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Novel capsid assembly modulator shows promise in HBV
For adults with chronic hepatitis B virus infection, treatment with a novel investigational capsid assembly modulator was well tolerated and showed antiviral activity against HBV, according to the results of a phase 1 study of 73 patients.
“Substantial and correlated reductions in serum HBV DNA and HBV RNA levels were observed consistently with the higher-dose cohorts and were notably greatest for combination treatment with NVR 3-778 and pegIFN [pegylated interferon],” Man Fung Yuen, MD, of the University of Hong Kong, and his associates wrote in a report published in Gastroenterology. Hence, this first-in-class capsid assembly modulator might help prolong treatment responses, “most likely as a component of new combination treatment regimens for HBV-infected patients.” However, one patient developed severe rash immediately after completing treatment that took 6 months of intensive outpatient treatment to resolve, they noted.
Chronic viral hepatitis due to HBV is a major cause of early death worldwide, and new therapies are needed to help prevent severe liver disease and liver death from this infection. Current treatments for HBV infection consist of nucleoside or nucleotide analogs or pegylated interferon. These suppress HBV replication in many patients, but most patients do not achieve durable responses. Consequently, most patients require long-term treatment with HBV nucleosides and nucleotide analogs, which they may find difficult to tolerate or adhere to and to which their infections can become resistant, the researchers said.
The HBV virion contains a viral core protein (HBc) that is required to encapsidate viral polymerase and pregenomic HBV RNA into a nucleocapsid. To target this process, researchers developed NVR 3-778, a first-in-class, orally bioavailable small molecule that binds HBc so that HBc forms a defective capsid that lacks nuclear material. Hence, NVR 3-778 is intended to stop the production of HBV nucleocapsids and keep infected cells from releasing the enveloped infectious viral particles that perpetuate HBV infection.
To assess the safety, pharmacokinetics, and antiviral activity of NVR 3-778, the researchers conducted a phase 1 study of 73 patients with chronic HBV infection who tested positive for hepatitis B e-antigen (HBeAg) and had no detectable cirrhosis. Patients were randomly assigned to receive oral NVR 3-778 (100 mg, 200 mg, or 400 mg daily or 600 mg or 1,000 mg twice daily ) or placebo for 28 days. Some patients received combination therapy with pegylated interferon plus either NVR 3-778 (600 mg twice daily) or placebo. Treatment was generally well tolerated, and adverse events were usually mild and deemed unrelated to therapy. No patient stopped treatment for adverse effects.
The only serious adverse event in the study consisted of grade 3 rash that developed in a 42-year-old male after 22 days of treatment at the lowest dose of NVR 3-778 (100 mg per day). This patient completed treatment and ultimately developed a severe papulovesicular rash with a predominantly acral distribution over the hands, arm, side of neck, and one leg (palmar plantar erythrodysesthesia), the researchers said. “There were no perioral or mucosal lesions, no ecchymotic skin involvement, no bullae, and no systemic manifestations or hematological abnormalities,” they wrote. “The rash was subsequently managed with a psoriasis-like treatment regimen of psoralen, ultraviolet light, and topical steroid ointment during outpatient follow-up and resolved after approximately 6 months.”
Another three cases of “minor” skin rash were considered probably related to treatment in the cohort that received 600 mg NVR 3-778 b.i.d. plus pegylated interferon, the investigators said. Two additional cases of mild rash were deemed unrelated to treatment.
“The observed reductions in HBV RNA confirmed the novel mechanism of NVR 3-778,” the researchers concluded. “This class of compounds can also inhibit replenishment of intranuclear covalently closed circular DNA over time and may have immunomodulatory properties.” Longer treatment periods would be needed to study these mechanisms and to quantify reductions in serum HBsAg and HBeAG, they noted.
Novira Therapeutics developed NVR 3-778 and is a Janssen Pharmaceutical Company. Janssen provided funding for editorial support. Dr. Yuen disclosed relationships with AbbVie, Biocartis, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Ionis, Roche, Vir Biotechnology, and several other pharmaceutical companies. Other coinvestigators disclosed ties to pharmaceutical companies; eight reported employment by Novira or a Janssen company.
SOURCE: Yuen MF et al. Gastroenterology. 2019 Jan 5. doi: 10.1053/j.gastro.2018.12.023.
For adults with chronic hepatitis B virus infection, treatment with a novel investigational capsid assembly modulator was well tolerated and showed antiviral activity against HBV, according to the results of a phase 1 study of 73 patients.
“Substantial and correlated reductions in serum HBV DNA and HBV RNA levels were observed consistently with the higher-dose cohorts and were notably greatest for combination treatment with NVR 3-778 and pegIFN [pegylated interferon],” Man Fung Yuen, MD, of the University of Hong Kong, and his associates wrote in a report published in Gastroenterology. Hence, this first-in-class capsid assembly modulator might help prolong treatment responses, “most likely as a component of new combination treatment regimens for HBV-infected patients.” However, one patient developed severe rash immediately after completing treatment that took 6 months of intensive outpatient treatment to resolve, they noted.
Chronic viral hepatitis due to HBV is a major cause of early death worldwide, and new therapies are needed to help prevent severe liver disease and liver death from this infection. Current treatments for HBV infection consist of nucleoside or nucleotide analogs or pegylated interferon. These suppress HBV replication in many patients, but most patients do not achieve durable responses. Consequently, most patients require long-term treatment with HBV nucleosides and nucleotide analogs, which they may find difficult to tolerate or adhere to and to which their infections can become resistant, the researchers said.
The HBV virion contains a viral core protein (HBc) that is required to encapsidate viral polymerase and pregenomic HBV RNA into a nucleocapsid. To target this process, researchers developed NVR 3-778, a first-in-class, orally bioavailable small molecule that binds HBc so that HBc forms a defective capsid that lacks nuclear material. Hence, NVR 3-778 is intended to stop the production of HBV nucleocapsids and keep infected cells from releasing the enveloped infectious viral particles that perpetuate HBV infection.
To assess the safety, pharmacokinetics, and antiviral activity of NVR 3-778, the researchers conducted a phase 1 study of 73 patients with chronic HBV infection who tested positive for hepatitis B e-antigen (HBeAg) and had no detectable cirrhosis. Patients were randomly assigned to receive oral NVR 3-778 (100 mg, 200 mg, or 400 mg daily or 600 mg or 1,000 mg twice daily ) or placebo for 28 days. Some patients received combination therapy with pegylated interferon plus either NVR 3-778 (600 mg twice daily) or placebo. Treatment was generally well tolerated, and adverse events were usually mild and deemed unrelated to therapy. No patient stopped treatment for adverse effects.
The only serious adverse event in the study consisted of grade 3 rash that developed in a 42-year-old male after 22 days of treatment at the lowest dose of NVR 3-778 (100 mg per day). This patient completed treatment and ultimately developed a severe papulovesicular rash with a predominantly acral distribution over the hands, arm, side of neck, and one leg (palmar plantar erythrodysesthesia), the researchers said. “There were no perioral or mucosal lesions, no ecchymotic skin involvement, no bullae, and no systemic manifestations or hematological abnormalities,” they wrote. “The rash was subsequently managed with a psoriasis-like treatment regimen of psoralen, ultraviolet light, and topical steroid ointment during outpatient follow-up and resolved after approximately 6 months.”
Another three cases of “minor” skin rash were considered probably related to treatment in the cohort that received 600 mg NVR 3-778 b.i.d. plus pegylated interferon, the investigators said. Two additional cases of mild rash were deemed unrelated to treatment.
“The observed reductions in HBV RNA confirmed the novel mechanism of NVR 3-778,” the researchers concluded. “This class of compounds can also inhibit replenishment of intranuclear covalently closed circular DNA over time and may have immunomodulatory properties.” Longer treatment periods would be needed to study these mechanisms and to quantify reductions in serum HBsAg and HBeAG, they noted.
Novira Therapeutics developed NVR 3-778 and is a Janssen Pharmaceutical Company. Janssen provided funding for editorial support. Dr. Yuen disclosed relationships with AbbVie, Biocartis, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Ionis, Roche, Vir Biotechnology, and several other pharmaceutical companies. Other coinvestigators disclosed ties to pharmaceutical companies; eight reported employment by Novira or a Janssen company.
SOURCE: Yuen MF et al. Gastroenterology. 2019 Jan 5. doi: 10.1053/j.gastro.2018.12.023.
For adults with chronic hepatitis B virus infection, treatment with a novel investigational capsid assembly modulator was well tolerated and showed antiviral activity against HBV, according to the results of a phase 1 study of 73 patients.
“Substantial and correlated reductions in serum HBV DNA and HBV RNA levels were observed consistently with the higher-dose cohorts and were notably greatest for combination treatment with NVR 3-778 and pegIFN [pegylated interferon],” Man Fung Yuen, MD, of the University of Hong Kong, and his associates wrote in a report published in Gastroenterology. Hence, this first-in-class capsid assembly modulator might help prolong treatment responses, “most likely as a component of new combination treatment regimens for HBV-infected patients.” However, one patient developed severe rash immediately after completing treatment that took 6 months of intensive outpatient treatment to resolve, they noted.
Chronic viral hepatitis due to HBV is a major cause of early death worldwide, and new therapies are needed to help prevent severe liver disease and liver death from this infection. Current treatments for HBV infection consist of nucleoside or nucleotide analogs or pegylated interferon. These suppress HBV replication in many patients, but most patients do not achieve durable responses. Consequently, most patients require long-term treatment with HBV nucleosides and nucleotide analogs, which they may find difficult to tolerate or adhere to and to which their infections can become resistant, the researchers said.
The HBV virion contains a viral core protein (HBc) that is required to encapsidate viral polymerase and pregenomic HBV RNA into a nucleocapsid. To target this process, researchers developed NVR 3-778, a first-in-class, orally bioavailable small molecule that binds HBc so that HBc forms a defective capsid that lacks nuclear material. Hence, NVR 3-778 is intended to stop the production of HBV nucleocapsids and keep infected cells from releasing the enveloped infectious viral particles that perpetuate HBV infection.
To assess the safety, pharmacokinetics, and antiviral activity of NVR 3-778, the researchers conducted a phase 1 study of 73 patients with chronic HBV infection who tested positive for hepatitis B e-antigen (HBeAg) and had no detectable cirrhosis. Patients were randomly assigned to receive oral NVR 3-778 (100 mg, 200 mg, or 400 mg daily or 600 mg or 1,000 mg twice daily ) or placebo for 28 days. Some patients received combination therapy with pegylated interferon plus either NVR 3-778 (600 mg twice daily) or placebo. Treatment was generally well tolerated, and adverse events were usually mild and deemed unrelated to therapy. No patient stopped treatment for adverse effects.
The only serious adverse event in the study consisted of grade 3 rash that developed in a 42-year-old male after 22 days of treatment at the lowest dose of NVR 3-778 (100 mg per day). This patient completed treatment and ultimately developed a severe papulovesicular rash with a predominantly acral distribution over the hands, arm, side of neck, and one leg (palmar plantar erythrodysesthesia), the researchers said. “There were no perioral or mucosal lesions, no ecchymotic skin involvement, no bullae, and no systemic manifestations or hematological abnormalities,” they wrote. “The rash was subsequently managed with a psoriasis-like treatment regimen of psoralen, ultraviolet light, and topical steroid ointment during outpatient follow-up and resolved after approximately 6 months.”
Another three cases of “minor” skin rash were considered probably related to treatment in the cohort that received 600 mg NVR 3-778 b.i.d. plus pegylated interferon, the investigators said. Two additional cases of mild rash were deemed unrelated to treatment.
“The observed reductions in HBV RNA confirmed the novel mechanism of NVR 3-778,” the researchers concluded. “This class of compounds can also inhibit replenishment of intranuclear covalently closed circular DNA over time and may have immunomodulatory properties.” Longer treatment periods would be needed to study these mechanisms and to quantify reductions in serum HBsAg and HBeAG, they noted.
Novira Therapeutics developed NVR 3-778 and is a Janssen Pharmaceutical Company. Janssen provided funding for editorial support. Dr. Yuen disclosed relationships with AbbVie, Biocartis, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Ionis, Roche, Vir Biotechnology, and several other pharmaceutical companies. Other coinvestigators disclosed ties to pharmaceutical companies; eight reported employment by Novira or a Janssen company.
SOURCE: Yuen MF et al. Gastroenterology. 2019 Jan 5. doi: 10.1053/j.gastro.2018.12.023.
FROM GASTROENTEROLOGY
AGA Clinical Practice Update: Surgical risk assessment and perioperative management in cirrhosis
Patients with cirrhosis should be risk stratified and counseled accordingly before all but the most urgent surgeries, cautions a clinical practice update from the American Gastroenterological Association.
These risks, which include mortality and reflect “the profound effects of hepatic synthetic dysfunction and portal hypertension,” require presurgical evaluation based on CTP score (Child-Pugh class), Model for End-Stage Liver Disease (MELD) score, Mayo Postoperative Mortality Risk Score, or another proven risk-stratification system, writes Patrick G. Northup, MD, of the University of Virginia, Charlottesville, together with his associates. “There is no single definitive risk-stratification system to determine operative risk in all patients with cirrhosis, and we recommend using multiple methods,” they elaborated in Clinical Gastroenterology and Hepatology.
The prevalence of cirrhosis is rising, affected patients are living longer, and liver disease is more advanced and may involve comorbidities that merit consideration of surgery, noted Dr. Northup and his associates. However, cirrhosis increases the risk for serious postoperative complications, including hepatic decompensation, worsening of liver synthetic function, exacerbated portal hypertension, wound dehiscence, pleural effusions, pneumonia, bacterial peritonitis, bleeding, and multiple organ failure. Because clinical trials of surgery in cirrhotic patients are lacking, the experts stress the need for case-by-case management.
There is no definite threshold that precludes all surgeries in cases of cirrhosis, but a Child-Pugh class C (CTP score over 10) or MELD score over 20 greatly increases the risk of postoperative decompensation and death. For these patients, “all but the most urgent and life-saving procedures” should be canceled or postponed until after liver transplantation, the experts wrote. For less severe cirrhosis, it is key to consider the type and anatomic site of the proposed surgery. Hepatobiliary surgeries, other intra-abdominal surgeries, cardiovascular surgeries, and thoracic procedures are most likely to lead to serious complications.
Preoperative care should emphasize control of ascites, variceal bleeding risk, and hepatic encephalopathy. Bleeding and clotting safety thresholds in cirrhosis are unknown, and individualized management, ideally with viscoelastic testing–directed therapy, is warranted instead of protocol transfusions to a target international normalized ratio (INR). Bleeding events are more common in critically ill patients with plasma fibrinogen ratios under 100 mg/dL.
Segmental hepatic resection (usually for malignancy), the most studied procedure in cirrhosis, is generally safe in the absence of clinically significant portal hypertension. For patients who do have portal hypertension, transjugular intrahepatic portosystemic shunt (TIPS) has not clearly been shown to outperform conservative management, although small case series have found that TIPS during deep pelvic or colonic resection decompresses abdominal collaterals.
Because of the risk of poor outcomes, patients with cirrhosis and incompletely controlled ascites should not undergo abdominal hernia repair unless they have an incarceration that is not manually reducible or suspected strangulation. Bariatric surgery is contraindicated in cases of clinically significant portal hypertension but otherwise can be performed at a center with cirrhosis expertise. Sleeve gastrectomy at the same time as liver transplantation is also an option for select patients with obesity.
Elective cholecystectomy should be avoided, and required cases should be performed in experienced centers. “The gallbladder wall may appear thickened on imaging, which may lead to the erroneous diagnosis of acute cholecystitis,” the experts noted. Hence, the diagnosis “should be made only in the appropriate clinical setting, usually in the presence of biliary pain.”
Hepatic decompensation after surgery can be severe enough to merit liver transplantation. There is no agreed-on MELD score that mandates liver transplant evaluation before elective surgery, but the experts recommend doing so if the MELD score is 15 or greater or if risk of mortality within 3 months after surgery exceeds 15%.
Postoperative management of patients with cirrhosis should include aggressive measures to prevent portal hypertension. Monitor renal function closely and avoid volume depletion or overload, the experts advised. Patients should receive only short-acting benzodiazepines and lower opiate doses, administered less often, than in the general population. Avoiding constipation is vital to minimize hepatic encephalopathy, which makes oral rifaximin a better choice than lactulose. Patients should not receive NSAIDs, which can impair renal blood flow. To prevent liver toxicity, they should not be discharged on opiate/acetaminophen combinations, which they might unknowingly take along with another drug that contains acetaminophen.
