Liver Disease

SAN FRANCISCO – Most years, when it comes to research to treat hepatitis viral infections, hepatitis C has been front and center at the annual meeting of the American Association for the Study of Liver Diseases. But things have changed in the past couple of years, with hepatitis C curative treatment maturing and altering the therapeutic landscape.

“Hepatitis C has been where all the action is, but that’s clearly changed in the last few years,” said Jordan Feld, MD, MPH, who summed up the hepatitis B findings during a wrap-up session on the final day of the conference. Dr. Feld is a clinician-scientist at the Toronto Western Hospital Liver Clinic and the McLaughlin-Rotman Centre for Global Health.

An analysis (Abstract 212) of a mixed North American and Asian cohort of more than 10,000 untreated patients showed just a 1.3% annual clearance rate of surface antigen, with little guidance for risk stratification. “This leaves us really needing new therapies,” said Dr. Feld.

Fortunately, the hepatitis B virus (HBV) life cycle offers various opportunities for therapeutic intervention, including blocking entry, targeting assembly and export of the virus, targeting HBV RNA, and targeting the capsid protein and viral packaging.

One study (Abstract 16) examined a hepatitis B entry inhibitor’s effect on hepatitis D virus (HDV), which requires coinfection with HBV to replicate. A phase 2 clinical trial found that treatment with Myrcludex B alone or in combination with interferon led to a decline in HDV RNA, but the result was most pronounced in patients who received the combination therapy. The combination was also associated with a greater probability of surface antigen decline. “I think that’s really important, that we see this synergistic effect. This is really promising phase 2 data that raises the possibility of curative therapy for this troubling infection,” said Dr. Feld.

Another study (Abstract LB-25) looked at an RNA inhibitor that targets both integrated and covalently closed circular DNA (cccDNA)–derived HBV RNA. The drug was given to 11 HBV patients who were positive for HBeAg (hepatitis B e-antigen) and 13 HBV patients who were HBeAg negative. It had similar effects in reducing HBV surface antigens and other correlated antigens in both groups of patients, and no evidence of a dose-response relationship. “Seeing a similar effect is quite important and suggests that it’s targeting both cccDNA-derived and integrated HBV DNA, and although there were some mild injection reactions, it generally seemed to be safe and pretty well tolerated,” said Dr. Feld.

Further down the life cycle, capsid assembly modulators (CAMs) have the potential to counter HBV by two mechanisms; blocking encapsulation of pregenomic RNA, and degrading capsids, which could prevent the replenishment of cccDNA. The latter effect could be important for achieving a cure, according to Dr. Feld.

A novel CAM, JNJ-6379 (Abstract 74), was tested at three different doses, and was well tolerated at higher doses, but it had limited dose response at the higher dose with respect to HBV DNA suppression. However, it could be that the two CAM mechanisms may require different doses. “These two things are hard to tease apart, and hopefully, we’ll see more data to separate them in the future,” said Dr. Feld.

Another CAM, ABI-HO731 (Abstract 73), had a potent effect on HBV DNA and HBV RNA, showing that it blocks encapsulation of both pregenomic RNA related to reverse transcription and pregenomic RNAs within the capsid. Stopping the medication led to some HBV DNA rebound, though no alanine aminotransferase flares, which Dr. Feld found reassuring. One patient had baseline resistance but was nevertheless able to achieve some suppression on the drug.

Another therapeutic approach used a nucleic acid polymer to block subviral particle release (Abstract 393). The study treated immunosuppressed patients with the polymer alone or in combination with interferon or tenofovir disoproxil, and led to “striking reductions in hepatitis B surface antigen quantities during therapy,” said Dr. Feld. An alanine aminotransferase flair did occur, which may signify an immune response, and it will be important to determine if this is indeed the case, he said. After stopping therapy there was a gain of anti–hepatitis B antibodies, which suggests that functional clearance of surface antigen is occurring.

Researchers also are recruiting the immune system to combat HBV. The novel agent inarigivir is a retinoic acid-inducible gene-1 agonist, which has both a direct antiviral effect and an indirect effect via the intrahepatic innate immune response, which it accomplishes by activating the interferon signaling pathway. It also directly interferes with the interaction between pregenomic RNA and the HBV polymerase, preventing replication. In the ACHIEVE trial, the researchers noted greater reduction in HBV RNA and DNA at higher doses (Abstract 75). “This is certainly an interesting molecule and an interesting proof of concept that you can potentially target HBV using two different pathways, and we’ll be interested to see more data with this approach,” said Dr. Feld.

Dr. Feld wrapped up the discussion of novel therapies with an animal model study (Abstract 77) that suggests future strategies for a cure. In it, the researchers combined a therapeutic vaccine with a stabilized, liver-targeted small interfering RNA to suppress surface antigen. Animals that received only the vaccine saw little benefit, but the combined approach led to viral clearance. The treatment also restored the immune response. “It gives us an inkling that we may need to both reduce the antigen load and stimulate immunity,” said Dr. Feld.

Dr. Feld has consulted for AbbVie, Gilead, ContraVir, MedImmune, and Merck. He has received funding from AbbVie, Gilead, Merck, and Janssen.

SAN FRANCISCO – Most years, when it comes to research to treat hepatitis viral infections, hepatitis C has been front and center at the annual meeting of the American Association for the Study of Liver Diseases. But things have changed in the past couple of years, with hepatitis C curative treatment maturing and altering the therapeutic landscape.

“Hepatitis C has been where all the action is, but that’s clearly changed in the last few years,” said Jordan Feld, MD, MPH, who summed up the hepatitis B findings during a wrap-up session on the final day of the conference. Dr. Feld is a clinician-scientist at the Toronto Western Hospital Liver Clinic and the McLaughlin-Rotman Centre for Global Health.

An analysis (Abstract 212) of a mixed North American and Asian cohort of more than 10,000 untreated patients showed just a 1.3% annual clearance rate of surface antigen, with little guidance for risk stratification. “This leaves us really needing new therapies,” said Dr. Feld.

Fortunately, the hepatitis B virus (HBV) life cycle offers various opportunities for therapeutic intervention, including blocking entry, targeting assembly and export of the virus, targeting HBV RNA, and targeting the capsid protein and viral packaging.

One study (Abstract 16) examined a hepatitis B entry inhibitor’s effect on hepatitis D virus (HDV), which requires coinfection with HBV to replicate. A phase 2 clinical trial found that treatment with Myrcludex B alone or in combination with interferon led to a decline in HDV RNA, but the result was most pronounced in patients who received the combination therapy. The combination was also associated with a greater probability of surface antigen decline. “I think that’s really important, that we see this synergistic effect. This is really promising phase 2 data that raises the possibility of curative therapy for this troubling infection,” said Dr. Feld.

Another study (Abstract LB-25) looked at an RNA inhibitor that targets both integrated and covalently closed circular DNA (cccDNA)–derived HBV RNA. The drug was given to 11 HBV patients who were positive for HBeAg (hepatitis B e-antigen) and 13 HBV patients who were HBeAg negative. It had similar effects in reducing HBV surface antigens and other correlated antigens in both groups of patients, and no evidence of a dose-response relationship. “Seeing a similar effect is quite important and suggests that it’s targeting both cccDNA-derived and integrated HBV DNA, and although there were some mild injection reactions, it generally seemed to be safe and pretty well tolerated,” said Dr. Feld.

Further down the life cycle, capsid assembly modulators (CAMs) have the potential to counter HBV by two mechanisms; blocking encapsulation of pregenomic RNA, and degrading capsids, which could prevent the replenishment of cccDNA. The latter effect could be important for achieving a cure, according to Dr. Feld.

A novel CAM, JNJ-6379 (Abstract 74), was tested at three different doses, and was well tolerated at higher doses, but it had limited dose response at the higher dose with respect to HBV DNA suppression. However, it could be that the two CAM mechanisms may require different doses. “These two things are hard to tease apart, and hopefully, we’ll see more data to separate them in the future,” said Dr. Feld.

Another CAM, ABI-HO731 (Abstract 73), had a potent effect on HBV DNA and HBV RNA, showing that it blocks encapsulation of both pregenomic RNA related to reverse transcription and pregenomic RNAs within the capsid. Stopping the medication led to some HBV DNA rebound, though no alanine aminotransferase flares, which Dr. Feld found reassuring. One patient had baseline resistance but was nevertheless able to achieve some suppression on the drug.

Another therapeutic approach used a nucleic acid polymer to block subviral particle release (Abstract 393). The study treated immunosuppressed patients with the polymer alone or in combination with interferon or tenofovir disoproxil, and led to “striking reductions in hepatitis B surface antigen quantities during therapy,” said Dr. Feld. An alanine aminotransferase flair did occur, which may signify an immune response, and it will be important to determine if this is indeed the case, he said. After stopping therapy there was a gain of anti–hepatitis B antibodies, which suggests that functional clearance of surface antigen is occurring.

Researchers also are recruiting the immune system to combat HBV. The novel agent inarigivir is a retinoic acid-inducible gene-1 agonist, which has both a direct antiviral effect and an indirect effect via the intrahepatic innate immune response, which it accomplishes by activating the interferon signaling pathway. It also directly interferes with the interaction between pregenomic RNA and the HBV polymerase, preventing replication. In the ACHIEVE trial, the researchers noted greater reduction in HBV RNA and DNA at higher doses (Abstract 75). “This is certainly an interesting molecule and an interesting proof of concept that you can potentially target HBV using two different pathways, and we’ll be interested to see more data with this approach,” said Dr. Feld.

Dr. Feld wrapped up the discussion of novel therapies with an animal model study (Abstract 77) that suggests future strategies for a cure. In it, the researchers combined a therapeutic vaccine with a stabilized, liver-targeted small interfering RNA to suppress surface antigen. Animals that received only the vaccine saw little benefit, but the combined approach led to viral clearance. The treatment also restored the immune response. “It gives us an inkling that we may need to both reduce the antigen load and stimulate immunity,” said Dr. Feld.

Dr. Feld has consulted for AbbVie, Gilead, ContraVir, MedImmune, and Merck. He has received funding from AbbVie, Gilead, Merck, and Janssen.

SAN FRANCISCO – Most years, when it comes to research to treat hepatitis viral infections, hepatitis C has been front and center at the annual meeting of the American Association for the Study of Liver Diseases. But things have changed in the past couple of years, with hepatitis C curative treatment maturing and altering the therapeutic landscape.

“Hepatitis C has been where all the action is, but that’s clearly changed in the last few years,” said Jordan Feld, MD, MPH, who summed up the hepatitis B findings during a wrap-up session on the final day of the conference. Dr. Feld is a clinician-scientist at the Toronto Western Hospital Liver Clinic and the McLaughlin-Rotman Centre for Global Health.

An analysis (Abstract 212) of a mixed North American and Asian cohort of more than 10,000 untreated patients showed just a 1.3% annual clearance rate of surface antigen, with little guidance for risk stratification. “This leaves us really needing new therapies,” said Dr. Feld.

Fortunately, the hepatitis B virus (HBV) life cycle offers various opportunities for therapeutic intervention, including blocking entry, targeting assembly and export of the virus, targeting HBV RNA, and targeting the capsid protein and viral packaging.

One study (Abstract 16) examined a hepatitis B entry inhibitor’s effect on hepatitis D virus (HDV), which requires coinfection with HBV to replicate. A phase 2 clinical trial found that treatment with Myrcludex B alone or in combination with interferon led to a decline in HDV RNA, but the result was most pronounced in patients who received the combination therapy. The combination was also associated with a greater probability of surface antigen decline. “I think that’s really important, that we see this synergistic effect. This is really promising phase 2 data that raises the possibility of curative therapy for this troubling infection,” said Dr. Feld.

