From the AGA Journals

Obesity promotes the localization of inducible nitric oxide synthase (iNOS) in hepatic lysosomes, leading to a cascade of downstream effects that include excess lysosomal nitric oxide production, reduced hepatic autophagy, and insulin resistance, investigators reported.

“It is well known that in the context of obesity, chronic inflammation and lysosome dysfunction coexist in the liver,” wrote Qingwen Qian, PhD, of the University of Iowa in Iowa City and associates in Cellular and Molecular Gastroenterology and Hepatology. “Our studies suggest that lysosomal iNOS-mediated nitric oxide signaling disrupts hepatic lysosomal function, contributing to obesity-associated defective hepatic autophagy and insulin resistance.” They noted that the findings could hasten the development of new treatments for metabolic diseases.

Lysosomes recycle autophagocytosed intracellular and extracellular material, which is crucial to maintain several types of homeostasis within the liver. Each hepatocyte has about 250 lysosomes, which help regulate nutrient sensing, glycogen metabolism, cholesterol trafficking, and viral defense.

Activation of iNOS is a hallmark of inflammation, and iNOS levels are known to be elevated in the livers of patients with hepatitis C, alcoholic cirrhosis, and alpha 1-anti-trypsin disorder, the researchers wrote. “At the cellular level, iNOS produces pathological nitric oxide [NO], which triggers downstream effects, such as aberrant S-nitrosylation. These downstream effects can disrupt the function of organelles such as the mitochondria and the endoplasmic reticulum.”

Studies indicate that pathologic NO impairs lysosomal function in neurodegenerative diseases, cardiovascular disease, nonalcoholic fatty liver disease, and kidney disease, Dr. Qian and associates noted. But it was unclear whether NO in hepatocytes was generated by local iNOS or localized to lysosomes.

The researchers therefore studied cell cultures of primary murine hepatocytes by measuring their lysosomal activity, autophagy levels, and NO levels. They also studied a murine model of diet-induced obesity in which 60% of calories were from fat. They performed glucose tolerance tests by means of intraperitoneal glucose injections and studied the effects of insulin infusion. Finally, they performed immunohistology, immunohistochemistry, electron microscopy, and measurements of nitrosylated proteins and lysosomal arginine in frozen liver sections from the mice. Lysosomal arginine is required to catalyze NO production in the setting of inflammation as observed in obesity. In fact, concomitant stimulation of lysosomal arginine transport and activation of mTOR (an enzyme which tightly regulates transcription factor EB) was sufficient to stimulate lysosomal NO production in hepatocytes even in the absence of an inflammatory stimulus; pointing to a central role for these processes.

The researchers found that a NO scavenger diminished lysosomal NO production, while overexpression of both mTOR and a lysomal arginine transporter upregulated lysosomal NO production and suppressed autophagy. In mice with diet-induced obesity, deleting iNOS also improved nitrosative stress in hepatic lysosomes, promoted lysosomal biogenesis by activating transcription factor EB, enhanced lysosomal function and autophagy, and improved hepatic insulin sensitivity. Improved insulin sensitivity diminished, however, when the researchers suppressed transcription factor EB or autophagy-related 7 (Atg7).

Usually, iNOS is primarily expressed in hepatic Kupffer cells, but obesity increases the expression of iNOS in hepatocytes, which promotes hepatic insulin resistance and inflammation, the researchers commented. Unpublished data indicate that deleting iNOS initially protects against obesity-linked fatty liver steatosis and insulin resistance, but that these benefits weaken over time. “Nevertheless, our data showed that liver-specific iNOS suppression has a protective role,” they wrote. “Specifically, we showed that iNOS inactivates transcription factor EB, and that suppression of transcription factor EB and Atg7 diminishes the improved hepatic insulin sensitivity by iNOS deletion.” Transcription factor EB both regulates autophagy and is a “key player in lipid metabolism,” they added. It remains unclear whether the metabolic effects of iNOS solely relate to autophagy, they noted.

Funders included the American Heart Association, American Diabetes Association, and National Institutes of Health. The researchers reported having no conflicts of interest.

SOURCE: Qingwen Qian, et al. Cell Molec Gastroenterol Hepatol. 2019;8(1):95-110.
 

Obesity promotes the localization of inducible nitric oxide synthase (iNOS) in hepatic lysosomes, leading to a cascade of downstream effects that include excess lysosomal nitric oxide production, reduced hepatic autophagy, and insulin resistance, investigators reported.

“It is well known that in the context of obesity, chronic inflammation and lysosome dysfunction coexist in the liver,” wrote Qingwen Qian, PhD, of the University of Iowa in Iowa City and associates in Cellular and Molecular Gastroenterology and Hepatology. “Our studies suggest that lysosomal iNOS-mediated nitric oxide signaling disrupts hepatic lysosomal function, contributing to obesity-associated defective hepatic autophagy and insulin resistance.” They noted that the findings could hasten the development of new treatments for metabolic diseases.

Lysosomes recycle autophagocytosed intracellular and extracellular material, which is crucial to maintain several types of homeostasis within the liver. Each hepatocyte has about 250 lysosomes, which help regulate nutrient sensing, glycogen metabolism, cholesterol trafficking, and viral defense.

Activation of iNOS is a hallmark of inflammation, and iNOS levels are known to be elevated in the livers of patients with hepatitis C, alcoholic cirrhosis, and alpha 1-anti-trypsin disorder, the researchers wrote. “At the cellular level, iNOS produces pathological nitric oxide [NO], which triggers downstream effects, such as aberrant S-nitrosylation. These downstream effects can disrupt the function of organelles such as the mitochondria and the endoplasmic reticulum.”

Studies indicate that pathologic NO impairs lysosomal function in neurodegenerative diseases, cardiovascular disease, nonalcoholic fatty liver disease, and kidney disease, Dr. Qian and associates noted. But it was unclear whether NO in hepatocytes was generated by local iNOS or localized to lysosomes.

The researchers therefore studied cell cultures of primary murine hepatocytes by measuring their lysosomal activity, autophagy levels, and NO levels. They also studied a murine model of diet-induced obesity in which 60% of calories were from fat. They performed glucose tolerance tests by means of intraperitoneal glucose injections and studied the effects of insulin infusion. Finally, they performed immunohistology, immunohistochemistry, electron microscopy, and measurements of nitrosylated proteins and lysosomal arginine in frozen liver sections from the mice. Lysosomal arginine is required to catalyze NO production in the setting of inflammation as observed in obesity. In fact, concomitant stimulation of lysosomal arginine transport and activation of mTOR (an enzyme which tightly regulates transcription factor EB) was sufficient to stimulate lysosomal NO production in hepatocytes even in the absence of an inflammatory stimulus; pointing to a central role for these processes.

The researchers found that a NO scavenger diminished lysosomal NO production, while overexpression of both mTOR and a lysomal arginine transporter upregulated lysosomal NO production and suppressed autophagy. In mice with diet-induced obesity, deleting iNOS also improved nitrosative stress in hepatic lysosomes, promoted lysosomal biogenesis by activating transcription factor EB, enhanced lysosomal function and autophagy, and improved hepatic insulin sensitivity. Improved insulin sensitivity diminished, however, when the researchers suppressed transcription factor EB or autophagy-related 7 (Atg7).

Usually, iNOS is primarily expressed in hepatic Kupffer cells, but obesity increases the expression of iNOS in hepatocytes, which promotes hepatic insulin resistance and inflammation, the researchers commented. Unpublished data indicate that deleting iNOS initially protects against obesity-linked fatty liver steatosis and insulin resistance, but that these benefits weaken over time. “Nevertheless, our data showed that liver-specific iNOS suppression has a protective role,” they wrote. “Specifically, we showed that iNOS inactivates transcription factor EB, and that suppression of transcription factor EB and Atg7 diminishes the improved hepatic insulin sensitivity by iNOS deletion.” Transcription factor EB both regulates autophagy and is a “key player in lipid metabolism,” they added. It remains unclear whether the metabolic effects of iNOS solely relate to autophagy, they noted.

Funders included the American Heart Association, American Diabetes Association, and National Institutes of Health. The researchers reported having no conflicts of interest.

SOURCE: Qingwen Qian, et al. Cell Molec Gastroenterol Hepatol. 2019;8(1):95-110.
 

Obesity promotes the localization of inducible nitric oxide synthase (iNOS) in hepatic lysosomes, leading to a cascade of downstream effects that include excess lysosomal nitric oxide production, reduced hepatic autophagy, and insulin resistance, investigators reported.

“It is well known that in the context of obesity, chronic inflammation and lysosome dysfunction coexist in the liver,” wrote Qingwen Qian, PhD, of the University of Iowa in Iowa City and associates in Cellular and Molecular Gastroenterology and Hepatology. “Our studies suggest that lysosomal iNOS-mediated nitric oxide signaling disrupts hepatic lysosomal function, contributing to obesity-associated defective hepatic autophagy and insulin resistance.” They noted that the findings could hasten the development of new treatments for metabolic diseases.

Lysosomes recycle autophagocytosed intracellular and extracellular material, which is crucial to maintain several types of homeostasis within the liver. Each hepatocyte has about 250 lysosomes, which help regulate nutrient sensing, glycogen metabolism, cholesterol trafficking, and viral defense.

Activation of iNOS is a hallmark of inflammation, and iNOS levels are known to be elevated in the livers of patients with hepatitis C, alcoholic cirrhosis, and alpha 1-anti-trypsin disorder, the researchers wrote. “At the cellular level, iNOS produces pathological nitric oxide [NO], which triggers downstream effects, such as aberrant S-nitrosylation. These downstream effects can disrupt the function of organelles such as the mitochondria and the endoplasmic reticulum.”

Studies indicate that pathologic NO impairs lysosomal function in neurodegenerative diseases, cardiovascular disease, nonalcoholic fatty liver disease, and kidney disease, Dr. Qian and associates noted. But it was unclear whether NO in hepatocytes was generated by local iNOS or localized to lysosomes.

The researchers therefore studied cell cultures of primary murine hepatocytes by measuring their lysosomal activity, autophagy levels, and NO levels. They also studied a murine model of diet-induced obesity in which 60% of calories were from fat. They performed glucose tolerance tests by means of intraperitoneal glucose injections and studied the effects of insulin infusion. Finally, they performed immunohistology, immunohistochemistry, electron microscopy, and measurements of nitrosylated proteins and lysosomal arginine in frozen liver sections from the mice. Lysosomal arginine is required to catalyze NO production in the setting of inflammation as observed in obesity. In fact, concomitant stimulation of lysosomal arginine transport and activation of mTOR (an enzyme which tightly regulates transcription factor EB) was sufficient to stimulate lysosomal NO production in hepatocytes even in the absence of an inflammatory stimulus; pointing to a central role for these processes.

The researchers found that a NO scavenger diminished lysosomal NO production, while overexpression of both mTOR and a lysomal arginine transporter upregulated lysosomal NO production and suppressed autophagy. In mice with diet-induced obesity, deleting iNOS also improved nitrosative stress in hepatic lysosomes, promoted lysosomal biogenesis by activating transcription factor EB, enhanced lysosomal function and autophagy, and improved hepatic insulin sensitivity. Improved insulin sensitivity diminished, however, when the researchers suppressed transcription factor EB or autophagy-related 7 (Atg7).

