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VIDEO: Angiogenesis has a role to play in NASH and NAFLD
BOSTON – A multimodal research process has provided clues to the role of angiogenesis in nonalcoholic fatty liver disease (NAFLD) and its more serious cousin, nonalcoholic steatohepatitis (NASH).
In constructing a protocol that began with patients, moved on to bioinformatics and then performed final validation in the petri dish, Savneet Kaur, PhD, and her colleagues were able to identify several angiogenesis genes likely to contribute to the development of NAFLD and NASH.
“We have seen angiogenic mechanisms and angiogenic genes in the pathophysiology of nonalcoholic fatty liver disease,” said Dr. Kaur, professor of biotechnology at Gautam Buddha Medical School, Greater Noida, India, in a video interview at the annual meeting of the American Association for the Study of Liver Diseases.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Kaur said that she and her coinvestigators began with a small group of eight patients with NASH, and seven patients with NAFLD, and also with seven healthy control participants. Genetic analysis and comparison of these patients yielded differential expression of certain genes already known to be associated with angiogenesis in the NASH and NAFLD, but not the healthy control participants.
“We did a microarray analysis, a high throughput gene expression study, and then we selected around 25 to 26 genes which were associated with oxidative stress and angiogenesis,” said Dr. Kaur.
For validation of these genes, Dr. Kaur and her associates used a larger study group of about 150 participants, again approximately evenly divided between those with mild NAFLD, those with more severe steatohepatitis, and healthy controls. “We validated the angiogenic genes in the subject group, and found that around 13 genes are preferentially expressed.”
“About 13 genes including VEGFR1, PIK3CA, CXCL8, NOS3, EREG, CCL2, PRKCE, PPar-gamma, PROK2, RUNX1, SIRT1, HMOX1 and CXCR4 showed significantly different gene expression in the [reverse transcription–polymerase chain reaction] analysis in Gr3 as compared to Gr1 (P less than .05 for each), whereas genes such as PIK3CA, CXCL8, NOS3, CCL2, PROK2, RUNX1, and HMOX1 were differentially expressed in Gr3 in comparison to Gr2 (P less than .05 each). A few genes, PPar-gamma, SIRT1, VEGFR1, HMOX1, PIK3CA, CXCR4, PROK2, and CCL2, showed correlations with fibrosis scores, angiogenesis scores, and NAFLD activity scores of the patients,” wrote Dr. Kaur and her colleagues in the abstract accompanying the poster presentation.
Taking these candidate genes, Dr. Kaur and her colleagues conducted a bioinformatics analysis to determine which transcription factors were controlling the genes. “We wanted to study the pathway – the mechanisms – to determine the upregulation and downregulation of these genes,” said Dr. Kaur.
Finally, Dr. Kaur and her associates took an in vitro approach, using human steatotic hepatocytes and endothelial cells, since “angiogenesis is a property of endothelial cells.” The two types of cells were cultured together, and angiogenic function and gene expression were examined, and checked against the genes and pathways identified in the first two steps. They again saw expression of the angiogenic pathways in the cell culture model. This was consistent with what is seen in patients with NAFLD and NASH: “Definitely, there’s an increase in angiogenesis. There’s an increase in the endothelial cell proliferation, with more fat, more steatosis in the patients,” said Dr. Kaur. Some genes, said Dr. Kaur, are “really important” to this process. Her group is now investigating how the genes are regulated, in order to understand better the precise role of angiogenesis in steatohepatitis.
The study was part of a joint Indo-German project, and sponsored by the Indian Council for Medical Research and the German Federal Ministry of Education and Research. Dr. Kaur reported no relevant conflicts of interest.
[email protected]
On Twitter @karioakes
BOSTON – A multimodal research process has provided clues to the role of angiogenesis in nonalcoholic fatty liver disease (NAFLD) and its more serious cousin, nonalcoholic steatohepatitis (NASH).
In constructing a protocol that began with patients, moved on to bioinformatics and then performed final validation in the petri dish, Savneet Kaur, PhD, and her colleagues were able to identify several angiogenesis genes likely to contribute to the development of NAFLD and NASH.
“We have seen angiogenic mechanisms and angiogenic genes in the pathophysiology of nonalcoholic fatty liver disease,” said Dr. Kaur, professor of biotechnology at Gautam Buddha Medical School, Greater Noida, India, in a video interview at the annual meeting of the American Association for the Study of Liver Diseases.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Kaur said that she and her coinvestigators began with a small group of eight patients with NASH, and seven patients with NAFLD, and also with seven healthy control participants. Genetic analysis and comparison of these patients yielded differential expression of certain genes already known to be associated with angiogenesis in the NASH and NAFLD, but not the healthy control participants.
“We did a microarray analysis, a high throughput gene expression study, and then we selected around 25 to 26 genes which were associated with oxidative stress and angiogenesis,” said Dr. Kaur.
For validation of these genes, Dr. Kaur and her associates used a larger study group of about 150 participants, again approximately evenly divided between those with mild NAFLD, those with more severe steatohepatitis, and healthy controls. “We validated the angiogenic genes in the subject group, and found that around 13 genes are preferentially expressed.”
“About 13 genes including VEGFR1, PIK3CA, CXCL8, NOS3, EREG, CCL2, PRKCE, PPar-gamma, PROK2, RUNX1, SIRT1, HMOX1 and CXCR4 showed significantly different gene expression in the [reverse transcription–polymerase chain reaction] analysis in Gr3 as compared to Gr1 (P less than .05 for each), whereas genes such as PIK3CA, CXCL8, NOS3, CCL2, PROK2, RUNX1, and HMOX1 were differentially expressed in Gr3 in comparison to Gr2 (P less than .05 each). A few genes, PPar-gamma, SIRT1, VEGFR1, HMOX1, PIK3CA, CXCR4, PROK2, and CCL2, showed correlations with fibrosis scores, angiogenesis scores, and NAFLD activity scores of the patients,” wrote Dr. Kaur and her colleagues in the abstract accompanying the poster presentation.
Taking these candidate genes, Dr. Kaur and her colleagues conducted a bioinformatics analysis to determine which transcription factors were controlling the genes. “We wanted to study the pathway – the mechanisms – to determine the upregulation and downregulation of these genes,” said Dr. Kaur.
Finally, Dr. Kaur and her associates took an in vitro approach, using human steatotic hepatocytes and endothelial cells, since “angiogenesis is a property of endothelial cells.” The two types of cells were cultured together, and angiogenic function and gene expression were examined, and checked against the genes and pathways identified in the first two steps. They again saw expression of the angiogenic pathways in the cell culture model. This was consistent with what is seen in patients with NAFLD and NASH: “Definitely, there’s an increase in angiogenesis. There’s an increase in the endothelial cell proliferation, with more fat, more steatosis in the patients,” said Dr. Kaur. Some genes, said Dr. Kaur, are “really important” to this process. Her group is now investigating how the genes are regulated, in order to understand better the precise role of angiogenesis in steatohepatitis.
The study was part of a joint Indo-German project, and sponsored by the Indian Council for Medical Research and the German Federal Ministry of Education and Research. Dr. Kaur reported no relevant conflicts of interest.
[email protected]
On Twitter @karioakes
BOSTON – A multimodal research process has provided clues to the role of angiogenesis in nonalcoholic fatty liver disease (NAFLD) and its more serious cousin, nonalcoholic steatohepatitis (NASH).
In constructing a protocol that began with patients, moved on to bioinformatics and then performed final validation in the petri dish, Savneet Kaur, PhD, and her colleagues were able to identify several angiogenesis genes likely to contribute to the development of NAFLD and NASH.
“We have seen angiogenic mechanisms and angiogenic genes in the pathophysiology of nonalcoholic fatty liver disease,” said Dr. Kaur, professor of biotechnology at Gautam Buddha Medical School, Greater Noida, India, in a video interview at the annual meeting of the American Association for the Study of Liver Diseases.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Kaur said that she and her coinvestigators began with a small group of eight patients with NASH, and seven patients with NAFLD, and also with seven healthy control participants. Genetic analysis and comparison of these patients yielded differential expression of certain genes already known to be associated with angiogenesis in the NASH and NAFLD, but not the healthy control participants.
“We did a microarray analysis, a high throughput gene expression study, and then we selected around 25 to 26 genes which were associated with oxidative stress and angiogenesis,” said Dr. Kaur.
For validation of these genes, Dr. Kaur and her associates used a larger study group of about 150 participants, again approximately evenly divided between those with mild NAFLD, those with more severe steatohepatitis, and healthy controls. “We validated the angiogenic genes in the subject group, and found that around 13 genes are preferentially expressed.”
“About 13 genes including VEGFR1, PIK3CA, CXCL8, NOS3, EREG, CCL2, PRKCE, PPar-gamma, PROK2, RUNX1, SIRT1, HMOX1 and CXCR4 showed significantly different gene expression in the [reverse transcription–polymerase chain reaction] analysis in Gr3 as compared to Gr1 (P less than .05 for each), whereas genes such as PIK3CA, CXCL8, NOS3, CCL2, PROK2, RUNX1, and HMOX1 were differentially expressed in Gr3 in comparison to Gr2 (P less than .05 each). A few genes, PPar-gamma, SIRT1, VEGFR1, HMOX1, PIK3CA, CXCR4, PROK2, and CCL2, showed correlations with fibrosis scores, angiogenesis scores, and NAFLD activity scores of the patients,” wrote Dr. Kaur and her colleagues in the abstract accompanying the poster presentation.
Taking these candidate genes, Dr. Kaur and her colleagues conducted a bioinformatics analysis to determine which transcription factors were controlling the genes. “We wanted to study the pathway – the mechanisms – to determine the upregulation and downregulation of these genes,” said Dr. Kaur.
Finally, Dr. Kaur and her associates took an in vitro approach, using human steatotic hepatocytes and endothelial cells, since “angiogenesis is a property of endothelial cells.” The two types of cells were cultured together, and angiogenic function and gene expression were examined, and checked against the genes and pathways identified in the first two steps. They again saw expression of the angiogenic pathways in the cell culture model. This was consistent with what is seen in patients with NAFLD and NASH: “Definitely, there’s an increase in angiogenesis. There’s an increase in the endothelial cell proliferation, with more fat, more steatosis in the patients,” said Dr. Kaur. Some genes, said Dr. Kaur, are “really important” to this process. Her group is now investigating how the genes are regulated, in order to understand better the precise role of angiogenesis in steatohepatitis.
The study was part of a joint Indo-German project, and sponsored by the Indian Council for Medical Research and the German Federal Ministry of Education and Research. Dr. Kaur reported no relevant conflicts of interest.
[email protected]
On Twitter @karioakes
AT THE LIVER MEETING 2016
Key clinical point:
Major finding: PPar-gamma, SIRT1, VEGFR1, and other genes are associated with fibrosis, angiogenesis, and steatosis.
Data source: Human bioinformatics–in vitro exploration of genetic pathways associated with angiogenesis in NASH and nonalcoholic fatty liver disease (NAFLD).
Disclosures: The study was part of a joint Indo-German project, and funded by the Indian Council for Medical Research and the German Federal Ministry of Education and Research. Dr. Kaur reported no relevant financial disclosures.
Nonalcoholic fatty liver disease accelerates brain aging
TORONTO – Nonalcoholic fatty liver disease seems to accelerate physical brain aging by up to 7 years, according to a new subanalysis of the ongoing Framingham Heart Study.