Another study (Abstract LB-25) looked at an RNA inhibitor that targets both integrated and covalently closed circular DNA (cccDNA)–derived HBV RNA. The drug was given to 11 HBV patients who were positive for HBeAg (hepatitis B e-antigen) and 13 HBV patients who were HBeAg negative. It had similar effects in reducing HBV surface antigens and other correlated antigens in both groups of patients, and no evidence of a dose-response relationship. “Seeing a similar effect is quite important and suggests that it’s targeting both cccDNA-derived and integrated HBV DNA, and although there were some mild injection reactions, it generally seemed to be safe and pretty well tolerated,” said Dr. Feld.

Further down the life cycle, capsid assembly modulators (CAMs) have the potential to counter HBV by two mechanisms; blocking encapsulation of pregenomic RNA, and degrading capsids, which could prevent the replenishment of cccDNA. The latter effect could be important for achieving a cure, according to Dr. Feld.

A novel CAM, JNJ-6379 (Abstract 74), was tested at three different doses, and was well tolerated at higher doses, but it had limited dose response at the higher dose with respect to HBV DNA suppression. However, it could be that the two CAM mechanisms may require different doses. “These two things are hard to tease apart, and hopefully, we’ll see more data to separate them in the future,” said Dr. Feld.

Another CAM, ABI-HO731 (Abstract 73), had a potent effect on HBV DNA and HBV RNA, showing that it blocks encapsulation of both pregenomic RNA related to reverse transcription and pregenomic RNAs within the capsid. Stopping the medication led to some HBV DNA rebound, though no alanine aminotransferase flares, which Dr. Feld found reassuring. One patient had baseline resistance but was nevertheless able to achieve some suppression on the drug.

Another therapeutic approach used a nucleic acid polymer to block subviral particle release (Abstract 393). The study treated immunosuppressed patients with the polymer alone or in combination with interferon or tenofovir disoproxil, and led to “striking reductions in hepatitis B surface antigen quantities during therapy,” said Dr. Feld. An alanine aminotransferase flair did occur, which may signify an immune response, and it will be important to determine if this is indeed the case, he said. After stopping therapy there was a gain of anti–hepatitis B antibodies, which suggests that functional clearance of surface antigen is occurring.

Researchers also are recruiting the immune system to combat HBV. The novel agent inarigivir is a retinoic acid-inducible gene-1 agonist, which has both a direct antiviral effect and an indirect effect via the intrahepatic innate immune response, which it accomplishes by activating the interferon signaling pathway. It also directly interferes with the interaction between pregenomic RNA and the HBV polymerase, preventing replication. In the ACHIEVE trial, the researchers noted greater reduction in HBV RNA and DNA at higher doses (Abstract 75). “This is certainly an interesting molecule and an interesting proof of concept that you can potentially target HBV using two different pathways, and we’ll be interested to see more data with this approach,” said Dr. Feld.

Dr. Feld wrapped up the discussion of novel therapies with an animal model study (Abstract 77) that suggests future strategies for a cure. In it, the researchers combined a therapeutic vaccine with a stabilized, liver-targeted small interfering RNA to suppress surface antigen. Animals that received only the vaccine saw little benefit, but the combined approach led to viral clearance. The treatment also restored the immune response. “It gives us an inkling that we may need to both reduce the antigen load and stimulate immunity,” said Dr. Feld.

Dr. Feld has consulted for AbbVie, Gilead, ContraVir, MedImmune, and Merck. He has received funding from AbbVie, Gilead, Merck, and Janssen.

Routine clinical and laboratory markers predicted histologic response to obeticholic acid therapy among patients with nonalcoholic steatohepatitis (NASH), investigators reported in Gastroenterology.

In a secondary analysis of data from the FLINT trial, histologic response at treatment week 24 correlated significantly with baseline nonalcoholic fatty liver disease activity score (NAS) greater than 5, baseline triglycerides 154 mg/dL or less, baseline international normalized ratio no greater than 1, baseline aspartate aminotransferase (AST) level no greater than 49 U/L, and at least a 17-U/L decrease from baseline in alanine aminotransferase (ALT) level.

A stepwise logistic regression model including these variables and receipt of obeticholic acid distinguished histologic responders from nonresponders with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% confidence interval, 0.77-0.89; P less than .0001). These parameters “are readily available clinical and biochemical characteristics that are routinely available to clinicians and may be applied to daily practice,” wrote Rohit Loomba, MD, of the University of California, San Diego, with his associates. They may show “that the patients most likely to achieve histologic response are those with higher disease activity, but still with largely conserved liver function, allowing for potential healing or improvement.”

NASH is expected to become the leading reason for liver transplantation in the next few decades. Several treatments can induce histologic hepatic improvement, but none are approved for NASH. Obeticholic acid (Ocaliva) is a selective agonist of the farsenoid X receptor ligand and is indicated for treating primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA).

In the 72-week, multicenter, randomized, double-blind FLINT trial, noncirrhotic adults with biopsy-confirmed NASH received once-daily obeticholic acid (25 mg) or placebo. Blinded pathologists interpreted biopsies. The primary endpoint (improvement in liver histology) was met in the interim analysis, so the researchers stopped collecting final liver biopsies.

The secondary analysis included all patients with baseline and final biopsies, including 73 histologic responders and 127 nonresponders. “[The] trends for each of the selected predictors was the same when comparing histologic responders to nonresponders, regardless of treatment group (obeticholic acid versus placebo),” the researchers wrote. The predictors are biologically feasible, the researchers contended – for example, high baseline NAS would be more susceptible to significant improvement, while lower baseline triglyceride levels might reflect a liver that “is less burdened by triglyceride secretion” and, therefore, might have greater capacity to heal. Both AST and ALT “are metrics of liver injury,” and lower baseline AST, in combination with greater reduction in ALT at week 24, probably reflected “AST and ALT levels that are closer to normal,” they added.

Nonetheless, the researchers acknowledged several possible sources of bias. Trial participants were recruited from tertiary care settings and had complete biopsy data, which might not reflect the overall NASH population. Overfitting also could have biased the model because the number of variables assessed approached the number of events being predicted. Furthermore, the model assessed no treatment other than obeticholic acid. “A more robust model could potentially be developed if multiple pharmacological interventions could be considered simultaneously,” the researchers noted. The ongoing phase 3 REGENERATE trial aims to confirm the benefit of obeticholic acid in patients with NASH, they added. Topline results are expected in October 2022.

The FLINT trial was funded by Intercept Pharmaceuticals and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Loomba cochaired the FLINT trial protocol writing committee, is on the steering committee of the ongoing REGENERATE trial, and has received research funding from Intercept Pharmaceuticals, which developed and markets obeticholic acid. Several other coinvestigators reported ties to Intercept and to other pharmaceutical companies.

SOURCE: Loomba R et al. Gastroenterology. 2018 Sep 14. doi: 10.1053/j.gastro.2018.09.021.

Routine clinical and laboratory markers predicted histologic response to obeticholic acid therapy among patients with nonalcoholic steatohepatitis (NASH), investigators reported in Gastroenterology.

In a secondary analysis of data from the FLINT trial, histologic response at treatment week 24 correlated significantly with baseline nonalcoholic fatty liver disease activity score (NAS) greater than 5, baseline triglycerides 154 mg/dL or less, baseline international normalized ratio no greater than 1, baseline aspartate aminotransferase (AST) level no greater than 49 U/L, and at least a 17-U/L decrease from baseline in alanine aminotransferase (ALT) level.

A stepwise logistic regression model including these variables and receipt of obeticholic acid distinguished histologic responders from nonresponders with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% confidence interval, 0.77-0.89; P less than .0001). These parameters “are readily available clinical and biochemical characteristics that are routinely available to clinicians and may be applied to daily practice,” wrote Rohit Loomba, MD, of the University of California, San Diego, with his associates. They may show “that the patients most likely to achieve histologic response are those with higher disease activity, but still with largely conserved liver function, allowing for potential healing or improvement.”

NASH is expected to become the leading reason for liver transplantation in the next few decades. Several treatments can induce histologic hepatic improvement, but none are approved for NASH. Obeticholic acid (Ocaliva) is a selective agonist of the farsenoid X receptor ligand and is indicated for treating primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA).

In the 72-week, multicenter, randomized, double-blind FLINT trial, noncirrhotic adults with biopsy-confirmed NASH received once-daily obeticholic acid (25 mg) or placebo. Blinded pathologists interpreted biopsies. The primary endpoint (improvement in liver histology) was met in the interim analysis, so the researchers stopped collecting final liver biopsies.

The secondary analysis included all patients with baseline and final biopsies, including 73 histologic responders and 127 nonresponders. “[The] trends for each of the selected predictors was the same when comparing histologic responders to nonresponders, regardless of treatment group (obeticholic acid versus placebo),” the researchers wrote. The predictors are biologically feasible, the researchers contended – for example, high baseline NAS would be more susceptible to significant improvement, while lower baseline triglyceride levels might reflect a liver that “is less burdened by triglyceride secretion” and, therefore, might have greater capacity to heal. Both AST and ALT “are metrics of liver injury,” and lower baseline AST, in combination with greater reduction in ALT at week 24, probably reflected “AST and ALT levels that are closer to normal,” they added.

Nonetheless, the researchers acknowledged several possible sources of bias. Trial participants were recruited from tertiary care settings and had complete biopsy data, which might not reflect the overall NASH population. Overfitting also could have biased the model because the number of variables assessed approached the number of events being predicted. Furthermore, the model assessed no treatment other than obeticholic acid. “A more robust model could potentially be developed if multiple pharmacological interventions could be considered simultaneously,” the researchers noted. The ongoing phase 3 REGENERATE trial aims to confirm the benefit of obeticholic acid in patients with NASH, they added. Topline results are expected in October 2022.

The FLINT trial was funded by Intercept Pharmaceuticals and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Loomba cochaired the FLINT trial protocol writing committee, is on the steering committee of the ongoing REGENERATE trial, and has received research funding from Intercept Pharmaceuticals, which developed and markets obeticholic acid. Several other coinvestigators reported ties to Intercept and to other pharmaceutical companies.

SOURCE: Loomba R et al. Gastroenterology. 2018 Sep 14. doi: 10.1053/j.gastro.2018.09.021.

Routine clinical and laboratory markers predicted histologic response to obeticholic acid therapy among patients with nonalcoholic steatohepatitis (NASH), investigators reported in Gastroenterology.

In a secondary analysis of data from the FLINT trial, histologic response at treatment week 24 correlated significantly with baseline nonalcoholic fatty liver disease activity score (NAS) greater than 5, baseline triglycerides 154 mg/dL or less, baseline international normalized ratio no greater than 1, baseline aspartate aminotransferase (AST) level no greater than 49 U/L, and at least a 17-U/L decrease from baseline in alanine aminotransferase (ALT) level.

A stepwise logistic regression model including these variables and receipt of obeticholic acid distinguished histologic responders from nonresponders with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% confidence interval, 0.77-0.89; P less than .0001). These parameters “are readily available clinical and biochemical characteristics that are routinely available to clinicians and may be applied to daily practice,” wrote Rohit Loomba, MD, of the University of California, San Diego, with his associates. They may show “that the patients most likely to achieve histologic response are those with higher disease activity, but still with largely conserved liver function, allowing for potential healing or improvement.”

NASH is expected to become the leading reason for liver transplantation in the next few decades. Several treatments can induce histologic hepatic improvement, but none are approved for NASH. Obeticholic acid (Ocaliva) is a selective agonist of the farsenoid X receptor ligand and is indicated for treating primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA).

In the 72-week, multicenter, randomized, double-blind FLINT trial, noncirrhotic adults with biopsy-confirmed NASH received once-daily obeticholic acid (25 mg) or placebo. Blinded pathologists interpreted biopsies. The primary endpoint (improvement in liver histology) was met in the interim analysis, so the researchers stopped collecting final liver biopsies.

The secondary analysis included all patients with baseline and final biopsies, including 73 histologic responders and 127 nonresponders. “[The] trends for each of the selected predictors was the same when comparing histologic responders to nonresponders, regardless of treatment group (obeticholic acid versus placebo),” the researchers wrote. The predictors are biologically feasible, the researchers contended – for example, high baseline NAS would be more susceptible to significant improvement, while lower baseline triglyceride levels might reflect a liver that “is less burdened by triglyceride secretion” and, therefore, might have greater capacity to heal. Both AST and ALT “are metrics of liver injury,” and lower baseline AST, in combination with greater reduction in ALT at week 24, probably reflected “AST and ALT levels that are closer to normal,” they added.