The experts disclosed no external funding sources and reported having no conflicts of interest.
SOURCE: Northup PG et al. Clin Gastroenterol Hepatol. 2018 Sep 28. doi: 10.1016/j.cgh.2018.09.043.
Patients with cirrhosis should be risk stratified and counseled accordingly before all but the most urgent surgeries, cautions a clinical practice update from the American Gastroenterological Association.
These risks, which include mortality and reflect “the profound effects of hepatic synthetic dysfunction and portal hypertension,” require presurgical evaluation based on CTP score (Child-Pugh class), Model for End-Stage Liver Disease (MELD) score, Mayo Postoperative Mortality Risk Score, or another proven risk-stratification system, writes Patrick G. Northup, MD, of the University of Virginia, Charlottesville, together with his associates. “There is no single definitive risk-stratification system to determine operative risk in all patients with cirrhosis, and we recommend using multiple methods,” they elaborated in Clinical Gastroenterology and Hepatology.
The prevalence of cirrhosis is rising, affected patients are living longer, and liver disease is more advanced and may involve comorbidities that merit consideration of surgery, noted Dr. Northup and his associates. However, cirrhosis increases the risk for serious postoperative complications, including hepatic decompensation, worsening of liver synthetic function, exacerbated portal hypertension, wound dehiscence, pleural effusions, pneumonia, bacterial peritonitis, bleeding, and multiple organ failure. Because clinical trials of surgery in cirrhotic patients are lacking, the experts stress the need for case-by-case management.
There is no definite threshold that precludes all surgeries in cases of cirrhosis, but a Child-Pugh class C (CTP score over 10) or MELD score over 20 greatly increases the risk of postoperative decompensation and death. For these patients, “all but the most urgent and life-saving procedures” should be canceled or postponed until after liver transplantation, the experts wrote. For less severe cirrhosis, it is key to consider the type and anatomic site of the proposed surgery. Hepatobiliary surgeries, other intra-abdominal surgeries, cardiovascular surgeries, and thoracic procedures are most likely to lead to serious complications.
Preoperative care should emphasize control of ascites, variceal bleeding risk, and hepatic encephalopathy. Bleeding and clotting safety thresholds in cirrhosis are unknown, and individualized management, ideally with viscoelastic testing–directed therapy, is warranted instead of protocol transfusions to a target international normalized ratio (INR). Bleeding events are more common in critically ill patients with plasma fibrinogen ratios under 100 mg/dL.
Segmental hepatic resection (usually for malignancy), the most studied procedure in cirrhosis, is generally safe in the absence of clinically significant portal hypertension. For patients who do have portal hypertension, transjugular intrahepatic portosystemic shunt (TIPS) has not clearly been shown to outperform conservative management, although small case series have found that TIPS during deep pelvic or colonic resection decompresses abdominal collaterals.
Because of the risk of poor outcomes, patients with cirrhosis and incompletely controlled ascites should not undergo abdominal hernia repair unless they have an incarceration that is not manually reducible or suspected strangulation. Bariatric surgery is contraindicated in cases of clinically significant portal hypertension but otherwise can be performed at a center with cirrhosis expertise. Sleeve gastrectomy at the same time as liver transplantation is also an option for select patients with obesity.
Elective cholecystectomy should be avoided, and required cases should be performed in experienced centers. “The gallbladder wall may appear thickened on imaging, which may lead to the erroneous diagnosis of acute cholecystitis,” the experts noted. Hence, the diagnosis “should be made only in the appropriate clinical setting, usually in the presence of biliary pain.”
Hepatic decompensation after surgery can be severe enough to merit liver transplantation. There is no agreed-on MELD score that mandates liver transplant evaluation before elective surgery, but the experts recommend doing so if the MELD score is 15 or greater or if risk of mortality within 3 months after surgery exceeds 15%.
Postoperative management of patients with cirrhosis should include aggressive measures to prevent portal hypertension. Monitor renal function closely and avoid volume depletion or overload, the experts advised. Patients should receive only short-acting benzodiazepines and lower opiate doses, administered less often, than in the general population. Avoiding constipation is vital to minimize hepatic encephalopathy, which makes oral rifaximin a better choice than lactulose. Patients should not receive NSAIDs, which can impair renal blood flow. To prevent liver toxicity, they should not be discharged on opiate/acetaminophen combinations, which they might unknowingly take along with another drug that contains acetaminophen.
The experts disclosed no external funding sources and reported having no conflicts of interest.
SOURCE: Northup PG et al. Clin Gastroenterol Hepatol. 2018 Sep 28. doi: 10.1016/j.cgh.2018.09.043.
Patients with cirrhosis should be risk stratified and counseled accordingly before all but the most urgent surgeries, cautions a clinical practice update from the American Gastroenterological Association.
These risks, which include mortality and reflect “the profound effects of hepatic synthetic dysfunction and portal hypertension,” require presurgical evaluation based on CTP score (Child-Pugh class), Model for End-Stage Liver Disease (MELD) score, Mayo Postoperative Mortality Risk Score, or another proven risk-stratification system, writes Patrick G. Northup, MD, of the University of Virginia, Charlottesville, together with his associates. “There is no single definitive risk-stratification system to determine operative risk in all patients with cirrhosis, and we recommend using multiple methods,” they elaborated in Clinical Gastroenterology and Hepatology.
The prevalence of cirrhosis is rising, affected patients are living longer, and liver disease is more advanced and may involve comorbidities that merit consideration of surgery, noted Dr. Northup and his associates. However, cirrhosis increases the risk for serious postoperative complications, including hepatic decompensation, worsening of liver synthetic function, exacerbated portal hypertension, wound dehiscence, pleural effusions, pneumonia, bacterial peritonitis, bleeding, and multiple organ failure. Because clinical trials of surgery in cirrhotic patients are lacking, the experts stress the need for case-by-case management.
There is no definite threshold that precludes all surgeries in cases of cirrhosis, but a Child-Pugh class C (CTP score over 10) or MELD score over 20 greatly increases the risk of postoperative decompensation and death. For these patients, “all but the most urgent and life-saving procedures” should be canceled or postponed until after liver transplantation, the experts wrote. For less severe cirrhosis, it is key to consider the type and anatomic site of the proposed surgery. Hepatobiliary surgeries, other intra-abdominal surgeries, cardiovascular surgeries, and thoracic procedures are most likely to lead to serious complications.
Preoperative care should emphasize control of ascites, variceal bleeding risk, and hepatic encephalopathy. Bleeding and clotting safety thresholds in cirrhosis are unknown, and individualized management, ideally with viscoelastic testing–directed therapy, is warranted instead of protocol transfusions to a target international normalized ratio (INR). Bleeding events are more common in critically ill patients with plasma fibrinogen ratios under 100 mg/dL.
Segmental hepatic resection (usually for malignancy), the most studied procedure in cirrhosis, is generally safe in the absence of clinically significant portal hypertension. For patients who do have portal hypertension, transjugular intrahepatic portosystemic shunt (TIPS) has not clearly been shown to outperform conservative management, although small case series have found that TIPS during deep pelvic or colonic resection decompresses abdominal collaterals.
Because of the risk of poor outcomes, patients with cirrhosis and incompletely controlled ascites should not undergo abdominal hernia repair unless they have an incarceration that is not manually reducible or suspected strangulation. Bariatric surgery is contraindicated in cases of clinically significant portal hypertension but otherwise can be performed at a center with cirrhosis expertise. Sleeve gastrectomy at the same time as liver transplantation is also an option for select patients with obesity.
Elective cholecystectomy should be avoided, and required cases should be performed in experienced centers. “The gallbladder wall may appear thickened on imaging, which may lead to the erroneous diagnosis of acute cholecystitis,” the experts noted. Hence, the diagnosis “should be made only in the appropriate clinical setting, usually in the presence of biliary pain.”
Hepatic decompensation after surgery can be severe enough to merit liver transplantation. There is no agreed-on MELD score that mandates liver transplant evaluation before elective surgery, but the experts recommend doing so if the MELD score is 15 or greater or if risk of mortality within 3 months after surgery exceeds 15%.
Postoperative management of patients with cirrhosis should include aggressive measures to prevent portal hypertension. Monitor renal function closely and avoid volume depletion or overload, the experts advised. Patients should receive only short-acting benzodiazepines and lower opiate doses, administered less often, than in the general population. Avoiding constipation is vital to minimize hepatic encephalopathy, which makes oral rifaximin a better choice than lactulose. Patients should not receive NSAIDs, which can impair renal blood flow. To prevent liver toxicity, they should not be discharged on opiate/acetaminophen combinations, which they might unknowingly take along with another drug that contains acetaminophen.
The experts disclosed no external funding sources and reported having no conflicts of interest.
SOURCE: Northup PG et al. Clin Gastroenterol Hepatol. 2018 Sep 28. doi: 10.1016/j.cgh.2018.09.043.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
AGA Clinical Practice Update: Changing utility of serology and histologic measures in celiac disease
For children and adolescents with strong clinical suspicion for celiac disease, repeated transglutaminase-2-IgA (TG2-IgA) levels that are more than 10 times higher than the upper limit of normal often suffices for diagnosis, according to an American Gastroenterological Association clinical practice update and expert review.
This approach precludes the need for esophagogastroduodenoscopy (EGD) in about 30%-50% of cases, wrote Steffen Husby, MD, PhD, of Odense University Hospital (Denmark), together with his associates in Gastroenterology. “When such a strongly positive TG2-IgA is combined with a positive endomysial antibody in a second blood sample, the positive predictive value for celiac disease is virtually 100%.” But for adults, they recommend confirmatory histologic analysis of duodenal biopsies with Marsh classification, counting of lymphocytes per high-power field, and morphometry.
Transglutaminase-2 is the major autoantigen present in celiac disease and can now be assessed with accurate, convenient, high-throughput tests, such as enzyme-linked immunosorbent assays. To maximize test TG2-IgA accuracy, Dr. Husby and his associates recommend testing patients who have compatible signs and symptoms of celiac disease or are asymptomatic but have other risk factors, such as confirmed autoimmune diseases (type 1 diabetes, autoimmune thyroid or liver diseases), chromosome abnormalities (Down or Turner syndrome), or first-degree relatives with celiac disease.
Several other serologic tests are available but have a more limited role in diagnosing celiac disease, according to the practice update. Perhaps most useful is the endomysial antibody (EMA) test, which evaluates tissue-bound TG2-IgA. This test is highly specific but labor-intensive and user-sensitive and thus is best used to confirm a positive TG2-IgA result. Deamidated gliadin peptide antibody assays are less accurate than TG2-IgA, while HLA-DQ2/DQ8 testing is best reserved for cases where the diagnosis is complicated by a prior gluten-free diet or inconclusive antibody titers or histology.
For adults from populations with less than a 5% prevalence of celiac disease, all guidelines recommend following serology with confirmatory biopsy, and the experts concur. If biopsy was part of the initial work-up, they recommend performing confirmatory serology before starting a gluten-free diet. If the biopsy was negative but celiac disease is strongly suspected, they recommend TG2-IgA testing followed by repeat biopsies, when possible, either at the same time or in the future.
For children with suspected celiac disease, the North American Society for Pediatric Gastroenterology Hepatology and Nutrition recommends starting with biopsy, while the European Society for Paediatric Gastroenterology Hepatology and Nutrition suggests starting with quantitative TG2-IgA testing, followed by TG2-IgA, EMA, or HLA-DQ2/DQ8 assays if TG2-IgA is 10 times higher than the upper limit of normal. However, EGD with biopsies and even a gluten challenge may be needed if serology results are unclear, the experts state. They recommend against gluten-free or low-gluten diets prior to diagnosis, since these can lower the sensitivity of both histology and serology. If a patient has unclear test results and is already on a gluten-free diet, they suggest resuming eating three slices of wheat bread daily for 1-3 months, followed by TG2-IgA testing.
A small but important subgroup of patients have strong suspicion for celiac disease but are negative on IgA isotype tests because of IgA deficiency. In such suspected cases, the experts recommend measuring total IgA, IgG deamidated gliadin antibodies, and TG2-IgG levels. They note that IgG isotype testing for TG2 antibodies is not celiac specific outside the setting of IgA deficiency.
Serology has a useful but more limited role in managing celiac disease, according to the practice update. Negative TG2-IgA and other serology does not guarantee that the intestinal mucosa has healed, so patients with ongoing or relapsing symptoms without another obvious cause should have repeat biopsies. However, serology that stays positive over time usually indicates ongoing mucosal damage and gluten exposure, so these follow-up tests are appropriate 6 and 12 months after diagnosing celiac disease and yearly thereafter.
Dr. Husby reported receiving grant support from the University of Southern Denmark, the Region of Southern Denmark, and the Novo Nordisk Research Fund. He also reported receiving payments from Thermo Fisher Scientific and an advisory relationship with Inova. Two coauthors reported ties to Alba Therapeutics, Celimmune, Intrexon, GlaxoSmithKline, and several other pharmaceutical companies.
SOURCE: Husby S et al. Gastroenterology. 2018 Dec 19. doi: 10.1053/j.gastro.2018.12.010.
For children and adolescents with strong clinical suspicion for celiac disease, repeated transglutaminase-2-IgA (TG2-IgA) levels that are more than 10 times higher than the upper limit of normal often suffices for diagnosis, according to an American Gastroenterological Association clinical practice update and expert review.
This approach precludes the need for esophagogastroduodenoscopy (EGD) in about 30%-50% of cases, wrote Steffen Husby, MD, PhD, of Odense University Hospital (Denmark), together with his associates in Gastroenterology. “When such a strongly positive TG2-IgA is combined with a positive endomysial antibody in a second blood sample, the positive predictive value for celiac disease is virtually 100%.” But for adults, they recommend confirmatory histologic analysis of duodenal biopsies with Marsh classification, counting of lymphocytes per high-power field, and morphometry.
Transglutaminase-2 is the major autoantigen present in celiac disease and can now be assessed with accurate, convenient, high-throughput tests, such as enzyme-linked immunosorbent assays. To maximize test TG2-IgA accuracy, Dr. Husby and his associates recommend testing patients who have compatible signs and symptoms of celiac disease or are asymptomatic but have other risk factors, such as confirmed autoimmune diseases (type 1 diabetes, autoimmune thyroid or liver diseases), chromosome abnormalities (Down or Turner syndrome), or first-degree relatives with celiac disease.
Several other serologic tests are available but have a more limited role in diagnosing celiac disease, according to the practice update. Perhaps most useful is the endomysial antibody (EMA) test, which evaluates tissue-bound TG2-IgA. This test is highly specific but labor-intensive and user-sensitive and thus is best used to confirm a positive TG2-IgA result. Deamidated gliadin peptide antibody assays are less accurate than TG2-IgA, while HLA-DQ2/DQ8 testing is best reserved for cases where the diagnosis is complicated by a prior gluten-free diet or inconclusive antibody titers or histology.
For adults from populations with less than a 5% prevalence of celiac disease, all guidelines recommend following serology with confirmatory biopsy, and the experts concur. If biopsy was part of the initial work-up, they recommend performing confirmatory serology before starting a gluten-free diet. If the biopsy was negative but celiac disease is strongly suspected, they recommend TG2-IgA testing followed by repeat biopsies, when possible, either at the same time or in the future.
For children with suspected celiac disease, the North American Society for Pediatric Gastroenterology Hepatology and Nutrition recommends starting with biopsy, while the European Society for Paediatric Gastroenterology Hepatology and Nutrition suggests starting with quantitative TG2-IgA testing, followed by TG2-IgA, EMA, or HLA-DQ2/DQ8 assays if TG2-IgA is 10 times higher than the upper limit of normal. However, EGD with biopsies and even a gluten challenge may be needed if serology results are unclear, the experts state. They recommend against gluten-free or low-gluten diets prior to diagnosis, since these can lower the sensitivity of both histology and serology. If a patient has unclear test results and is already on a gluten-free diet, they suggest resuming eating three slices of wheat bread daily for 1-3 months, followed by TG2-IgA testing.