However, while finding that the liver disorder directly endangers brains, the study also offers hope, Galit Weinstein, PhD, said at the Alzheimer’s Association International Conference 2016. “If indeed nonalcoholic fatty liver disease is a risk factor for brain aging and subsequent dementia, then it is a modifiable one,” said Dr. Weinstein of Boston University. “We have reason to hope that NAFLD remission could possibly improve cognitive outcomes” as patients age.
For this study, the researchers assessed the presence of NAFLD by abdominal CT scans and white-matter hyperintensities and brain volume (total, frontal, and hippocampal) by MRI. The resulting associations were then adjusted for age, sex, alcohol consumption, visceral adipose tissue, body mass index, menopausal status, systolic blood pressure, current smoking, diabetes, history of cardiovascular disease, physical activity, insulin resistance, and C-reactive protein.
There were no significant associations with white-matter hyperintensities or with hippocampal volume, but the researches did find a significant association with total brain volume: Even after adjustment for all of the covariates, patients with NAFLD had smaller-than-normal brains for their age. This can be seen as a pathologic acceleration of the brain aging process, Dr. Weinstein said.
The finding was most striking among the youngest subjects, she said, accounting for about a 7-year advance in brain aging for those younger than 60 years. Older patients with NAFLD showed about a 2-year advance in brain aging.
The effect is probably mediated by the liver’s complex interplay in metabolism and vascular functions, Dr. Weinstein said.
She had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
TORONTO – Nonalcoholic fatty liver disease seems to accelerate physical brain aging by up to 7 years, according to a new subanalysis of the ongoing Framingham Heart Study.
However, while finding that the liver disorder directly endangers brains, the study also offers hope, Galit Weinstein, PhD, said at the Alzheimer’s Association International Conference 2016. “If indeed nonalcoholic fatty liver disease is a risk factor for brain aging and subsequent dementia, then it is a modifiable one,” said Dr. Weinstein of Boston University. “We have reason to hope that NAFLD remission could possibly improve cognitive outcomes” as patients age.
For this study, the researchers assessed the presence of NAFLD by abdominal CT scans and white-matter hyperintensities and brain volume (total, frontal, and hippocampal) by MRI. The resulting associations were then adjusted for age, sex, alcohol consumption, visceral adipose tissue, body mass index, menopausal status, systolic blood pressure, current smoking, diabetes, history of cardiovascular disease, physical activity, insulin resistance, and C-reactive protein.
There were no significant associations with white-matter hyperintensities or with hippocampal volume, but the researches did find a significant association with total brain volume: Even after adjustment for all of the covariates, patients with NAFLD had smaller-than-normal brains for their age. This can be seen as a pathologic acceleration of the brain aging process, Dr. Weinstein said.
The finding was most striking among the youngest subjects, she said, accounting for about a 7-year advance in brain aging for those younger than 60 years. Older patients with NAFLD showed about a 2-year advance in brain aging.
The effect is probably mediated by the liver’s complex interplay in metabolism and vascular functions, Dr. Weinstein said.
She had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
TORONTO – Nonalcoholic fatty liver disease seems to accelerate physical brain aging by up to 7 years, according to a new subanalysis of the ongoing Framingham Heart Study.
However, while finding that the liver disorder directly endangers brains, the study also offers hope, Galit Weinstein, PhD, said at the Alzheimer’s Association International Conference 2016. “If indeed nonalcoholic fatty liver disease is a risk factor for brain aging and subsequent dementia, then it is a modifiable one,” said Dr. Weinstein of Boston University. “We have reason to hope that NAFLD remission could possibly improve cognitive outcomes” as patients age.
For this study, the researchers assessed the presence of NAFLD by abdominal CT scans and white-matter hyperintensities and brain volume (total, frontal, and hippocampal) by MRI. The resulting associations were then adjusted for age, sex, alcohol consumption, visceral adipose tissue, body mass index, menopausal status, systolic blood pressure, current smoking, diabetes, history of cardiovascular disease, physical activity, insulin resistance, and C-reactive protein.
There were no significant associations with white-matter hyperintensities or with hippocampal volume, but the researches did find a significant association with total brain volume: Even after adjustment for all of the covariates, patients with NAFLD had smaller-than-normal brains for their age. This can be seen as a pathologic acceleration of the brain aging process, Dr. Weinstein said.
The finding was most striking among the youngest subjects, she said, accounting for about a 7-year advance in brain aging for those younger than 60 years. Older patients with NAFLD showed about a 2-year advance in brain aging.
The effect is probably mediated by the liver’s complex interplay in metabolism and vascular functions, Dr. Weinstein said.
She had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
AT AAIC 2016
Key clinical point:
Major finding: NAFLD was associated with a 7-year advance in brain aging in people younger than 60 years.
Data source: An analysis of 906 members of the Framingham Offspring Cohort.
Disclosures: Dr. Weinstein had no financial declarations.
The Liver Meeting 2016 debrief – key abstracts
BOSTON – Amid a plethora of quality research, several abstracts stood out at the annual meeting of the American Association for the Study of Liver Diseases, Arun J. Sanyal, MD, said during the final debrief.
He focused first on nonalcoholic fatty liver disease (NAFLD), which has lacked rigorous studies of disease evolution. Consequently, “current therapeutic development is based on small retrospective data sets with heterogenous populations,” Dr. Sanyal said. Therefore, he and his associates correlated serial biopsies with clinical data (abstract 37). The results confirmed the waxing and waning nature of NAFLD and linked regressing or progressive fibrosis to several factors, including NAFLD Disease Activity score (NAS). NAFLD and nonalcoholic steatohepatitis (NASH) are “not two different diseases, it’s the same disease,” Dr. Sanyal said. “Establishing disease activity as a driver of disease progression is highly relevant for development of noninvasive biomarkers, and also gives us a foundation for the development of clinical trials in this space.”
Several studies of NASH biomarkers yielded notable results at the meeting. In the largest study to date of circulating microRNAs as markers of NASH, (LB2) the miRNAs 34a, 122a, and 200a distinguished patients with and without NAS scores of at least 4 and at least stage 2 fibrosis with areas under the receiver operating characteristic curve (AUROC) between 0.59 and 0.80. “MicroRNAs appear promising, but likely need to be combined with additional biomarkers,” Dr. Sanyal said.
He also noted a study (abstract 40) in which metabolomics of liquid biopsies comprehensively evaluated NAFLD, including fibrosis stage, with AUROCs up to 0.95. Metabolomics “holds promise as a diagnostic tool that can be operationalized for point-of-care testing,” he said.
When it comes to NAFLD, hepatologists “often struggle with what to tell our patients about alcohol,” Dr. Sanyal said. To help clarify the issue, abstract 31 compared NAFLD patients who did or did not report habitually consuming up to two drinks a day in formal prospective questionnaires. After adjustment for baseline histology, abstainers and modest drinkers did not differ on any measure of histologic change, except that abstainers had a greater decrease in steatosis on follow-up biopsy. These findings negate several retrospective studies by suggesting that alcohol consumption does not positively affect the trajectory of NAFLD, Dr. Sanyal concluded.
Many new compounds for treating NASH are in early development, he noted. Among those further along the pipeline, the immunomodulator and CCR2/CCR5 inhibitor cenicriviroc (CVC) missed its primary endpoint (improved NAS and no worsening of fibrosis) but was associated with significantly improved fibrosis without worsening of NASH in the phase 2b CENTAUR study (LB1).
“We also saw highly promising evidence for the effects of ASK1 [apoptosis signal regulating kinase] inhibition on hepatic fibrosis and disease activity in NASH,” Dr. Sanyal added. In a randomized phase II trial (LB3), the ASK1 inhibitor GS-4997 was associated with significant improvement in fibrosis without worsening of NASH when given in combination with simtuzumab, and also improved liver stiffness and magnetic resonance imaging–estimated proton density fat fraction (MRI-PDFF). “These very promising and exciting results need confirmation in more advanced, placebo-controlled trials,” Dr. Sanyal said.
Studies of alcohol use disorders of the liver confirmed that prednisolone has marginal benefits, that the benefits of steroids in general are offset by sepsis, and that pentoxifylline produced no mortality benefit, Dr. Sanyal noted. In studies of primary biliary cirrhosis, the farnesoid-X receptor agonist obeticholic acid (OCA), which was approved by the Food and Drug Administration in 2016, was associated with significantly improved AST to Platelet Ratio Index (APRI) and liver stiffness measures by transient elastography at doses of 10 mg or titrated from 5 mg to 10 mg, with or without ursodeoxycholic acid (abstract 209). In another study, patients with PBC who received norUDCA, a side chain–shortened version of UDCA, experienced decreases in serum ALP levels that were dose dependent and differed significantly from trends in the placebo group (abstract 210).
In another study, the investigational ileal bile acid transporter inhibitor GSK2330672 was associated with significant reductions in itch, compared with placebo, and with lower serum bile acids among pruritic PBC patients (abstract 205). Treatment was associated with diarrhea, but it was usually mild and transient.
Dr. Sanyal concluded by reviewing several studies of cirrhosis and hepatic encephalopathy. In a prospective randomized controlled trial (abstract 247), lactulose with albumin significantly outperformed lactulose monotherapy for reversing hepatic encephalopathy, reducing hospital stays, and preventing mortality, especially sepsis-related death.
In another multicenter, 24-week, phase IV open-label study (abstract 248), 25% of patients experienced breakthrough hepatic encephalopathy when treated with rifaximin monotherapy, compared with only 14% of patients who received both rifaximin and lactulose.
Finally, in a phase II trial (abstract 2064), rifaximin immediate-release (40 mg) significantly outperformed placebo in terms of cirrhosis-related mortality, hospitalizations for cirrhosis, and breakthrough hepatic encephalopathy. The takeaways? “Use albumin with lactulose for acute hepatic encephalopathy,” Dr. Sanyal said. “Rifaximin with lactulose is better than rifaximin alone for secondary prophylaxis, and rifaximin immediate-release may decrease the need for hospitalization and the first bout of hepatic encephalopathy.”
The Liver Meeting next convenes October 20-24, 2017, in Washington, D.C.
Dr. Sanyal disclosed ties to Genfit, NewCo, Akarna, Elsevier, UptoDate, Novartis, Pfizer, Lilly, Astra Zeneca, and a number of other companies.
BOSTON – Amid a plethora of quality research, several abstracts stood out at the annual meeting of the American Association for the Study of Liver Diseases, Arun J. Sanyal, MD, said during the final debrief.
He focused first on nonalcoholic fatty liver disease (NAFLD), which has lacked rigorous studies of disease evolution. Consequently, “current therapeutic development is based on small retrospective data sets with heterogenous populations,” Dr. Sanyal said. Therefore, he and his associates correlated serial biopsies with clinical data (abstract 37). The results confirmed the waxing and waning nature of NAFLD and linked regressing or progressive fibrosis to several factors, including NAFLD Disease Activity score (NAS). NAFLD and nonalcoholic steatohepatitis (NASH) are “not two different diseases, it’s the same disease,” Dr. Sanyal said. “Establishing disease activity as a driver of disease progression is highly relevant for development of noninvasive biomarkers, and also gives us a foundation for the development of clinical trials in this space.”
Several studies of NASH biomarkers yielded notable results at the meeting. In the largest study to date of circulating microRNAs as markers of NASH, (LB2) the miRNAs 34a, 122a, and 200a distinguished patients with and without NAS scores of at least 4 and at least stage 2 fibrosis with areas under the receiver operating characteristic curve (AUROC) between 0.59 and 0.80. “MicroRNAs appear promising, but likely need to be combined with additional biomarkers,” Dr. Sanyal said.