Nonetheless, the researchers acknowledged several possible sources of bias. Trial participants were recruited from tertiary care settings and had complete biopsy data, which might not reflect the overall NASH population. Overfitting also could have biased the model because the number of variables assessed approached the number of events being predicted. Furthermore, the model assessed no treatment other than obeticholic acid. “A more robust model could potentially be developed if multiple pharmacological interventions could be considered simultaneously,” the researchers noted. The ongoing phase 3 REGENERATE trial aims to confirm the benefit of obeticholic acid in patients with NASH, they added. Topline results are expected in October 2022.

The FLINT trial was funded by Intercept Pharmaceuticals and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Loomba cochaired the FLINT trial protocol writing committee, is on the steering committee of the ongoing REGENERATE trial, and has received research funding from Intercept Pharmaceuticals, which developed and markets obeticholic acid. Several other coinvestigators reported ties to Intercept and to other pharmaceutical companies.

SOURCE: Loomba R et al. Gastroenterology. 2018 Sep 14. doi: 10.1053/j.gastro.2018.09.021.

SAN FRANCISCO – A new analysis shows that hepatitis C–infected livers can be safely transplanted into recipients with no effect on graft survival, retransplantation, or mortality. The work confirms that readily available direct-acting antiviral therapy can protect organ recipients and open a source of organs that is typically overlooked.

Jim Kling/MDedge News

The work should encourage both physicians and patients to take a closer look at hepatitis C–infected organs, especially for sicker patients, according to Sonali Paul, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Disease 2018.

“A lot of people have an ethical issue with it because we’re actively transplanting a virus into someone. We’re giving someone a disease. My take on it is that we give people Epstein Barr virus or cytomegalovirus all the time – we just [provide] prophylaxis against it, and we don’t even bat an eye. Hepatitis C can be devastating, but we have totally effective treatments for it,” said Dr. Paul, who is an assistant professor of medicine at the University of Chicago.

She cited one colleague at the University of Chicago who several years ago transplanted an organ that had been passed over 700 times, though times have changed since then. “I think people more and more are doing this practice because we know it’s so successful,” said Dr. Paul.

It’s also cost effective. Another study, presented during the same session by Jag Chhatwal, PhD, assistant professor at Harvard Medical School, Boston, showed that accepting a hepatitis C–positive liver is cost effective in patients with Model for End-Stage Liver Disease (MELD) scores ranging from 22 to 40.

“I think we’re going to find across all organ systems, if we can transplant patients rather than keep them on dialysis or keep them on wait lists, it’s got to be cost effective, especially if you think of the health care–associated costs – like a heart transplant patient waiting on the list in the ICU. That’s a huge health care cost,” said Dr. Paul.

Dr. Paul’s team performed an analysis of the Scientific Registry of Transplant Recipients, including single organ transplants from deceased donors, during 2014-2018. Over that period, the number of transplants from hepatitis C–positive donors to hepatitis C–positive recipients rose from 8 in 2014 to 269, and the number of transplants from hepatitis C–positive donors to hepatitis C–negative recipients rose from 0 to 46.

The researchers compared trends from hepatitis C–negative donors with hepatitis C–negative recipients (n = 11,270), negative donors with positive recipients (n = 4,748), positive donors with negative recipients (n = 87), and positive donors with positive recipients (n = 753). Donor status had no effect on graft survival times at 1 or 2 years, with values ranging from 92.6% (negative to negative) to 94.3% (positive to positive) at 1 year and between 85.7% (positive to negative) and 89.7% (positive to positive) at 2 years.

“For someone who has a MELD score of over 20, who has a declining quality of life and really can’t do anything, I think this is a great opportunity. And most patients are absolutely willing to take these organs. We haven’t had many people say no, especially if they feel poorly,” said Dr. Paul.

She also underscored the importance of ensuring that the patient is informed of the status of the donor liver and the need to complete treatment: “The patient has to know what’s happening, and the hospital has to have a safety net if the insurance doesn’t pay for hepatitis C treatment.”
 

SOURCE: AASLD 2018, Abstract 0249.

SAN FRANCISCO – A new analysis shows that hepatitis C–infected livers can be safely transplanted into recipients with no effect on graft survival, retransplantation, or mortality. The work confirms that readily available direct-acting antiviral therapy can protect organ recipients and open a source of organs that is typically overlooked.

Jim Kling/MDedge News

The work should encourage both physicians and patients to take a closer look at hepatitis C–infected organs, especially for sicker patients, according to Sonali Paul, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Disease 2018.

“A lot of people have an ethical issue with it because we’re actively transplanting a virus into someone. We’re giving someone a disease. My take on it is that we give people Epstein Barr virus or cytomegalovirus all the time – we just [provide] prophylaxis against it, and we don’t even bat an eye. Hepatitis C can be devastating, but we have totally effective treatments for it,” said Dr. Paul, who is an assistant professor of medicine at the University of Chicago.

She cited one colleague at the University of Chicago who several years ago transplanted an organ that had been passed over 700 times, though times have changed since then. “I think people more and more are doing this practice because we know it’s so successful,” said Dr. Paul.

It’s also cost effective. Another study, presented during the same session by Jag Chhatwal, PhD, assistant professor at Harvard Medical School, Boston, showed that accepting a hepatitis C–positive liver is cost effective in patients with Model for End-Stage Liver Disease (MELD) scores ranging from 22 to 40.

“I think we’re going to find across all organ systems, if we can transplant patients rather than keep them on dialysis or keep them on wait lists, it’s got to be cost effective, especially if you think of the health care–associated costs – like a heart transplant patient waiting on the list in the ICU. That’s a huge health care cost,” said Dr. Paul.

Dr. Paul’s team performed an analysis of the Scientific Registry of Transplant Recipients, including single organ transplants from deceased donors, during 2014-2018. Over that period, the number of transplants from hepatitis C–positive donors to hepatitis C–positive recipients rose from 8 in 2014 to 269, and the number of transplants from hepatitis C–positive donors to hepatitis C–negative recipients rose from 0 to 46.

The researchers compared trends from hepatitis C–negative donors with hepatitis C–negative recipients (n = 11,270), negative donors with positive recipients (n = 4,748), positive donors with negative recipients (n = 87), and positive donors with positive recipients (n = 753). Donor status had no effect on graft survival times at 1 or 2 years, with values ranging from 92.6% (negative to negative) to 94.3% (positive to positive) at 1 year and between 85.7% (positive to negative) and 89.7% (positive to positive) at 2 years.

“For someone who has a MELD score of over 20, who has a declining quality of life and really can’t do anything, I think this is a great opportunity. And most patients are absolutely willing to take these organs. We haven’t had many people say no, especially if they feel poorly,” said Dr. Paul.

She also underscored the importance of ensuring that the patient is informed of the status of the donor liver and the need to complete treatment: “The patient has to know what’s happening, and the hospital has to have a safety net if the insurance doesn’t pay for hepatitis C treatment.”
 

SOURCE: AASLD 2018, Abstract 0249.

SAN FRANCISCO – A new analysis shows that hepatitis C–infected livers can be safely transplanted into recipients with no effect on graft survival, retransplantation, or mortality. The work confirms that readily available direct-acting antiviral therapy can protect organ recipients and open a source of organs that is typically overlooked.

Jim Kling/MDedge News

The work should encourage both physicians and patients to take a closer look at hepatitis C–infected organs, especially for sicker patients, according to Sonali Paul, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Disease 2018.

“A lot of people have an ethical issue with it because we’re actively transplanting a virus into someone. We’re giving someone a disease. My take on it is that we give people Epstein Barr virus or cytomegalovirus all the time – we just [provide] prophylaxis against it, and we don’t even bat an eye. Hepatitis C can be devastating, but we have totally effective treatments for it,” said Dr. Paul, who is an assistant professor of medicine at the University of Chicago.

She cited one colleague at the University of Chicago who several years ago transplanted an organ that had been passed over 700 times, though times have changed since then. “I think people more and more are doing this practice because we know it’s so successful,” said Dr. Paul.

It’s also cost effective. Another study, presented during the same session by Jag Chhatwal, PhD, assistant professor at Harvard Medical School, Boston, showed that accepting a hepatitis C–positive liver is cost effective in patients with Model for End-Stage Liver Disease (MELD) scores ranging from 22 to 40.

“I think we’re going to find across all organ systems, if we can transplant patients rather than keep them on dialysis or keep them on wait lists, it’s got to be cost effective, especially if you think of the health care–associated costs – like a heart transplant patient waiting on the list in the ICU. That’s a huge health care cost,” said Dr. Paul.

Dr. Paul’s team performed an analysis of the Scientific Registry of Transplant Recipients, including single organ transplants from deceased donors, during 2014-2018. Over that period, the number of transplants from hepatitis C–positive donors to hepatitis C–positive recipients rose from 8 in 2014 to 269, and the number of transplants from hepatitis C–positive donors to hepatitis C–negative recipients rose from 0 to 46.

The researchers compared trends from hepatitis C–negative donors with hepatitis C–negative recipients (n = 11,270), negative donors with positive recipients (n = 4,748), positive donors with negative recipients (n = 87), and positive donors with positive recipients (n = 753). Donor status had no effect on graft survival times at 1 or 2 years, with values ranging from 92.6% (negative to negative) to 94.3% (positive to positive) at 1 year and between 85.7% (positive to negative) and 89.7% (positive to positive) at 2 years.

“For someone who has a MELD score of over 20, who has a declining quality of life and really can’t do anything, I think this is a great opportunity. And most patients are absolutely willing to take these organs. We haven’t had many people say no, especially if they feel poorly,” said Dr. Paul.

She also underscored the importance of ensuring that the patient is informed of the status of the donor liver and the need to complete treatment: “The patient has to know what’s happening, and the hospital has to have a safety net if the insurance doesn’t pay for hepatitis C treatment.”
 

SOURCE: AASLD 2018, Abstract 0249.

SAN FRANCISCO – The risk of malignancy among patients with nonalcoholic fatty liver disease (NAFLD) is 91% higher than it is among age- and sex-matched control subjects, with gastrointestinal sites being the most commonly affected.

Doug Brunk/MDedge News

Those are key findings from a community cohort study with up to 21 years of follow-up, which one of the authors, Alina M. Allen, MD, discussed during a press briefing at the annual meeting of the American Association for the Study of Liver Diseases.

“NAFLD is the most common chronic liver disease in the Western world,” said Dr. Allen, a gastroenterologist at the Mayo Clinic, Rochester, Minn. “It affects one in four adults in the U.S. It is related to fat accumulation in the liver in people who are overweight or obese and can lead to cirrhosis and liver-related mortality. However, the most common cause of death in this population is not liver disease but malignancy and cardiovascular disease. There is a paucity of epidemiologic studies of extrahepatic cancer in NAFLD. It is not clear what types of cancers and how much higher their cancer risk is in reference to the general population.”

In an effort to determine the incidence of cancer diagnoses in NALFD, compared with controls, in a U.S. community, Dr. Allen and her colleagues drew from the Rochester Epidemiology Project to evaluate 4,791 adults diagnosed with NAFLD and 14,432 age- and sex-matched control subjects in Olmstead County, Minn., during 1997-2017. The researchers obtained corresponding Surveillance, Epidemiology, and End Results Program (SEER) rates as a quality check and used a regression model to assess the malignancy risk in NAFLD overall and by cancer type, age, sex, and body mass index. They recorded all new diagnoses of cancers that developed in both groups until 2018, for a total possible follow-up of 21 years, and they reported results in incidence rate ratios, a risk estimate similar to hazard ratios.