Usually, iNOS is primarily expressed in hepatic Kupffer cells, but obesity increases the expression of iNOS in hepatocytes, which promotes hepatic insulin resistance and inflammation, the researchers commented. Unpublished data indicate that deleting iNOS initially protects against obesity-linked fatty liver steatosis and insulin resistance, but that these benefits weaken over time. “Nevertheless, our data showed that liver-specific iNOS suppression has a protective role,” they wrote. “Specifically, we showed that iNOS inactivates transcription factor EB, and that suppression of transcription factor EB and Atg7 diminishes the improved hepatic insulin sensitivity by iNOS deletion.” Transcription factor EB both regulates autophagy and is a “key player in lipid metabolism,” they added. It remains unclear whether the metabolic effects of iNOS solely relate to autophagy, they noted.

Funders included the American Heart Association, American Diabetes Association, and National Institutes of Health. The researchers reported having no conflicts of interest.

SOURCE: Qingwen Qian, et al. Cell Molec Gastroenterol Hepatol. 2019;8(1):95-110.
 

For adults with Crohn’s disease in remission at baseline, eating red and processed meat no more than once per month did not reduce risk of relapse in a randomized control trial.

Fuse/Thinkstock

After 49 weeks, there were no significant differences in time to relapse, time to moderate or severe relapse, or time to persistent relapse between the low- and high-meat groups, reported Lindsey G. Aldenberg, DO, of the Children’s Hospital of Philadelphia and coinvestigators. The findings were published in Gastroenterology.

The randomized study included 213 adults with Crohn’s disease whose short Crohn’s Disease Activity Index (sCDAI) score was 150 or less at baseline and who consumed red meat at least once weekly. They were instructed to consume one serving (3 ounces) of red meat or any processed (smoked, salted, or otherwise preserved) meat at least twice weekly (high-meat group) or no more than once monthly (low-meat group). To create a placebo-like effect, all patients were told to drink at least 16 ounces of water daily. Each week, patients were emailed a web-based survey of disease status and dietary adherence. At baseline and during six other weeks, they also received a daily survey of disease activity and current medications. The primary outcome was symptomatic relapse, defined as at least a 70-point rise such that sCDAI score exceeded 150, surgery for Crohn’s disease flare, or self-reported initiation or dose increase of mesalamine, thiopurine, methotrexate, corticosteroid, anti–tumor necrosis factor-alpha therapy, or natalizumab.

In all, 78% (166) of patients either completed the study or experienced an outcome. Symptomatic relapse occurred in 62% of these 166 patients, while 42% and 35% had moderate to severe or persistent relapses, respectively. “There were no significant differences in time to relapse for any of the outcomes (P greater than .3 for all outcomes),” the researchers wrote. Results were similar when they assumed that patients who completed no surveys all relapsed at week 1.

At week 20, median fecal calprotectin levels were higher in the high-meat arm (74.5 mcg/g) than in the low-meat arm (36.0 mcg/g), but the difference was not statistically significant. Proportions of patients with fecal calprotectin levels above 150 or 250 mcg/g also did not significantly differ between arms.

Adherence to the diets was reasonable: Patients in the high-meat group reported consuming at least two servings of red or processed meat during 98.5% of weeks, while patients in the low-meat arm completely abstained from red or processed meat during 57.3% of weeks. A logistic regression model showed that the high-meat group was much more likely to consume a least two servings of red or processed meat in the prior week than the low-meat group (P less than .0001). Approximately 90% of patients in both arms drank the recommended amount of water.

Study participants were part of IBD Partners, an Internet-based cohort of more than 15,000 patients with inflammatory bowel disease. Recruitment into the trial occurred through emails, social media, educational and fundraising events, and the Crohn’s & Colitis Foundation website, the researchers said.

“Based on these results, there is insufficient evidence to recommend reduction of red and processed meat consumption solely for the purpose of improving Crohn’s disease outcomes, although there may be some benefit for other health conditions,” Dr. Aldenberg and associates concluded.

The Crohn’s and Colitis Foundation and the National Institutes of Health supported the work. Dr. Aldenberg disclosed receiving research funding from Seres Therapeutics. Two of six coinvestigators disclosed ties to Nestle Health Science, AbbVie, Pfizer, Eli Lilly, and several other pharmaceutical companies.

SOURCE: Aldenberg L et al. Gastroenterology. 2019 Mar 11. doi: 10.1053/j.gastro.2019.03.01.

For adults with Crohn’s disease in remission at baseline, eating red and processed meat no more than once per month did not reduce risk of relapse in a randomized control trial.

Fuse/Thinkstock

After 49 weeks, there were no significant differences in time to relapse, time to moderate or severe relapse, or time to persistent relapse between the low- and high-meat groups, reported Lindsey G. Aldenberg, DO, of the Children’s Hospital of Philadelphia and coinvestigators. The findings were published in Gastroenterology.

The randomized study included 213 adults with Crohn’s disease whose short Crohn’s Disease Activity Index (sCDAI) score was 150 or less at baseline and who consumed red meat at least once weekly. They were instructed to consume one serving (3 ounces) of red meat or any processed (smoked, salted, or otherwise preserved) meat at least twice weekly (high-meat group) or no more than once monthly (low-meat group). To create a placebo-like effect, all patients were told to drink at least 16 ounces of water daily. Each week, patients were emailed a web-based survey of disease status and dietary adherence. At baseline and during six other weeks, they also received a daily survey of disease activity and current medications. The primary outcome was symptomatic relapse, defined as at least a 70-point rise such that sCDAI score exceeded 150, surgery for Crohn’s disease flare, or self-reported initiation or dose increase of mesalamine, thiopurine, methotrexate, corticosteroid, anti–tumor necrosis factor-alpha therapy, or natalizumab.

In all, 78% (166) of patients either completed the study or experienced an outcome. Symptomatic relapse occurred in 62% of these 166 patients, while 42% and 35% had moderate to severe or persistent relapses, respectively. “There were no significant differences in time to relapse for any of the outcomes (P greater than .3 for all outcomes),” the researchers wrote. Results were similar when they assumed that patients who completed no surveys all relapsed at week 1.

At week 20, median fecal calprotectin levels were higher in the high-meat arm (74.5 mcg/g) than in the low-meat arm (36.0 mcg/g), but the difference was not statistically significant. Proportions of patients with fecal calprotectin levels above 150 or 250 mcg/g also did not significantly differ between arms.

Adherence to the diets was reasonable: Patients in the high-meat group reported consuming at least two servings of red or processed meat during 98.5% of weeks, while patients in the low-meat arm completely abstained from red or processed meat during 57.3% of weeks. A logistic regression model showed that the high-meat group was much more likely to consume a least two servings of red or processed meat in the prior week than the low-meat group (P less than .0001). Approximately 90% of patients in both arms drank the recommended amount of water.

Study participants were part of IBD Partners, an Internet-based cohort of more than 15,000 patients with inflammatory bowel disease. Recruitment into the trial occurred through emails, social media, educational and fundraising events, and the Crohn’s & Colitis Foundation website, the researchers said.

“Based on these results, there is insufficient evidence to recommend reduction of red and processed meat consumption solely for the purpose of improving Crohn’s disease outcomes, although there may be some benefit for other health conditions,” Dr. Aldenberg and associates concluded.

The Crohn’s and Colitis Foundation and the National Institutes of Health supported the work. Dr. Aldenberg disclosed receiving research funding from Seres Therapeutics. Two of six coinvestigators disclosed ties to Nestle Health Science, AbbVie, Pfizer, Eli Lilly, and several other pharmaceutical companies.

SOURCE: Aldenberg L et al. Gastroenterology. 2019 Mar 11. doi: 10.1053/j.gastro.2019.03.01.

For adults with Crohn’s disease in remission at baseline, eating red and processed meat no more than once per month did not reduce risk of relapse in a randomized control trial.

Fuse/Thinkstock

After 49 weeks, there were no significant differences in time to relapse, time to moderate or severe relapse, or time to persistent relapse between the low- and high-meat groups, reported Lindsey G. Aldenberg, DO, of the Children’s Hospital of Philadelphia and coinvestigators. The findings were published in Gastroenterology.

The randomized study included 213 adults with Crohn’s disease whose short Crohn’s Disease Activity Index (sCDAI) score was 150 or less at baseline and who consumed red meat at least once weekly. They were instructed to consume one serving (3 ounces) of red meat or any processed (smoked, salted, or otherwise preserved) meat at least twice weekly (high-meat group) or no more than once monthly (low-meat group). To create a placebo-like effect, all patients were told to drink at least 16 ounces of water daily. Each week, patients were emailed a web-based survey of disease status and dietary adherence. At baseline and during six other weeks, they also received a daily survey of disease activity and current medications. The primary outcome was symptomatic relapse, defined as at least a 70-point rise such that sCDAI score exceeded 150, surgery for Crohn’s disease flare, or self-reported initiation or dose increase of mesalamine, thiopurine, methotrexate, corticosteroid, anti–tumor necrosis factor-alpha therapy, or natalizumab.

In all, 78% (166) of patients either completed the study or experienced an outcome. Symptomatic relapse occurred in 62% of these 166 patients, while 42% and 35% had moderate to severe or persistent relapses, respectively. “There were no significant differences in time to relapse for any of the outcomes (P greater than .3 for all outcomes),” the researchers wrote. Results were similar when they assumed that patients who completed no surveys all relapsed at week 1.

At week 20, median fecal calprotectin levels were higher in the high-meat arm (74.5 mcg/g) than in the low-meat arm (36.0 mcg/g), but the difference was not statistically significant. Proportions of patients with fecal calprotectin levels above 150 or 250 mcg/g also did not significantly differ between arms.

Adherence to the diets was reasonable: Patients in the high-meat group reported consuming at least two servings of red or processed meat during 98.5% of weeks, while patients in the low-meat arm completely abstained from red or processed meat during 57.3% of weeks. A logistic regression model showed that the high-meat group was much more likely to consume a least two servings of red or processed meat in the prior week than the low-meat group (P less than .0001). Approximately 90% of patients in both arms drank the recommended amount of water.

Study participants were part of IBD Partners, an Internet-based cohort of more than 15,000 patients with inflammatory bowel disease. Recruitment into the trial occurred through emails, social media, educational and fundraising events, and the Crohn’s & Colitis Foundation website, the researchers said.

“Based on these results, there is insufficient evidence to recommend reduction of red and processed meat consumption solely for the purpose of improving Crohn’s disease outcomes, although there may be some benefit for other health conditions,” Dr. Aldenberg and associates concluded.

The Crohn’s and Colitis Foundation and the National Institutes of Health supported the work. Dr. Aldenberg disclosed receiving research funding from Seres Therapeutics. Two of six coinvestigators disclosed ties to Nestle Health Science, AbbVie, Pfizer, Eli Lilly, and several other pharmaceutical companies.

SOURCE: Aldenberg L et al. Gastroenterology. 2019 Mar 11. doi: 10.1053/j.gastro.2019.03.01.

For men with inflammatory bowel disease, herpes zoster vaccination was associated with about a 46% decrease in risk of associated infection, according to the results of a retrospective study from the national Veterans Affairs Healthcare System.

Crude rates of herpes zoster infection were 4.09 cases per 1,000 person-years among vaccinated patients versus 6.97 cases per 1,000 person-years among unvaccinated patients, for an adjusted hazard ratio of 0.54 (95% confidence interval, 0.44-0.68), reported Nabeel Khan, MD, of the University of Pennsylvania, Philadelphia, and associates. “This vaccine is therefore effective in patients with IBD, but underused,” they wrote in Clinical Gastroenterology and Hepatology.

Studies have linked IBD with a 1.2- to 1.8-fold increased risk of herpes zoster infection, the researchers noted. Relevant risk factors include older age, disease flare, recent use or high cumulative use of prednisone, and use of thiopurines, either alone or in combination with a tumor necrosis factor (TNF) inhibitor. Although the American College of Gastroenterology recommends that all patients with IBD receive the herpes zoster vaccine by age 50 years, the efficacy of the vaccine in these patients remains unclear.