He also noted a study (abstract 40) in which metabolomics of liquid biopsies comprehensively evaluated NAFLD, including fibrosis stage, with AUROCs up to 0.95. Metabolomics “holds promise as a diagnostic tool that can be operationalized for point-of-care testing,” he said.
When it comes to NAFLD, hepatologists “often struggle with what to tell our patients about alcohol,” Dr. Sanyal said. To help clarify the issue, abstract 31 compared NAFLD patients who did or did not report habitually consuming up to two drinks a day in formal prospective questionnaires. After adjustment for baseline histology, abstainers and modest drinkers did not differ on any measure of histologic change, except that abstainers had a greater decrease in steatosis on follow-up biopsy. These findings negate several retrospective studies by suggesting that alcohol consumption does not positively affect the trajectory of NAFLD, Dr. Sanyal concluded.
Many new compounds for treating NASH are in early development, he noted. Among those further along the pipeline, the immunomodulator and CCR2/CCR5 inhibitor cenicriviroc (CVC) missed its primary endpoint (improved NAS and no worsening of fibrosis) but was associated with significantly improved fibrosis without worsening of NASH in the phase 2b CENTAUR study (LB1).
“We also saw highly promising evidence for the effects of ASK1 [apoptosis signal regulating kinase] inhibition on hepatic fibrosis and disease activity in NASH,” Dr. Sanyal added. In a randomized phase II trial (LB3), the ASK1 inhibitor GS-4997 was associated with significant improvement in fibrosis without worsening of NASH when given in combination with simtuzumab, and also improved liver stiffness and magnetic resonance imaging–estimated proton density fat fraction (MRI-PDFF). “These very promising and exciting results need confirmation in more advanced, placebo-controlled trials,” Dr. Sanyal said.
Studies of alcohol use disorders of the liver confirmed that prednisolone has marginal benefits, that the benefits of steroids in general are offset by sepsis, and that pentoxifylline produced no mortality benefit, Dr. Sanyal noted. In studies of primary biliary cirrhosis, the farnesoid-X receptor agonist obeticholic acid (OCA), which was approved by the Food and Drug Administration in 2016, was associated with significantly improved AST to Platelet Ratio Index (APRI) and liver stiffness measures by transient elastography at doses of 10 mg or titrated from 5 mg to 10 mg, with or without ursodeoxycholic acid (abstract 209). In another study, patients with PBC who received norUDCA, a side chain–shortened version of UDCA, experienced decreases in serum ALP levels that were dose dependent and differed significantly from trends in the placebo group (abstract 210).
In another study, the investigational ileal bile acid transporter inhibitor GSK2330672 was associated with significant reductions in itch, compared with placebo, and with lower serum bile acids among pruritic PBC patients (abstract 205). Treatment was associated with diarrhea, but it was usually mild and transient.
Dr. Sanyal concluded by reviewing several studies of cirrhosis and hepatic encephalopathy. In a prospective randomized controlled trial (abstract 247), lactulose with albumin significantly outperformed lactulose monotherapy for reversing hepatic encephalopathy, reducing hospital stays, and preventing mortality, especially sepsis-related death.
In another multicenter, 24-week, phase IV open-label study (abstract 248), 25% of patients experienced breakthrough hepatic encephalopathy when treated with rifaximin monotherapy, compared with only 14% of patients who received both rifaximin and lactulose.
Finally, in a phase II trial (abstract 2064), rifaximin immediate-release (40 mg) significantly outperformed placebo in terms of cirrhosis-related mortality, hospitalizations for cirrhosis, and breakthrough hepatic encephalopathy. The takeaways? “Use albumin with lactulose for acute hepatic encephalopathy,” Dr. Sanyal said. “Rifaximin with lactulose is better than rifaximin alone for secondary prophylaxis, and rifaximin immediate-release may decrease the need for hospitalization and the first bout of hepatic encephalopathy.”
The Liver Meeting next convenes October 20-24, 2017, in Washington, D.C.
Dr. Sanyal disclosed ties to Genfit, NewCo, Akarna, Elsevier, UptoDate, Novartis, Pfizer, Lilly, Astra Zeneca, and a number of other companies.
BOSTON – Amid a plethora of quality research, several abstracts stood out at the annual meeting of the American Association for the Study of Liver Diseases, Arun J. Sanyal, MD, said during the final debrief.
He focused first on nonalcoholic fatty liver disease (NAFLD), which has lacked rigorous studies of disease evolution. Consequently, “current therapeutic development is based on small retrospective data sets with heterogenous populations,” Dr. Sanyal said. Therefore, he and his associates correlated serial biopsies with clinical data (abstract 37). The results confirmed the waxing and waning nature of NAFLD and linked regressing or progressive fibrosis to several factors, including NAFLD Disease Activity score (NAS). NAFLD and nonalcoholic steatohepatitis (NASH) are “not two different diseases, it’s the same disease,” Dr. Sanyal said. “Establishing disease activity as a driver of disease progression is highly relevant for development of noninvasive biomarkers, and also gives us a foundation for the development of clinical trials in this space.”
Several studies of NASH biomarkers yielded notable results at the meeting. In the largest study to date of circulating microRNAs as markers of NASH, (LB2) the miRNAs 34a, 122a, and 200a distinguished patients with and without NAS scores of at least 4 and at least stage 2 fibrosis with areas under the receiver operating characteristic curve (AUROC) between 0.59 and 0.80. “MicroRNAs appear promising, but likely need to be combined with additional biomarkers,” Dr. Sanyal said.
He also noted a study (abstract 40) in which metabolomics of liquid biopsies comprehensively evaluated NAFLD, including fibrosis stage, with AUROCs up to 0.95. Metabolomics “holds promise as a diagnostic tool that can be operationalized for point-of-care testing,” he said.
When it comes to NAFLD, hepatologists “often struggle with what to tell our patients about alcohol,” Dr. Sanyal said. To help clarify the issue, abstract 31 compared NAFLD patients who did or did not report habitually consuming up to two drinks a day in formal prospective questionnaires. After adjustment for baseline histology, abstainers and modest drinkers did not differ on any measure of histologic change, except that abstainers had a greater decrease in steatosis on follow-up biopsy. These findings negate several retrospective studies by suggesting that alcohol consumption does not positively affect the trajectory of NAFLD, Dr. Sanyal concluded.
Many new compounds for treating NASH are in early development, he noted. Among those further along the pipeline, the immunomodulator and CCR2/CCR5 inhibitor cenicriviroc (CVC) missed its primary endpoint (improved NAS and no worsening of fibrosis) but was associated with significantly improved fibrosis without worsening of NASH in the phase 2b CENTAUR study (LB1).
“We also saw highly promising evidence for the effects of ASK1 [apoptosis signal regulating kinase] inhibition on hepatic fibrosis and disease activity in NASH,” Dr. Sanyal added. In a randomized phase II trial (LB3), the ASK1 inhibitor GS-4997 was associated with significant improvement in fibrosis without worsening of NASH when given in combination with simtuzumab, and also improved liver stiffness and magnetic resonance imaging–estimated proton density fat fraction (MRI-PDFF). “These very promising and exciting results need confirmation in more advanced, placebo-controlled trials,” Dr. Sanyal said.
Studies of alcohol use disorders of the liver confirmed that prednisolone has marginal benefits, that the benefits of steroids in general are offset by sepsis, and that pentoxifylline produced no mortality benefit, Dr. Sanyal noted. In studies of primary biliary cirrhosis, the farnesoid-X receptor agonist obeticholic acid (OCA), which was approved by the Food and Drug Administration in 2016, was associated with significantly improved AST to Platelet Ratio Index (APRI) and liver stiffness measures by transient elastography at doses of 10 mg or titrated from 5 mg to 10 mg, with or without ursodeoxycholic acid (abstract 209). In another study, patients with PBC who received norUDCA, a side chain–shortened version of UDCA, experienced decreases in serum ALP levels that were dose dependent and differed significantly from trends in the placebo group (abstract 210).
In another study, the investigational ileal bile acid transporter inhibitor GSK2330672 was associated with significant reductions in itch, compared with placebo, and with lower serum bile acids among pruritic PBC patients (abstract 205). Treatment was associated with diarrhea, but it was usually mild and transient.
Dr. Sanyal concluded by reviewing several studies of cirrhosis and hepatic encephalopathy. In a prospective randomized controlled trial (abstract 247), lactulose with albumin significantly outperformed lactulose monotherapy for reversing hepatic encephalopathy, reducing hospital stays, and preventing mortality, especially sepsis-related death.
In another multicenter, 24-week, phase IV open-label study (abstract 248), 25% of patients experienced breakthrough hepatic encephalopathy when treated with rifaximin monotherapy, compared with only 14% of patients who received both rifaximin and lactulose.
Finally, in a phase II trial (abstract 2064), rifaximin immediate-release (40 mg) significantly outperformed placebo in terms of cirrhosis-related mortality, hospitalizations for cirrhosis, and breakthrough hepatic encephalopathy. The takeaways? “Use albumin with lactulose for acute hepatic encephalopathy,” Dr. Sanyal said. “Rifaximin with lactulose is better than rifaximin alone for secondary prophylaxis, and rifaximin immediate-release may decrease the need for hospitalization and the first bout of hepatic encephalopathy.”
The Liver Meeting next convenes October 20-24, 2017, in Washington, D.C.
Dr. Sanyal disclosed ties to Genfit, NewCo, Akarna, Elsevier, UptoDate, Novartis, Pfizer, Lilly, Astra Zeneca, and a number of other companies.
AT THE LIVER MEETING 2016
VIDEO: Hepato-adrenal syndrome is an under-recognized source of ICU morbidity
BOSTON – Patients with serious liver disease who also had hepato-adrenal syndrome had significantly longer hospital stays; these patients had significantly longer ICU courses as well.
According to a recent study of this under-recognized syndrome, patients with cirrhosis, acute liver failure, or acute liver injury who also had clinically significant adrenocortical dysfunction had longer hospital stays when compared to patients without hepato-adrenal syndrome (HAS).
Presenting the study findings at a poster session at the annual meeting of the American Association for the Study of Liver Disease, Christina Lindenmeyer, MD, and her associates noted that the longer stays for HAS patients with serious liver disease held true even after adjustment for gender, blood glucose levels, and Child-Pugh score (median 29 days, HAS; 17 days, non-HAS; P = .001).
Further, the patients with HAS were more likely to have a prolonged ICU stay, after multivariable analysis adjusted for a variety of factors including the need for mechanical ventilation, age, bilirubin level, Model for End-stage Liver Disease (MELD) score, and severity of encephalopathy (13.5 vs. 4.9 days; P = .002).
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Patients with cirrhosis commonly have hypotension, and I think it’s underrecognized that the elevated levels of endotoxin and the low levels of lipoprotein circulating in patients with cirrhosis can lead to adrenocortical dysfunction,” Dr. Lindenmeyer said in a video interview.
The single-center study enrolled ICU patients with cirrhosis, acute liver injury, and/or acute liver failure who had random cortisol or adrenocorticotropin-releasing hormone (ACTH) stimulation test results. From 2008 to 2014, the tertiary care center saw 69 patients meeting these criteria; 32 patients (46%) had HAS. The mean age was 57.4 years, and 63.8% of enrolled patients were male. There were no significant differences in these demographics between the groups. Serum bicarbonate was higher in patients with HAS (21.4 vs. 17.5 mEq/L; P = .020); other blood chemistries, mean arterial pressures, and the MELD and Child-Pugh scores did not differ significantly between groups.