The mean age of the study population was 53 years, 53% were female, and the mean follow-up was 8 years with a range from 1 to 21 years. New cancers were identified in 16% of subjects with NALFD and in 12% of control subjects. The overall risk of malignancy was 91% higher in NAFLD subjects, compared with control subjects; there were higher rates in the NAFLD subjects for most types of cancers, but the largest increases were in GI cancers. The greatest malignancy risk was for cancer of the liver (RR, 3.24), followed by cancer of the uterus (RR, 2.39), stomach (RR, 2.34), pancreas (RR, 2.09), and colon (RR, 1.75). “Interestingly, the risk of colon cancer increased only in men but not in women,” Dr. Allen said. “These data provide an important hierarchical overview of the top most important malignancy risks associated with NAFLD that the medical community should be aware of.”

When the researchers looked for differences in age at cancer diagnosis between NAFLD and controls, they found that pancreas cancer occurred at a younger age among subjects with NAFLD. They also observed that colon cancer occurred at a younger age in men with NAFLD, but not in women with the disease. “What was most interesting to us was the assessment of cancer risk in NAFLD versus obesity alone,” Dr. Allen said. “Previous studies from the general population have linked obesity to a higher risk of cancer. Whether the presence of fatty liver disease would impact that risk has not been assessed. We showed that obesity is associated with a higher risk of cancer only in those with NAFLD, not in those without. If validated in independent cohorts, these findings could change our understanding of the relationship between obesity and cancer and the importance of screening for NAFLD – not only to risk-stratify liver disease but also for the risk of extrahepatic malignancy.”

Dr. Allen concluded her presentation by noting that findings from large population-based studies such as the Rochester Epidemiology Project “can offer important epidemiologic data regarding the biggest threats to the health of a community,” she said. “Such data increase awareness, enable appropriate counseling, and could inform screening policies. There is a signal in the fact that the GI cancers are increased [in NAFLD]. It’s an interesting signal that needs to be studied further.”

Dr. Allen reported having no financial conflicts.

dbrunk@mdedge.com

Source: Allen AM. Hepatol. 2018;68[S1]: Abstract 31.

SAN FRANCISCO – The risk of malignancy among patients with nonalcoholic fatty liver disease (NAFLD) is 91% higher than it is among age- and sex-matched control subjects, with gastrointestinal sites being the most commonly affected.

Doug Brunk/MDedge News

Those are key findings from a community cohort study with up to 21 years of follow-up, which one of the authors, Alina M. Allen, MD, discussed during a press briefing at the annual meeting of the American Association for the Study of Liver Diseases.

“NAFLD is the most common chronic liver disease in the Western world,” said Dr. Allen, a gastroenterologist at the Mayo Clinic, Rochester, Minn. “It affects one in four adults in the U.S. It is related to fat accumulation in the liver in people who are overweight or obese and can lead to cirrhosis and liver-related mortality. However, the most common cause of death in this population is not liver disease but malignancy and cardiovascular disease. There is a paucity of epidemiologic studies of extrahepatic cancer in NAFLD. It is not clear what types of cancers and how much higher their cancer risk is in reference to the general population.”

In an effort to determine the incidence of cancer diagnoses in NALFD, compared with controls, in a U.S. community, Dr. Allen and her colleagues drew from the Rochester Epidemiology Project to evaluate 4,791 adults diagnosed with NAFLD and 14,432 age- and sex-matched control subjects in Olmstead County, Minn., during 1997-2017. The researchers obtained corresponding Surveillance, Epidemiology, and End Results Program (SEER) rates as a quality check and used a regression model to assess the malignancy risk in NAFLD overall and by cancer type, age, sex, and body mass index. They recorded all new diagnoses of cancers that developed in both groups until 2018, for a total possible follow-up of 21 years, and they reported results in incidence rate ratios, a risk estimate similar to hazard ratios.


The mean age of the study population was 53 years, 53% were female, and the mean follow-up was 8 years with a range from 1 to 21 years. New cancers were identified in 16% of subjects with NALFD and in 12% of control subjects. The overall risk of malignancy was 91% higher in NAFLD subjects, compared with control subjects; there were higher rates in the NAFLD subjects for most types of cancers, but the largest increases were in GI cancers. The greatest malignancy risk was for cancer of the liver (RR, 3.24), followed by cancer of the uterus (RR, 2.39), stomach (RR, 2.34), pancreas (RR, 2.09), and colon (RR, 1.75). “Interestingly, the risk of colon cancer increased only in men but not in women,” Dr. Allen said. “These data provide an important hierarchical overview of the top most important malignancy risks associated with NAFLD that the medical community should be aware of.”

When the researchers looked for differences in age at cancer diagnosis between NAFLD and controls, they found that pancreas cancer occurred at a younger age among subjects with NAFLD. They also observed that colon cancer occurred at a younger age in men with NAFLD, but not in women with the disease. “What was most interesting to us was the assessment of cancer risk in NAFLD versus obesity alone,” Dr. Allen said. “Previous studies from the general population have linked obesity to a higher risk of cancer. Whether the presence of fatty liver disease would impact that risk has not been assessed. We showed that obesity is associated with a higher risk of cancer only in those with NAFLD, not in those without. If validated in independent cohorts, these findings could change our understanding of the relationship between obesity and cancer and the importance of screening for NAFLD – not only to risk-stratify liver disease but also for the risk of extrahepatic malignancy.”

Dr. Allen concluded her presentation by noting that findings from large population-based studies such as the Rochester Epidemiology Project “can offer important epidemiologic data regarding the biggest threats to the health of a community,” she said. “Such data increase awareness, enable appropriate counseling, and could inform screening policies. There is a signal in the fact that the GI cancers are increased [in NAFLD]. It’s an interesting signal that needs to be studied further.”

Dr. Allen reported having no financial conflicts.

dbrunk@mdedge.com

Source: Allen AM. Hepatol. 2018;68[S1]: Abstract 31.

SAN FRANCISCO – The risk of malignancy among patients with nonalcoholic fatty liver disease (NAFLD) is 91% higher than it is among age- and sex-matched control subjects, with gastrointestinal sites being the most commonly affected.

Doug Brunk/MDedge News

Those are key findings from a community cohort study with up to 21 years of follow-up, which one of the authors, Alina M. Allen, MD, discussed during a press briefing at the annual meeting of the American Association for the Study of Liver Diseases.

“NAFLD is the most common chronic liver disease in the Western world,” said Dr. Allen, a gastroenterologist at the Mayo Clinic, Rochester, Minn. “It affects one in four adults in the U.S. It is related to fat accumulation in the liver in people who are overweight or obese and can lead to cirrhosis and liver-related mortality. However, the most common cause of death in this population is not liver disease but malignancy and cardiovascular disease. There is a paucity of epidemiologic studies of extrahepatic cancer in NAFLD. It is not clear what types of cancers and how much higher their cancer risk is in reference to the general population.”

In an effort to determine the incidence of cancer diagnoses in NALFD, compared with controls, in a U.S. community, Dr. Allen and her colleagues drew from the Rochester Epidemiology Project to evaluate 4,791 adults diagnosed with NAFLD and 14,432 age- and sex-matched control subjects in Olmstead County, Minn., during 1997-2017. The researchers obtained corresponding Surveillance, Epidemiology, and End Results Program (SEER) rates as a quality check and used a regression model to assess the malignancy risk in NAFLD overall and by cancer type, age, sex, and body mass index. They recorded all new diagnoses of cancers that developed in both groups until 2018, for a total possible follow-up of 21 years, and they reported results in incidence rate ratios, a risk estimate similar to hazard ratios.


The mean age of the study population was 53 years, 53% were female, and the mean follow-up was 8 years with a range from 1 to 21 years. New cancers were identified in 16% of subjects with NALFD and in 12% of control subjects. The overall risk of malignancy was 91% higher in NAFLD subjects, compared with control subjects; there were higher rates in the NAFLD subjects for most types of cancers, but the largest increases were in GI cancers. The greatest malignancy risk was for cancer of the liver (RR, 3.24), followed by cancer of the uterus (RR, 2.39), stomach (RR, 2.34), pancreas (RR, 2.09), and colon (RR, 1.75). “Interestingly, the risk of colon cancer increased only in men but not in women,” Dr. Allen said. “These data provide an important hierarchical overview of the top most important malignancy risks associated with NAFLD that the medical community should be aware of.”

When the researchers looked for differences in age at cancer diagnosis between NAFLD and controls, they found that pancreas cancer occurred at a younger age among subjects with NAFLD. They also observed that colon cancer occurred at a younger age in men with NAFLD, but not in women with the disease. “What was most interesting to us was the assessment of cancer risk in NAFLD versus obesity alone,” Dr. Allen said. “Previous studies from the general population have linked obesity to a higher risk of cancer. Whether the presence of fatty liver disease would impact that risk has not been assessed. We showed that obesity is associated with a higher risk of cancer only in those with NAFLD, not in those without. If validated in independent cohorts, these findings could change our understanding of the relationship between obesity and cancer and the importance of screening for NAFLD – not only to risk-stratify liver disease but also for the risk of extrahepatic malignancy.”

Dr. Allen concluded her presentation by noting that findings from large population-based studies such as the Rochester Epidemiology Project “can offer important epidemiologic data regarding the biggest threats to the health of a community,” she said. “Such data increase awareness, enable appropriate counseling, and could inform screening policies. There is a signal in the fact that the GI cancers are increased [in NAFLD]. It’s an interesting signal that needs to be studied further.”

Dr. Allen reported having no financial conflicts.

dbrunk@mdedge.com

Source: Allen AM. Hepatol. 2018;68[S1]: Abstract 31.

SAN FRANCISCO – Chronic liver disease (CLD) is independently associated with an increased risk of falls and fall injuries, results from a large study of nationally representative data showed.

Doug Brunk/MDedge News

“We have previously known that having cirrhosis, for example, is associated with the risk of falling, but we didn’t have any data from a nationally representative sample,” lead study author Maria Camila Pérez-Matos, MD, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “What surprised us is that just by having chronic liver disease – any subtype – you’re more likely to fall, and also to have a fracture after you have fallen.”

In an effort to define the association between CLD and fall history and its related injuries, Dr. Pérez-Matos of the division of gastroenterology and hepatology at Beth Israel Deaconess Medical Center, Boston, and her associates examined data from 5,363 subjects aged 60 years and older in the Third National Health and Nutrition Examination Survey, which represents the noninstitutionalized civilian population in the United States. Their outcomes of interest were one or more falls occurring in the previous 12 months and fall-related injuries. The main exposure was definitive CLD, defined by chronic viral hepatitis (hepatitis C RNA or hepatitis B surface antigen), nonalcoholic steatohepatitis (NASH; hepatosteatosis by ultrasound with abnormal transaminases), and alcohol-related liver disease (females consuming more than 7 drinks/week and males consuming 14 drinks/week among, plus having abnormal transaminases). Suspected CLD was defined as having abnormal alanine aminotransferase levels (males greater than 30 IU/L, females greater than 19 IU/L), aspartate aminotransferase levels above 33 IU/L, or alkaline phosphatase levels above 100 IU/L. The researchers used univariate and multivariate logistic regression to examine associations.

The average age of subjects was 70 years, and 59% were female. Of the 5,363 subjects, 340 had definitive CLD. Of these, 234 (69%) had NASH, 85 (25%) had viral hepatitis, and 21 (6%) had alcoholic liver disease. Subjects with definitive CLD were more likely to be female and have diabetes mellitus, a higher body mass index, and physical/functional impairment. Dr. Pérez-Matos and her colleagues found that definitive CLD was associated with a 52% increase in the odds of having a history of falls (odds ratio, 1.52; P = .01). The association remained significant after controlling for age, sex, smoking, race, physical or functional impairment, impaired vision, polypharmacy, and body mass index. The degree of excess falling risk posed by CLD was similar to that of having impaired vision (OR, 1.48; P less than .001).

Of the CLD subtypes, subjects with viral hepatitis had the strongest association with a history of falls (OR, 2.2; P = .001). In addition, definitive CLD was found to have significant association with any physical impairment, even after adjusting for relevant covariates (OR, 1.63; P = .001).

