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Nanoparticle encapsulation may unlock HCC therapy
Nanoparticle encapsulation may enable targeting of aberrant glucose metabolism in hepatocellular carcinoma (HCC), potentially amplifying the effects of existing therapies and overcoming resistance mechanisms, according to investigators.
In a preclinical trial involving cell lines, xenograft tumors, and mouse models, encapsulated 2-deoxy-D-glucose (2DG) nanoparticles enhanced the antineoplastic effects of sorafenib and checkpoint inhibitors and suppressed anti-programmed cell death protein 1 (PD1)–resistant tumors, reported lead author Kyo Sasaki, PhD, of Kyushu University in Fukuoka, Japan, and colleagues.
As a glycolysis inhibitor, 2DG acts against the Warburg effect, a cancer immune-resistance mechanism “in which a substantial amount of pyruvate is reduced to lactic acid instead of being directed into mitochondria,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology.
But this isn’t new information, and Dr. Sasaki and colleagues weren’t the first to address the Warburg effect with 2DG; two clinical trials reported signs of efficacy in patients with solid tumors, one in 2010 and the other in 2013.
“However, 2DG does not seem to have a significant effect on tumor growth at a dose that does not induce serious adverse effects,” wrote Dr. Sasaki and colleagues. “These results suggest a need to develop an efficient drug delivery system for 2DG.”
The investigators turned to nanoparticles, which accumulate in tumor tissue more than healthy tissue, thereby limiting off-target toxicity. Specifically, they encapsulated 2DG in nanoparticles of poly(lactic-co-glycolic acid) (PLGA), a Food and Drug Administration–approved biodegradable polymer.
After characterizing the physical properties of the encapsulated 2DG nanoparticles (2DG-PLGA-NPs), and observing tumor localization in nude mice with xenograft liver tumors, the investigators assessed cytotoxic effects.
Treatment resulted in “significant growth reduction” of not only xenograft liver tumors, but also xenograft renal, colon, and pancreatic tumors, “indicating the potential antitumor effects of this method against various tumors.” Furthermore, mice treated with encapsulated 2DG nanoparticles had significantly less weight loss compared with those receiving conventional 2DG, suggesting a reduction in 2DG-related adverse effects.
Additional experiments involving two immunocompetent mouse models with multiple large liver tumors added data to support to the relative efficacy of encapsulated versus nonencapsulated 2DG. Both mouse models had significant reductions in liver tumors when treated with 2DG-PLGA-NPs; in contrast, treatment with 2DG alone reduced tumor number in only one of the two mouse models and to a lesser degree than treatment with 2DG nanoparticles.
Further in vivo and ex vivo testing revealed that encapsulated 2DG nanoparticles exerted their cytotoxic effects via endoplasmic reticulum stress, oxidative stress, and inactivation of mTOR. Simultaneously, treatment was associated with CD8+ T-cell migration into tumor tissue via increased glucose uptake and IFN-gamma production in CD8+ T cells, reduced lactate production in tumors, and increased production of CXCL9/CXCL10/CXCL11 in both the tumors and CD8+ T cells.
According to the investigators, these findings suggested that 2DG-PLGA-NPs might upregulate PD-1 positive T cells in tumors, thereby enhancing the effects of a checkpoint inhibitor. Indeed, when syngeneic mice with anti-PD-1–resistant tumors were treated with encapsulated 2DG nanoparticles, the investigators observed significant reductions in tumor growth, compared with treatment using an isotype control, PLGA alone, or an anti-PD-1 antibody. And in nude mice with xenograft tumors, combination therapy with 2DG-PLGA-NPs and sorafenib significantly reduced tumor growth, compared with no treatment, 2DG, PLGA, or PLGA with sorafenib.
“2DG-PLGA-NPs amplified the antitumor effect of anti-PD1 or sorafenib, and showed an antitumor effect against anti-PD1–resistant tumors,” the investigators wrote.
Dr. Sasaki and colleagues also noted that encapsulated 2DG nanoparticles did not accumulate in nontumorous cirrhotic hepatocytes, which suggests that treatment would be safe for patients with chronic liver diseases.
“Another practical concern is the extent to which 2DG is effectively taken up by HCC cells,” the investigators wrote.
PET showed that the hepatic accumulation rate of F-2-fluoro-2-deoxyglucose (F-FDG), a radioactive tracer of 2DG, was 50% in well-differentiated HCC, and “much higher” in sorafenib-resistant HCC cells and poorly and moderately differentiated HCC cells.
“Thus, 2DG-PLGA-NPs are expected to be good therapeutic agent candidates for patients with advanced HCC,” the investigators concluded.
The investigators disclosed no conflicts of interest. Some authors received grants from the Japan Society for the Promotion of Science.
Treatment of cancer remains a large task, also in the far future. Noninvasive imaging of tumors and thereby potential early diagnosis will very likely be the key for an ever-improving cancer therapy. The so-called Warburg effect of tumors remains a key dogma in oncologic diagnosis: Most tumors consume glucose at a higher rate than normal tissues. However, energetically, this glucose consumption is quite inefficient, and questions remain here. A dogma that maybe never gets “old” was challenged and apparently is revisited here using cutting edge nanotechnologies.
Novel avenues appear to get opened by drug encapsulation as presented by Dr. Sasaki and colleagues. Drug encapsulation in general allows at first a very basic principle: protecting the body from the drug, and also the drug from the body. Notably, only drug encapsulation through nanomedicines enables mRNA-based vaccines for the current pandemic. Here, encapsulation has pointed to a way to beat tumors with their own armory and survival mechanism: Hitting the glucose metabolism.
Nevertheless, the highly efficient route into the malignant cells is surely worth additional investigation: Which molecular routes are taken by the encapsulated drug here? Do the particles also accumulate in macrophages? If yes, in which, and if not, how can the PLGA formulation overcome the accumulation in macrophages, the “big eaters,” that are known to clear vast amounts of nanomaterials from the body?
Matthias Bartneck, PhD, PD, is a group leader specialized in liver immunology at Uniklinik RWTH Aachen (Germany). He has received strong support to develop cell type–specific interventions with tailored drugs for encapsulated nucleic acids, particularly different types of RNA. Dr. Bartneck is actively developing smart nanomedicines to find new cures for liver disease with high unmet need. He has no conflicts.
Treatment of cancer remains a large task, also in the far future. Noninvasive imaging of tumors and thereby potential early diagnosis will very likely be the key for an ever-improving cancer therapy. The so-called Warburg effect of tumors remains a key dogma in oncologic diagnosis: Most tumors consume glucose at a higher rate than normal tissues. However, energetically, this glucose consumption is quite inefficient, and questions remain here. A dogma that maybe never gets “old” was challenged and apparently is revisited here using cutting edge nanotechnologies.
Novel avenues appear to get opened by drug encapsulation as presented by Dr. Sasaki and colleagues. Drug encapsulation in general allows at first a very basic principle: protecting the body from the drug, and also the drug from the body. Notably, only drug encapsulation through nanomedicines enables mRNA-based vaccines for the current pandemic. Here, encapsulation has pointed to a way to beat tumors with their own armory and survival mechanism: Hitting the glucose metabolism.
Nevertheless, the highly efficient route into the malignant cells is surely worth additional investigation: Which molecular routes are taken by the encapsulated drug here? Do the particles also accumulate in macrophages? If yes, in which, and if not, how can the PLGA formulation overcome the accumulation in macrophages, the “big eaters,” that are known to clear vast amounts of nanomaterials from the body?
Matthias Bartneck, PhD, PD, is a group leader specialized in liver immunology at Uniklinik RWTH Aachen (Germany). He has received strong support to develop cell type–specific interventions with tailored drugs for encapsulated nucleic acids, particularly different types of RNA. Dr. Bartneck is actively developing smart nanomedicines to find new cures for liver disease with high unmet need. He has no conflicts.
Treatment of cancer remains a large task, also in the far future. Noninvasive imaging of tumors and thereby potential early diagnosis will very likely be the key for an ever-improving cancer therapy. The so-called Warburg effect of tumors remains a key dogma in oncologic diagnosis: Most tumors consume glucose at a higher rate than normal tissues. However, energetically, this glucose consumption is quite inefficient, and questions remain here. A dogma that maybe never gets “old” was challenged and apparently is revisited here using cutting edge nanotechnologies.
Novel avenues appear to get opened by drug encapsulation as presented by Dr. Sasaki and colleagues. Drug encapsulation in general allows at first a very basic principle: protecting the body from the drug, and also the drug from the body. Notably, only drug encapsulation through nanomedicines enables mRNA-based vaccines for the current pandemic. Here, encapsulation has pointed to a way to beat tumors with their own armory and survival mechanism: Hitting the glucose metabolism.
Nevertheless, the highly efficient route into the malignant cells is surely worth additional investigation: Which molecular routes are taken by the encapsulated drug here? Do the particles also accumulate in macrophages? If yes, in which, and if not, how can the PLGA formulation overcome the accumulation in macrophages, the “big eaters,” that are known to clear vast amounts of nanomaterials from the body?
Matthias Bartneck, PhD, PD, is a group leader specialized in liver immunology at Uniklinik RWTH Aachen (Germany). He has received strong support to develop cell type–specific interventions with tailored drugs for encapsulated nucleic acids, particularly different types of RNA. Dr. Bartneck is actively developing smart nanomedicines to find new cures for liver disease with high unmet need. He has no conflicts.
Nanoparticle encapsulation may enable targeting of aberrant glucose metabolism in hepatocellular carcinoma (HCC), potentially amplifying the effects of existing therapies and overcoming resistance mechanisms, according to investigators.
In a preclinical trial involving cell lines, xenograft tumors, and mouse models, encapsulated 2-deoxy-D-glucose (2DG) nanoparticles enhanced the antineoplastic effects of sorafenib and checkpoint inhibitors and suppressed anti-programmed cell death protein 1 (PD1)–resistant tumors, reported lead author Kyo Sasaki, PhD, of Kyushu University in Fukuoka, Japan, and colleagues.
As a glycolysis inhibitor, 2DG acts against the Warburg effect, a cancer immune-resistance mechanism “in which a substantial amount of pyruvate is reduced to lactic acid instead of being directed into mitochondria,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology.
But this isn’t new information, and Dr. Sasaki and colleagues weren’t the first to address the Warburg effect with 2DG; two clinical trials reported signs of efficacy in patients with solid tumors, one in 2010 and the other in 2013.
“However, 2DG does not seem to have a significant effect on tumor growth at a dose that does not induce serious adverse effects,” wrote Dr. Sasaki and colleagues. “These results suggest a need to develop an efficient drug delivery system for 2DG.”
The investigators turned to nanoparticles, which accumulate in tumor tissue more than healthy tissue, thereby limiting off-target toxicity. Specifically, they encapsulated 2DG in nanoparticles of poly(lactic-co-glycolic acid) (PLGA), a Food and Drug Administration–approved biodegradable polymer.
After characterizing the physical properties of the encapsulated 2DG nanoparticles (2DG-PLGA-NPs), and observing tumor localization in nude mice with xenograft liver tumors, the investigators assessed cytotoxic effects.
Treatment resulted in “significant growth reduction” of not only xenograft liver tumors, but also xenograft renal, colon, and pancreatic tumors, “indicating the potential antitumor effects of this method against various tumors.” Furthermore, mice treated with encapsulated 2DG nanoparticles had significantly less weight loss compared with those receiving conventional 2DG, suggesting a reduction in 2DG-related adverse effects.
Additional experiments involving two immunocompetent mouse models with multiple large liver tumors added data to support to the relative efficacy of encapsulated versus nonencapsulated 2DG. Both mouse models had significant reductions in liver tumors when treated with 2DG-PLGA-NPs; in contrast, treatment with 2DG alone reduced tumor number in only one of the two mouse models and to a lesser degree than treatment with 2DG nanoparticles.
Further in vivo and ex vivo testing revealed that encapsulated 2DG nanoparticles exerted their cytotoxic effects via endoplasmic reticulum stress, oxidative stress, and inactivation of mTOR. Simultaneously, treatment was associated with CD8+ T-cell migration into tumor tissue via increased glucose uptake and IFN-gamma production in CD8+ T cells, reduced lactate production in tumors, and increased production of CXCL9/CXCL10/CXCL11 in both the tumors and CD8+ T cells.
According to the investigators, these findings suggested that 2DG-PLGA-NPs might upregulate PD-1 positive T cells in tumors, thereby enhancing the effects of a checkpoint inhibitor. Indeed, when syngeneic mice with anti-PD-1–resistant tumors were treated with encapsulated 2DG nanoparticles, the investigators observed significant reductions in tumor growth, compared with treatment using an isotype control, PLGA alone, or an anti-PD-1 antibody. And in nude mice with xenograft tumors, combination therapy with 2DG-PLGA-NPs and sorafenib significantly reduced tumor growth, compared with no treatment, 2DG, PLGA, or PLGA with sorafenib.
“2DG-PLGA-NPs amplified the antitumor effect of anti-PD1 or sorafenib, and showed an antitumor effect against anti-PD1–resistant tumors,” the investigators wrote.
Dr. Sasaki and colleagues also noted that encapsulated 2DG nanoparticles did not accumulate in nontumorous cirrhotic hepatocytes, which suggests that treatment would be safe for patients with chronic liver diseases.
“Another practical concern is the extent to which 2DG is effectively taken up by HCC cells,” the investigators wrote.
PET showed that the hepatic accumulation rate of F-2-fluoro-2-deoxyglucose (F-FDG), a radioactive tracer of 2DG, was 50% in well-differentiated HCC, and “much higher” in sorafenib-resistant HCC cells and poorly and moderately differentiated HCC cells.
“Thus, 2DG-PLGA-NPs are expected to be good therapeutic agent candidates for patients with advanced HCC,” the investigators concluded.
The investigators disclosed no conflicts of interest. Some authors received grants from the Japan Society for the Promotion of Science.
Nanoparticle encapsulation may enable targeting of aberrant glucose metabolism in hepatocellular carcinoma (HCC), potentially amplifying the effects of existing therapies and overcoming resistance mechanisms, according to investigators.
In a preclinical trial involving cell lines, xenograft tumors, and mouse models, encapsulated 2-deoxy-D-glucose (2DG) nanoparticles enhanced the antineoplastic effects of sorafenib and checkpoint inhibitors and suppressed anti-programmed cell death protein 1 (PD1)–resistant tumors, reported lead author Kyo Sasaki, PhD, of Kyushu University in Fukuoka, Japan, and colleagues.
As a glycolysis inhibitor, 2DG acts against the Warburg effect, a cancer immune-resistance mechanism “in which a substantial amount of pyruvate is reduced to lactic acid instead of being directed into mitochondria,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology.
But this isn’t new information, and Dr. Sasaki and colleagues weren’t the first to address the Warburg effect with 2DG; two clinical trials reported signs of efficacy in patients with solid tumors, one in 2010 and the other in 2013.
“However, 2DG does not seem to have a significant effect on tumor growth at a dose that does not induce serious adverse effects,” wrote Dr. Sasaki and colleagues. “These results suggest a need to develop an efficient drug delivery system for 2DG.”
The investigators turned to nanoparticles, which accumulate in tumor tissue more than healthy tissue, thereby limiting off-target toxicity. Specifically, they encapsulated 2DG in nanoparticles of poly(lactic-co-glycolic acid) (PLGA), a Food and Drug Administration–approved biodegradable polymer.
After characterizing the physical properties of the encapsulated 2DG nanoparticles (2DG-PLGA-NPs), and observing tumor localization in nude mice with xenograft liver tumors, the investigators assessed cytotoxic effects.
Treatment resulted in “significant growth reduction” of not only xenograft liver tumors, but also xenograft renal, colon, and pancreatic tumors, “indicating the potential antitumor effects of this method against various tumors.” Furthermore, mice treated with encapsulated 2DG nanoparticles had significantly less weight loss compared with those receiving conventional 2DG, suggesting a reduction in 2DG-related adverse effects.
Additional experiments involving two immunocompetent mouse models with multiple large liver tumors added data to support to the relative efficacy of encapsulated versus nonencapsulated 2DG. Both mouse models had significant reductions in liver tumors when treated with 2DG-PLGA-NPs; in contrast, treatment with 2DG alone reduced tumor number in only one of the two mouse models and to a lesser degree than treatment with 2DG nanoparticles.
Further in vivo and ex vivo testing revealed that encapsulated 2DG nanoparticles exerted their cytotoxic effects via endoplasmic reticulum stress, oxidative stress, and inactivation of mTOR. Simultaneously, treatment was associated with CD8+ T-cell migration into tumor tissue via increased glucose uptake and IFN-gamma production in CD8+ T cells, reduced lactate production in tumors, and increased production of CXCL9/CXCL10/CXCL11 in both the tumors and CD8+ T cells.
According to the investigators, these findings suggested that 2DG-PLGA-NPs might upregulate PD-1 positive T cells in tumors, thereby enhancing the effects of a checkpoint inhibitor. Indeed, when syngeneic mice with anti-PD-1–resistant tumors were treated with encapsulated 2DG nanoparticles, the investigators observed significant reductions in tumor growth, compared with treatment using an isotype control, PLGA alone, or an anti-PD-1 antibody. And in nude mice with xenograft tumors, combination therapy with 2DG-PLGA-NPs and sorafenib significantly reduced tumor growth, compared with no treatment, 2DG, PLGA, or PLGA with sorafenib.
