlier in the course of therapy than did those who maintained the outcome, the investigators said.

“In general, the lower the infliximab concentration at a given time point, the more likely the patients were to fail to maintain remission,” they wrote.

The findings demonstrate a strong association between serum infliximab concentration and efficacy outcomes in patients with ulcerative colitis, and highlight the possibility of infliximab dose optimization – particularly in patients who are likely to lose efficacy while receiving a standard dose of infliximab, the investigators said.

Target threshold concentrations identified by this analysis could help clinicians understand why an individual patient fails to achieve the expected efficacy, but a prospective study designed to confirm the importance of optimizing infliximab concentrations is needed before it can be determined whether these results can be exploited to achieve better outcomes for patients with ulcerative colitis, Mr. Adedokun and coinvestigators said.

The ACT trials were funded by Janssen Research and Development, which also employs Mr. Adedokun.

Higher serum concentrations of infliximab are associated with clinical response, mucosal healing, and clinical remission in adults with moderate to severe ulcerative colitis, according to post hoc analyses of data from the Active Ulcerative Colitis Trials, ACT-1 and ACT-2.

In the 728 patients from the two randomized, controlled phase III pivotal trials, median serum concentrations of infliximab at week 8 were higher among patients with clinical response or mucosal healing during induction than in those who did not achieve these endpoints. For example, the median concentration among those who received 5-mg/kg doses of infliximab was 35.0 mcg/mL in responders, compared with 25.8 mcg/mL in nonresponders, Omoniyi J. Adedokun of Janssen Research and Development, Spring House, Pa., and colleagues reported in the December issue of Gastroenterology [doi:10.1053/j.gastro.2014.08.035].

“Similar results were observed for clinical response and mucosal healing during maintenance at week 30 and week 54,” the investigators wrote, noting that in the 5-mg/kg group, the median trough serum infliximab concentration was several-fold higher in responders than in nonresponders (3.9 vs. 1.2 mcg/mL at week 30 and 5.0 vs. 0.7 mcg/mL at week 54).

Concentrations did not differ significantly at 8 weeks in remitters and nonremitters in the 5-mg/kg group, but they did in patients who received 10 mg/kg and in patients in both dose groups at weeks 30 and 54, the investigators reported.

When assessed by infliximab concentration quartiles, treatment efficacy – defined by clinical response, mucosal healing, and/or clinical remission – generally improved with increasing concentrations in patients in both the 5- and 10-mg/kg groups; those with concentrations in the lowest quartile consistently were less likely to show clinical response, clinical remission, or mucosal healing, and had rates of success approaching those observed in the placebo groups.

Optimal infliximab concentration target thresholds associated with clinical improvement in ulcerative colitis patients in these analyses were 41 mcg/mL at week 8 (sensitivity, specificity, and positive predictive values of 63%, 62%, and 80%, respectively) and 3.7 mcg/mL at week 30 for maintenance of clinical response (sensitivity, specificity, and positive predictive values of 65%, 71%, and 82%, respectively). The data at week 54 suggested a range for serum infliximab concentrations of similar sensitivity, specificity, and positive predictive value, but those data represented only a subset of patients assessed, the investigators said.

Patients who achieved an efficacy outcome, but who failed to maintain that outcome, had lower serum infliximab concentrations earlier in the course of therapy than did those who maintained the outcome, the investigators said.

“In general, the lower the infliximab concentration at a given time point, the more likely the patients were to fail to maintain remission,” they wrote.

The findings demonstrate a strong association between serum infliximab concentration and efficacy outcomes in patients with ulcerative colitis, and highlight the possibility of infliximab dose optimization – particularly in patients who are likely to lose efficacy while receiving a standard dose of infliximab, the investigators said.

Target threshold concentrations identified by this analysis could help clinicians understand why an individual patient fails to achieve the expected efficacy, but a prospective study designed to confirm the importance of optimizing infliximab concentrations is needed before it can be determined whether these results can be exploited to achieve better outcomes for patients with ulcerative colitis, Mr. Adedokun and coinvestigators said.

The ACT trials were funded by Janssen Research and Development, which also employs Mr. Adedokun.

With the exception of those diagnosed between the age of 25 and 29 years, women with celiac disease are no more likely than are women without celiac disease to have fertility problems, according to findings from a large population-based study in the United Kingdom.

Of more than 2.4 million women with prospective primary care records available during their childbearing years (ages 15-49 years) between 1990 and 2013, 6,506 were diagnosed with celiac disease. The women with celiac disease had a similar rate of recorded fertility problems as did those without celiac disease (4.4% vs. 4.1%), Nafeesa N. Dhalwani of the University of Nottingham and City Hospital Nottingham, U.K., and colleagues reported in the December issue of Gastroenterology (doi:10.1053/j.gastro.2014.08.025).

Source: American Gastroenterological Association

Further, the rates of infertility in those with celiac disease were similar to those without celiac disease both before and after diagnosis except in those aged 25-29 years at the time of diagnosis; the rates in those women were 41% higher, compared with those without celiac disease who were the same age (incidence rate ratio, 1.41), the investigators said.

“However, the absolute excess risk [for those diagnosed at age 25-29 years] was only 0.5% (5.2/1,000 person-years), they said.

Women included in the analysis were identified from the Health Improvement Network database. Rates of new clinically recorded fertility problems among those with and without diagnosed celiac disease were stratified by timing of celiac disease diagnosis after adjustment for sociodemographics, comorbidities, and calendar year.

The findings contrast with those from a number of smaller studies that demonstrated an association between infertility and celiac disease, but those studies included small numbers of women, including many who were receiving infertility specialist services, the investigators said, explaining that the women may not have been representative of the general population, and that other small studies found no link between celiac disease and fertility problems.

Celiac disease affects about 1% of the population in North America and Western Europe, and between 60% and 70% of those who are diagnosed are women. Several mechanisms through which celiac disease might affect a woman’s fertility have been described in the literature, but no conclusive evidence exists to support them, they noted.

Despite this lack of evidence and the inconsistent findings from small studies, a number of reviews include infertility as a key nongastrointestinal manifestation of celiac disease. The current findings suggest that most women with celiac disease – whether diagnosed or undiagnosed – do not have a substantially greater likelihood of having clinically recorded fertility problems than do those without celiac disease.

“Therefore, screening when women initially present with fertility problems may not identify a significant number of women with celiac disease, beyond the general population prevalence. This may not always apply to subgroups of women with severe celiac disease. However, in terms of the clinical burden of fertility problems at a population level, these findings should be reassuring for women with celiac disease and all stakeholders involved in their care,” the investigators concluded.

This study was supported by CORE/Coeliac UK, and by a University of Nottingham/Nottingham University Hospitals National Health Service Trust Senior Clinical Research Fellowship. The authors reported having no disclosures.

With the exception of those diagnosed between the age of 25 and 29 years, women with celiac disease are no more likely than are women without celiac disease to have fertility problems, according to findings from a large population-based study in the United Kingdom.

Of more than 2.4 million women with prospective primary care records available during their childbearing years (ages 15-49 years) between 1990 and 2013, 6,506 were diagnosed with celiac disease. The women with celiac disease had a similar rate of recorded fertility problems as did those without celiac disease (4.4% vs. 4.1%), Nafeesa N. Dhalwani of the University of Nottingham and City Hospital Nottingham, U.K., and colleagues reported in the December issue of Gastroenterology (doi:10.1053/j.gastro.2014.08.025).