Finally, multivariate logistic regression revealed that both suspected and definitive CLD were associated with injurious falls (OR, 1.40 and OR of 1.67, respectively). “Everyone is interested in preventing falls because of its public health impact, and predictors of falls are relatively limited,” said Elliott B. Tapper, MD, the study’s principal investigator, who is with the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor. “Because chronic liver disease is increasingly common, our data is speaking to a hitherto unknown risk factor: one which if you apply it to other data sets might help figure out why more people are falling. The lesson is, there’s something about chronic liver disease; it’s a sign. If it’s fatty liver disease, it’s a sign that diabetes has taken its toll on the body – its nerves and muscles. There’s something about what’s going on in that person that’s worse than it is for other people. We don’t know cause or effect, but the association is strong and deserves further study, particularly when it comes to determining [which patients] in our clinics are at higher risk and making sure they’re doing physical therapy to prevent falls in the future.”

Dr. Tapper disclosed that she has a career development award from the National Institutes of Health. Dr. Pérez-Matos reported having no monetary conflicts.

dbrunk@mdedge.com

Source: Hepatol. 2018;68[S1], Abstract 756.

SAN FRANCISCO – Chronic liver disease (CLD) is independently associated with an increased risk of falls and fall injuries, results from a large study of nationally representative data showed.

Doug Brunk/MDedge News

“We have previously known that having cirrhosis, for example, is associated with the risk of falling, but we didn’t have any data from a nationally representative sample,” lead study author Maria Camila Pérez-Matos, MD, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “What surprised us is that just by having chronic liver disease – any subtype – you’re more likely to fall, and also to have a fracture after you have fallen.”

In an effort to define the association between CLD and fall history and its related injuries, Dr. Pérez-Matos of the division of gastroenterology and hepatology at Beth Israel Deaconess Medical Center, Boston, and her associates examined data from 5,363 subjects aged 60 years and older in the Third National Health and Nutrition Examination Survey, which represents the noninstitutionalized civilian population in the United States. Their outcomes of interest were one or more falls occurring in the previous 12 months and fall-related injuries. The main exposure was definitive CLD, defined by chronic viral hepatitis (hepatitis C RNA or hepatitis B surface antigen), nonalcoholic steatohepatitis (NASH; hepatosteatosis by ultrasound with abnormal transaminases), and alcohol-related liver disease (females consuming more than 7 drinks/week and males consuming 14 drinks/week among, plus having abnormal transaminases). Suspected CLD was defined as having abnormal alanine aminotransferase levels (males greater than 30 IU/L, females greater than 19 IU/L), aspartate aminotransferase levels above 33 IU/L, or alkaline phosphatase levels above 100 IU/L. The researchers used univariate and multivariate logistic regression to examine associations.

The average age of subjects was 70 years, and 59% were female. Of the 5,363 subjects, 340 had definitive CLD. Of these, 234 (69%) had NASH, 85 (25%) had viral hepatitis, and 21 (6%) had alcoholic liver disease. Subjects with definitive CLD were more likely to be female and have diabetes mellitus, a higher body mass index, and physical/functional impairment. Dr. Pérez-Matos and her colleagues found that definitive CLD was associated with a 52% increase in the odds of having a history of falls (odds ratio, 1.52; P = .01). The association remained significant after controlling for age, sex, smoking, race, physical or functional impairment, impaired vision, polypharmacy, and body mass index. The degree of excess falling risk posed by CLD was similar to that of having impaired vision (OR, 1.48; P less than .001).

Of the CLD subtypes, subjects with viral hepatitis had the strongest association with a history of falls (OR, 2.2; P = .001). In addition, definitive CLD was found to have significant association with any physical impairment, even after adjusting for relevant covariates (OR, 1.63; P = .001).

Finally, multivariate logistic regression revealed that both suspected and definitive CLD were associated with injurious falls (OR, 1.40 and OR of 1.67, respectively). “Everyone is interested in preventing falls because of its public health impact, and predictors of falls are relatively limited,” said Elliott B. Tapper, MD, the study’s principal investigator, who is with the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor. “Because chronic liver disease is increasingly common, our data is speaking to a hitherto unknown risk factor: one which if you apply it to other data sets might help figure out why more people are falling. The lesson is, there’s something about chronic liver disease; it’s a sign. If it’s fatty liver disease, it’s a sign that diabetes has taken its toll on the body – its nerves and muscles. There’s something about what’s going on in that person that’s worse than it is for other people. We don’t know cause or effect, but the association is strong and deserves further study, particularly when it comes to determining [which patients] in our clinics are at higher risk and making sure they’re doing physical therapy to prevent falls in the future.”

Dr. Tapper disclosed that she has a career development award from the National Institutes of Health. Dr. Pérez-Matos reported having no monetary conflicts.

dbrunk@mdedge.com

Source: Hepatol. 2018;68[S1], Abstract 756.

SAN FRANCISCO – Chronic liver disease (CLD) is independently associated with an increased risk of falls and fall injuries, results from a large study of nationally representative data showed.

Doug Brunk/MDedge News

“We have previously known that having cirrhosis, for example, is associated with the risk of falling, but we didn’t have any data from a nationally representative sample,” lead study author Maria Camila Pérez-Matos, MD, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “What surprised us is that just by having chronic liver disease – any subtype – you’re more likely to fall, and also to have a fracture after you have fallen.”

In an effort to define the association between CLD and fall history and its related injuries, Dr. Pérez-Matos of the division of gastroenterology and hepatology at Beth Israel Deaconess Medical Center, Boston, and her associates examined data from 5,363 subjects aged 60 years and older in the Third National Health and Nutrition Examination Survey, which represents the noninstitutionalized civilian population in the United States. Their outcomes of interest were one or more falls occurring in the previous 12 months and fall-related injuries. The main exposure was definitive CLD, defined by chronic viral hepatitis (hepatitis C RNA or hepatitis B surface antigen), nonalcoholic steatohepatitis (NASH; hepatosteatosis by ultrasound with abnormal transaminases), and alcohol-related liver disease (females consuming more than 7 drinks/week and males consuming 14 drinks/week among, plus having abnormal transaminases). Suspected CLD was defined as having abnormal alanine aminotransferase levels (males greater than 30 IU/L, females greater than 19 IU/L), aspartate aminotransferase levels above 33 IU/L, or alkaline phosphatase levels above 100 IU/L. The researchers used univariate and multivariate logistic regression to examine associations.

The average age of subjects was 70 years, and 59% were female. Of the 5,363 subjects, 340 had definitive CLD. Of these, 234 (69%) had NASH, 85 (25%) had viral hepatitis, and 21 (6%) had alcoholic liver disease. Subjects with definitive CLD were more likely to be female and have diabetes mellitus, a higher body mass index, and physical/functional impairment. Dr. Pérez-Matos and her colleagues found that definitive CLD was associated with a 52% increase in the odds of having a history of falls (odds ratio, 1.52; P = .01). The association remained significant after controlling for age, sex, smoking, race, physical or functional impairment, impaired vision, polypharmacy, and body mass index. The degree of excess falling risk posed by CLD was similar to that of having impaired vision (OR, 1.48; P less than .001).

Of the CLD subtypes, subjects with viral hepatitis had the strongest association with a history of falls (OR, 2.2; P = .001). In addition, definitive CLD was found to have significant association with any physical impairment, even after adjusting for relevant covariates (OR, 1.63; P = .001).

Finally, multivariate logistic regression revealed that both suspected and definitive CLD were associated with injurious falls (OR, 1.40 and OR of 1.67, respectively). “Everyone is interested in preventing falls because of its public health impact, and predictors of falls are relatively limited,” said Elliott B. Tapper, MD, the study’s principal investigator, who is with the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor. “Because chronic liver disease is increasingly common, our data is speaking to a hitherto unknown risk factor: one which if you apply it to other data sets might help figure out why more people are falling. The lesson is, there’s something about chronic liver disease; it’s a sign. If it’s fatty liver disease, it’s a sign that diabetes has taken its toll on the body – its nerves and muscles. There’s something about what’s going on in that person that’s worse than it is for other people. We don’t know cause or effect, but the association is strong and deserves further study, particularly when it comes to determining [which patients] in our clinics are at higher risk and making sure they’re doing physical therapy to prevent falls in the future.”

Dr. Tapper disclosed that she has a career development award from the National Institutes of Health. Dr. Pérez-Matos reported having no monetary conflicts.

dbrunk@mdedge.com

Source: Hepatol. 2018;68[S1], Abstract 756.

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with hepatocellular carcinoma who were previously treated with sorafenib.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Approval was based on results of KEYNOTE-224, a single-arm, open-label, multicenter trial evaluating pembrolizumab in a group of 104 patients with hepatocellular carcinoma who were either intolerant to or had disease progression with sorafenib, according to a company press release.

The objective response rate was 17%, with a complete response rate of 1% and a partial response rate of 16%. In responding patients, 89% had a response duration of at least 6 months, and 56% had a response duration of at least 12 months.

Adverse events were generally similar to those seen in trials of patients with melanoma or non–small cell lung cancer, and included pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and allogeneic hematopoietic stem cell transplantation complications.

“Hepatocellular carcinoma is the most common type of liver cancer in adults, and while we have seen recent therapeutic advancements, there are still limited treatment options for advanced recurrent disease. Today’s approval of Keytruda is important, as it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib,” Andrew X. Zhu, MD, lead investigator and director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, said in the press release.

lfranki@mdedge.com

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with hepatocellular carcinoma who were previously treated with sorafenib.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Approval was based on results of KEYNOTE-224, a single-arm, open-label, multicenter trial evaluating pembrolizumab in a group of 104 patients with hepatocellular carcinoma who were either intolerant to or had disease progression with sorafenib, according to a company press release.

The objective response rate was 17%, with a complete response rate of 1% and a partial response rate of 16%. In responding patients, 89% had a response duration of at least 6 months, and 56% had a response duration of at least 12 months.

Adverse events were generally similar to those seen in trials of patients with melanoma or non–small cell lung cancer, and included pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and allogeneic hematopoietic stem cell transplantation complications.

“Hepatocellular carcinoma is the most common type of liver cancer in adults, and while we have seen recent therapeutic advancements, there are still limited treatment options for advanced recurrent disease. Today’s approval of Keytruda is important, as it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib,” Andrew X. Zhu, MD, lead investigator and director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, said in the press release.

lfranki@mdedge.com

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with hepatocellular carcinoma who were previously treated with sorafenib.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Approval was based on results of KEYNOTE-224, a single-arm, open-label, multicenter trial evaluating pembrolizumab in a group of 104 patients with hepatocellular carcinoma who were either intolerant to or had disease progression with sorafenib, according to a company press release.

The objective response rate was 17%, with a complete response rate of 1% and a partial response rate of 16%. In responding patients, 89% had a response duration of at least 6 months, and 56% had a response duration of at least 12 months.

Adverse events were generally similar to those seen in trials of patients with melanoma or non–small cell lung cancer, and included pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and allogeneic hematopoietic stem cell transplantation complications.

“Hepatocellular carcinoma is the most common type of liver cancer in adults, and while we have seen recent therapeutic advancements, there are still limited treatment options for advanced recurrent disease. Today’s approval of Keytruda is important, as it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib,” Andrew X. Zhu, MD, lead investigator and director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, said in the press release.

lfranki@mdedge.com

SAN FRANCISCO – The prevalence of PTSD among adult liver transplant recipients is about twice that of the general population and on par with other chronic diseases, results from a pilot study suggest.

Doug Brunk/MDedge News

“Serving the emotional and mental health of these patients is just as important as [improving] liver function and their immunosuppression,” study author Meg O’Meara, NP, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases.