Dr. Lindenmeyer, a fellow in the Cleveland Clinic’s department of gastroenterology and hepatology, said that the accepted definition of HAS is a random cortisol level of less than 15 mcg/dL in “patients who were highly stressed in the ICU, typically with respiratory failure or hypotension,” she said. For non-ICU patients, the random cortisol level should be less than 20 mcg/dL. An alternative criterion is a post-ACTH stimulation test cortisol level of less than 20 mcg/dL.
Though there was no statistically significant difference between in-hospital mortality for those patients meeting HAS criteria, the trend was actually for those patients to have lower in-hospital mortality (44% vs. 51%; P = .53). This was true even after correction for MELD scores and serum potassium levels. Dr. Lindenmeyer said these results were “a little surprising,” and noted that the study didn’t examine 90-day or 1-year mortality. “That would be something interesting to look at,” she said.
“Early recognition and treatment of HAS may improve judicious allocation of critical care and hospital resources,” wrote Dr. Lindenmeyer and her colleagues.
Dr. Lindenmeyer reported no conflicts of interest, and there were no outside sources of funding reported.
[email protected]
On Twitter @karioakes
BOSTON – Patients with serious liver disease who also had hepato-adrenal syndrome had significantly longer hospital stays; these patients had significantly longer ICU courses as well.
According to a recent study of this under-recognized syndrome, patients with cirrhosis, acute liver failure, or acute liver injury who also had clinically significant adrenocortical dysfunction had longer hospital stays when compared to patients without hepato-adrenal syndrome (HAS).
Presenting the study findings at a poster session at the annual meeting of the American Association for the Study of Liver Disease, Christina Lindenmeyer, MD, and her associates noted that the longer stays for HAS patients with serious liver disease held true even after adjustment for gender, blood glucose levels, and Child-Pugh score (median 29 days, HAS; 17 days, non-HAS; P = .001).
Further, the patients with HAS were more likely to have a prolonged ICU stay, after multivariable analysis adjusted for a variety of factors including the need for mechanical ventilation, age, bilirubin level, Model for End-stage Liver Disease (MELD) score, and severity of encephalopathy (13.5 vs. 4.9 days; P = .002).
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Patients with cirrhosis commonly have hypotension, and I think it’s underrecognized that the elevated levels of endotoxin and the low levels of lipoprotein circulating in patients with cirrhosis can lead to adrenocortical dysfunction,” Dr. Lindenmeyer said in a video interview.
The single-center study enrolled ICU patients with cirrhosis, acute liver injury, and/or acute liver failure who had random cortisol or adrenocorticotropin-releasing hormone (ACTH) stimulation test results. From 2008 to 2014, the tertiary care center saw 69 patients meeting these criteria; 32 patients (46%) had HAS. The mean age was 57.4 years, and 63.8% of enrolled patients were male. There were no significant differences in these demographics between the groups. Serum bicarbonate was higher in patients with HAS (21.4 vs. 17.5 mEq/L; P = .020); other blood chemistries, mean arterial pressures, and the MELD and Child-Pugh scores did not differ significantly between groups.
Dr. Lindenmeyer, a fellow in the Cleveland Clinic’s department of gastroenterology and hepatology, said that the accepted definition of HAS is a random cortisol level of less than 15 mcg/dL in “patients who were highly stressed in the ICU, typically with respiratory failure or hypotension,” she said. For non-ICU patients, the random cortisol level should be less than 20 mcg/dL. An alternative criterion is a post-ACTH stimulation test cortisol level of less than 20 mcg/dL.
Though there was no statistically significant difference between in-hospital mortality for those patients meeting HAS criteria, the trend was actually for those patients to have lower in-hospital mortality (44% vs. 51%; P = .53). This was true even after correction for MELD scores and serum potassium levels. Dr. Lindenmeyer said these results were “a little surprising,” and noted that the study didn’t examine 90-day or 1-year mortality. “That would be something interesting to look at,” she said.
“Early recognition and treatment of HAS may improve judicious allocation of critical care and hospital resources,” wrote Dr. Lindenmeyer and her colleagues.
Dr. Lindenmeyer reported no conflicts of interest, and there were no outside sources of funding reported.
[email protected]
On Twitter @karioakes
BOSTON – Patients with serious liver disease who also had hepato-adrenal syndrome had significantly longer hospital stays; these patients had significantly longer ICU courses as well.
According to a recent study of this under-recognized syndrome, patients with cirrhosis, acute liver failure, or acute liver injury who also had clinically significant adrenocortical dysfunction had longer hospital stays when compared to patients without hepato-adrenal syndrome (HAS).
Presenting the study findings at a poster session at the annual meeting of the American Association for the Study of Liver Disease, Christina Lindenmeyer, MD, and her associates noted that the longer stays for HAS patients with serious liver disease held true even after adjustment for gender, blood glucose levels, and Child-Pugh score (median 29 days, HAS; 17 days, non-HAS; P = .001).
Further, the patients with HAS were more likely to have a prolonged ICU stay, after multivariable analysis adjusted for a variety of factors including the need for mechanical ventilation, age, bilirubin level, Model for End-stage Liver Disease (MELD) score, and severity of encephalopathy (13.5 vs. 4.9 days; P = .002).
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Patients with cirrhosis commonly have hypotension, and I think it’s underrecognized that the elevated levels of endotoxin and the low levels of lipoprotein circulating in patients with cirrhosis can lead to adrenocortical dysfunction,” Dr. Lindenmeyer said in a video interview.
The single-center study enrolled ICU patients with cirrhosis, acute liver injury, and/or acute liver failure who had random cortisol or adrenocorticotropin-releasing hormone (ACTH) stimulation test results. From 2008 to 2014, the tertiary care center saw 69 patients meeting these criteria; 32 patients (46%) had HAS. The mean age was 57.4 years, and 63.8% of enrolled patients were male. There were no significant differences in these demographics between the groups. Serum bicarbonate was higher in patients with HAS (21.4 vs. 17.5 mEq/L; P = .020); other blood chemistries, mean arterial pressures, and the MELD and Child-Pugh scores did not differ significantly between groups.
Dr. Lindenmeyer, a fellow in the Cleveland Clinic’s department of gastroenterology and hepatology, said that the accepted definition of HAS is a random cortisol level of less than 15 mcg/dL in “patients who were highly stressed in the ICU, typically with respiratory failure or hypotension,” she said. For non-ICU patients, the random cortisol level should be less than 20 mcg/dL. An alternative criterion is a post-ACTH stimulation test cortisol level of less than 20 mcg/dL.
Though there was no statistically significant difference between in-hospital mortality for those patients meeting HAS criteria, the trend was actually for those patients to have lower in-hospital mortality (44% vs. 51%; P = .53). This was true even after correction for MELD scores and serum potassium levels. Dr. Lindenmeyer said these results were “a little surprising,” and noted that the study didn’t examine 90-day or 1-year mortality. “That would be something interesting to look at,” she said.
“Early recognition and treatment of HAS may improve judicious allocation of critical care and hospital resources,” wrote Dr. Lindenmeyer and her colleagues.
Dr. Lindenmeyer reported no conflicts of interest, and there were no outside sources of funding reported.
[email protected]
On Twitter @karioakes
AT THE LIVER MEETING 2016
Key clinical point:
Major finding: Patients with HAS had a longer length of hospital stay (median 29 days, HAS; 17 days, non-HAS; P = .001)
Data source: Single-center study of 69 consecutively enrolled ICU patients with serious liver disease and random cortisol or adrenocorticotropin-releasing hormone results.
Disclosures: The study investigators reported no disclosures, and no external sources of funding.
HCV patients with early-stage hepatocellular carcinoma can achieve SVR
BOSTON – Among patients with hepatocellular carcinoma (HCC), rates of sustained viral response (SVR) to direct-acting regimens for hepatitis C virus were 79% for genotype 1, 69% for genotype 2, and 47% for genotype 3 infections, reported George N. Ioannou, MD.
“These rates are lower than in patients who do not have hepatocellular carcinoma [HCC], but are still remarkably high,” Dr. Ioannou said during an oral presentation at the annual meeting of the American Association for the Study of Liver Diseases. “Antiviral therapy should be considered in patients with early-stage hepatocellular carcinoma, ideally after adequate locoregional treatments.”
The study included Veterans Affairs Health Care System data on 17,487 recipients of direct-acting anti-HCV regimens. When patients did not have HCC, SVR rates were 93% for genotype 1 infection, 87% for genotype 2 (GT2), and 76% for GT3. Among the 624 (3.6%) patients with a history of HCC, 142 underwent antiviral treatment after transplantation and 482 received other types of cancer therapy.
Why HCC is associated with lower SVR in HCV patients remains unclear, Dr. Ioannou noted. Age does not seem to explain the effect, and neither does sex, race, or ethnicity; cirrhosis or decompensated cirrhosis; renal disease; diabetes; HCV viral load; genotype or subgenotype; HCV regimen; or treatment experience, he said.
Dr. Ioannou noted several study limitations. Nine percent of patients lacked data on SVR, and the imputation to correct for this lowered SVR rates by about 1%-2%. The dataset also did not include information on HCC tumor size or number, and the researchers have not yet examined how antiviral therapy affects the likelihood of de novo HCC, recurrent HCC, or progression of cirrhosis and liver dysfunction.
The Veterans Affairs Office of Research and Development sponsored the study. Dr. Ioannou had no disclosures.
BOSTON – Among patients with hepatocellular carcinoma (HCC), rates of sustained viral response (SVR) to direct-acting regimens for hepatitis C virus were 79% for genotype 1, 69% for genotype 2, and 47% for genotype 3 infections, reported George N. Ioannou, MD.
“These rates are lower than in patients who do not have hepatocellular carcinoma [HCC], but are still remarkably high,” Dr. Ioannou said during an oral presentation at the annual meeting of the American Association for the Study of Liver Diseases. “Antiviral therapy should be considered in patients with early-stage hepatocellular carcinoma, ideally after adequate locoregional treatments.”
The study included Veterans Affairs Health Care System data on 17,487 recipients of direct-acting anti-HCV regimens. When patients did not have HCC, SVR rates were 93% for genotype 1 infection, 87% for genotype 2 (GT2), and 76% for GT3. Among the 624 (3.6%) patients with a history of HCC, 142 underwent antiviral treatment after transplantation and 482 received other types of cancer therapy.
Why HCC is associated with lower SVR in HCV patients remains unclear, Dr. Ioannou noted. Age does not seem to explain the effect, and neither does sex, race, or ethnicity; cirrhosis or decompensated cirrhosis; renal disease; diabetes; HCV viral load; genotype or subgenotype; HCV regimen; or treatment experience, he said.
Dr. Ioannou noted several study limitations. Nine percent of patients lacked data on SVR, and the imputation to correct for this lowered SVR rates by about 1%-2%. The dataset also did not include information on HCC tumor size or number, and the researchers have not yet examined how antiviral therapy affects the likelihood of de novo HCC, recurrent HCC, or progression of cirrhosis and liver dysfunction.
The Veterans Affairs Office of Research and Development sponsored the study. Dr. Ioannou had no disclosures.