“2DG-PLGA-NPs amplified the antitumor effect of anti-PD1 or sorafenib, and showed an antitumor effect against anti-PD1–resistant tumors,” the investigators wrote.
Dr. Sasaki and colleagues also noted that encapsulated 2DG nanoparticles did not accumulate in nontumorous cirrhotic hepatocytes, which suggests that treatment would be safe for patients with chronic liver diseases.
“Another practical concern is the extent to which 2DG is effectively taken up by HCC cells,” the investigators wrote.
PET showed that the hepatic accumulation rate of F-2-fluoro-2-deoxyglucose (F-FDG), a radioactive tracer of 2DG, was 50% in well-differentiated HCC, and “much higher” in sorafenib-resistant HCC cells and poorly and moderately differentiated HCC cells.
“Thus, 2DG-PLGA-NPs are expected to be good therapeutic agent candidates for patients with advanced HCC,” the investigators concluded.
The investigators disclosed no conflicts of interest. Some authors received grants from the Japan Society for the Promotion of Science.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
AGA Clinical Practice Update: Bariatric surgery in patients with cirrhosis
Obesity, a risk factor for nonalcoholic fatty liver disease (NAFLD) and a prevalent comorbidity among people with cirrhosis of all etiologies, is associated with a number of untoward health outcomes, and weight loss is an important goal, according to a clinical practice update from the American Gastroenterological Association. According to one study cited in the update, approximately 30% of patients with cirrhosis have comorbid obesity, and this figure may increase even further as the epidemic of NAFLD progresses.
For obese patients with cirrhosis, weight loss “is an important therapeutic goal” because obesity heightens risks of portal vein thrombosis, portal hypertension, hepatocellular carcinoma, liver failure in acute on chronic liver disease, and other concerns. Despite no longer being an absolute contraindication, obesity can also complicate liver transplantation considerations, Heather Patton, MD, of the Veterans Affairs San Diego Healthcare System and associates wrote in Clinical Gastroenterology and Hepatology. Consideration of individuals with cirrhosis, however, requires careful scrutiny of surgical candidacy, appropriate resources for care of patients with advanced liver disease, and a high-volume bariatric surgical center given the inherent risks of surgical procedures in this patient population.
For patients with cirrhosis and obesity, laparoscopic sleeve gastrectomy is probably the best option for bariatric surgery because it preserves endoscopic access to the biliary tree, facilitates gradual weight loss, and does not cause malabsorption, according to the update.
Clinicians and patients should time bariatric surgery based on liver disease stage – for patients with decompensated disease, surgery should be performed only at the same time as or after liver transplantation, the experts wrote. Clinicians should also evaluate candidacy for liver transplantation before bariatric surgery “so that patients who are ineligible for transplant (and their families) have a clear understanding of this, avoiding the need for the medical team to address this issue urgently if the patient’s condition deteriorates postoperatively.”
One review suggested that bariatric surgery is “the most effective and durable” means of weight loss, according to the authors of the update; however, another review suggested increased surgical risk for bariatric surgery among patients with cirrhosis, so the update’s authors advised individualized risk-benefit assessments. These assessments are made even more complicated by scarcity of relevant randomized trial data, so the experts identified PubMed-indexed, peer-reviewed articles published between 2000 and 2020 and used these to make 10 best practice advice statements for bariatric surgery in obese patients with cirrhosis.
The surgical, anesthesia, and medical teams must be well versed in assessing and operating on patients with portal hypertension and cirrhosis and in managing these patients postoperatively, the experts wrote. The preoperative assessment should include cirrhosis status (compensated versus decompensated), the presence and severity of sarcopenia, ascites, and portal hypertension, and candidacy for liver transplantation. It is vital to check for clinically significant portal hypertension (CSPH) because endoscopic devices should not be used in patients with gastric and/or esophageal varices. To do so, upper endoscopy and cross-sectional imaging are advised, pending better data on noninvasive assessment methods. For patients without CSPH, endoscopic bariatric treatment can be somewhat less effective for weight loss but also might be less likely to lead to postoperative complications. However, head-to-head and long-term safety data are not yet available.
The experts also noted that bariatric surgery increases the effects (blood levels) of alcohol and can increase patients’ risk for developing an alcohol use disorder. Therefore, clinicians should carefully the history of alcohol use and repeatedly educate patients about the risks of consuming alcohol after bariatric surgery. According to a study from 2012 and a review from 2015, male sex, younger age, less social support, and regular or “problematic” alcohol use before bariatric surgery heighten the risk for developing an alcohol use disorder afterward, the experts noted.
Funding sources included the Robert H. Yauk Charitable Trust Gift for Liver Transplant Research 2017-2020 and Regenerative Medicine for Prevention of Post-Transplant Biliary Complications. The authors reported having no conflicts of interest.
This article was updated Feb. 23, 2021.
Obesity, a risk factor for nonalcoholic fatty liver disease (NAFLD) and a prevalent comorbidity among people with cirrhosis of all etiologies, is associated with a number of untoward health outcomes, and weight loss is an important goal, according to a clinical practice update from the American Gastroenterological Association. According to one study cited in the update, approximately 30% of patients with cirrhosis have comorbid obesity, and this figure may increase even further as the epidemic of NAFLD progresses.
For obese patients with cirrhosis, weight loss “is an important therapeutic goal” because obesity heightens risks of portal vein thrombosis, portal hypertension, hepatocellular carcinoma, liver failure in acute on chronic liver disease, and other concerns. Despite no longer being an absolute contraindication, obesity can also complicate liver transplantation considerations, Heather Patton, MD, of the Veterans Affairs San Diego Healthcare System and associates wrote in Clinical Gastroenterology and Hepatology. Consideration of individuals with cirrhosis, however, requires careful scrutiny of surgical candidacy, appropriate resources for care of patients with advanced liver disease, and a high-volume bariatric surgical center given the inherent risks of surgical procedures in this patient population.
For patients with cirrhosis and obesity, laparoscopic sleeve gastrectomy is probably the best option for bariatric surgery because it preserves endoscopic access to the biliary tree, facilitates gradual weight loss, and does not cause malabsorption, according to the update.
Clinicians and patients should time bariatric surgery based on liver disease stage – for patients with decompensated disease, surgery should be performed only at the same time as or after liver transplantation, the experts wrote. Clinicians should also evaluate candidacy for liver transplantation before bariatric surgery “so that patients who are ineligible for transplant (and their families) have a clear understanding of this, avoiding the need for the medical team to address this issue urgently if the patient’s condition deteriorates postoperatively.”
One review suggested that bariatric surgery is “the most effective and durable” means of weight loss, according to the authors of the update; however, another review suggested increased surgical risk for bariatric surgery among patients with cirrhosis, so the update’s authors advised individualized risk-benefit assessments. These assessments are made even more complicated by scarcity of relevant randomized trial data, so the experts identified PubMed-indexed, peer-reviewed articles published between 2000 and 2020 and used these to make 10 best practice advice statements for bariatric surgery in obese patients with cirrhosis.
The surgical, anesthesia, and medical teams must be well versed in assessing and operating on patients with portal hypertension and cirrhosis and in managing these patients postoperatively, the experts wrote. The preoperative assessment should include cirrhosis status (compensated versus decompensated), the presence and severity of sarcopenia, ascites, and portal hypertension, and candidacy for liver transplantation. It is vital to check for clinically significant portal hypertension (CSPH) because endoscopic devices should not be used in patients with gastric and/or esophageal varices. To do so, upper endoscopy and cross-sectional imaging are advised, pending better data on noninvasive assessment methods. For patients without CSPH, endoscopic bariatric treatment can be somewhat less effective for weight loss but also might be less likely to lead to postoperative complications. However, head-to-head and long-term safety data are not yet available.
The experts also noted that bariatric surgery increases the effects (blood levels) of alcohol and can increase patients’ risk for developing an alcohol use disorder. Therefore, clinicians should carefully the history of alcohol use and repeatedly educate patients about the risks of consuming alcohol after bariatric surgery. According to a study from 2012 and a review from 2015, male sex, younger age, less social support, and regular or “problematic” alcohol use before bariatric surgery heighten the risk for developing an alcohol use disorder afterward, the experts noted.
Funding sources included the Robert H. Yauk Charitable Trust Gift for Liver Transplant Research 2017-2020 and Regenerative Medicine for Prevention of Post-Transplant Biliary Complications. The authors reported having no conflicts of interest.
This article was updated Feb. 23, 2021.
Obesity, a risk factor for nonalcoholic fatty liver disease (NAFLD) and a prevalent comorbidity among people with cirrhosis of all etiologies, is associated with a number of untoward health outcomes, and weight loss is an important goal, according to a clinical practice update from the American Gastroenterological Association. According to one study cited in the update, approximately 30% of patients with cirrhosis have comorbid obesity, and this figure may increase even further as the epidemic of NAFLD progresses.
For obese patients with cirrhosis, weight loss “is an important therapeutic goal” because obesity heightens risks of portal vein thrombosis, portal hypertension, hepatocellular carcinoma, liver failure in acute on chronic liver disease, and other concerns. Despite no longer being an absolute contraindication, obesity can also complicate liver transplantation considerations, Heather Patton, MD, of the Veterans Affairs San Diego Healthcare System and associates wrote in Clinical Gastroenterology and Hepatology. Consideration of individuals with cirrhosis, however, requires careful scrutiny of surgical candidacy, appropriate resources for care of patients with advanced liver disease, and a high-volume bariatric surgical center given the inherent risks of surgical procedures in this patient population.
For patients with cirrhosis and obesity, laparoscopic sleeve gastrectomy is probably the best option for bariatric surgery because it preserves endoscopic access to the biliary tree, facilitates gradual weight loss, and does not cause malabsorption, according to the update.
Clinicians and patients should time bariatric surgery based on liver disease stage – for patients with decompensated disease, surgery should be performed only at the same time as or after liver transplantation, the experts wrote. Clinicians should also evaluate candidacy for liver transplantation before bariatric surgery “so that patients who are ineligible for transplant (and their families) have a clear understanding of this, avoiding the need for the medical team to address this issue urgently if the patient’s condition deteriorates postoperatively.”
One review suggested that bariatric surgery is “the most effective and durable” means of weight loss, according to the authors of the update; however, another review suggested increased surgical risk for bariatric surgery among patients with cirrhosis, so the update’s authors advised individualized risk-benefit assessments. These assessments are made even more complicated by scarcity of relevant randomized trial data, so the experts identified PubMed-indexed, peer-reviewed articles published between 2000 and 2020 and used these to make 10 best practice advice statements for bariatric surgery in obese patients with cirrhosis.
The surgical, anesthesia, and medical teams must be well versed in assessing and operating on patients with portal hypertension and cirrhosis and in managing these patients postoperatively, the experts wrote. The preoperative assessment should include cirrhosis status (compensated versus decompensated), the presence and severity of sarcopenia, ascites, and portal hypertension, and candidacy for liver transplantation. It is vital to check for clinically significant portal hypertension (CSPH) because endoscopic devices should not be used in patients with gastric and/or esophageal varices. To do so, upper endoscopy and cross-sectional imaging are advised, pending better data on noninvasive assessment methods. For patients without CSPH, endoscopic bariatric treatment can be somewhat less effective for weight loss but also might be less likely to lead to postoperative complications. However, head-to-head and long-term safety data are not yet available.
The experts also noted that bariatric surgery increases the effects (blood levels) of alcohol and can increase patients’ risk for developing an alcohol use disorder. Therefore, clinicians should carefully the history of alcohol use and repeatedly educate patients about the risks of consuming alcohol after bariatric surgery. According to a study from 2012 and a review from 2015, male sex, younger age, less social support, and regular or “problematic” alcohol use before bariatric surgery heighten the risk for developing an alcohol use disorder afterward, the experts noted.
Funding sources included the Robert H. Yauk Charitable Trust Gift for Liver Transplant Research 2017-2020 and Regenerative Medicine for Prevention of Post-Transplant Biliary Complications. The authors reported having no conflicts of interest.
This article was updated Feb. 23, 2021.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
AGA Clinical Practice Update: Diagnosis and management of immune checkpoint inhibitor enterocolitis and hepatitis
Endoscopy with biopsies is best for diagnosing immune-mediated enterocolitis in patients receiving immune checkpoint inhibitors (ICIs), but another option is to first test the stool for lactoferrin or calprotectin to identify patients with mild diarrhea who could benefit from endoscopy, according to a clinical practice update from the American Gastroenterological Association.
Writing in Gastroenterology, Michael Dougan, MD, PhD, of Harvard Medical School, Boston, and colleagues noted that stool lactoferrin had been found in one study to be 90% sensitive for detecting histologic inflammation, while another study found that mucosal inflammation is absent in 20%-30% of patients with suspected ICI enterocolitis. Nonetheless, clinicians should consider diagnostic endoscopy before starting high-dose corticosteroids for ICI enterocolitis, especially because “colonic ulceration identified by endoscopy is the only established factor that predicts how ICI enterocolitis will respond to treatment,” Dr. Dougan and colleagues wrote. If performed, endoscopy must be prompt because ICI colitis can progress within days, especially if patients are receiving ipilimumab.
ICIs can induce autoimmune inflammation in almost any organ system because they target pathways that play “key roles in regulating autoimmunity,” the experts wrote. The gastrointestinal tract is one of the most common sites of toxicity: One study from 2006 and another from 2019 suggested that colitis, with or without enteritis, affects up to 40% of patients depending on the pathway targeted by the treatment. Oncologists manage most gastrointestinal ICI toxicities, but gastroenterologists and hepatologists often help with diagnosis, risk assessment, and managing complex, atypical, or treatment-refractory cases; to help guide this process, the experts reviewed the literature and made 15 relevant recommendations.
The authors noted that the differential diagnosis is broad, but suggested that Clostridioides difficile testing and stool culture (or stool pathogen testing, where available) should be performed in all patients to rule out infectious causes prior to any immunosuppressive treatments, such as corticosteroids. Abdominal imaging is not recommended if a patient only has diarrhea but can help rule out complications if fever, bleeding, or abdominal pain are also present. Laboratory blood tests are rarely informative.
High-dose glucocorticoids are usually effective, often being started at 0.5-2.0 mg/kg prednisone or equivalent daily and tapered over 4-6 weeks after clinical improvement, but these doses and schedules have not been rigorously examined. For glucocorticoid-refractory ICI enterocolitis, infliximab and vedolizumab “are reasonable options” for second line immunosuppression and should be individualized based on the underlying cancer and other risk factors; patients usually respond to these immunomodulators in less than a week, “an important contrast with IBD,” the experts wrote. Most cases of ICI enterocolitis do not recur unless the ICI is restarted, but “many patients require the full loading dose for infliximab or vedolizumab, and maintenance therapy may still be required for certain cases.”
ICI-induced hepatitis is less common, affecting less than 5% of patients in clinical trials according to the authors, but incidence rises if patients are on ICI combinations or an ICI plus chemotherapy. Before starting any ICI, patients’ total bilirubin, alkaline phosphatase, AST, and ALT levels should be checked, as should testing for hepatitis B. Liver chemistries should be repeated before each ICI cycle, and rising chemistries should trigger an assessment for other causes of liver injury.
Patients with Common Terminology Criteria for Adverse Events (CTCAE) grade 1 hepatitis – defined as AST or ALT 1-3 times the upper limit of normal or total bilirubin 1-1.5 times upper limit of normal – should receive liver function tests once or twice weekly. For CTCAE grade 2 hepatitis, (AST/ALT more than 3-5 times upper limit of normal or total bilirubin more than 1.5-3 times upper limit of normal), ICI should be held until resolution to grade 1, and corticosteroids (prednisone or its equivalent dosed at 0.5-1.0 mg/kg daily) should be considered if there are clinical symptoms of liver toxicity. For grade 3 hepatitis (AST/ALT greater than 5-20 times upper limit of normal or total bilirubin more than 3-10 times upper limit of normal), ICI therapy should be halted, “and urgent consultation with a gastroenterologist/hepatologist is appropriate.” In this context, methylprednisone (1-2 mg/kg) is suggested, and azathioprine or mycophenolate mofetil can be considered if clinical hepatitis does not improve in 3-5 days. For CTCAE grade 4 hepatitis, hospitalization is recommended, and patients should permanently stop the ICI and receive 2 mg/kg per day of methylprednisolone or its equivalent.
The authors received no funding support. Dr. Dougan reported consulting or advisory relationships with Neoleukin Therapeutics, Genentech, Tillotts Pharma, and Partner Therapeutics and grant support from Novartis and Genentech. Two coauthors also reported ties to several pharmaceutical companies.
Endoscopy with biopsies is best for diagnosing immune-mediated enterocolitis in patients receiving immune checkpoint inhibitors (ICIs), but another option is to first test the stool for lactoferrin or calprotectin to identify patients with mild diarrhea who could benefit from endoscopy, according to a clinical practice update from the American Gastroenterological Association.