Recent data suggests that patients who undergo significant medical events like solid organ transplantation face a risk of developing PTSD, but limited information exists regarding the psychological effects following adult liver transplantation, said Ms. O’Meara, a nurse practitioner in the division of gastroenterology and hepatology at the University of Colorado at Denver, Aurora. In an effort to determine the prevalence of and risk factors for PTSD in adult liver transplant recipients, she and her associates used the PCL-5 to screen 71 patients seen at the university’s posttransplant clinic from Dec. 1, 2017, to May 31, 2018. The PCL-5 is a validated 20-item questionnaire that corresponds to the DSM-5 symptom criteria for PTSD.

The researchers also collected clinical and demographic information including pretransplant disease severity, history of psychiatric disease, duration of transplant hospitalization, and need for rehospitalization. They used a multivariable regression model to evaluate associations between clinical and demographic variables and a positive screen for PTSD.

The median age of the 71 patients was 58 years; 61% were male. A preexisting diagnosis of depression was present in 25 patients (35%), their mean Model for End-Stage Liver Disease (MELD) score at time of transplant was 31, and their median time from transplant was 1,163 days. In all, nine patients (12.7%) tested positive for PTSD on the PCL-5, and all met criteria for a provisional diagnosis of PTSD based on the DSM-5 criteria. This prevalence is about two times higher than the prevalence of PTSD in the general population (6.7%), comparable with that reported for heart transplant recipients (10.8%) and coronary artery disease (9%), but lower than that reported for ICU patients (38%), HIV patients (35.3%), and in those with Crohn’s disease (19.1%).

On multivariable logistic regression, only three factors were found to be significantly associated with the development of PTSD: younger age at transplant (P = .019), history of depression (P = .008), and a history of PTSD (P less than .001). “What I found surprising was that the MELD score at the time of transplant and the number of readmissions or complications around the time of transplant were not predictive of PTSD,” Ms. O’Meara said.

One possible explanation for the finding of younger age being a predictor of PTSD, she continued, is that younger liver transplant patients may lack certain coping skills, compared with their older counterparts. “Maybe patients who have had more years to deal with their disease are more accepting of it and they learn how to use productive tools to manage it.”

In their abstract, the researchers acknowledged certain limitations of the study, including its cross-sectional design, small sample size, and lack of corresponding pretransplant data.

The researchers reported having no financial disclosures.

dbrunk@mdedge.com

SAN FRANCISCO – The prevalence of PTSD among adult liver transplant recipients is about twice that of the general population and on par with other chronic diseases, results from a pilot study suggest.

Doug Brunk/MDedge News

“Serving the emotional and mental health of these patients is just as important as [improving] liver function and their immunosuppression,” study author Meg O’Meara, NP, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases.

Recent data suggests that patients who undergo significant medical events like solid organ transplantation face a risk of developing PTSD, but limited information exists regarding the psychological effects following adult liver transplantation, said Ms. O’Meara, a nurse practitioner in the division of gastroenterology and hepatology at the University of Colorado at Denver, Aurora. In an effort to determine the prevalence of and risk factors for PTSD in adult liver transplant recipients, she and her associates used the PCL-5 to screen 71 patients seen at the university’s posttransplant clinic from Dec. 1, 2017, to May 31, 2018. The PCL-5 is a validated 20-item questionnaire that corresponds to the DSM-5 symptom criteria for PTSD.

The researchers also collected clinical and demographic information including pretransplant disease severity, history of psychiatric disease, duration of transplant hospitalization, and need for rehospitalization. They used a multivariable regression model to evaluate associations between clinical and demographic variables and a positive screen for PTSD.

The median age of the 71 patients was 58 years; 61% were male. A preexisting diagnosis of depression was present in 25 patients (35%), their mean Model for End-Stage Liver Disease (MELD) score at time of transplant was 31, and their median time from transplant was 1,163 days. In all, nine patients (12.7%) tested positive for PTSD on the PCL-5, and all met criteria for a provisional diagnosis of PTSD based on the DSM-5 criteria. This prevalence is about two times higher than the prevalence of PTSD in the general population (6.7%), comparable with that reported for heart transplant recipients (10.8%) and coronary artery disease (9%), but lower than that reported for ICU patients (38%), HIV patients (35.3%), and in those with Crohn’s disease (19.1%).

On multivariable logistic regression, only three factors were found to be significantly associated with the development of PTSD: younger age at transplant (P = .019), history of depression (P = .008), and a history of PTSD (P less than .001). “What I found surprising was that the MELD score at the time of transplant and the number of readmissions or complications around the time of transplant were not predictive of PTSD,” Ms. O’Meara said.

One possible explanation for the finding of younger age being a predictor of PTSD, she continued, is that younger liver transplant patients may lack certain coping skills, compared with their older counterparts. “Maybe patients who have had more years to deal with their disease are more accepting of it and they learn how to use productive tools to manage it.”

In their abstract, the researchers acknowledged certain limitations of the study, including its cross-sectional design, small sample size, and lack of corresponding pretransplant data.

The researchers reported having no financial disclosures.

dbrunk@mdedge.com

SAN FRANCISCO – The prevalence of PTSD among adult liver transplant recipients is about twice that of the general population and on par with other chronic diseases, results from a pilot study suggest.

Doug Brunk/MDedge News

“Serving the emotional and mental health of these patients is just as important as [improving] liver function and their immunosuppression,” study author Meg O’Meara, NP, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases.

Recent data suggests that patients who undergo significant medical events like solid organ transplantation face a risk of developing PTSD, but limited information exists regarding the psychological effects following adult liver transplantation, said Ms. O’Meara, a nurse practitioner in the division of gastroenterology and hepatology at the University of Colorado at Denver, Aurora. In an effort to determine the prevalence of and risk factors for PTSD in adult liver transplant recipients, she and her associates used the PCL-5 to screen 71 patients seen at the university’s posttransplant clinic from Dec. 1, 2017, to May 31, 2018. The PCL-5 is a validated 20-item questionnaire that corresponds to the DSM-5 symptom criteria for PTSD.

The researchers also collected clinical and demographic information including pretransplant disease severity, history of psychiatric disease, duration of transplant hospitalization, and need for rehospitalization. They used a multivariable regression model to evaluate associations between clinical and demographic variables and a positive screen for PTSD.

The median age of the 71 patients was 58 years; 61% were male. A preexisting diagnosis of depression was present in 25 patients (35%), their mean Model for End-Stage Liver Disease (MELD) score at time of transplant was 31, and their median time from transplant was 1,163 days. In all, nine patients (12.7%) tested positive for PTSD on the PCL-5, and all met criteria for a provisional diagnosis of PTSD based on the DSM-5 criteria. This prevalence is about two times higher than the prevalence of PTSD in the general population (6.7%), comparable with that reported for heart transplant recipients (10.8%) and coronary artery disease (9%), but lower than that reported for ICU patients (38%), HIV patients (35.3%), and in those with Crohn’s disease (19.1%).

On multivariable logistic regression, only three factors were found to be significantly associated with the development of PTSD: younger age at transplant (P = .019), history of depression (P = .008), and a history of PTSD (P less than .001). “What I found surprising was that the MELD score at the time of transplant and the number of readmissions or complications around the time of transplant were not predictive of PTSD,” Ms. O’Meara said.

One possible explanation for the finding of younger age being a predictor of PTSD, she continued, is that younger liver transplant patients may lack certain coping skills, compared with their older counterparts. “Maybe patients who have had more years to deal with their disease are more accepting of it and they learn how to use productive tools to manage it.”

In their abstract, the researchers acknowledged certain limitations of the study, including its cross-sectional design, small sample size, and lack of corresponding pretransplant data.

The researchers reported having no financial disclosures.

dbrunk@mdedge.com

SAN FRANCISCO – A novel therapeutic strategy shows initial promise in dampening hepatic cell injury in mice caused by overexposure to acetaminophen. The approach relies on a synthetic version of heparan sulfate, which is believed to interfere with recruitment of neutrophils to the site of hepatic injury. That reduces harm caused by inflammation and may offer a longer therapeutic window than N-acetyl cysteine, which is the current standard therapy but is only effective if given within 8 hours of the injury.

The endogenous syndecan-1, which is a heparan sulfate, is also known to act as a native defense mechanism against inflammatory injury to hepatocytes. “It looks like heparan sulfate attenuates inflammatory responses,” said Jian Liu, PhD, during a presentation of his research at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Liu is a professor of chemical biology and medicinal chemistry at the University of North Carolina at Chapel Hill.

The heparan sulfate analogue heparin has long been used as an anticoagulant, of course, which suggests that a novel heparan sulfate has a good chance of also being safe.

Dr. Liu’s team had to identify a heparan sulfate that had a hepatoprotective effect, but a heparan sulfate’s unique biological activity depends on the specific pattern of sulfation on the heparan molecule. Heparans isolated from natural sources are generally a complex mixture, which makes them difficult to study and produce in large enough quantities to be therapeutically useful.

Dr. Liu’s team used a combinatory approach, harnessing various enzymes to produce hundreds of different heparan sulfate variants, and then screened them for hepatoprotective activity. That process identified an 18-chain heparan sulfate with hepatoprotective activity. With an active formula in hand, they could employ the enzymes to create enough of the pure compound to further the research. “It’s probably two to three hundred times more efficient than the traditional chemical synthesis,” said Dr. Liu.

In mice, researchers injected the 18-mer 30 minutes after a hepatotoxic dose of acetaminophen and again after 12 hours. Tissue staining showed less migration of neutrophils, as well as lower concentrations of tumor necrosis factor–alpha. The animals also had lower alanine transferase levels than did the untreated animals, as well as greater survival after 4 days.

The pathological process surrounding acetaminophen overdose involves release of the high mobility group box 1 (HMGB1) protein from necrotic hepatocytes, which in turn binds to the receptor for advanced glycation end-products (RAGE). The HMGB1/RAGE complex then binds to neutrophils, recruiting them to the site of the injury and initiating inflammation.

To better understand the molecule’s role in the pathological process, the researchers studied RAGE knockout mice, and found that the 18-mer had no protective effect in these animals, suggesting that it relies on RAGE for its biological activity.

Heparan sulfates are widely present in the body, which prompted the researchers to investigate their endogenous effect. In the liver, the primary heparan sulfate is syndecan-1. The researchers demonstrated that the molecule is shed from cell surfaces in response to acetaminophen toxicity and that the levels correlate with HMGB1 release.

Dr. Liu believes that syndecan-1 acts as a natural buffer to inflammation, helping to neutralize HMGB1 and limit damage. “The problem is that when the damage is massive, the shed of syndecan-1 is not enough,” said Dr. Liu. He hopes that something like his team’s heparan sulfate 18-mer can be used therapeutically to bolster these endogenous controls and prevent further damage.

The research was funded by Glycan Therapeutics. Dr. Liu founded Glycan, which offers custom-synthesized heparan sulfates and chondroitin sulfates for research purposes.

SOURCE: Liu J. AASLD 2018, Abstract 0040.

SAN FRANCISCO – A novel therapeutic strategy shows initial promise in dampening hepatic cell injury in mice caused by overexposure to acetaminophen. The approach relies on a synthetic version of heparan sulfate, which is believed to interfere with recruitment of neutrophils to the site of hepatic injury. That reduces harm caused by inflammation and may offer a longer therapeutic window than N-acetyl cysteine, which is the current standard therapy but is only effective if given within 8 hours of the injury.

The endogenous syndecan-1, which is a heparan sulfate, is also known to act as a native defense mechanism against inflammatory injury to hepatocytes. “It looks like heparan sulfate attenuates inflammatory responses,” said Jian Liu, PhD, during a presentation of his research at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Liu is a professor of chemical biology and medicinal chemistry at the University of North Carolina at Chapel Hill.

The heparan sulfate analogue heparin has long been used as an anticoagulant, of course, which suggests that a novel heparan sulfate has a good chance of also being safe.

Dr. Liu’s team had to identify a heparan sulfate that had a hepatoprotective effect, but a heparan sulfate’s unique biological activity depends on the specific pattern of sulfation on the heparan molecule. Heparans isolated from natural sources are generally a complex mixture, which makes them difficult to study and produce in large enough quantities to be therapeutically useful.