BOSTON – Among patients with hepatocellular carcinoma (HCC), rates of sustained viral response (SVR) to direct-acting regimens for hepatitis C virus were 79% for genotype 1, 69% for genotype 2, and 47% for genotype 3 infections, reported George N. Ioannou, MD.
“These rates are lower than in patients who do not have hepatocellular carcinoma [HCC], but are still remarkably high,” Dr. Ioannou said during an oral presentation at the annual meeting of the American Association for the Study of Liver Diseases. “Antiviral therapy should be considered in patients with early-stage hepatocellular carcinoma, ideally after adequate locoregional treatments.”
The study included Veterans Affairs Health Care System data on 17,487 recipients of direct-acting anti-HCV regimens. When patients did not have HCC, SVR rates were 93% for genotype 1 infection, 87% for genotype 2 (GT2), and 76% for GT3. Among the 624 (3.6%) patients with a history of HCC, 142 underwent antiviral treatment after transplantation and 482 received other types of cancer therapy.
Why HCC is associated with lower SVR in HCV patients remains unclear, Dr. Ioannou noted. Age does not seem to explain the effect, and neither does sex, race, or ethnicity; cirrhosis or decompensated cirrhosis; renal disease; diabetes; HCV viral load; genotype or subgenotype; HCV regimen; or treatment experience, he said.
Dr. Ioannou noted several study limitations. Nine percent of patients lacked data on SVR, and the imputation to correct for this lowered SVR rates by about 1%-2%. The dataset also did not include information on HCC tumor size or number, and the researchers have not yet examined how antiviral therapy affects the likelihood of de novo HCC, recurrent HCC, or progression of cirrhosis and liver dysfunction.
The Veterans Affairs Office of Research and Development sponsored the study. Dr. Ioannou had no disclosures.
AT THE LIVER MEETING
Key clinical point: Consider direct-acting antiviral therapy in HCV-infected patients with early-stage HCC.
Major finding: Rates of sustained viral response were 79% in HCC patients with GT1 HCV infection, 69% in GT2 patients, and 47% in GT3 patients.
Data source: An analysis of Veterans Affairs Health Care System data on 17,487 recipients of direct-acting antiviral regimens, including 624 patients with HCC.
Disclosures: The Veterans Affairs Office of Research and Development sponsored the study.
Early TIPS effective in high-risk cirrhosis patients, but still underutilized
BOSTON – High-risk cirrhosis patients treated early with a transjugular intrahepatic portosystemic shunt (TIPS) showed increased survival rates and reduced rates of adverse events, according to a study.
The data were presented at the American Association for the Study of Liver Diseases by Virginia Hernandez-Gea, MD, a hepatologist at the Hospital Clinic in Barcelona.
In each study arm, three-quarters were men in their mid-50s. Cirrhosis in the non-TIPS group was alcohol-related in 57.4% of the cohort, compared with 71.2% of the group given early TIPS; roughly half of each group mentioned alcohol use in the past 3 months.
Also similar were Model for End-stage Liver Disease (MELD) scores: an average of 15.5 in the non-TIPS group, compared with 15 on average in the TIPS group. Nearly three-quarters of the TIPS group had a Child-Pugh C score, compared with 64% in the non-TIPS group. A Child-Pugh score with active bleeding was recorded in 28.8% of the TIPS group, compared with 36% in the non-TIPS group.
The transplant-free survival rate at 1 year in the standard care group was 61%, compared with 76% in the early TIPS group (P = .0175). The failure and bleeding rate at 1 year was significantly higher in the standard care group: 91%, compared with 68% in the early TIPS group (P = .004). Failure and bleeding rates in the Child-Pugh B and C groups across the study were similar.
Ascites at 1 year was seen in 88% of the standard care group, compared with in 64% of the study group. Rates of hepatic encephalopathy were similar in those with Child-Pugh B with active bleeding, and Child-Pugh C across both groups: 22% in the standard care group vs. 25% in the early TIPS group.
That there was no associated significant risk of hepatic encephalopathy in persons with acute variceal bleeding who were given early TIPS “strongly suggests that early TIPS should be included in clinical practice,” Dr. Hernandez-Gea said, noting that only 10% of the 34 sites in the study had used early TIPS. “We don’t really know why centers are not using this, since it is very difficult to find treatments that extend survival rates in this population.”
[email protected]
On Twitter @whitneymcknight
BOSTON – High-risk cirrhosis patients treated early with a transjugular intrahepatic portosystemic shunt (TIPS) showed increased survival rates and reduced rates of adverse events, according to a study.
The data were presented at the American Association for the Study of Liver Diseases by Virginia Hernandez-Gea, MD, a hepatologist at the Hospital Clinic in Barcelona.
In each study arm, three-quarters were men in their mid-50s. Cirrhosis in the non-TIPS group was alcohol-related in 57.4% of the cohort, compared with 71.2% of the group given early TIPS; roughly half of each group mentioned alcohol use in the past 3 months.
Also similar were Model for End-stage Liver Disease (MELD) scores: an average of 15.5 in the non-TIPS group, compared with 15 on average in the TIPS group. Nearly three-quarters of the TIPS group had a Child-Pugh C score, compared with 64% in the non-TIPS group. A Child-Pugh score with active bleeding was recorded in 28.8% of the TIPS group, compared with 36% in the non-TIPS group.
The transplant-free survival rate at 1 year in the standard care group was 61%, compared with 76% in the early TIPS group (P = .0175). The failure and bleeding rate at 1 year was significantly higher in the standard care group: 91%, compared with 68% in the early TIPS group (P = .004). Failure and bleeding rates in the Child-Pugh B and C groups across the study were similar.
Ascites at 1 year was seen in 88% of the standard care group, compared with in 64% of the study group. Rates of hepatic encephalopathy were similar in those with Child-Pugh B with active bleeding, and Child-Pugh C across both groups: 22% in the standard care group vs. 25% in the early TIPS group.
That there was no associated significant risk of hepatic encephalopathy in persons with acute variceal bleeding who were given early TIPS “strongly suggests that early TIPS should be included in clinical practice,” Dr. Hernandez-Gea said, noting that only 10% of the 34 sites in the study had used early TIPS. “We don’t really know why centers are not using this, since it is very difficult to find treatments that extend survival rates in this population.”
[email protected]
On Twitter @whitneymcknight
BOSTON – High-risk cirrhosis patients treated early with a transjugular intrahepatic portosystemic shunt (TIPS) showed increased survival rates and reduced rates of adverse events, according to a study.
The data were presented at the American Association for the Study of Liver Diseases by Virginia Hernandez-Gea, MD, a hepatologist at the Hospital Clinic in Barcelona.
In each study arm, three-quarters were men in their mid-50s. Cirrhosis in the non-TIPS group was alcohol-related in 57.4% of the cohort, compared with 71.2% of the group given early TIPS; roughly half of each group mentioned alcohol use in the past 3 months.
Also similar were Model for End-stage Liver Disease (MELD) scores: an average of 15.5 in the non-TIPS group, compared with 15 on average in the TIPS group. Nearly three-quarters of the TIPS group had a Child-Pugh C score, compared with 64% in the non-TIPS group. A Child-Pugh score with active bleeding was recorded in 28.8% of the TIPS group, compared with 36% in the non-TIPS group.
The transplant-free survival rate at 1 year in the standard care group was 61%, compared with 76% in the early TIPS group (P = .0175). The failure and bleeding rate at 1 year was significantly higher in the standard care group: 91%, compared with 68% in the early TIPS group (P = .004). Failure and bleeding rates in the Child-Pugh B and C groups across the study were similar.
Ascites at 1 year was seen in 88% of the standard care group, compared with in 64% of the study group. Rates of hepatic encephalopathy were similar in those with Child-Pugh B with active bleeding, and Child-Pugh C across both groups: 22% in the standard care group vs. 25% in the early TIPS group.
That there was no associated significant risk of hepatic encephalopathy in persons with acute variceal bleeding who were given early TIPS “strongly suggests that early TIPS should be included in clinical practice,” Dr. Hernandez-Gea said, noting that only 10% of the 34 sites in the study had used early TIPS. “We don’t really know why centers are not using this, since it is very difficult to find treatments that extend survival rates in this population.”
[email protected]
On Twitter @whitneymcknight
AT THE LIVER MEETING
Key clinical point:
Major finding: At 1 year post procedure, early TIPS was associated with better rates of survival and lower rates of adverse events, compared with those who did not receive early TIPS.
Data source: Multicenter, international observational study between 2011 and 2015 of 671 high-risk patients with cirrhosis managed according to current guidelines.
Disclosures: Dr. Hernandez-Gea did not have any relevant disclosures.
Metabolomics of liquid biopsies offer a comprehensive look at NAFLD
BOSTON – Metabolomics of liquid biopsies noninvasively identified nonalcoholic fatty liver disease (NAFLD) with and without steatosis, and assessed the severity of both steatosis and fibrosis, Puneet Puri, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases.
“These data provide proof of concept that liquid biopsy metabolomics can be used to resolve diagnostic questions in NAFLD management,” said Dr. Puri of Virginia Commonwealth University Medical Center in Richmond.
The researchers first developed a model that distinguished NAFLD patients from controls based on body mass index and the relative plasma concentrations of 11 triglycerides. This model correctly classified patients and controls 90% of the time (area under the receiver operating characteristic curve [AUROC], 0.90; standard deviation, 0.02) in the discovery cohort, and 93% of the time in the validation cohort (AUROC, 0.93; SD, 0.03). The sensitivity of the model was 98% in the discovery cohort and 97% in the validation cohort, and its specificity was 78% in the discovery cohort and 82% in the validation cohort.
The investigators then developed a lipodomic signature to assess the severity of steatosis in NAFLD patients, using magnetic resonance (MR) hepatic fat fraction data as the standard. This lipodomic signature correlated with MR with an r value of 0.81 (P less than .0001).
Next, they evaluated metabolomics for diagnosing nonalcoholic steatohepatitis (NASH). A model that accounted for body mass index (BMI) and the relative concentrations of 20 triglycerides distinguished biopsy-confirmed nonalcoholic fatty liver without steatosis from NASH with an AUROC of 0.95, a sensitivity of 0.83, and a specificity of 0.94 in the discovery cohort. In the validation cohort, the AUROC was 0.84, sensitivity was 79%, and specificity was 92%.
Finally, the researchers developed a way to use metabolomics to evaluate the severity of fibrosis. An algorithm that incorporated 16 variables for phospholipids, triacylglycerols, and nonesterified fatty acids distinguished F0 from F1 through F4 fibrosis with an AUROC of 0.92. Its sensitivity was 90%, and its specificity was 77%. A separate algorithm that incorporated five variables for phospholipids, triacylglycerols, acylcarnitines, sphingolipids, and sterols distinguished F1/F2 fibrosis from F3/F4 fibrosis with an AUROC of 0.89. Its sensitivity was only 62%, but its specificity was 93%.
This proof-of-concept study supports the idea that NAFLD and NASH cause metabolic changes, which in turn alter the circulating metabolome and can be noninvasively measured for diagnostic purposes, Dr. Puri concluded.
Dr. Puri did not list funding sources. He reported having no relevant financial conflicts of interest.
BOSTON – Metabolomics of liquid biopsies noninvasively identified nonalcoholic fatty liver disease (NAFLD) with and without steatosis, and assessed the severity of both steatosis and fibrosis, Puneet Puri, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases.
“These data provide proof of concept that liquid biopsy metabolomics can be used to resolve diagnostic questions in NAFLD management,” said Dr. Puri of Virginia Commonwealth University Medical Center in Richmond.
The researchers first developed a model that distinguished NAFLD patients from controls based on body mass index and the relative plasma concentrations of 11 triglycerides. This model correctly classified patients and controls 90% of the time (area under the receiver operating characteristic curve [AUROC], 0.90; standard deviation, 0.02) in the discovery cohort, and 93% of the time in the validation cohort (AUROC, 0.93; SD, 0.03). The sensitivity of the model was 98% in the discovery cohort and 97% in the validation cohort, and its specificity was 78% in the discovery cohort and 82% in the validation cohort.
The investigators then developed a lipodomic signature to assess the severity of steatosis in NAFLD patients, using magnetic resonance (MR) hepatic fat fraction data as the standard. This lipodomic signature correlated with MR with an r value of 0.81 (P less than .0001).
Next, they evaluated metabolomics for diagnosing nonalcoholic steatohepatitis (NASH). A model that accounted for body mass index (BMI) and the relative concentrations of 20 triglycerides distinguished biopsy-confirmed nonalcoholic fatty liver without steatosis from NASH with an AUROC of 0.95, a sensitivity of 0.83, and a specificity of 0.94 in the discovery cohort. In the validation cohort, the AUROC was 0.84, sensitivity was 79%, and specificity was 92%.
Finally, the researchers developed a way to use metabolomics to evaluate the severity of fibrosis. An algorithm that incorporated 16 variables for phospholipids, triacylglycerols, and nonesterified fatty acids distinguished F0 from F1 through F4 fibrosis with an AUROC of 0.92. Its sensitivity was 90%, and its specificity was 77%. A separate algorithm that incorporated five variables for phospholipids, triacylglycerols, acylcarnitines, sphingolipids, and sterols distinguished F1/F2 fibrosis from F3/F4 fibrosis with an AUROC of 0.89. Its sensitivity was only 62%, but its specificity was 93%.
This proof-of-concept study supports the idea that NAFLD and NASH cause metabolic changes, which in turn alter the circulating metabolome and can be noninvasively measured for diagnostic purposes, Dr. Puri concluded.
Dr. Puri did not list funding sources. He reported having no relevant financial conflicts of interest.
BOSTON – Metabolomics of liquid biopsies noninvasively identified nonalcoholic fatty liver disease (NAFLD) with and without steatosis, and assessed the severity of both steatosis and fibrosis, Puneet Puri, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases.
“These data provide proof of concept that liquid biopsy metabolomics can be used to resolve diagnostic questions in NAFLD management,” said Dr. Puri of Virginia Commonwealth University Medical Center in Richmond.
The researchers first developed a model that distinguished NAFLD patients from controls based on body mass index and the relative plasma concentrations of 11 triglycerides. This model correctly classified patients and controls 90% of the time (area under the receiver operating characteristic curve [AUROC], 0.90; standard deviation, 0.02) in the discovery cohort, and 93% of the time in the validation cohort (AUROC, 0.93; SD, 0.03). The sensitivity of the model was 98% in the discovery cohort and 97% in the validation cohort, and its specificity was 78% in the discovery cohort and 82% in the validation cohort.
The investigators then developed a lipodomic signature to assess the severity of steatosis in NAFLD patients, using magnetic resonance (MR) hepatic fat fraction data as the standard. This lipodomic signature correlated with MR with an r value of 0.81 (P less than .0001).
Next, they evaluated metabolomics for diagnosing nonalcoholic steatohepatitis (NASH). A model that accounted for body mass index (BMI) and the relative concentrations of 20 triglycerides distinguished biopsy-confirmed nonalcoholic fatty liver without steatosis from NASH with an AUROC of 0.95, a sensitivity of 0.83, and a specificity of 0.94 in the discovery cohort. In the validation cohort, the AUROC was 0.84, sensitivity was 79%, and specificity was 92%.
Finally, the researchers developed a way to use metabolomics to evaluate the severity of fibrosis. An algorithm that incorporated 16 variables for phospholipids, triacylglycerols, and nonesterified fatty acids distinguished F0 from F1 through F4 fibrosis with an AUROC of 0.92. Its sensitivity was 90%, and its specificity was 77%. A separate algorithm that incorporated five variables for phospholipids, triacylglycerols, acylcarnitines, sphingolipids, and sterols distinguished F1/F2 fibrosis from F3/F4 fibrosis with an AUROC of 0.89. Its sensitivity was only 62%, but its specificity was 93%.
This proof-of-concept study supports the idea that NAFLD and NASH cause metabolic changes, which in turn alter the circulating metabolome and can be noninvasively measured for diagnostic purposes, Dr. Puri concluded.
Dr. Puri did not list funding sources. He reported having no relevant financial conflicts of interest.
AT THE LIVER MEETING 2016
Key clinical point: Metabolomics of liquid biopsies identified and characterized nonalcoholic fatty liver disease in a proof-of-concept study.
Major finding: Four distinct models diagnosed NAFLD, diagnosed NASH, and characterized the severity of steatosis and fibrosis.
Data source: A multicenter study of 817 patients with biopsy-confirmed NAFLD and 130 biopsy-confirmed controls.
Disclosures: Dr. Puri did not list funding sources. He reported having no relevant financial conflicts of interest.
Time to consider cirrhosis medical homes
BOSTON – As part of the push to create value-based care across the specialties, hepatologists should consider medical homes for their patients, such as those with cirrhosis, according to experts.
“Cirrhosis is a chronic condition, highly symptomatic, and occurs in highly comorbid individuals. Treating them in a medical home scenario means we can offer services that we don’t otherwise do, but which are associated with better outcomes for our patients,” Fasiha Kanwal, MD, of the department of medicine at Baylor College of Medicine, Houston, said in a panel presentation at the annual meeting of the American Association for the Study of Liver Diseases.
Essentially, value-based care is the evolution of evidence-based medicine, according to Zobair M. Younossi, MD, AGAF, FAASLD, chair of the department of medicine at Inova Fairfax (Va.) Hospital. With value-based care, aligned incentives across all the specialties will lead to more precise accounting and efficiencies of care, said Dr. Younossi, who was also on the panel. “It would be very difficult right now to ask a hospital to tell you exactly what the cost of their liver care would be,” he said.
However, at present there are no true value-based models for hepatology in the United States, according to Dr. Kanwal, so clinicians should start by defining what will “truly constitute value for our patients.”
Because psychosocial support is essential to improved outcomes in patients with cirrhosis, she suggested adding case managers in practice, as they can help coordinate with services in the community at large. Other suggestions she offered included extending office hours, operating an after-hours hotline, and building teams that include general internists, additional nursing staff, and nutritionists.
Even though such changes in clinical practice models now are inevitable, Dr. Kanwal said there are few data at present that support how to innovate care in hospitalized patients with cirrhosis. This matters, as how patients present for outpatient follow-up care will impact reimbursements to the clinicians who treat them.
Some possible ways to improve hospital outcomes for patients with cirrhosis include creating a “best practice alert” that prompts a hepatology consult and triggers the implementation of a standardized set of guidelines for addressing ascites, bleeding, acute kidney injury, encephalopathy, and hepatorenal syndrome. For those with decompensated cirrhosis or for those who need transplants, a similar standardized checklist can be systematized between the hospital and clinic, emphasizing inpatient rifaximin and prophylactic antibiotics in case of spontaneous bacterial peritonitis.
With an overt emphasis on the needs of patients and payers, clinicians now must compete with one another to offer the most comprehensive, cost-effective care supported by information technology structures that can assess real time costs and outcomes, said Dr. Younossi. “Hepatology is lagging behind other fields in all this,” he added.
This worries Dr. Kanwal: “We should be the ones to determine what the value should be. We should be the ones to decide what the model will be and to engage with other fields, and the payers. Otherwise we will not have a seat at the table.”
Dr. Kanwal and Dr. Younossi did not have any relevant financial disclosures.
On Twitter @whitneymcknight
BOSTON – As part of the push to create value-based care across the specialties, hepatologists should consider medical homes for their patients, such as those with cirrhosis, according to experts.
“Cirrhosis is a chronic condition, highly symptomatic, and occurs in highly comorbid individuals. Treating them in a medical home scenario means we can offer services that we don’t otherwise do, but which are associated with better outcomes for our patients,” Fasiha Kanwal, MD, of the department of medicine at Baylor College of Medicine, Houston, said in a panel presentation at the annual meeting of the American Association for the Study of Liver Diseases.
Essentially, value-based care is the evolution of evidence-based medicine, according to Zobair M. Younossi, MD, AGAF, FAASLD, chair of the department of medicine at Inova Fairfax (Va.) Hospital. With value-based care, aligned incentives across all the specialties will lead to more precise accounting and efficiencies of care, said Dr. Younossi, who was also on the panel. “It would be very difficult right now to ask a hospital to tell you exactly what the cost of their liver care would be,” he said.
However, at present there are no true value-based models for hepatology in the United States, according to Dr. Kanwal, so clinicians should start by defining what will “truly constitute value for our patients.”
Because psychosocial support is essential to improved outcomes in patients with cirrhosis, she suggested adding case managers in practice, as they can help coordinate with services in the community at large. Other suggestions she offered included extending office hours, operating an after-hours hotline, and building teams that include general internists, additional nursing staff, and nutritionists.
Even though such changes in clinical practice models now are inevitable, Dr. Kanwal said there are few data at present that support how to innovate care in hospitalized patients with cirrhosis. This matters, as how patients present for outpatient follow-up care will impact reimbursements to the clinicians who treat them.
Some possible ways to improve hospital outcomes for patients with cirrhosis include creating a “best practice alert” that prompts a hepatology consult and triggers the implementation of a standardized set of guidelines for addressing ascites, bleeding, acute kidney injury, encephalopathy, and hepatorenal syndrome. For those with decompensated cirrhosis or for those who need transplants, a similar standardized checklist can be systematized between the hospital and clinic, emphasizing inpatient rifaximin and prophylactic antibiotics in case of spontaneous bacterial peritonitis.
With an overt emphasis on the needs of patients and payers, clinicians now must compete with one another to offer the most comprehensive, cost-effective care supported by information technology structures that can assess real time costs and outcomes, said Dr. Younossi. “Hepatology is lagging behind other fields in all this,” he added.
This worries Dr. Kanwal: “We should be the ones to determine what the value should be. We should be the ones to decide what the model will be and to engage with other fields, and the payers. Otherwise we will not have a seat at the table.”
Dr. Kanwal and Dr. Younossi did not have any relevant financial disclosures.
On Twitter @whitneymcknight
BOSTON – As part of the push to create value-based care across the specialties, hepatologists should consider medical homes for their patients, such as those with cirrhosis, according to experts.
“Cirrhosis is a chronic condition, highly symptomatic, and occurs in highly comorbid individuals. Treating them in a medical home scenario means we can offer services that we don’t otherwise do, but which are associated with better outcomes for our patients,” Fasiha Kanwal, MD, of the department of medicine at Baylor College of Medicine, Houston, said in a panel presentation at the annual meeting of the American Association for the Study of Liver Diseases.
Essentially, value-based care is the evolution of evidence-based medicine, according to Zobair M. Younossi, MD, AGAF, FAASLD, chair of the department of medicine at Inova Fairfax (Va.) Hospital. With value-based care, aligned incentives across all the specialties will lead to more precise accounting and efficiencies of care, said Dr. Younossi, who was also on the panel. “It would be very difficult right now to ask a hospital to tell you exactly what the cost of their liver care would be,” he said.