Writing in Gastroenterology, Michael Dougan, MD, PhD, of Harvard Medical School, Boston, and colleagues noted that stool lactoferrin had been found in one study to be 90% sensitive for detecting histologic inflammation, while another study found that mucosal inflammation is absent in 20%-30% of patients with suspected ICI enterocolitis. Nonetheless, clinicians should consider diagnostic endoscopy before starting high-dose corticosteroids for ICI enterocolitis, especially because “colonic ulceration identified by endoscopy is the only established factor that predicts how ICI enterocolitis will respond to treatment,” Dr. Dougan and colleagues wrote. If performed, endoscopy must be prompt because ICI colitis can progress within days, especially if patients are receiving ipilimumab.
ICIs can induce autoimmune inflammation in almost any organ system because they target pathways that play “key roles in regulating autoimmunity,” the experts wrote. The gastrointestinal tract is one of the most common sites of toxicity: One study from 2006 and another from 2019 suggested that colitis, with or without enteritis, affects up to 40% of patients depending on the pathway targeted by the treatment. Oncologists manage most gastrointestinal ICI toxicities, but gastroenterologists and hepatologists often help with diagnosis, risk assessment, and managing complex, atypical, or treatment-refractory cases; to help guide this process, the experts reviewed the literature and made 15 relevant recommendations.
The authors noted that the differential diagnosis is broad, but suggested that Clostridioides difficile testing and stool culture (or stool pathogen testing, where available) should be performed in all patients to rule out infectious causes prior to any immunosuppressive treatments, such as corticosteroids. Abdominal imaging is not recommended if a patient only has diarrhea but can help rule out complications if fever, bleeding, or abdominal pain are also present. Laboratory blood tests are rarely informative.
High-dose glucocorticoids are usually effective, often being started at 0.5-2.0 mg/kg prednisone or equivalent daily and tapered over 4-6 weeks after clinical improvement, but these doses and schedules have not been rigorously examined. For glucocorticoid-refractory ICI enterocolitis, infliximab and vedolizumab “are reasonable options” for second line immunosuppression and should be individualized based on the underlying cancer and other risk factors; patients usually respond to these immunomodulators in less than a week, “an important contrast with IBD,” the experts wrote. Most cases of ICI enterocolitis do not recur unless the ICI is restarted, but “many patients require the full loading dose for infliximab or vedolizumab, and maintenance therapy may still be required for certain cases.”
ICI-induced hepatitis is less common, affecting less than 5% of patients in clinical trials according to the authors, but incidence rises if patients are on ICI combinations or an ICI plus chemotherapy. Before starting any ICI, patients’ total bilirubin, alkaline phosphatase, AST, and ALT levels should be checked, as should testing for hepatitis B. Liver chemistries should be repeated before each ICI cycle, and rising chemistries should trigger an assessment for other causes of liver injury.
Patients with Common Terminology Criteria for Adverse Events (CTCAE) grade 1 hepatitis – defined as AST or ALT 1-3 times the upper limit of normal or total bilirubin 1-1.5 times upper limit of normal – should receive liver function tests once or twice weekly. For CTCAE grade 2 hepatitis, (AST/ALT more than 3-5 times upper limit of normal or total bilirubin more than 1.5-3 times upper limit of normal), ICI should be held until resolution to grade 1, and corticosteroids (prednisone or its equivalent dosed at 0.5-1.0 mg/kg daily) should be considered if there are clinical symptoms of liver toxicity. For grade 3 hepatitis (AST/ALT greater than 5-20 times upper limit of normal or total bilirubin more than 3-10 times upper limit of normal), ICI therapy should be halted, “and urgent consultation with a gastroenterologist/hepatologist is appropriate.” In this context, methylprednisone (1-2 mg/kg) is suggested, and azathioprine or mycophenolate mofetil can be considered if clinical hepatitis does not improve in 3-5 days. For CTCAE grade 4 hepatitis, hospitalization is recommended, and patients should permanently stop the ICI and receive 2 mg/kg per day of methylprednisolone or its equivalent.
The authors received no funding support. Dr. Dougan reported consulting or advisory relationships with Neoleukin Therapeutics, Genentech, Tillotts Pharma, and Partner Therapeutics and grant support from Novartis and Genentech. Two coauthors also reported ties to several pharmaceutical companies.
Endoscopy with biopsies is best for diagnosing immune-mediated enterocolitis in patients receiving immune checkpoint inhibitors (ICIs), but another option is to first test the stool for lactoferrin or calprotectin to identify patients with mild diarrhea who could benefit from endoscopy, according to a clinical practice update from the American Gastroenterological Association.
Writing in Gastroenterology, Michael Dougan, MD, PhD, of Harvard Medical School, Boston, and colleagues noted that stool lactoferrin had been found in one study to be 90% sensitive for detecting histologic inflammation, while another study found that mucosal inflammation is absent in 20%-30% of patients with suspected ICI enterocolitis. Nonetheless, clinicians should consider diagnostic endoscopy before starting high-dose corticosteroids for ICI enterocolitis, especially because “colonic ulceration identified by endoscopy is the only established factor that predicts how ICI enterocolitis will respond to treatment,” Dr. Dougan and colleagues wrote. If performed, endoscopy must be prompt because ICI colitis can progress within days, especially if patients are receiving ipilimumab.
ICIs can induce autoimmune inflammation in almost any organ system because they target pathways that play “key roles in regulating autoimmunity,” the experts wrote. The gastrointestinal tract is one of the most common sites of toxicity: One study from 2006 and another from 2019 suggested that colitis, with or without enteritis, affects up to 40% of patients depending on the pathway targeted by the treatment. Oncologists manage most gastrointestinal ICI toxicities, but gastroenterologists and hepatologists often help with diagnosis, risk assessment, and managing complex, atypical, or treatment-refractory cases; to help guide this process, the experts reviewed the literature and made 15 relevant recommendations.
The authors noted that the differential diagnosis is broad, but suggested that Clostridioides difficile testing and stool culture (or stool pathogen testing, where available) should be performed in all patients to rule out infectious causes prior to any immunosuppressive treatments, such as corticosteroids. Abdominal imaging is not recommended if a patient only has diarrhea but can help rule out complications if fever, bleeding, or abdominal pain are also present. Laboratory blood tests are rarely informative.
High-dose glucocorticoids are usually effective, often being started at 0.5-2.0 mg/kg prednisone or equivalent daily and tapered over 4-6 weeks after clinical improvement, but these doses and schedules have not been rigorously examined. For glucocorticoid-refractory ICI enterocolitis, infliximab and vedolizumab “are reasonable options” for second line immunosuppression and should be individualized based on the underlying cancer and other risk factors; patients usually respond to these immunomodulators in less than a week, “an important contrast with IBD,” the experts wrote. Most cases of ICI enterocolitis do not recur unless the ICI is restarted, but “many patients require the full loading dose for infliximab or vedolizumab, and maintenance therapy may still be required for certain cases.”
ICI-induced hepatitis is less common, affecting less than 5% of patients in clinical trials according to the authors, but incidence rises if patients are on ICI combinations or an ICI plus chemotherapy. Before starting any ICI, patients’ total bilirubin, alkaline phosphatase, AST, and ALT levels should be checked, as should testing for hepatitis B. Liver chemistries should be repeated before each ICI cycle, and rising chemistries should trigger an assessment for other causes of liver injury.
Patients with Common Terminology Criteria for Adverse Events (CTCAE) grade 1 hepatitis – defined as AST or ALT 1-3 times the upper limit of normal or total bilirubin 1-1.5 times upper limit of normal – should receive liver function tests once or twice weekly. For CTCAE grade 2 hepatitis, (AST/ALT more than 3-5 times upper limit of normal or total bilirubin more than 1.5-3 times upper limit of normal), ICI should be held until resolution to grade 1, and corticosteroids (prednisone or its equivalent dosed at 0.5-1.0 mg/kg daily) should be considered if there are clinical symptoms of liver toxicity. For grade 3 hepatitis (AST/ALT greater than 5-20 times upper limit of normal or total bilirubin more than 3-10 times upper limit of normal), ICI therapy should be halted, “and urgent consultation with a gastroenterologist/hepatologist is appropriate.” In this context, methylprednisone (1-2 mg/kg) is suggested, and azathioprine or mycophenolate mofetil can be considered if clinical hepatitis does not improve in 3-5 days. For CTCAE grade 4 hepatitis, hospitalization is recommended, and patients should permanently stop the ICI and receive 2 mg/kg per day of methylprednisolone or its equivalent.
The authors received no funding support. Dr. Dougan reported consulting or advisory relationships with Neoleukin Therapeutics, Genentech, Tillotts Pharma, and Partner Therapeutics and grant support from Novartis and Genentech. Two coauthors also reported ties to several pharmaceutical companies.
FROM GASTROENTEROLOGY
Incidence of autoimmune hepatitis may be rising
The incidence of autoimmune hepatitis (AIH) may be rising, according to a prospective population-based study conducted in New Zealand.
From 2008 to 2016, the rising incidence of AIH led to a 40% increase in point prevalence, reported lead author Mehul Lamba, MD, of Christchurch (New Zealand) Hospital and colleagues.
The present study, which also assessed rates of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), adds data to an area of inquiry historically characterized by limited and inconsistent results, the investigators wrote in Clinical Gastroenterology and Hepatology. They suggested that mixed findings from previous studies may be because of differences in population and environmental factors, but also varying diagnostic criteria.
“The epidemiological trends of these autoimmune liver diseases therefore remain incompletely understood,” wrote Dr. Lamba and colleagues.
Their study evaluated trends in autoimmune liver diseases over a 9-year time frame in Canterbury, New Zealand. According to the investigators, this region is well suited to an epidemiological investigation because it is a clearly defined geographic area with approximately 600,000 people, most of whom rely on one tertiary care center: Christchurch Hospital. The bulk of the data therefore came from this center, while a minority of cases were gathered from local private gastroenterology practices, “making complete case ascertainment possible.”
Incidence of AIH, PBC, and PSC was assessed at three time points: 2008-2010, 2011-2013, and 2014-2016. AIH had the highest overall incidence, at 1.93 cases per 100,000 people, followed by PSC (0.92) and PBC (0.51).
While the rates of PBC and PSC did not change significantly over time, the incidence of AIH rose from 1.37 cases per 100,000 people in the period from 2008-2010 to 2.39 per 100,000 in 2014-2016 (P = .04), which computes to an incidence rate ratio of 1.69 (95% confidence interval, 1.02-2.84). Point prevalence was also significantly higher in 2016, compared with 2008, at 27.5 per 100,000 versus 19.7 per 100,000 (P < .01). The investigators described a bimodal age of presentation, with the first peak among patients younger than 20 years, and a second, larger peak among individuals aged 50-69 years.
According to the investigators, these findings “are concordant with the results observed in the European cohort,” citing a Danish study spanning 1994-2012 and a Dutch study spanning 2000-2010. They noted that the Danish study also reported a bimodal distribution of age incidence, as did a Swedish study, and another study from New Zealand. The stable levels of PBC and PSC align with two recent retrospective studies conducted in the United States and, they added.
“We believe that the observed differential trends in the incidence of these autoimmune liver diseases truly reflects their contemporary epidemiology,” the investigators wrote. They went on to suggest that the findings did not stem from an increase in diagnostic scrutiny because the study period did not include any significant changes in gastroenterology service, coding, or diagnostic criteria in the region studied.
“The increased incidence of AIH parallels rising incidence and prevalence of other autoimmune disorders such as [inflammatory bowel disease], type 1 diabetes, and multiple sclerosis in New Zealand, and it is unclear whether these autoimmune conditions share a common local environmental trigger,” they wrote. “Environmental factors likely play a central role augmenting phenotypic expression in genetically predisposed individuals.”
While Dr. Lamba and colleagues proposed several possible factors, such as increased exposure to pharmaceuticals, definitive factors remain elusive, which the authors cited as one limitation of their study. Another limitation they cited is the possibility that other etiologies were mistakenly classified as “probable” AIH; however, the chances of that are small, and the proportion of probable versus definitive AIH noted in this study do reflect those seen in other epidemiological studies.
“The reason for observed differential change in incidence of these autoimmune liver diseases is unclear,” they wrote, “and future collaborative prospective epidemiological study would be required to assess this further.”
The investigators reported no conflicts of interest.
Historically, autoimmune hepatitis (AIH) was a rare disease in reproductive-age women with chronic active hepatitis and autoantibodies. Today with worldwide information available at our fingertips, autoimmune liver diseases such as AIH and variants are in our armamentarium of differential diagnosis for patients with chronic hepatitis. Autoimmune liver conditions are now diagnosed in a wide range of ethnic groups and age groups.
Unlike highly prevalent chronic liver diseases such as alcohol-related and viral hepatitis, we do not know the trigger for AIH in predisposed patients. It could be difficult to explain to patients how they became susceptible to and acquired AIH. In this geographically defined population with centralized access to health care, it would be curious to know triggers, such as infections, medications, personal habits, dietary and gut microbiome changes, or emerging comorbid conditions that may influence the occurrence of AIH. Population studies helped identify common epidemiologic traits and combined with serologies and clinical criteria, we have become more adept at diagnosis of AIH. Future studies could look at clustering in communities and susceptibility patterns in ethnic groups that may implicate etiologic factors.
Avegail Flores, MD, is with the section of gastroenterology and hepatology at Baylor College of Medicine, Houston, and is the medical director of liver transplant at Michael E. DeBakey Houston Veterans Affairs Medical Center. She has nothing to disclose.
Historically, autoimmune hepatitis (AIH) was a rare disease in reproductive-age women with chronic active hepatitis and autoantibodies. Today with worldwide information available at our fingertips, autoimmune liver diseases such as AIH and variants are in our armamentarium of differential diagnosis for patients with chronic hepatitis. Autoimmune liver conditions are now diagnosed in a wide range of ethnic groups and age groups.
Unlike highly prevalent chronic liver diseases such as alcohol-related and viral hepatitis, we do not know the trigger for AIH in predisposed patients. It could be difficult to explain to patients how they became susceptible to and acquired AIH. In this geographically defined population with centralized access to health care, it would be curious to know triggers, such as infections, medications, personal habits, dietary and gut microbiome changes, or emerging comorbid conditions that may influence the occurrence of AIH. Population studies helped identify common epidemiologic traits and combined with serologies and clinical criteria, we have become more adept at diagnosis of AIH. Future studies could look at clustering in communities and susceptibility patterns in ethnic groups that may implicate etiologic factors.
Avegail Flores, MD, is with the section of gastroenterology and hepatology at Baylor College of Medicine, Houston, and is the medical director of liver transplant at Michael E. DeBakey Houston Veterans Affairs Medical Center. She has nothing to disclose.
Historically, autoimmune hepatitis (AIH) was a rare disease in reproductive-age women with chronic active hepatitis and autoantibodies. Today with worldwide information available at our fingertips, autoimmune liver diseases such as AIH and variants are in our armamentarium of differential diagnosis for patients with chronic hepatitis. Autoimmune liver conditions are now diagnosed in a wide range of ethnic groups and age groups.
Unlike highly prevalent chronic liver diseases such as alcohol-related and viral hepatitis, we do not know the trigger for AIH in predisposed patients. It could be difficult to explain to patients how they became susceptible to and acquired AIH. In this geographically defined population with centralized access to health care, it would be curious to know triggers, such as infections, medications, personal habits, dietary and gut microbiome changes, or emerging comorbid conditions that may influence the occurrence of AIH. Population studies helped identify common epidemiologic traits and combined with serologies and clinical criteria, we have become more adept at diagnosis of AIH. Future studies could look at clustering in communities and susceptibility patterns in ethnic groups that may implicate etiologic factors.
Avegail Flores, MD, is with the section of gastroenterology and hepatology at Baylor College of Medicine, Houston, and is the medical director of liver transplant at Michael E. DeBakey Houston Veterans Affairs Medical Center. She has nothing to disclose.
The incidence of autoimmune hepatitis (AIH) may be rising, according to a prospective population-based study conducted in New Zealand.
From 2008 to 2016, the rising incidence of AIH led to a 40% increase in point prevalence, reported lead author Mehul Lamba, MD, of Christchurch (New Zealand) Hospital and colleagues.
The present study, which also assessed rates of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), adds data to an area of inquiry historically characterized by limited and inconsistent results, the investigators wrote in Clinical Gastroenterology and Hepatology. They suggested that mixed findings from previous studies may be because of differences in population and environmental factors, but also varying diagnostic criteria.
“The epidemiological trends of these autoimmune liver diseases therefore remain incompletely understood,” wrote Dr. Lamba and colleagues.
Their study evaluated trends in autoimmune liver diseases over a 9-year time frame in Canterbury, New Zealand. According to the investigators, this region is well suited to an epidemiological investigation because it is a clearly defined geographic area with approximately 600,000 people, most of whom rely on one tertiary care center: Christchurch Hospital. The bulk of the data therefore came from this center, while a minority of cases were gathered from local private gastroenterology practices, “making complete case ascertainment possible.”
Incidence of AIH, PBC, and PSC was assessed at three time points: 2008-2010, 2011-2013, and 2014-2016. AIH had the highest overall incidence, at 1.93 cases per 100,000 people, followed by PSC (0.92) and PBC (0.51).