Dr. Liu’s team used a combinatory approach, harnessing various enzymes to produce hundreds of different heparan sulfate variants, and then screened them for hepatoprotective activity. That process identified an 18-chain heparan sulfate with hepatoprotective activity. With an active formula in hand, they could employ the enzymes to create enough of the pure compound to further the research. “It’s probably two to three hundred times more efficient than the traditional chemical synthesis,” said Dr. Liu.

In mice, researchers injected the 18-mer 30 minutes after a hepatotoxic dose of acetaminophen and again after 12 hours. Tissue staining showed less migration of neutrophils, as well as lower concentrations of tumor necrosis factor–alpha. The animals also had lower alanine transferase levels than did the untreated animals, as well as greater survival after 4 days.

The pathological process surrounding acetaminophen overdose involves release of the high mobility group box 1 (HMGB1) protein from necrotic hepatocytes, which in turn binds to the receptor for advanced glycation end-products (RAGE). The HMGB1/RAGE complex then binds to neutrophils, recruiting them to the site of the injury and initiating inflammation.

To better understand the molecule’s role in the pathological process, the researchers studied RAGE knockout mice, and found that the 18-mer had no protective effect in these animals, suggesting that it relies on RAGE for its biological activity.

Heparan sulfates are widely present in the body, which prompted the researchers to investigate their endogenous effect. In the liver, the primary heparan sulfate is syndecan-1. The researchers demonstrated that the molecule is shed from cell surfaces in response to acetaminophen toxicity and that the levels correlate with HMGB1 release.

Dr. Liu believes that syndecan-1 acts as a natural buffer to inflammation, helping to neutralize HMGB1 and limit damage. “The problem is that when the damage is massive, the shed of syndecan-1 is not enough,” said Dr. Liu. He hopes that something like his team’s heparan sulfate 18-mer can be used therapeutically to bolster these endogenous controls and prevent further damage.

The research was funded by Glycan Therapeutics. Dr. Liu founded Glycan, which offers custom-synthesized heparan sulfates and chondroitin sulfates for research purposes.

SOURCE: Liu J. AASLD 2018, Abstract 0040.

SAN FRANCISCO – A novel therapeutic strategy shows initial promise in dampening hepatic cell injury in mice caused by overexposure to acetaminophen. The approach relies on a synthetic version of heparan sulfate, which is believed to interfere with recruitment of neutrophils to the site of hepatic injury. That reduces harm caused by inflammation and may offer a longer therapeutic window than N-acetyl cysteine, which is the current standard therapy but is only effective if given within 8 hours of the injury.

The endogenous syndecan-1, which is a heparan sulfate, is also known to act as a native defense mechanism against inflammatory injury to hepatocytes. “It looks like heparan sulfate attenuates inflammatory responses,” said Jian Liu, PhD, during a presentation of his research at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Liu is a professor of chemical biology and medicinal chemistry at the University of North Carolina at Chapel Hill.

The heparan sulfate analogue heparin has long been used as an anticoagulant, of course, which suggests that a novel heparan sulfate has a good chance of also being safe.

Dr. Liu’s team had to identify a heparan sulfate that had a hepatoprotective effect, but a heparan sulfate’s unique biological activity depends on the specific pattern of sulfation on the heparan molecule. Heparans isolated from natural sources are generally a complex mixture, which makes them difficult to study and produce in large enough quantities to be therapeutically useful.

Dr. Liu’s team used a combinatory approach, harnessing various enzymes to produce hundreds of different heparan sulfate variants, and then screened them for hepatoprotective activity. That process identified an 18-chain heparan sulfate with hepatoprotective activity. With an active formula in hand, they could employ the enzymes to create enough of the pure compound to further the research. “It’s probably two to three hundred times more efficient than the traditional chemical synthesis,” said Dr. Liu.

In mice, researchers injected the 18-mer 30 minutes after a hepatotoxic dose of acetaminophen and again after 12 hours. Tissue staining showed less migration of neutrophils, as well as lower concentrations of tumor necrosis factor–alpha. The animals also had lower alanine transferase levels than did the untreated animals, as well as greater survival after 4 days.

The pathological process surrounding acetaminophen overdose involves release of the high mobility group box 1 (HMGB1) protein from necrotic hepatocytes, which in turn binds to the receptor for advanced glycation end-products (RAGE). The HMGB1/RAGE complex then binds to neutrophils, recruiting them to the site of the injury and initiating inflammation.

To better understand the molecule’s role in the pathological process, the researchers studied RAGE knockout mice, and found that the 18-mer had no protective effect in these animals, suggesting that it relies on RAGE for its biological activity.

Heparan sulfates are widely present in the body, which prompted the researchers to investigate their endogenous effect. In the liver, the primary heparan sulfate is syndecan-1. The researchers demonstrated that the molecule is shed from cell surfaces in response to acetaminophen toxicity and that the levels correlate with HMGB1 release.

Dr. Liu believes that syndecan-1 acts as a natural buffer to inflammation, helping to neutralize HMGB1 and limit damage. “The problem is that when the damage is massive, the shed of syndecan-1 is not enough,” said Dr. Liu. He hopes that something like his team’s heparan sulfate 18-mer can be used therapeutically to bolster these endogenous controls and prevent further damage.

The research was funded by Glycan Therapeutics. Dr. Liu founded Glycan, which offers custom-synthesized heparan sulfates and chondroitin sulfates for research purposes.

SOURCE: Liu J. AASLD 2018, Abstract 0040.

SAN FRANCISCO – Patients with chronic liver disease are prescribed opioids and benzodiazepines at very high rates, despite risk for adverse consequences because of hepatic metabolism, according to results from a large longitudinal study of national data.

“Middle-aged individuals and those with a background of substance abuse and mental health conditions appear to have highest rates of use and represent populations for which targeted interventions to curb use could be highest yield,” lead study author Monica Konerman, MD, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases.

In an effort to better understand the rates of prescription opioid and benzodiazepine use in chronic liver disease, Dr. Konerman, director of the Michigan Medicine NAFLD Clinic at the University of Michigan, Ann Arbor, and her colleagues drew from the Truven Health Analytics Marketscan databases from 2009 to 2015. They limited the analysis to individuals with drug coverage who had chronic hepatitis C (HCV) without cirrhosis, cirrhosis, congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD), and examined pharmacy files for outpatient prescriptions.

Dr. Konerman reported data from 210,191 patients with HCV, 79,332 with cirrhosis, 766,840 with CHF, and 1,438,798 with COPD. Their median age was 59 years, and 51% were female. In per person-years, the prevalence of prescription opioid use was 25% among patients with chronic HCV, 53% among patients with cirrhosis, 26% among those with CHF, and 24% among those with COPD. At the same time, in per person-years, the prevalence of benzodiazepine use was 12% among patients with chronic HCV, 21% among patients with cirrhosis, 12% among those with CHF, and 13% among those with COPD. Use of opioids was greatest in adults 40-59 years of age (P less than .001). High-dose opioid use, defined as 100 opioid morphine equivalents per day or greater, occurred in 23% of those with cirrhosis and in 22% of those with HCV.

“The significant increase in rates of use in chronic liver disease, compared to other chronic conditions was remarkable, particularly given that patients with liver disease are at higher risk for adverse consequences of use due to hepatic metabolism of these medications,” Dr. Konerman said.

She went on to acknowledge “inherent limitations to studies that are secondary database analyses that rely on diagnosis codes for categorization of disease with potential for both over and under classification. We also did not capture inpatient prescriptions,” she said.

Dr. Konerman reported having no financial disclosures.

dbrunk@mdedge.com

SAN FRANCISCO – Patients with chronic liver disease are prescribed opioids and benzodiazepines at very high rates, despite risk for adverse consequences because of hepatic metabolism, according to results from a large longitudinal study of national data.

“Middle-aged individuals and those with a background of substance abuse and mental health conditions appear to have highest rates of use and represent populations for which targeted interventions to curb use could be highest yield,” lead study author Monica Konerman, MD, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases.

In an effort to better understand the rates of prescription opioid and benzodiazepine use in chronic liver disease, Dr. Konerman, director of the Michigan Medicine NAFLD Clinic at the University of Michigan, Ann Arbor, and her colleagues drew from the Truven Health Analytics Marketscan databases from 2009 to 2015. They limited the analysis to individuals with drug coverage who had chronic hepatitis C (HCV) without cirrhosis, cirrhosis, congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD), and examined pharmacy files for outpatient prescriptions.

Dr. Konerman reported data from 210,191 patients with HCV, 79,332 with cirrhosis, 766,840 with CHF, and 1,438,798 with COPD. Their median age was 59 years, and 51% were female. In per person-years, the prevalence of prescription opioid use was 25% among patients with chronic HCV, 53% among patients with cirrhosis, 26% among those with CHF, and 24% among those with COPD. At the same time, in per person-years, the prevalence of benzodiazepine use was 12% among patients with chronic HCV, 21% among patients with cirrhosis, 12% among those with CHF, and 13% among those with COPD. Use of opioids was greatest in adults 40-59 years of age (P less than .001). High-dose opioid use, defined as 100 opioid morphine equivalents per day or greater, occurred in 23% of those with cirrhosis and in 22% of those with HCV.

“The significant increase in rates of use in chronic liver disease, compared to other chronic conditions was remarkable, particularly given that patients with liver disease are at higher risk for adverse consequences of use due to hepatic metabolism of these medications,” Dr. Konerman said.

She went on to acknowledge “inherent limitations to studies that are secondary database analyses that rely on diagnosis codes for categorization of disease with potential for both over and under classification. We also did not capture inpatient prescriptions,” she said.

Dr. Konerman reported having no financial disclosures.

dbrunk@mdedge.com

SAN FRANCISCO – Patients with chronic liver disease are prescribed opioids and benzodiazepines at very high rates, despite risk for adverse consequences because of hepatic metabolism, according to results from a large longitudinal study of national data.

“Middle-aged individuals and those with a background of substance abuse and mental health conditions appear to have highest rates of use and represent populations for which targeted interventions to curb use could be highest yield,” lead study author Monica Konerman, MD, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases.

In an effort to better understand the rates of prescription opioid and benzodiazepine use in chronic liver disease, Dr. Konerman, director of the Michigan Medicine NAFLD Clinic at the University of Michigan, Ann Arbor, and her colleagues drew from the Truven Health Analytics Marketscan databases from 2009 to 2015. They limited the analysis to individuals with drug coverage who had chronic hepatitis C (HCV) without cirrhosis, cirrhosis, congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD), and examined pharmacy files for outpatient prescriptions.

Dr. Konerman reported data from 210,191 patients with HCV, 79,332 with cirrhosis, 766,840 with CHF, and 1,438,798 with COPD. Their median age was 59 years, and 51% were female. In per person-years, the prevalence of prescription opioid use was 25% among patients with chronic HCV, 53% among patients with cirrhosis, 26% among those with CHF, and 24% among those with COPD. At the same time, in per person-years, the prevalence of benzodiazepine use was 12% among patients with chronic HCV, 21% among patients with cirrhosis, 12% among those with CHF, and 13% among those with COPD. Use of opioids was greatest in adults 40-59 years of age (P less than .001). High-dose opioid use, defined as 100 opioid morphine equivalents per day or greater, occurred in 23% of those with cirrhosis and in 22% of those with HCV.

“The significant increase in rates of use in chronic liver disease, compared to other chronic conditions was remarkable, particularly given that patients with liver disease are at higher risk for adverse consequences of use due to hepatic metabolism of these medications,” Dr. Konerman said.

She went on to acknowledge “inherent limitations to studies that are secondary database analyses that rely on diagnosis codes for categorization of disease with potential for both over and under classification. We also did not capture inpatient prescriptions,” she said.

Dr. Konerman reported having no financial disclosures.

dbrunk@mdedge.com

SAN FRANCISCO – Chronic liver disease mortality continues to rise in the United States, driven largely by a spike in nonalcoholic fatty liver disease (NAFLD), according to results from an analysis of national data.