A small but important subgroup of patients have strong suspicion for celiac disease but are negative on IgA isotype tests because of IgA deficiency. In such suspected cases, the experts recommend measuring total IgA, IgG deamidated gliadin antibodies, and TG2-IgG levels. They note that IgG isotype testing for TG2 antibodies is not celiac specific outside the setting of IgA deficiency.
Serology has a useful but more limited role in managing celiac disease, according to the practice update. Negative TG2-IgA and other serology does not guarantee that the intestinal mucosa has healed, so patients with ongoing or relapsing symptoms without another obvious cause should have repeat biopsies. However, serology that stays positive over time usually indicates ongoing mucosal damage and gluten exposure, so these follow-up tests are appropriate 6 and 12 months after diagnosing celiac disease and yearly thereafter.
Dr. Husby reported receiving grant support from the University of Southern Denmark, the Region of Southern Denmark, and the Novo Nordisk Research Fund. He also reported receiving payments from Thermo Fisher Scientific and an advisory relationship with Inova. Two coauthors reported ties to Alba Therapeutics, Celimmune, Intrexon, GlaxoSmithKline, and several other pharmaceutical companies.
SOURCE: Husby S et al. Gastroenterology. 2018 Dec 19. doi: 10.1053/j.gastro.2018.12.010.
For children and adolescents with strong clinical suspicion for celiac disease, repeated transglutaminase-2-IgA (TG2-IgA) levels that are more than 10 times higher than the upper limit of normal often suffices for diagnosis, according to an American Gastroenterological Association clinical practice update and expert review.
This approach precludes the need for esophagogastroduodenoscopy (EGD) in about 30%-50% of cases, wrote Steffen Husby, MD, PhD, of Odense University Hospital (Denmark), together with his associates in Gastroenterology. “When such a strongly positive TG2-IgA is combined with a positive endomysial antibody in a second blood sample, the positive predictive value for celiac disease is virtually 100%.” But for adults, they recommend confirmatory histologic analysis of duodenal biopsies with Marsh classification, counting of lymphocytes per high-power field, and morphometry.
Transglutaminase-2 is the major autoantigen present in celiac disease and can now be assessed with accurate, convenient, high-throughput tests, such as enzyme-linked immunosorbent assays. To maximize test TG2-IgA accuracy, Dr. Husby and his associates recommend testing patients who have compatible signs and symptoms of celiac disease or are asymptomatic but have other risk factors, such as confirmed autoimmune diseases (type 1 diabetes, autoimmune thyroid or liver diseases), chromosome abnormalities (Down or Turner syndrome), or first-degree relatives with celiac disease.
Several other serologic tests are available but have a more limited role in diagnosing celiac disease, according to the practice update. Perhaps most useful is the endomysial antibody (EMA) test, which evaluates tissue-bound TG2-IgA. This test is highly specific but labor-intensive and user-sensitive and thus is best used to confirm a positive TG2-IgA result. Deamidated gliadin peptide antibody assays are less accurate than TG2-IgA, while HLA-DQ2/DQ8 testing is best reserved for cases where the diagnosis is complicated by a prior gluten-free diet or inconclusive antibody titers or histology.
For adults from populations with less than a 5% prevalence of celiac disease, all guidelines recommend following serology with confirmatory biopsy, and the experts concur. If biopsy was part of the initial work-up, they recommend performing confirmatory serology before starting a gluten-free diet. If the biopsy was negative but celiac disease is strongly suspected, they recommend TG2-IgA testing followed by repeat biopsies, when possible, either at the same time or in the future.
For children with suspected celiac disease, the North American Society for Pediatric Gastroenterology Hepatology and Nutrition recommends starting with biopsy, while the European Society for Paediatric Gastroenterology Hepatology and Nutrition suggests starting with quantitative TG2-IgA testing, followed by TG2-IgA, EMA, or HLA-DQ2/DQ8 assays if TG2-IgA is 10 times higher than the upper limit of normal. However, EGD with biopsies and even a gluten challenge may be needed if serology results are unclear, the experts state. They recommend against gluten-free or low-gluten diets prior to diagnosis, since these can lower the sensitivity of both histology and serology. If a patient has unclear test results and is already on a gluten-free diet, they suggest resuming eating three slices of wheat bread daily for 1-3 months, followed by TG2-IgA testing.
A small but important subgroup of patients have strong suspicion for celiac disease but are negative on IgA isotype tests because of IgA deficiency. In such suspected cases, the experts recommend measuring total IgA, IgG deamidated gliadin antibodies, and TG2-IgG levels. They note that IgG isotype testing for TG2 antibodies is not celiac specific outside the setting of IgA deficiency.
Serology has a useful but more limited role in managing celiac disease, according to the practice update. Negative TG2-IgA and other serology does not guarantee that the intestinal mucosa has healed, so patients with ongoing or relapsing symptoms without another obvious cause should have repeat biopsies. However, serology that stays positive over time usually indicates ongoing mucosal damage and gluten exposure, so these follow-up tests are appropriate 6 and 12 months after diagnosing celiac disease and yearly thereafter.
Dr. Husby reported receiving grant support from the University of Southern Denmark, the Region of Southern Denmark, and the Novo Nordisk Research Fund. He also reported receiving payments from Thermo Fisher Scientific and an advisory relationship with Inova. Two coauthors reported ties to Alba Therapeutics, Celimmune, Intrexon, GlaxoSmithKline, and several other pharmaceutical companies.
SOURCE: Husby S et al. Gastroenterology. 2018 Dec 19. doi: 10.1053/j.gastro.2018.12.010.
FROM GASTROENTEROLOGY
Interactive online module improved detection of Barrett’s esophagus neoplasia
An online educational tool for endoscopists helped improve their detection of Barrett’s esophagus–related neoplasia (BORN), researchers reported in the April issue of Gastroenterology.
In tests administered before and after training, endoscopists increased their rates of BORN detection by a median of 30% (P less than .001), reported J.J. Bergman, MD, PhD, of the University of Amsterdam, together with his associates. “To our knowledge, this is the first validated online, interactive endoscopic training program in our field,” they wrote. “Widespread use of this tool might improve management of Barrett’s esophagus by general endoscopists.”
To develop the program, the investigators recorded high-definition videos of upper endoscopies of patients with either BORN or nondysplastic Barrett’s esophagus. They sent these videos to three experts, who used special tools to superimpose their delineations of lesions.
Next, 68 general endoscopists (fellows, early-career general gastroenterologists, and senior general gastroenterologists) watched four batches of 20 videos each. The researchers compared the assessors’ interpretations with the experts’ to identify the 25 videos with the most educational impact. These were then shown in four batches of five to 121 new assessors (five videos were reserved for pre- and post testing).
From the first to the fourth batch of training videos, assessors sequentially improved their scores for detection, delineation, agreement delineation, and relative delineation of BORN, the researchers said. Among the 121 assessors in the second phase of development, median rates of detection of BORN rose by 30% after training. Furthermore, from baseline to the end of the study, scores rose by 46% for detection, 129% for delineation, 105% for agreement delineation, and 106% for relative delineation (all P less than .001). These improvements did not depend on the country of origin of the assessors or their level of endoscopic experience.
This module requires the use of high-definition videos whose resolution is not lost during replay or when viewed on the web, the researchers emphasized. They noted that the module is active, not passive – learners select the video frame to position a biopsy mark and delineate the lesion, and the software then gives them tailored feedback on their choice. Learners also can add and remove the experts’ delineations as well as their own during feedback sessions at the end of each batch of videos. This enables them to “fully appreciate the subtle appearance of the lesion on the selected time frame,” the investigators wrote.
By completing the training module, “general endoscopists with a wide range of experience and from different countries of origin can substantially and conveniently increase their skills for detection and delineation of early BORN lesions,” they concluded. “Therefore, the module could provide training in an essential upper gastrointestinal endoscopic skill that is not otherwise readily available.”
The investigators disclosed no external funding sources. They reported having no conflicts of interest.
SOURCE: Bergman JJ et al. Gastroenterology. 2019 Jan 2. doi: 10.1053/j.gastro.2018.12.021.
Endoscopic mucosal resection and ablation strategies offer the potential for minimally invasive, curative treatment for patients with Barrett’s esophagus–associated intramucosal neoplasia. For the gastroenterologist interested in endoscopic prevention and management of esophageal cancer, however, achieving proficiency in performance of these endoscopic techniques represents only part of the requisite preparatory experience. Acquisition of cognitive skills in lesion recognition is a fundamental and underappreciated component to a successful endoscopic treatment paradigm.
General endoscopist assessors were grouped into three groups based on level of experience. Following completion of the training module, scores in lesion detection and delineation increased irrespective of level of endoscopist experience.
The module is free, CME-accredited, and available for online use. Any endoscopist who performs Barrett’s screening, surveillance, and therapy should be motivated and incentivized to engage with this important educational tool.
Patrick Yachimski, MD, MPH, AGAF, is associate professor of medicine, director of pancreatobiliary endoscopy, division of gastroenterology, hepatology & nutrition, Vanderbilt University Medical Center, Nashville, Tenn. He has no conflicts.
Endoscopic mucosal resection and ablation strategies offer the potential for minimally invasive, curative treatment for patients with Barrett’s esophagus–associated intramucosal neoplasia. For the gastroenterologist interested in endoscopic prevention and management of esophageal cancer, however, achieving proficiency in performance of these endoscopic techniques represents only part of the requisite preparatory experience. Acquisition of cognitive skills in lesion recognition is a fundamental and underappreciated component to a successful endoscopic treatment paradigm.
General endoscopist assessors were grouped into three groups based on level of experience. Following completion of the training module, scores in lesion detection and delineation increased irrespective of level of endoscopist experience.
The module is free, CME-accredited, and available for online use. Any endoscopist who performs Barrett’s screening, surveillance, and therapy should be motivated and incentivized to engage with this important educational tool.
Patrick Yachimski, MD, MPH, AGAF, is associate professor of medicine, director of pancreatobiliary endoscopy, division of gastroenterology, hepatology & nutrition, Vanderbilt University Medical Center, Nashville, Tenn. He has no conflicts.
Endoscopic mucosal resection and ablation strategies offer the potential for minimally invasive, curative treatment for patients with Barrett’s esophagus–associated intramucosal neoplasia. For the gastroenterologist interested in endoscopic prevention and management of esophageal cancer, however, achieving proficiency in performance of these endoscopic techniques represents only part of the requisite preparatory experience. Acquisition of cognitive skills in lesion recognition is a fundamental and underappreciated component to a successful endoscopic treatment paradigm.
General endoscopist assessors were grouped into three groups based on level of experience. Following completion of the training module, scores in lesion detection and delineation increased irrespective of level of endoscopist experience.
The module is free, CME-accredited, and available for online use. Any endoscopist who performs Barrett’s screening, surveillance, and therapy should be motivated and incentivized to engage with this important educational tool.
Patrick Yachimski, MD, MPH, AGAF, is associate professor of medicine, director of pancreatobiliary endoscopy, division of gastroenterology, hepatology & nutrition, Vanderbilt University Medical Center, Nashville, Tenn. He has no conflicts.
An online educational tool for endoscopists helped improve their detection of Barrett’s esophagus–related neoplasia (BORN), researchers reported in the April issue of Gastroenterology.
In tests administered before and after training, endoscopists increased their rates of BORN detection by a median of 30% (P less than .001), reported J.J. Bergman, MD, PhD, of the University of Amsterdam, together with his associates. “To our knowledge, this is the first validated online, interactive endoscopic training program in our field,” they wrote. “Widespread use of this tool might improve management of Barrett’s esophagus by general endoscopists.”
To develop the program, the investigators recorded high-definition videos of upper endoscopies of patients with either BORN or nondysplastic Barrett’s esophagus. They sent these videos to three experts, who used special tools to superimpose their delineations of lesions.
Next, 68 general endoscopists (fellows, early-career general gastroenterologists, and senior general gastroenterologists) watched four batches of 20 videos each. The researchers compared the assessors’ interpretations with the experts’ to identify the 25 videos with the most educational impact. These were then shown in four batches of five to 121 new assessors (five videos were reserved for pre- and post testing).
From the first to the fourth batch of training videos, assessors sequentially improved their scores for detection, delineation, agreement delineation, and relative delineation of BORN, the researchers said. Among the 121 assessors in the second phase of development, median rates of detection of BORN rose by 30% after training. Furthermore, from baseline to the end of the study, scores rose by 46% for detection, 129% for delineation, 105% for agreement delineation, and 106% for relative delineation (all P less than .001). These improvements did not depend on the country of origin of the assessors or their level of endoscopic experience.
This module requires the use of high-definition videos whose resolution is not lost during replay or when viewed on the web, the researchers emphasized. They noted that the module is active, not passive – learners select the video frame to position a biopsy mark and delineate the lesion, and the software then gives them tailored feedback on their choice. Learners also can add and remove the experts’ delineations as well as their own during feedback sessions at the end of each batch of videos. This enables them to “fully appreciate the subtle appearance of the lesion on the selected time frame,” the investigators wrote.
By completing the training module, “general endoscopists with a wide range of experience and from different countries of origin can substantially and conveniently increase their skills for detection and delineation of early BORN lesions,” they concluded. “Therefore, the module could provide training in an essential upper gastrointestinal endoscopic skill that is not otherwise readily available.”
The investigators disclosed no external funding sources. They reported having no conflicts of interest.
SOURCE: Bergman JJ et al. Gastroenterology. 2019 Jan 2. doi: 10.1053/j.gastro.2018.12.021.
An online educational tool for endoscopists helped improve their detection of Barrett’s esophagus–related neoplasia (BORN), researchers reported in the April issue of Gastroenterology.
In tests administered before and after training, endoscopists increased their rates of BORN detection by a median of 30% (P less than .001), reported J.J. Bergman, MD, PhD, of the University of Amsterdam, together with his associates. “To our knowledge, this is the first validated online, interactive endoscopic training program in our field,” they wrote. “Widespread use of this tool might improve management of Barrett’s esophagus by general endoscopists.”
To develop the program, the investigators recorded high-definition videos of upper endoscopies of patients with either BORN or nondysplastic Barrett’s esophagus. They sent these videos to three experts, who used special tools to superimpose their delineations of lesions.
Next, 68 general endoscopists (fellows, early-career general gastroenterologists, and senior general gastroenterologists) watched four batches of 20 videos each. The researchers compared the assessors’ interpretations with the experts’ to identify the 25 videos with the most educational impact. These were then shown in four batches of five to 121 new assessors (five videos were reserved for pre- and post testing).
From the first to the fourth batch of training videos, assessors sequentially improved their scores for detection, delineation, agreement delineation, and relative delineation of BORN, the researchers said. Among the 121 assessors in the second phase of development, median rates of detection of BORN rose by 30% after training. Furthermore, from baseline to the end of the study, scores rose by 46% for detection, 129% for delineation, 105% for agreement delineation, and 106% for relative delineation (all P less than .001). These improvements did not depend on the country of origin of the assessors or their level of endoscopic experience.
This module requires the use of high-definition videos whose resolution is not lost during replay or when viewed on the web, the researchers emphasized. They noted that the module is active, not passive – learners select the video frame to position a biopsy mark and delineate the lesion, and the software then gives them tailored feedback on their choice. Learners also can add and remove the experts’ delineations as well as their own during feedback sessions at the end of each batch of videos. This enables them to “fully appreciate the subtle appearance of the lesion on the selected time frame,” the investigators wrote.
By completing the training module, “general endoscopists with a wide range of experience and from different countries of origin can substantially and conveniently increase their skills for detection and delineation of early BORN lesions,” they concluded. “Therefore, the module could provide training in an essential upper gastrointestinal endoscopic skill that is not otherwise readily available.”
The investigators disclosed no external funding sources. They reported having no conflicts of interest.
SOURCE: Bergman JJ et al. Gastroenterology. 2019 Jan 2. doi: 10.1053/j.gastro.2018.12.021.
FROM GASTROENTEROLOGY
Barrett’s esophagus uncommon in patients with uncomplicated GERD
Uncomplicated gastroesophageal reflux disease (GERD) accounted for 13.5% of esophagogastroduodenoscopies, but 5.6% of these patients had suspected Barrett’s esophagus and only 1.4% had suspected long-segment Barrett’s esophagus, researchers reported. The study appears in the April issue of Clinical Gastroenterology and Hepatology.
“The prevalence of suspected Barrett’s esophagus is lower than in prior time periods. This raises questions about the utility of esophagogastroduodenoscopies to detect Barrett’s esophagus in patients with uncomplicated GERD,” wrote Emery C. Lin, MD, of Oregon Health and Science University, Portland, and his associates there and at Massachusetts General Hospital, Boston.
Symptoms of GERD affect more than one in four U.S. adults and are a risk factor for Barrett’s esophagus. However, the prevalence of Barrett’s esophagus is unclear in patients with dysphagia and in the era of proton pump inhibitors, the researchers said. The American Gastroenterological Association strongly discourages reflexively screening patients with GERD for Barrett’s esophagus, but “weakly recommends” screening GERD patients with multiple risk factors for Barrett’s esophagus, including chronic GERD, hiatal hernia, older age (50 years and up), white race, male sex, increased body mass index, and intra-abdominal adiposity.
To understand the prevalence and findings of esophagogastroduodenoscopy in patients with GERD without alarm symptoms (including weight loss, dysphagia, and bleeding), the investigators studied 543,103 of these procedures performed at 82 sites in the United States between 2003 and 2013. The data came from the National Endoscopic Database, which generates endoscopy reports using a structured computer form.
A total of 73,535 esophagogastroduodenoscopies (13.5%) were performed for GERD without alarm symptoms. Among these patients, 4,122 (5.6%) had suspected Barrett’s esophagus, of which 24.2% had suspected long-segment Barrett’s esophagus (3 cm or longer). Among patients with uncomplicated GERD, the prevalence of suspected Barrett’s esophagus was 5.6%, and the prevalence of long-segment disease was 1.4%.
Although male sex, older age, and white race were significant risk factors for suspected Barrett’s esophagus and suspected long-segment disease, 23.6% of esophagogastroduodenoscopies were performed in white men older than 50 years. “We find that low-risk populations with uncomplicated GERD make up a significant number of esophagogastroduodenoscopies done for uncomplicated GERD,” the investigators wrote. “If esophagogastroduodenoscopies were limited to patients that met the AGA criteria of being male, white, and age over 50, we would have detected 34 of 47 (72.3%) of esophageal tumors and found suspected Barrett’s esophagus in nearly 10%, while reducing the burden of endoscopy by more than 75%.”
Hiatal hernia was a significant correlate of suspected Barrett’s esophagus (odds ratio, 1.6), the researchers noted. Esophagitis was not associated with suspected Barrett’s esophagus overall but did correlate with long-segment disease. Esophagitis might mask underlying short-segment Barrett’s esophagus, and short-segment Barrett’s esophagus might be milder in nature and more responsive to antisecretory therapy, the researchers said. They noted that severe (grade C/D) esophagitis was strongly linked with both short-segment and long-segment Barrett’s esophagus.
The National Institute of Diabetes and Digestive and Kidney Diseases provided funding. The researchers reported having no conflicts of interest.
SOURCE: Lin EC et al. Clin Gastroenterol Hepatol. 2019 Apr. doi: 10.1016/j.cgh.2018.08.066.
The utility and cost-effectiveness of screening for Barrett’s esophagus with esophagogastroduodenoscopy (EGD) remain contentious issues. National GI societies currently recommend screening in only a limited high-risk population, mainly white men aged 50 or older with chronic GERD and one or more additional risk factors. It is unclear to what degree those guidelines are adhered to in clinical practice. This study by Lin et al. sheds further light on this issue. The investigators showed that a significant proportion (more than 10%) of EGDs were performed for uncomplicated GERD, with less than one-quarter of those patients meeting the minimal criteria for screening for Barrett’s esophagus. Among this group, the prevalence of Barrett’s esophagus was found to be lower than previously reported. The data offer compelling evidence that screening low-risk patients with uncomplicated GERD by using upper endoscopy is not cost effective, and is at best marginally cost effective if limited to the high-risk group identified by national GI societies. The question arises whether we should abandon screening for Barrett’s esophagus altogether.
The challenge, however, is that the incidence of esophageal adenocarcinoma continues to rise (albeit at a slower pace in recent years), and 5-year survival of patients diagnosed with esophageal adenocarcinoma remains extremely poor. Therefore, prevention remains the optimal strategy. The solution may lie in adopting a lower-cost screening modality that can replace endoscopy for this purpose, and while many such techniques are under investigation, further studies are required to find a widely applicable alternative to EGD.
Nabil M. Mansour, MD, is an assistant professor, department of medicine, section of gastroenterology and hepatology, Baylor College of Medicine, Houston. He has no conflicts of interest.
The utility and cost-effectiveness of screening for Barrett’s esophagus with esophagogastroduodenoscopy (EGD) remain contentious issues. National GI societies currently recommend screening in only a limited high-risk population, mainly white men aged 50 or older with chronic GERD and one or more additional risk factors. It is unclear to what degree those guidelines are adhered to in clinical practice. This study by Lin et al. sheds further light on this issue. The investigators showed that a significant proportion (more than 10%) of EGDs were performed for uncomplicated GERD, with less than one-quarter of those patients meeting the minimal criteria for screening for Barrett’s esophagus. Among this group, the prevalence of Barrett’s esophagus was found to be lower than previously reported. The data offer compelling evidence that screening low-risk patients with uncomplicated GERD by using upper endoscopy is not cost effective, and is at best marginally cost effective if limited to the high-risk group identified by national GI societies. The question arises whether we should abandon screening for Barrett’s esophagus altogether.
The challenge, however, is that the incidence of esophageal adenocarcinoma continues to rise (albeit at a slower pace in recent years), and 5-year survival of patients diagnosed with esophageal adenocarcinoma remains extremely poor. Therefore, prevention remains the optimal strategy. The solution may lie in adopting a lower-cost screening modality that can replace endoscopy for this purpose, and while many such techniques are under investigation, further studies are required to find a widely applicable alternative to EGD.
Nabil M. Mansour, MD, is an assistant professor, department of medicine, section of gastroenterology and hepatology, Baylor College of Medicine, Houston. He has no conflicts of interest.
The utility and cost-effectiveness of screening for Barrett’s esophagus with esophagogastroduodenoscopy (EGD) remain contentious issues. National GI societies currently recommend screening in only a limited high-risk population, mainly white men aged 50 or older with chronic GERD and one or more additional risk factors. It is unclear to what degree those guidelines are adhered to in clinical practice. This study by Lin et al. sheds further light on this issue. The investigators showed that a significant proportion (more than 10%) of EGDs were performed for uncomplicated GERD, with less than one-quarter of those patients meeting the minimal criteria for screening for Barrett’s esophagus. Among this group, the prevalence of Barrett’s esophagus was found to be lower than previously reported. The data offer compelling evidence that screening low-risk patients with uncomplicated GERD by using upper endoscopy is not cost effective, and is at best marginally cost effective if limited to the high-risk group identified by national GI societies. The question arises whether we should abandon screening for Barrett’s esophagus altogether.
The challenge, however, is that the incidence of esophageal adenocarcinoma continues to rise (albeit at a slower pace in recent years), and 5-year survival of patients diagnosed with esophageal adenocarcinoma remains extremely poor. Therefore, prevention remains the optimal strategy. The solution may lie in adopting a lower-cost screening modality that can replace endoscopy for this purpose, and while many such techniques are under investigation, further studies are required to find a widely applicable alternative to EGD.
Nabil M. Mansour, MD, is an assistant professor, department of medicine, section of gastroenterology and hepatology, Baylor College of Medicine, Houston. He has no conflicts of interest.
Uncomplicated gastroesophageal reflux disease (GERD) accounted for 13.5% of esophagogastroduodenoscopies, but 5.6% of these patients had suspected Barrett’s esophagus and only 1.4% had suspected long-segment Barrett’s esophagus, researchers reported. The study appears in the April issue of Clinical Gastroenterology and Hepatology.
“The prevalence of suspected Barrett’s esophagus is lower than in prior time periods. This raises questions about the utility of esophagogastroduodenoscopies to detect Barrett’s esophagus in patients with uncomplicated GERD,” wrote Emery C. Lin, MD, of Oregon Health and Science University, Portland, and his associates there and at Massachusetts General Hospital, Boston.
Symptoms of GERD affect more than one in four U.S. adults and are a risk factor for Barrett’s esophagus. However, the prevalence of Barrett’s esophagus is unclear in patients with dysphagia and in the era of proton pump inhibitors, the researchers said. The American Gastroenterological Association strongly discourages reflexively screening patients with GERD for Barrett’s esophagus, but “weakly recommends” screening GERD patients with multiple risk factors for Barrett’s esophagus, including chronic GERD, hiatal hernia, older age (50 years and up), white race, male sex, increased body mass index, and intra-abdominal adiposity.
To understand the prevalence and findings of esophagogastroduodenoscopy in patients with GERD without alarm symptoms (including weight loss, dysphagia, and bleeding), the investigators studied 543,103 of these procedures performed at 82 sites in the United States between 2003 and 2013. The data came from the National Endoscopic Database, which generates endoscopy reports using a structured computer form.
A total of 73,535 esophagogastroduodenoscopies (13.5%) were performed for GERD without alarm symptoms. Among these patients, 4,122 (5.6%) had suspected Barrett’s esophagus, of which 24.2% had suspected long-segment Barrett’s esophagus (3 cm or longer). Among patients with uncomplicated GERD, the prevalence of suspected Barrett’s esophagus was 5.6%, and the prevalence of long-segment disease was 1.4%.
Although male sex, older age, and white race were significant risk factors for suspected Barrett’s esophagus and suspected long-segment disease, 23.6% of esophagogastroduodenoscopies were performed in white men older than 50 years. “We find that low-risk populations with uncomplicated GERD make up a significant number of esophagogastroduodenoscopies done for uncomplicated GERD,” the investigators wrote. “If esophagogastroduodenoscopies were limited to patients that met the AGA criteria of being male, white, and age over 50, we would have detected 34 of 47 (72.3%) of esophageal tumors and found suspected Barrett’s esophagus in nearly 10%, while reducing the burden of endoscopy by more than 75%.”
Hiatal hernia was a significant correlate of suspected Barrett’s esophagus (odds ratio, 1.6), the researchers noted. Esophagitis was not associated with suspected Barrett’s esophagus overall but did correlate with long-segment disease. Esophagitis might mask underlying short-segment Barrett’s esophagus, and short-segment Barrett’s esophagus might be milder in nature and more responsive to antisecretory therapy, the researchers said. They noted that severe (grade C/D) esophagitis was strongly linked with both short-segment and long-segment Barrett’s esophagus.
The National Institute of Diabetes and Digestive and Kidney Diseases provided funding. The researchers reported having no conflicts of interest.
SOURCE: Lin EC et al. Clin Gastroenterol Hepatol. 2019 Apr. doi: 10.1016/j.cgh.2018.08.066.
Uncomplicated gastroesophageal reflux disease (GERD) accounted for 13.5% of esophagogastroduodenoscopies, but 5.6% of these patients had suspected Barrett’s esophagus and only 1.4% had suspected long-segment Barrett’s esophagus, researchers reported. The study appears in the April issue of Clinical Gastroenterology and Hepatology.
“The prevalence of suspected Barrett’s esophagus is lower than in prior time periods. This raises questions about the utility of esophagogastroduodenoscopies to detect Barrett’s esophagus in patients with uncomplicated GERD,” wrote Emery C. Lin, MD, of Oregon Health and Science University, Portland, and his associates there and at Massachusetts General Hospital, Boston.
Symptoms of GERD affect more than one in four U.S. adults and are a risk factor for Barrett’s esophagus. However, the prevalence of Barrett’s esophagus is unclear in patients with dysphagia and in the era of proton pump inhibitors, the researchers said. The American Gastroenterological Association strongly discourages reflexively screening patients with GERD for Barrett’s esophagus, but “weakly recommends” screening GERD patients with multiple risk factors for Barrett’s esophagus, including chronic GERD, hiatal hernia, older age (50 years and up), white race, male sex, increased body mass index, and intra-abdominal adiposity.
To understand the prevalence and findings of esophagogastroduodenoscopy in patients with GERD without alarm symptoms (including weight loss, dysphagia, and bleeding), the investigators studied 543,103 of these procedures performed at 82 sites in the United States between 2003 and 2013. The data came from the National Endoscopic Database, which generates endoscopy reports using a structured computer form.
A total of 73,535 esophagogastroduodenoscopies (13.5%) were performed for GERD without alarm symptoms. Among these patients, 4,122 (5.6%) had suspected Barrett’s esophagus, of which 24.2% had suspected long-segment Barrett’s esophagus (3 cm or longer). Among patients with uncomplicated GERD, the prevalence of suspected Barrett’s esophagus was 5.6%, and the prevalence of long-segment disease was 1.4%.
Although male sex, older age, and white race were significant risk factors for suspected Barrett’s esophagus and suspected long-segment disease, 23.6% of esophagogastroduodenoscopies were performed in white men older than 50 years. “We find that low-risk populations with uncomplicated GERD make up a significant number of esophagogastroduodenoscopies done for uncomplicated GERD,” the investigators wrote. “If esophagogastroduodenoscopies were limited to patients that met the AGA criteria of being male, white, and age over 50, we would have detected 34 of 47 (72.3%) of esophageal tumors and found suspected Barrett’s esophagus in nearly 10%, while reducing the burden of endoscopy by more than 75%.”
Hiatal hernia was a significant correlate of suspected Barrett’s esophagus (odds ratio, 1.6), the researchers noted. Esophagitis was not associated with suspected Barrett’s esophagus overall but did correlate with long-segment disease. Esophagitis might mask underlying short-segment Barrett’s esophagus, and short-segment Barrett’s esophagus might be milder in nature and more responsive to antisecretory therapy, the researchers said. They noted that severe (grade C/D) esophagitis was strongly linked with both short-segment and long-segment Barrett’s esophagus.
The National Institute of Diabetes and Digestive and Kidney Diseases provided funding. The researchers reported having no conflicts of interest.
SOURCE: Lin EC et al. Clin Gastroenterol Hepatol. 2019 Apr. doi: 10.1016/j.cgh.2018.08.066.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Acceptance and commitment therapy reduced IBD stress, depression
Eight weeks of a mindfulness intervention known as acceptance and commitment therapy (ACT) significantly improved stress and depression among patients with inflammatory bowel disease, and these improvements persisted for at least 12 weeks after therapy ended, according to the results of a randomized, controlled trial.
Source: The American Gastroenterological Association
In the intention-to-treat analysis, stress symptoms, as measured by the Depression Anxiety and Stress Scales (DASS-21), improved by 39% at week 8 and by 45% at week 20, reported Brona Wynne, PhD, of University College Dublin together with her associates. These improvements were highly significant compared with baseline and treatment as usual (P = .001 for both comparisons). “Post hoc analyses indicated that baseline stress levels were similar in control and treatment groups,” the researchers wrote in Gastroenterology. “The results of the per protocol analysis were comparable, with a 43% and 49% reduction in stress in the treatment group from baseline to 8 and 20 weeks.”
Multiple studies have documented high levels of stress and psychological dysfunction among patients with Crohn’s disease and ulcerative colitis. Studies of various mindfulness therapy, relaxation, stress management, cognitive-behavioral therapy, and hypnotherapy interventions often failed to collect key clinical data or were underpowered, uncontrolled, and unrandomized. Acceptance and commitment therapy uses mindfulness to identify adverse thoughts and experiences, accept these as part of life, and recommit to “move towards values that have been identified and adopted by the individual,” the investigators wrote. “This can be defined as the ability to contact the present moment more fully as a conscious human being and to change, or persist in, behavior when doing so serves valued ends.”
Their single-center study, which they said was the first to evaluate ACT in IBD patients, included 79 individuals with stable or mildly active Crohn’s disease (38 patients) or ulcerative colitis (41 patients) who were randomly assigned to ACT (37 patients) or control treatment as usual (42 patients). The two comparison groups were demographically and clinically similar. The ACT program involved eight 90-minute, weekly sessions of groups of 14-16 individuals, led by a single psychologist who tailored the course material toward IBD with a focus on lowering stress. An independent psychologist observed each session to assess adherence to protocol.
Not only did ACT meet the primary study endpoint, it also produced a 25% decrease in perceived stress (on a 1-10 scale) by week 8 and a 27% decrease in perceived stress by week 20 (P less than .001 versus treatment as usual). Depression scores in the ACT group also fell by 47% by week 8 and by 45% at week 20 (P = .01 versus treatment as usual). Anxiety levels decreased by 29% at week 8 and by 31% at week 20, but these improvements did not significantly differ from those in the control group (P = .39).
Interestingly, ACT did not significantly improve symptom burden, activities of daily living, disease-related worry, general well-being, C-reactive protein (CRP) levels, fecal calprotectin levels, or scores on the version used of the Clinical Assessment of Depression (CAD) or the short Mayo assessment. Hair cortisol levels showed an association with baseline stress and anxiety, but not with treatment response.
Care programs for IBD increasingly emphasize mental health services despite a lack of robust trials to support these interventions, the investigators noted. Thus, their findings highlight “the need for researchers and clinicians to further develop and optimize the content and delivery of psychological programs for IBD patients.”
Tillotts Pharma and Boston Scientific provided partial funding, but had no other role in the study. The researchers reported having no relevant conflicts of interest.
SOURCE: Wynne B et al. Gastroenterology. 2018 Nov 16. doi: 10.1053/j.gastro.2018.11.030.
Factors that affect stress level and mood symptoms are vast when it comes to living with inflammatory bowel disease (IBD). Comorbid mood symptoms are common in patients with IBD, and psychological interventions are increasingly recommended as part of holistic, multidisciplinary treatment planning. Additionally, patients are open to GI-focused psychology treatments given the recognition that the complexities of living with IBD strongly influence emotional factors.
What must be acknowledged is the importance of long-term adherence to skills learned during the 8 weeks of ACT. Stress and mood symptoms tend to be more prevalent during times of flare. Given the relapsing and remitting nature of IBD, it must be conveyed that patients will need to continue the practice of this mindfulness-based intervention in the long term. Future studies are encouraged to look at longitudinal data assessing the manner in which these patients used their skill set during periods of flare or disease-related stress.
Factors that affect stress level and mood symptoms are vast when it comes to living with inflammatory bowel disease (IBD). Comorbid mood symptoms are common in patients with IBD, and psychological interventions are increasingly recommended as part of holistic, multidisciplinary treatment planning. Additionally, patients are open to GI-focused psychology treatments given the recognition that the complexities of living with IBD strongly influence emotional factors.
What must be acknowledged is the importance of long-term adherence to skills learned during the 8 weeks of ACT. Stress and mood symptoms tend to be more prevalent during times of flare. Given the relapsing and remitting nature of IBD, it must be conveyed that patients will need to continue the practice of this mindfulness-based intervention in the long term. Future studies are encouraged to look at longitudinal data assessing the manner in which these patients used their skill set during periods of flare or disease-related stress.
Factors that affect stress level and mood symptoms are vast when it comes to living with inflammatory bowel disease (IBD). Comorbid mood symptoms are common in patients with IBD, and psychological interventions are increasingly recommended as part of holistic, multidisciplinary treatment planning. Additionally, patients are open to GI-focused psychology treatments given the recognition that the complexities of living with IBD strongly influence emotional factors.
What must be acknowledged is the importance of long-term adherence to skills learned during the 8 weeks of ACT. Stress and mood symptoms tend to be more prevalent during times of flare. Given the relapsing and remitting nature of IBD, it must be conveyed that patients will need to continue the practice of this mindfulness-based intervention in the long term. Future studies are encouraged to look at longitudinal data assessing the manner in which these patients used their skill set during periods of flare or disease-related stress.
Eight weeks of a mindfulness intervention known as acceptance and commitment therapy (ACT) significantly improved stress and depression among patients with inflammatory bowel disease, and these improvements persisted for at least 12 weeks after therapy ended, according to the results of a randomized, controlled trial.
Source: The American Gastroenterological Association
In the intention-to-treat analysis, stress symptoms, as measured by the Depression Anxiety and Stress Scales (DASS-21), improved by 39% at week 8 and by 45% at week 20, reported Brona Wynne, PhD, of University College Dublin together with her associates. These improvements were highly significant compared with baseline and treatment as usual (P = .001 for both comparisons). “Post hoc analyses indicated that baseline stress levels were similar in control and treatment groups,” the researchers wrote in Gastroenterology. “The results of the per protocol analysis were comparable, with a 43% and 49% reduction in stress in the treatment group from baseline to 8 and 20 weeks.”
Multiple studies have documented high levels of stress and psychological dysfunction among patients with Crohn’s disease and ulcerative colitis. Studies of various mindfulness therapy, relaxation, stress management, cognitive-behavioral therapy, and hypnotherapy interventions often failed to collect key clinical data or were underpowered, uncontrolled, and unrandomized. Acceptance and commitment therapy uses mindfulness to identify adverse thoughts and experiences, accept these as part of life, and recommit to “move towards values that have been identified and adopted by the individual,” the investigators wrote. “This can be defined as the ability to contact the present moment more fully as a conscious human being and to change, or persist in, behavior when doing so serves valued ends.”
Their single-center study, which they said was the first to evaluate ACT in IBD patients, included 79 individuals with stable or mildly active Crohn’s disease (38 patients) or ulcerative colitis (41 patients) who were randomly assigned to ACT (37 patients) or control treatment as usual (42 patients). The two comparison groups were demographically and clinically similar. The ACT program involved eight 90-minute, weekly sessions of groups of 14-16 individuals, led by a single psychologist who tailored the course material toward IBD with a focus on lowering stress. An independent psychologist observed each session to assess adherence to protocol.
Not only did ACT meet the primary study endpoint, it also produced a 25% decrease in perceived stress (on a 1-10 scale) by week 8 and a 27% decrease in perceived stress by week 20 (P less than .001 versus treatment as usual). Depression scores in the ACT group also fell by 47% by week 8 and by 45% at week 20 (P = .01 versus treatment as usual). Anxiety levels decreased by 29% at week 8 and by 31% at week 20, but these improvements did not significantly differ from those in the control group (P = .39).
Interestingly, ACT did not significantly improve symptom burden, activities of daily living, disease-related worry, general well-being, C-reactive protein (CRP) levels, fecal calprotectin levels, or scores on the version used of the Clinical Assessment of Depression (CAD) or the short Mayo assessment. Hair cortisol levels showed an association with baseline stress and anxiety, but not with treatment response.
Care programs for IBD increasingly emphasize mental health services despite a lack of robust trials to support these interventions, the investigators noted. Thus, their findings highlight “the need for researchers and clinicians to further develop and optimize the content and delivery of psychological programs for IBD patients.”
Tillotts Pharma and Boston Scientific provided partial funding, but had no other role in the study. The researchers reported having no relevant conflicts of interest.
SOURCE: Wynne B et al. Gastroenterology. 2018 Nov 16. doi: 10.1053/j.gastro.2018.11.030.
Eight weeks of a mindfulness intervention known as acceptance and commitment therapy (ACT) significantly improved stress and depression among patients with inflammatory bowel disease, and these improvements persisted for at least 12 weeks after therapy ended, according to the results of a randomized, controlled trial.
Source: The American Gastroenterological Association
In the intention-to-treat analysis, stress symptoms, as measured by the Depression Anxiety and Stress Scales (DASS-21), improved by 39% at week 8 and by 45% at week 20, reported Brona Wynne, PhD, of University College Dublin together with her associates. These improvements were highly significant compared with baseline and treatment as usual (P = .001 for both comparisons). “Post hoc analyses indicated that baseline stress levels were similar in control and treatment groups,” the researchers wrote in Gastroenterology. “The results of the per protocol analysis were comparable, with a 43% and 49% reduction in stress in the treatment group from baseline to 8 and 20 weeks.”
Multiple studies have documented high levels of stress and psychological dysfunction among patients with Crohn’s disease and ulcerative colitis. Studies of various mindfulness therapy, relaxation, stress management, cognitive-behavioral therapy, and hypnotherapy interventions often failed to collect key clinical data or were underpowered, uncontrolled, and unrandomized. Acceptance and commitment therapy uses mindfulness to identify adverse thoughts and experiences, accept these as part of life, and recommit to “move towards values that have been identified and adopted by the individual,” the investigators wrote. “This can be defined as the ability to contact the present moment more fully as a conscious human being and to change, or persist in, behavior when doing so serves valued ends.”
Their single-center study, which they said was the first to evaluate ACT in IBD patients, included 79 individuals with stable or mildly active Crohn’s disease (38 patients) or ulcerative colitis (41 patients) who were randomly assigned to ACT (37 patients) or control treatment as usual (42 patients). The two comparison groups were demographically and clinically similar. The ACT program involved eight 90-minute, weekly sessions of groups of 14-16 individuals, led by a single psychologist who tailored the course material toward IBD with a focus on lowering stress. An independent psychologist observed each session to assess adherence to protocol.
Not only did ACT meet the primary study endpoint, it also produced a 25% decrease in perceived stress (on a 1-10 scale) by week 8 and a 27% decrease in perceived stress by week 20 (P less than .001 versus treatment as usual). Depression scores in the ACT group also fell by 47% by week 8 and by 45% at week 20 (P = .01 versus treatment as usual). Anxiety levels decreased by 29% at week 8 and by 31% at week 20, but these improvements did not significantly differ from those in the control group (P = .39).
Interestingly, ACT did not significantly improve symptom burden, activities of daily living, disease-related worry, general well-being, C-reactive protein (CRP) levels, fecal calprotectin levels, or scores on the version used of the Clinical Assessment of Depression (CAD) or the short Mayo assessment. Hair cortisol levels showed an association with baseline stress and anxiety, but not with treatment response.
Care programs for IBD increasingly emphasize mental health services despite a lack of robust trials to support these interventions, the investigators noted. Thus, their findings highlight “the need for researchers and clinicians to further develop and optimize the content and delivery of psychological programs for IBD patients.”
Tillotts Pharma and Boston Scientific provided partial funding, but had no other role in the study. The researchers reported having no relevant conflicts of interest.
SOURCE: Wynne B et al. Gastroenterology. 2018 Nov 16. doi: 10.1053/j.gastro.2018.11.030.
FROM GASTROENTEROLOGY
Key clinical point: An 8-week course of acceptance and commitment therapy improved stress and depression in patients with inflammatory bowel disease.
Major finding: Compared with controls, the intervention group experienced significant improvements in stress (P = .001) and depression (P = .01), but not anxiety.
Study details: Randomized controlled trial of 79 patients.
Disclosures: Tillotts Pharma and Boston Scientific provided partial funding but had no other role in the study. The researchers reported having no relevant conflicts of interest.
Source: Wynne B et al. Gastroenterology. 2018 Nov 16. doi: 10.1053/j.gastro.2018.11.030.
Meta-analysis generally supports LI-RADS classification accuracy
Higher (more severe) Liver Imaging Reporting and Data System (LI-RADS) categories contained increasing proportions of hepatocellular carcinomas and overall malignancies, supporting the general reliability of the system, according to a systematic review and meta-analysis of 17 retrospective studies.
But 13% of LR-2 (“probably benign”) observations were actually hepatocellular carcinomas, as were 38% of LR-3 (“intermediate probability of malignancy”) observations, reported Christian B. van der Pol, MD, of McMaster University, Hamilton, Ont., and Christopher S. Lim, BBS, of Harvard Medical School, Boston, and their associates. Thus, clinicians should consider biopsy of many LR-3s, and LR-2s might need “more active management” than the currently recommended “return to surveillance,” including consideration for biopsy of solid LR-2 nodules measuring 1 cm or more, they wrote in Gastroenterology.
Histopathology confirmed that 93% of CT and MRI observations designated as LR-M (“definite or probable malignancy”) were indeed malignancies and that 36% were hepatocellular carcinomas,
The LI-RADS system, like its counterparts in breast and prostate imaging (BI-RADS and PI-RADS), classifies CT and MRI findings based on level of suspicion for malignancy. These categories include LR-M, LR-3, LR-2, LR-1 (“definitely benign”), LR-TIV (“definitely tumor in vein”), and LR-4 and LR-5 (“probably” and “definitely” hepatocellular carcinoma). However, CT and MRI interpretation is only as useful as it is accurate. To calculate actual percentages of hepatocellular carcinomas and overall malignancies within each LI-RADS category, the investigators analyzed aggregate data from studies found by searching MEDLINE, Embase, Cochrane CENTRAL, and Scopus during 2014-2018.
These 17 studies included 2,760 patients and 3,556 imaging observations. Pathology was the reference standard for LR-M, but for other LI-RADS categories, the researchers accepted strong clinical indicators of hepatocellular carcinoma, such as a 50% increase in lesion size within 6 months, or posttreatment recurrence of a previously confirmed malignancy. They classified observations as negative if they stayed stable in size for at least 12 months, spontaneously diminished in size, or disappeared without treatment.
In all, 94% and 97% of LR-5 observations were (respectively) hepatocellular carcinomas and other malignancies, as were 79% and 92% of LR-TIVs, 36% and 93% of LR-Ms, 74% and 80% of LR-4s, 38% and 40% of LR-3s, and 13% and 14% of LR-2s. No LR-1s were confirmed as malignant.
“Our data suggest biopsy of LI-RADS 3 observations should be considered in many patients, as a risk of 38% of HCC would usually provoke biopsy of a lesion elsewhere in the body,” the researchers wrote. They suggested consideration for biopsy of certain LR-2 lesions, but added that many “are small, perfusional alterations caused by arterioportal shunts, which are often not reported” and would be difficult or impossible to biopsy.
The study did not cover the most recent (2018) LI-RADS system, which featured several changes to simplify and better align it with American Association for the Study of Liver Diseases criteria, the researchers noted. They called for prospective studies to help confirm the accuracy of the LI-RADS system, particularly with regard to intermediate categories, such as LR-2.
The researchers disclosed no funding sources. Dr. van der Pol, Dr. Lim, and three other investigators reported having no conflicts of interest. Five researchers reported that they are members of the LI-RADS Steering Committee and four disclosed ties to pharmaceutical companies.
SOURCE: Van der Pol CB et al. Gastroenterology. 2018 Nov 13. doi: 10.1053/j.gastro.2018.11.020.
Higher (more severe) Liver Imaging Reporting and Data System (LI-RADS) categories contained increasing proportions of hepatocellular carcinomas and overall malignancies, supporting the general reliability of the system, according to a systematic review and meta-analysis of 17 retrospective studies.
But 13% of LR-2 (“probably benign”) observations were actually hepatocellular carcinomas, as were 38% of LR-3 (“intermediate probability of malignancy”) observations, reported Christian B. van der Pol, MD, of McMaster University, Hamilton, Ont., and Christopher S. Lim, BBS, of Harvard Medical School, Boston, and their associates. Thus, clinicians should consider biopsy of many LR-3s, and LR-2s might need “more active management” than the currently recommended “return to surveillance,” including consideration for biopsy of solid LR-2 nodules measuring 1 cm or more, they wrote in Gastroenterology.
Histopathology confirmed that 93% of CT and MRI observations designated as LR-M (“definite or probable malignancy”) were indeed malignancies and that 36% were hepatocellular carcinomas,
The LI-RADS system, like its counterparts in breast and prostate imaging (BI-RADS and PI-RADS), classifies CT and MRI findings based on level of suspicion for malignancy. These categories include LR-M, LR-3, LR-2, LR-1 (“definitely benign”), LR-TIV (“definitely tumor in vein”), and LR-4 and LR-5 (“probably” and “definitely” hepatocellular carcinoma). However, CT and MRI interpretation is only as useful as it is accurate. To calculate actual percentages of hepatocellular carcinomas and overall malignancies within each LI-RADS category, the investigators analyzed aggregate data from studies found by searching MEDLINE, Embase, Cochrane CENTRAL, and Scopus during 2014-2018.
These 17 studies included 2,760 patients and 3,556 imaging observations. Pathology was the reference standard for LR-M, but for other LI-RADS categories, the researchers accepted strong clinical indicators of hepatocellular carcinoma, such as a 50% increase in lesion size within 6 months, or posttreatment recurrence of a previously confirmed malignancy. They classified observations as negative if they stayed stable in size for at least 12 months, spontaneously diminished in size, or disappeared without treatment.
In all, 94% and 97% of LR-5 observations were (respectively) hepatocellular carcinomas and other malignancies, as were 79% and 92% of LR-TIVs, 36% and 93% of LR-Ms, 74% and 80% of LR-4s, 38% and 40% of LR-3s, and 13% and 14% of LR-2s. No LR-1s were confirmed as malignant.
“Our data suggest biopsy of LI-RADS 3 observations should be considered in many patients, as a risk of 38% of HCC would usually provoke biopsy of a lesion elsewhere in the body,” the researchers wrote. They suggested consideration for biopsy of certain LR-2 lesions, but added that many “are small, perfusional alterations caused by arterioportal shunts, which are often not reported” and would be difficult or impossible to biopsy.
The study did not cover the most recent (2018) LI-RADS system, which featured several changes to simplify and better align it with American Association for the Study of Liver Diseases criteria, the researchers noted. They called for prospective studies to help confirm the accuracy of the LI-RADS system, particularly with regard to intermediate categories, such as LR-2.
The researchers disclosed no funding sources. Dr. van der Pol, Dr. Lim, and three other investigators reported having no conflicts of interest. Five researchers reported that they are members of the LI-RADS Steering Committee and four disclosed ties to pharmaceutical companies.
SOURCE: Van der Pol CB et al. Gastroenterology. 2018 Nov 13. doi: 10.1053/j.gastro.2018.11.020.
Higher (more severe) Liver Imaging Reporting and Data System (LI-RADS) categories contained increasing proportions of hepatocellular carcinomas and overall malignancies, supporting the general reliability of the system, according to a systematic review and meta-analysis of 17 retrospective studies.
But 13% of LR-2 (“probably benign”) observations were actually hepatocellular carcinomas, as were 38% of LR-3 (“intermediate probability of malignancy”) observations, reported Christian B. van der Pol, MD, of McMaster University, Hamilton, Ont., and Christopher S. Lim, BBS, of Harvard Medical School, Boston, and their associates. Thus, clinicians should consider biopsy of many LR-3s, and LR-2s might need “more active management” than the currently recommended “return to surveillance,” including consideration for biopsy of solid LR-2 nodules measuring 1 cm or more, they wrote in Gastroenterology.
Histopathology confirmed that 93% of CT and MRI observations designated as LR-M (“definite or probable malignancy”) were indeed malignancies and that 36% were hepatocellular carcinomas,
The LI-RADS system, like its counterparts in breast and prostate imaging (BI-RADS and PI-RADS), classifies CT and MRI findings based on level of suspicion for malignancy. These categories include LR-M, LR-3, LR-2, LR-1 (“definitely benign”), LR-TIV (“definitely tumor in vein”), and LR-4 and LR-5 (“probably” and “definitely” hepatocellular carcinoma). However, CT and MRI interpretation is only as useful as it is accurate. To calculate actual percentages of hepatocellular carcinomas and overall malignancies within each LI-RADS category, the investigators analyzed aggregate data from studies found by searching MEDLINE, Embase, Cochrane CENTRAL, and Scopus during 2014-2018.
These 17 studies included 2,760 patients and 3,556 imaging observations. Pathology was the reference standard for LR-M, but for other LI-RADS categories, the researchers accepted strong clinical indicators of hepatocellular carcinoma, such as a 50% increase in lesion size within 6 months, or posttreatment recurrence of a previously confirmed malignancy. They classified observations as negative if they stayed stable in size for at least 12 months, spontaneously diminished in size, or disappeared without treatment.
In all, 94% and 97% of LR-5 observations were (respectively) hepatocellular carcinomas and other malignancies, as were 79% and 92% of LR-TIVs, 36% and 93% of LR-Ms, 74% and 80% of LR-4s, 38% and 40% of LR-3s, and 13% and 14% of LR-2s. No LR-1s were confirmed as malignant.
“Our data suggest biopsy of LI-RADS 3 observations should be considered in many patients, as a risk of 38% of HCC would usually provoke biopsy of a lesion elsewhere in the body,” the researchers wrote. They suggested consideration for biopsy of certain LR-2 lesions, but added that many “are small, perfusional alterations caused by arterioportal shunts, which are often not reported” and would be difficult or impossible to biopsy.
The study did not cover the most recent (2018) LI-RADS system, which featured several changes to simplify and better align it with American Association for the Study of Liver Diseases criteria, the researchers noted. They called for prospective studies to help confirm the accuracy of the LI-RADS system, particularly with regard to intermediate categories, such as LR-2.
The researchers disclosed no funding sources. Dr. van der Pol, Dr. Lim, and three other investigators reported having no conflicts of interest. Five researchers reported that they are members of the LI-RADS Steering Committee and four disclosed ties to pharmaceutical companies.
SOURCE: Van der Pol CB et al. Gastroenterology. 2018 Nov 13. doi: 10.1053/j.gastro.2018.11.020.
FROM GASTROENTEROLOGY
Key clinical point: Consider biopsy of CT/MRI observations classified as LI-RADS 3 (intermediate probability of malignancy), as well as LI-RADS 2 (probably benign) observations that are solid nodules measuring at least 1 cm.
Major finding: In all, 13% of LR-2 observations were confirmed to be hepatocellular carcinomas, as were 38% of LR-3 observations.
Study details: Systematic review and meta-analysis of 17 retrospective studies.
Disclosures: The researchers disclosed no external funding sources. Dr. van der Pol, Dr. Lim, and three other investigators reported having no conflicts of interest. Five researchers reported that they are members of the LI-RADS Steering Committee and four disclosed ties to pharmaceutical companies.
Source: Van der Pol CB et al. Gastroenterology. 2018 Nov 13. doi: 10.1053/j.gastro.2018.11.020.
Maltodextrin may increase colitis risk
The food additive maltodextrin may increase risk of inflammatory bowel disease, according to a recent study.
Compared with control subjects, mice given drinking water that contained 5% maltodextrin were significantly more likely to develop colitis and lose weight when challenged with dextran sodium sulfate (DSS), reported lead author Federica Laudisi, PhD, of the department of systems medicine at the University of Rome Tor Vergata in Rome, and her colleagues.
Further experiments with murine intestinal crypts and a human cell line echoed these results and offered mechanistic insight. Treatment with maltodextrin stressed the endoplasmic reticulum of goblet cells, predisposing the intestinal epithelium to mucus depletion and inflammation. With these results, maltodextrin joins polysorbate 80 and carboxymethylcellulose on a growing list of food additives in the Western diet with proinflammatory potential.
“Although the U.S. Food and Drug Administration recognizes these dietary elements as safe,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, “their use has been linked to the development of intestinal pathologies in both animals and human beings.
“It also has been shown that the polysaccharide maltodextrin, which is commonly used as a filler and thickener during food processing, can alter microbial phenotype and host antibacterial defenses. Maltodextrin expands the Escherichia coli population in the ileum and induces necrotizing enterocolitis in preterm piglets (Am J Physiol Gastrointest Liver Physiol. 2009 Dec;297:G1115-25).”
The present study began by administering three compounds dissolved in drinking water to wild-type Balb/c mice for 45 days: 5% maltodextrin, 0.5% propylene glycol, or 5 g/L animal gelatin. Control mice drank plain water. None of the treatments triggered clinical or histologic signs of colitis, and stool levels of lipocalin-2 (Lcn-2), a biomarker of intestinal inflammation, remained comparable with that of control mice. However, outcomes changed when mice were challenged with DSS (1.75% in drinking water) on days 35-45 or injected subcutaneously with indomethacin (5 mg/kg) on day 35 and sacrificed 24 hours later. When challenged with DSS, mice in the maltodextrin group developed severe colitis and lost 10%-15% of body weight, compared with minimal colitis and negligible weight loss in the other groups. In addition, compared with other mice, maltodextrin-fed mice had increased colon tissue expression of Lcn-2 and inflammatory cytokine interleukin (IL)-1beta. These initial findings suggested that dietary maltodextrin could increase susceptibility to clinical colitis.
To determine the pathophysiology of this phenomenon, the investigators performed microarray analysis of colonic samples. Multiple genes associated with carbohydrate and lipid metabolism were upregulated in maltodextrin-fed mice, including genes that controlled the unfolded protein response (UPR), a process in which unfolded proteins accumulate in the endoplasmic reticulum (ER) during ER stress. The most prominently expressed among the UPR-related genes was Ern-2, which regulates inositol-requiring enzyme 1beta, found exclusively in the ER of goblet cells in the small intestine and colon. When maltodextrin causes ER stress in goblet cells, it leads to misfolding of mucin glycoprotein Mucin-2 (Muc-2), a major component of gut mucus, causing gut mucus levels to drop. A diminished mucus barrier exposes the intestine to infection and damage, as demonstrated by higher rates of pathogenic bacteria in Muc-2–deficient mice than in control mice, and more severe intestinal damage than in controls when Muc-2 mice are deliberately infected with pathogens.
The investigators found that humans likely have similar responses to dietary maltodextrin. Treating the mucus-secreting HT29-methotrexate treated (HT29-MTX) cell line with 5% maltodextrin resulted in upregulation of Ern-2, which is the same mechanism observed in mice. Additional testing showed that this process was mediated by p38 mitogen-activated protein kinase, and pharmacologic inhibition or knockdown of p38 suppressed RNA expression of Ern-2. The investigators found that p38 was similarly involved in maltodextrin-fed mice.
To show that maltodextrin enhances susceptibility to inflammation via ER stress, the investigators used tauroursodeoxycholic acid (TUDCA) to inhibit ER stress. Indeed, inhibition led to reduced Ern-2 expression in HT29-MTX cells and in mice treated with maltodextrin. Giving TUDCA to maltodextrin-fed mice resulted in less weight loss, improved histology, and lower expression of Lcn-2 and IL-1beta.
The study concluded with three final experiments: The first showed that maltodextrin did not alter mucosa-associated microbiota; the second showed that mice fed 5% maltodextrin long term (for 10 weeks) had low-grade intestinal inflammation on histology, albeit without clinical colitis or weight loss; and the third showed that mice consuming maltodextrin long term had higher 15-hour fasting blood glycemic levels than control mice, supporting recent research suggesting that food additives can disrupt metabolism in a nonsusceptible host.
“In conclusion,” the investigators wrote, “this study shows that a maltodextrin-enriched diet reduces the intestinal content of Muc-2, thus making the host more sensitive to colitogenic stimuli. These data, together with the demonstration that maltodextrin can promote epithelial intestinal adhesion of pathogenic bacteria, supports the hypothesis that Western diets rich in maltodextrin can contribute to gut disease susceptibility.”
The study was funded by the Italian Ministry of Education, Universities, and Research. The authors reported no conflicts of interest.
SOURCE: Laudisi F et al. CMGH. 2019 Jan 18. doi: 10.1016/j.jcmgh.2018.09.002.
Maltodextrin is a polysaccharide derived from starch hydrolysis and broadly used as a thickener and filler in processed food. While it is regarded as inert and considered “generally regarded as safe” by the U.S. Food and Drug Administration, multiple recent studies have demonstrated detrimental roles played by maltodextrin in the intestinal environment, suggesting that this broadly used food additive may play a role in chronic inflammatory diseases.
Importantly, in addition to the use of a murine model of colitis, Laudisi and colleagues also investigated the impact that maltodextrin may have on a “normal” host, i.e. without genetic susceptibility nor induced colitis. While maltodextrin did not induce visible levels of intestinal inflammation, it led to the development of low-grade intestinal inflammation, characterized by subtle but nonetheless consistent elevation in intestinal inflammatory markers, ultimately leading to metabolic abnormalities.
Altogether, these recent results, together with previous reports, suggest that consumption of the food additive maltodextrin may be a risk factor for the IBD-prone population, as well as a factor promoting chronic low-grade intestinal inflammation leading to metabolic abnormalities in the general population. These findings further support the concept that FDA testing of food additives should be performed in disease-prone and resistant host models, designed to detect chronic and low-grade inflammation, as well as consider impacts on the gut microbiota.
Benoit Chassaing, PhD, is an assistant professor in the Neuroscience Institute and Institute for Biomedical Sciences, Georgia State University, Atlanta. He has no conflicts. These remarks are excerpted from an editorial accompanying Dr. Laudisi’s article (CMGH. 2019 Jan 18. doi.org/10.1016/j.jcmgh.2018.09.002).
Maltodextrin is a polysaccharide derived from starch hydrolysis and broadly used as a thickener and filler in processed food. While it is regarded as inert and considered “generally regarded as safe” by the U.S. Food and Drug Administration, multiple recent studies have demonstrated detrimental roles played by maltodextrin in the intestinal environment, suggesting that this broadly used food additive may play a role in chronic inflammatory diseases.
Importantly, in addition to the use of a murine model of colitis, Laudisi and colleagues also investigated the impact that maltodextrin may have on a “normal” host, i.e. without genetic susceptibility nor induced colitis. While maltodextrin did not induce visible levels of intestinal inflammation, it led to the development of low-grade intestinal inflammation, characterized by subtle but nonetheless consistent elevation in intestinal inflammatory markers, ultimately leading to metabolic abnormalities.
Altogether, these recent results, together with previous reports, suggest that consumption of the food additive maltodextrin may be a risk factor for the IBD-prone population, as well as a factor promoting chronic low-grade intestinal inflammation leading to metabolic abnormalities in the general population. These findings further support the concept that FDA testing of food additives should be performed in disease-prone and resistant host models, designed to detect chronic and low-grade inflammation, as well as consider impacts on the gut microbiota.
Benoit Chassaing, PhD, is an assistant professor in the Neuroscience Institute and Institute for Biomedical Sciences, Georgia State University, Atlanta. He has no conflicts. These remarks are excerpted from an editorial accompanying Dr. Laudisi’s article (CMGH. 2019 Jan 18. doi.org/10.1016/j.jcmgh.2018.09.002).
Maltodextrin is a polysaccharide derived from starch hydrolysis and broadly used as a thickener and filler in processed food. While it is regarded as inert and considered “generally regarded as safe” by the U.S. Food and Drug Administration, multiple recent studies have demonstrated detrimental roles played by maltodextrin in the intestinal environment, suggesting that this broadly used food additive may play a role in chronic inflammatory diseases.
Importantly, in addition to the use of a murine model of colitis, Laudisi and colleagues also investigated the impact that maltodextrin may have on a “normal” host, i.e. without genetic susceptibility nor induced colitis. While maltodextrin did not induce visible levels of intestinal inflammation, it led to the development of low-grade intestinal inflammation, characterized by subtle but nonetheless consistent elevation in intestinal inflammatory markers, ultimately leading to metabolic abnormalities.
Altogether, these recent results, together with previous reports, suggest that consumption of the food additive maltodextrin may be a risk factor for the IBD-prone population, as well as a factor promoting chronic low-grade intestinal inflammation leading to metabolic abnormalities in the general population. These findings further support the concept that FDA testing of food additives should be performed in disease-prone and resistant host models, designed to detect chronic and low-grade inflammation, as well as consider impacts on the gut microbiota.
Benoit Chassaing, PhD, is an assistant professor in the Neuroscience Institute and Institute for Biomedical Sciences, Georgia State University, Atlanta. He has no conflicts. These remarks are excerpted from an editorial accompanying Dr. Laudisi’s article (CMGH. 2019 Jan 18. doi.org/10.1016/j.jcmgh.2018.09.002).
The food additive maltodextrin may increase risk of inflammatory bowel disease, according to a recent study.
Compared with control subjects, mice given drinking water that contained 5% maltodextrin were significantly more likely to develop colitis and lose weight when challenged with dextran sodium sulfate (DSS), reported lead author Federica Laudisi, PhD, of the department of systems medicine at the University of Rome Tor Vergata in Rome, and her colleagues.
Further experiments with murine intestinal crypts and a human cell line echoed these results and offered mechanistic insight. Treatment with maltodextrin stressed the endoplasmic reticulum of goblet cells, predisposing the intestinal epithelium to mucus depletion and inflammation. With these results, maltodextrin joins polysorbate 80 and carboxymethylcellulose on a growing list of food additives in the Western diet with proinflammatory potential.
“Although the U.S. Food and Drug Administration recognizes these dietary elements as safe,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, “their use has been linked to the development of intestinal pathologies in both animals and human beings.
“It also has been shown that the polysaccharide maltodextrin, which is commonly used as a filler and thickener during food processing, can alter microbial phenotype and host antibacterial defenses. Maltodextrin expands the Escherichia coli population in the ileum and induces necrotizing enterocolitis in preterm piglets (Am J Physiol Gastrointest Liver Physiol. 2009 Dec;297:G1115-25).”