While the rates of PBC and PSC did not change significantly over time, the incidence of AIH rose from 1.37 cases per 100,000 people in the period from 2008-2010 to 2.39 per 100,000 in 2014-2016 (P = .04), which computes to an incidence rate ratio of 1.69 (95% confidence interval, 1.02-2.84). Point prevalence was also significantly higher in 2016, compared with 2008, at 27.5 per 100,000 versus 19.7 per 100,000 (P < .01). The investigators described a bimodal age of presentation, with the first peak among patients younger than 20 years, and a second, larger peak among individuals aged 50-69 years.
According to the investigators, these findings “are concordant with the results observed in the European cohort,” citing a Danish study spanning 1994-2012 and a Dutch study spanning 2000-2010. They noted that the Danish study also reported a bimodal distribution of age incidence, as did a Swedish study, and another study from New Zealand. The stable levels of PBC and PSC align with two recent retrospective studies conducted in the United States and, they added.
“We believe that the observed differential trends in the incidence of these autoimmune liver diseases truly reflects their contemporary epidemiology,” the investigators wrote. They went on to suggest that the findings did not stem from an increase in diagnostic scrutiny because the study period did not include any significant changes in gastroenterology service, coding, or diagnostic criteria in the region studied.
“The increased incidence of AIH parallels rising incidence and prevalence of other autoimmune disorders such as [inflammatory bowel disease], type 1 diabetes, and multiple sclerosis in New Zealand, and it is unclear whether these autoimmune conditions share a common local environmental trigger,” they wrote. “Environmental factors likely play a central role augmenting phenotypic expression in genetically predisposed individuals.”
While Dr. Lamba and colleagues proposed several possible factors, such as increased exposure to pharmaceuticals, definitive factors remain elusive, which the authors cited as one limitation of their study. Another limitation they cited is the possibility that other etiologies were mistakenly classified as “probable” AIH; however, the chances of that are small, and the proportion of probable versus definitive AIH noted in this study do reflect those seen in other epidemiological studies.
“The reason for observed differential change in incidence of these autoimmune liver diseases is unclear,” they wrote, “and future collaborative prospective epidemiological study would be required to assess this further.”
The investigators reported no conflicts of interest.
The incidence of autoimmune hepatitis (AIH) may be rising, according to a prospective population-based study conducted in New Zealand.
From 2008 to 2016, the rising incidence of AIH led to a 40% increase in point prevalence, reported lead author Mehul Lamba, MD, of Christchurch (New Zealand) Hospital and colleagues.
The present study, which also assessed rates of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), adds data to an area of inquiry historically characterized by limited and inconsistent results, the investigators wrote in Clinical Gastroenterology and Hepatology. They suggested that mixed findings from previous studies may be because of differences in population and environmental factors, but also varying diagnostic criteria.
“The epidemiological trends of these autoimmune liver diseases therefore remain incompletely understood,” wrote Dr. Lamba and colleagues.
Their study evaluated trends in autoimmune liver diseases over a 9-year time frame in Canterbury, New Zealand. According to the investigators, this region is well suited to an epidemiological investigation because it is a clearly defined geographic area with approximately 600,000 people, most of whom rely on one tertiary care center: Christchurch Hospital. The bulk of the data therefore came from this center, while a minority of cases were gathered from local private gastroenterology practices, “making complete case ascertainment possible.”
Incidence of AIH, PBC, and PSC was assessed at three time points: 2008-2010, 2011-2013, and 2014-2016. AIH had the highest overall incidence, at 1.93 cases per 100,000 people, followed by PSC (0.92) and PBC (0.51).
While the rates of PBC and PSC did not change significantly over time, the incidence of AIH rose from 1.37 cases per 100,000 people in the period from 2008-2010 to 2.39 per 100,000 in 2014-2016 (P = .04), which computes to an incidence rate ratio of 1.69 (95% confidence interval, 1.02-2.84). Point prevalence was also significantly higher in 2016, compared with 2008, at 27.5 per 100,000 versus 19.7 per 100,000 (P < .01). The investigators described a bimodal age of presentation, with the first peak among patients younger than 20 years, and a second, larger peak among individuals aged 50-69 years.
According to the investigators, these findings “are concordant with the results observed in the European cohort,” citing a Danish study spanning 1994-2012 and a Dutch study spanning 2000-2010. They noted that the Danish study also reported a bimodal distribution of age incidence, as did a Swedish study, and another study from New Zealand. The stable levels of PBC and PSC align with two recent retrospective studies conducted in the United States and, they added.
“We believe that the observed differential trends in the incidence of these autoimmune liver diseases truly reflects their contemporary epidemiology,” the investigators wrote. They went on to suggest that the findings did not stem from an increase in diagnostic scrutiny because the study period did not include any significant changes in gastroenterology service, coding, or diagnostic criteria in the region studied.
“The increased incidence of AIH parallels rising incidence and prevalence of other autoimmune disorders such as [inflammatory bowel disease], type 1 diabetes, and multiple sclerosis in New Zealand, and it is unclear whether these autoimmune conditions share a common local environmental trigger,” they wrote. “Environmental factors likely play a central role augmenting phenotypic expression in genetically predisposed individuals.”
While Dr. Lamba and colleagues proposed several possible factors, such as increased exposure to pharmaceuticals, definitive factors remain elusive, which the authors cited as one limitation of their study. Another limitation they cited is the possibility that other etiologies were mistakenly classified as “probable” AIH; however, the chances of that are small, and the proportion of probable versus definitive AIH noted in this study do reflect those seen in other epidemiological studies.
“The reason for observed differential change in incidence of these autoimmune liver diseases is unclear,” they wrote, “and future collaborative prospective epidemiological study would be required to assess this further.”
The investigators reported no conflicts of interest.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Study reveals how aspirin may inhibit colorectal cancer
Aspirin “rescued” a cystic intestinal phenotype driven by the Wnt pathway, reduced stem cell expression and function, and increased the expression of Dickkopf (DKK)–1, a Wnt antagonist that is frequently lost as colorectal cancer (CRC) progresses, according to recent study findings.
“Dysregulated Wnt signaling, [which is] primarily driven by adenomatous polyposis coli (APC) gene mutations, is fundamental to cancer initiation in both sporadic CRC and familial adenomatous polyposis (FAP). ... Our observations reveal a novel mechanism of aspirin-mediated Wnt inhibition through DKK-1 increase and potential ‘pheno-markers’ for chemoprevention and adjuvant aspirin human trials,” wrote Karen Dunbar, PhD, and her associates in Cellular and Molecular Gastroenterology and Hepatology.
Aspirin shows benefits in sporadic and familial adenoma, significantly reduces CRC incidence, and may delay disease progression while improving survival. “Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use,” wrote Dr. Dunbar, now with the University of Dundee (Scotland) and colleagues.
She and her coinvestigators found that aspirin promoted the wild-type (budding, noncystic) phenotype in intestinal organoids derived from APC-deficient mice and humans with FAP. They saw the same effect in live APC-deficient mice. With the help of an RNAscope, they confirmed that aspirin significantly reduced RNA transcripts for Lgr5 and TROY, which are stem cell markers in CRC. Aspirin also reduced Lgr5 expression in APC-deficient mice and in human organoids derived from normal colonic mucosa, sporadic colorectal tumors, and colorectal tumors from patients with FAP.
In wound-closure models, aspirin inhibited Wnt and epithelial-mesenchymal transition (EMT) while decreasing migration and invasion by colorectal cancer cells. Aspirin accomplished this by increasing the phosphorylation of GSK-3beta and beta-catenin. Notably, aspirin increased the production of E-cadherin, which buffers excess beta-catenin and thereby limits overactivated Wnt to promote an epithelial, rather than mesenchymal, phenotype. “The novel observation that the aspirin-mediated E-cadherin increase is paralleled by greater E-cadherin–beta-catenin binding further supports the hypothesis that aspirin promotes an epithelial phenotype through Wnt inhibition,” the researchers wrote.
In colorectal cells and FAP organoids, aspirin also increased the expression of the Wnt antagonist DKK-1, which in turn correlated with lower stem cell function. “In humans, high serum DKK-1 correlates with increasing colorectal cancer stage, whereas tissue DKK-1 expression is lost with cancer progression,” the researchers explained. “Here, we demonstrate that aspirin robustly increases DKK-1 expression in CRC models, which contributes to EMT and [cancer stem cell] inhibition observed with aspirin.”
Taken together, the findings “highlight two novel phenotypic indicators of aspirin response, the cystic-phenotype rescue and reduced stem cell marker expression, which may serve as enhanced biomarkers, compared with individual Wnt components,” they concluded. “Through targeting Wnt signaling at multiple levels, aspirin enhances commitment to differentiation, and hence, phenotypic markers of Wnt inhibition represent better targets [for] therapeutic exploitation.”
Dr. Dunbar and her associates reported having no relevant conflicts of interest. The work was supported by Cancer Research UK and the Chief Scientist Office of Scotland, the MRC Centre, and the CRUK.
SOURCE: Dunbar K et al. Cell Mol Gastroenterol Hepatol. 2020 Sep 21. doi: 10.1016/j.jcmgh.2020.09.010.
It is well known that aspirin protects against colorectal polyps and cancers, but the molecular mechanisms by which aspirin confers this protection remain obscure. By developing new models and identifying the molecular targets of aspirin, therapies may be developed that prevent colorectal polyps and cancers but avoid the negative effects of aspirin. Most colorectal cancers (CRC), both spontaneous and familiar, arise from abnormal activation of an important molecular pathway known as the Wnt signaling pathway. Specific mutations in a key member of this pathway, the tumor suppressor APC, are an early event in spontaneous cancers and are the cause of a condition known as familial adenomatous polyposis (FAP). Wnt signaling also drives CRC by regulating cancer stem cells and a process known as epithelial-mesenchymal transition (EMT).
With use of established CRC cell lines, mouse models of FAP, and organoids – three-dimensional models of colonic epithelium – from mice and from human FAP patients, Dunbar and colleagues performed a comprehensive study to define the mechanisms by which aspirin acts to prevent the development and progression of CRC. Here, Dunbar and colleagues found that aspirin limits cancer stem cell populations and the development of EMT, which together are important for tumor cell propagation, invasion, and dissemination. Importantly, they also showed that aspirin increases the expression of a natural Wnt pathway antagonist known as DKK-1, providing a mechanism by which aspirin inhibits Wnt signaling in the context of CRC. Future studies can build on this work by exploring these findings to develop targeted approaches to Wnt inhibition and to prevent colorectal polyps and cancers.
Jonathan P. Katz, MD, is an associate professor of medicine in the division of gastroenterology, department of medicine at the University of Pennsylvania, Philadelphia. He has no conflicts of interest.
It is well known that aspirin protects against colorectal polyps and cancers, but the molecular mechanisms by which aspirin confers this protection remain obscure. By developing new models and identifying the molecular targets of aspirin, therapies may be developed that prevent colorectal polyps and cancers but avoid the negative effects of aspirin. Most colorectal cancers (CRC), both spontaneous and familiar, arise from abnormal activation of an important molecular pathway known as the Wnt signaling pathway. Specific mutations in a key member of this pathway, the tumor suppressor APC, are an early event in spontaneous cancers and are the cause of a condition known as familial adenomatous polyposis (FAP). Wnt signaling also drives CRC by regulating cancer stem cells and a process known as epithelial-mesenchymal transition (EMT).
With use of established CRC cell lines, mouse models of FAP, and organoids – three-dimensional models of colonic epithelium – from mice and from human FAP patients, Dunbar and colleagues performed a comprehensive study to define the mechanisms by which aspirin acts to prevent the development and progression of CRC. Here, Dunbar and colleagues found that aspirin limits cancer stem cell populations and the development of EMT, which together are important for tumor cell propagation, invasion, and dissemination. Importantly, they also showed that aspirin increases the expression of a natural Wnt pathway antagonist known as DKK-1, providing a mechanism by which aspirin inhibits Wnt signaling in the context of CRC. Future studies can build on this work by exploring these findings to develop targeted approaches to Wnt inhibition and to prevent colorectal polyps and cancers.
Jonathan P. Katz, MD, is an associate professor of medicine in the division of gastroenterology, department of medicine at the University of Pennsylvania, Philadelphia. He has no conflicts of interest.
It is well known that aspirin protects against colorectal polyps and cancers, but the molecular mechanisms by which aspirin confers this protection remain obscure. By developing new models and identifying the molecular targets of aspirin, therapies may be developed that prevent colorectal polyps and cancers but avoid the negative effects of aspirin. Most colorectal cancers (CRC), both spontaneous and familiar, arise from abnormal activation of an important molecular pathway known as the Wnt signaling pathway. Specific mutations in a key member of this pathway, the tumor suppressor APC, are an early event in spontaneous cancers and are the cause of a condition known as familial adenomatous polyposis (FAP). Wnt signaling also drives CRC by regulating cancer stem cells and a process known as epithelial-mesenchymal transition (EMT).
With use of established CRC cell lines, mouse models of FAP, and organoids – three-dimensional models of colonic epithelium – from mice and from human FAP patients, Dunbar and colleagues performed a comprehensive study to define the mechanisms by which aspirin acts to prevent the development and progression of CRC. Here, Dunbar and colleagues found that aspirin limits cancer stem cell populations and the development of EMT, which together are important for tumor cell propagation, invasion, and dissemination. Importantly, they also showed that aspirin increases the expression of a natural Wnt pathway antagonist known as DKK-1, providing a mechanism by which aspirin inhibits Wnt signaling in the context of CRC. Future studies can build on this work by exploring these findings to develop targeted approaches to Wnt inhibition and to prevent colorectal polyps and cancers.
Jonathan P. Katz, MD, is an associate professor of medicine in the division of gastroenterology, department of medicine at the University of Pennsylvania, Philadelphia. He has no conflicts of interest.
Aspirin “rescued” a cystic intestinal phenotype driven by the Wnt pathway, reduced stem cell expression and function, and increased the expression of Dickkopf (DKK)–1, a Wnt antagonist that is frequently lost as colorectal cancer (CRC) progresses, according to recent study findings.
“Dysregulated Wnt signaling, [which is] primarily driven by adenomatous polyposis coli (APC) gene mutations, is fundamental to cancer initiation in both sporadic CRC and familial adenomatous polyposis (FAP). ... Our observations reveal a novel mechanism of aspirin-mediated Wnt inhibition through DKK-1 increase and potential ‘pheno-markers’ for chemoprevention and adjuvant aspirin human trials,” wrote Karen Dunbar, PhD, and her associates in Cellular and Molecular Gastroenterology and Hepatology.
Aspirin shows benefits in sporadic and familial adenoma, significantly reduces CRC incidence, and may delay disease progression while improving survival. “Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use,” wrote Dr. Dunbar, now with the University of Dundee (Scotland) and colleagues.
She and her coinvestigators found that aspirin promoted the wild-type (budding, noncystic) phenotype in intestinal organoids derived from APC-deficient mice and humans with FAP. They saw the same effect in live APC-deficient mice. With the help of an RNAscope, they confirmed that aspirin significantly reduced RNA transcripts for Lgr5 and TROY, which are stem cell markers in CRC. Aspirin also reduced Lgr5 expression in APC-deficient mice and in human organoids derived from normal colonic mucosa, sporadic colorectal tumors, and colorectal tumors from patients with FAP.
In wound-closure models, aspirin inhibited Wnt and epithelial-mesenchymal transition (EMT) while decreasing migration and invasion by colorectal cancer cells. Aspirin accomplished this by increasing the phosphorylation of GSK-3beta and beta-catenin. Notably, aspirin increased the production of E-cadherin, which buffers excess beta-catenin and thereby limits overactivated Wnt to promote an epithelial, rather than mesenchymal, phenotype. “The novel observation that the aspirin-mediated E-cadherin increase is paralleled by greater E-cadherin–beta-catenin binding further supports the hypothesis that aspirin promotes an epithelial phenotype through Wnt inhibition,” the researchers wrote.
In colorectal cells and FAP organoids, aspirin also increased the expression of the Wnt antagonist DKK-1, which in turn correlated with lower stem cell function. “In humans, high serum DKK-1 correlates with increasing colorectal cancer stage, whereas tissue DKK-1 expression is lost with cancer progression,” the researchers explained. “Here, we demonstrate that aspirin robustly increases DKK-1 expression in CRC models, which contributes to EMT and [cancer stem cell] inhibition observed with aspirin.”
Taken together, the findings “highlight two novel phenotypic indicators of aspirin response, the cystic-phenotype rescue and reduced stem cell marker expression, which may serve as enhanced biomarkers, compared with individual Wnt components,” they concluded. “Through targeting Wnt signaling at multiple levels, aspirin enhances commitment to differentiation, and hence, phenotypic markers of Wnt inhibition represent better targets [for] therapeutic exploitation.”
Dr. Dunbar and her associates reported having no relevant conflicts of interest. The work was supported by Cancer Research UK and the Chief Scientist Office of Scotland, the MRC Centre, and the CRUK.
SOURCE: Dunbar K et al. Cell Mol Gastroenterol Hepatol. 2020 Sep 21. doi: 10.1016/j.jcmgh.2020.09.010.