Source: American Gastroenterological Association

Further, the rates of infertility in those with celiac disease were similar to those without celiac disease both before and after diagnosis except in those aged 25-29 years at the time of diagnosis; the rates in those women were 41% higher, compared with those without celiac disease who were the same age (incidence rate ratio, 1.41), the investigators said.

“However, the absolute excess risk [for those diagnosed at age 25-29 years] was only 0.5% (5.2/1,000 person-years), they said.

Women included in the analysis were identified from the Health Improvement Network database. Rates of new clinically recorded fertility problems among those with and without diagnosed celiac disease were stratified by timing of celiac disease diagnosis after adjustment for sociodemographics, comorbidities, and calendar year.

The findings contrast with those from a number of smaller studies that demonstrated an association between infertility and celiac disease, but those studies included small numbers of women, including many who were receiving infertility specialist services, the investigators said, explaining that the women may not have been representative of the general population, and that other small studies found no link between celiac disease and fertility problems.

Celiac disease affects about 1% of the population in North America and Western Europe, and between 60% and 70% of those who are diagnosed are women. Several mechanisms through which celiac disease might affect a woman’s fertility have been described in the literature, but no conclusive evidence exists to support them, they noted.

Despite this lack of evidence and the inconsistent findings from small studies, a number of reviews include infertility as a key nongastrointestinal manifestation of celiac disease. The current findings suggest that most women with celiac disease – whether diagnosed or undiagnosed – do not have a substantially greater likelihood of having clinically recorded fertility problems than do those without celiac disease.

“Therefore, screening when women initially present with fertility problems may not identify a significant number of women with celiac disease, beyond the general population prevalence. This may not always apply to subgroups of women with severe celiac disease. However, in terms of the clinical burden of fertility problems at a population level, these findings should be reassuring for women with celiac disease and all stakeholders involved in their care,” the investigators concluded.

This study was supported by CORE/Coeliac UK, and by a University of Nottingham/Nottingham University Hospitals National Health Service Trust Senior Clinical Research Fellowship. The authors reported having no disclosures.

With the exception of those diagnosed between the age of 25 and 29 years, women with celiac disease are no more likely than are women without celiac disease to have fertility problems, according to findings from a large population-based study in the United Kingdom.

Of more than 2.4 million women with prospective primary care records available during their childbearing years (ages 15-49 years) between 1990 and 2013, 6,506 were diagnosed with celiac disease. The women with celiac disease had a similar rate of recorded fertility problems as did those without celiac disease (4.4% vs. 4.1%), Nafeesa N. Dhalwani of the University of Nottingham and City Hospital Nottingham, U.K., and colleagues reported in the December issue of Gastroenterology (doi:10.1053/j.gastro.2014.08.025).

Source: American Gastroenterological Association

Further, the rates of infertility in those with celiac disease were similar to those without celiac disease both before and after diagnosis except in those aged 25-29 years at the time of diagnosis; the rates in those women were 41% higher, compared with those without celiac disease who were the same age (incidence rate ratio, 1.41), the investigators said.

“However, the absolute excess risk [for those diagnosed at age 25-29 years] was only 0.5% (5.2/1,000 person-years), they said.

Women included in the analysis were identified from the Health Improvement Network database. Rates of new clinically recorded fertility problems among those with and without diagnosed celiac disease were stratified by timing of celiac disease diagnosis after adjustment for sociodemographics, comorbidities, and calendar year.

The findings contrast with those from a number of smaller studies that demonstrated an association between infertility and celiac disease, but those studies included small numbers of women, including many who were receiving infertility specialist services, the investigators said, explaining that the women may not have been representative of the general population, and that other small studies found no link between celiac disease and fertility problems.

Celiac disease affects about 1% of the population in North America and Western Europe, and between 60% and 70% of those who are diagnosed are women. Several mechanisms through which celiac disease might affect a woman’s fertility have been described in the literature, but no conclusive evidence exists to support them, they noted.

Despite this lack of evidence and the inconsistent findings from small studies, a number of reviews include infertility as a key nongastrointestinal manifestation of celiac disease. The current findings suggest that most women with celiac disease – whether diagnosed or undiagnosed – do not have a substantially greater likelihood of having clinically recorded fertility problems than do those without celiac disease.

“Therefore, screening when women initially present with fertility problems may not identify a significant number of women with celiac disease, beyond the general population prevalence. This may not always apply to subgroups of women with severe celiac disease. However, in terms of the clinical burden of fertility problems at a population level, these findings should be reassuring for women with celiac disease and all stakeholders involved in their care,” the investigators concluded.

This study was supported by CORE/Coeliac UK, and by a University of Nottingham/Nottingham University Hospitals National Health Service Trust Senior Clinical Research Fellowship. The authors reported having no disclosures.

Fecal immunochemical testing with a low hemoglobin threshold for colonoscopy resembled one-time, primary colonoscopy for detecting advanced neoplasias in the first-degree relatives of colorectal cancer patients, investigators reported in the November issue of Gastroenterology.

Annual fecal immunochemical testing (FIT), followed by colonoscopy if hemoglobin levels met or exceeded 10 mcg per gram of feces, detected all cases of colorectal cancer (CRC) and 61% of advanced adenomas in the study population, said Dr. Enrique Quintero and Dr. Maria Carrillo at the Universidad de la Laguna in Spain and their associates.

But one-time colonoscopy was better than FIT for detecting all neoplasms as a whole in first-degree relatives of patients with CRC, the researchers reported. Based on the findings, initial screening with FIT should be considered when access to colonoscopy is limited, especially if patients are more likely to accept FIT than colonoscopy, the investigators said (Gastroenterology [doi: 10.1053/j.gastro.2014.08.004]).

Courtesy: American Gastroenterological Association

The trial included 1,918 first-degree relatives of patients with CRC. In all, 782 relatives were randomized to one-time colonoscopy, while 784 were assigned to annual FIT for 3 years, the researchers reported. Advanced neoplasia was detected in 3.9% of the FIT group and in 5.8% of the primary colonoscopy group, the investigators said (odds ratio, 1.56; 95% confidence interval, 0.95-2.56; P = .08). Rates of detection of advanced neoplasia also were similar between the FIT and primary colonoscopy groups when participants were stratified by age, sex, age of family member with CRC, type of familial relationship, and number of relatives with CRC, the researchers reported. However, primary colonoscopy identified significantly more nonadvanced adenomas (19.8%) than did FIT (5.4%), they added (OR, 4.71; 95% CI, 3.22-6.89; P less than .001).

Participants with negative FIT results were invited to undergo colonoscopy at the end of the study, the researchers said. Follow-up colonoscopies in these relatives showed that FIT had missed 39% of advanced adenomas but no cases of CRC, they reported. To detect one case of advanced CRC, only 4 relatives in the FIT group needed to undergo colonoscopy, compared with 18 members in the primary colonoscopy group, they added. “A potential benefit of FIT over primary colonoscopy in familial CRC screening is that it may save a substantial number of unnecessary colonoscopies, thus preventing harm and lowering costs,” the investigators concluded.