The present study began by administering three compounds dissolved in drinking water to wild-type Balb/c mice for 45 days: 5% maltodextrin, 0.5% propylene glycol, or 5 g/L animal gelatin. Control mice drank plain water. None of the treatments triggered clinical or histologic signs of colitis, and stool levels of lipocalin-2 (Lcn-2), a biomarker of intestinal inflammation, remained comparable with that of control mice. However, outcomes changed when mice were challenged with DSS (1.75% in drinking water) on days 35-45 or injected subcutaneously with indomethacin (5 mg/kg) on day 35 and sacrificed 24 hours later. When challenged with DSS, mice in the maltodextrin group developed severe colitis and lost 10%-15% of body weight, compared with minimal colitis and negligible weight loss in the other groups. In addition, compared with other mice, maltodextrin-fed mice had increased colon tissue expression of Lcn-2 and inflammatory cytokine interleukin (IL)-1beta. These initial findings suggested that dietary maltodextrin could increase susceptibility to clinical colitis.
To determine the pathophysiology of this phenomenon, the investigators performed microarray analysis of colonic samples. Multiple genes associated with carbohydrate and lipid metabolism were upregulated in maltodextrin-fed mice, including genes that controlled the unfolded protein response (UPR), a process in which unfolded proteins accumulate in the endoplasmic reticulum (ER) during ER stress. The most prominently expressed among the UPR-related genes was Ern-2, which regulates inositol-requiring enzyme 1beta, found exclusively in the ER of goblet cells in the small intestine and colon. When maltodextrin causes ER stress in goblet cells, it leads to misfolding of mucin glycoprotein Mucin-2 (Muc-2), a major component of gut mucus, causing gut mucus levels to drop. A diminished mucus barrier exposes the intestine to infection and damage, as demonstrated by higher rates of pathogenic bacteria in Muc-2–deficient mice than in control mice, and more severe intestinal damage than in controls when Muc-2 mice are deliberately infected with pathogens.
The investigators found that humans likely have similar responses to dietary maltodextrin. Treating the mucus-secreting HT29-methotrexate treated (HT29-MTX) cell line with 5% maltodextrin resulted in upregulation of Ern-2, which is the same mechanism observed in mice. Additional testing showed that this process was mediated by p38 mitogen-activated protein kinase, and pharmacologic inhibition or knockdown of p38 suppressed RNA expression of Ern-2. The investigators found that p38 was similarly involved in maltodextrin-fed mice.
To show that maltodextrin enhances susceptibility to inflammation via ER stress, the investigators used tauroursodeoxycholic acid (TUDCA) to inhibit ER stress. Indeed, inhibition led to reduced Ern-2 expression in HT29-MTX cells and in mice treated with maltodextrin. Giving TUDCA to maltodextrin-fed mice resulted in less weight loss, improved histology, and lower expression of Lcn-2 and IL-1beta.
The study concluded with three final experiments: The first showed that maltodextrin did not alter mucosa-associated microbiota; the second showed that mice fed 5% maltodextrin long term (for 10 weeks) had low-grade intestinal inflammation on histology, albeit without clinical colitis or weight loss; and the third showed that mice consuming maltodextrin long term had higher 15-hour fasting blood glycemic levels than control mice, supporting recent research suggesting that food additives can disrupt metabolism in a nonsusceptible host.
“In conclusion,” the investigators wrote, “this study shows that a maltodextrin-enriched diet reduces the intestinal content of Muc-2, thus making the host more sensitive to colitogenic stimuli. These data, together with the demonstration that maltodextrin can promote epithelial intestinal adhesion of pathogenic bacteria, supports the hypothesis that Western diets rich in maltodextrin can contribute to gut disease susceptibility.”
The study was funded by the Italian Ministry of Education, Universities, and Research. The authors reported no conflicts of interest.
SOURCE: Laudisi F et al. CMGH. 2019 Jan 18. doi: 10.1016/j.jcmgh.2018.09.002.
The food additive maltodextrin may increase risk of inflammatory bowel disease, according to a recent study.
Compared with control subjects, mice given drinking water that contained 5% maltodextrin were significantly more likely to develop colitis and lose weight when challenged with dextran sodium sulfate (DSS), reported lead author Federica Laudisi, PhD, of the department of systems medicine at the University of Rome Tor Vergata in Rome, and her colleagues.
Further experiments with murine intestinal crypts and a human cell line echoed these results and offered mechanistic insight. Treatment with maltodextrin stressed the endoplasmic reticulum of goblet cells, predisposing the intestinal epithelium to mucus depletion and inflammation. With these results, maltodextrin joins polysorbate 80 and carboxymethylcellulose on a growing list of food additives in the Western diet with proinflammatory potential.
“Although the U.S. Food and Drug Administration recognizes these dietary elements as safe,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, “their use has been linked to the development of intestinal pathologies in both animals and human beings.
“It also has been shown that the polysaccharide maltodextrin, which is commonly used as a filler and thickener during food processing, can alter microbial phenotype and host antibacterial defenses. Maltodextrin expands the Escherichia coli population in the ileum and induces necrotizing enterocolitis in preterm piglets (Am J Physiol Gastrointest Liver Physiol. 2009 Dec;297:G1115-25).”
The present study began by administering three compounds dissolved in drinking water to wild-type Balb/c mice for 45 days: 5% maltodextrin, 0.5% propylene glycol, or 5 g/L animal gelatin. Control mice drank plain water. None of the treatments triggered clinical or histologic signs of colitis, and stool levels of lipocalin-2 (Lcn-2), a biomarker of intestinal inflammation, remained comparable with that of control mice. However, outcomes changed when mice were challenged with DSS (1.75% in drinking water) on days 35-45 or injected subcutaneously with indomethacin (5 mg/kg) on day 35 and sacrificed 24 hours later. When challenged with DSS, mice in the maltodextrin group developed severe colitis and lost 10%-15% of body weight, compared with minimal colitis and negligible weight loss in the other groups. In addition, compared with other mice, maltodextrin-fed mice had increased colon tissue expression of Lcn-2 and inflammatory cytokine interleukin (IL)-1beta. These initial findings suggested that dietary maltodextrin could increase susceptibility to clinical colitis.
To determine the pathophysiology of this phenomenon, the investigators performed microarray analysis of colonic samples. Multiple genes associated with carbohydrate and lipid metabolism were upregulated in maltodextrin-fed mice, including genes that controlled the unfolded protein response (UPR), a process in which unfolded proteins accumulate in the endoplasmic reticulum (ER) during ER stress. The most prominently expressed among the UPR-related genes was Ern-2, which regulates inositol-requiring enzyme 1beta, found exclusively in the ER of goblet cells in the small intestine and colon. When maltodextrin causes ER stress in goblet cells, it leads to misfolding of mucin glycoprotein Mucin-2 (Muc-2), a major component of gut mucus, causing gut mucus levels to drop. A diminished mucus barrier exposes the intestine to infection and damage, as demonstrated by higher rates of pathogenic bacteria in Muc-2–deficient mice than in control mice, and more severe intestinal damage than in controls when Muc-2 mice are deliberately infected with pathogens.
The investigators found that humans likely have similar responses to dietary maltodextrin. Treating the mucus-secreting HT29-methotrexate treated (HT29-MTX) cell line with 5% maltodextrin resulted in upregulation of Ern-2, which is the same mechanism observed in mice. Additional testing showed that this process was mediated by p38 mitogen-activated protein kinase, and pharmacologic inhibition or knockdown of p38 suppressed RNA expression of Ern-2. The investigators found that p38 was similarly involved in maltodextrin-fed mice.
To show that maltodextrin enhances susceptibility to inflammation via ER stress, the investigators used tauroursodeoxycholic acid (TUDCA) to inhibit ER stress. Indeed, inhibition led to reduced Ern-2 expression in HT29-MTX cells and in mice treated with maltodextrin. Giving TUDCA to maltodextrin-fed mice resulted in less weight loss, improved histology, and lower expression of Lcn-2 and IL-1beta.
The study concluded with three final experiments: The first showed that maltodextrin did not alter mucosa-associated microbiota; the second showed that mice fed 5% maltodextrin long term (for 10 weeks) had low-grade intestinal inflammation on histology, albeit without clinical colitis or weight loss; and the third showed that mice consuming maltodextrin long term had higher 15-hour fasting blood glycemic levels than control mice, supporting recent research suggesting that food additives can disrupt metabolism in a nonsusceptible host.
“In conclusion,” the investigators wrote, “this study shows that a maltodextrin-enriched diet reduces the intestinal content of Muc-2, thus making the host more sensitive to colitogenic stimuli. These data, together with the demonstration that maltodextrin can promote epithelial intestinal adhesion of pathogenic bacteria, supports the hypothesis that Western diets rich in maltodextrin can contribute to gut disease susceptibility.”
The study was funded by the Italian Ministry of Education, Universities, and Research. The authors reported no conflicts of interest.
SOURCE: Laudisi F et al. CMGH. 2019 Jan 18. doi: 10.1016/j.jcmgh.2018.09.002.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: The food additive maltodextrin may increase risk of inflammatory bowel disease.
Major finding: When challenged with dextran sulfate sodium, mice consuming maltodextrin developed colitis and lost about 10%-15% of original body weight, compared with negligible inflammation and weight loss in mice not receiving maltodextrin.
Study details: A prospective study involving in vivo experiments with wild-type Balb/c mice and in vitro experiments with murine intestinal crypts and a human intestinal cell line.
Disclosures: The study was funded by the Italian Ministry of Education, Universities, and Research. The investigators reported no conflicts of interest.
Source: Laudisi F et al. CMGH. 2019 Jan 18. doi: 10.1016/j.jcmgh.2018.09.002.
NASH: Fastest-growing cause of liver cancer in transplant candidates
Nonalcoholic steatohepatitis may soon supplant chronic hepatitis C as the leading cause of hepatocellular carcinoma among patients awaiting liver transplantation, according to the findings of a national longitudinal registry study.
The proportion of affected patients with nonalcoholic steatohepatitis (NASH) rose nearly 700% between 2002 and 2017 (P less than .0001), making NASH the only etiology to significantly rise in prevalence, reported Zobair Younossi, MD, MPH, of Inova Health System in Falls Church, Va., and his associates. Chronic hepatitis C remained the most common cause of liver cancer during the study period, but its prevalence fell by more than 10% in the last 3 years (2014-2017). These trends reflect the advent of “new, highly effective antiviral regimens” for hepatitis C, the global epidemic of obesity and metabolic syndrome, and the urgent need for effective, safe treatments for NASH, they wrote in Clinical Gastroenterology and Hepatology.
Historically, hepatocellular carcinoma is usually caused by chronic hepatitis C or B infection, but the global rise of obesity and type 2 diabetes mellitus has led to epidemic levels of NASH, a progressive form of nonalcoholic fatty liver disease that lacks useful predictive noninvasive biomarkers or safe treatments. This phenomenon, coupled with the advent of new, often-curative treatments for viral hepatitis, is making NASH a leading driver of both fibrosis and liver transplantation in the United States. To compare trends in liver cancer etiologies among transplant candidates, Dr. Younossi and his associates analyzed data on 158,347 adults who were wait-listed between 2002 and 2017 and captured by the national Scientific Registry of Transplant Recipients.
A total of 26,121 (16.5%) patients awaiting liver transplant had hepatocellular carcinoma. This proportion nearly quadrupled over the study period, from 6% to 23% (P less than .0001) and rose significantly (P less than .0001) for all liver cancer etiologies (hepatitis C and B, alcoholic liver disease, and NASH). However, the absolute rise in prevalence was far greater for NASH (1050%) than for chronic hepatitis C (more than 500%) or any other etiology.
Furthermore, while most (65%) liver cancer cases involved chronic hepatitis C, the proportion of cases involving NASH rose from 2% in 2002 to 18% in 2017 (P less than .0001). By 2017, NASH topped alcoholic liver disease, comorbid hepatitis C with alcoholic liver disease, and chronic hepatitis B as an etiology of hepatocellular carcinoma among patients listed for transplant. Conversely, by 2017, less than 50% of liver cancers were caused by hepatitis C – a more than 10% drop from 2014. Over the study period, NASH was the only etiology whose prevalence significantly increased among transplant-listed patients with hepatocellular carcinoma.
In this study, etiology of liver cancer did not seem to affect the likelihood of either death or transplantation. However, serious cardiovascular disease or late-stage cancer diagnosis might exclude many NASH patients from transplantation, the researchers wrote. “Thus, the population reported here actually may underestimate the true proportion of hepatocellular carcinoma cases related to nonalcoholic fatty liver disease and NASH in the United States. Because NASH is on a trajectory to become the most common cause of hepatocellular carcinoma in the United States, effective prevention strategies and treatment options are urgently needed for this currently underserved patient population.”
Minneapolis Medical Research Foundation is the contractor for the registry and supplied the data. Dr. Younossi reported ties to Bristol-Myers Squibb, Gilead Sciences, AbbVie, Intercept Pharmaceuticals, and GlaxoSmithKline.
SOURCE: Younossi Z et al. Clin Gastroenterol Hepatol. 2018 Jun 14. doi: 10.1016/j.cgh.2018.05.057.
Nonalcoholic steatohepatitis may soon supplant chronic hepatitis C as the leading cause of hepatocellular carcinoma among patients awaiting liver transplantation, according to the findings of a national longitudinal registry study.
The proportion of affected patients with nonalcoholic steatohepatitis (NASH) rose nearly 700% between 2002 and 2017 (P less than .0001), making NASH the only etiology to significantly rise in prevalence, reported Zobair Younossi, MD, MPH, of Inova Health System in Falls Church, Va., and his associates. Chronic hepatitis C remained the most common cause of liver cancer during the study period, but its prevalence fell by more than 10% in the last 3 years (2014-2017). These trends reflect the advent of “new, highly effective antiviral regimens” for hepatitis C, the global epidemic of obesity and metabolic syndrome, and the urgent need for effective, safe treatments for NASH, they wrote in Clinical Gastroenterology and Hepatology.
Historically, hepatocellular carcinoma is usually caused by chronic hepatitis C or B infection, but the global rise of obesity and type 2 diabetes mellitus has led to epidemic levels of NASH, a progressive form of nonalcoholic fatty liver disease that lacks useful predictive noninvasive biomarkers or safe treatments. This phenomenon, coupled with the advent of new, often-curative treatments for viral hepatitis, is making NASH a leading driver of both fibrosis and liver transplantation in the United States. To compare trends in liver cancer etiologies among transplant candidates, Dr. Younossi and his associates analyzed data on 158,347 adults who were wait-listed between 2002 and 2017 and captured by the national Scientific Registry of Transplant Recipients.
A total of 26,121 (16.5%) patients awaiting liver transplant had hepatocellular carcinoma. This proportion nearly quadrupled over the study period, from 6% to 23% (P less than .0001) and rose significantly (P less than .0001) for all liver cancer etiologies (hepatitis C and B, alcoholic liver disease, and NASH). However, the absolute rise in prevalence was far greater for NASH (1050%) than for chronic hepatitis C (more than 500%) or any other etiology.
Furthermore, while most (65%) liver cancer cases involved chronic hepatitis C, the proportion of cases involving NASH rose from 2% in 2002 to 18% in 2017 (P less than .0001). By 2017, NASH topped alcoholic liver disease, comorbid hepatitis C with alcoholic liver disease, and chronic hepatitis B as an etiology of hepatocellular carcinoma among patients listed for transplant. Conversely, by 2017, less than 50% of liver cancers were caused by hepatitis C – a more than 10% drop from 2014. Over the study period, NASH was the only etiology whose prevalence significantly increased among transplant-listed patients with hepatocellular carcinoma.
In this study, etiology of liver cancer did not seem to affect the likelihood of either death or transplantation. However, serious cardiovascular disease or late-stage cancer diagnosis might exclude many NASH patients from transplantation, the researchers wrote. “Thus, the population reported here actually may underestimate the true proportion of hepatocellular carcinoma cases related to nonalcoholic fatty liver disease and NASH in the United States. Because NASH is on a trajectory to become the most common cause of hepatocellular carcinoma in the United States, effective prevention strategies and treatment options are urgently needed for this currently underserved patient population.”
Minneapolis Medical Research Foundation is the contractor for the registry and supplied the data. Dr. Younossi reported ties to Bristol-Myers Squibb, Gilead Sciences, AbbVie, Intercept Pharmaceuticals, and GlaxoSmithKline.
SOURCE: Younossi Z et al. Clin Gastroenterol Hepatol. 2018 Jun 14. doi: 10.1016/j.cgh.2018.05.057.