Aspirin “rescued” a cystic intestinal phenotype driven by the Wnt pathway, reduced stem cell expression and function, and increased the expression of Dickkopf (DKK)–1, a Wnt antagonist that is frequently lost as colorectal cancer (CRC) progresses, according to recent study findings.
“Dysregulated Wnt signaling, [which is] primarily driven by adenomatous polyposis coli (APC) gene mutations, is fundamental to cancer initiation in both sporadic CRC and familial adenomatous polyposis (FAP). ... Our observations reveal a novel mechanism of aspirin-mediated Wnt inhibition through DKK-1 increase and potential ‘pheno-markers’ for chemoprevention and adjuvant aspirin human trials,” wrote Karen Dunbar, PhD, and her associates in Cellular and Molecular Gastroenterology and Hepatology.
Aspirin shows benefits in sporadic and familial adenoma, significantly reduces CRC incidence, and may delay disease progression while improving survival. “Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use,” wrote Dr. Dunbar, now with the University of Dundee (Scotland) and colleagues.
She and her coinvestigators found that aspirin promoted the wild-type (budding, noncystic) phenotype in intestinal organoids derived from APC-deficient mice and humans with FAP. They saw the same effect in live APC-deficient mice. With the help of an RNAscope, they confirmed that aspirin significantly reduced RNA transcripts for Lgr5 and TROY, which are stem cell markers in CRC. Aspirin also reduced Lgr5 expression in APC-deficient mice and in human organoids derived from normal colonic mucosa, sporadic colorectal tumors, and colorectal tumors from patients with FAP.
In wound-closure models, aspirin inhibited Wnt and epithelial-mesenchymal transition (EMT) while decreasing migration and invasion by colorectal cancer cells. Aspirin accomplished this by increasing the phosphorylation of GSK-3beta and beta-catenin. Notably, aspirin increased the production of E-cadherin, which buffers excess beta-catenin and thereby limits overactivated Wnt to promote an epithelial, rather than mesenchymal, phenotype. “The novel observation that the aspirin-mediated E-cadherin increase is paralleled by greater E-cadherin–beta-catenin binding further supports the hypothesis that aspirin promotes an epithelial phenotype through Wnt inhibition,” the researchers wrote.
In colorectal cells and FAP organoids, aspirin also increased the expression of the Wnt antagonist DKK-1, which in turn correlated with lower stem cell function. “In humans, high serum DKK-1 correlates with increasing colorectal cancer stage, whereas tissue DKK-1 expression is lost with cancer progression,” the researchers explained. “Here, we demonstrate that aspirin robustly increases DKK-1 expression in CRC models, which contributes to EMT and [cancer stem cell] inhibition observed with aspirin.”
Taken together, the findings “highlight two novel phenotypic indicators of aspirin response, the cystic-phenotype rescue and reduced stem cell marker expression, which may serve as enhanced biomarkers, compared with individual Wnt components,” they concluded. “Through targeting Wnt signaling at multiple levels, aspirin enhances commitment to differentiation, and hence, phenotypic markers of Wnt inhibition represent better targets [for] therapeutic exploitation.”
Dr. Dunbar and her associates reported having no relevant conflicts of interest. The work was supported by Cancer Research UK and the Chief Scientist Office of Scotland, the MRC Centre, and the CRUK.
SOURCE: Dunbar K et al. Cell Mol Gastroenterol Hepatol. 2020 Sep 21. doi: 10.1016/j.jcmgh.2020.09.010.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Bezafibrate eased pruritus in patients with fibrosing cholangiopathies
Once-daily treatment with the lipid-lowering agent bezafibrate significantly reduced moderate to severe pruritis among patients with cholestasis, according to the findings of a multicenter, double-blind, randomized, placebo-controlled study (Fibrates for Itch, or FITCH).
Two weeks after completing treatment, 45% of bezafibrate recipients met the primary endpoint, reporting at least a 50% decrease in itch on a 10-point visual analog scale (VAS), compared with 11% of patients in the placebo group (P = .003). There was also a statistically significant decrease in serum alkaline phosphatase (ALP) levels from baseline (35% vs. 6%, respectively; P = .03) that corresponded with improved pruritus, and bezafibrate significantly improved both morning and evening pruritus. Bezafibrate was not associated with myalgia, rhabdomyolysis, or serum alanine transaminase elevations but did lead to a 3% increase in serum creatinine that “was not different from the placebo group,” wrote Elsemieke de Vries, MD, PhD, of the department of gastroenterology & hepatology at Tytgat Institute for Liver and Intestinal Research, Amsterdam, and of department of gastroenterology & metabolism at Amsterdam University Medical Centers, and associates. Their report is in Gastroenterology.
Up to 70% of patients with cholangitis experience pruritus. Current guidelines recommend management with cholestyramine, rifampin, naltrexone, or sertraline, but efficacy and tolerability are subpar, the investigators wrote. In a recent study, a selective inhibitor of an ileal bile acid transporter (GSK2330672) reduced pruritus in primary biliary cholangitis but frequently was associated with diarrhea. In another recent study of patients with primary biliary cholangitis who had responded inadequately to ursodeoxycholic acid (BEZURSO), bezafibrate induced biochemical responses that correlated with improvements in pruritis (a secondary endpoint).
Lysophosphatidic acid (LPA) has been implicated in cholangiopathy-associated pruritus but is not found in bile. However, biliary drainage rapidly improves severe itch in patients with primary biliary cholangitis. Therefore, Dr. de Vries and associates hypothesized that an as-yet unknown factor in bile contributes to pruritus in fibrosing cholangiopathies and that bezafibrate reduces itch by “alleviating hepatobiliary cholestasis and injury and, thereby, reducing formation and biliary secretion of this biliary factor X.”
The FITCH study, which was conducted at seven academic hospitals in the Netherlands and one in Spain, enrolled 74 patients 18 years and older with primary biliary cholangitis or primary or secondary sclerosing cholangitis who reported having pruritus with an intensity of at least 5 on the 10-point VAS at baseline (with 10 indicating “worst itch possible”; median, 7; interquartile range, 7-8). Patients with hepatocellular cholestasis caused by medications or pregnancy were excluded. Ages among most participants ranged from 30s to 50s, and approximately two-thirds were female. None had received another pruritus treatment within 10 days of enrollment, and prior treatment with bezafibrate was not allowed. Patients received once-daily bezafibrate (400 mg) or placebo tablets for 21 days, with visits to the outpatient clinic on days 0, 21, and 35.
There were no serious adverse events or new safety signals. One event of oral pain was considered possibly related to bezafibrate, and itch and jaundice worsened in two patients after completing treatment. As in the 24-month BEZURSO study, increases in serum creatinine were modest and similar between groups (3% with bezafibrate and 5% with placebo). Myalgia and increases in serum alanine transaminase were observed in BEZURSO but not in FITCH. However, the short treatment duration provides “no judgment on long-term safety [of bezafibrate] in complex diseases such as primary sclerosing cholangitis or primary biliary cholangitis,” the investigators wrote.
Four patients discontinued treatment – three stopped placebo because of “unbearable pruritus,” and one stopped bezafibrate after developing acute bacterial cholangitis that required emergency treatment. Although FITCH excluded patients whose estimated glomerular filtration rate was less than 60 mL/min per 1.73 m2, one such patient was accidentally enrolled. Her serum creatinine, measured in mmol/L, rose from 121 at baseline to 148 on day 21, and then dropped to 134 after 2 weeks off treatment.
The trial was supported by patient donations, the Netherlands Society of Gastroenterology, and Instituto de Salud Carlos III. The investigators reported having no conflicts of interest.
SOURCE: de Vries E et al. Gastroenterology. 2020 Oct 5. doi: 10.1053/j.gastro.2020.10.001.
Itch really matters to patients with cholestatic liver diseases, and effective treatment can make a significant difference to life quality. Although therapies exist for cholestatic itch (such as cholestyramine, rifampin, and naltrexone) recent data from the United Kingdom and United States suggest that therapy in practice is poor. It is likely that this results, at least in part, from the limitations of the existing treatments which can be unpleasant to take (cholestyramine) or difficult to use because of monitoring needs and side-effects (rifampin and naltrexone). Itch has therefore been identified as an area of real unmet need in cholestatic disease and there are a number of trials in progress or in set-up. This is extremely positive for patients.
The FITCH trial is one of the first of these “new generation” cholestatic itch trials to report and explore the efficacy of the PPAR-agonist bezafibrate in a mixed cholestatic population. Clear benefit was seen with around 50% of all disease groups meeting the primary endpoint and good drug tolerance. Is bezafibrate therefore the answer to cholestatic itch? The cautious answer is ... possibly, but more experience is needed. The trial duration was only 21 days, which means that long-term safety and efficacy remain to be explored. Bezafibrate is now being used in practice to treat cholestatic itch with effects similar to those reported in the trial. It is therefore clearly an important new option. Where it ultimately ends up in the treatment pathway only time and experience will tell.
David Jones, BM, BCh, PhD, is a professor of liver immunology at Newcastle University, Newcastle Upon Tyne, England. He reported having no disclosures relevant to this commentary.
Itch really matters to patients with cholestatic liver diseases, and effective treatment can make a significant difference to life quality. Although therapies exist for cholestatic itch (such as cholestyramine, rifampin, and naltrexone) recent data from the United Kingdom and United States suggest that therapy in practice is poor. It is likely that this results, at least in part, from the limitations of the existing treatments which can be unpleasant to take (cholestyramine) or difficult to use because of monitoring needs and side-effects (rifampin and naltrexone). Itch has therefore been identified as an area of real unmet need in cholestatic disease and there are a number of trials in progress or in set-up. This is extremely positive for patients.
The FITCH trial is one of the first of these “new generation” cholestatic itch trials to report and explore the efficacy of the PPAR-agonist bezafibrate in a mixed cholestatic population. Clear benefit was seen with around 50% of all disease groups meeting the primary endpoint and good drug tolerance. Is bezafibrate therefore the answer to cholestatic itch? The cautious answer is ... possibly, but more experience is needed. The trial duration was only 21 days, which means that long-term safety and efficacy remain to be explored. Bezafibrate is now being used in practice to treat cholestatic itch with effects similar to those reported in the trial. It is therefore clearly an important new option. Where it ultimately ends up in the treatment pathway only time and experience will tell.
David Jones, BM, BCh, PhD, is a professor of liver immunology at Newcastle University, Newcastle Upon Tyne, England. He reported having no disclosures relevant to this commentary.
Itch really matters to patients with cholestatic liver diseases, and effective treatment can make a significant difference to life quality. Although therapies exist for cholestatic itch (such as cholestyramine, rifampin, and naltrexone) recent data from the United Kingdom and United States suggest that therapy in practice is poor. It is likely that this results, at least in part, from the limitations of the existing treatments which can be unpleasant to take (cholestyramine) or difficult to use because of monitoring needs and side-effects (rifampin and naltrexone). Itch has therefore been identified as an area of real unmet need in cholestatic disease and there are a number of trials in progress or in set-up. This is extremely positive for patients.
The FITCH trial is one of the first of these “new generation” cholestatic itch trials to report and explore the efficacy of the PPAR-agonist bezafibrate in a mixed cholestatic population. Clear benefit was seen with around 50% of all disease groups meeting the primary endpoint and good drug tolerance. Is bezafibrate therefore the answer to cholestatic itch? The cautious answer is ... possibly, but more experience is needed. The trial duration was only 21 days, which means that long-term safety and efficacy remain to be explored. Bezafibrate is now being used in practice to treat cholestatic itch with effects similar to those reported in the trial. It is therefore clearly an important new option. Where it ultimately ends up in the treatment pathway only time and experience will tell.
David Jones, BM, BCh, PhD, is a professor of liver immunology at Newcastle University, Newcastle Upon Tyne, England. He reported having no disclosures relevant to this commentary.
Once-daily treatment with the lipid-lowering agent bezafibrate significantly reduced moderate to severe pruritis among patients with cholestasis, according to the findings of a multicenter, double-blind, randomized, placebo-controlled study (Fibrates for Itch, or FITCH).
Two weeks after completing treatment, 45% of bezafibrate recipients met the primary endpoint, reporting at least a 50% decrease in itch on a 10-point visual analog scale (VAS), compared with 11% of patients in the placebo group (P = .003). There was also a statistically significant decrease in serum alkaline phosphatase (ALP) levels from baseline (35% vs. 6%, respectively; P = .03) that corresponded with improved pruritus, and bezafibrate significantly improved both morning and evening pruritus. Bezafibrate was not associated with myalgia, rhabdomyolysis, or serum alanine transaminase elevations but did lead to a 3% increase in serum creatinine that “was not different from the placebo group,” wrote Elsemieke de Vries, MD, PhD, of the department of gastroenterology & hepatology at Tytgat Institute for Liver and Intestinal Research, Amsterdam, and of department of gastroenterology & metabolism at Amsterdam University Medical Centers, and associates. Their report is in Gastroenterology.
Up to 70% of patients with cholangitis experience pruritus. Current guidelines recommend management with cholestyramine, rifampin, naltrexone, or sertraline, but efficacy and tolerability are subpar, the investigators wrote. In a recent study, a selective inhibitor of an ileal bile acid transporter (GSK2330672) reduced pruritus in primary biliary cholangitis but frequently was associated with diarrhea. In another recent study of patients with primary biliary cholangitis who had responded inadequately to ursodeoxycholic acid (BEZURSO), bezafibrate induced biochemical responses that correlated with improvements in pruritis (a secondary endpoint).
Lysophosphatidic acid (LPA) has been implicated in cholangiopathy-associated pruritus but is not found in bile. However, biliary drainage rapidly improves severe itch in patients with primary biliary cholangitis. Therefore, Dr. de Vries and associates hypothesized that an as-yet unknown factor in bile contributes to pruritus in fibrosing cholangiopathies and that bezafibrate reduces itch by “alleviating hepatobiliary cholestasis and injury and, thereby, reducing formation and biliary secretion of this biliary factor X.”
The FITCH study, which was conducted at seven academic hospitals in the Netherlands and one in Spain, enrolled 74 patients 18 years and older with primary biliary cholangitis or primary or secondary sclerosing cholangitis who reported having pruritus with an intensity of at least 5 on the 10-point VAS at baseline (with 10 indicating “worst itch possible”; median, 7; interquartile range, 7-8). Patients with hepatocellular cholestasis caused by medications or pregnancy were excluded. Ages among most participants ranged from 30s to 50s, and approximately two-thirds were female. None had received another pruritus treatment within 10 days of enrollment, and prior treatment with bezafibrate was not allowed. Patients received once-daily bezafibrate (400 mg) or placebo tablets for 21 days, with visits to the outpatient clinic on days 0, 21, and 35.
There were no serious adverse events or new safety signals. One event of oral pain was considered possibly related to bezafibrate, and itch and jaundice worsened in two patients after completing treatment. As in the 24-month BEZURSO study, increases in serum creatinine were modest and similar between groups (3% with bezafibrate and 5% with placebo). Myalgia and increases in serum alanine transaminase were observed in BEZURSO but not in FITCH. However, the short treatment duration provides “no judgment on long-term safety [of bezafibrate] in complex diseases such as primary sclerosing cholangitis or primary biliary cholangitis,” the investigators wrote.
Four patients discontinued treatment – three stopped placebo because of “unbearable pruritus,” and one stopped bezafibrate after developing acute bacterial cholangitis that required emergency treatment. Although FITCH excluded patients whose estimated glomerular filtration rate was less than 60 mL/min per 1.73 m2, one such patient was accidentally enrolled. Her serum creatinine, measured in mmol/L, rose from 121 at baseline to 148 on day 21, and then dropped to 134 after 2 weeks off treatment.
The trial was supported by patient donations, the Netherlands Society of Gastroenterology, and Instituto de Salud Carlos III. The investigators reported having no conflicts of interest.
SOURCE: de Vries E et al. Gastroenterology. 2020 Oct 5. doi: 10.1053/j.gastro.2020.10.001.
Once-daily treatment with the lipid-lowering agent bezafibrate significantly reduced moderate to severe pruritis among patients with cholestasis, according to the findings of a multicenter, double-blind, randomized, placebo-controlled study (Fibrates for Itch, or FITCH).
Two weeks after completing treatment, 45% of bezafibrate recipients met the primary endpoint, reporting at least a 50% decrease in itch on a 10-point visual analog scale (VAS), compared with 11% of patients in the placebo group (P = .003). There was also a statistically significant decrease in serum alkaline phosphatase (ALP) levels from baseline (35% vs. 6%, respectively; P = .03) that corresponded with improved pruritus, and bezafibrate significantly improved both morning and evening pruritus. Bezafibrate was not associated with myalgia, rhabdomyolysis, or serum alanine transaminase elevations but did lead to a 3% increase in serum creatinine that “was not different from the placebo group,” wrote Elsemieke de Vries, MD, PhD, of the department of gastroenterology & hepatology at Tytgat Institute for Liver and Intestinal Research, Amsterdam, and of department of gastroenterology & metabolism at Amsterdam University Medical Centers, and associates. Their report is in Gastroenterology.