For their study, Dr. Khan and associates analyzed International Classification of Diseases (ICD) codes and other medical record data from 39,983 veterans with IBD who had not received the herpes zoster vaccine by age 60 years. In all, 97% of patients were male, and 94% were white. Most patients had high rates of health care utilization: Approximately half visited VA clinics or hospitals at least 13 times per year, and another third made 6-12 annual visits.

Despite their many contacts with VA health care systems, only 7,170 (17.9%) patients received the herpes zoster vaccine during 2000-2016, the researchers found. Vaccination rates varied substantially by region – they were highest in the Midwest (35%) and North Atlantic states (29%) but reached only 9% in Montana, Utah, Wyoming, Colorado, Oklahoma, Texas, Arkansas, and Louisiana, collectively.

The crude rate of herpes zoster infection among unvaccinated patients with IBD resembled the incidence reported in prior studies, the researchers said. After researchers accounted for differences in geography, demographics, and health care utilization between vaccinated and unvaccinated veterans with IBD, they found that vaccination was associated with an approximately 46% decrease in the risk of herpes zoster infection.

Very few patients were vaccinated for herpes zoster while on a TNF inhibitor, precluding the ability to study this subgroup. However, the vaccine showed a protective effect (adjusted HR, 0.63) among patients who received thiopurines without a TNF inhibitor. This effect did not reach statistical significance, perhaps because of lack of power, the researchers noted. “Among the 315 patients who were [vaccinated while] on thiopurines, none developed a documented painful or painless vesicular rash within 42 days of herpes zoster vaccination,” they added. One patient developed a painful blister 20 days post vaccination without vesicles or long-term sequelae.

Pfizer provided funding. Dr. Khan disclosed research funding from Pfizer, Luitpold, and Takeda Pharmaceuticals. One coinvestigator disclosed ties to Pfizer, Gilead, Merck, AbbVie, Lilly, Janssen, Johnson & Johnson, UCB, and Nestle Health Science. The remaining researchers disclosed no conflicts.

SOURCE: Khan N et al. Clin Gastroenterol Hepatol. 2018 Oct 13. doi: 10.1016/j.cgh.2018.10.016.

For men with inflammatory bowel disease, herpes zoster vaccination was associated with about a 46% decrease in risk of associated infection, according to the results of a retrospective study from the national Veterans Affairs Healthcare System.

Crude rates of herpes zoster infection were 4.09 cases per 1,000 person-years among vaccinated patients versus 6.97 cases per 1,000 person-years among unvaccinated patients, for an adjusted hazard ratio of 0.54 (95% confidence interval, 0.44-0.68), reported Nabeel Khan, MD, of the University of Pennsylvania, Philadelphia, and associates. “This vaccine is therefore effective in patients with IBD, but underused,” they wrote in Clinical Gastroenterology and Hepatology.

Studies have linked IBD with a 1.2- to 1.8-fold increased risk of herpes zoster infection, the researchers noted. Relevant risk factors include older age, disease flare, recent use or high cumulative use of prednisone, and use of thiopurines, either alone or in combination with a tumor necrosis factor (TNF) inhibitor. Although the American College of Gastroenterology recommends that all patients with IBD receive the herpes zoster vaccine by age 50 years, the efficacy of the vaccine in these patients remains unclear.

For their study, Dr. Khan and associates analyzed International Classification of Diseases (ICD) codes and other medical record data from 39,983 veterans with IBD who had not received the herpes zoster vaccine by age 60 years. In all, 97% of patients were male, and 94% were white. Most patients had high rates of health care utilization: Approximately half visited VA clinics or hospitals at least 13 times per year, and another third made 6-12 annual visits.

Despite their many contacts with VA health care systems, only 7,170 (17.9%) patients received the herpes zoster vaccine during 2000-2016, the researchers found. Vaccination rates varied substantially by region – they were highest in the Midwest (35%) and North Atlantic states (29%) but reached only 9% in Montana, Utah, Wyoming, Colorado, Oklahoma, Texas, Arkansas, and Louisiana, collectively.

The crude rate of herpes zoster infection among unvaccinated patients with IBD resembled the incidence reported in prior studies, the researchers said. After researchers accounted for differences in geography, demographics, and health care utilization between vaccinated and unvaccinated veterans with IBD, they found that vaccination was associated with an approximately 46% decrease in the risk of herpes zoster infection.

Very few patients were vaccinated for herpes zoster while on a TNF inhibitor, precluding the ability to study this subgroup. However, the vaccine showed a protective effect (adjusted HR, 0.63) among patients who received thiopurines without a TNF inhibitor. This effect did not reach statistical significance, perhaps because of lack of power, the researchers noted. “Among the 315 patients who were [vaccinated while] on thiopurines, none developed a documented painful or painless vesicular rash within 42 days of herpes zoster vaccination,” they added. One patient developed a painful blister 20 days post vaccination without vesicles or long-term sequelae.

Pfizer provided funding. Dr. Khan disclosed research funding from Pfizer, Luitpold, and Takeda Pharmaceuticals. One coinvestigator disclosed ties to Pfizer, Gilead, Merck, AbbVie, Lilly, Janssen, Johnson & Johnson, UCB, and Nestle Health Science. The remaining researchers disclosed no conflicts.

SOURCE: Khan N et al. Clin Gastroenterol Hepatol. 2018 Oct 13. doi: 10.1016/j.cgh.2018.10.016.

For men with inflammatory bowel disease, herpes zoster vaccination was associated with about a 46% decrease in risk of associated infection, according to the results of a retrospective study from the national Veterans Affairs Healthcare System.

Crude rates of herpes zoster infection were 4.09 cases per 1,000 person-years among vaccinated patients versus 6.97 cases per 1,000 person-years among unvaccinated patients, for an adjusted hazard ratio of 0.54 (95% confidence interval, 0.44-0.68), reported Nabeel Khan, MD, of the University of Pennsylvania, Philadelphia, and associates. “This vaccine is therefore effective in patients with IBD, but underused,” they wrote in Clinical Gastroenterology and Hepatology.

Studies have linked IBD with a 1.2- to 1.8-fold increased risk of herpes zoster infection, the researchers noted. Relevant risk factors include older age, disease flare, recent use or high cumulative use of prednisone, and use of thiopurines, either alone or in combination with a tumor necrosis factor (TNF) inhibitor. Although the American College of Gastroenterology recommends that all patients with IBD receive the herpes zoster vaccine by age 50 years, the efficacy of the vaccine in these patients remains unclear.

For their study, Dr. Khan and associates analyzed International Classification of Diseases (ICD) codes and other medical record data from 39,983 veterans with IBD who had not received the herpes zoster vaccine by age 60 years. In all, 97% of patients were male, and 94% were white. Most patients had high rates of health care utilization: Approximately half visited VA clinics or hospitals at least 13 times per year, and another third made 6-12 annual visits.

Despite their many contacts with VA health care systems, only 7,170 (17.9%) patients received the herpes zoster vaccine during 2000-2016, the researchers found. Vaccination rates varied substantially by region – they were highest in the Midwest (35%) and North Atlantic states (29%) but reached only 9% in Montana, Utah, Wyoming, Colorado, Oklahoma, Texas, Arkansas, and Louisiana, collectively.

The crude rate of herpes zoster infection among unvaccinated patients with IBD resembled the incidence reported in prior studies, the researchers said. After researchers accounted for differences in geography, demographics, and health care utilization between vaccinated and unvaccinated veterans with IBD, they found that vaccination was associated with an approximately 46% decrease in the risk of herpes zoster infection.

Very few patients were vaccinated for herpes zoster while on a TNF inhibitor, precluding the ability to study this subgroup. However, the vaccine showed a protective effect (adjusted HR, 0.63) among patients who received thiopurines without a TNF inhibitor. This effect did not reach statistical significance, perhaps because of lack of power, the researchers noted. “Among the 315 patients who were [vaccinated while] on thiopurines, none developed a documented painful or painless vesicular rash within 42 days of herpes zoster vaccination,” they added. One patient developed a painful blister 20 days post vaccination without vesicles or long-term sequelae.

Pfizer provided funding. Dr. Khan disclosed research funding from Pfizer, Luitpold, and Takeda Pharmaceuticals. One coinvestigator disclosed ties to Pfizer, Gilead, Merck, AbbVie, Lilly, Janssen, Johnson & Johnson, UCB, and Nestle Health Science. The remaining researchers disclosed no conflicts.

SOURCE: Khan N et al. Clin Gastroenterol Hepatol. 2018 Oct 13. doi: 10.1016/j.cgh.2018.10.016.

Tumor specimens from 17% of patients with pancreatic ductal adenocarcinomas contained genomic alterations for which targeted therapies exist, researchers reported in Gastroenterology.

“We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection,” wrote Aatur D. Singhi, MD, PhD, of the University of Pittsburgh and associates.

The most common genomic mutations in pancreatic ductal adenocarcinoma (PDAC) involve KRAS, TP53, CDKN2A, and SMAD4, none of which can be treated by currently approved targeted agents. But PDACs are genomically very heterogeneous and contain low levels (less than 5%) of many other mutations, the researchers noted. In small studies, these low-prevalence mutations included kinase gene amplifications and rearrangements, which may be useful as treatment targets or predictive biomarkers of response.

To further characterize PDAC mutations and their relative penetrance, the researchers performed targeted genomic profile analyses of 3,594 PDAC tumor specimens from an international cohort. The tests included capture-based targeted genomic profiling of up to 315 cancer-linked genes and the intron regions of 28 genes that are rearranged in cancer cells. The researchers classified genomic alterations based on published signaling pathways, including receptor tyrosine kinase/ras/mitogen-activated protein kinase (RTK/ras/MAPK) activation, DNA damage repair, cell cycle control, transforming growth factor beta signaling, histone modification, switching/sucrose nonfermenting complex, phosphoinositide 3-kinase/mammalian target of rapamycin signaling, Wnt/beta-catenin pathway, RNA splicing, Notch pathway, angiogenesis, and hedgehog signaling. In addition, they analyzed tumor mutation burden in 1,021 samples and microsatellite instability status in 2,563 samples.

In all, the samples contained 19,120 genomic alterations of 317 genes. A total of 608 (17%) specimens harbored mutations considered actionable targets. These involved either the RTK/ras/MAPK signaling or DNA damage repair pathways. As expected, KRAS mutations were most common, but their penetrance (88%) was lower than in prior studies. This might be because the current study covered both resectable and nonresectable PDACs, while past studies tended to focus on resected PDACs only, the researchers said. Importantly, the 12% of KRAS wild-type PDACs often harbored other potentially targetable alterations of genes in the RTK/ras/MAPK pathway, such as kinase fusion, amplification, missense mutations, and intragenic-in-frame deletions.

A total of 81% of samples contained alterations of TP53 or other genes involved in DNA damage repair. Reflecting prior studies, the penetrance of individual DNA damage repair mutations was low – usually less than 5%. Most germline mutations involved the BRCA-FANC DNA repair pathway, and these may be targetable with agents such as poly (ADP-ribose) polymerase inhibitors and DNA strand-damaging, platinum-based cytotoxic regimens, the investigators wrote.

Among 3,117 samples with clinicopathologic data, 51% were from the primary tumor and the rest were from distal metastases of the liver, lung, nonregional lymph nodes, peritoneum, omentum, and other sites. Not surprisingly, BRCA1 and BRCA2 mutations were more common in younger patients, but KRAS, SMAD4, DNMT3A, and AP mutations were more common in older patients, and mutational frequencies also varied by sex, primary versus metastatic tumor status, and site of metastasis.