Ethical concerns prevented the researchers from assessing the efficacy of FIT for more than 3 years, they said. In addition, participants knew they could opt out of their assigned screening method before providing informed consent, which could have biased rates of detection of advanced CRC, the researchers noted. However, these rates did not significantly differ between diagnostic groups, they said. The study did not look at sessile serrated or traditional serrated polyps, because the study was designed when these polyps were still considered hyperplastic and nonmalignant, the investigators noted.

Future studies should evaluate the acceptance of FIT-based screening and its effects on mortality in familial CRC, the researchers concluded.

Their study was supported by grants from Fundación Canaria para la Investigación Sanitaria, Caja de Canarias, and Departmento de Medicina Interna de la Universidad de La Laguna. They reported having no conflicts of interest.

Fecal immunochemical testing with a low hemoglobin threshold for colonoscopy resembled one-time, primary colonoscopy for detecting advanced neoplasias in the first-degree relatives of colorectal cancer patients, investigators reported in the November issue of Gastroenterology.

Annual fecal immunochemical testing (FIT), followed by colonoscopy if hemoglobin levels met or exceeded 10 mcg per gram of feces, detected all cases of colorectal cancer (CRC) and 61% of advanced adenomas in the study population, said Dr. Enrique Quintero and Dr. Maria Carrillo at the Universidad de la Laguna in Spain and their associates.

But one-time colonoscopy was better than FIT for detecting all neoplasms as a whole in first-degree relatives of patients with CRC, the researchers reported. Based on the findings, initial screening with FIT should be considered when access to colonoscopy is limited, especially if patients are more likely to accept FIT than colonoscopy, the investigators said (Gastroenterology [doi: 10.1053/j.gastro.2014.08.004]).

Courtesy: American Gastroenterological Association

The trial included 1,918 first-degree relatives of patients with CRC. In all, 782 relatives were randomized to one-time colonoscopy, while 784 were assigned to annual FIT for 3 years, the researchers reported. Advanced neoplasia was detected in 3.9% of the FIT group and in 5.8% of the primary colonoscopy group, the investigators said (odds ratio, 1.56; 95% confidence interval, 0.95-2.56; P = .08). Rates of detection of advanced neoplasia also were similar between the FIT and primary colonoscopy groups when participants were stratified by age, sex, age of family member with CRC, type of familial relationship, and number of relatives with CRC, the researchers reported. However, primary colonoscopy identified significantly more nonadvanced adenomas (19.8%) than did FIT (5.4%), they added (OR, 4.71; 95% CI, 3.22-6.89; P less than .001).

Participants with negative FIT results were invited to undergo colonoscopy at the end of the study, the researchers said. Follow-up colonoscopies in these relatives showed that FIT had missed 39% of advanced adenomas but no cases of CRC, they reported. To detect one case of advanced CRC, only 4 relatives in the FIT group needed to undergo colonoscopy, compared with 18 members in the primary colonoscopy group, they added. “A potential benefit of FIT over primary colonoscopy in familial CRC screening is that it may save a substantial number of unnecessary colonoscopies, thus preventing harm and lowering costs,” the investigators concluded.

Ethical concerns prevented the researchers from assessing the efficacy of FIT for more than 3 years, they said. In addition, participants knew they could opt out of their assigned screening method before providing informed consent, which could have biased rates of detection of advanced CRC, the researchers noted. However, these rates did not significantly differ between diagnostic groups, they said. The study did not look at sessile serrated or traditional serrated polyps, because the study was designed when these polyps were still considered hyperplastic and nonmalignant, the investigators noted.

Future studies should evaluate the acceptance of FIT-based screening and its effects on mortality in familial CRC, the researchers concluded.

Their study was supported by grants from Fundación Canaria para la Investigación Sanitaria, Caja de Canarias, and Departmento de Medicina Interna de la Universidad de La Laguna. They reported having no conflicts of interest.

Fecal immunochemical testing with a low hemoglobin threshold for colonoscopy resembled one-time, primary colonoscopy for detecting advanced neoplasias in the first-degree relatives of colorectal cancer patients, investigators reported in the November issue of Gastroenterology.

Annual fecal immunochemical testing (FIT), followed by colonoscopy if hemoglobin levels met or exceeded 10 mcg per gram of feces, detected all cases of colorectal cancer (CRC) and 61% of advanced adenomas in the study population, said Dr. Enrique Quintero and Dr. Maria Carrillo at the Universidad de la Laguna in Spain and their associates.

But one-time colonoscopy was better than FIT for detecting all neoplasms as a whole in first-degree relatives of patients with CRC, the researchers reported. Based on the findings, initial screening with FIT should be considered when access to colonoscopy is limited, especially if patients are more likely to accept FIT than colonoscopy, the investigators said (Gastroenterology [doi: 10.1053/j.gastro.2014.08.004]).

Courtesy: American Gastroenterological Association

The trial included 1,918 first-degree relatives of patients with CRC. In all, 782 relatives were randomized to one-time colonoscopy, while 784 were assigned to annual FIT for 3 years, the researchers reported. Advanced neoplasia was detected in 3.9% of the FIT group and in 5.8% of the primary colonoscopy group, the investigators said (odds ratio, 1.56; 95% confidence interval, 0.95-2.56; P = .08). Rates of detection of advanced neoplasia also were similar between the FIT and primary colonoscopy groups when participants were stratified by age, sex, age of family member with CRC, type of familial relationship, and number of relatives with CRC, the researchers reported. However, primary colonoscopy identified significantly more nonadvanced adenomas (19.8%) than did FIT (5.4%), they added (OR, 4.71; 95% CI, 3.22-6.89; P less than .001).

Participants with negative FIT results were invited to undergo colonoscopy at the end of the study, the researchers said. Follow-up colonoscopies in these relatives showed that FIT had missed 39% of advanced adenomas but no cases of CRC, they reported. To detect one case of advanced CRC, only 4 relatives in the FIT group needed to undergo colonoscopy, compared with 18 members in the primary colonoscopy group, they added. “A potential benefit of FIT over primary colonoscopy in familial CRC screening is that it may save a substantial number of unnecessary colonoscopies, thus preventing harm and lowering costs,” the investigators concluded.

Ethical concerns prevented the researchers from assessing the efficacy of FIT for more than 3 years, they said. In addition, participants knew they could opt out of their assigned screening method before providing informed consent, which could have biased rates of detection of advanced CRC, the researchers noted. However, these rates did not significantly differ between diagnostic groups, they said. The study did not look at sessile serrated or traditional serrated polyps, because the study was designed when these polyps were still considered hyperplastic and nonmalignant, the investigators noted.

Future studies should evaluate the acceptance of FIT-based screening and its effects on mortality in familial CRC, the researchers concluded.

Their study was supported by grants from Fundación Canaria para la Investigación Sanitaria, Caja de Canarias, and Departmento de Medicina Interna de la Universidad de La Laguna. They reported having no conflicts of interest.

Increasing dosages of mesalamine by 2.4 g/d for patients with quiescent ulcerative colitis can dramatically reduce concentrations of fecal calprotectin and ultimately decrease the likelihood of relapse, according to the results of a new Dose Escalation and Remission (DEAR) study published in the November issue of Clinical Gastroenterology and Hepatology (2014;12:1887-93.e3).