“I believe it’s all related to a big increase in obesity and type 2 diabetes in this country,” lead study author Zobair M. Younossi, MD, MPH, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases. “Those two risk factors drive NAFLD and its progressive type, nonalcoholic steatohepatitis (NASH). That accounts for at least part of the increase in mortality related to liver disease.”

In an effort to evaluate recent mortality trends in chronic liver disease in the United States, Dr. Younossi and his colleagues drew from National Vital Statistics Data during 2007-2016. They used ICD-10 codes to select mortality data for alcoholic liver disease, chronic hepatitis B and C, iron overload, NAFLD, cirrhosis, and hepatocellular carcinoma. NAFLD cases were defined as those having an ICD-10 code for NAFLD/NASH or an ICD-10 code for “cirrhosis of unknown etiology.” Next, the researchers adjusted age-standardized death rates to the 2000 U.S. Census population and used logistic regression and propensity scores to estimate predictors of chronic liver disease-related deaths.

Dr. Younossi, who chairs the department of medicine at Inova Fairfax Medical Campus, in Falls Church, Va., and his colleagues reported findings from 838,809 chronic liver disease–related deaths during the study period. They found that the age-standardized death rate for chronic liver disease increased from 21.9/100,000 population in 2007 to 24.9/100,000 population in 2016, which translated into an annual percentage change of 1.3% for males and 2.5% for females. Chronic liver disease–related deaths increased with age and were highest among those aged 55-64 years, followed by those aged 65-74 years – an average annual percentage change of 3.4% and 3.1% in each group.

Among chronic liver disease–related deaths, the most common diagnostic etiology was NAFLD (34.7%), followed by alcoholic liver disease (28.8%) and chronic hepatitis C (21.1%). Between 2007 and 2016, death rates increased from 7.6 to 9.0 per 100,000 population for NAFLD (an average annual percentage change of 2.1%) and from 6.1 to 7.9 per 100,000 population for alcoholic liver disease (an average annual percentage change of 3.1%). “What surprised me was that, despite highly effective treatment for HCV, we still have a burden of hepatitis C in this country,” Dr. Younossi said. “It’s still the most common cause of liver disease in the U.S. But it seems like hepatitis C–related liver disease is being replaced quickly by liver disease from nonalcoholic steatohepatitis. This transition between hepatitis C as the most important cause of liver disease and liver mortality to NASH or obesity-related NASH is becoming more rapid than I expected.”

On multivariate analysis, three factors were independently associated with an increased risk of death in NAFLD: the presence of type 2 diabetes (odds ratio, 1.78), cardiovascular disease (OR, 1.07), and renal failure (OR, 1.08).

“One important message from this study is that NASH is very common in the U.S. population,” said Dr. Younossi, who is also a professor of medicine at Virginia Commonwealth University, Richmond. “These patients are underrecognized and underdiagnosed because they are asymptomatic. The second message is that there is a subtype of patients with fatty liver disease – even a subtype of NASH – that can progress to cirrhosis and its complications. We have to pay attention to this silent disease to identify patients who are at risk for progressive liver disease and try to address some of the risk issues, such as tight control of diabetes, obesity, and control of hypertension and hyperlipidemia. Short of that, right now we have very few medical treatments such as vitamin E and pioglitazone recommended for a very selected group. In contrast, there are plenty of new medications that are being developed. The first step in tackling this disease is to identify who the patients are with fatty liver disease who are at risk for bad outcomes and make sure they’re linked to care by a knowledgeable caregiver [who] understands the importance of NASH.”

Dr. Younossi acknowledged certain limitations of the study, including the fact that liver disease diagnoses were based on ICD-10 coding. He disclosed that he is a consultant for Gilead, Intercept, Novo Nordisk, BMS, AbbVie, Viking, Term Quest Diagnostics, Echosens,and Shionogi. He has also received grant/research support from Gilead, Intercept, and BMS.

dbrunk@mdedge.com

Source: Hepatol. 2018;68[S1], Abstract 763.

SAN FRANCISCO – Chronic liver disease mortality continues to rise in the United States, driven largely by a spike in nonalcoholic fatty liver disease (NAFLD), according to results from an analysis of national data.

“I believe it’s all related to a big increase in obesity and type 2 diabetes in this country,” lead study author Zobair M. Younossi, MD, MPH, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases. “Those two risk factors drive NAFLD and its progressive type, nonalcoholic steatohepatitis (NASH). That accounts for at least part of the increase in mortality related to liver disease.”

In an effort to evaluate recent mortality trends in chronic liver disease in the United States, Dr. Younossi and his colleagues drew from National Vital Statistics Data during 2007-2016. They used ICD-10 codes to select mortality data for alcoholic liver disease, chronic hepatitis B and C, iron overload, NAFLD, cirrhosis, and hepatocellular carcinoma. NAFLD cases were defined as those having an ICD-10 code for NAFLD/NASH or an ICD-10 code for “cirrhosis of unknown etiology.” Next, the researchers adjusted age-standardized death rates to the 2000 U.S. Census population and used logistic regression and propensity scores to estimate predictors of chronic liver disease-related deaths.

Dr. Younossi, who chairs the department of medicine at Inova Fairfax Medical Campus, in Falls Church, Va., and his colleagues reported findings from 838,809 chronic liver disease–related deaths during the study period. They found that the age-standardized death rate for chronic liver disease increased from 21.9/100,000 population in 2007 to 24.9/100,000 population in 2016, which translated into an annual percentage change of 1.3% for males and 2.5% for females. Chronic liver disease–related deaths increased with age and were highest among those aged 55-64 years, followed by those aged 65-74 years – an average annual percentage change of 3.4% and 3.1% in each group.

Among chronic liver disease–related deaths, the most common diagnostic etiology was NAFLD (34.7%), followed by alcoholic liver disease (28.8%) and chronic hepatitis C (21.1%). Between 2007 and 2016, death rates increased from 7.6 to 9.0 per 100,000 population for NAFLD (an average annual percentage change of 2.1%) and from 6.1 to 7.9 per 100,000 population for alcoholic liver disease (an average annual percentage change of 3.1%). “What surprised me was that, despite highly effective treatment for HCV, we still have a burden of hepatitis C in this country,” Dr. Younossi said. “It’s still the most common cause of liver disease in the U.S. But it seems like hepatitis C–related liver disease is being replaced quickly by liver disease from nonalcoholic steatohepatitis. This transition between hepatitis C as the most important cause of liver disease and liver mortality to NASH or obesity-related NASH is becoming more rapid than I expected.”

On multivariate analysis, three factors were independently associated with an increased risk of death in NAFLD: the presence of type 2 diabetes (odds ratio, 1.78), cardiovascular disease (OR, 1.07), and renal failure (OR, 1.08).

“One important message from this study is that NASH is very common in the U.S. population,” said Dr. Younossi, who is also a professor of medicine at Virginia Commonwealth University, Richmond. “These patients are underrecognized and underdiagnosed because they are asymptomatic. The second message is that there is a subtype of patients with fatty liver disease – even a subtype of NASH – that can progress to cirrhosis and its complications. We have to pay attention to this silent disease to identify patients who are at risk for progressive liver disease and try to address some of the risk issues, such as tight control of diabetes, obesity, and control of hypertension and hyperlipidemia. Short of that, right now we have very few medical treatments such as vitamin E and pioglitazone recommended for a very selected group. In contrast, there are plenty of new medications that are being developed. The first step in tackling this disease is to identify who the patients are with fatty liver disease who are at risk for bad outcomes and make sure they’re linked to care by a knowledgeable caregiver [who] understands the importance of NASH.”

Dr. Younossi acknowledged certain limitations of the study, including the fact that liver disease diagnoses were based on ICD-10 coding. He disclosed that he is a consultant for Gilead, Intercept, Novo Nordisk, BMS, AbbVie, Viking, Term Quest Diagnostics, Echosens,and Shionogi. He has also received grant/research support from Gilead, Intercept, and BMS.

dbrunk@mdedge.com

Source: Hepatol. 2018;68[S1], Abstract 763.

SAN FRANCISCO – Chronic liver disease mortality continues to rise in the United States, driven largely by a spike in nonalcoholic fatty liver disease (NAFLD), according to results from an analysis of national data.

“I believe it’s all related to a big increase in obesity and type 2 diabetes in this country,” lead study author Zobair M. Younossi, MD, MPH, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases. “Those two risk factors drive NAFLD and its progressive type, nonalcoholic steatohepatitis (NASH). That accounts for at least part of the increase in mortality related to liver disease.”

In an effort to evaluate recent mortality trends in chronic liver disease in the United States, Dr. Younossi and his colleagues drew from National Vital Statistics Data during 2007-2016. They used ICD-10 codes to select mortality data for alcoholic liver disease, chronic hepatitis B and C, iron overload, NAFLD, cirrhosis, and hepatocellular carcinoma. NAFLD cases were defined as those having an ICD-10 code for NAFLD/NASH or an ICD-10 code for “cirrhosis of unknown etiology.” Next, the researchers adjusted age-standardized death rates to the 2000 U.S. Census population and used logistic regression and propensity scores to estimate predictors of chronic liver disease-related deaths.

Dr. Younossi, who chairs the department of medicine at Inova Fairfax Medical Campus, in Falls Church, Va., and his colleagues reported findings from 838,809 chronic liver disease–related deaths during the study period. They found that the age-standardized death rate for chronic liver disease increased from 21.9/100,000 population in 2007 to 24.9/100,000 population in 2016, which translated into an annual percentage change of 1.3% for males and 2.5% for females. Chronic liver disease–related deaths increased with age and were highest among those aged 55-64 years, followed by those aged 65-74 years – an average annual percentage change of 3.4% and 3.1% in each group.

Among chronic liver disease–related deaths, the most common diagnostic etiology was NAFLD (34.7%), followed by alcoholic liver disease (28.8%) and chronic hepatitis C (21.1%). Between 2007 and 2016, death rates increased from 7.6 to 9.0 per 100,000 population for NAFLD (an average annual percentage change of 2.1%) and from 6.1 to 7.9 per 100,000 population for alcoholic liver disease (an average annual percentage change of 3.1%). “What surprised me was that, despite highly effective treatment for HCV, we still have a burden of hepatitis C in this country,” Dr. Younossi said. “It’s still the most common cause of liver disease in the U.S. But it seems like hepatitis C–related liver disease is being replaced quickly by liver disease from nonalcoholic steatohepatitis. This transition between hepatitis C as the most important cause of liver disease and liver mortality to NASH or obesity-related NASH is becoming more rapid than I expected.”

On multivariate analysis, three factors were independently associated with an increased risk of death in NAFLD: the presence of type 2 diabetes (odds ratio, 1.78), cardiovascular disease (OR, 1.07), and renal failure (OR, 1.08).

“One important message from this study is that NASH is very common in the U.S. population,” said Dr. Younossi, who is also a professor of medicine at Virginia Commonwealth University, Richmond. “These patients are underrecognized and underdiagnosed because they are asymptomatic. The second message is that there is a subtype of patients with fatty liver disease – even a subtype of NASH – that can progress to cirrhosis and its complications. We have to pay attention to this silent disease to identify patients who are at risk for progressive liver disease and try to address some of the risk issues, such as tight control of diabetes, obesity, and control of hypertension and hyperlipidemia. Short of that, right now we have very few medical treatments such as vitamin E and pioglitazone recommended for a very selected group. In contrast, there are plenty of new medications that are being developed. The first step in tackling this disease is to identify who the patients are with fatty liver disease who are at risk for bad outcomes and make sure they’re linked to care by a knowledgeable caregiver [who] understands the importance of NASH.”

Dr. Younossi acknowledged certain limitations of the study, including the fact that liver disease diagnoses were based on ICD-10 coding. He disclosed that he is a consultant for Gilead, Intercept, Novo Nordisk, BMS, AbbVie, Viking, Term Quest Diagnostics, Echosens,and Shionogi. He has also received grant/research support from Gilead, Intercept, and BMS.

dbrunk@mdedge.com

Source: Hepatol. 2018;68[S1], Abstract 763.