However, at present there are no true value-based models for hepatology in the United States, according to Dr. Kanwal, so clinicians should start by defining what will “truly constitute value for our patients.”
Because psychosocial support is essential to improved outcomes in patients with cirrhosis, she suggested adding case managers in practice, as they can help coordinate with services in the community at large. Other suggestions she offered included extending office hours, operating an after-hours hotline, and building teams that include general internists, additional nursing staff, and nutritionists.
Even though such changes in clinical practice models now are inevitable, Dr. Kanwal said there are few data at present that support how to innovate care in hospitalized patients with cirrhosis. This matters, as how patients present for outpatient follow-up care will impact reimbursements to the clinicians who treat them.
Some possible ways to improve hospital outcomes for patients with cirrhosis include creating a “best practice alert” that prompts a hepatology consult and triggers the implementation of a standardized set of guidelines for addressing ascites, bleeding, acute kidney injury, encephalopathy, and hepatorenal syndrome. For those with decompensated cirrhosis or for those who need transplants, a similar standardized checklist can be systematized between the hospital and clinic, emphasizing inpatient rifaximin and prophylactic antibiotics in case of spontaneous bacterial peritonitis.
With an overt emphasis on the needs of patients and payers, clinicians now must compete with one another to offer the most comprehensive, cost-effective care supported by information technology structures that can assess real time costs and outcomes, said Dr. Younossi. “Hepatology is lagging behind other fields in all this,” he added.
This worries Dr. Kanwal: “We should be the ones to determine what the value should be. We should be the ones to decide what the model will be and to engage with other fields, and the payers. Otherwise we will not have a seat at the table.”
Dr. Kanwal and Dr. Younossi did not have any relevant financial disclosures.
On Twitter @whitneymcknight
EXPERT ANALYSIS FROM THE LIVER MEETING 2016
Sofosbuvir/velpatasvir improved patient-reported outcomes, knocked out HCV genotypes 1-6
BOSTON – When given with ribavirin, a fixed-dose combination of sofosbuvir/velpatasvir (Epclusa) achieved a sustained viral response at 12 weeks (SVR-12) in 94% of decompensated cirrhotic patients with hepatitis C virus (HCV) genotypes 1-6 infection, according to Zobair M. Younossi, MD.
Patients with and without cirrhosis also reported meaningful improvements across a variety of outcome measures after successfully completing treatment with Epclusa or sofosbuvir (Harvoni), said Dr. Younossi of Inova Fairfax Hospital in Falls Church, Va. “Although on-treatment patient-reported outcomes improved more with ribavirin-free regimens, post-SVR improvements were similar,” regardless of whether patients had received ribavirin, he reported at the annual meeting of the American Association for the Study of Liver Diseases.
Epclusa without ribavirin led to SVR-12 in 85% of decompensated cirrhotic patients and nearly 99% of noncirrhotic patients of all HCV genotypes, Dr. Younossi reported. For sofosbuvir with ribavirin, rates of SVR-12 were 66% in genotype 3 cirrhotic patients and 95% in cirrhotic patients of other HCV genotypes.
At baseline, cirrhotic patients scored up to 33.5 points worse than noncirrhotics on a universal 100-point scale covering 26 patient-reported domains (P less than .05 for all but 3 domains). Decompensated cirrhotics reported more baseline depression and fatigue than other patients (P less than .002 for each comparison), while patients without cirrhosis were more likely to be treatment naive and employed (both P less than .0001). But after the investigators controlled for these differences, decompensated cirrhotics who received Epclusa reported an additional 5.5-9 points of improvement in treatment-emergent outcomes than those who received sofosbuvir plus ribavirin (P less than .002). Patients with compensated cirrhosis reported 2.3-5 points more improvement in treatment-emergent outcomes on Epclusa than on sofosbuvir plus ribavirin (P less than .05). “Decompensated cirrhotics experienced the best and greatest improvement of patient-reported outcome scores during treatment with sofosbuvir/velpatasvir,” Dr. Younossi said.
Patients who received ribavirin reported similar changes across domains at the end of treatment, regardless of cirrhosis status. Among patients who achieved SVR-12, decompensated cirrhotics reported significantly more improvement 12 weeks later than did patients with less severe liver disease, although both groups showed long-term improvements (5.8 points vs. 4.1 points, P less than .05). Clearly, patients continue to report improvements in various domains as time goes on, “suggesting that all the benefit of cure is not achieved by 12 weeks of follow-up,” said Dr. Younossi.
Gilead Sciences makes Epclusa and Harvoni and funded the study. Dr. Younossi reported having no relevant financial conflicts.
BOSTON – When given with ribavirin, a fixed-dose combination of sofosbuvir/velpatasvir (Epclusa) achieved a sustained viral response at 12 weeks (SVR-12) in 94% of decompensated cirrhotic patients with hepatitis C virus (HCV) genotypes 1-6 infection, according to Zobair M. Younossi, MD.
Patients with and without cirrhosis also reported meaningful improvements across a variety of outcome measures after successfully completing treatment with Epclusa or sofosbuvir (Harvoni), said Dr. Younossi of Inova Fairfax Hospital in Falls Church, Va. “Although on-treatment patient-reported outcomes improved more with ribavirin-free regimens, post-SVR improvements were similar,” regardless of whether patients had received ribavirin, he reported at the annual meeting of the American Association for the Study of Liver Diseases.
Epclusa without ribavirin led to SVR-12 in 85% of decompensated cirrhotic patients and nearly 99% of noncirrhotic patients of all HCV genotypes, Dr. Younossi reported. For sofosbuvir with ribavirin, rates of SVR-12 were 66% in genotype 3 cirrhotic patients and 95% in cirrhotic patients of other HCV genotypes.
At baseline, cirrhotic patients scored up to 33.5 points worse than noncirrhotics on a universal 100-point scale covering 26 patient-reported domains (P less than .05 for all but 3 domains). Decompensated cirrhotics reported more baseline depression and fatigue than other patients (P less than .002 for each comparison), while patients without cirrhosis were more likely to be treatment naive and employed (both P less than .0001). But after the investigators controlled for these differences, decompensated cirrhotics who received Epclusa reported an additional 5.5-9 points of improvement in treatment-emergent outcomes than those who received sofosbuvir plus ribavirin (P less than .002). Patients with compensated cirrhosis reported 2.3-5 points more improvement in treatment-emergent outcomes on Epclusa than on sofosbuvir plus ribavirin (P less than .05). “Decompensated cirrhotics experienced the best and greatest improvement of patient-reported outcome scores during treatment with sofosbuvir/velpatasvir,” Dr. Younossi said.
Patients who received ribavirin reported similar changes across domains at the end of treatment, regardless of cirrhosis status. Among patients who achieved SVR-12, decompensated cirrhotics reported significantly more improvement 12 weeks later than did patients with less severe liver disease, although both groups showed long-term improvements (5.8 points vs. 4.1 points, P less than .05). Clearly, patients continue to report improvements in various domains as time goes on, “suggesting that all the benefit of cure is not achieved by 12 weeks of follow-up,” said Dr. Younossi.
Gilead Sciences makes Epclusa and Harvoni and funded the study. Dr. Younossi reported having no relevant financial conflicts.
BOSTON – When given with ribavirin, a fixed-dose combination of sofosbuvir/velpatasvir (Epclusa) achieved a sustained viral response at 12 weeks (SVR-12) in 94% of decompensated cirrhotic patients with hepatitis C virus (HCV) genotypes 1-6 infection, according to Zobair M. Younossi, MD.
Patients with and without cirrhosis also reported meaningful improvements across a variety of outcome measures after successfully completing treatment with Epclusa or sofosbuvir (Harvoni), said Dr. Younossi of Inova Fairfax Hospital in Falls Church, Va. “Although on-treatment patient-reported outcomes improved more with ribavirin-free regimens, post-SVR improvements were similar,” regardless of whether patients had received ribavirin, he reported at the annual meeting of the American Association for the Study of Liver Diseases.
Epclusa without ribavirin led to SVR-12 in 85% of decompensated cirrhotic patients and nearly 99% of noncirrhotic patients of all HCV genotypes, Dr. Younossi reported. For sofosbuvir with ribavirin, rates of SVR-12 were 66% in genotype 3 cirrhotic patients and 95% in cirrhotic patients of other HCV genotypes.
At baseline, cirrhotic patients scored up to 33.5 points worse than noncirrhotics on a universal 100-point scale covering 26 patient-reported domains (P less than .05 for all but 3 domains). Decompensated cirrhotics reported more baseline depression and fatigue than other patients (P less than .002 for each comparison), while patients without cirrhosis were more likely to be treatment naive and employed (both P less than .0001). But after the investigators controlled for these differences, decompensated cirrhotics who received Epclusa reported an additional 5.5-9 points of improvement in treatment-emergent outcomes than those who received sofosbuvir plus ribavirin (P less than .002). Patients with compensated cirrhosis reported 2.3-5 points more improvement in treatment-emergent outcomes on Epclusa than on sofosbuvir plus ribavirin (P less than .05). “Decompensated cirrhotics experienced the best and greatest improvement of patient-reported outcome scores during treatment with sofosbuvir/velpatasvir,” Dr. Younossi said.
Patients who received ribavirin reported similar changes across domains at the end of treatment, regardless of cirrhosis status. Among patients who achieved SVR-12, decompensated cirrhotics reported significantly more improvement 12 weeks later than did patients with less severe liver disease, although both groups showed long-term improvements (5.8 points vs. 4.1 points, P less than .05). Clearly, patients continue to report improvements in various domains as time goes on, “suggesting that all the benefit of cure is not achieved by 12 weeks of follow-up,” said Dr. Younossi.
Gilead Sciences makes Epclusa and Harvoni and funded the study. Dr. Younossi reported having no relevant financial conflicts.
AT THE LIVER MEETING 2016
Key clinical point: Sofosbuvir/velpatasvir with ribavirin effectively cured most hepatitis C virus–infected patients with decompensated cirrhosis.
Major finding: In all, 94% of patients achieved a sustained viral response at 12 weeks, regardless of HCV genotype.
Data source: The phase III ASTRAL trials involving 1,701 patients with pangenotypic hepatitis C virus infections.
Disclosures: Gilead Sciences makes Epclusa and Harvoni and funded the study. Dr. Younossi reported having no relevant financial conflicts.
NAFLD can regress with weight loss, activity
BOSTON – All phenotypes of nonalcoholic fatty liver disease (NAFLD) can progress or regress even without pharmacologic intervention, according to a prospective longitudinal study of 394 patients.
Weight loss and baseline NAFLD Activity Score predicted resolution of NAFLD, while weight gain and rising serum transaminases predicted progression to nonalcoholic steatohepatitis (NASH), Arun J. Sanyal, MD, said at the annual meeting of the American Association for the Study of Liver Diseases. Baseline and subsequent NAFLD Activity Score also was “a strong predictor of fibrosis progression or regression,” as was AST, portal inflammation, and baseline fibrosis stage, said Dr. Sanyal of Virginia Commonwealth University in Richmond, Va.
NAFLD comprises two main phenotypes, fatty liver and steatohepatitis. “The phenotype can change over time, and both phenotypes can be associated with fibrosis,” Dr. Sanyal noted. To better understand trends and clinical correlates for these phenotypes, he and his associates analyzed prospectively collected clinical and biopsy data from the NASH Clinical Research Network of the National Institutes of Diabetes and Digestive and Kidney Diseases. Each patient attended multiple clinic visits and underwent two liver biopsies at least 1 year and usually 4-5 years apart, which were interpreted by a masked central pathology review committee.
At baseline, 75 patients had fatty liver without steatohepatitis, of which only 13% resolved and 44% progressed to borderline or definite steatohepatitis. Similarly, among 74 patients with borderline steatohepatitis at baseline, only 22% regressed to fatty liver disease without steatohepatitis, while 43% progressed to definite steatohepatitis. The remaining 245 patients had definite steatohepatitis at baseline, of which 58% failed to regress at all, 20% regressed to borderline, 11% regressed to fatty liver disease without steatohepatitis, and 11% regressed to normal.
The investigators also performed a multivariable analysis of 197 patients with complete data. After the investigators controlled for serum insulin level, alkaline phosphatase level, NAS, and the presence of metabolic syndrome, each 10-U/L increase in ALT more than doubled the odds of progression from fatty liver without steatohepatitis to NASH (odds ratio, 2.2; 95% confidence interval, 1.1 to 4.1; P = .02). The association was even stronger for AST (OR, 3.5; 95% CI, 1.2 to 10.4; P = .03), and each 1-kg gain in body weight increased the odds of progression to NASH by 70% (OR, 1.7; 95% CI, 1.1 to 2.5; P = .01). In contrast, resolution of NAFLD was associated with weight loss (OR per 1 kg, 0.9; P less than .001) and lower baseline NAFLD Activity Score (OR, 0.7; P = .04).
About one in four patients had evidence of fibrosis at baseline, and 44% had at least stage 1 fibrosis at follow-up biopsy. Patients whose NAFLD progressed to a more severe phenotype were much more likely to have evidence of progressive fibrosis than were those whose NAFLD did not progress (OR, 7.2; 95% CI, 2.1 to 21.5; P less than .001), and there was no evidence that time between liver biopsies influenced this relationship. Among patients with definite NASH who had stage 0 fibrosis at baseline, 50% progressed to at least 1 fibrosis stage over the next 6.8 years, and 50% progressed to at least 2 stages over 9.6 years. Patients whose baseline NAFLD Activity Scores were between 1 and 4 were most likely to experience regression of fibrosis, while those with scores between 5 and 8 were more likely to have worsening fibrosis. Patients with severe baseline NAFLD Activity Score component scores for steatosis, lobular inflammation, and ballooning also were significantly more likely to have progressive fibrosis than were those with baseline NAFLD Activity Scores of 0 or 1. Furthermore, increasing NAFLD Activity Score over time predicted fibrosis progression.
Diabetes did not seem to affect fibrosis progression or regression, Dr. Sanyal noted. However, baseline portal inflammation predicted worsening fibrosis (P less than .01), as did baseline and subsequent elevations in AST (P less than .001), insulin (P = .03), and NAS (P less than 001), and baseline ballooning (P less than .01).
The investigators reported that the study had no sponsors. Dr. Sanyal disclosed ties to a wide number of drug companies.
BOSTON – All phenotypes of nonalcoholic fatty liver disease (NAFLD) can progress or regress even without pharmacologic intervention, according to a prospective longitudinal study of 394 patients.
Weight loss and baseline NAFLD Activity Score predicted resolution of NAFLD, while weight gain and rising serum transaminases predicted progression to nonalcoholic steatohepatitis (NASH), Arun J. Sanyal, MD, said at the annual meeting of the American Association for the Study of Liver Diseases. Baseline and subsequent NAFLD Activity Score also was “a strong predictor of fibrosis progression or regression,” as was AST, portal inflammation, and baseline fibrosis stage, said Dr. Sanyal of Virginia Commonwealth University in Richmond, Va.
NAFLD comprises two main phenotypes, fatty liver and steatohepatitis. “The phenotype can change over time, and both phenotypes can be associated with fibrosis,” Dr. Sanyal noted. To better understand trends and clinical correlates for these phenotypes, he and his associates analyzed prospectively collected clinical and biopsy data from the NASH Clinical Research Network of the National Institutes of Diabetes and Digestive and Kidney Diseases. Each patient attended multiple clinic visits and underwent two liver biopsies at least 1 year and usually 4-5 years apart, which were interpreted by a masked central pathology review committee.
At baseline, 75 patients had fatty liver without steatohepatitis, of which only 13% resolved and 44% progressed to borderline or definite steatohepatitis. Similarly, among 74 patients with borderline steatohepatitis at baseline, only 22% regressed to fatty liver disease without steatohepatitis, while 43% progressed to definite steatohepatitis. The remaining 245 patients had definite steatohepatitis at baseline, of which 58% failed to regress at all, 20% regressed to borderline, 11% regressed to fatty liver disease without steatohepatitis, and 11% regressed to normal.
The investigators also performed a multivariable analysis of 197 patients with complete data. After the investigators controlled for serum insulin level, alkaline phosphatase level, NAS, and the presence of metabolic syndrome, each 10-U/L increase in ALT more than doubled the odds of progression from fatty liver without steatohepatitis to NASH (odds ratio, 2.2; 95% confidence interval, 1.1 to 4.1; P = .02). The association was even stronger for AST (OR, 3.5; 95% CI, 1.2 to 10.4; P = .03), and each 1-kg gain in body weight increased the odds of progression to NASH by 70% (OR, 1.7; 95% CI, 1.1 to 2.5; P = .01). In contrast, resolution of NAFLD was associated with weight loss (OR per 1 kg, 0.9; P less than .001) and lower baseline NAFLD Activity Score (OR, 0.7; P = .04).
About one in four patients had evidence of fibrosis at baseline, and 44% had at least stage 1 fibrosis at follow-up biopsy. Patients whose NAFLD progressed to a more severe phenotype were much more likely to have evidence of progressive fibrosis than were those whose NAFLD did not progress (OR, 7.2; 95% CI, 2.1 to 21.5; P less than .001), and there was no evidence that time between liver biopsies influenced this relationship. Among patients with definite NASH who had stage 0 fibrosis at baseline, 50% progressed to at least 1 fibrosis stage over the next 6.8 years, and 50% progressed to at least 2 stages over 9.6 years. Patients whose baseline NAFLD Activity Scores were between 1 and 4 were most likely to experience regression of fibrosis, while those with scores between 5 and 8 were more likely to have worsening fibrosis. Patients with severe baseline NAFLD Activity Score component scores for steatosis, lobular inflammation, and ballooning also were significantly more likely to have progressive fibrosis than were those with baseline NAFLD Activity Scores of 0 or 1. Furthermore, increasing NAFLD Activity Score over time predicted fibrosis progression.
Diabetes did not seem to affect fibrosis progression or regression, Dr. Sanyal noted. However, baseline portal inflammation predicted worsening fibrosis (P less than .01), as did baseline and subsequent elevations in AST (P less than .001), insulin (P = .03), and NAS (P less than 001), and baseline ballooning (P less than .01).
The investigators reported that the study had no sponsors. Dr. Sanyal disclosed ties to a wide number of drug companies.
BOSTON – All phenotypes of nonalcoholic fatty liver disease (NAFLD) can progress or regress even without pharmacologic intervention, according to a prospective longitudinal study of 394 patients.
Weight loss and baseline NAFLD Activity Score predicted resolution of NAFLD, while weight gain and rising serum transaminases predicted progression to nonalcoholic steatohepatitis (NASH), Arun J. Sanyal, MD, said at the annual meeting of the American Association for the Study of Liver Diseases. Baseline and subsequent NAFLD Activity Score also was “a strong predictor of fibrosis progression or regression,” as was AST, portal inflammation, and baseline fibrosis stage, said Dr. Sanyal of Virginia Commonwealth University in Richmond, Va.
NAFLD comprises two main phenotypes, fatty liver and steatohepatitis. “The phenotype can change over time, and both phenotypes can be associated with fibrosis,” Dr. Sanyal noted. To better understand trends and clinical correlates for these phenotypes, he and his associates analyzed prospectively collected clinical and biopsy data from the NASH Clinical Research Network of the National Institutes of Diabetes and Digestive and Kidney Diseases. Each patient attended multiple clinic visits and underwent two liver biopsies at least 1 year and usually 4-5 years apart, which were interpreted by a masked central pathology review committee.
At baseline, 75 patients had fatty liver without steatohepatitis, of which only 13% resolved and 44% progressed to borderline or definite steatohepatitis. Similarly, among 74 patients with borderline steatohepatitis at baseline, only 22% regressed to fatty liver disease without steatohepatitis, while 43% progressed to definite steatohepatitis. The remaining 245 patients had definite steatohepatitis at baseline, of which 58% failed to regress at all, 20% regressed to borderline, 11% regressed to fatty liver disease without steatohepatitis, and 11% regressed to normal.
The investigators also performed a multivariable analysis of 197 patients with complete data. After the investigators controlled for serum insulin level, alkaline phosphatase level, NAS, and the presence of metabolic syndrome, each 10-U/L increase in ALT more than doubled the odds of progression from fatty liver without steatohepatitis to NASH (odds ratio, 2.2; 95% confidence interval, 1.1 to 4.1; P = .02). The association was even stronger for AST (OR, 3.5; 95% CI, 1.2 to 10.4; P = .03), and each 1-kg gain in body weight increased the odds of progression to NASH by 70% (OR, 1.7; 95% CI, 1.1 to 2.5; P = .01). In contrast, resolution of NAFLD was associated with weight loss (OR per 1 kg, 0.9; P less than .001) and lower baseline NAFLD Activity Score (OR, 0.7; P = .04).
About one in four patients had evidence of fibrosis at baseline, and 44% had at least stage 1 fibrosis at follow-up biopsy. Patients whose NAFLD progressed to a more severe phenotype were much more likely to have evidence of progressive fibrosis than were those whose NAFLD did not progress (OR, 7.2; 95% CI, 2.1 to 21.5; P less than .001), and there was no evidence that time between liver biopsies influenced this relationship. Among patients with definite NASH who had stage 0 fibrosis at baseline, 50% progressed to at least 1 fibrosis stage over the next 6.8 years, and 50% progressed to at least 2 stages over 9.6 years. Patients whose baseline NAFLD Activity Scores were between 1 and 4 were most likely to experience regression of fibrosis, while those with scores between 5 and 8 were more likely to have worsening fibrosis. Patients with severe baseline NAFLD Activity Score component scores for steatosis, lobular inflammation, and ballooning also were significantly more likely to have progressive fibrosis than were those with baseline NAFLD Activity Scores of 0 or 1. Furthermore, increasing NAFLD Activity Score over time predicted fibrosis progression.
Diabetes did not seem to affect fibrosis progression or regression, Dr. Sanyal noted. However, baseline portal inflammation predicted worsening fibrosis (P less than .01), as did baseline and subsequent elevations in AST (P less than .001), insulin (P = .03), and NAS (P less than 001), and baseline ballooning (P less than .01).
The investigators reported that the study had no sponsors. Dr. Sanyal disclosed ties to a wide number of drug companies.
AT THE LIVER MEETING 2016
Key clinical point: Phenotypes of nonalcoholic fatty liver disease can progress or regress over time.
Major finding: Resolution of NAFLD was associated with weight loss (OR per 1 kg, 0.9; P less than .001) and lower baseline NAFLD Activity Score (OR, 0.7; P = .04).
Data source: A prospective study of 394 patients with nonalcoholic fatty liver disease.
Disclosures: The investigators reported that the study had no sponsors. Dr. Sanyal disclosed ties to several drug companies.