In an open-label, randomized controlled trial, 119 patients with quiescent ulcerative colitis (UC) in remission were screened for Simple Clinical Colitis Activity Index scores, fecal calprotectin (FC) of 50 mcg/gram, and intake of no more than 3 g of mesalamine per day between October 2008 and March 2012. These subjects were divided into four groups based on FC levels, with Group 1 comprising 58 representing a baseline of FC < 50 mcg/gram, and groups 2-4 having 61 individuals with elevated baseline FC levels. Group 1 patients were retained for an observational follow-up study but were not included in the randomized controlled trial.

© selvanegra / thinkstockphotos.com

Participants were either told to maintain their current medication regimen or were prescribed a multimatrix mesalamine of either 2.4 or 4.8 g/d for 6 weeks, depending on their initial FC levels, after which point FC levels were taken. Participants in Group 2 with FC < 50 mcg/g were kept in an observational follow-up study group, while the rest of the participants were randomly assigned to continue their 2.4 g/d regimen, or increase their intake to 4.8 g/d.

Individuals in Group 3 with FC levels greater than 50 mcg/g were randomly assigned to either the 2.4- or 4.8-g/d regimen for 6 weeks; after that point, those whose FC levels had decreased below 50 continued with their regimen while those whose FC levels remained high were upped to 4.8 g/d. Subjects in Group 4 who were not already on a multimatrix mesalamine regimen and whose FC levels were above 50 mcg/g were randomized to continue their medication or add 2.4 g/d of mesalamine; after 6 weeks, if FC levels remained above 50, the dosage was increased to 4.8 g/d.

The primary outcome of continued remission with FC no greater than 50 mcg/g was observed in 3.8% of controls and 26.9% of participants in the dose escalation group (P = .0496). Others within the same group experienced secondary outcomes of FC levels below 100 mcg/gram (P = .04) and below 200 mcg/g (P = .005). Furthermore, among patients who were in remission during the randomization phase of the study, relapse occurred far sooner in those whose FC was above 200 mcg/g than those whose FC levels were below that mark.

“Our study adds to the evidence supporting FC concentration as a valid biomarker for UC,” said lead authors Dr. Mark T. Osterman and Dr. Faten N. Aberra of the University of Pennsylvania’s department of medicine, Philadelphia. “Perhaps more importantly, our results offer a novel way to use FC testing to positively impact outcomes in UC. We demonstrated efficacy of intervention to reduce FC (a surrogate for mucosal inflammation) before symptoms develop in patients at potentially increased risk of relapse.”

Dr. Osterman is a consultant for AbbVie, Elan, Janssen, and UCB and receives research funding from UCB. Dr. Aberra is a consultant for Janssen and research investigator for Amgen, Janssen, and UCB. Other coauthors disclosed ties to numerous pharmaceutical companies.

[email protected]

Increasing dosages of mesalamine by 2.4 g/d for patients with quiescent ulcerative colitis can dramatically reduce concentrations of fecal calprotectin and ultimately decrease the likelihood of relapse, according to the results of a new Dose Escalation and Remission (DEAR) study published in the November issue of Clinical Gastroenterology and Hepatology (2014;12:1887-93.e3).

In an open-label, randomized controlled trial, 119 patients with quiescent ulcerative colitis (UC) in remission were screened for Simple Clinical Colitis Activity Index scores, fecal calprotectin (FC) of 50 mcg/gram, and intake of no more than 3 g of mesalamine per day between October 2008 and March 2012. These subjects were divided into four groups based on FC levels, with Group 1 comprising 58 representing a baseline of FC < 50 mcg/gram, and groups 2-4 having 61 individuals with elevated baseline FC levels. Group 1 patients were retained for an observational follow-up study but were not included in the randomized controlled trial.

© selvanegra / thinkstockphotos.com

Participants were either told to maintain their current medication regimen or were prescribed a multimatrix mesalamine of either 2.4 or 4.8 g/d for 6 weeks, depending on their initial FC levels, after which point FC levels were taken. Participants in Group 2 with FC < 50 mcg/g were kept in an observational follow-up study group, while the rest of the participants were randomly assigned to continue their 2.4 g/d regimen, or increase their intake to 4.8 g/d.

Individuals in Group 3 with FC levels greater than 50 mcg/g were randomly assigned to either the 2.4- or 4.8-g/d regimen for 6 weeks; after that point, those whose FC levels had decreased below 50 continued with their regimen while those whose FC levels remained high were upped to 4.8 g/d. Subjects in Group 4 who were not already on a multimatrix mesalamine regimen and whose FC levels were above 50 mcg/g were randomized to continue their medication or add 2.4 g/d of mesalamine; after 6 weeks, if FC levels remained above 50, the dosage was increased to 4.8 g/d.

The primary outcome of continued remission with FC no greater than 50 mcg/g was observed in 3.8% of controls and 26.9% of participants in the dose escalation group (P = .0496). Others within the same group experienced secondary outcomes of FC levels below 100 mcg/gram (P = .04) and below 200 mcg/g (P = .005). Furthermore, among patients who were in remission during the randomization phase of the study, relapse occurred far sooner in those whose FC was above 200 mcg/g than those whose FC levels were below that mark.

“Our study adds to the evidence supporting FC concentration as a valid biomarker for UC,” said lead authors Dr. Mark T. Osterman and Dr. Faten N. Aberra of the University of Pennsylvania’s department of medicine, Philadelphia. “Perhaps more importantly, our results offer a novel way to use FC testing to positively impact outcomes in UC. We demonstrated efficacy of intervention to reduce FC (a surrogate for mucosal inflammation) before symptoms develop in patients at potentially increased risk of relapse.”

Dr. Osterman is a consultant for AbbVie, Elan, Janssen, and UCB and receives research funding from UCB. Dr. Aberra is a consultant for Janssen and research investigator for Amgen, Janssen, and UCB. Other coauthors disclosed ties to numerous pharmaceutical companies.

[email protected]

Increasing dosages of mesalamine by 2.4 g/d for patients with quiescent ulcerative colitis can dramatically reduce concentrations of fecal calprotectin and ultimately decrease the likelihood of relapse, according to the results of a new Dose Escalation and Remission (DEAR) study published in the November issue of Clinical Gastroenterology and Hepatology (2014;12:1887-93.e3).

In an open-label, randomized controlled trial, 119 patients with quiescent ulcerative colitis (UC) in remission were screened for Simple Clinical Colitis Activity Index scores, fecal calprotectin (FC) of 50 mcg/gram, and intake of no more than 3 g of mesalamine per day between October 2008 and March 2012. These subjects were divided into four groups based on FC levels, with Group 1 comprising 58 representing a baseline of FC < 50 mcg/gram, and groups 2-4 having 61 individuals with elevated baseline FC levels. Group 1 patients were retained for an observational follow-up study but were not included in the randomized controlled trial.

© selvanegra / thinkstockphotos.com

Participants were either told to maintain their current medication regimen or were prescribed a multimatrix mesalamine of either 2.4 or 4.8 g/d for 6 weeks, depending on their initial FC levels, after which point FC levels were taken. Participants in Group 2 with FC < 50 mcg/g were kept in an observational follow-up study group, while the rest of the participants were randomly assigned to continue their 2.4 g/d regimen, or increase their intake to 4.8 g/d.

Individuals in Group 3 with FC levels greater than 50 mcg/g were randomly assigned to either the 2.4- or 4.8-g/d regimen for 6 weeks; after that point, those whose FC levels had decreased below 50 continued with their regimen while those whose FC levels remained high were upped to 4.8 g/d. Subjects in Group 4 who were not already on a multimatrix mesalamine regimen and whose FC levels were above 50 mcg/g were randomized to continue their medication or add 2.4 g/d of mesalamine; after 6 weeks, if FC levels remained above 50, the dosage was increased to 4.8 g/d.

The primary outcome of continued remission with FC no greater than 50 mcg/g was observed in 3.8% of controls and 26.9% of participants in the dose escalation group (P = .0496). Others within the same group experienced secondary outcomes of FC levels below 100 mcg/gram (P = .04) and below 200 mcg/g (P = .005). Furthermore, among patients who were in remission during the randomization phase of the study, relapse occurred far sooner in those whose FC was above 200 mcg/g than those whose FC levels were below that mark.

“Our study adds to the evidence supporting FC concentration as a valid biomarker for UC,” said lead authors Dr. Mark T. Osterman and Dr. Faten N. Aberra of the University of Pennsylvania’s department of medicine, Philadelphia. “Perhaps more importantly, our results offer a novel way to use FC testing to positively impact outcomes in UC. We demonstrated efficacy of intervention to reduce FC (a surrogate for mucosal inflammation) before symptoms develop in patients at potentially increased risk of relapse.”

Dr. Osterman is a consultant for AbbVie, Elan, Janssen, and UCB and receives research funding from UCB. Dr. Aberra is a consultant for Janssen and research investigator for Amgen, Janssen, and UCB. Other coauthors disclosed ties to numerous pharmaceutical companies.

[email protected]

A mutation in the hepatitis E virus might contribute to ribavirin treatment failure in transplant recipients with chronic HEV infection, according to a small study published in the November issue of Gastroenterology.

The study is the first to find in vitro evidence for a virulence mutation in HEV, said Dr. Yannick Debing at the University of Leuven in Belgium, Dr. Annett Gisa at the Hanover Medical School in Germany, and their associates.

Courtesy: American Gastroenterological Association

The researchers studied 15 solid-organ transplant recipients who received ribavirin monotherapy for chronic HEV infection. Thirteen patients were successfully treated, but two with genotype 3c infections failed therapy. Viral RNA levels in both of these patients initially dropped and then rose, suggesting emerging resistance to ribavirin therapy, the investigators said (Gastroenterology 2014 Aug. 30 [doi: 10.1053/j.gastro.2014.08.040]).

When the researchers sequenced HEV genomes from the nonresponders, they found a G1634R mutation in HEV viral polymerase that conferred greater replication capacity compared with wild-type HEV, even after in vitro ribavirin treatment, they reported. “It may be interesting to assess the possible use of position 1634 as a prognostic marker, and accordingly to adjust the dose and duration of ribavirin therapy based on the presence of the G1634R variant,” Dr. Debing and his associates said.

The mutation consisted of a G-to-A nucleotide substitution in the C-terminal region of viral polymerase, the investigators said. By comparing HEV sequences in GenBank (an open-access collection of publicly available nucleotide sequences and their proteins), they found that G1634 was the most common amino acid sequence in genotype 3 HEV, while the K1634 sequence predominated in genotypes 1 and 4.

A subgenomic replicon of genotype 3 HEV with the 1634R mutation showed no increase in ribavirin sensitivity, compared with the wild-type replicon (50% effective concentration [EC50] values, 5.1 ± 4.1 mcM and 5.1 ± 3.7 mcM, respectively), the investigators said. But when they tested the 1634R variant in human hepatoma cells, they observed a 3.4-fold increase in luminescence signaling, compared with cells transfected with capped replicon RNA from wild-type HEV (P = .04). Greater luminescence indicated that the 1634R mutation increased viral replication, they said.

In addition, an HEV replicon with the K1634 mutation showed 2.7 times more luminescence compared with cells transfected with wild-type viral RNA (P = .07), the researchers reported.

The investigators next studied the effects of the 1634 R/K mutations on the full-length HEV genome. They introduced HEV with the two variants into human hepatoma cells, measured the amounts of viral RNA released, and found that both variants replicated at higher levels than did wild-type virus. When they treated these cells with 10- or 25-mcM ribavirin, replication levels dropped for the 1634 R/K variants and for wild-type virus, but remained at least twice as high for the variants, they said.

“The increased replication capacity of the mutant may have contributed to the persistent disease courses despite [ribavirin] treatment, although other patient- and virus-related factors could have contributed as well,” the investigators said.

The research was supported by the Research Foundation–Flanders, KU Leuven University, the Robert Koch Institute, Geconcerteerde Onderzoeksactie, the German Federal Ministry for Education and Research, and EU FP7 project SILVER. The authors reported having no conflicts of interest.

A mutation in the hepatitis E virus might contribute to ribavirin treatment failure in transplant recipients with chronic HEV infection, according to a small study published in the November issue of Gastroenterology.

The study is the first to find in vitro evidence for a virulence mutation in HEV, said Dr. Yannick Debing at the University of Leuven in Belgium, Dr. Annett Gisa at the Hanover Medical School in Germany, and their associates.

Courtesy: American Gastroenterological Association

The researchers studied 15 solid-organ transplant recipients who received ribavirin monotherapy for chronic HEV infection. Thirteen patients were successfully treated, but two with genotype 3c infections failed therapy. Viral RNA levels in both of these patients initially dropped and then rose, suggesting emerging resistance to ribavirin therapy, the investigators said (Gastroenterology 2014 Aug. 30 [doi: 10.1053/j.gastro.2014.08.040]).

When the researchers sequenced HEV genomes from the nonresponders, they found a G1634R mutation in HEV viral polymerase that conferred greater replication capacity compared with wild-type HEV, even after in vitro ribavirin treatment, they reported. “It may be interesting to assess the possible use of position 1634 as a prognostic marker, and accordingly to adjust the dose and duration of ribavirin therapy based on the presence of the G1634R variant,” Dr. Debing and his associates said.

The mutation consisted of a G-to-A nucleotide substitution in the C-terminal region of viral polymerase, the investigators said. By comparing HEV sequences in GenBank (an open-access collection of publicly available nucleotide sequences and their proteins), they found that G1634 was the most common amino acid sequence in genotype 3 HEV, while the K1634 sequence predominated in genotypes 1 and 4.

A subgenomic replicon of genotype 3 HEV with the 1634R mutation showed no increase in ribavirin sensitivity, compared with the wild-type replicon (50% effective concentration [EC50] values, 5.1 ± 4.1 mcM and 5.1 ± 3.7 mcM, respectively), the investigators said. But when they tested the 1634R variant in human hepatoma cells, they observed a 3.4-fold increase in luminescence signaling, compared with cells transfected with capped replicon RNA from wild-type HEV (P = .04). Greater luminescence indicated that the 1634R mutation increased viral replication, they said.

In addition, an HEV replicon with the K1634 mutation showed 2.7 times more luminescence compared with cells transfected with wild-type viral RNA (P = .07), the researchers reported.

The investigators next studied the effects of the 1634 R/K mutations on the full-length HEV genome. They introduced HEV with the two variants into human hepatoma cells, measured the amounts of viral RNA released, and found that both variants replicated at higher levels than did wild-type virus. When they treated these cells with 10- or 25-mcM ribavirin, replication levels dropped for the 1634 R/K variants and for wild-type virus, but remained at least twice as high for the variants, they said.

“The increased replication capacity of the mutant may have contributed to the persistent disease courses despite [ribavirin] treatment, although other patient- and virus-related factors could have contributed as well,” the investigators said.

The research was supported by the Research Foundation–Flanders, KU Leuven University, the Robert Koch Institute, Geconcerteerde Onderzoeksactie, the German Federal Ministry for Education and Research, and EU FP7 project SILVER. The authors reported having no conflicts of interest.

A mutation in the hepatitis E virus might contribute to ribavirin treatment failure in transplant recipients with chronic HEV infection, according to a small study published in the November issue of Gastroenterology.

The study is the first to find in vitro evidence for a virulence mutation in HEV, said Dr. Yannick Debing at the University of Leuven in Belgium, Dr. Annett Gisa at the Hanover Medical School in Germany, and their associates.

Courtesy: American Gastroenterological Association

The researchers studied 15 solid-organ transplant recipients who received ribavirin monotherapy for chronic HEV infection. Thirteen patients were successfully treated, but two with genotype 3c infections failed therapy. Viral RNA levels in both of these patients initially dropped and then rose, suggesting emerging resistance to ribavirin therapy, the investigators said (Gastroenterology 2014 Aug. 30 [doi: 10.1053/j.gastro.2014.08.040]).

When the researchers sequenced HEV genomes from the nonresponders, they found a G1634R mutation in HEV viral polymerase that conferred greater replication capacity compared with wild-type HEV, even after in vitro ribavirin treatment, they reported. “It may be interesting to assess the possible use of position 1634 as a prognostic marker, and accordingly to adjust the dose and duration of ribavirin therapy based on the presence of the G1634R variant,” Dr. Debing and his associates said.

The mutation consisted of a G-to-A nucleotide substitution in the C-terminal region of viral polymerase, the investigators said. By comparing HEV sequences in GenBank (an open-access collection of publicly available nucleotide sequences and their proteins), they found that G1634 was the most common amino acid sequence in genotype 3 HEV, while the K1634 sequence predominated in genotypes 1 and 4.

A subgenomic replicon of genotype 3 HEV with the 1634R mutation showed no increase in ribavirin sensitivity, compared with the wild-type replicon (50% effective concentration [EC50] values, 5.1 ± 4.1 mcM and 5.1 ± 3.7 mcM, respectively), the investigators said. But when they tested the 1634R variant in human hepatoma cells, they observed a 3.4-fold increase in luminescence signaling, compared with cells transfected with capped replicon RNA from wild-type HEV (P = .04). Greater luminescence indicated that the 1634R mutation increased viral replication, they said.

In addition, an HEV replicon with the K1634 mutation showed 2.7 times more luminescence compared with cells transfected with wild-type viral RNA (P = .07), the researchers reported.

The investigators next studied the effects of the 1634 R/K mutations on the full-length HEV genome. They introduced HEV with the two variants into human hepatoma cells, measured the amounts of viral RNA released, and found that both variants replicated at higher levels than did wild-type virus. When they treated these cells with 10- or 25-mcM ribavirin, replication levels dropped for the 1634 R/K variants and for wild-type virus, but remained at least twice as high for the variants, they said.

“The increased replication capacity of the mutant may have contributed to the persistent disease courses despite [ribavirin] treatment, although other patient- and virus-related factors could have contributed as well,” the investigators said.

The research was supported by the Research Foundation–Flanders, KU Leuven University, the Robert Koch Institute, Geconcerteerde Onderzoeksactie, the German Federal Ministry for Education and Research, and EU FP7 project SILVER. The authors reported having no conflicts of interest.

A risk stratification model that determined whether patients with Crohn’s disease needed computed tomography cut scans of these patients in emergency departments by 43%, with a miss rate of only 0.8%, researchers reported online in Clinical Gastroenterology and Hepatology.

Computed tomography scans yield nonsignificant findings for almost one-third of patients with Crohn’s disease (CD) who present to emergency departments, said Dr. Shail Govani of the University of Michigan in Ann Arbor and his associates. By using their model to identify patients with serious gastrointestinal complications as opposed to straightforward intestinal inflammation, emergency departments could prevent more than 250 cancer cases and save more than $80 million per decade in the United States, the investigators added.

Source: American Gastroenterological Association

Patients with CD may be exposed to increasing cumulative radiation levels, and 30% of this exposure occurs in emergency departments, with 75% due to CT scans, the researchers said (Clin. Gastroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.036]).

For the study, the investigators retrospectively reviewed electronic medical records from the University of Michigan from 2000 through 2011, identifying 613 adults with CD who made 1,095 visits that included CT scans within 24 hours of presentation. The researchers then modeled associations between laboratory values and perforation, abscess, or other serious complications as opposed to intestinal inflammation.

Patients averaged 1.8 CT scans during the decade-long study period, and the overall rate of CT scans during that time rose from 63% to 87%, the investigators said. Only 16.8% of scans revealed a complication that would change clinical management, they reported.

Only C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were significantly associated with complications (odds ratio for CRP, 1.10; 95% confidence interval, 1.05-1.15; P less than .001; odds ratio for ESR, 1.02; 95% CI, 1.01-1.03; P less than .001), the researchers said. Adding ESR to 5 x CRP and not scanning patients with a resulting value of 10 or less would avoid CT scans in 18.5% of patients, they reported. But by using the more complex logistic regression model instead of the simpler equation, scans could be avoided for 43.0% of patients, with a miss rate of 0.8%, they said.

Based on the study, patients assessed as likely to have complications should undergo a standard CT scan of the abdomen and pelvis with nonbarium contrast to avoid barium peritonitis, said Dr. Govani and associates. Other patients should forego CT scans, have a consult with a gastroenterologist prior to further imaging, or undergo lower-radiation CT enterography, depending on presenting signs and probability of inflammation, they added.

The researchers said they were unable to construct good models that included obstruction as an outcome. Patients with suspected obstructions should have abdominal x-rays and then CT if an obstruction remained likely, they said.

"These models are limited in that they are retrospective and represent data from one center," the investigators added. "Although our internal validation with 10-fold cross-validation shows that these models have good performance characteristics, further external validation studies are needed to determine whether these models are generalizable to CD patients elsewhere."

The authors are prospectively testing the algorithms and hope to continue to validate and study them in emergency departments, they said.

The Inflammatory Bowel Disease Working Group, the Department of Veterans Affairs, and UCB supported the research. The authors reported having no conflicts of interest.

A risk stratification model that determined whether patients with Crohn’s disease needed computed tomography cut scans of these patients in emergency departments by 43%, with a miss rate of only 0.8%, researchers reported online in Clinical Gastroenterology and Hepatology.

Computed tomography scans yield nonsignificant findings for almost one-third of patients with Crohn’s disease (CD) who present to emergency departments, said Dr. Shail Govani of the University of Michigan in Ann Arbor and his associates. By using their model to identify patients with serious gastrointestinal complications as opposed to straightforward intestinal inflammation, emergency departments could prevent more than 250 cancer cases and save more than $80 million per decade in the United States, the investigators added.

Source: American Gastroenterological Association

Patients with CD may be exposed to increasing cumulative radiation levels, and 30% of this exposure occurs in emergency departments, with 75% due to CT scans, the researchers said (Clin. Gastroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.036]).

For the study, the investigators retrospectively reviewed electronic medical records from the University of Michigan from 2000 through 2011, identifying 613 adults with CD who made 1,095 visits that included CT scans within 24 hours of presentation. The researchers then modeled associations between laboratory values and perforation, abscess, or other serious complications as opposed to intestinal inflammation.

Patients averaged 1.8 CT scans during the decade-long study period, and the overall rate of CT scans during that time rose from 63% to 87%, the investigators said. Only 16.8% of scans revealed a complication that would change clinical management, they reported.

Only C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were significantly associated with complications (odds ratio for CRP, 1.10; 95% confidence interval, 1.05-1.15; P less than .001; odds ratio for ESR, 1.02; 95% CI, 1.01-1.03; P less than .001), the researchers said. Adding ESR to 5 x CRP and not scanning patients with a resulting value of 10 or less would avoid CT scans in 18.5% of patients, they reported. But by using the more complex logistic regression model instead of the simpler equation, scans could be avoided for 43.0% of patients, with a miss rate of 0.8%, they said.

Based on the study, patients assessed as likely to have complications should undergo a standard CT scan of the abdomen and pelvis with nonbarium contrast to avoid barium peritonitis, said Dr. Govani and associates. Other patients should forego CT scans, have a consult with a gastroenterologist prior to further imaging, or undergo lower-radiation CT enterography, depending on presenting signs and probability of inflammation, they added.

The researchers said they were unable to construct good models that included obstruction as an outcome. Patients with suspected obstructions should have abdominal x-rays and then CT if an obstruction remained likely, they said.

"These models are limited in that they are retrospective and represent data from one center," the investigators added. "Although our internal validation with 10-fold cross-validation shows that these models have good performance characteristics, further external validation studies are needed to determine whether these models are generalizable to CD patients elsewhere."

The authors are prospectively testing the algorithms and hope to continue to validate and study them in emergency departments, they said.

The Inflammatory Bowel Disease Working Group, the Department of Veterans Affairs, and UCB supported the research. The authors reported having no conflicts of interest.

A risk stratification model that determined whether patients with Crohn’s disease needed computed tomography cut scans of these patients in emergency departments by 43%, with a miss rate of only 0.8%, researchers reported online in Clinical Gastroenterology and Hepatology.

Computed tomography scans yield nonsignificant findings for almost one-third of patients with Crohn’s disease (CD) who present to emergency departments, said Dr. Shail Govani of the University of Michigan in Ann Arbor and his associates. By using their model to identify patients with serious gastrointestinal complications as opposed to straightforward intestinal inflammation, emergency departments could prevent more than 250 cancer cases and save more than $80 million per decade in the United States, the investigators added.

Source: American Gastroenterological Association

Patients with CD may be exposed to increasing cumulative radiation levels, and 30% of this exposure occurs in emergency departments, with 75% due to CT scans, the researchers said (Clin. Gastroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.036]).

For the study, the investigators retrospectively reviewed electronic medical records from the University of Michigan from 2000 through 2011, identifying 613 adults with CD who made 1,095 visits that included CT scans within 24 hours of presentation. The researchers then modeled associations between laboratory values and perforation, abscess, or other serious complications as opposed to intestinal inflammation.

Patients averaged 1.8 CT scans during the decade-long study period, and the overall rate of CT scans during that time rose from 63% to 87%, the investigators said. Only 16.8% of scans revealed a complication that would change clinical management, they reported.

Only C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were significantly associated with complications (odds ratio for CRP, 1.10; 95% confidence interval, 1.05-1.15; P less than .001; odds ratio for ESR, 1.02; 95% CI, 1.01-1.03; P less than .001), the researchers said. Adding ESR to 5 x CRP and not scanning patients with a resulting value of 10 or less would avoid CT scans in 18.5% of patients, they reported. But by using the more complex logistic regression model instead of the simpler equation, scans could be avoided for 43.0% of patients, with a miss rate of 0.8%, they said.

Based on the study, patients assessed as likely to have complications should undergo a standard CT scan of the abdomen and pelvis with nonbarium contrast to avoid barium peritonitis, said Dr. Govani and associates. Other patients should forego CT scans, have a consult with a gastroenterologist prior to further imaging, or undergo lower-radiation CT enterography, depending on presenting signs and probability of inflammation, they added.

The researchers said they were unable to construct good models that included obstruction as an outcome. Patients with suspected obstructions should have abdominal x-rays and then CT if an obstruction remained likely, they said.

"These models are limited in that they are retrospective and represent data from one center," the investigators added. "Although our internal validation with 10-fold cross-validation shows that these models have good performance characteristics, further external validation studies are needed to determine whether these models are generalizable to CD patients elsewhere."

The authors are prospectively testing the algorithms and hope to continue to validate and study them in emergency departments, they said.

The Inflammatory Bowel Disease Working Group, the Department of Veterans Affairs, and UCB supported the research. The authors reported having no conflicts of interest.

Cytology and a microRNA-based test identified pancreatic cancer 91% of the time in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration – a substantial improvement, compared with cytology alone, researchers reported in the October issue of Clinical Gastroenterology and Hepatology.

The microRNA-based test could help reduce repeated fine-needle aspirations (FNAs) due to indeterminate cytologies, said Dr. Randall Brand of the University of Pittsburgh Medical Center and his associates. Correctly assessing pancreatic cancer before surgery also could help patients start neoadjuvant therapy sooner if appropriate, they noted.

© goa_novi / ThinkStockPhotos.com

Several microRNAs are expressed abnormally in patients with pancreatic ductal adenocarcinoma. The new test contains five of these sequences and is the first of its type for pancreatic cancer, the researchers said. To evaluate the assay, they assessed and compared relative quantitative polymerase chain reaction and cytology results from 95 formalin-fixed paraffin-embedded specimens and 228 endoscopic ultrasound-guided FNAs. Specimens were collected during routine visits by patients with solid pancreatic masses, the investigators said (Clin. Gastroenterol. Hepatol. 2014 October [doi:10.1016/j.cgh.2014.02.038]).

The test used together with cytology correctly identified pancreatic cancer in 91% of positive specimens (95% confidence interval, 85.6%-94.5%), while cytology alone had a sensitivity of 79% (95% CI, 72.2%-84.5%), the researchers reported. Cytology and the microRNA test each had positive predictive values greater than 99% (95% CI, 96%-100%), they added.

When used alone, the microRNA test had a diagnostic sensitivity of more than 82% and a specificity of 96% – better than cytology on the same specimens, the investigators said. And the test correctly found pancreatic cancer in 22 of 39 specimens previously assessed as benign, indeterminate, or nondiagnostic by cytology, they said.

The researchers separately assessed 46 specimens collected percutaneously instead of by endoscopic ultrasound-guided FNA and found much lower (58%) diagnostic sensitivity and a higher rate of technical failures, although specificity and predictive value still approached 90%, said the investigators. The percutaneous specimens all were collected from two study sites outside the United States, so further studies would need to validate whether a percutaneous approach could replace endoscopic ultrasound-guided FNA, they said.

Cytology and microRNA testing also had to be performed on different FNA specimens, a limitation that "could have contributed to some of the observed discrepancies between cytology and molecular results," the investigators said.

Pancreatic cancer remains notoriously difficult to treat, with overall 5-year survival rates of only about 6%. MicroRNA sequences are stable and can reliably be recovered from both formalin-fixed and FNA specimens, making them a "particularly promising" class of biomarkers for pancreatic and other cancers, the researchers said. Based on the study results, future studies should explore the test’s prognostic potential, such as for distinguishing patients with resectable tumors that are likely to progress early or to guide choice of therapies, they said.

The study was supported by Asuragen and by a grant from the German Federal Ministry of Education and Research. Dr. Brand and another author reported that they are on the clinical advisory board of Asuragen, and six of 27 coauthors reported being employees of the company. The rest reported no conflicts of interest.

Cytology and a microRNA-based test identified pancreatic cancer 91% of the time in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration – a substantial improvement, compared with cytology alone, researchers reported in the October issue of Clinical Gastroenterology and Hepatology.

The microRNA-based test could help reduce repeated fine-needle aspirations (FNAs) due to indeterminate cytologies, said Dr. Randall Brand of the University of Pittsburgh Medical Center and his associates. Correctly assessing pancreatic cancer before surgery also could help patients start neoadjuvant therapy sooner if appropriate, they noted.

© goa_novi / ThinkStockPhotos.com

Several microRNAs are expressed abnormally in patients with pancreatic ductal adenocarcinoma. The new test contains five of these sequences and is the first of its type for pancreatic cancer, the researchers said. To evaluate the assay, they assessed and compared relative quantitative polymerase chain reaction and cytology results from 95 formalin-fixed paraffin-embedded specimens and 228 endoscopic ultrasound-guided FNAs. Specimens were collected during routine visits by patients with solid pancreatic masses, the investigators said (Clin. Gastroenterol. Hepatol. 2014 October [doi:10.1016/j.cgh.2014.02.038]).

The test used together with cytology correctly identified pancreatic cancer in 91% of positive specimens (95% confidence interval, 85.6%-94.5%), while cytology alone had a sensitivity of 79% (95% CI, 72.2%-84.5%), the researchers reported. Cytology and the microRNA test each had positive predictive values greater than 99% (95% CI, 96%-100%), they added.

When used alone, the microRNA test had a diagnostic sensitivity of more than 82% and a specificity of 96% – better than cytology on the same specimens, the investigators said. And the test correctly found pancreatic cancer in 22 of 39 specimens previously assessed as benign, indeterminate, or nondiagnostic by cytology, they said.

The researchers separately assessed 46 specimens collected percutaneously instead of by endoscopic ultrasound-guided FNA and found much lower (58%) diagnostic sensitivity and a higher rate of technical failures, although specificity and predictive value still approached 90%, said the investigators. The percutaneous specimens all were collected from two study sites outside the United States, so further studies would need to validate whether a percutaneous approach could replace endoscopic ultrasound-guided FNA, they said.

Cytology and microRNA testing also had to be performed on different FNA specimens, a limitation that "could have contributed to some of the observed discrepancies between cytology and molecular results," the investigators said.

Pancreatic cancer remains notoriously difficult to treat, with overall 5-year survival rates of only about 6%. MicroRNA sequences are stable and can reliably be recovered from both formalin-fixed and FNA specimens, making them a "particularly promising" class of biomarkers for pancreatic and other cancers, the researchers said. Based on the study results, future studies should explore the test’s prognostic potential, such as for distinguishing patients with resectable tumors that are likely to progress early or to guide choice of therapies, they said.

The study was supported by Asuragen and by a grant from the German Federal Ministry of Education and Research. Dr. Brand and another author reported that they are on the clinical advisory board of Asuragen, and six of 27 coauthors reported being employees of the company. The rest reported no conflicts of interest.

Cytology and a microRNA-based test identified pancreatic cancer 91% of the time in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration – a substantial improvement, compared with cytology alone, researchers reported in the October issue of Clinical Gastroenterology and Hepatology.

The microRNA-based test could help reduce repeated fine-needle aspirations (FNAs) due to indeterminate cytologies, said Dr. Randall Brand of the University of Pittsburgh Medical Center and his associates. Correctly assessing pancreatic cancer before surgery also could help patients start neoadjuvant therapy sooner if appropriate, they noted.

© goa_novi / ThinkStockPhotos.com

Several microRNAs are expressed abnormally in patients with pancreatic ductal adenocarcinoma. The new test contains five of these sequences and is the first of its type for pancreatic cancer, the researchers said. To evaluate the assay, they assessed and compared relative quantitative polymerase chain reaction and cytology results from 95 formalin-fixed paraffin-embedded specimens and 228 endoscopic ultrasound-guided FNAs. Specimens were collected during routine visits by patients with solid pancreatic masses, the investigators said (Clin. Gastroenterol. Hepatol. 2014 October [doi:10.1016/j.cgh.2014.02.038]).

The test used together with cytology correctly identified pancreatic cancer in 91% of positive specimens (95% confidence interval, 85.6%-94.5%), while cytology alone had a sensitivity of 79% (95% CI, 72.2%-84.5%), the researchers reported. Cytology and the microRNA test each had positive predictive values greater than 99% (95% CI, 96%-100%), they added.

When used alone, the microRNA test had a diagnostic sensitivity of more than 82% and a specificity of 96% – better than cytology on the same specimens, the investigators said. And the test correctly found pancreatic cancer in 22 of 39 specimens previously assessed as benign, indeterminate, or nondiagnostic by cytology, they said.

The researchers separately assessed 46 specimens collected percutaneously instead of by endoscopic ultrasound-guided FNA and found much lower (58%) diagnostic sensitivity and a higher rate of technical failures, although specificity and predictive value still approached 90%, said the investigators. The percutaneous specimens all were collected from two study sites outside the United States, so further studies would need to validate whether a percutaneous approach could replace endoscopic ultrasound-guided FNA, they said.

Cytology and microRNA testing also had to be performed on different FNA specimens, a limitation that "could have contributed to some of the observed discrepancies between cytology and molecular results," the investigators said.

Pancreatic cancer remains notoriously difficult to treat, with overall 5-year survival rates of only about 6%. MicroRNA sequences are stable and can reliably be recovered from both formalin-fixed and FNA specimens, making them a "particularly promising" class of biomarkers for pancreatic and other cancers, the researchers said. Based on the study results, future studies should explore the test’s prognostic potential, such as for distinguishing patients with resectable tumors that are likely to progress early or to guide choice of therapies, they said.

The study was supported by Asuragen and by a grant from the German Federal Ministry of Education and Research. Dr. Brand and another author reported that they are on the clinical advisory board of Asuragen, and six of 27 coauthors reported being employees of the company. The rest reported no conflicts of interest.