Up to 70% of patients with cholangitis experience pruritus. Current guidelines recommend management with cholestyramine, rifampin, naltrexone, or sertraline, but efficacy and tolerability are subpar, the investigators wrote. In a recent study, a selective inhibitor of an ileal bile acid transporter (GSK2330672) reduced pruritus in primary biliary cholangitis but frequently was associated with diarrhea. In another recent study of patients with primary biliary cholangitis who had responded inadequately to ursodeoxycholic acid (BEZURSO), bezafibrate induced biochemical responses that correlated with improvements in pruritis (a secondary endpoint).
Lysophosphatidic acid (LPA) has been implicated in cholangiopathy-associated pruritus but is not found in bile. However, biliary drainage rapidly improves severe itch in patients with primary biliary cholangitis. Therefore, Dr. de Vries and associates hypothesized that an as-yet unknown factor in bile contributes to pruritus in fibrosing cholangiopathies and that bezafibrate reduces itch by “alleviating hepatobiliary cholestasis and injury and, thereby, reducing formation and biliary secretion of this biliary factor X.”
The FITCH study, which was conducted at seven academic hospitals in the Netherlands and one in Spain, enrolled 74 patients 18 years and older with primary biliary cholangitis or primary or secondary sclerosing cholangitis who reported having pruritus with an intensity of at least 5 on the 10-point VAS at baseline (with 10 indicating “worst itch possible”; median, 7; interquartile range, 7-8). Patients with hepatocellular cholestasis caused by medications or pregnancy were excluded. Ages among most participants ranged from 30s to 50s, and approximately two-thirds were female. None had received another pruritus treatment within 10 days of enrollment, and prior treatment with bezafibrate was not allowed. Patients received once-daily bezafibrate (400 mg) or placebo tablets for 21 days, with visits to the outpatient clinic on days 0, 21, and 35.
There were no serious adverse events or new safety signals. One event of oral pain was considered possibly related to bezafibrate, and itch and jaundice worsened in two patients after completing treatment. As in the 24-month BEZURSO study, increases in serum creatinine were modest and similar between groups (3% with bezafibrate and 5% with placebo). Myalgia and increases in serum alanine transaminase were observed in BEZURSO but not in FITCH. However, the short treatment duration provides “no judgment on long-term safety [of bezafibrate] in complex diseases such as primary sclerosing cholangitis or primary biliary cholangitis,” the investigators wrote.
Four patients discontinued treatment – three stopped placebo because of “unbearable pruritus,” and one stopped bezafibrate after developing acute bacterial cholangitis that required emergency treatment. Although FITCH excluded patients whose estimated glomerular filtration rate was less than 60 mL/min per 1.73 m2, one such patient was accidentally enrolled. Her serum creatinine, measured in mmol/L, rose from 121 at baseline to 148 on day 21, and then dropped to 134 after 2 weeks off treatment.
The trial was supported by patient donations, the Netherlands Society of Gastroenterology, and Instituto de Salud Carlos III. The investigators reported having no conflicts of interest.
SOURCE: de Vries E et al. Gastroenterology. 2020 Oct 5. doi: 10.1053/j.gastro.2020.10.001.
FROM GASTROENTEROLOGY
AGA Clinical Practice Update: Medical management of colonic diverticulitis
A new clinical practice update from the American Gastroenterological Association seeks to provide gastroenterologists with practical and evidence-based advice for management of colonic diverticulitis.
For example, clinicians should consider lower endoscopy and CT scans of the abdomen and pelvis with oral and intravenous contrast to rule out chronic diverticular inflammation, diverticular stricture or fistula, ischemic colitis, constipation, and inflammatory bowel disease, Anne F. Peery, MD, MSCR, of the University of North Carolina, Chapel Hill, and associates wrote in Gastroenterology.
“In our practice, patients are reassured to know that ongoing symptoms are common and often attributable to visceral hypersensitivity,” they wrote. “This conversation is particularly important after a negative workup. If needed, ongoing abdominal pain can be treated with a low to modest dose of a tricyclic antidepressant.”
The update from the AGA includes 13 other recommendations, with noteworthy advice to use antibiotics selectively, rather than routinely, in cases of acute uncomplicated diverticulitis in immunocompetent patients. In a recent large meta-analysis, antibiotics did not shorten symptom duration or reduce rates of hospitalization, complications, or surgery in this setting. The clinical practice update advises using antibiotics if patients are frail or have comorbidities, vomiting or refractory symptoms, a C-reactive protein level above 140 mg/L, a baseline white blood cell count above 15 × 109 cells/L, or fluid collection or a longer segment of inflammation on CT scan. Antibiotics also are strongly advised for immunocompromised patients, who are at greater risk for complications and severe diverticulitis. Because of this risk, clinicians should have “a low threshold” for cross-sectional imaging, antibiotic treatment, and consultation with a colorectal surgeon, according to the update.
The authors recommend CT if patients have severe symptoms or have not previously been diagnosed with diverticulitis based on imaging. Clinicians also should consider imaging if patients have had multiple recurrences, are not responding to treatment, are immunocompromised, or are considering prophylactic surgery (in which case imaging is used to pinpoint areas of disease).
Colonoscopy is advised after episodes of complicated diverticulitis or after a first episode of uncomplicated diverticulitis if no high-quality colonoscopy has been performed in the past year. This colonoscopy is advised to rule out malignancy, which can be misdiagnosed as diverticulitis, and because diverticulitis (particularly complicated diverticulitis) has been associated with colon cancer in some studies, the update notes. Unless patients have “alarm symptoms” – that is, a change in stool caliber, iron deficiency anemia, bloody stools, weight loss, or abdominal pain – colonoscopy should be delayed until 6-8 weeks after the diverticulitis episode or until the acute symptoms resolve, whichever occurs later.
The decision to discuss elective segmental resection should be based on disease severity, not the prior number of episodes. Although elective surgery for diverticulitis has become increasingly common, patients should be aware that surgery often does not improve chronic gastrointestinal symptoms, such as abdominal pain, and that surgery reduces but does not eliminate the risk for recurrence. The authors recommended against surgery to prevent complicated diverticulitis in immunocompetent patients with a history of uncomplicated episodes. “In this population, complicated diverticulitis is most often the first presentation of diverticulitis and is less likely with recurrences,” the update states. For acute complicated diverticulitis that has been effectively managed without surgery, patients are at heightened risk for recurrence, but “a growing literature suggest[s] a more conservative and personalized approach” rather than the routine use of interval elective resection, the authors noted. For all patients, counseling regarding surgery should incorporate thoughtful discussions of immune status, values and preferences, and operative risks versus benefits, including effects on quality of life.
Dr. Peery and another author were supported by grants from the National Institutes of Health. The authors reported having no conflicts of interest.
SOURCE: Peery AF et al. Gastroenterology. 2020 Dec 3. doi: 10.1053/j.gastro.2020.09.059.
This article was updated Feb. 10, 2021.
A new clinical practice update from the American Gastroenterological Association seeks to provide gastroenterologists with practical and evidence-based advice for management of colonic diverticulitis.
For example, clinicians should consider lower endoscopy and CT scans of the abdomen and pelvis with oral and intravenous contrast to rule out chronic diverticular inflammation, diverticular stricture or fistula, ischemic colitis, constipation, and inflammatory bowel disease, Anne F. Peery, MD, MSCR, of the University of North Carolina, Chapel Hill, and associates wrote in Gastroenterology.
“In our practice, patients are reassured to know that ongoing symptoms are common and often attributable to visceral hypersensitivity,” they wrote. “This conversation is particularly important after a negative workup. If needed, ongoing abdominal pain can be treated with a low to modest dose of a tricyclic antidepressant.”
The update from the AGA includes 13 other recommendations, with noteworthy advice to use antibiotics selectively, rather than routinely, in cases of acute uncomplicated diverticulitis in immunocompetent patients. In a recent large meta-analysis, antibiotics did not shorten symptom duration or reduce rates of hospitalization, complications, or surgery in this setting. The clinical practice update advises using antibiotics if patients are frail or have comorbidities, vomiting or refractory symptoms, a C-reactive protein level above 140 mg/L, a baseline white blood cell count above 15 × 109 cells/L, or fluid collection or a longer segment of inflammation on CT scan. Antibiotics also are strongly advised for immunocompromised patients, who are at greater risk for complications and severe diverticulitis. Because of this risk, clinicians should have “a low threshold” for cross-sectional imaging, antibiotic treatment, and consultation with a colorectal surgeon, according to the update.
The authors recommend CT if patients have severe symptoms or have not previously been diagnosed with diverticulitis based on imaging. Clinicians also should consider imaging if patients have had multiple recurrences, are not responding to treatment, are immunocompromised, or are considering prophylactic surgery (in which case imaging is used to pinpoint areas of disease).
Colonoscopy is advised after episodes of complicated diverticulitis or after a first episode of uncomplicated diverticulitis if no high-quality colonoscopy has been performed in the past year. This colonoscopy is advised to rule out malignancy, which can be misdiagnosed as diverticulitis, and because diverticulitis (particularly complicated diverticulitis) has been associated with colon cancer in some studies, the update notes. Unless patients have “alarm symptoms” – that is, a change in stool caliber, iron deficiency anemia, bloody stools, weight loss, or abdominal pain – colonoscopy should be delayed until 6-8 weeks after the diverticulitis episode or until the acute symptoms resolve, whichever occurs later.
The decision to discuss elective segmental resection should be based on disease severity, not the prior number of episodes. Although elective surgery for diverticulitis has become increasingly common, patients should be aware that surgery often does not improve chronic gastrointestinal symptoms, such as abdominal pain, and that surgery reduces but does not eliminate the risk for recurrence. The authors recommended against surgery to prevent complicated diverticulitis in immunocompetent patients with a history of uncomplicated episodes. “In this population, complicated diverticulitis is most often the first presentation of diverticulitis and is less likely with recurrences,” the update states. For acute complicated diverticulitis that has been effectively managed without surgery, patients are at heightened risk for recurrence, but “a growing literature suggest[s] a more conservative and personalized approach” rather than the routine use of interval elective resection, the authors noted. For all patients, counseling regarding surgery should incorporate thoughtful discussions of immune status, values and preferences, and operative risks versus benefits, including effects on quality of life.
Dr. Peery and another author were supported by grants from the National Institutes of Health. The authors reported having no conflicts of interest.
SOURCE: Peery AF et al. Gastroenterology. 2020 Dec 3. doi: 10.1053/j.gastro.2020.09.059.
This article was updated Feb. 10, 2021.
A new clinical practice update from the American Gastroenterological Association seeks to provide gastroenterologists with practical and evidence-based advice for management of colonic diverticulitis.
For example, clinicians should consider lower endoscopy and CT scans of the abdomen and pelvis with oral and intravenous contrast to rule out chronic diverticular inflammation, diverticular stricture or fistula, ischemic colitis, constipation, and inflammatory bowel disease, Anne F. Peery, MD, MSCR, of the University of North Carolina, Chapel Hill, and associates wrote in Gastroenterology.
“In our practice, patients are reassured to know that ongoing symptoms are common and often attributable to visceral hypersensitivity,” they wrote. “This conversation is particularly important after a negative workup. If needed, ongoing abdominal pain can be treated with a low to modest dose of a tricyclic antidepressant.”
The update from the AGA includes 13 other recommendations, with noteworthy advice to use antibiotics selectively, rather than routinely, in cases of acute uncomplicated diverticulitis in immunocompetent patients. In a recent large meta-analysis, antibiotics did not shorten symptom duration or reduce rates of hospitalization, complications, or surgery in this setting. The clinical practice update advises using antibiotics if patients are frail or have comorbidities, vomiting or refractory symptoms, a C-reactive protein level above 140 mg/L, a baseline white blood cell count above 15 × 109 cells/L, or fluid collection or a longer segment of inflammation on CT scan. Antibiotics also are strongly advised for immunocompromised patients, who are at greater risk for complications and severe diverticulitis. Because of this risk, clinicians should have “a low threshold” for cross-sectional imaging, antibiotic treatment, and consultation with a colorectal surgeon, according to the update.
The authors recommend CT if patients have severe symptoms or have not previously been diagnosed with diverticulitis based on imaging. Clinicians also should consider imaging if patients have had multiple recurrences, are not responding to treatment, are immunocompromised, or are considering prophylactic surgery (in which case imaging is used to pinpoint areas of disease).
Colonoscopy is advised after episodes of complicated diverticulitis or after a first episode of uncomplicated diverticulitis if no high-quality colonoscopy has been performed in the past year. This colonoscopy is advised to rule out malignancy, which can be misdiagnosed as diverticulitis, and because diverticulitis (particularly complicated diverticulitis) has been associated with colon cancer in some studies, the update notes. Unless patients have “alarm symptoms” – that is, a change in stool caliber, iron deficiency anemia, bloody stools, weight loss, or abdominal pain – colonoscopy should be delayed until 6-8 weeks after the diverticulitis episode or until the acute symptoms resolve, whichever occurs later.
The decision to discuss elective segmental resection should be based on disease severity, not the prior number of episodes. Although elective surgery for diverticulitis has become increasingly common, patients should be aware that surgery often does not improve chronic gastrointestinal symptoms, such as abdominal pain, and that surgery reduces but does not eliminate the risk for recurrence. The authors recommended against surgery to prevent complicated diverticulitis in immunocompetent patients with a history of uncomplicated episodes. “In this population, complicated diverticulitis is most often the first presentation of diverticulitis and is less likely with recurrences,” the update states. For acute complicated diverticulitis that has been effectively managed without surgery, patients are at heightened risk for recurrence, but “a growing literature suggest[s] a more conservative and personalized approach” rather than the routine use of interval elective resection, the authors noted. For all patients, counseling regarding surgery should incorporate thoughtful discussions of immune status, values and preferences, and operative risks versus benefits, including effects on quality of life.
Dr. Peery and another author were supported by grants from the National Institutes of Health. The authors reported having no conflicts of interest.
SOURCE: Peery AF et al. Gastroenterology. 2020 Dec 3. doi: 10.1053/j.gastro.2020.09.059.
This article was updated Feb. 10, 2021.
FROM GASTROENTEROLOGY
PDAC: Tumor reduction after neoadjuvant therapy may predict postsurgical survival
In patients who undergo resection of pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy, reduction in tumor size between diagnosis and surgery is associated with improved survival, according to a new single-center, retrospective analysis. The researchers compared tumor size as measured by endoscopic ultrasound (EUS) and found that a threshold of 47% or greater reduction in tumor size at resection was associated with a doubling in the 3-year survival rate.
The study, led by Rohit Das, MD, of the University of Pittsburgh Medical Center, was published in Clinical Gastroenterology and Hepatology.
The research represents only a small percentage of patients since most diagnosed with PDAC have locally advanced or metastatic disease that rules out surgery. Still, the work puts more emphasis on measuring tumor size while performing EUS, according to Robert Jay Sealock, MD, who is an assistant professor of medicine at Baylor College of Medicine, Houston.
“This is some helpful information that you can relay to the patient, saying that you have a significant decrease in the size of the tumor based on your initial EUS, and your chance of 3- to 5-year survival is going to be a lot higher, compared to somebody that didn’t have that tumor regression. Most of these patients will undergo an EUS anyway, and you’ll commonly if not always measure the tumor size while you’re in there. Now you can apply this information that you already have to give the patients some additional information if they do undergo surgery,” said Dr. Sealock, who was not involved in the research.
Previous efforts to prognosticate postsurgical survival focused on overall tumor burden using multidetector CT (MDCT), carbohydrate antigen 19-9 (CA19-9) levels, and histologic examination following surgery, but all suffer from various limitations. MDCT is not always accurate in its measurement of tumor size, other conditions can also raise CA19-9 levels, and pathologic findings are subjective because sometimes the amount of tumor before neoadjuvant therapy is uncertain.
The researchers mapped survival statistics to EUS and pathologic findings for 340 treatment-naive and 365 neoadjuvant-treated PDAC patients at the University of Pittsburgh Medical Center. They used a 200 patient cohort from the same center who had been treated with neoadjuvant therapy for validation.
Pathology examination revealed that, in the treatment-naive group, 71% of tumors were larger than the size determined during EUS. In 9% of cases there was no change in size (EUS versus pathology T-staging Pearson correlation coefficient, 0.586; P < .001). A similar analysis of MDCT showed a weaker correlation. There was no correlation between preoperative EUS/MDCT findings and postoperative pathology among patients who received neoadjuvant therapy.
In the neoadjuvant therapy group, tumor size was reduced in 31%, was unchanged in 53%, and actually grew in 16%. Three-year overall survival was highest in the reduced group (50%), and lower in the unchanged (37%) and tumor-growth (34%) groups. At 5 years, overall survival was 31%, 19%, and 16%, respectively (P = .003). Compared with those whose tumor size remained the same or grew, those with reduced tumor size had higher 3-year overall survival (50% vs. 33%) and 5-year overall survival (31% vs. 18%; P < .001).
The researchers used recursive positioning to identify the optimal threshold for tumor reduction, and found that a 47% or greater reduction was associated with 67% overall survival at 3 years and 47% at 5 years, compared with 32% and 16% for those with smaller reduction or tumors that maintained or increased in size (P < .001).