“The complex genomic heterogeneity in otherwise histologically similar PDACs suggests a one-size-fits-all approach to treating patients will not be successful,” they concluded. “Targeted genomic profiling of known genomic alterations across multiple tumor types highlights potentially targetable and predictive biomarkers for treatment in a significant subset of PDACs.”

Funders included the Pancreatic Cancer Action Network, the National Pancreas Foundation, and the Sky Foundation. Dr. Singhi and two coinvestigators reported receiving honoraria from Foundation Medicine, and seven other coinvestigators reported employment by and stock ownership in Foundation Medicine. No other disclosures were reported.

SOURCE: Singhi AD et al. Gastroenterology. 2019 Mar 2. doi: 10.1053/j.gastro.2019.02.03.

Tumor specimens from 17% of patients with pancreatic ductal adenocarcinomas contained genomic alterations for which targeted therapies exist, researchers reported in Gastroenterology.

“We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection,” wrote Aatur D. Singhi, MD, PhD, of the University of Pittsburgh and associates.

The most common genomic mutations in pancreatic ductal adenocarcinoma (PDAC) involve KRAS, TP53, CDKN2A, and SMAD4, none of which can be treated by currently approved targeted agents. But PDACs are genomically very heterogeneous and contain low levels (less than 5%) of many other mutations, the researchers noted. In small studies, these low-prevalence mutations included kinase gene amplifications and rearrangements, which may be useful as treatment targets or predictive biomarkers of response.

To further characterize PDAC mutations and their relative penetrance, the researchers performed targeted genomic profile analyses of 3,594 PDAC tumor specimens from an international cohort. The tests included capture-based targeted genomic profiling of up to 315 cancer-linked genes and the intron regions of 28 genes that are rearranged in cancer cells. The researchers classified genomic alterations based on published signaling pathways, including receptor tyrosine kinase/ras/mitogen-activated protein kinase (RTK/ras/MAPK) activation, DNA damage repair, cell cycle control, transforming growth factor beta signaling, histone modification, switching/sucrose nonfermenting complex, phosphoinositide 3-kinase/mammalian target of rapamycin signaling, Wnt/beta-catenin pathway, RNA splicing, Notch pathway, angiogenesis, and hedgehog signaling. In addition, they analyzed tumor mutation burden in 1,021 samples and microsatellite instability status in 2,563 samples.

In all, the samples contained 19,120 genomic alterations of 317 genes. A total of 608 (17%) specimens harbored mutations considered actionable targets. These involved either the RTK/ras/MAPK signaling or DNA damage repair pathways. As expected, KRAS mutations were most common, but their penetrance (88%) was lower than in prior studies. This might be because the current study covered both resectable and nonresectable PDACs, while past studies tended to focus on resected PDACs only, the researchers said. Importantly, the 12% of KRAS wild-type PDACs often harbored other potentially targetable alterations of genes in the RTK/ras/MAPK pathway, such as kinase fusion, amplification, missense mutations, and intragenic-in-frame deletions.

A total of 81% of samples contained alterations of TP53 or other genes involved in DNA damage repair. Reflecting prior studies, the penetrance of individual DNA damage repair mutations was low – usually less than 5%. Most germline mutations involved the BRCA-FANC DNA repair pathway, and these may be targetable with agents such as poly (ADP-ribose) polymerase inhibitors and DNA strand-damaging, platinum-based cytotoxic regimens, the investigators wrote.

Among 3,117 samples with clinicopathologic data, 51% were from the primary tumor and the rest were from distal metastases of the liver, lung, nonregional lymph nodes, peritoneum, omentum, and other sites. Not surprisingly, BRCA1 and BRCA2 mutations were more common in younger patients, but KRAS, SMAD4, DNMT3A, and AP mutations were more common in older patients, and mutational frequencies also varied by sex, primary versus metastatic tumor status, and site of metastasis.

“The complex genomic heterogeneity in otherwise histologically similar PDACs suggests a one-size-fits-all approach to treating patients will not be successful,” they concluded. “Targeted genomic profiling of known genomic alterations across multiple tumor types highlights potentially targetable and predictive biomarkers for treatment in a significant subset of PDACs.”

Funders included the Pancreatic Cancer Action Network, the National Pancreas Foundation, and the Sky Foundation. Dr. Singhi and two coinvestigators reported receiving honoraria from Foundation Medicine, and seven other coinvestigators reported employment by and stock ownership in Foundation Medicine. No other disclosures were reported.

SOURCE: Singhi AD et al. Gastroenterology. 2019 Mar 2. doi: 10.1053/j.gastro.2019.02.03.

Tumor specimens from 17% of patients with pancreatic ductal adenocarcinomas contained genomic alterations for which targeted therapies exist, researchers reported in Gastroenterology.

“We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection,” wrote Aatur D. Singhi, MD, PhD, of the University of Pittsburgh and associates.

The most common genomic mutations in pancreatic ductal adenocarcinoma (PDAC) involve KRAS, TP53, CDKN2A, and SMAD4, none of which can be treated by currently approved targeted agents. But PDACs are genomically very heterogeneous and contain low levels (less than 5%) of many other mutations, the researchers noted. In small studies, these low-prevalence mutations included kinase gene amplifications and rearrangements, which may be useful as treatment targets or predictive biomarkers of response.

To further characterize PDAC mutations and their relative penetrance, the researchers performed targeted genomic profile analyses of 3,594 PDAC tumor specimens from an international cohort. The tests included capture-based targeted genomic profiling of up to 315 cancer-linked genes and the intron regions of 28 genes that are rearranged in cancer cells. The researchers classified genomic alterations based on published signaling pathways, including receptor tyrosine kinase/ras/mitogen-activated protein kinase (RTK/ras/MAPK) activation, DNA damage repair, cell cycle control, transforming growth factor beta signaling, histone modification, switching/sucrose nonfermenting complex, phosphoinositide 3-kinase/mammalian target of rapamycin signaling, Wnt/beta-catenin pathway, RNA splicing, Notch pathway, angiogenesis, and hedgehog signaling. In addition, they analyzed tumor mutation burden in 1,021 samples and microsatellite instability status in 2,563 samples.

In all, the samples contained 19,120 genomic alterations of 317 genes. A total of 608 (17%) specimens harbored mutations considered actionable targets. These involved either the RTK/ras/MAPK signaling or DNA damage repair pathways. As expected, KRAS mutations were most common, but their penetrance (88%) was lower than in prior studies. This might be because the current study covered both resectable and nonresectable PDACs, while past studies tended to focus on resected PDACs only, the researchers said. Importantly, the 12% of KRAS wild-type PDACs often harbored other potentially targetable alterations of genes in the RTK/ras/MAPK pathway, such as kinase fusion, amplification, missense mutations, and intragenic-in-frame deletions.

A total of 81% of samples contained alterations of TP53 or other genes involved in DNA damage repair. Reflecting prior studies, the penetrance of individual DNA damage repair mutations was low – usually less than 5%. Most germline mutations involved the BRCA-FANC DNA repair pathway, and these may be targetable with agents such as poly (ADP-ribose) polymerase inhibitors and DNA strand-damaging, platinum-based cytotoxic regimens, the investigators wrote.

Among 3,117 samples with clinicopathologic data, 51% were from the primary tumor and the rest were from distal metastases of the liver, lung, nonregional lymph nodes, peritoneum, omentum, and other sites. Not surprisingly, BRCA1 and BRCA2 mutations were more common in younger patients, but KRAS, SMAD4, DNMT3A, and AP mutations were more common in older patients, and mutational frequencies also varied by sex, primary versus metastatic tumor status, and site of metastasis.

“The complex genomic heterogeneity in otherwise histologically similar PDACs suggests a one-size-fits-all approach to treating patients will not be successful,” they concluded. “Targeted genomic profiling of known genomic alterations across multiple tumor types highlights potentially targetable and predictive biomarkers for treatment in a significant subset of PDACs.”

Funders included the Pancreatic Cancer Action Network, the National Pancreas Foundation, and the Sky Foundation. Dr. Singhi and two coinvestigators reported receiving honoraria from Foundation Medicine, and seven other coinvestigators reported employment by and stock ownership in Foundation Medicine. No other disclosures were reported.

SOURCE: Singhi AD et al. Gastroenterology. 2019 Mar 2. doi: 10.1053/j.gastro.2019.02.03.

Infections during the first year of life were a significant risk factor for inflammatory bowel disease throughout the lifespan but especially prior to the age of 10 years, according to the findings of a large population-based study.

It remains unclear whether the risk reflects infections in themselves or the use of antibiotic therapy, wrote Charles N. Bernstein, MD, of the University of Manitoba, Winnipeg, and associates. Infections did not appear to be a proxy for immunodeficiency disorders, which were similarly infrequent among cases and controls, they noted. Limiting antibiotic usage, while desirable, would be difficult to do for infections as serious as many in the study. Hence, they suggested research to determine “exactly what antibiotic intake does to infant gut microflora or intestinal or systemic immune responses,” and whether giving probiotics or prebiotics after antibiotic therapy helps attenuate the risk of inflammatory bowel disease (IBD) and other autoimmune disorders. The findings were published in Gastroenterology.

IBD is probably multifactorial, but specific causal factors remain unclear. Based on mounting evidence for the role of gut dysbiosis, the researchers explored whether IBD is associated with higher rates of infections and other critical events during the neonatal period and the first year of life by comparing 825 patients with IBD and 5,999 controls matched by age, sex, and area of residence. The data source was the University of Manitoba IBD Epidemiology Database, which includes all Manitobans diagnosed with IBD from 1984 to 2010. The researchers also compared patients with 1,740 unaffected siblings.

Gastrointestinal infections, gastrointestinal disease, and abdominal pain during the first year of life did not predict subsequent IBD. Maternal IBD was the strongest risk factor (odds ratio, 4.5; 95% confidence interval, 3.1-6.7). Among neonatal events, the only significant risk factor was being in the highest versus the lowest socioeconomic quintile (OR, 1.35; 95% CI, 1.01-1.79). This association persisted during the first year of life.

Infections during the first year of life were a significant risk factor for IBD before age 10 (OR, 3.1; 95% CI, 1.1-8.8) and age 20 years (OR, 1.6; 95% CI, 1.2-2.2) in the population-based analysis. In contrast, patients and their unaffected siblings had similar rates of infection during early life. The study may have missed differences in exposures between these groups, or perhaps patients lack certain protective genes possessed by healthy siblings, the researchers wrote.

Numbers of antibiotic prescriptions during the first year and the first decade of life did not significantly differ between 33 cases and 270 controls with available data. However, there was a trend toward more antibiotics prescribed to patients versus controls.

“Together with our past reports that neither cesarean section birth nor antenatal or perinatal maternal use of antibiotics predict ultimate development of IBD, it seems that neonatal changes to the microbiome are subsumed by those occurring in the first year of life,” the investigators concluded. They recommended studying the infant gut microbiome before and for several months after infections and antibiotic exposure to determine which shifts in microbiota predict IBD onset.

The Manitoba Centre for Health Policy provided access to the Population Health Research Data Repository. Dr. Bernstein is supported by the Bingham Chair in Gastroenterology. He reported ties to AbbVie Canada, Ferring Canada, Janssen Canada, Shire Canada, Takeda Canada, Pfizer Canada, Napo Pharmaceuticals, 4D Pharma, and Mylan.

SOURCE: Bernstein CN et al. Gastroenterology. 2019 Feb 14. doi: 10.1053/j.gastro.2019.02.004.

Infections during the first year of life were a significant risk factor for inflammatory bowel disease throughout the lifespan but especially prior to the age of 10 years, according to the findings of a large population-based study.

It remains unclear whether the risk reflects infections in themselves or the use of antibiotic therapy, wrote Charles N. Bernstein, MD, of the University of Manitoba, Winnipeg, and associates. Infections did not appear to be a proxy for immunodeficiency disorders, which were similarly infrequent among cases and controls, they noted. Limiting antibiotic usage, while desirable, would be difficult to do for infections as serious as many in the study. Hence, they suggested research to determine “exactly what antibiotic intake does to infant gut microflora or intestinal or systemic immune responses,” and whether giving probiotics or prebiotics after antibiotic therapy helps attenuate the risk of inflammatory bowel disease (IBD) and other autoimmune disorders. The findings were published in Gastroenterology.

IBD is probably multifactorial, but specific causal factors remain unclear. Based on mounting evidence for the role of gut dysbiosis, the researchers explored whether IBD is associated with higher rates of infections and other critical events during the neonatal period and the first year of life by comparing 825 patients with IBD and 5,999 controls matched by age, sex, and area of residence. The data source was the University of Manitoba IBD Epidemiology Database, which includes all Manitobans diagnosed with IBD from 1984 to 2010. The researchers also compared patients with 1,740 unaffected siblings.

Gastrointestinal infections, gastrointestinal disease, and abdominal pain during the first year of life did not predict subsequent IBD. Maternal IBD was the strongest risk factor (odds ratio, 4.5; 95% confidence interval, 3.1-6.7). Among neonatal events, the only significant risk factor was being in the highest versus the lowest socioeconomic quintile (OR, 1.35; 95% CI, 1.01-1.79). This association persisted during the first year of life.

Infections during the first year of life were a significant risk factor for IBD before age 10 (OR, 3.1; 95% CI, 1.1-8.8) and age 20 years (OR, 1.6; 95% CI, 1.2-2.2) in the population-based analysis. In contrast, patients and their unaffected siblings had similar rates of infection during early life. The study may have missed differences in exposures between these groups, or perhaps patients lack certain protective genes possessed by healthy siblings, the researchers wrote.

Numbers of antibiotic prescriptions during the first year and the first decade of life did not significantly differ between 33 cases and 270 controls with available data. However, there was a trend toward more antibiotics prescribed to patients versus controls.

“Together with our past reports that neither cesarean section birth nor antenatal or perinatal maternal use of antibiotics predict ultimate development of IBD, it seems that neonatal changes to the microbiome are subsumed by those occurring in the first year of life,” the investigators concluded. They recommended studying the infant gut microbiome before and for several months after infections and antibiotic exposure to determine which shifts in microbiota predict IBD onset.

The Manitoba Centre for Health Policy provided access to the Population Health Research Data Repository. Dr. Bernstein is supported by the Bingham Chair in Gastroenterology. He reported ties to AbbVie Canada, Ferring Canada, Janssen Canada, Shire Canada, Takeda Canada, Pfizer Canada, Napo Pharmaceuticals, 4D Pharma, and Mylan.

SOURCE: Bernstein CN et al. Gastroenterology. 2019 Feb 14. doi: 10.1053/j.gastro.2019.02.004.

Infections during the first year of life were a significant risk factor for inflammatory bowel disease throughout the lifespan but especially prior to the age of 10 years, according to the findings of a large population-based study.

It remains unclear whether the risk reflects infections in themselves or the use of antibiotic therapy, wrote Charles N. Bernstein, MD, of the University of Manitoba, Winnipeg, and associates. Infections did not appear to be a proxy for immunodeficiency disorders, which were similarly infrequent among cases and controls, they noted. Limiting antibiotic usage, while desirable, would be difficult to do for infections as serious as many in the study. Hence, they suggested research to determine “exactly what antibiotic intake does to infant gut microflora or intestinal or systemic immune responses,” and whether giving probiotics or prebiotics after antibiotic therapy helps attenuate the risk of inflammatory bowel disease (IBD) and other autoimmune disorders. The findings were published in Gastroenterology.

IBD is probably multifactorial, but specific causal factors remain unclear. Based on mounting evidence for the role of gut dysbiosis, the researchers explored whether IBD is associated with higher rates of infections and other critical events during the neonatal period and the first year of life by comparing 825 patients with IBD and 5,999 controls matched by age, sex, and area of residence. The data source was the University of Manitoba IBD Epidemiology Database, which includes all Manitobans diagnosed with IBD from 1984 to 2010. The researchers also compared patients with 1,740 unaffected siblings.

Gastrointestinal infections, gastrointestinal disease, and abdominal pain during the first year of life did not predict subsequent IBD. Maternal IBD was the strongest risk factor (odds ratio, 4.5; 95% confidence interval, 3.1-6.7). Among neonatal events, the only significant risk factor was being in the highest versus the lowest socioeconomic quintile (OR, 1.35; 95% CI, 1.01-1.79). This association persisted during the first year of life.

Infections during the first year of life were a significant risk factor for IBD before age 10 (OR, 3.1; 95% CI, 1.1-8.8) and age 20 years (OR, 1.6; 95% CI, 1.2-2.2) in the population-based analysis. In contrast, patients and their unaffected siblings had similar rates of infection during early life. The study may have missed differences in exposures between these groups, or perhaps patients lack certain protective genes possessed by healthy siblings, the researchers wrote.

Numbers of antibiotic prescriptions during the first year and the first decade of life did not significantly differ between 33 cases and 270 controls with available data. However, there was a trend toward more antibiotics prescribed to patients versus controls.

“Together with our past reports that neither cesarean section birth nor antenatal or perinatal maternal use of antibiotics predict ultimate development of IBD, it seems that neonatal changes to the microbiome are subsumed by those occurring in the first year of life,” the investigators concluded. They recommended studying the infant gut microbiome before and for several months after infections and antibiotic exposure to determine which shifts in microbiota predict IBD onset.

The Manitoba Centre for Health Policy provided access to the Population Health Research Data Repository. Dr. Bernstein is supported by the Bingham Chair in Gastroenterology. He reported ties to AbbVie Canada, Ferring Canada, Janssen Canada, Shire Canada, Takeda Canada, Pfizer Canada, Napo Pharmaceuticals, 4D Pharma, and Mylan.

SOURCE: Bernstein CN et al. Gastroenterology. 2019 Feb 14. doi: 10.1053/j.gastro.2019.02.004.

Achieving sustained virologic response to direct-acting antiviral therapy for chronic hepatitis C virus infection cuts lifetime hepatocellular carcinoma risk by approximately 70%, even when patients have baseline cirrhosis, experts wrote in Gastroenterology.

When used after curative-intent treatment for hepatocellular carcinoma, direct-acting antiviral (DAA) therapy also does not appear to make recurrent cancer more probable or more aggressive, wrote Amit G. Singal, MD, and associates in an American Gastroenterological Association clinical practice update. Studies that compared DAA therapy with either interferon-based therapy or no treatment have found “similar if not lower recurrence than the comparator groups,” they wrote. Rather, hepatocellular carcinoma is in itself highly recurrent: “While surgical resection and local ablative therapies are considered curative, [probability of] recurrence approaches 25%-35% within the first year, and 50%-60% within 2 years.”

Direct-acting antiviral therapy for chronic hepatitis C infection improves several aspects of liver health, but experts have debated whether and how these benefits affect the risk and behavior of hepatocellular carcinoma. To explore the issue, Dr. Singal, medical director of the liver tumor program and clinical chief of hepatology at UT Southwestern Medical Center in Dallas and associates reviewed published clinical trials, observational studies, and systematic reviews. Among 11 studies of more than 3,000 patients in five countries, sustained virologic response (SVR) to DAA therapy was associated with about a 70% reduction in the risk of liver cancer, even after adjustment for clinical and demographic variables. “The relative reduction is similar in patients with and without cirrhosis,” the experts wrote.

Since patients with fibrosis (F3) or cirrhosis are at highest risk for hepatocellular carcinoma, they should undergo baseline imaging and remain under indefinite post-SVR surveillance as long as they are eligible for potentially curative treatment, the practice update states. The experts recommended twice-yearly ultrasound, with or without serum alpha-fetoprotein, noting that current evidence supports neither shorter surveillance intervals nor alternative imaging modalities.

“The presence of active hepatocellular carcinoma is associated with a small but statistically significant decrease in SVR with DAA therapy,” the experts confirmed, based on the results of three studies. They recommended that, when possible, patients with hepatocellular carcinoma first receive curative-intent treatment, such as with liver resection or ablation. Direct-acting antiviral therapy can begin 4-6 months later, once there has been time to confirm response to hepatocellular carcinoma treatment.

For patients who are listed for liver transplantation, timing of DAA therapy “should be determined on a case-by-case basis with consideration of median wait times for the region, availability of HCV-positive organs, and degree of liver dysfunction,” they added. “For example, DAA therapy may be beneficial pretransplant for patients in regions with long wait times or limited hepatitis C virus–positive donor organ availability, whereas therapy may be delayed until posttransplant in regions with shorter wait times or a high proportion of hepatitis C virus–positive donor organs that would otherwise go unused.”

For patients with active intermediate or advanced liver cancer, it remains unclear whether DAA therapy is usually worth the costs and risks, they noted. This is because the likelihood of complete response is lower and the competing risk of death is higher than in patients with earlier-stage hepatocellular carcinoma. Pending further data, they recommend basing the decision on patients’ preferences, tumor burden, degree of liver dysfunction, and life expectancy. At their institutions, the researchers do not treat patients with DAA therapy unless their life expectancy exceeds 2 years.

The experts disclosed research funding from the National Cancer Institute, U.S. Veterans Administration, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Singal reported personal fees or research funding from AbbVie, Bayer, Bristol-Myers Squibb, Eisai, Exact Sciences, Exelixis, Gilead, Glycotest, Roche, and Wako Diagnostics. His coauthors disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Conatus, Genfit, Gilead, Intercept, and Merck.

SOURCE: Singal AG et al. Gastroenterology. 2019 Mar 13. doi: 10.1053/j.gastro.2019.02.046.

Achieving sustained virologic response to direct-acting antiviral therapy for chronic hepatitis C virus infection cuts lifetime hepatocellular carcinoma risk by approximately 70%, even when patients have baseline cirrhosis, experts wrote in Gastroenterology.

When used after curative-intent treatment for hepatocellular carcinoma, direct-acting antiviral (DAA) therapy also does not appear to make recurrent cancer more probable or more aggressive, wrote Amit G. Singal, MD, and associates in an American Gastroenterological Association clinical practice update. Studies that compared DAA therapy with either interferon-based therapy or no treatment have found “similar if not lower recurrence than the comparator groups,” they wrote. Rather, hepatocellular carcinoma is in itself highly recurrent: “While surgical resection and local ablative therapies are considered curative, [probability of] recurrence approaches 25%-35% within the first year, and 50%-60% within 2 years.”

Direct-acting antiviral therapy for chronic hepatitis C infection improves several aspects of liver health, but experts have debated whether and how these benefits affect the risk and behavior of hepatocellular carcinoma. To explore the issue, Dr. Singal, medical director of the liver tumor program and clinical chief of hepatology at UT Southwestern Medical Center in Dallas and associates reviewed published clinical trials, observational studies, and systematic reviews. Among 11 studies of more than 3,000 patients in five countries, sustained virologic response (SVR) to DAA therapy was associated with about a 70% reduction in the risk of liver cancer, even after adjustment for clinical and demographic variables. “The relative reduction is similar in patients with and without cirrhosis,” the experts wrote.

Since patients with fibrosis (F3) or cirrhosis are at highest risk for hepatocellular carcinoma, they should undergo baseline imaging and remain under indefinite post-SVR surveillance as long as they are eligible for potentially curative treatment, the practice update states. The experts recommended twice-yearly ultrasound, with or without serum alpha-fetoprotein, noting that current evidence supports neither shorter surveillance intervals nor alternative imaging modalities.

“The presence of active hepatocellular carcinoma is associated with a small but statistically significant decrease in SVR with DAA therapy,” the experts confirmed, based on the results of three studies. They recommended that, when possible, patients with hepatocellular carcinoma first receive curative-intent treatment, such as with liver resection or ablation. Direct-acting antiviral therapy can begin 4-6 months later, once there has been time to confirm response to hepatocellular carcinoma treatment.

For patients who are listed for liver transplantation, timing of DAA therapy “should be determined on a case-by-case basis with consideration of median wait times for the region, availability of HCV-positive organs, and degree of liver dysfunction,” they added. “For example, DAA therapy may be beneficial pretransplant for patients in regions with long wait times or limited hepatitis C virus–positive donor organ availability, whereas therapy may be delayed until posttransplant in regions with shorter wait times or a high proportion of hepatitis C virus–positive donor organs that would otherwise go unused.”

For patients with active intermediate or advanced liver cancer, it remains unclear whether DAA therapy is usually worth the costs and risks, they noted. This is because the likelihood of complete response is lower and the competing risk of death is higher than in patients with earlier-stage hepatocellular carcinoma. Pending further data, they recommend basing the decision on patients’ preferences, tumor burden, degree of liver dysfunction, and life expectancy. At their institutions, the researchers do not treat patients with DAA therapy unless their life expectancy exceeds 2 years.

The experts disclosed research funding from the National Cancer Institute, U.S. Veterans Administration, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Singal reported personal fees or research funding from AbbVie, Bayer, Bristol-Myers Squibb, Eisai, Exact Sciences, Exelixis, Gilead, Glycotest, Roche, and Wako Diagnostics. His coauthors disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Conatus, Genfit, Gilead, Intercept, and Merck.

SOURCE: Singal AG et al. Gastroenterology. 2019 Mar 13. doi: 10.1053/j.gastro.2019.02.046.

Achieving sustained virologic response to direct-acting antiviral therapy for chronic hepatitis C virus infection cuts lifetime hepatocellular carcinoma risk by approximately 70%, even when patients have baseline cirrhosis, experts wrote in Gastroenterology.

When used after curative-intent treatment for hepatocellular carcinoma, direct-acting antiviral (DAA) therapy also does not appear to make recurrent cancer more probable or more aggressive, wrote Amit G. Singal, MD, and associates in an American Gastroenterological Association clinical practice update. Studies that compared DAA therapy with either interferon-based therapy or no treatment have found “similar if not lower recurrence than the comparator groups,” they wrote. Rather, hepatocellular carcinoma is in itself highly recurrent: “While surgical resection and local ablative therapies are considered curative, [probability of] recurrence approaches 25%-35% within the first year, and 50%-60% within 2 years.”

Direct-acting antiviral therapy for chronic hepatitis C infection improves several aspects of liver health, but experts have debated whether and how these benefits affect the risk and behavior of hepatocellular carcinoma. To explore the issue, Dr. Singal, medical director of the liver tumor program and clinical chief of hepatology at UT Southwestern Medical Center in Dallas and associates reviewed published clinical trials, observational studies, and systematic reviews. Among 11 studies of more than 3,000 patients in five countries, sustained virologic response (SVR) to DAA therapy was associated with about a 70% reduction in the risk of liver cancer, even after adjustment for clinical and demographic variables. “The relative reduction is similar in patients with and without cirrhosis,” the experts wrote.

Since patients with fibrosis (F3) or cirrhosis are at highest risk for hepatocellular carcinoma, they should undergo baseline imaging and remain under indefinite post-SVR surveillance as long as they are eligible for potentially curative treatment, the practice update states. The experts recommended twice-yearly ultrasound, with or without serum alpha-fetoprotein, noting that current evidence supports neither shorter surveillance intervals nor alternative imaging modalities.

“The presence of active hepatocellular carcinoma is associated with a small but statistically significant decrease in SVR with DAA therapy,” the experts confirmed, based on the results of three studies. They recommended that, when possible, patients with hepatocellular carcinoma first receive curative-intent treatment, such as with liver resection or ablation. Direct-acting antiviral therapy can begin 4-6 months later, once there has been time to confirm response to hepatocellular carcinoma treatment.

For patients who are listed for liver transplantation, timing of DAA therapy “should be determined on a case-by-case basis with consideration of median wait times for the region, availability of HCV-positive organs, and degree of liver dysfunction,” they added. “For example, DAA therapy may be beneficial pretransplant for patients in regions with long wait times or limited hepatitis C virus–positive donor organ availability, whereas therapy may be delayed until posttransplant in regions with shorter wait times or a high proportion of hepatitis C virus–positive donor organs that would otherwise go unused.”

For patients with active intermediate or advanced liver cancer, it remains unclear whether DAA therapy is usually worth the costs and risks, they noted. This is because the likelihood of complete response is lower and the competing risk of death is higher than in patients with earlier-stage hepatocellular carcinoma. Pending further data, they recommend basing the decision on patients’ preferences, tumor burden, degree of liver dysfunction, and life expectancy. At their institutions, the researchers do not treat patients with DAA therapy unless their life expectancy exceeds 2 years.

The experts disclosed research funding from the National Cancer Institute, U.S. Veterans Administration, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Singal reported personal fees or research funding from AbbVie, Bayer, Bristol-Myers Squibb, Eisai, Exact Sciences, Exelixis, Gilead, Glycotest, Roche, and Wako Diagnostics. His coauthors disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Conatus, Genfit, Gilead, Intercept, and Merck.

SOURCE: Singal AG et al. Gastroenterology. 2019 Mar 13. doi: 10.1053/j.gastro.2019.02.046.

Hepatologists and gastroenterologists see multiple and substantial barriers to the use of palliative care in patients with end-stage liver disease, results of a recent survey show.

©Lighthaunter/Thinkstock

Cultural factors, unrealistic expectations of the patient, lack of reimbursement, and competing demands for physicians’ time were some of the barriers to palliative care cited most frequently in the survey, said the researchers, in their report on the survey results that appears in Clinical Gastroenterology and Hepatology.

Moreover, most responding physicians said they felt end-of-life advance care planning discussions take place too late in the course of illness, according to Nneka N. Ufere, MD, of the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, and co-authors of the report.

“Multiple interventions targeted at patients, caregivers, institutions, and clinicians are needed to overcome barriers to improve the delivery of high-quality palliative and end-of-life care for patients with end-stage liver disease,” the researchers said.

Specialty palliative care can improve quality of life for patients with life-limiting conditions such as end-stage liver disease, which is associated with poor quality of life and a median survival of just two years without liver transplant, the authors said.

Advance care planning, in which patients discuss goals and care preferences in light of the expected course of illness, was a “critical component” of palliative care that can improve the quality of end-of-life care, Dr. Ufere and co-authors said.

Unfortunately, palliative care planning services are underutilized in end-stage liver disease, studies show, while rates of timely advance care planning discussions are low.

To find out why, Dr. Ufere and colleagues asked 1,238 physicians to fill out a web-based questionnaire designed to assess their perceptions of barriers to use of palliative care and barriers to timely advance care planning discussions. A total of 396 physicians (32%) completed the survey between February and April 2018.

Sixty percent were transplant hepatologists, and 79% of the survey participants said they worked in a teaching hospital, according to Dr. Ufere and co-authors, who added that no respondents had formal palliative care training.

Almost all respondents (95%) agreed that centers providing care for end-stage liver disease patients should have palliative care services, and most (86%) said they thought such patients would benefit from palliative care earlier in the course of disease.

While most (84%) agreed that a hepatologist was the best provider to discuss advance care planning with the patient, only about one-quarter (27%) said the hepatologist was best suited to provide palliative care, while most (88%) said the palliative care specialist was best for that role.

When asked about patient and caregiver barriers, nearly all respondents (95%) agreed that cultural factors that influenced palliative care perception was an issue, while 93% said patients’ unrealistic expectations was an issue.

Clinician barriers that respondents perceived included competing demands for clinicians’ time, cited by 91%, fear that palliative care might destroy the patient’s hope, cited by 82%, and the misperception that palliative care starts when active treatment ends, cited by 81%.

One potential solution to the competing demands on clinicians’ time would be development of “collaborative care models” between palliative care and hepatology services, according to Dr. Ufere and co-authors.

“Outpatient specialty palliative care visits, ideally temporally coordinated with the hepatology visits, can play a role not only in attending to symptom assessment and ACP, but also in addressing important psychosocial aspects of care, such as patient coping and well-being,” they said in their report on the survey.

Institutional barriers of note included limited reimbursement for time spent providing palliative care, cited by 76% and lack of a palliative care service, cited by nearly half (46%).

Some of the most commonly affirmed barriers to timely advance care planning discussions included insufficient training in end-of-life communication issues, and insufficient training in cultural competency issues related to the discussions.

In terms of timeliness, only 17% said advance care planning discussions happen at the right time, while 81% said they happen too late, investigators found.

Funding for the research came from the National Institutes of Health. The authors had no disclosures or conflicts of interest related to the report.

SOURCE: Ufere NN, et al. Clin Gastroenterol Hepatol. 2019 Mar 15. doi: 10.1016/j.cgh.2019.03.022.

Hepatologists and gastroenterologists see multiple and substantial barriers to the use of palliative care in patients with end-stage liver disease, results of a recent survey show.

©Lighthaunter/Thinkstock

Cultural factors, unrealistic expectations of the patient, lack of reimbursement, and competing demands for physicians’ time were some of the barriers to palliative care cited most frequently in the survey, said the researchers, in their report on the survey results that appears in Clinical Gastroenterology and Hepatology.

Moreover, most responding physicians said they felt end-of-life advance care planning discussions take place too late in the course of illness, according to Nneka N. Ufere, MD, of the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, and co-authors of the report.

“Multiple interventions targeted at patients, caregivers, institutions, and clinicians are needed to overcome barriers to improve the delivery of high-quality palliative and end-of-life care for patients with end-stage liver disease,” the researchers said.

Specialty palliative care can improve quality of life for patients with life-limiting conditions such as end-stage liver disease, which is associated with poor quality of life and a median survival of just two years without liver transplant, the authors said.

Advance care planning, in which patients discuss goals and care preferences in light of the expected course of illness, was a “critical component” of palliative care that can improve the quality of end-of-life care, Dr. Ufere and co-authors said.

Unfortunately, palliative care planning services are underutilized in end-stage liver disease, studies show, while rates of timely advance care planning discussions are low.

To find out why, Dr. Ufere and colleagues asked 1,238 physicians to fill out a web-based questionnaire designed to assess their perceptions of barriers to use of palliative care and barriers to timely advance care planning discussions. A total of 396 physicians (32%) completed the survey between February and April 2018.

Sixty percent were transplant hepatologists, and 79% of the survey participants said they worked in a teaching hospital, according to Dr. Ufere and co-authors, who added that no respondents had formal palliative care training.

Almost all respondents (95%) agreed that centers providing care for end-stage liver disease patients should have palliative care services, and most (86%) said they thought such patients would benefit from palliative care earlier in the course of disease.

While most (84%) agreed that a hepatologist was the best provider to discuss advance care planning with the patient, only about one-quarter (27%) said the hepatologist was best suited to provide palliative care, while most (88%) said the palliative care specialist was best for that role.

When asked about patient and caregiver barriers, nearly all respondents (95%) agreed that cultural factors that influenced palliative care perception was an issue, while 93% said patients’ unrealistic expectations was an issue.

Clinician barriers that respondents perceived included competing demands for clinicians’ time, cited by 91%, fear that palliative care might destroy the patient’s hope, cited by 82%, and the misperception that palliative care starts when active treatment ends, cited by 81%.

One potential solution to the competing demands on clinicians’ time would be development of “collaborative care models” between palliative care and hepatology services, according to Dr. Ufere and co-authors.

“Outpatient specialty palliative care visits, ideally temporally coordinated with the hepatology visits, can play a role not only in attending to symptom assessment and ACP, but also in addressing important psychosocial aspects of care, such as patient coping and well-being,” they said in their report on the survey.

Institutional barriers of note included limited reimbursement for time spent providing palliative care, cited by 76% and lack of a palliative care service, cited by nearly half (46%).

Some of the most commonly affirmed barriers to timely advance care planning discussions included insufficient training in end-of-life communication issues, and insufficient training in cultural competency issues related to the discussions.

In terms of timeliness, only 17% said advance care planning discussions happen at the right time, while 81% said they happen too late, investigators found.

Funding for the research came from the National Institutes of Health. The authors had no disclosures or conflicts of interest related to the report.

SOURCE: Ufere NN, et al. Clin Gastroenterol Hepatol. 2019 Mar 15. doi: 10.1016/j.cgh.2019.03.022.

Hepatologists and gastroenterologists see multiple and substantial barriers to the use of palliative care in patients with end-stage liver disease, results of a recent survey show.

©Lighthaunter/Thinkstock

Cultural factors, unrealistic expectations of the patient, lack of reimbursement, and competing demands for physicians’ time were some of the barriers to palliative care cited most frequently in the survey, said the researchers, in their report on the survey results that appears in Clinical Gastroenterology and Hepatology.

Moreover, most responding physicians said they felt end-of-life advance care planning discussions take place too late in the course of illness, according to Nneka N. Ufere, MD, of the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, and co-authors of the report.

“Multiple interventions targeted at patients, caregivers, institutions, and clinicians are needed to overcome barriers to improve the delivery of high-quality palliative and end-of-life care for patients with end-stage liver disease,” the researchers said.

Specialty palliative care can improve quality of life for patients with life-limiting conditions such as end-stage liver disease, which is associated with poor quality of life and a median survival of just two years without liver transplant, the authors said.

Advance care planning, in which patients discuss goals and care preferences in light of the expected course of illness, was a “critical component” of palliative care that can improve the quality of end-of-life care, Dr. Ufere and co-authors said.

Unfortunately, palliative care planning services are underutilized in end-stage liver disease, studies show, while rates of timely advance care planning discussions are low.

To find out why, Dr. Ufere and colleagues asked 1,238 physicians to fill out a web-based questionnaire designed to assess their perceptions of barriers to use of palliative care and barriers to timely advance care planning discussions. A total of 396 physicians (32%) completed the survey between February and April 2018.

Sixty percent were transplant hepatologists, and 79% of the survey participants said they worked in a teaching hospital, according to Dr. Ufere and co-authors, who added that no respondents had formal palliative care training.

Almost all respondents (95%) agreed that centers providing care for end-stage liver disease patients should have palliative care services, and most (86%) said they thought such patients would benefit from palliative care earlier in the course of disease.

While most (84%) agreed that a hepatologist was the best provider to discuss advance care planning with the patient, only about one-quarter (27%) said the hepatologist was best suited to provide palliative care, while most (88%) said the palliative care specialist was best for that role.

When asked about patient and caregiver barriers, nearly all respondents (95%) agreed that cultural factors that influenced palliative care perception was an issue, while 93% said patients’ unrealistic expectations was an issue.

Clinician barriers that respondents perceived included competing demands for clinicians’ time, cited by 91%, fear that palliative care might destroy the patient’s hope, cited by 82%, and the misperception that palliative care starts when active treatment ends, cited by 81%.

One potential solution to the competing demands on clinicians’ time would be development of “collaborative care models” between palliative care and hepatology services, according to Dr. Ufere and co-authors.

“Outpatient specialty palliative care visits, ideally temporally coordinated with the hepatology visits, can play a role not only in attending to symptom assessment and ACP, but also in addressing important psychosocial aspects of care, such as patient coping and well-being,” they said in their report on the survey.

Institutional barriers of note included limited reimbursement for time spent providing palliative care, cited by 76% and lack of a palliative care service, cited by nearly half (46%).

Some of the most commonly affirmed barriers to timely advance care planning discussions included insufficient training in end-of-life communication issues, and insufficient training in cultural competency issues related to the discussions.

In terms of timeliness, only 17% said advance care planning discussions happen at the right time, while 81% said they happen too late, investigators found.

Funding for the research came from the National Institutes of Health. The authors had no disclosures or conflicts of interest related to the report.

SOURCE: Ufere NN, et al. Clin Gastroenterol Hepatol. 2019 Mar 15. doi: 10.1016/j.cgh.2019.03.022.

Adults with nonalcoholic fatty liver disease (NAFLD) were more likely to implement the Mediterranean diet when they had greater nutritional knowledge and skills, family support, nutritional care, and positive reinforcement in the media, according to an in-depth study of 19 patients.

snyferok/ThinkStock

Barriers to adopting the diet included “an obesogenic environment, life stressors, and demand for convenience. Poor understanding of the causes and significance of NAFLD adversely affected readiness to change dietary habits,” wrote Laura Haigh of Newcastle University in Newcastle Upon Tyne, England, and associates. The study, which included both standard quantitative methods and semistructured interviews, was published in Clinical Gastroenterology and Hepatology.

The Mediterranean diet emphasizes vegetables, legumes, fish, fruits, whole grains, nuts, and olive oil in lieu of processed foods, sweets, saturated fats, and red meat. This diet has been definitively shown to improve insulin sensitivity and steatosis, even when patients do not lose weight. This has sparked interest in its use for NAFLD disease, but keys to its successful adoption in Northern Europe are not well understood.

Therefore, the researchers recruited 19 NAFLD patients from a tertiary care center in the United Kingdom for a 12-week Mediterranean diet intervention. Most were female, white, in their late 50s, obese, and had type 2 diabetes. “Participants were taught behavioral strategies through the provision of shopping lists, meal planners, and recipes. No advice was given on calorie allowances or physical activities,” the investigators noted.

By using a 14-point assessment tool, they found that dietary adherence rose significantly at 12 weeks, compared with baseline (P = .006). In all, 79% of patients lost weight (mean, 2.4 kg; P = .001 versus baseline), and 72% significantly increased their serum level of HDL cholesterol. Interviews linked successful adoption of the diet with diverse factors, such as believing that NAFLD is lifestyle associated, realizing that healthier nutrition can improve health outcomes, and having access to transportation and budget grocery stories. Patients generally saw the Mediterranean diet as flexible and affordable, but they struggled to adopt it if they worked irregular hours, experienced substantial life stress or were very busy, or tended to eat for self-reward or self-comfort.

Other cited barriers included “diet saboteurs” (including spouses), the plethora of unhealthy foods available in patients’ environments, low nutritional or medical knowledge, and cultural, social, or taste incompatibility, the researchers reported. Taken together, the findings underscore “the futility of a one-size-fits-all approach” when implementing the Mediterranean diet in this population, they concluded. Instead, their patients valued a collaborative, tailored approach – ideally one that incorporated in-person and group-based treatment, as well as online support.

Funders included the North East of England hub of the Allied Health Professions Research Network, the Elucidating Pathways of Steatohepatitis consortium, the Horizon 2020 Framework Program of the European Union, and the Newcastle NIHR Biomedical Research Centre. The researchers reported having no conflicts of interest.

SOURCE: Haigh L et al. Clin Gastroenterol Hepatol. 2018 Oct 31. doi: 10.1016/j.cgh.2018.10.044.

Adults with nonalcoholic fatty liver disease (NAFLD) were more likely to implement the Mediterranean diet when they had greater nutritional knowledge and skills, family support, nutritional care, and positive reinforcement in the media, according to an in-depth study of 19 patients.

snyferok/ThinkStock

Barriers to adopting the diet included “an obesogenic environment, life stressors, and demand for convenience. Poor understanding of the causes and significance of NAFLD adversely affected readiness to change dietary habits,” wrote Laura Haigh of Newcastle University in Newcastle Upon Tyne, England, and associates. The study, which included both standard quantitative methods and semistructured interviews, was published in Clinical Gastroenterology and Hepatology.

The Mediterranean diet emphasizes vegetables, legumes, fish, fruits, whole grains, nuts, and olive oil in lieu of processed foods, sweets, saturated fats, and red meat. This diet has been definitively shown to improve insulin sensitivity and steatosis, even when patients do not lose weight. This has sparked interest in its use for NAFLD disease, but keys to its successful adoption in Northern Europe are not well understood.

Therefore, the researchers recruited 19 NAFLD patients from a tertiary care center in the United Kingdom for a 12-week Mediterranean diet intervention. Most were female, white, in their late 50s, obese, and had type 2 diabetes. “Participants were taught behavioral strategies through the provision of shopping lists, meal planners, and recipes. No advice was given on calorie allowances or physical activities,” the investigators noted.

By using a 14-point assessment tool, they found that dietary adherence rose significantly at 12 weeks, compared with baseline (P = .006). In all, 79% of patients lost weight (mean, 2.4 kg; P = .001 versus baseline), and 72% significantly increased their serum level of HDL cholesterol. Interviews linked successful adoption of the diet with diverse factors, such as believing that NAFLD is lifestyle associated, realizing that healthier nutrition can improve health outcomes, and having access to transportation and budget grocery stories. Patients generally saw the Mediterranean diet as flexible and affordable, but they struggled to adopt it if they worked irregular hours, experienced substantial life stress or were very busy, or tended to eat for self-reward or self-comfort.

Other cited barriers included “diet saboteurs” (including spouses), the plethora of unhealthy foods available in patients’ environments, low nutritional or medical knowledge, and cultural, social, or taste incompatibility, the researchers reported. Taken together, the findings underscore “the futility of a one-size-fits-all approach” when implementing the Mediterranean diet in this population, they concluded. Instead, their patients valued a collaborative, tailored approach – ideally one that incorporated in-person and group-based treatment, as well as online support.

Funders included the North East of England hub of the Allied Health Professions Research Network, the Elucidating Pathways of Steatohepatitis consortium, the Horizon 2020 Framework Program of the European Union, and the Newcastle NIHR Biomedical Research Centre. The researchers reported having no conflicts of interest.

SOURCE: Haigh L et al. Clin Gastroenterol Hepatol. 2018 Oct 31. doi: 10.1016/j.cgh.2018.10.044.

Adults with nonalcoholic fatty liver disease (NAFLD) were more likely to implement the Mediterranean diet when they had greater nutritional knowledge and skills, family support, nutritional care, and positive reinforcement in the media, according to an in-depth study of 19 patients.

snyferok/ThinkStock

Barriers to adopting the diet included “an obesogenic environment, life stressors, and demand for convenience. Poor understanding of the causes and significance of NAFLD adversely affected readiness to change dietary habits,” wrote Laura Haigh of Newcastle University in Newcastle Upon Tyne, England, and associates. The study, which included both standard quantitative methods and semistructured interviews, was published in Clinical Gastroenterology and Hepatology.

The Mediterranean diet emphasizes vegetables, legumes, fish, fruits, whole grains, nuts, and olive oil in lieu of processed foods, sweets, saturated fats, and red meat. This diet has been definitively shown to improve insulin sensitivity and steatosis, even when patients do not lose weight. This has sparked interest in its use for NAFLD disease, but keys to its successful adoption in Northern Europe are not well understood.

Therefore, the researchers recruited 19 NAFLD patients from a tertiary care center in the United Kingdom for a 12-week Mediterranean diet intervention. Most were female, white, in their late 50s, obese, and had type 2 diabetes. “Participants were taught behavioral strategies through the provision of shopping lists, meal planners, and recipes. No advice was given on calorie allowances or physical activities,” the investigators noted.

By using a 14-point assessment tool, they found that dietary adherence rose significantly at 12 weeks, compared with baseline (P = .006). In all, 79% of patients lost weight (mean, 2.4 kg; P = .001 versus baseline), and 72% significantly increased their serum level of HDL cholesterol. Interviews linked successful adoption of the diet with diverse factors, such as believing that NAFLD is lifestyle associated, realizing that healthier nutrition can improve health outcomes, and having access to transportation and budget grocery stories. Patients generally saw the Mediterranean diet as flexible and affordable, but they struggled to adopt it if they worked irregular hours, experienced substantial life stress or were very busy, or tended to eat for self-reward or self-comfort.

Other cited barriers included “diet saboteurs” (including spouses), the plethora of unhealthy foods available in patients’ environments, low nutritional or medical knowledge, and cultural, social, or taste incompatibility, the researchers reported. Taken together, the findings underscore “the futility of a one-size-fits-all approach” when implementing the Mediterranean diet in this population, they concluded. Instead, their patients valued a collaborative, tailored approach – ideally one that incorporated in-person and group-based treatment, as well as online support.

Funders included the North East of England hub of the Allied Health Professions Research Network, the Elucidating Pathways of Steatohepatitis consortium, the Horizon 2020 Framework Program of the European Union, and the Newcastle NIHR Biomedical Research Centre. The researchers reported having no conflicts of interest.

SOURCE: Haigh L et al. Clin Gastroenterol Hepatol. 2018 Oct 31. doi: 10.1016/j.cgh.2018.10.044.

Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.

Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.

“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.

FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.

“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.

Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.

First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.

The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.

Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).

“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.

Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.

Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.

“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.

“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.

SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.

Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.

Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.

“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.

FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.

“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.

Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.

First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.

The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.

Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).

“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.

Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.

Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.

“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.

“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.

SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.

Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.

Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.

“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.

FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.

“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.

Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.

First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.

The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.

Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).

“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.

Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.

Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.

“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.

“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.

SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.

In a small, first-in-kind study, functional heartburn or reflux hypersensitivity affected fully 75% of patients whose gastroesophageal reflux disease symptoms had not improved with once-daily proton pump inhibitor therapy.

At the same time, proton pump inhibitor (PPI) responders and nonresponders had similar impedance and pH parameters, reported Jason Abdallah, MD, of Case Western Reserve University, Cleveland, and his associates. The findings show “the important role of esophageal hypersensitivity in this patient population.” For these patients, the investigators suggested adding a neuromodulator and possibly psychotherapy, such as cognitive-behavioral therapy, hypnotherapy, relaxation techniques, mindfulness, and biofeedback.

Symptoms in up to 45% of patients with gastroesophageal reflux disease (GERD) persist despite once-daily PPI therapy, Dr. Abdallah and his associates wrote in Clinical Gastroenterology and Hepatology. For the study, they compared reflux characteristics and patterns between 13 patients whose GERD symptoms had fully resolved on standard once-daily PPIs and 16 patients who reported at least twice-weekly heartburn, regurgitation, or both for at least 3 months, despite treatment. Patients in both groups continued PPIs and underwent upper endoscopy and combined esophageal impedance–pH monitoring.

The average age of patients in this study was 54.5 years, with a standard deviation of 14.5 years. Demographic and clinical characteristics were similar between groups, and patients in both groups were receiving omeprazole, esomeprazole, or pantoprazole. Four (31%) PPI responders had abnormal pH test results, as did four (25%) nonresponders. Responders and nonresponders had similar numbers of reflux events; proportions of events that were acidic, weakly acidic, or alkaline; and mean total time with pH less than 4.0.

Additionally, most patients in both groups had normal endoscopic findings. One PPI responder had Los Angeles grade A erosive esophagitis, and two PPI responders had short-segment Barrett’s esophagus. Three PPI responders and two PPI nonresponders had nonobstructive Schatzki rings, and one PPI nonresponder had an esophageal stricture. Finally, five PPI responders (38%) and three nonresponders (19%) had hiatal hernias (P = .41).

In patients with GERD, “PPI failure” does not reflect a unique pattern of reflux events, acid exposure, or nonacidic reflux parameters, Dr. Abdallah and his associates concluded. The fact that most PPI nonresponders had a concurrent functional esophageal disorder – either reflux hypersensitivity or functional heartburn – “support[s] the hypothesis that PPI failure is primarily driven by esophageal hypersensitivity.”

This was a small study – recruitment “was hampered by the invasive nature of some of the procedures,” they wrote. “In addition, it is our experience that many patients who have responded to PPI [therapy] are reluctant to undergo invasive testing as part of a study protocol. Therefore, we believe that these types of prospective, invasive studies are rather difficult to perform but, at the same time, provide essential insight into the understanding of refractory GERD.”

No external funding sources were acknowledged. The senior author reported ties to Ironwood Pharmaceuticals, Mederi Therapeutics, Ethicon, AstraZeneca, and Takeda. The other researchers reported no conflicts of interest.

SOURCE: Abdallah J et al. Clin Gastroenterol Hepatol. 2018 Jun 15. doi: 10.1016/j.cgh.2018.09.006.

In a small, first-in-kind study, functional heartburn or reflux hypersensitivity affected fully 75% of patients whose gastroesophageal reflux disease symptoms had not improved with once-daily proton pump inhibitor therapy.

At the same time, proton pump inhibitor (PPI) responders and nonresponders had similar impedance and pH parameters, reported Jason Abdallah, MD, of Case Western Reserve University, Cleveland, and his associates. The findings show “the important role of esophageal hypersensitivity in this patient population.” For these patients, the investigators suggested adding a neuromodulator and possibly psychotherapy, such as cognitive-behavioral therapy, hypnotherapy, relaxation techniques, mindfulness, and biofeedback.

Symptoms in up to 45% of patients with gastroesophageal reflux disease (GERD) persist despite once-daily PPI therapy, Dr. Abdallah and his associates wrote in Clinical Gastroenterology and Hepatology. For the study, they compared reflux characteristics and patterns between 13 patients whose GERD symptoms had fully resolved on standard once-daily PPIs and 16 patients who reported at least twice-weekly heartburn, regurgitation, or both for at least 3 months, despite treatment. Patients in both groups continued PPIs and underwent upper endoscopy and combined esophageal impedance–pH monitoring.

The average age of patients in this study was 54.5 years, with a standard deviation of 14.5 years. Demographic and clinical characteristics were similar between groups, and patients in both groups were receiving omeprazole, esomeprazole, or pantoprazole. Four (31%) PPI responders had abnormal pH test results, as did four (25%) nonresponders. Responders and nonresponders had similar numbers of reflux events; proportions of events that were acidic, weakly acidic, or alkaline; and mean total time with pH less than 4.0.

Additionally, most patients in both groups had normal endoscopic findings. One PPI responder had Los Angeles grade A erosive esophagitis, and two PPI responders had short-segment Barrett’s esophagus. Three PPI responders and two PPI nonresponders had nonobstructive Schatzki rings, and one PPI nonresponder had an esophageal stricture. Finally, five PPI responders (38%) and three nonresponders (19%) had hiatal hernias (P = .41).

In patients with GERD, “PPI failure” does not reflect a unique pattern of reflux events, acid exposure, or nonacidic reflux parameters, Dr. Abdallah and his associates concluded. The fact that most PPI nonresponders had a concurrent functional esophageal disorder – either reflux hypersensitivity or functional heartburn – “support[s] the hypothesis that PPI failure is primarily driven by esophageal hypersensitivity.”

This was a small study – recruitment “was hampered by the invasive nature of some of the procedures,” they wrote. “In addition, it is our experience that many patients who have responded to PPI [therapy] are reluctant to undergo invasive testing as part of a study protocol. Therefore, we believe that these types of prospective, invasive studies are rather difficult to perform but, at the same time, provide essential insight into the understanding of refractory GERD.”

No external funding sources were acknowledged. The senior author reported ties to Ironwood Pharmaceuticals, Mederi Therapeutics, Ethicon, AstraZeneca, and Takeda. The other researchers reported no conflicts of interest.

SOURCE: Abdallah J et al. Clin Gastroenterol Hepatol. 2018 Jun 15. doi: 10.1016/j.cgh.2018.09.006.

In a small, first-in-kind study, functional heartburn or reflux hypersensitivity affected fully 75% of patients whose gastroesophageal reflux disease symptoms had not improved with once-daily proton pump inhibitor therapy.

At the same time, proton pump inhibitor (PPI) responders and nonresponders had similar impedance and pH parameters, reported Jason Abdallah, MD, of Case Western Reserve University, Cleveland, and his associates. The findings show “the important role of esophageal hypersensitivity in this patient population.” For these patients, the investigators suggested adding a neuromodulator and possibly psychotherapy, such as cognitive-behavioral therapy, hypnotherapy, relaxation techniques, mindfulness, and biofeedback.

Symptoms in up to 45% of patients with gastroesophageal reflux disease (GERD) persist despite once-daily PPI therapy, Dr. Abdallah and his associates wrote in Clinical Gastroenterology and Hepatology. For the study, they compared reflux characteristics and patterns between 13 patients whose GERD symptoms had fully resolved on standard once-daily PPIs and 16 patients who reported at least twice-weekly heartburn, regurgitation, or both for at least 3 months, despite treatment. Patients in both groups continued PPIs and underwent upper endoscopy and combined esophageal impedance–pH monitoring.

The average age of patients in this study was 54.5 years, with a standard deviation of 14.5 years. Demographic and clinical characteristics were similar between groups, and patients in both groups were receiving omeprazole, esomeprazole, or pantoprazole. Four (31%) PPI responders had abnormal pH test results, as did four (25%) nonresponders. Responders and nonresponders had similar numbers of reflux events; proportions of events that were acidic, weakly acidic, or alkaline; and mean total time with pH less than 4.0.

Additionally, most patients in both groups had normal endoscopic findings. One PPI responder had Los Angeles grade A erosive esophagitis, and two PPI responders had short-segment Barrett’s esophagus. Three PPI responders and two PPI nonresponders had nonobstructive Schatzki rings, and one PPI nonresponder had an esophageal stricture. Finally, five PPI responders (38%) and three nonresponders (19%) had hiatal hernias (P = .41).

In patients with GERD, “PPI failure” does not reflect a unique pattern of reflux events, acid exposure, or nonacidic reflux parameters, Dr. Abdallah and his associates concluded. The fact that most PPI nonresponders had a concurrent functional esophageal disorder – either reflux hypersensitivity or functional heartburn – “support[s] the hypothesis that PPI failure is primarily driven by esophageal hypersensitivity.”

This was a small study – recruitment “was hampered by the invasive nature of some of the procedures,” they wrote. “In addition, it is our experience that many patients who have responded to PPI [therapy] are reluctant to undergo invasive testing as part of a study protocol. Therefore, we believe that these types of prospective, invasive studies are rather difficult to perform but, at the same time, provide essential insight into the understanding of refractory GERD.”

No external funding sources were acknowledged. The senior author reported ties to Ironwood Pharmaceuticals, Mederi Therapeutics, Ethicon, AstraZeneca, and Takeda. The other researchers reported no conflicts of interest.

SOURCE: Abdallah J et al. Clin Gastroenterol Hepatol. 2018 Jun 15. doi: 10.1016/j.cgh.2018.09.006.