Nonalcoholic steatohepatitis may soon supplant chronic hepatitis C as the leading cause of hepatocellular carcinoma among patients awaiting liver transplantation, according to the findings of a national longitudinal registry study.
The proportion of affected patients with nonalcoholic steatohepatitis (NASH) rose nearly 700% between 2002 and 2017 (P less than .0001), making NASH the only etiology to significantly rise in prevalence, reported Zobair Younossi, MD, MPH, of Inova Health System in Falls Church, Va., and his associates. Chronic hepatitis C remained the most common cause of liver cancer during the study period, but its prevalence fell by more than 10% in the last 3 years (2014-2017). These trends reflect the advent of “new, highly effective antiviral regimens” for hepatitis C, the global epidemic of obesity and metabolic syndrome, and the urgent need for effective, safe treatments for NASH, they wrote in Clinical Gastroenterology and Hepatology.
Historically, hepatocellular carcinoma is usually caused by chronic hepatitis C or B infection, but the global rise of obesity and type 2 diabetes mellitus has led to epidemic levels of NASH, a progressive form of nonalcoholic fatty liver disease that lacks useful predictive noninvasive biomarkers or safe treatments. This phenomenon, coupled with the advent of new, often-curative treatments for viral hepatitis, is making NASH a leading driver of both fibrosis and liver transplantation in the United States. To compare trends in liver cancer etiologies among transplant candidates, Dr. Younossi and his associates analyzed data on 158,347 adults who were wait-listed between 2002 and 2017 and captured by the national Scientific Registry of Transplant Recipients.
A total of 26,121 (16.5%) patients awaiting liver transplant had hepatocellular carcinoma. This proportion nearly quadrupled over the study period, from 6% to 23% (P less than .0001) and rose significantly (P less than .0001) for all liver cancer etiologies (hepatitis C and B, alcoholic liver disease, and NASH). However, the absolute rise in prevalence was far greater for NASH (1050%) than for chronic hepatitis C (more than 500%) or any other etiology.
Furthermore, while most (65%) liver cancer cases involved chronic hepatitis C, the proportion of cases involving NASH rose from 2% in 2002 to 18% in 2017 (P less than .0001). By 2017, NASH topped alcoholic liver disease, comorbid hepatitis C with alcoholic liver disease, and chronic hepatitis B as an etiology of hepatocellular carcinoma among patients listed for transplant. Conversely, by 2017, less than 50% of liver cancers were caused by hepatitis C – a more than 10% drop from 2014. Over the study period, NASH was the only etiology whose prevalence significantly increased among transplant-listed patients with hepatocellular carcinoma.
In this study, etiology of liver cancer did not seem to affect the likelihood of either death or transplantation. However, serious cardiovascular disease or late-stage cancer diagnosis might exclude many NASH patients from transplantation, the researchers wrote. “Thus, the population reported here actually may underestimate the true proportion of hepatocellular carcinoma cases related to nonalcoholic fatty liver disease and NASH in the United States. Because NASH is on a trajectory to become the most common cause of hepatocellular carcinoma in the United States, effective prevention strategies and treatment options are urgently needed for this currently underserved patient population.”
Minneapolis Medical Research Foundation is the contractor for the registry and supplied the data. Dr. Younossi reported ties to Bristol-Myers Squibb, Gilead Sciences, AbbVie, Intercept Pharmaceuticals, and GlaxoSmithKline.
SOURCE: Younossi Z et al. Clin Gastroenterol Hepatol. 2018 Jun 14. doi: 10.1016/j.cgh.2018.05.057.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Nonalcoholic steatohepatitis may soon become the leading cause of hepatocellular carcinoma among patients awaiting liver transplantation.
Major finding: The proportion of these patients with NASH rose nearly 700% between 2002 and 2017 (P less than .0001).
Study details: A longitudinal registry study of 26,121 patients listed for liver transplantation in the United States.
Disclosures: Minneapolis Medical Research Foundation is the contractor for the registry and supplied the data. Dr. Younossi reported ties to Bristol-Myers Squibb, Gilead Sciences, AbbVie, Intercept Pharmaceuticals, and GlaxoSmithKline.
Source: Younossi Z et al. Clin Gastroenterol Hepatol. 2018 Jun 14. doi: 10.1016/j.cgh.2018.05.057.
Long-term budesonide oral suspension well tolerated in EoE
Treatment with budesonide oral suspension (BOS) was generally well tolerated and maintained a histologic response in some patients with eosinophilic esophagitis (EoE), according to the results of the 24-week, open-label extension phase of a multicenter, randomized, placebo-controlled, industry-sponsored trial.
Rates of histologic response (up to 6 eosinophils per high-power field) were “modest” – 23% among patients who stayed on BOS throughout the study and 48.5% among patients who initiated BOS after 12 weeks on placebo, reported Evan S. Dellon, MD, MPH, of the University of North Carolina in Chapel Hill and his associates. However, these rates “need to be viewed in the context of a highly symptomatic and histologically severe population with eosinophilic esophagitis,” they contended. A total of 11% of budesonide initiators developed esophageal candidiasis, they reported in Clinical Gastroenterology and Hepatology.
Budesonide oral suspension is a mucoadherent formulation of topical corticosteroid that has recently been developed to treat EoE. Previously, during the randomized, double-blind component of this phase 2 trial, 93 patients aged 11-40 years with active EoE and dysphagia received either BOS (2 mg) or placebo twice daily (Gastroenterology. 2017 Mar;157[4]:776-86). After 12 weeks, rates of histologic response were 39% for BOS versus 3% for placebo, and BOS significantly improved patients’ mean peak eosinophil count and scores on the Dysphagia Symptom Questionnaire, compared with baseline and compared with the response in the placebo group. During the open-label extension phase, 45 BOS continuers and 37 BOS initiators received 2 mg once daily for 12 weeks and then had the option to increase the BOS dose to 1.5-2.0 mg twice daily.
The rate of drug-related adverse events was 19% among BOS initiators and 4% among BOS continuers. One patient in each group developed oral candidiasis, while four BOS initiators (11%) developed esophageal candidiasis. Three BOS continuers had subnormal morning cortisol levels; while these were subclinical cases, they merit attention since long-term corticosteroids for EoE have been linked with possible hypothalamic–pituitary–adrenal axis suppression, the researchers noted.
In addition, while BOS initiators tended to maintain their endoscopic response, only 42% of those with an initial histologic response maintained a histologic response after 36 weeks of treatment or when leaving the study. Post hoc analyses confirmed that prolonged BOS treatment does not increase the chances of histologic or endoscopic response. Prior studies have suggested that EoE can become steroid-refractory over time and that certain molecular and histologic markers might predict resistance, the investigators noted.
Meritage Pharma (now part of Shire) was involved in the study design and conduct, data collection and management, and manuscript review. Dr. Dellon disclosed research funding from Meritage and Shire and a consulting relationship with Shire, along with ties to several other pharmaceutical companies. All six coinvestigators also disclosed ties to Meritage, Shire, or both, and two are Shire employees and stockholders.
*This story was updated on Feb. 7, 2019.
SOURCE: Dellon ES et al. Clin Gastroenterol Hepatol. 2018 Jun 11. doi: 10.1016/j.cgh.2018.05.051.
Guidelines regarding the management of eosinophilic esophagitis (EoE) with topical steroids are still unclear with regard to dosing and duration. Here, Dellon et al. present evidence that long-term budesonide oral suspension (BOS) therapy is safe and efficacious. Both the BOS and placebo cohorts of the initial, 12-week trial demonstrated clinical and histologic improvement on BOS over this 24-week period, with few adverse events. Maintenance of histologic response was only seen in 42% in initial BOS responders, suggesting steroid tolerance or resistance may develop. Another important observation was that peak eosinphil count decreased steroid dosing.
Finally, these data support the notion that initial responders are unlikely to gain response with continued therapy and may be better served with early transition to alternatives. Further research is needed to clarify these issues and which patients may be predisposed to nonresponse or loss of response.
Reena V. Chokshi, MD , is assistant professor of medicine in the department of gastroenterology at Baylor College of Medicine, Houston.
Guidelines regarding the management of eosinophilic esophagitis (EoE) with topical steroids are still unclear with regard to dosing and duration. Here, Dellon et al. present evidence that long-term budesonide oral suspension (BOS) therapy is safe and efficacious. Both the BOS and placebo cohorts of the initial, 12-week trial demonstrated clinical and histologic improvement on BOS over this 24-week period, with few adverse events. Maintenance of histologic response was only seen in 42% in initial BOS responders, suggesting steroid tolerance or resistance may develop. Another important observation was that peak eosinphil count decreased steroid dosing.
Finally, these data support the notion that initial responders are unlikely to gain response with continued therapy and may be better served with early transition to alternatives. Further research is needed to clarify these issues and which patients may be predisposed to nonresponse or loss of response.
Reena V. Chokshi, MD , is assistant professor of medicine in the department of gastroenterology at Baylor College of Medicine, Houston.
Guidelines regarding the management of eosinophilic esophagitis (EoE) with topical steroids are still unclear with regard to dosing and duration. Here, Dellon et al. present evidence that long-term budesonide oral suspension (BOS) therapy is safe and efficacious. Both the BOS and placebo cohorts of the initial, 12-week trial demonstrated clinical and histologic improvement on BOS over this 24-week period, with few adverse events. Maintenance of histologic response was only seen in 42% in initial BOS responders, suggesting steroid tolerance or resistance may develop. Another important observation was that peak eosinphil count decreased steroid dosing.
Finally, these data support the notion that initial responders are unlikely to gain response with continued therapy and may be better served with early transition to alternatives. Further research is needed to clarify these issues and which patients may be predisposed to nonresponse or loss of response.
Reena V. Chokshi, MD , is assistant professor of medicine in the department of gastroenterology at Baylor College of Medicine, Houston.
Treatment with budesonide oral suspension (BOS) was generally well tolerated and maintained a histologic response in some patients with eosinophilic esophagitis (EoE), according to the results of the 24-week, open-label extension phase of a multicenter, randomized, placebo-controlled, industry-sponsored trial.
Rates of histologic response (up to 6 eosinophils per high-power field) were “modest” – 23% among patients who stayed on BOS throughout the study and 48.5% among patients who initiated BOS after 12 weeks on placebo, reported Evan S. Dellon, MD, MPH, of the University of North Carolina in Chapel Hill and his associates. However, these rates “need to be viewed in the context of a highly symptomatic and histologically severe population with eosinophilic esophagitis,” they contended. A total of 11% of budesonide initiators developed esophageal candidiasis, they reported in Clinical Gastroenterology and Hepatology.
Budesonide oral suspension is a mucoadherent formulation of topical corticosteroid that has recently been developed to treat EoE. Previously, during the randomized, double-blind component of this phase 2 trial, 93 patients aged 11-40 years with active EoE and dysphagia received either BOS (2 mg) or placebo twice daily (Gastroenterology. 2017 Mar;157[4]:776-86). After 12 weeks, rates of histologic response were 39% for BOS versus 3% for placebo, and BOS significantly improved patients’ mean peak eosinophil count and scores on the Dysphagia Symptom Questionnaire, compared with baseline and compared with the response in the placebo group. During the open-label extension phase, 45 BOS continuers and 37 BOS initiators received 2 mg once daily for 12 weeks and then had the option to increase the BOS dose to 1.5-2.0 mg twice daily.
The rate of drug-related adverse events was 19% among BOS initiators and 4% among BOS continuers. One patient in each group developed oral candidiasis, while four BOS initiators (11%) developed esophageal candidiasis. Three BOS continuers had subnormal morning cortisol levels; while these were subclinical cases, they merit attention since long-term corticosteroids for EoE have been linked with possible hypothalamic–pituitary–adrenal axis suppression, the researchers noted.
In addition, while BOS initiators tended to maintain their endoscopic response, only 42% of those with an initial histologic response maintained a histologic response after 36 weeks of treatment or when leaving the study. Post hoc analyses confirmed that prolonged BOS treatment does not increase the chances of histologic or endoscopic response. Prior studies have suggested that EoE can become steroid-refractory over time and that certain molecular and histologic markers might predict resistance, the investigators noted.
Meritage Pharma (now part of Shire) was involved in the study design and conduct, data collection and management, and manuscript review. Dr. Dellon disclosed research funding from Meritage and Shire and a consulting relationship with Shire, along with ties to several other pharmaceutical companies. All six coinvestigators also disclosed ties to Meritage, Shire, or both, and two are Shire employees and stockholders.
*This story was updated on Feb. 7, 2019.
SOURCE: Dellon ES et al. Clin Gastroenterol Hepatol. 2018 Jun 11. doi: 10.1016/j.cgh.2018.05.051.
Treatment with budesonide oral suspension (BOS) was generally well tolerated and maintained a histologic response in some patients with eosinophilic esophagitis (EoE), according to the results of the 24-week, open-label extension phase of a multicenter, randomized, placebo-controlled, industry-sponsored trial.
Rates of histologic response (up to 6 eosinophils per high-power field) were “modest” – 23% among patients who stayed on BOS throughout the study and 48.5% among patients who initiated BOS after 12 weeks on placebo, reported Evan S. Dellon, MD, MPH, of the University of North Carolina in Chapel Hill and his associates. However, these rates “need to be viewed in the context of a highly symptomatic and histologically severe population with eosinophilic esophagitis,” they contended. A total of 11% of budesonide initiators developed esophageal candidiasis, they reported in Clinical Gastroenterology and Hepatology.
Budesonide oral suspension is a mucoadherent formulation of topical corticosteroid that has recently been developed to treat EoE. Previously, during the randomized, double-blind component of this phase 2 trial, 93 patients aged 11-40 years with active EoE and dysphagia received either BOS (2 mg) or placebo twice daily (Gastroenterology. 2017 Mar;157[4]:776-86). After 12 weeks, rates of histologic response were 39% for BOS versus 3% for placebo, and BOS significantly improved patients’ mean peak eosinophil count and scores on the Dysphagia Symptom Questionnaire, compared with baseline and compared with the response in the placebo group. During the open-label extension phase, 45 BOS continuers and 37 BOS initiators received 2 mg once daily for 12 weeks and then had the option to increase the BOS dose to 1.5-2.0 mg twice daily.
The rate of drug-related adverse events was 19% among BOS initiators and 4% among BOS continuers. One patient in each group developed oral candidiasis, while four BOS initiators (11%) developed esophageal candidiasis. Three BOS continuers had subnormal morning cortisol levels; while these were subclinical cases, they merit attention since long-term corticosteroids for EoE have been linked with possible hypothalamic–pituitary–adrenal axis suppression, the researchers noted.
In addition, while BOS initiators tended to maintain their endoscopic response, only 42% of those with an initial histologic response maintained a histologic response after 36 weeks of treatment or when leaving the study. Post hoc analyses confirmed that prolonged BOS treatment does not increase the chances of histologic or endoscopic response. Prior studies have suggested that EoE can become steroid-refractory over time and that certain molecular and histologic markers might predict resistance, the investigators noted.
Meritage Pharma (now part of Shire) was involved in the study design and conduct, data collection and management, and manuscript review. Dr. Dellon disclosed research funding from Meritage and Shire and a consulting relationship with Shire, along with ties to several other pharmaceutical companies. All six coinvestigators also disclosed ties to Meritage, Shire, or both, and two are Shire employees and stockholders.
*This story was updated on Feb. 7, 2019.
SOURCE: Dellon ES et al. Clin Gastroenterol Hepatol. 2018 Jun 11. doi: 10.1016/j.cgh.2018.05.051.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Budesonide oral suspension was well tolerated and maintained a histologic response in some patients with eosinophilic esophagitis.
Major finding: A total of 42% of initial histologic responders maintained a histologic response (less than 6 eosinophils per high-power field) after 24 weeks. Treatment was generally well tolerated, but 11% of initiators developed esophageal candidiasis.
Study details: Open-label extension study of a 12-week, multicenter, randomized, double-blind, placebo-controlled trial.
Disclosures: Meritage Pharma (now part of Shire) was involved in the study design and conduct, data collection and management, and manuscript review. Dr. Dellon disclosed research funding from Meritage and Shire and a consulting relationship with Shire, along with ties to several other pharmaceutical companies. All six coinvestigators also disclosed ties to Meritage, Shire, or both, and two are Shire employees and stockholders.
Source: Dellon ES et al. Clin Gastroenterol Hepatol. 2018 Jun 11. https://doi.org/10.1016/j.cgh.2018.05.051