The researchers noted that, although their study is large, it remains retrospective in design. Another limitation they cited was that not all patients received the same neoadjuvant therapy. Furthermore, both EUS and pathologic evaluation can be subjective, and it can be difficult to correct for that.
“While additional studies are required, incorporating preoperative EUS and postoperative pathologic tumor size measurements into the standard evaluation of neoadjuvant-treated PDAC patients may guide subsequent management in the adjuvant setting,” the researchers concluded.
The study was funded in part by the National Pancreas Foundation, Sky Foundation, and the Pittsburgh Liver Research Center at the University of Pittsburgh. One author disclosed receiving an honorarium from Foundation Medicine, but the rest reported having nothing to disclose. Dr. Sealock has no relevant financial disclosures.
SOURCE: Das R et al. Clin Gastroenterol Hepatol. 2020 Dec 2. doi: 10.1016/j.cgh.2020.11.041.
In patients who undergo resection of pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy, reduction in tumor size between diagnosis and surgery is associated with improved survival, according to a new single-center, retrospective analysis. The researchers compared tumor size as measured by endoscopic ultrasound (EUS) and found that a threshold of 47% or greater reduction in tumor size at resection was associated with a doubling in the 3-year survival rate.
The study, led by Rohit Das, MD, of the University of Pittsburgh Medical Center, was published in Clinical Gastroenterology and Hepatology.
The research represents only a small percentage of patients since most diagnosed with PDAC have locally advanced or metastatic disease that rules out surgery. Still, the work puts more emphasis on measuring tumor size while performing EUS, according to Robert Jay Sealock, MD, who is an assistant professor of medicine at Baylor College of Medicine, Houston.
“This is some helpful information that you can relay to the patient, saying that you have a significant decrease in the size of the tumor based on your initial EUS, and your chance of 3- to 5-year survival is going to be a lot higher, compared to somebody that didn’t have that tumor regression. Most of these patients will undergo an EUS anyway, and you’ll commonly if not always measure the tumor size while you’re in there. Now you can apply this information that you already have to give the patients some additional information if they do undergo surgery,” said Dr. Sealock, who was not involved in the research.
Previous efforts to prognosticate postsurgical survival focused on overall tumor burden using multidetector CT (MDCT), carbohydrate antigen 19-9 (CA19-9) levels, and histologic examination following surgery, but all suffer from various limitations. MDCT is not always accurate in its measurement of tumor size, other conditions can also raise CA19-9 levels, and pathologic findings are subjective because sometimes the amount of tumor before neoadjuvant therapy is uncertain.
The researchers mapped survival statistics to EUS and pathologic findings for 340 treatment-naive and 365 neoadjuvant-treated PDAC patients at the University of Pittsburgh Medical Center. They used a 200 patient cohort from the same center who had been treated with neoadjuvant therapy for validation.
Pathology examination revealed that, in the treatment-naive group, 71% of tumors were larger than the size determined during EUS. In 9% of cases there was no change in size (EUS versus pathology T-staging Pearson correlation coefficient, 0.586; P < .001). A similar analysis of MDCT showed a weaker correlation. There was no correlation between preoperative EUS/MDCT findings and postoperative pathology among patients who received neoadjuvant therapy.
In the neoadjuvant therapy group, tumor size was reduced in 31%, was unchanged in 53%, and actually grew in 16%. Three-year overall survival was highest in the reduced group (50%), and lower in the unchanged (37%) and tumor-growth (34%) groups. At 5 years, overall survival was 31%, 19%, and 16%, respectively (P = .003). Compared with those whose tumor size remained the same or grew, those with reduced tumor size had higher 3-year overall survival (50% vs. 33%) and 5-year overall survival (31% vs. 18%; P < .001).
The researchers used recursive positioning to identify the optimal threshold for tumor reduction, and found that a 47% or greater reduction was associated with 67% overall survival at 3 years and 47% at 5 years, compared with 32% and 16% for those with smaller reduction or tumors that maintained or increased in size (P < .001).
The researchers noted that, although their study is large, it remains retrospective in design. Another limitation they cited was that not all patients received the same neoadjuvant therapy. Furthermore, both EUS and pathologic evaluation can be subjective, and it can be difficult to correct for that.
“While additional studies are required, incorporating preoperative EUS and postoperative pathologic tumor size measurements into the standard evaluation of neoadjuvant-treated PDAC patients may guide subsequent management in the adjuvant setting,” the researchers concluded.
The study was funded in part by the National Pancreas Foundation, Sky Foundation, and the Pittsburgh Liver Research Center at the University of Pittsburgh. One author disclosed receiving an honorarium from Foundation Medicine, but the rest reported having nothing to disclose. Dr. Sealock has no relevant financial disclosures.
SOURCE: Das R et al. Clin Gastroenterol Hepatol. 2020 Dec 2. doi: 10.1016/j.cgh.2020.11.041.
In patients who undergo resection of pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy, reduction in tumor size between diagnosis and surgery is associated with improved survival, according to a new single-center, retrospective analysis. The researchers compared tumor size as measured by endoscopic ultrasound (EUS) and found that a threshold of 47% or greater reduction in tumor size at resection was associated with a doubling in the 3-year survival rate.
The study, led by Rohit Das, MD, of the University of Pittsburgh Medical Center, was published in Clinical Gastroenterology and Hepatology.
The research represents only a small percentage of patients since most diagnosed with PDAC have locally advanced or metastatic disease that rules out surgery. Still, the work puts more emphasis on measuring tumor size while performing EUS, according to Robert Jay Sealock, MD, who is an assistant professor of medicine at Baylor College of Medicine, Houston.
“This is some helpful information that you can relay to the patient, saying that you have a significant decrease in the size of the tumor based on your initial EUS, and your chance of 3- to 5-year survival is going to be a lot higher, compared to somebody that didn’t have that tumor regression. Most of these patients will undergo an EUS anyway, and you’ll commonly if not always measure the tumor size while you’re in there. Now you can apply this information that you already have to give the patients some additional information if they do undergo surgery,” said Dr. Sealock, who was not involved in the research.
Previous efforts to prognosticate postsurgical survival focused on overall tumor burden using multidetector CT (MDCT), carbohydrate antigen 19-9 (CA19-9) levels, and histologic examination following surgery, but all suffer from various limitations. MDCT is not always accurate in its measurement of tumor size, other conditions can also raise CA19-9 levels, and pathologic findings are subjective because sometimes the amount of tumor before neoadjuvant therapy is uncertain.
The researchers mapped survival statistics to EUS and pathologic findings for 340 treatment-naive and 365 neoadjuvant-treated PDAC patients at the University of Pittsburgh Medical Center. They used a 200 patient cohort from the same center who had been treated with neoadjuvant therapy for validation.
Pathology examination revealed that, in the treatment-naive group, 71% of tumors were larger than the size determined during EUS. In 9% of cases there was no change in size (EUS versus pathology T-staging Pearson correlation coefficient, 0.586; P < .001). A similar analysis of MDCT showed a weaker correlation. There was no correlation between preoperative EUS/MDCT findings and postoperative pathology among patients who received neoadjuvant therapy.
In the neoadjuvant therapy group, tumor size was reduced in 31%, was unchanged in 53%, and actually grew in 16%. Three-year overall survival was highest in the reduced group (50%), and lower in the unchanged (37%) and tumor-growth (34%) groups. At 5 years, overall survival was 31%, 19%, and 16%, respectively (P = .003). Compared with those whose tumor size remained the same or grew, those with reduced tumor size had higher 3-year overall survival (50% vs. 33%) and 5-year overall survival (31% vs. 18%; P < .001).
The researchers used recursive positioning to identify the optimal threshold for tumor reduction, and found that a 47% or greater reduction was associated with 67% overall survival at 3 years and 47% at 5 years, compared with 32% and 16% for those with smaller reduction or tumors that maintained or increased in size (P < .001).
The researchers noted that, although their study is large, it remains retrospective in design. Another limitation they cited was that not all patients received the same neoadjuvant therapy. Furthermore, both EUS and pathologic evaluation can be subjective, and it can be difficult to correct for that.
“While additional studies are required, incorporating preoperative EUS and postoperative pathologic tumor size measurements into the standard evaluation of neoadjuvant-treated PDAC patients may guide subsequent management in the adjuvant setting,” the researchers concluded.
The study was funded in part by the National Pancreas Foundation, Sky Foundation, and the Pittsburgh Liver Research Center at the University of Pittsburgh. One author disclosed receiving an honorarium from Foundation Medicine, but the rest reported having nothing to disclose. Dr. Sealock has no relevant financial disclosures.
SOURCE: Das R et al. Clin Gastroenterol Hepatol. 2020 Dec 2. doi: 10.1016/j.cgh.2020.11.041.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
AGA Clinical Practice Update: How diet and exercise can help manage NAFLD
Exercise and a hypocaloric, Mediterranean-style diet remain first-line interventions that can benefit all patients with nonalcoholic fatty liver disease (NAFLD), according to a clinical practice update from the American Gastroenterological Association.
“[W]eight loss is associated with a reduction in liver fat, which provides a potential for reversal of disease progression,” wrote Zobair M. Younossi, MD, MPH, of Inova Fairfax Medical Campus in Falls Church, Va., with his associates. Lifestyle modifications remain “the cornerstone for management” because, even though NAFLD affects approximately 25% of individuals worldwide according to one meta-analytic assessment, interventions such as medications, bariatric endoscopy, and surgery are usually reserved for the subset of patients with severe obesity, comorbid diabetes, or nonalcoholic steatohepatitis (NASH) with at least stage 2 fibrosis, the experts wrote in Gastroenterology.
They note that clinically significant weight loss typically requires a hypocaloric diet of 1,200-1,500 kilocalories/day or a decrease of 500-1,000 kilocalories/day from baseline. A Mediterranean diet of fresh vegetables, fruits, legumes, minimally processed whole grains, fish, olive oil, nuts, and seeds is recommended because its antioxidant, anti-inflammatory effects may slow NAFLD progression. This diet minimizes or eliminates sweets, refined grains, and red and processed meats. Fructose from fruit is not associated with NAFLD, but patients should consume little or no commercially prepared fructose, which has been linked to visceral adiposity, insulin resistance, hepatic inflammation, and fibrosis progression. Other hypocaloric diets have not been studied enough to support their routine use in NAFLD treatment, according to the clinical practice update.
For patients with NASH, which is the more severe form of NAFLD and is associated with significant morbidity and mortality caused by complications from cirrhosis, hepatic decompensation, and hepatocellular carcinoma, weight loss also has a big impact: Losing at least 5% of total body weight can decrease hepatic steatosis, losing at least 7% can resolve NASH, and losing at least 10% can lessen or stabilize hepatic fibrosis, according to level 1 evidence cited by the update. Weight loss “can significantly impact all aspects of NAFLD histology including fibrosis, but a goal of 10% total body weight loss should be considered for patients with overweight or obese NAFLD,” the authors wrote. Fat loss also improves liver histology in patients with lean NAFLD (body mass index, 26 kg/m2 in non-Asian patients or 24 in Asians), for whom a hypocaloric diet targeting a more modest 3%-5% total body weight loss is recommended.
Because aerobic exercise reduces hepatic fat levels independently of hypocaloric diet, patients with NAFLD should consider a weekly regimen of 150-300 minutes of moderate-intensity exercise or 75-150 minutes of vigorous activity. Resistance training can complement aerobic exercise “but [is] not a replacement,” the authors noted. In addition, patients with NAFLD should restrict alcohol consumption to reduce the risk for liver-related events, and those with advanced hepatic fibrosis should “avoid alcohol entirely.” These recommendations reflect the findings of a large prospective study in which the consumption of even low amounts of alcohol led to worse liver-related outcomes among patients with NAFLD.
Clinicians should screen for and “aggressively” manage common NAFLD comorbidities, including diabetes mellitus, hypertension, and obstructive sleep apnea, according to the clinical practice update. Patients with coexisting metabolic conditions should be risk-stratified for cardiovascular disease and treated based on guidelines from the American College of Cardiology and the American Heart Association.
It is believed that sarcopenia affects patients with NASH cirrhosis because their livers cannot effectively store, metabolize, or mobilize carbohydrates, which leads to a catabolic state in which protein and fat are used as energy sources, according to the update. To avoid exacerbations, these patients may need to optimize their protein intake – a minimum of 1.2-1.5 g/kg of body weight is recommended – from sources of branched-chain amino acids, such as chicken, fish, eggs, nuts, lentils, or soy. Patients with sarcopenic NAFLD also should consume small, frequent meals spaced no more than 4-6 hours apart. When possible, they should consult with a specialized nutritionist. Moderate-intensity exercise may also benefit patients experiencing sarcopenia.
The researchers disclosed ties to Gilead Sciences, Intercept, Bristol Myers Squibb, Novo Nordisk, and several other companies. The review was commissioned and approved by the AGA Institute’s Clinical Practice Updates Committee and the AGA Governing Board.
SOURCE: Younossi ZM et al. Gastroenterology. 2020 Dec 8. doi: 10.1053/j.gastro.2020.11.051.
This article was updated Feb. 10, 2021.
Exercise and a hypocaloric, Mediterranean-style diet remain first-line interventions that can benefit all patients with nonalcoholic fatty liver disease (NAFLD), according to a clinical practice update from the American Gastroenterological Association.
“[W]eight loss is associated with a reduction in liver fat, which provides a potential for reversal of disease progression,” wrote Zobair M. Younossi, MD, MPH, of Inova Fairfax Medical Campus in Falls Church, Va., with his associates. Lifestyle modifications remain “the cornerstone for management” because, even though NAFLD affects approximately 25% of individuals worldwide according to one meta-analytic assessment, interventions such as medications, bariatric endoscopy, and surgery are usually reserved for the subset of patients with severe obesity, comorbid diabetes, or nonalcoholic steatohepatitis (NASH) with at least stage 2 fibrosis, the experts wrote in Gastroenterology.
They note that clinically significant weight loss typically requires a hypocaloric diet of 1,200-1,500 kilocalories/day or a decrease of 500-1,000 kilocalories/day from baseline. A Mediterranean diet of fresh vegetables, fruits, legumes, minimally processed whole grains, fish, olive oil, nuts, and seeds is recommended because its antioxidant, anti-inflammatory effects may slow NAFLD progression. This diet minimizes or eliminates sweets, refined grains, and red and processed meats. Fructose from fruit is not associated with NAFLD, but patients should consume little or no commercially prepared fructose, which has been linked to visceral adiposity, insulin resistance, hepatic inflammation, and fibrosis progression. Other hypocaloric diets have not been studied enough to support their routine use in NAFLD treatment, according to the clinical practice update.
For patients with NASH, which is the more severe form of NAFLD and is associated with significant morbidity and mortality caused by complications from cirrhosis, hepatic decompensation, and hepatocellular carcinoma, weight loss also has a big impact: Losing at least 5% of total body weight can decrease hepatic steatosis, losing at least 7% can resolve NASH, and losing at least 10% can lessen or stabilize hepatic fibrosis, according to level 1 evidence cited by the update. Weight loss “can significantly impact all aspects of NAFLD histology including fibrosis, but a goal of 10% total body weight loss should be considered for patients with overweight or obese NAFLD,” the authors wrote. Fat loss also improves liver histology in patients with lean NAFLD (body mass index, 26 kg/m2 in non-Asian patients or 24 in Asians), for whom a hypocaloric diet targeting a more modest 3%-5% total body weight loss is recommended.
Because aerobic exercise reduces hepatic fat levels independently of hypocaloric diet, patients with NAFLD should consider a weekly regimen of 150-300 minutes of moderate-intensity exercise or 75-150 minutes of vigorous activity. Resistance training can complement aerobic exercise “but [is] not a replacement,” the authors noted. In addition, patients with NAFLD should restrict alcohol consumption to reduce the risk for liver-related events, and those with advanced hepatic fibrosis should “avoid alcohol entirely.” These recommendations reflect the findings of a large prospective study in which the consumption of even low amounts of alcohol led to worse liver-related outcomes among patients with NAFLD.
Clinicians should screen for and “aggressively” manage common NAFLD comorbidities, including diabetes mellitus, hypertension, and obstructive sleep apnea, according to the clinical practice update. Patients with coexisting metabolic conditions should be risk-stratified for cardiovascular disease and treated based on guidelines from the American College of Cardiology and the American Heart Association.
It is believed that sarcopenia affects patients with NASH cirrhosis because their livers cannot effectively store, metabolize, or mobilize carbohydrates, which leads to a catabolic state in which protein and fat are used as energy sources, according to the update. To avoid exacerbations, these patients may need to optimize their protein intake – a minimum of 1.2-1.5 g/kg of body weight is recommended – from sources of branched-chain amino acids, such as chicken, fish, eggs, nuts, lentils, or soy. Patients with sarcopenic NAFLD also should consume small, frequent meals spaced no more than 4-6 hours apart. When possible, they should consult with a specialized nutritionist. Moderate-intensity exercise may also benefit patients experiencing sarcopenia.
The researchers disclosed ties to Gilead Sciences, Intercept, Bristol Myers Squibb, Novo Nordisk, and several other companies. The review was commissioned and approved by the AGA Institute’s Clinical Practice Updates Committee and the AGA Governing Board.
SOURCE: Younossi ZM et al. Gastroenterology. 2020 Dec 8. doi: 10.1053/j.gastro.2020.11.051.
This article was updated Feb. 10, 2021.
Exercise and a hypocaloric, Mediterranean-style diet remain first-line interventions that can benefit all patients with nonalcoholic fatty liver disease (NAFLD), according to a clinical practice update from the American Gastroenterological Association.
“[W]eight loss is associated with a reduction in liver fat, which provides a potential for reversal of disease progression,” wrote Zobair M. Younossi, MD, MPH, of Inova Fairfax Medical Campus in Falls Church, Va., with his associates. Lifestyle modifications remain “the cornerstone for management” because, even though NAFLD affects approximately 25% of individuals worldwide according to one meta-analytic assessment, interventions such as medications, bariatric endoscopy, and surgery are usually reserved for the subset of patients with severe obesity, comorbid diabetes, or nonalcoholic steatohepatitis (NASH) with at least stage 2 fibrosis, the experts wrote in Gastroenterology.
They note that clinically significant weight loss typically requires a hypocaloric diet of 1,200-1,500 kilocalories/day or a decrease of 500-1,000 kilocalories/day from baseline. A Mediterranean diet of fresh vegetables, fruits, legumes, minimally processed whole grains, fish, olive oil, nuts, and seeds is recommended because its antioxidant, anti-inflammatory effects may slow NAFLD progression. This diet minimizes or eliminates sweets, refined grains, and red and processed meats. Fructose from fruit is not associated with NAFLD, but patients should consume little or no commercially prepared fructose, which has been linked to visceral adiposity, insulin resistance, hepatic inflammation, and fibrosis progression. Other hypocaloric diets have not been studied enough to support their routine use in NAFLD treatment, according to the clinical practice update.
For patients with NASH, which is the more severe form of NAFLD and is associated with significant morbidity and mortality caused by complications from cirrhosis, hepatic decompensation, and hepatocellular carcinoma, weight loss also has a big impact: Losing at least 5% of total body weight can decrease hepatic steatosis, losing at least 7% can resolve NASH, and losing at least 10% can lessen or stabilize hepatic fibrosis, according to level 1 evidence cited by the update. Weight loss “can significantly impact all aspects of NAFLD histology including fibrosis, but a goal of 10% total body weight loss should be considered for patients with overweight or obese NAFLD,” the authors wrote. Fat loss also improves liver histology in patients with lean NAFLD (body mass index, 26 kg/m2 in non-Asian patients or 24 in Asians), for whom a hypocaloric diet targeting a more modest 3%-5% total body weight loss is recommended.
Because aerobic exercise reduces hepatic fat levels independently of hypocaloric diet, patients with NAFLD should consider a weekly regimen of 150-300 minutes of moderate-intensity exercise or 75-150 minutes of vigorous activity. Resistance training can complement aerobic exercise “but [is] not a replacement,” the authors noted. In addition, patients with NAFLD should restrict alcohol consumption to reduce the risk for liver-related events, and those with advanced hepatic fibrosis should “avoid alcohol entirely.” These recommendations reflect the findings of a large prospective study in which the consumption of even low amounts of alcohol led to worse liver-related outcomes among patients with NAFLD.
Clinicians should screen for and “aggressively” manage common NAFLD comorbidities, including diabetes mellitus, hypertension, and obstructive sleep apnea, according to the clinical practice update. Patients with coexisting metabolic conditions should be risk-stratified for cardiovascular disease and treated based on guidelines from the American College of Cardiology and the American Heart Association.
It is believed that sarcopenia affects patients with NASH cirrhosis because their livers cannot effectively store, metabolize, or mobilize carbohydrates, which leads to a catabolic state in which protein and fat are used as energy sources, according to the update. To avoid exacerbations, these patients may need to optimize their protein intake – a minimum of 1.2-1.5 g/kg of body weight is recommended – from sources of branched-chain amino acids, such as chicken, fish, eggs, nuts, lentils, or soy. Patients with sarcopenic NAFLD also should consume small, frequent meals spaced no more than 4-6 hours apart. When possible, they should consult with a specialized nutritionist. Moderate-intensity exercise may also benefit patients experiencing sarcopenia.
The researchers disclosed ties to Gilead Sciences, Intercept, Bristol Myers Squibb, Novo Nordisk, and several other companies. The review was commissioned and approved by the AGA Institute’s Clinical Practice Updates Committee and the AGA Governing Board.
SOURCE: Younossi ZM et al. Gastroenterology. 2020 Dec 8. doi: 10.1053/j.gastro.2020.11.051.
This article was updated Feb. 10, 2021.
FROM GASTROENTEROLOGY
DOACs look safe in elective endoscopic procedures
Among patients taking direct oral anticoagulants (DOACs), elective endoscopy procedures carry a risk of bleeding and thromboembolic events similar to that seen in those receiving vitamin K antagonists (VKAs), according to a multicenter, prospective observational study conducted at 12 Spanish academic and community centers.
DOACs have several advantages over VKAs, including more predictable pharmacokinetic profiles and fewer food and drug interactions, but they have not been well studied in the elective endoscopy setting. Some previous studies suggested a lower risk with DOACs than with VKAs, but they were retrospective or based on administrative databases.
It also remains unclear when anticoagulant therapy should be resumed following high-risk procedures. The new study, which was led by Enrique Rodríguez de Santiago of Universidad de Alcalá (Spain) and published in Clinical Gastroenterology and Hepatology, suggested that early resumption may be safe. “It certainly showed there was an acceptable rate of clinically significant rate of bleeding for patients on anticoagulants, and the thing I appreciated the most was that there was no statistically significant difference in terms of bleeding depending on when you resumed the anticoagulant,” said Robert Jay Sealock, MD, assistant professor of medicine at Baylor College of Medicine in Houston. Dr. Sealock was not involved in the study.
The researchers examined data from 1,623 patients who underwent 1,874 endoscopic procedures. Among these patients, 62.7% were taking VKAs, and 37.3% were taking DOACs; 58.9% were men, and the mean age was 74.2 years. Overall, 75.5% were on anticoagulant therapy for atrial fibrillation.
The most common procedures were colonoscopy (68.3%) and esophagogastroduodenoscopy (27.3%).
Within 30 days, The risk of bleeding was similar between patients taking VKAs (6.2%; 95% confidence interval, 4.8-7.8%) and DOACs (6.7%; 95% CI, 4.9-9%). This was true regardless of intervention and site. Overall, 1.4% of subjects experienced a thromboembolic event (95% CI, 0.9-2.1%), and there was no significant difference between the VKA group (1.3%; 95% CI, 0.8-2.2%) and the DOAC group (1.5%; 95% CI, 0.8-2.8%).
Clinically significant gastrointestinal bleeding occurred in 6.4% of subjects (95% CI, 5.3-7.7%); 2.7% of clinically significant gastrointestinal bleeding events were intraprocedural and 4.1% were delayed. The lowest risk of bleeding occurred with diagnostic endoscopy (1.1%) and biopsy (2.2%). The risk of bleeding for high-risk procedures was 11.5% (95% CI, 9.4-14%).
The overall mortality was 1.4%, with two deaths related to thromboembolic events, both in the DOAC group. The other deaths were considered to be unrelated to the procedure or periprocedural interruption of anticoagulants.
The researchers also examined the timing of anticoagulant resumption. Overall, 59.2% of subjects received bridging therapy, including 85% of the VKA group and 16% of the DOAC group (P < .001). This was not associated with increased endoscopy-related bleeding in either the VKA (3.3% with bridging therapy vs. 6.4% without; P = .14) or the DOAC group (8.3% vs. 6.4%; P = .48).
A total of 747 patients underwent a high-risk procedure, 46.3% of patients resumed anticoagulant therapy within 24 hours of the procedure, and 46.2% between 24 and 48 hours. After inverse probability of treatment weighting adjustment, a delay in anticoagulant resumption was not associated with a reduction in the frequency of postprocedural clinically significant gastrointestinal bleeding.
Still, the research left some questions unanswered. Most of the high-risk procedures were hot (41.8%) or cold snare polypectomies (39.8%). There weren’t enough data in the study to evaluate risk in patients undergoing other high-risk procedures such as balloon dilation for strictures, endoscopic ultrasound with fine-needle aspiration, and sphincterotomy. “That’s one group that we still don’t really have enough data about, particularly those patients who are on DOACs,” said Dr. Sealock.
The study also found a high number of patients on bridging therapy. “It highlighted the fact that we probably use bridging therapy too much in patients undergoing endoscopy,” said Dr. Sealock. He recommended using tools that generate recommendations for bridging therapy and timing for withholding and resuming anticoagulants based on procedure and patient characteristics.
SOURCE: de Santiago ER et al. Clin Gastroenterol Hepatol. 2020 Dec 03. doi: 10.1016/j.cgh.2020.11.037.
Among patients taking direct oral anticoagulants (DOACs), elective endoscopy procedures carry a risk of bleeding and thromboembolic events similar to that seen in those receiving vitamin K antagonists (VKAs), according to a multicenter, prospective observational study conducted at 12 Spanish academic and community centers.
DOACs have several advantages over VKAs, including more predictable pharmacokinetic profiles and fewer food and drug interactions, but they have not been well studied in the elective endoscopy setting. Some previous studies suggested a lower risk with DOACs than with VKAs, but they were retrospective or based on administrative databases.
It also remains unclear when anticoagulant therapy should be resumed following high-risk procedures. The new study, which was led by Enrique Rodríguez de Santiago of Universidad de Alcalá (Spain) and published in Clinical Gastroenterology and Hepatology, suggested that early resumption may be safe. “It certainly showed there was an acceptable rate of clinically significant rate of bleeding for patients on anticoagulants, and the thing I appreciated the most was that there was no statistically significant difference in terms of bleeding depending on when you resumed the anticoagulant,” said Robert Jay Sealock, MD, assistant professor of medicine at Baylor College of Medicine in Houston. Dr. Sealock was not involved in the study.
The researchers examined data from 1,623 patients who underwent 1,874 endoscopic procedures. Among these patients, 62.7% were taking VKAs, and 37.3% were taking DOACs; 58.9% were men, and the mean age was 74.2 years. Overall, 75.5% were on anticoagulant therapy for atrial fibrillation.
The most common procedures were colonoscopy (68.3%) and esophagogastroduodenoscopy (27.3%).
Within 30 days, The risk of bleeding was similar between patients taking VKAs (6.2%; 95% confidence interval, 4.8-7.8%) and DOACs (6.7%; 95% CI, 4.9-9%). This was true regardless of intervention and site. Overall, 1.4% of subjects experienced a thromboembolic event (95% CI, 0.9-2.1%), and there was no significant difference between the VKA group (1.3%; 95% CI, 0.8-2.2%) and the DOAC group (1.5%; 95% CI, 0.8-2.8%).
Clinically significant gastrointestinal bleeding occurred in 6.4% of subjects (95% CI, 5.3-7.7%); 2.7% of clinically significant gastrointestinal bleeding events were intraprocedural and 4.1% were delayed. The lowest risk of bleeding occurred with diagnostic endoscopy (1.1%) and biopsy (2.2%). The risk of bleeding for high-risk procedures was 11.5% (95% CI, 9.4-14%).
The overall mortality was 1.4%, with two deaths related to thromboembolic events, both in the DOAC group. The other deaths were considered to be unrelated to the procedure or periprocedural interruption of anticoagulants.
The researchers also examined the timing of anticoagulant resumption. Overall, 59.2% of subjects received bridging therapy, including 85% of the VKA group and 16% of the DOAC group (P < .001). This was not associated with increased endoscopy-related bleeding in either the VKA (3.3% with bridging therapy vs. 6.4% without; P = .14) or the DOAC group (8.3% vs. 6.4%; P = .48).
A total of 747 patients underwent a high-risk procedure, 46.3% of patients resumed anticoagulant therapy within 24 hours of the procedure, and 46.2% between 24 and 48 hours. After inverse probability of treatment weighting adjustment, a delay in anticoagulant resumption was not associated with a reduction in the frequency of postprocedural clinically significant gastrointestinal bleeding.
Still, the research left some questions unanswered. Most of the high-risk procedures were hot (41.8%) or cold snare polypectomies (39.8%). There weren’t enough data in the study to evaluate risk in patients undergoing other high-risk procedures such as balloon dilation for strictures, endoscopic ultrasound with fine-needle aspiration, and sphincterotomy. “That’s one group that we still don’t really have enough data about, particularly those patients who are on DOACs,” said Dr. Sealock.
The study also found a high number of patients on bridging therapy. “It highlighted the fact that we probably use bridging therapy too much in patients undergoing endoscopy,” said Dr. Sealock. He recommended using tools that generate recommendations for bridging therapy and timing for withholding and resuming anticoagulants based on procedure and patient characteristics.
SOURCE: de Santiago ER et al. Clin Gastroenterol Hepatol. 2020 Dec 03. doi: 10.1016/j.cgh.2020.11.037.
Among patients taking direct oral anticoagulants (DOACs), elective endoscopy procedures carry a risk of bleeding and thromboembolic events similar to that seen in those receiving vitamin K antagonists (VKAs), according to a multicenter, prospective observational study conducted at 12 Spanish academic and community centers.
DOACs have several advantages over VKAs, including more predictable pharmacokinetic profiles and fewer food and drug interactions, but they have not been well studied in the elective endoscopy setting. Some previous studies suggested a lower risk with DOACs than with VKAs, but they were retrospective or based on administrative databases.
It also remains unclear when anticoagulant therapy should be resumed following high-risk procedures. The new study, which was led by Enrique Rodríguez de Santiago of Universidad de Alcalá (Spain) and published in Clinical Gastroenterology and Hepatology, suggested that early resumption may be safe. “It certainly showed there was an acceptable rate of clinically significant rate of bleeding for patients on anticoagulants, and the thing I appreciated the most was that there was no statistically significant difference in terms of bleeding depending on when you resumed the anticoagulant,” said Robert Jay Sealock, MD, assistant professor of medicine at Baylor College of Medicine in Houston. Dr. Sealock was not involved in the study.
The researchers examined data from 1,623 patients who underwent 1,874 endoscopic procedures. Among these patients, 62.7% were taking VKAs, and 37.3% were taking DOACs; 58.9% were men, and the mean age was 74.2 years. Overall, 75.5% were on anticoagulant therapy for atrial fibrillation.
The most common procedures were colonoscopy (68.3%) and esophagogastroduodenoscopy (27.3%).
Within 30 days, The risk of bleeding was similar between patients taking VKAs (6.2%; 95% confidence interval, 4.8-7.8%) and DOACs (6.7%; 95% CI, 4.9-9%). This was true regardless of intervention and site. Overall, 1.4% of subjects experienced a thromboembolic event (95% CI, 0.9-2.1%), and there was no significant difference between the VKA group (1.3%; 95% CI, 0.8-2.2%) and the DOAC group (1.5%; 95% CI, 0.8-2.8%).
Clinically significant gastrointestinal bleeding occurred in 6.4% of subjects (95% CI, 5.3-7.7%); 2.7% of clinically significant gastrointestinal bleeding events were intraprocedural and 4.1% were delayed. The lowest risk of bleeding occurred with diagnostic endoscopy (1.1%) and biopsy (2.2%). The risk of bleeding for high-risk procedures was 11.5% (95% CI, 9.4-14%).
The overall mortality was 1.4%, with two deaths related to thromboembolic events, both in the DOAC group. The other deaths were considered to be unrelated to the procedure or periprocedural interruption of anticoagulants.
The researchers also examined the timing of anticoagulant resumption. Overall, 59.2% of subjects received bridging therapy, including 85% of the VKA group and 16% of the DOAC group (P < .001). This was not associated with increased endoscopy-related bleeding in either the VKA (3.3% with bridging therapy vs. 6.4% without; P = .14) or the DOAC group (8.3% vs. 6.4%; P = .48).
A total of 747 patients underwent a high-risk procedure, 46.3% of patients resumed anticoagulant therapy within 24 hours of the procedure, and 46.2% between 24 and 48 hours. After inverse probability of treatment weighting adjustment, a delay in anticoagulant resumption was not associated with a reduction in the frequency of postprocedural clinically significant gastrointestinal bleeding.
Still, the research left some questions unanswered. Most of the high-risk procedures were hot (41.8%) or cold snare polypectomies (39.8%). There weren’t enough data in the study to evaluate risk in patients undergoing other high-risk procedures such as balloon dilation for strictures, endoscopic ultrasound with fine-needle aspiration, and sphincterotomy. “That’s one group that we still don’t really have enough data about, particularly those patients who are on DOACs,” said Dr. Sealock.
The study also found a high number of patients on bridging therapy. “It highlighted the fact that we probably use bridging therapy too much in patients undergoing endoscopy,” said Dr. Sealock. He recommended using tools that generate recommendations for bridging therapy and timing for withholding and resuming anticoagulants based on procedure and patient characteristics.
SOURCE: de Santiago ER et al. Clin Gastroenterol Hepatol. 2020 Dec 03. doi: 10.1016/j.cgh.2020.11.037.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY