Liver Disease

WASHINGTON – In patients with cirrhosis associated with nonalcoholic steatohepatitis, 1 year of treatment with the investigational oral thyromimetic agent resmetirom (MGL-3196) was safe and effective at lowering markers of both cardiovascular risk and NASH fibrosis, new research has found.

Two cohorts comprising a total of 180 patients with well-compensated NASH cirrhosis enrolled in an open-label arm of the phase 3 MAESTRO-NAFLD-1 trial. Researchers found that 52 weeks of treatment with resmetirom was associated with reductions in MRI proton density fat fraction (MRI-PDFF), FibroScan controlled attenuation parameter, FibroScan vibration-controlled transient elastography (VCTE), magnetic resonance elastography, liver and spleen volumes, liver enzyme levels, and lipids.

“Importantly, there was a statistically significant reduction in liver volume by an average of 20%, and also the potential to monitor spleen volume as a surrogate for portal hypertension, with the caveat that further research needs to be done in this area to understand that better,” said Stephen Harrison, MD, medical director for Pinnacle Clinical Research in San Antonio, Tex.

Dr. Harrison presented the findings at the annual meeting of the American Association for the Study of Liver Diseases.
 

Building on early findings

The thyroid hormone receptor–beta pathway helps to maintain liver health through control of de novo lipogenesis, fatty acid oxidation, mitophagy and mitochondrial biogenesis, cholesterol metabolism, and anti-inflammatory and antifibrotic effects, Dr. Harrison said.

Resmetirom (Madrigal Pharmaceuticals) is a selective thyroid hormone receptor-beta agonist that is reputed to offer optimal beneficial effects on the liver, while minimizing adverse cardiovascular and bone metabolic events that are mediated through a different pathway by the thyroid hormone receptor–alpha.

In 2019, Dr. Harrison and colleagues reported results of a phase 2, double-blind, placebo-controlled trial of resmetirom in adults with biopsy-confirmed NASH (fibrosis stages 1-3) and hepatic fat content greater than 10% as assessed by MRI-PDFF.

In that study, patients who received resmetirom had significantly greater reductions in relative hepatic fat content compared with patients who received placebo at both 12 weeks and 36 weeks of follow-up. Overall, 60% of patients who took resmetirom had at least a 30% fat reduction compared with 18% of those who took placebo.

In addition, the investigators presented data on a cohort of 105 patients with well-compensated NASH cirrhosis who were treated in an open-label study. Those data were presented at the International Liver Conference in London in June.

At the AASLD meeting, Dr. Harrison presented data on the same cohort combined with data on an additional cohort of 75 patients with well-compensated NASH cirrhosis and no prior history of decompensation.
 

‘Real-world’ conditions

In an attempt to mimic real-world conditions, patients in the trial did not receive a baseline biopsy but were determined to have NASH or presumed NASH with either results of a previous liver biopsy or noninvasive techniques, including FibroScan and MRI-PDFF.

Patients were started on oral resmetirom 80 mg daily, which could be titrated upward to 100 mg daily based on pharmacokinetic data from a 2-week sample.

The investigators first compared reductions in liver enzymes in both cohorts, with median reductions in ALT, AST, and gamma-glutamyl transferase of –20%, –18%, and –32%, respectively, in the original cohort, and –30%, –23%, and –37% in the more recent cohort.

Reductions in other parameters, including MRI-PDFF, liver volume, and lipids were also similar between the cohorts.

Given the similarities, researchers opted to treat the second cohort as a validation set, and combined data from the two cohorts to look at additional differences between baseline and 1-year follow-up.

Looking at imaging biomarkers in the combined cohorts of patients with responses, they saw that of patients with at least a 25% change over baseline in FibroScan VCTE, 48% of patients with baseline PDFF of 5% or less, and 42% of those with baseline PDFF greater than 5% had significant improvement at 1 year.

Among patients with changes in MR elastography of at least 15%, a fifth (22%) of those with baseline PDFF of 5% or less and about a quarter (26%) with baseline PDFF greater than 5% had improvement.

Independent of baseline cirrhosis severity, 73% of patients had a 15% or greater reduction in liver volume after 52 weeks of resmetirom. The investigators did not find a correlation of liver reduction with MRI-PDFF reduction among patients with PDFF of 5% or less at baseline.

The study found similar reductions in harmful lipids across all patient subgroups in both cohorts. Decreases in both systolic and diastolic blood pressure consistent with those seen in noncirrhotic NASH patients were also seen, independent of cirrhosis severity.

Among patients with at least a 10% change in spleen volume, 31% of those with low baseline PDFF readings and 45% of those with high readings had a decrease in volume.

The investigators found no differences in adverse events between cirrhosis severity groups or compared with noncirrhotic NASH patients.

The most common adverse events were intermittent loose stools or nausea at start of resmetirom therapy, and most were mild.

There were no changes in the central thyroid axis, apart from about a 10% decrease in prohormone FT4, which had been reported in other studies of resmetirom. No changes in active hormone FT3 or thyroid-stimulating hormone were found.

Although the study did not have a placebo control, it supports the rationale for the ongoing MAESTRO-NASH Outcomes trial, an event-driven trial comparing outcomes with resmetirom versus placebo in patients with well-compensated Child-Pugh A NASH cirrhosis, Dr. Harrison concluded.
 

Encouraging data

The data on resmetirom look promising as an approach to the treatment of NASH and related diseases, Cyrielle Caussy, MD, PhD, from the University Hospital of Lyon (France), said in an interview. Dr. Caussy, who was not involved in the study, was a moderator of the session where Dr. Harrison presented the data.

It does seem to be beneficial in NASH, she said. But we also have seen improvements in lipid metabolism with this drug; as shown in Dr. Harrison’s presentation, there is a difference in cardiovascular risk factors, Dr. Caussy added.

“I do think it could be one of the drugs that really improves outcomes for patients with NASH,” Dr. Caussy said.

The study was supported by Madrigal Pharmaceuticals. Dr. Harrison reported conflict of interest with numerous pharmaceutical companies.

A version of this article first appeared on Medscape.com.

WASHINGTON – In patients with cirrhosis associated with nonalcoholic steatohepatitis, 1 year of treatment with the investigational oral thyromimetic agent resmetirom (MGL-3196) was safe and effective at lowering markers of both cardiovascular risk and NASH fibrosis, new research has found.

Two cohorts comprising a total of 180 patients with well-compensated NASH cirrhosis enrolled in an open-label arm of the phase 3 MAESTRO-NAFLD-1 trial. Researchers found that 52 weeks of treatment with resmetirom was associated with reductions in MRI proton density fat fraction (MRI-PDFF), FibroScan controlled attenuation parameter, FibroScan vibration-controlled transient elastography (VCTE), magnetic resonance elastography, liver and spleen volumes, liver enzyme levels, and lipids.

“Importantly, there was a statistically significant reduction in liver volume by an average of 20%, and also the potential to monitor spleen volume as a surrogate for portal hypertension, with the caveat that further research needs to be done in this area to understand that better,” said Stephen Harrison, MD, medical director for Pinnacle Clinical Research in San Antonio, Tex.

Dr. Harrison presented the findings at the annual meeting of the American Association for the Study of Liver Diseases.
 

Building on early findings

The thyroid hormone receptor–beta pathway helps to maintain liver health through control of de novo lipogenesis, fatty acid oxidation, mitophagy and mitochondrial biogenesis, cholesterol metabolism, and anti-inflammatory and antifibrotic effects, Dr. Harrison said.

Resmetirom (Madrigal Pharmaceuticals) is a selective thyroid hormone receptor-beta agonist that is reputed to offer optimal beneficial effects on the liver, while minimizing adverse cardiovascular and bone metabolic events that are mediated through a different pathway by the thyroid hormone receptor–alpha.

In 2019, Dr. Harrison and colleagues reported results of a phase 2, double-blind, placebo-controlled trial of resmetirom in adults with biopsy-confirmed NASH (fibrosis stages 1-3) and hepatic fat content greater than 10% as assessed by MRI-PDFF.

In that study, patients who received resmetirom had significantly greater reductions in relative hepatic fat content compared with patients who received placebo at both 12 weeks and 36 weeks of follow-up. Overall, 60% of patients who took resmetirom had at least a 30% fat reduction compared with 18% of those who took placebo.

In addition, the investigators presented data on a cohort of 105 patients with well-compensated NASH cirrhosis who were treated in an open-label study. Those data were presented at the International Liver Conference in London in June.

At the AASLD meeting, Dr. Harrison presented data on the same cohort combined with data on an additional cohort of 75 patients with well-compensated NASH cirrhosis and no prior history of decompensation.
 

‘Real-world’ conditions

In an attempt to mimic real-world conditions, patients in the trial did not receive a baseline biopsy but were determined to have NASH or presumed NASH with either results of a previous liver biopsy or noninvasive techniques, including FibroScan and MRI-PDFF.

Patients were started on oral resmetirom 80 mg daily, which could be titrated upward to 100 mg daily based on pharmacokinetic data from a 2-week sample.

The investigators first compared reductions in liver enzymes in both cohorts, with median reductions in ALT, AST, and gamma-glutamyl transferase of –20%, –18%, and –32%, respectively, in the original cohort, and –30%, –23%, and –37% in the more recent cohort.

Reductions in other parameters, including MRI-PDFF, liver volume, and lipids were also similar between the cohorts.

Given the similarities, researchers opted to treat the second cohort as a validation set, and combined data from the two cohorts to look at additional differences between baseline and 1-year follow-up.

Looking at imaging biomarkers in the combined cohorts of patients with responses, they saw that of patients with at least a 25% change over baseline in FibroScan VCTE, 48% of patients with baseline PDFF of 5% or less, and 42% of those with baseline PDFF greater than 5% had significant improvement at 1 year.

Among patients with changes in MR elastography of at least 15%, a fifth (22%) of those with baseline PDFF of 5% or less and about a quarter (26%) with baseline PDFF greater than 5% had improvement.

Independent of baseline cirrhosis severity, 73% of patients had a 15% or greater reduction in liver volume after 52 weeks of resmetirom. The investigators did not find a correlation of liver reduction with MRI-PDFF reduction among patients with PDFF of 5% or less at baseline.

The study found similar reductions in harmful lipids across all patient subgroups in both cohorts. Decreases in both systolic and diastolic blood pressure consistent with those seen in noncirrhotic NASH patients were also seen, independent of cirrhosis severity.

Among patients with at least a 10% change in spleen volume, 31% of those with low baseline PDFF readings and 45% of those with high readings had a decrease in volume.

The investigators found no differences in adverse events between cirrhosis severity groups or compared with noncirrhotic NASH patients.

The most common adverse events were intermittent loose stools or nausea at start of resmetirom therapy, and most were mild.

There were no changes in the central thyroid axis, apart from about a 10% decrease in prohormone FT4, which had been reported in other studies of resmetirom. No changes in active hormone FT3 or thyroid-stimulating hormone were found.

Although the study did not have a placebo control, it supports the rationale for the ongoing MAESTRO-NASH Outcomes trial, an event-driven trial comparing outcomes with resmetirom versus placebo in patients with well-compensated Child-Pugh A NASH cirrhosis, Dr. Harrison concluded.
 

Encouraging data

The data on resmetirom look promising as an approach to the treatment of NASH and related diseases, Cyrielle Caussy, MD, PhD, from the University Hospital of Lyon (France), said in an interview. Dr. Caussy, who was not involved in the study, was a moderator of the session where Dr. Harrison presented the data.

It does seem to be beneficial in NASH, she said. But we also have seen improvements in lipid metabolism with this drug; as shown in Dr. Harrison’s presentation, there is a difference in cardiovascular risk factors, Dr. Caussy added.

“I do think it could be one of the drugs that really improves outcomes for patients with NASH,” Dr. Caussy said.

The study was supported by Madrigal Pharmaceuticals. Dr. Harrison reported conflict of interest with numerous pharmaceutical companies.

A version of this article first appeared on Medscape.com.

WASHINGTON – In patients with cirrhosis associated with nonalcoholic steatohepatitis, 1 year of treatment with the investigational oral thyromimetic agent resmetirom (MGL-3196) was safe and effective at lowering markers of both cardiovascular risk and NASH fibrosis, new research has found.

Two cohorts comprising a total of 180 patients with well-compensated NASH cirrhosis enrolled in an open-label arm of the phase 3 MAESTRO-NAFLD-1 trial. Researchers found that 52 weeks of treatment with resmetirom was associated with reductions in MRI proton density fat fraction (MRI-PDFF), FibroScan controlled attenuation parameter, FibroScan vibration-controlled transient elastography (VCTE), magnetic resonance elastography, liver and spleen volumes, liver enzyme levels, and lipids.

“Importantly, there was a statistically significant reduction in liver volume by an average of 20%, and also the potential to monitor spleen volume as a surrogate for portal hypertension, with the caveat that further research needs to be done in this area to understand that better,” said Stephen Harrison, MD, medical director for Pinnacle Clinical Research in San Antonio, Tex.

Dr. Harrison presented the findings at the annual meeting of the American Association for the Study of Liver Diseases.
 

Building on early findings

The thyroid hormone receptor–beta pathway helps to maintain liver health through control of de novo lipogenesis, fatty acid oxidation, mitophagy and mitochondrial biogenesis, cholesterol metabolism, and anti-inflammatory and antifibrotic effects, Dr. Harrison said.

Resmetirom (Madrigal Pharmaceuticals) is a selective thyroid hormone receptor-beta agonist that is reputed to offer optimal beneficial effects on the liver, while minimizing adverse cardiovascular and bone metabolic events that are mediated through a different pathway by the thyroid hormone receptor–alpha.

In 2019, Dr. Harrison and colleagues reported results of a phase 2, double-blind, placebo-controlled trial of resmetirom in adults with biopsy-confirmed NASH (fibrosis stages 1-3) and hepatic fat content greater than 10% as assessed by MRI-PDFF.

In that study, patients who received resmetirom had significantly greater reductions in relative hepatic fat content compared with patients who received placebo at both 12 weeks and 36 weeks of follow-up. Overall, 60% of patients who took resmetirom had at least a 30% fat reduction compared with 18% of those who took placebo.

In addition, the investigators presented data on a cohort of 105 patients with well-compensated NASH cirrhosis who were treated in an open-label study. Those data were presented at the International Liver Conference in London in June.

At the AASLD meeting, Dr. Harrison presented data on the same cohort combined with data on an additional cohort of 75 patients with well-compensated NASH cirrhosis and no prior history of decompensation.
 

‘Real-world’ conditions

In an attempt to mimic real-world conditions, patients in the trial did not receive a baseline biopsy but were determined to have NASH or presumed NASH with either results of a previous liver biopsy or noninvasive techniques, including FibroScan and MRI-PDFF.

Patients were started on oral resmetirom 80 mg daily, which could be titrated upward to 100 mg daily based on pharmacokinetic data from a 2-week sample.

The investigators first compared reductions in liver enzymes in both cohorts, with median reductions in ALT, AST, and gamma-glutamyl transferase of –20%, –18%, and –32%, respectively, in the original cohort, and –30%, –23%, and –37% in the more recent cohort.

Reductions in other parameters, including MRI-PDFF, liver volume, and lipids were also similar between the cohorts.

Given the similarities, researchers opted to treat the second cohort as a validation set, and combined data from the two cohorts to look at additional differences between baseline and 1-year follow-up.

Looking at imaging biomarkers in the combined cohorts of patients with responses, they saw that of patients with at least a 25% change over baseline in FibroScan VCTE, 48% of patients with baseline PDFF of 5% or less, and 42% of those with baseline PDFF greater than 5% had significant improvement at 1 year.

Among patients with changes in MR elastography of at least 15%, a fifth (22%) of those with baseline PDFF of 5% or less and about a quarter (26%) with baseline PDFF greater than 5% had improvement.

Independent of baseline cirrhosis severity, 73% of patients had a 15% or greater reduction in liver volume after 52 weeks of resmetirom. The investigators did not find a correlation of liver reduction with MRI-PDFF reduction among patients with PDFF of 5% or less at baseline.

The study found similar reductions in harmful lipids across all patient subgroups in both cohorts. Decreases in both systolic and diastolic blood pressure consistent with those seen in noncirrhotic NASH patients were also seen, independent of cirrhosis severity.

Among patients with at least a 10% change in spleen volume, 31% of those with low baseline PDFF readings and 45% of those with high readings had a decrease in volume.

The investigators found no differences in adverse events between cirrhosis severity groups or compared with noncirrhotic NASH patients.

The most common adverse events were intermittent loose stools or nausea at start of resmetirom therapy, and most were mild.

There were no changes in the central thyroid axis, apart from about a 10% decrease in prohormone FT4, which had been reported in other studies of resmetirom. No changes in active hormone FT3 or thyroid-stimulating hormone were found.

Although the study did not have a placebo control, it supports the rationale for the ongoing MAESTRO-NASH Outcomes trial, an event-driven trial comparing outcomes with resmetirom versus placebo in patients with well-compensated Child-Pugh A NASH cirrhosis, Dr. Harrison concluded.
 

Encouraging data

The data on resmetirom look promising as an approach to the treatment of NASH and related diseases, Cyrielle Caussy, MD, PhD, from the University Hospital of Lyon (France), said in an interview. Dr. Caussy, who was not involved in the study, was a moderator of the session where Dr. Harrison presented the data.

It does seem to be beneficial in NASH, she said. But we also have seen improvements in lipid metabolism with this drug; as shown in Dr. Harrison’s presentation, there is a difference in cardiovascular risk factors, Dr. Caussy added.

“I do think it could be one of the drugs that really improves outcomes for patients with NASH,” Dr. Caussy said.

The study was supported by Madrigal Pharmaceuticals. Dr. Harrison reported conflict of interest with numerous pharmaceutical companies.

A version of this article first appeared on Medscape.com.

Noninvasive ultrasound- and serum-based fibrosis biomarkers have similar prognostic performance to histology for nonalcoholic fatty liver disease (NAFLD), according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

Fibrosis stages and liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE) through FibroScan were significant predictors of event-free survival, said Ferenc Mozes, DPhil, a postdoctoral research assistant at the University of Oxford, England, who has worked on biomarker evaluation of nonalcoholic steatohepatitis (NASH) as a member of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) consortium.

“Liver histology is highly prognostic of liver-related outcomes in patients with NAFLD and NASH,” he said. “Not just that, but liver histology is also accepted, and furthermore mandated by the FDA, as a surrogate endpoint in pharmaceutical trials for NASH.”

Noninvasive ultrasound- and serum-based fibrosis biomarkers have similar prognostic performance to histology for nonalcoholic fatty liver disease (NAFLD), according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

Fibrosis stages and liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE) through FibroScan were significant predictors of event-free survival, said Ferenc Mozes, DPhil, a postdoctoral research assistant at the University of Oxford, England, who has worked on biomarker evaluation of nonalcoholic steatohepatitis (NASH) as a member of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) consortium.

“Liver histology is highly prognostic of liver-related outcomes in patients with NAFLD and NASH,” he said. “Not just that, but liver histology is also accepted, and furthermore mandated by the FDA, as a surrogate endpoint in pharmaceutical trials for NASH.”

Noninvasive ultrasound- and serum-based fibrosis biomarkers have similar prognostic performance to histology for nonalcoholic fatty liver disease (NAFLD), according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

Fibrosis stages and liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE) through FibroScan were significant predictors of event-free survival, said Ferenc Mozes, DPhil, a postdoctoral research assistant at the University of Oxford, England, who has worked on biomarker evaluation of nonalcoholic steatohepatitis (NASH) as a member of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) consortium.

“Liver histology is highly prognostic of liver-related outcomes in patients with NAFLD and NASH,” he said. “Not just that, but liver histology is also accepted, and furthermore mandated by the FDA, as a surrogate endpoint in pharmaceutical trials for NASH.”

A low-carbohydrate diet appears to be an effective weight-loss intervention in liver transplant recipients with obesity as compared with a calorie-restrictive diet, according to interim findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

In particular, the intervention showed significant improvements in the metabophenotype profile, including visceral adipose tissue and abdominal subcutaneous adipose tissue, said Mohammad Siddiqui, MD, a gastroenterologist and liver transplant specialist at Virginia Commonwealth University, Richmond.

“Weight gain and obesity after liver transplantation is common,” he said. “Posttransplant obesity is associated with increased cardiometabolic risk burden, increased risk of cardiovascular disease and mortality, and overall mortality.”

Previously, Dr. Siddiqui and colleagues have shown that posttransplant weight loss is difficult because of metabolic inflexibility and mitochondrial inefficiency. By specifically targeting carbohydrate utilization, metabolic flexibility could be restored in liver transplant recipients, he noted.

Dr. Siddiqui and colleagues conducted a randomized controlled trial of 27 adult liver transplant recipients with obesity for 24 weeks. The primary endpoint was change in weight, and the secondary endpoints involved metabophenotype, metabolic flexibility, mitochondrial function, and metabolic risk. The research team excluded patients with end-stage disease, terminal disease, use of weight-loss medications, pregnancy, or uncontrolled psychiatric illness that could interfere with adherence.

Among the participants, 13 were randomized to a calorie restrictive diet of less than 1,200-1,500 calories per day, and 14 were randomized to a low-carbohydrate diet of 20 grams or less per day. At enrollment, the participants underwent dietary, activity, skeletal muscle, and body composition assessments, as well as metabophenotype measurements of visceral adipose tissue, abdominal subcutaneous adipose tissue, muscle fat infiltration, fat-free muscle volume, and proton density fat fraction.

All participants were advised to maintain the same level of physical activity, which was measured through 7-day accelerometry. In addition, the patients were contacted every 2 weeks throughout the 24-week study period.

“We wanted to reinforce the dietary advice. We wanted to identify factors that may lead to compliance,” Dr. Siddiqui said. “Multiple studies have documented that the more contact that patients have during weight-loss studies with medical personnel, the more effective those strategies are.”

Overall, the dietary interventions were well tolerated, and neither group showed a significant change in renal function.

The average weight loss was –7.6 kg over 6 months in the low-carbohydrate group, as compared with –0.6 kg in the calorie-restrictive group.

The low carbohydrate diet also positively affected participants’ metabophenotype profile, particularly fat deposits. As compared with the calorie-restrictive group, the low-carbohydrate group showed statistically significant improvements in visceral adipose tissue, abdominal subcutaneous adipose tissue, and muscle fat infiltration.

The liver proton density fat fraction, which is associated with fatty liver disease, decreased by 0.53% in the low-carbohydrate group and increased by 0.46% in the calorie-restrictive group, but the difference didn’t reach statistical significance.

The fat-free muscle volume decreased by about 5% in the low-carbohydrate group. Dr. Siddiqui noted that the researchers don’t know yet whether this translates to a decrease in muscle function.

In terms of metabolic risk, the low-carbohydrate diet did not affect serum lipids (such as triglycerides or cholesterol measures), renal function (such as serum creatinine, glomerular filtration rate, or blood urea nitrogen), or insulin resistance (through glucose or hemoglobin A1c). At the same time, among patients taking insulin at the time of enrollment, about 90% of patients randomized to the low-carbohydrate group were able to reduce insulin to zero during the study.

Upon completion of the current study, Dr. Siddiqui and colleagues hope to provide foundational safety and efficacy data for carbohydrate restriction in liver transplant recipients. In the ongoing study, the researchers are further investigating the dietary intervention impacts on metabolic flexibility, skeletal muscle mitochondrial function, atherogenic lipoproteins, and vascular function.

“Are we actually, on a molecular level, fixing the fundamental problem that liver transplant recipients have to improve outcomes?” he said. “We’re doing very detailed profiling of these patients, so we will have data that shows how this actually affects them.”

Dr. Siddiqui was asked about the sustainability of the low-carbohydrate diet, particularly with a restrictive parameter of 20 grams per day. During the COVID-19 pandemic, Dr. Siddiqui noted, the study was slowed and the research team was able to collect follow-up data.

“Surprisingly, we have a high rate of compliance, even after 6 months of therapy, and I think this has to do with a patient population that’s been through cirrhosis and has almost died,” he said. “They’re far more compliant, and we’re seeing that. We’re also changing the physiology and improving mitochondrial function, which improves the weight loss and weight maintenance, though I don’t know how long that’s going to last.”

The study sponsorship was not disclosed. Dr. Siddiqui reported no relevant conflicts of interest.
 

A low-carbohydrate diet appears to be an effective weight-loss intervention in liver transplant recipients with obesity as compared with a calorie-restrictive diet, according to interim findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

In particular, the intervention showed significant improvements in the metabophenotype profile, including visceral adipose tissue and abdominal subcutaneous adipose tissue, said Mohammad Siddiqui, MD, a gastroenterologist and liver transplant specialist at Virginia Commonwealth University, Richmond.

“Weight gain and obesity after liver transplantation is common,” he said. “Posttransplant obesity is associated with increased cardiometabolic risk burden, increased risk of cardiovascular disease and mortality, and overall mortality.”

Previously, Dr. Siddiqui and colleagues have shown that posttransplant weight loss is difficult because of metabolic inflexibility and mitochondrial inefficiency. By specifically targeting carbohydrate utilization, metabolic flexibility could be restored in liver transplant recipients, he noted.

Dr. Siddiqui and colleagues conducted a randomized controlled trial of 27 adult liver transplant recipients with obesity for 24 weeks. The primary endpoint was change in weight, and the secondary endpoints involved metabophenotype, metabolic flexibility, mitochondrial function, and metabolic risk. The research team excluded patients with end-stage disease, terminal disease, use of weight-loss medications, pregnancy, or uncontrolled psychiatric illness that could interfere with adherence.

Among the participants, 13 were randomized to a calorie restrictive diet of less than 1,200-1,500 calories per day, and 14 were randomized to a low-carbohydrate diet of 20 grams or less per day. At enrollment, the participants underwent dietary, activity, skeletal muscle, and body composition assessments, as well as metabophenotype measurements of visceral adipose tissue, abdominal subcutaneous adipose tissue, muscle fat infiltration, fat-free muscle volume, and proton density fat fraction.

All participants were advised to maintain the same level of physical activity, which was measured through 7-day accelerometry. In addition, the patients were contacted every 2 weeks throughout the 24-week study period.

“We wanted to reinforce the dietary advice. We wanted to identify factors that may lead to compliance,” Dr. Siddiqui said. “Multiple studies have documented that the more contact that patients have during weight-loss studies with medical personnel, the more effective those strategies are.”

Overall, the dietary interventions were well tolerated, and neither group showed a significant change in renal function.

The average weight loss was –7.6 kg over 6 months in the low-carbohydrate group, as compared with –0.6 kg in the calorie-restrictive group.

The low carbohydrate diet also positively affected participants’ metabophenotype profile, particularly fat deposits. As compared with the calorie-restrictive group, the low-carbohydrate group showed statistically significant improvements in visceral adipose tissue, abdominal subcutaneous adipose tissue, and muscle fat infiltration.

The liver proton density fat fraction, which is associated with fatty liver disease, decreased by 0.53% in the low-carbohydrate group and increased by 0.46% in the calorie-restrictive group, but the difference didn’t reach statistical significance.

The fat-free muscle volume decreased by about 5% in the low-carbohydrate group. Dr. Siddiqui noted that the researchers don’t know yet whether this translates to a decrease in muscle function.

In terms of metabolic risk, the low-carbohydrate diet did not affect serum lipids (such as triglycerides or cholesterol measures), renal function (such as serum creatinine, glomerular filtration rate, or blood urea nitrogen), or insulin resistance (through glucose or hemoglobin A1c). At the same time, among patients taking insulin at the time of enrollment, about 90% of patients randomized to the low-carbohydrate group were able to reduce insulin to zero during the study.

Upon completion of the current study, Dr. Siddiqui and colleagues hope to provide foundational safety and efficacy data for carbohydrate restriction in liver transplant recipients. In the ongoing study, the researchers are further investigating the dietary intervention impacts on metabolic flexibility, skeletal muscle mitochondrial function, atherogenic lipoproteins, and vascular function.

“Are we actually, on a molecular level, fixing the fundamental problem that liver transplant recipients have to improve outcomes?” he said. “We’re doing very detailed profiling of these patients, so we will have data that shows how this actually affects them.”

Dr. Siddiqui was asked about the sustainability of the low-carbohydrate diet, particularly with a restrictive parameter of 20 grams per day. During the COVID-19 pandemic, Dr. Siddiqui noted, the study was slowed and the research team was able to collect follow-up data.

“Surprisingly, we have a high rate of compliance, even after 6 months of therapy, and I think this has to do with a patient population that’s been through cirrhosis and has almost died,” he said. “They’re far more compliant, and we’re seeing that. We’re also changing the physiology and improving mitochondrial function, which improves the weight loss and weight maintenance, though I don’t know how long that’s going to last.”

The study sponsorship was not disclosed. Dr. Siddiqui reported no relevant conflicts of interest.
 

A low-carbohydrate diet appears to be an effective weight-loss intervention in liver transplant recipients with obesity as compared with a calorie-restrictive diet, according to interim findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

In particular, the intervention showed significant improvements in the metabophenotype profile, including visceral adipose tissue and abdominal subcutaneous adipose tissue, said Mohammad Siddiqui, MD, a gastroenterologist and liver transplant specialist at Virginia Commonwealth University, Richmond.

“Weight gain and obesity after liver transplantation is common,” he said. “Posttransplant obesity is associated with increased cardiometabolic risk burden, increased risk of cardiovascular disease and mortality, and overall mortality.”

Previously, Dr. Siddiqui and colleagues have shown that posttransplant weight loss is difficult because of metabolic inflexibility and mitochondrial inefficiency. By specifically targeting carbohydrate utilization, metabolic flexibility could be restored in liver transplant recipients, he noted.

Dr. Siddiqui and colleagues conducted a randomized controlled trial of 27 adult liver transplant recipients with obesity for 24 weeks. The primary endpoint was change in weight, and the secondary endpoints involved metabophenotype, metabolic flexibility, mitochondrial function, and metabolic risk. The research team excluded patients with end-stage disease, terminal disease, use of weight-loss medications, pregnancy, or uncontrolled psychiatric illness that could interfere with adherence.

Among the participants, 13 were randomized to a calorie restrictive diet of less than 1,200-1,500 calories per day, and 14 were randomized to a low-carbohydrate diet of 20 grams or less per day. At enrollment, the participants underwent dietary, activity, skeletal muscle, and body composition assessments, as well as metabophenotype measurements of visceral adipose tissue, abdominal subcutaneous adipose tissue, muscle fat infiltration, fat-free muscle volume, and proton density fat fraction.

All participants were advised to maintain the same level of physical activity, which was measured through 7-day accelerometry. In addition, the patients were contacted every 2 weeks throughout the 24-week study period.

“We wanted to reinforce the dietary advice. We wanted to identify factors that may lead to compliance,” Dr. Siddiqui said. “Multiple studies have documented that the more contact that patients have during weight-loss studies with medical personnel, the more effective those strategies are.”

Overall, the dietary interventions were well tolerated, and neither group showed a significant change in renal function.

The average weight loss was –7.6 kg over 6 months in the low-carbohydrate group, as compared with –0.6 kg in the calorie-restrictive group.

The low carbohydrate diet also positively affected participants’ metabophenotype profile, particularly fat deposits. As compared with the calorie-restrictive group, the low-carbohydrate group showed statistically significant improvements in visceral adipose tissue, abdominal subcutaneous adipose tissue, and muscle fat infiltration.

The liver proton density fat fraction, which is associated with fatty liver disease, decreased by 0.53% in the low-carbohydrate group and increased by 0.46% in the calorie-restrictive group, but the difference didn’t reach statistical significance.

The fat-free muscle volume decreased by about 5% in the low-carbohydrate group. Dr. Siddiqui noted that the researchers don’t know yet whether this translates to a decrease in muscle function.

In terms of metabolic risk, the low-carbohydrate diet did not affect serum lipids (such as triglycerides or cholesterol measures), renal function (such as serum creatinine, glomerular filtration rate, or blood urea nitrogen), or insulin resistance (through glucose or hemoglobin A1c). At the same time, among patients taking insulin at the time of enrollment, about 90% of patients randomized to the low-carbohydrate group were able to reduce insulin to zero during the study.

Upon completion of the current study, Dr. Siddiqui and colleagues hope to provide foundational safety and efficacy data for carbohydrate restriction in liver transplant recipients. In the ongoing study, the researchers are further investigating the dietary intervention impacts on metabolic flexibility, skeletal muscle mitochondrial function, atherogenic lipoproteins, and vascular function.

“Are we actually, on a molecular level, fixing the fundamental problem that liver transplant recipients have to improve outcomes?” he said. “We’re doing very detailed profiling of these patients, so we will have data that shows how this actually affects them.”

Dr. Siddiqui was asked about the sustainability of the low-carbohydrate diet, particularly with a restrictive parameter of 20 grams per day. During the COVID-19 pandemic, Dr. Siddiqui noted, the study was slowed and the research team was able to collect follow-up data.

“Surprisingly, we have a high rate of compliance, even after 6 months of therapy, and I think this has to do with a patient population that’s been through cirrhosis and has almost died,” he said. “They’re far more compliant, and we’re seeing that. We’re also changing the physiology and improving mitochondrial function, which improves the weight loss and weight maintenance, though I don’t know how long that’s going to last.”

The study sponsorship was not disclosed. Dr. Siddiqui reported no relevant conflicts of interest.
 

The Food and Drug Administration has expanded the indication for tenofovir alafenamide (Vemlidy) to children aged 12 years and older with chronic hepatitis B virus (HBV) infection with compensated liver disease, the drug’s manufacturer has announced.

The approval in the pediatric patient population was supported by 24-week data from a phase 2 clinical trial comparing treatment with tenofovir alafenamide (25 mg once daily) with placebo in 70 treatment-naive and treatment-experienced patients aged 12-18 years weighing at least 35 kg.

The study met its primary endpoint of percentage of patients with HBV DNA levels less than 20 IU/mL at 24 weeks of therapy, Gilead Sciences said in a press release.

Overall, 10 of 47 (21%) patients treated with tenofovir alafenamide achieved HBV DNA less than 20 IU/mL at 24 weeks, compared with 0 of 23 (0%) treated with placebo.

The rates of serum ALT normalization were higher with tenofovir alafenamide than with placebo (44% vs 0%).

The mean percent changes in bone mineral density (BMD) from baseline to 24 weeks were numerically similar for tenofovir alafenamide– and placebo-treated patients (2.4% and 1.9% for lumbar spine, and 1.5% and 1.9% for whole body, respectively).

The mean changes from baseline BMD z scores were –0.03 and –0.09 for lumbar spine, and –0.05 and –0.01 for whole body, for tenofovir alafenamide and placebo groups, respectively.

The FDA initially approved the nucleoside analog reverse transcriptase inhibitor in 2016 for adults with chronic HBV.

The drug was approved in Europe in 2017 for chronic HBV infection in adults and adolescents aged 12 years and older weighing at least 35 kg.

Tenofovir alafenamide carries a boxed warning citing risks for lactic acidosis/severe hepatomegaly with steatosis and posttreatment severe acute exacerbation of HBV.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has expanded the indication for tenofovir alafenamide (Vemlidy) to children aged 12 years and older with chronic hepatitis B virus (HBV) infection with compensated liver disease, the drug’s manufacturer has announced.

The approval in the pediatric patient population was supported by 24-week data from a phase 2 clinical trial comparing treatment with tenofovir alafenamide (25 mg once daily) with placebo in 70 treatment-naive and treatment-experienced patients aged 12-18 years weighing at least 35 kg.

The study met its primary endpoint of percentage of patients with HBV DNA levels less than 20 IU/mL at 24 weeks of therapy, Gilead Sciences said in a press release.

Overall, 10 of 47 (21%) patients treated with tenofovir alafenamide achieved HBV DNA less than 20 IU/mL at 24 weeks, compared with 0 of 23 (0%) treated with placebo.

The rates of serum ALT normalization were higher with tenofovir alafenamide than with placebo (44% vs 0%).

The mean percent changes in bone mineral density (BMD) from baseline to 24 weeks were numerically similar for tenofovir alafenamide– and placebo-treated patients (2.4% and 1.9% for lumbar spine, and 1.5% and 1.9% for whole body, respectively).

The mean changes from baseline BMD z scores were –0.03 and –0.09 for lumbar spine, and –0.05 and –0.01 for whole body, for tenofovir alafenamide and placebo groups, respectively.

The FDA initially approved the nucleoside analog reverse transcriptase inhibitor in 2016 for adults with chronic HBV.

The drug was approved in Europe in 2017 for chronic HBV infection in adults and adolescents aged 12 years and older weighing at least 35 kg.

Tenofovir alafenamide carries a boxed warning citing risks for lactic acidosis/severe hepatomegaly with steatosis and posttreatment severe acute exacerbation of HBV.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has expanded the indication for tenofovir alafenamide (Vemlidy) to children aged 12 years and older with chronic hepatitis B virus (HBV) infection with compensated liver disease, the drug’s manufacturer has announced.

The approval in the pediatric patient population was supported by 24-week data from a phase 2 clinical trial comparing treatment with tenofovir alafenamide (25 mg once daily) with placebo in 70 treatment-naive and treatment-experienced patients aged 12-18 years weighing at least 35 kg.

The study met its primary endpoint of percentage of patients with HBV DNA levels less than 20 IU/mL at 24 weeks of therapy, Gilead Sciences said in a press release.

Overall, 10 of 47 (21%) patients treated with tenofovir alafenamide achieved HBV DNA less than 20 IU/mL at 24 weeks, compared with 0 of 23 (0%) treated with placebo.

The rates of serum ALT normalization were higher with tenofovir alafenamide than with placebo (44% vs 0%).

The mean percent changes in bone mineral density (BMD) from baseline to 24 weeks were numerically similar for tenofovir alafenamide– and placebo-treated patients (2.4% and 1.9% for lumbar spine, and 1.5% and 1.9% for whole body, respectively).

The mean changes from baseline BMD z scores were –0.03 and –0.09 for lumbar spine, and –0.05 and –0.01 for whole body, for tenofovir alafenamide and placebo groups, respectively.

The FDA initially approved the nucleoside analog reverse transcriptase inhibitor in 2016 for adults with chronic HBV.

The drug was approved in Europe in 2017 for chronic HBV infection in adults and adolescents aged 12 years and older weighing at least 35 kg.

Tenofovir alafenamide carries a boxed warning citing risks for lactic acidosis/severe hepatomegaly with steatosis and posttreatment severe acute exacerbation of HBV.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration (FDA) has declined to approve bulevirtide, Gilead Sciences’ drug for the treatment of hepatitis delta virus (HDV) infection and compensated liver disease.

In a complete response letter, the FDA voiced concerns over the production and delivery of bulevirtide, an investigational, first-in-class HDV entry-inhibitor that received conditional approved in Europe in 2020.

The FDA did not request new studies to evaluate the safety and efficacy of bulevirtide.

As reported previously by this news organization, data from an ongoing phase 3 trial showed that after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable HDV RNA levels and normalized alanine aminotransferase levels.

Chronic HDV infection is the most severe form of viral hepatitis. It is associated with a poor prognosis and high mortality rates.

There are currently no approved treatments for HDV in the United States. Bulevirtide was granted breakthrough therapy and orphan drug designations by the FDA.

Merdad Parsey, MD, PhD, chief medical officer, Gilead Sciences, wrote in a news release that the company looks forward to “continuing our active discussions with FDA so that we may bring bulevirtide to people living with HDV in the U.S. as soon as possible.”

This is the second manufacturing-related complete response letter Gilead has received in the past 8 months. In March, the FDA rejected the long-acting HIV drug lenacapavir. The drug was sanctioned in Europe and the United Kingdom in September.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration (FDA) has declined to approve bulevirtide, Gilead Sciences’ drug for the treatment of hepatitis delta virus (HDV) infection and compensated liver disease.

In a complete response letter, the FDA voiced concerns over the production and delivery of bulevirtide, an investigational, first-in-class HDV entry-inhibitor that received conditional approved in Europe in 2020.

The FDA did not request new studies to evaluate the safety and efficacy of bulevirtide.

As reported previously by this news organization, data from an ongoing phase 3 trial showed that after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable HDV RNA levels and normalized alanine aminotransferase levels.

Chronic HDV infection is the most severe form of viral hepatitis. It is associated with a poor prognosis and high mortality rates.

There are currently no approved treatments for HDV in the United States. Bulevirtide was granted breakthrough therapy and orphan drug designations by the FDA.

Merdad Parsey, MD, PhD, chief medical officer, Gilead Sciences, wrote in a news release that the company looks forward to “continuing our active discussions with FDA so that we may bring bulevirtide to people living with HDV in the U.S. as soon as possible.”

This is the second manufacturing-related complete response letter Gilead has received in the past 8 months. In March, the FDA rejected the long-acting HIV drug lenacapavir. The drug was sanctioned in Europe and the United Kingdom in September.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration (FDA) has declined to approve bulevirtide, Gilead Sciences’ drug for the treatment of hepatitis delta virus (HDV) infection and compensated liver disease.

In a complete response letter, the FDA voiced concerns over the production and delivery of bulevirtide, an investigational, first-in-class HDV entry-inhibitor that received conditional approved in Europe in 2020.

The FDA did not request new studies to evaluate the safety and efficacy of bulevirtide.

As reported previously by this news organization, data from an ongoing phase 3 trial showed that after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable HDV RNA levels and normalized alanine aminotransferase levels.

Chronic HDV infection is the most severe form of viral hepatitis. It is associated with a poor prognosis and high mortality rates.

There are currently no approved treatments for HDV in the United States. Bulevirtide was granted breakthrough therapy and orphan drug designations by the FDA.

Merdad Parsey, MD, PhD, chief medical officer, Gilead Sciences, wrote in a news release that the company looks forward to “continuing our active discussions with FDA so that we may bring bulevirtide to people living with HDV in the U.S. as soon as possible.”

This is the second manufacturing-related complete response letter Gilead has received in the past 8 months. In March, the FDA rejected the long-acting HIV drug lenacapavir. The drug was sanctioned in Europe and the United Kingdom in September.

A version of this article first appeared on Medscape.com.

Interleukin-22 may mitigate nonalcoholic fatty liver disease (NAFLD)–related fibrosis in females but not males, suggesting a sex-linked hepatoprotective pathway, according to investigators.

These differences between men and women should be considered when conducting clinical trials for IL-22–targeting therapies, reported lead author Mohamed N. Abdelnabi, MSc, of the Centre de Recherche du Centre Hospitalier de l’Université de Montréal and colleagues.

“IL-22 is a pleiotropic cytokine with both inflammatory and protective effects during injury and repair in various tissues including the liver,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, noting that IL-22 activity has been linked with both antifibrotic and profibrotic outcomes in previous preclinical studies. “These different observations highlight the dual nature of IL-22 that likely is dictated by multiple factors including the tissue involved, pathologic environment, endogenous vs. exogenous IL-22 level, and the time of exposure.”

Prior research has left some questions unanswered, the investigators noted, because many studies have relied on exogenous administration of IL-22 in mouse models, some of which lack all the metabolic abnormalities observed in human disease. Furthermore, these mice were all male, which has prevented detection of possible sex-linked differences in IL-22–related pathophysiology, they added.

To address these gaps, the investigators conducted a series of experiments involving men and women with NAFLD, plus mice of both sexes with NAFLD induced by a high-fat diet, both wild-type and with knock-out of the IL-22 receptor.
 

Human data

To characterize IL-22 activity in men versus women with NAFLD, the investigators first analyzed two publicly available microarray datasets. These revealed notably increased expression of hepatic IL-22 mRNA in the livers of females compared with males. Supporting this finding, liver biopsies from 11 men and 9 women with NAFLD with similar levels of fibrosis showed significantly increased IL-22–producing cells in female patients compared with male patients.

“These results suggest a sexual dimorphic expression of IL-22 in the context of NAFLD,” the investigators wrote.
 

Mouse data

Echoing the human data, the livers of female wild-type mice with NAFLD had significantly greater IL-22 expression than male mice at both mRNA and protein levels.

Next, the investigators explored the effects of IL-22–receptor knockout. In addition to NAFLD, these knockout mice developed weight gain and metabolic alterations, especially insulin resistance, supporting previous work that highlighted the protective role of IL-22 against these outcomes. More relevant to the present study, female knockout mice had significantly worse hepatic liver injury, apoptosis, inflammation, and fibrosis than male knockout mice, suggesting that IL-22 signaling confers hepatoprotection in females but not males.

“These observations may suggest a regulation of IL-22 expression by the female sex hormone estrogen,” the investigators wrote. “Indeed, estrogen is known to modulate inflammatory responses in NAFLD, but the underlying mechanisms remain undefined. ... Further in vivo studies are warranted to investigate whether endogenous estrogen regulates hepatic IL-22 expression in the context of NAFLD.”

In the meantime, the present data may steer drug development.

“These findings should be considered in clinical trials testing IL-22–based therapeutic approaches in treatment of female vs. male subjects with NAFLD,” the investigators concluded.

The study was partially funded by the Canadian Liver Foundation and the Canadian Institutes of Health Research, the Bourse d’Exemption des Droits de Scolarité Supplémentaires from the Université de Montréal, the Canadian Network on Hepatitis, and others. The investigators disclosed no competing interests.

Interleukin-22 may mitigate nonalcoholic fatty liver disease (NAFLD)–related fibrosis in females but not males, suggesting a sex-linked hepatoprotective pathway, according to investigators.

These differences between men and women should be considered when conducting clinical trials for IL-22–targeting therapies, reported lead author Mohamed N. Abdelnabi, MSc, of the Centre de Recherche du Centre Hospitalier de l’Université de Montréal and colleagues.

“IL-22 is a pleiotropic cytokine with both inflammatory and protective effects during injury and repair in various tissues including the liver,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, noting that IL-22 activity has been linked with both antifibrotic and profibrotic outcomes in previous preclinical studies. “These different observations highlight the dual nature of IL-22 that likely is dictated by multiple factors including the tissue involved, pathologic environment, endogenous vs. exogenous IL-22 level, and the time of exposure.”

Prior research has left some questions unanswered, the investigators noted, because many studies have relied on exogenous administration of IL-22 in mouse models, some of which lack all the metabolic abnormalities observed in human disease. Furthermore, these mice were all male, which has prevented detection of possible sex-linked differences in IL-22–related pathophysiology, they added.

To address these gaps, the investigators conducted a series of experiments involving men and women with NAFLD, plus mice of both sexes with NAFLD induced by a high-fat diet, both wild-type and with knock-out of the IL-22 receptor.
 

Human data

To characterize IL-22 activity in men versus women with NAFLD, the investigators first analyzed two publicly available microarray datasets. These revealed notably increased expression of hepatic IL-22 mRNA in the livers of females compared with males. Supporting this finding, liver biopsies from 11 men and 9 women with NAFLD with similar levels of fibrosis showed significantly increased IL-22–producing cells in female patients compared with male patients.

“These results suggest a sexual dimorphic expression of IL-22 in the context of NAFLD,” the investigators wrote.
 

Mouse data

Echoing the human data, the livers of female wild-type mice with NAFLD had significantly greater IL-22 expression than male mice at both mRNA and protein levels.

Next, the investigators explored the effects of IL-22–receptor knockout. In addition to NAFLD, these knockout mice developed weight gain and metabolic alterations, especially insulin resistance, supporting previous work that highlighted the protective role of IL-22 against these outcomes. More relevant to the present study, female knockout mice had significantly worse hepatic liver injury, apoptosis, inflammation, and fibrosis than male knockout mice, suggesting that IL-22 signaling confers hepatoprotection in females but not males.

“These observations may suggest a regulation of IL-22 expression by the female sex hormone estrogen,” the investigators wrote. “Indeed, estrogen is known to modulate inflammatory responses in NAFLD, but the underlying mechanisms remain undefined. ... Further in vivo studies are warranted to investigate whether endogenous estrogen regulates hepatic IL-22 expression in the context of NAFLD.”

In the meantime, the present data may steer drug development.

“These findings should be considered in clinical trials testing IL-22–based therapeutic approaches in treatment of female vs. male subjects with NAFLD,” the investigators concluded.

The study was partially funded by the Canadian Liver Foundation and the Canadian Institutes of Health Research, the Bourse d’Exemption des Droits de Scolarité Supplémentaires from the Université de Montréal, the Canadian Network on Hepatitis, and others. The investigators disclosed no competing interests.

Interleukin-22 may mitigate nonalcoholic fatty liver disease (NAFLD)–related fibrosis in females but not males, suggesting a sex-linked hepatoprotective pathway, according to investigators.

These differences between men and women should be considered when conducting clinical trials for IL-22–targeting therapies, reported lead author Mohamed N. Abdelnabi, MSc, of the Centre de Recherche du Centre Hospitalier de l’Université de Montréal and colleagues.

“IL-22 is a pleiotropic cytokine with both inflammatory and protective effects during injury and repair in various tissues including the liver,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, noting that IL-22 activity has been linked with both antifibrotic and profibrotic outcomes in previous preclinical studies. “These different observations highlight the dual nature of IL-22 that likely is dictated by multiple factors including the tissue involved, pathologic environment, endogenous vs. exogenous IL-22 level, and the time of exposure.”

Prior research has left some questions unanswered, the investigators noted, because many studies have relied on exogenous administration of IL-22 in mouse models, some of which lack all the metabolic abnormalities observed in human disease. Furthermore, these mice were all male, which has prevented detection of possible sex-linked differences in IL-22–related pathophysiology, they added.

To address these gaps, the investigators conducted a series of experiments involving men and women with NAFLD, plus mice of both sexes with NAFLD induced by a high-fat diet, both wild-type and with knock-out of the IL-22 receptor.
 

Human data

To characterize IL-22 activity in men versus women with NAFLD, the investigators first analyzed two publicly available microarray datasets. These revealed notably increased expression of hepatic IL-22 mRNA in the livers of females compared with males. Supporting this finding, liver biopsies from 11 men and 9 women with NAFLD with similar levels of fibrosis showed significantly increased IL-22–producing cells in female patients compared with male patients.

“These results suggest a sexual dimorphic expression of IL-22 in the context of NAFLD,” the investigators wrote.
 

Mouse data

Echoing the human data, the livers of female wild-type mice with NAFLD had significantly greater IL-22 expression than male mice at both mRNA and protein levels.

Next, the investigators explored the effects of IL-22–receptor knockout. In addition to NAFLD, these knockout mice developed weight gain and metabolic alterations, especially insulin resistance, supporting previous work that highlighted the protective role of IL-22 against these outcomes. More relevant to the present study, female knockout mice had significantly worse hepatic liver injury, apoptosis, inflammation, and fibrosis than male knockout mice, suggesting that IL-22 signaling confers hepatoprotection in females but not males.

“These observations may suggest a regulation of IL-22 expression by the female sex hormone estrogen,” the investigators wrote. “Indeed, estrogen is known to modulate inflammatory responses in NAFLD, but the underlying mechanisms remain undefined. ... Further in vivo studies are warranted to investigate whether endogenous estrogen regulates hepatic IL-22 expression in the context of NAFLD.”

In the meantime, the present data may steer drug development.

“These findings should be considered in clinical trials testing IL-22–based therapeutic approaches in treatment of female vs. male subjects with NAFLD,” the investigators concluded.

The study was partially funded by the Canadian Liver Foundation and the Canadian Institutes of Health Research, the Bourse d’Exemption des Droits de Scolarité Supplémentaires from the Université de Montréal, the Canadian Network on Hepatitis, and others. The investigators disclosed no competing interests.

CHARLOTTE, N.C. – Metabolic and genetic risk factors for nonalcoholic fatty liver disease (NAFLD) vary across the age spectrum, but once steatosis has started, the risk of progression to cirrhosis is similar for both young and old, investigators found.

At a large Midwest medical center, younger adults were more likely than older patients to have a high-risk gene variant predisposing carriers to NAFLD. And they were less likely than their senior counterparts to have metabolic risk factors, reported Matthew J. Miller, MD, a 3rd-year resident in the department of internal medicine at the University of Michigan Hospital in Ann Arbor.

“Progression to cirrhosis was similar in patients younger than 40, compared to older patients, suggesting NAFLD in the young should not be considered more benign than in older patients,” he said in an oral abstract presented at the annual meeting of the American College of Gastroenterology.

MDedge News/Neil Osterweil

The prevalence of NAFLD among younger adults is increasing, but it’s still unknown whether the course of NAFLD is more benign in these patients than in older adults.

In addition, the rate of progression to cirrhosis in patients with NAFLD can vary, making it difficult to predict those patients most at risk for advanced liver disease, Dr. Miller said.

He and his colleagues sought to characterize genetic and metabolic risk factors for NAFLD and their effects on disease progression in patients from 18 to 40 years, 40 to 59 years, and 60 and older.

The investigators collected data on patients with documented objective evidence of NAFLD seen at the Michigan Medicine health care system from 2010 through 2021.

They identified NAFLD by hepatic steatosis on imaging, biopsy, or transient elastography in the absence of other chronic liver diseases, with the earliest date of a hepatic steatosis diagnosis determined to be the index date.

The investigators determined the presence of cirrhosis using validated International Classification of Diseases version 9 or 10 codes, with incident cirrhosis defined as any new cirrhosis diagnosis at least 1 year after the index date.

They also looked at the frequency of known NAFLD risk alleles in a subset of patients with available genetic data.

They divided 31,505 patients into three age groups for comparison: 8,252 patients age 18-39 at the time of steatosis identification, 15,035 age 40-59, and 8,218 age 60 or older.

Of the full cohort, 804 had cirrhosis at the index date, and 388 others developed incident cirrhosis during 128,090 person-years of follow-up.

The prevalence of hypertension, hyperlipidemia, and diabetes were significantly lower in the youngest group, compared with the two older groups, but the youngest patients had a higher prevalence of obesity than the other two groups, with a significantly higher prevalence of class 3 (morbid) obesity.

Of the 4,359 patients with genetic data available, the NAFLD-promoting PNPLA3-rs738409-G allele was more common in the young, compared with the other two age groups (P = .016).

When the investigators looked at the ability of three laboratory tests – the AST to Platelet Ratio Index (APRI), Fibrosis-4 (FIB4), and NAFLD fibrosis score for identifying prevalent cirrhosis – they found that the scores performed similarly for patients in the 40-59 group, but the NFS did less well among patients in the 18-39 group. There were no significant differences among the three age groups in the risk for incident cirrhosis over 10 years.

The study helps to answer some of the questions surrounding differences in risk factors across the age spectrum, commented Patricia Jones, MD, MSCR, from the University of Miami.

“We wonder how these people with fatty liver are different. Do younger people have a more malignant course? Are they going to progress more rapidly than others, or not? Because if you think of a disease like fatty liver or for that matter any metabolic syndrome–based disease, it’s a spectrum and a continuum, and by the time you’re diagnosed you’ve already had that condition, so it’s really more interesting to me when people are diagnosed, because diagnosing at a younger age allows you to intervene earlier,” she said in an interview.

Dr. Jones said that she was also interested in exploring how the genetic data might be used to improve care for patients, perhaps by testing for the high-risk allele in routine clinical practice.

“It will be interesting to see how people with this allele progress, independently of whether they’re diagnosed at 40, 50, or 60,” she said.

Dr. Jones was a moderator of the session where Dr. Williams presented his data.

Comoderator Mitchell A. Mah’moud, MD, FACG from Duke University in Durham, N.C., commented in an interview that, “with the medications we have available, maybe we can target these patients and prevent progression to cirrhosis and some of the decompensation that we see.”

The study authors did not disclose a funding source. Dr. Miller, Dr. Jones, and Dr. Mah’moud all reported having no relevant financial disclosures.

CHARLOTTE, N.C. – Metabolic and genetic risk factors for nonalcoholic fatty liver disease (NAFLD) vary across the age spectrum, but once steatosis has started, the risk of progression to cirrhosis is similar for both young and old, investigators found.

At a large Midwest medical center, younger adults were more likely than older patients to have a high-risk gene variant predisposing carriers to NAFLD. And they were less likely than their senior counterparts to have metabolic risk factors, reported Matthew J. Miller, MD, a 3rd-year resident in the department of internal medicine at the University of Michigan Hospital in Ann Arbor.

“Progression to cirrhosis was similar in patients younger than 40, compared to older patients, suggesting NAFLD in the young should not be considered more benign than in older patients,” he said in an oral abstract presented at the annual meeting of the American College of Gastroenterology.

MDedge News/Neil Osterweil

The prevalence of NAFLD among younger adults is increasing, but it’s still unknown whether the course of NAFLD is more benign in these patients than in older adults.

In addition, the rate of progression to cirrhosis in patients with NAFLD can vary, making it difficult to predict those patients most at risk for advanced liver disease, Dr. Miller said.

He and his colleagues sought to characterize genetic and metabolic risk factors for NAFLD and their effects on disease progression in patients from 18 to 40 years, 40 to 59 years, and 60 and older.

The investigators collected data on patients with documented objective evidence of NAFLD seen at the Michigan Medicine health care system from 2010 through 2021.

They identified NAFLD by hepatic steatosis on imaging, biopsy, or transient elastography in the absence of other chronic liver diseases, with the earliest date of a hepatic steatosis diagnosis determined to be the index date.

The investigators determined the presence of cirrhosis using validated International Classification of Diseases version 9 or 10 codes, with incident cirrhosis defined as any new cirrhosis diagnosis at least 1 year after the index date.

They also looked at the frequency of known NAFLD risk alleles in a subset of patients with available genetic data.

They divided 31,505 patients into three age groups for comparison: 8,252 patients age 18-39 at the time of steatosis identification, 15,035 age 40-59, and 8,218 age 60 or older.

Of the full cohort, 804 had cirrhosis at the index date, and 388 others developed incident cirrhosis during 128,090 person-years of follow-up.

The prevalence of hypertension, hyperlipidemia, and diabetes were significantly lower in the youngest group, compared with the two older groups, but the youngest patients had a higher prevalence of obesity than the other two groups, with a significantly higher prevalence of class 3 (morbid) obesity.

Of the 4,359 patients with genetic data available, the NAFLD-promoting PNPLA3-rs738409-G allele was more common in the young, compared with the other two age groups (P = .016).

When the investigators looked at the ability of three laboratory tests – the AST to Platelet Ratio Index (APRI), Fibrosis-4 (FIB4), and NAFLD fibrosis score for identifying prevalent cirrhosis – they found that the scores performed similarly for patients in the 40-59 group, but the NFS did less well among patients in the 18-39 group. There were no significant differences among the three age groups in the risk for incident cirrhosis over 10 years.

The study helps to answer some of the questions surrounding differences in risk factors across the age spectrum, commented Patricia Jones, MD, MSCR, from the University of Miami.

“We wonder how these people with fatty liver are different. Do younger people have a more malignant course? Are they going to progress more rapidly than others, or not? Because if you think of a disease like fatty liver or for that matter any metabolic syndrome–based disease, it’s a spectrum and a continuum, and by the time you’re diagnosed you’ve already had that condition, so it’s really more interesting to me when people are diagnosed, because diagnosing at a younger age allows you to intervene earlier,” she said in an interview.

Dr. Jones said that she was also interested in exploring how the genetic data might be used to improve care for patients, perhaps by testing for the high-risk allele in routine clinical practice.

“It will be interesting to see how people with this allele progress, independently of whether they’re diagnosed at 40, 50, or 60,” she said.

Dr. Jones was a moderator of the session where Dr. Williams presented his data.

Comoderator Mitchell A. Mah’moud, MD, FACG from Duke University in Durham, N.C., commented in an interview that, “with the medications we have available, maybe we can target these patients and prevent progression to cirrhosis and some of the decompensation that we see.”

The study authors did not disclose a funding source. Dr. Miller, Dr. Jones, and Dr. Mah’moud all reported having no relevant financial disclosures.

CHARLOTTE, N.C. – Metabolic and genetic risk factors for nonalcoholic fatty liver disease (NAFLD) vary across the age spectrum, but once steatosis has started, the risk of progression to cirrhosis is similar for both young and old, investigators found.

At a large Midwest medical center, younger adults were more likely than older patients to have a high-risk gene variant predisposing carriers to NAFLD. And they were less likely than their senior counterparts to have metabolic risk factors, reported Matthew J. Miller, MD, a 3rd-year resident in the department of internal medicine at the University of Michigan Hospital in Ann Arbor.

“Progression to cirrhosis was similar in patients younger than 40, compared to older patients, suggesting NAFLD in the young should not be considered more benign than in older patients,” he said in an oral abstract presented at the annual meeting of the American College of Gastroenterology.

MDedge News/Neil Osterweil

The prevalence of NAFLD among younger adults is increasing, but it’s still unknown whether the course of NAFLD is more benign in these patients than in older adults.

In addition, the rate of progression to cirrhosis in patients with NAFLD can vary, making it difficult to predict those patients most at risk for advanced liver disease, Dr. Miller said.

He and his colleagues sought to characterize genetic and metabolic risk factors for NAFLD and their effects on disease progression in patients from 18 to 40 years, 40 to 59 years, and 60 and older.

The investigators collected data on patients with documented objective evidence of NAFLD seen at the Michigan Medicine health care system from 2010 through 2021.

They identified NAFLD by hepatic steatosis on imaging, biopsy, or transient elastography in the absence of other chronic liver diseases, with the earliest date of a hepatic steatosis diagnosis determined to be the index date.

The investigators determined the presence of cirrhosis using validated International Classification of Diseases version 9 or 10 codes, with incident cirrhosis defined as any new cirrhosis diagnosis at least 1 year after the index date.

They also looked at the frequency of known NAFLD risk alleles in a subset of patients with available genetic data.

They divided 31,505 patients into three age groups for comparison: 8,252 patients age 18-39 at the time of steatosis identification, 15,035 age 40-59, and 8,218 age 60 or older.

Of the full cohort, 804 had cirrhosis at the index date, and 388 others developed incident cirrhosis during 128,090 person-years of follow-up.

The prevalence of hypertension, hyperlipidemia, and diabetes were significantly lower in the youngest group, compared with the two older groups, but the youngest patients had a higher prevalence of obesity than the other two groups, with a significantly higher prevalence of class 3 (morbid) obesity.

Of the 4,359 patients with genetic data available, the NAFLD-promoting PNPLA3-rs738409-G allele was more common in the young, compared with the other two age groups (P = .016).

When the investigators looked at the ability of three laboratory tests – the AST to Platelet Ratio Index (APRI), Fibrosis-4 (FIB4), and NAFLD fibrosis score for identifying prevalent cirrhosis – they found that the scores performed similarly for patients in the 40-59 group, but the NFS did less well among patients in the 18-39 group. There were no significant differences among the three age groups in the risk for incident cirrhosis over 10 years.

The study helps to answer some of the questions surrounding differences in risk factors across the age spectrum, commented Patricia Jones, MD, MSCR, from the University of Miami.

“We wonder how these people with fatty liver are different. Do younger people have a more malignant course? Are they going to progress more rapidly than others, or not? Because if you think of a disease like fatty liver or for that matter any metabolic syndrome–based disease, it’s a spectrum and a continuum, and by the time you’re diagnosed you’ve already had that condition, so it’s really more interesting to me when people are diagnosed, because diagnosing at a younger age allows you to intervene earlier,” she said in an interview.

Dr. Jones said that she was also interested in exploring how the genetic data might be used to improve care for patients, perhaps by testing for the high-risk allele in routine clinical practice.

“It will be interesting to see how people with this allele progress, independently of whether they’re diagnosed at 40, 50, or 60,” she said.

Dr. Jones was a moderator of the session where Dr. Williams presented his data.

Comoderator Mitchell A. Mah’moud, MD, FACG from Duke University in Durham, N.C., commented in an interview that, “with the medications we have available, maybe we can target these patients and prevent progression to cirrhosis and some of the decompensation that we see.”

The study authors did not disclose a funding source. Dr. Miller, Dr. Jones, and Dr. Mah’moud all reported having no relevant financial disclosures.

In a subgroup of patients with hepatorenal syndrome type 1 (HRS) who received a liver transplant, terlipressin treatment appears to reduce the need for renal replacement therapy (RRT) through 12 months of follow-up, according to a study presented at the annual meeting of the American College of Gastroenterology.

Among transplant recipients, overall 12-month survival was 11% higher for those treated with terlipressin compared with placebo, said K. Rajender Reddy, MD, director of hepatology and medical director of liver transplantation at the University of Pennsylvania, Philadelphia.

“Hepatorenal syndrome type 1 is a potentially reversible form of acute kidney injury that occurs in the setting of end-stage liver disease,” he said.

Liver transplantation, which eliminates end-stage liver disease, is the only definitive treatment for HRS. However, renal replacement therapy is common and associated with poor clinical outcomes and low patient survival rates in both the pretransplant and posttransplant settings, he noted.

Terlipressin, an injectable synthetic vasopressin analogue, restores renal blood flow and reverses HRS in 20%-40% of patients, Dr. Reddy said. In September, the U.S. Food and Drug Administration approved terlipressin (Terlivaz) for patients with HRS type 1. The label has a boxed warning for serious or fatal respiratory failure.

The safety and efficacy were assessed in the phase 3 CONFIRM trial, which Dr. Reddy and colleagues previously published. The randomized, placebo-controlled study demonstrated that terlipressin reversed HRS and reduced the need for RRT through day 30. The reversal of HRS with terlipressin did not improve 90-day survival as compared with placebo, which researchers attributed to a higher death rate within 90 days after the first dose despite improved kidney function.

A closer look at the liver transplant patients

In the subgroup analysis of the CONFIRM study, Dr. Reddy and colleagues analyzed the clinical outcomes through 12 months of follow-up in patients with HRS who received a liver transplant. They looked at the incidence of verified HRS reversal, HRS reversal, need for RRT, and overall survival.

Verified HRS reversal was defined as two consecutive serum creatinine measurements of 1.5 mg/dL or less at least 2 hours apart up to day 14 and survival without RRT for at least 10 days. HRS reversal was defined as a serum creatinine level of 1.5 mg/dL or less while on treatment. In addition, the need for RRT and overall survival were assessed at days 30, 60, 90, 180, and 365.

RRT was defined as any procedure that replaced nonendocrine kidney function, including continuous hemofiltration and hemodialysis, intermittent hemodialysis, peritoneal dialysis, ultrafiltration, or other dialysis and filtration techniques.

In the CONFIRM study, 199 patients with HRS were treated with terlipressin plus albumin, and 101 patients were treated with placebo plus albumin for up to 14 days. In the terlipressin group, 46 patients received liver transplants within the first 2 months of the study, as did 29 in the placebo group. Two patients in the terlipressin group and one in the placebo group received a simultaneous liver-kidney transplant.
 

Meaningful clinical outcomes

In the 12-month follow-up subgroup analysis, verified HRS reversal was statistically comparable between the groups, with a 30% decrease in the terlipressin group and 17% decrease in the placebo group, Dr. Reddy reported.

HRS reversal was higher in the terlipressin group, at 37%, as compared with 14% in the placebo group.

The pretransplant need for RRT was lower in the terlipressin group, at 30%, as compared with 62% in the placebo group. The posttransplant need for RRT remained numerically lower in the terlipressin group at all time points and was significantly lower at day 180 and day 365.

Overall survival for transplant recipients in the terlipressin group was 94%, as compared with 83% in the placebo group. Posttreatment adverse events and severe adverse events were similar between the groups.

“Collectively, these data indicate that terlipressin treatment in patients with HRS led to better long-term clinical outcomes in those who received a liver transplant,” Dr. Reddy said.

The study was funded by Mallinckrodt Pharmaceuticals, which manufactures terlipressin. One author is an employee of Mallinckrodt, and the other authors have served in an advisory role or received grant support from Mallinckrodt. The authors also disclosed consultant roles and research support from several other pharmaceutical companies.

In a subgroup of patients with hepatorenal syndrome type 1 (HRS) who received a liver transplant, terlipressin treatment appears to reduce the need for renal replacement therapy (RRT) through 12 months of follow-up, according to a study presented at the annual meeting of the American College of Gastroenterology.

Among transplant recipients, overall 12-month survival was 11% higher for those treated with terlipressin compared with placebo, said K. Rajender Reddy, MD, director of hepatology and medical director of liver transplantation at the University of Pennsylvania, Philadelphia.

“Hepatorenal syndrome type 1 is a potentially reversible form of acute kidney injury that occurs in the setting of end-stage liver disease,” he said.

Liver transplantation, which eliminates end-stage liver disease, is the only definitive treatment for HRS. However, renal replacement therapy is common and associated with poor clinical outcomes and low patient survival rates in both the pretransplant and posttransplant settings, he noted.

Terlipressin, an injectable synthetic vasopressin analogue, restores renal blood flow and reverses HRS in 20%-40% of patients, Dr. Reddy said. In September, the U.S. Food and Drug Administration approved terlipressin (Terlivaz) for patients with HRS type 1. The label has a boxed warning for serious or fatal respiratory failure.

The safety and efficacy were assessed in the phase 3 CONFIRM trial, which Dr. Reddy and colleagues previously published. The randomized, placebo-controlled study demonstrated that terlipressin reversed HRS and reduced the need for RRT through day 30. The reversal of HRS with terlipressin did not improve 90-day survival as compared with placebo, which researchers attributed to a higher death rate within 90 days after the first dose despite improved kidney function.

A closer look at the liver transplant patients

In the subgroup analysis of the CONFIRM study, Dr. Reddy and colleagues analyzed the clinical outcomes through 12 months of follow-up in patients with HRS who received a liver transplant. They looked at the incidence of verified HRS reversal, HRS reversal, need for RRT, and overall survival.

Verified HRS reversal was defined as two consecutive serum creatinine measurements of 1.5 mg/dL or less at least 2 hours apart up to day 14 and survival without RRT for at least 10 days. HRS reversal was defined as a serum creatinine level of 1.5 mg/dL or less while on treatment. In addition, the need for RRT and overall survival were assessed at days 30, 60, 90, 180, and 365.

RRT was defined as any procedure that replaced nonendocrine kidney function, including continuous hemofiltration and hemodialysis, intermittent hemodialysis, peritoneal dialysis, ultrafiltration, or other dialysis and filtration techniques.

In the CONFIRM study, 199 patients with HRS were treated with terlipressin plus albumin, and 101 patients were treated with placebo plus albumin for up to 14 days. In the terlipressin group, 46 patients received liver transplants within the first 2 months of the study, as did 29 in the placebo group. Two patients in the terlipressin group and one in the placebo group received a simultaneous liver-kidney transplant.
 

Meaningful clinical outcomes

In the 12-month follow-up subgroup analysis, verified HRS reversal was statistically comparable between the groups, with a 30% decrease in the terlipressin group and 17% decrease in the placebo group, Dr. Reddy reported.

HRS reversal was higher in the terlipressin group, at 37%, as compared with 14% in the placebo group.

The pretransplant need for RRT was lower in the terlipressin group, at 30%, as compared with 62% in the placebo group. The posttransplant need for RRT remained numerically lower in the terlipressin group at all time points and was significantly lower at day 180 and day 365.

Overall survival for transplant recipients in the terlipressin group was 94%, as compared with 83% in the placebo group. Posttreatment adverse events and severe adverse events were similar between the groups.

“Collectively, these data indicate that terlipressin treatment in patients with HRS led to better long-term clinical outcomes in those who received a liver transplant,” Dr. Reddy said.

The study was funded by Mallinckrodt Pharmaceuticals, which manufactures terlipressin. One author is an employee of Mallinckrodt, and the other authors have served in an advisory role or received grant support from Mallinckrodt. The authors also disclosed consultant roles and research support from several other pharmaceutical companies.

In a subgroup of patients with hepatorenal syndrome type 1 (HRS) who received a liver transplant, terlipressin treatment appears to reduce the need for renal replacement therapy (RRT) through 12 months of follow-up, according to a study presented at the annual meeting of the American College of Gastroenterology.

Among transplant recipients, overall 12-month survival was 11% higher for those treated with terlipressin compared with placebo, said K. Rajender Reddy, MD, director of hepatology and medical director of liver transplantation at the University of Pennsylvania, Philadelphia.

“Hepatorenal syndrome type 1 is a potentially reversible form of acute kidney injury that occurs in the setting of end-stage liver disease,” he said.

Liver transplantation, which eliminates end-stage liver disease, is the only definitive treatment for HRS. However, renal replacement therapy is common and associated with poor clinical outcomes and low patient survival rates in both the pretransplant and posttransplant settings, he noted.

Terlipressin, an injectable synthetic vasopressin analogue, restores renal blood flow and reverses HRS in 20%-40% of patients, Dr. Reddy said. In September, the U.S. Food and Drug Administration approved terlipressin (Terlivaz) for patients with HRS type 1. The label has a boxed warning for serious or fatal respiratory failure.

The safety and efficacy were assessed in the phase 3 CONFIRM trial, which Dr. Reddy and colleagues previously published. The randomized, placebo-controlled study demonstrated that terlipressin reversed HRS and reduced the need for RRT through day 30. The reversal of HRS with terlipressin did not improve 90-day survival as compared with placebo, which researchers attributed to a higher death rate within 90 days after the first dose despite improved kidney function.

A closer look at the liver transplant patients

In the subgroup analysis of the CONFIRM study, Dr. Reddy and colleagues analyzed the clinical outcomes through 12 months of follow-up in patients with HRS who received a liver transplant. They looked at the incidence of verified HRS reversal, HRS reversal, need for RRT, and overall survival.

Verified HRS reversal was defined as two consecutive serum creatinine measurements of 1.5 mg/dL or less at least 2 hours apart up to day 14 and survival without RRT for at least 10 days. HRS reversal was defined as a serum creatinine level of 1.5 mg/dL or less while on treatment. In addition, the need for RRT and overall survival were assessed at days 30, 60, 90, 180, and 365.

RRT was defined as any procedure that replaced nonendocrine kidney function, including continuous hemofiltration and hemodialysis, intermittent hemodialysis, peritoneal dialysis, ultrafiltration, or other dialysis and filtration techniques.

In the CONFIRM study, 199 patients with HRS were treated with terlipressin plus albumin, and 101 patients were treated with placebo plus albumin for up to 14 days. In the terlipressin group, 46 patients received liver transplants within the first 2 months of the study, as did 29 in the placebo group. Two patients in the terlipressin group and one in the placebo group received a simultaneous liver-kidney transplant.
 

Meaningful clinical outcomes

In the 12-month follow-up subgroup analysis, verified HRS reversal was statistically comparable between the groups, with a 30% decrease in the terlipressin group and 17% decrease in the placebo group, Dr. Reddy reported.

HRS reversal was higher in the terlipressin group, at 37%, as compared with 14% in the placebo group.

The pretransplant need for RRT was lower in the terlipressin group, at 30%, as compared with 62% in the placebo group. The posttransplant need for RRT remained numerically lower in the terlipressin group at all time points and was significantly lower at day 180 and day 365.

Overall survival for transplant recipients in the terlipressin group was 94%, as compared with 83% in the placebo group. Posttreatment adverse events and severe adverse events were similar between the groups.

“Collectively, these data indicate that terlipressin treatment in patients with HRS led to better long-term clinical outcomes in those who received a liver transplant,” Dr. Reddy said.

The study was funded by Mallinckrodt Pharmaceuticals, which manufactures terlipressin. One author is an employee of Mallinckrodt, and the other authors have served in an advisory role or received grant support from Mallinckrodt. The authors also disclosed consultant roles and research support from several other pharmaceutical companies.

The COVID-19 pandemic fueled a sharp uptick in deaths related to chronic liver disease and cirrhosis among people with diabetes, largely owing to nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), new data show.

“Our observations confirm that COVID-19 had a higher likelihood of impacting vulnerable populations with pre-existing chronic liver diseases and diabetes, with a death rate as high as 10% in individuals with co-existing chronic liver disease and diabetes,” write the authors.

“The inability to attend regular outpatient clinics for close monitoring and treatment accompanied by diversion of health care resources to COVID-19 care may have resulted in the suboptimal or delayed clinical care of individuals with diabetes and chronic liver disease during the COVID-19 pandemic,” they add.

Donghee Kim, MD, PhD, with the Division of Gastroenterology and Hepatology, Stanford (Calif.) University School of Medicine, and colleagues report their findings in the journal Digestive and Liver Disease.
 

Vulnerable group

The researchers used U.S. national mortality data (2017-2020) to estimate chronic liver disease–related mortality trends among individuals with diabetes before and during the COVID-19 pandemic.

Before the pandemic, the quarterly mortality for chronic liver disease remained stable (quarterly percentage change, 0.6%) but then sharply increased during the pandemic (QPC, 8.6%).

A similar trend was seen with cirrhosis-related mortality (QPC, 0.3% before the pandemic vs. 8.4% during the pandemic).

NAFLD and ALD mortality among individuals with diabetes was steadily increasing before the pandemic (QPC, 4.2% and 3.5%, respectively) but showed a more rapid increase during the pandemic (QPC, 9.6% and 7.7%, respectively).

ALD-related mortality in men was more than threefold higher than in women, while NAFLD-related mortality in women was more than twofold higher than in men.

Mortality for hepatitis C virus infection declined before the pandemic (QPC, −3.3%) and remained stable during the pandemic.

COVID-19–related mortality among adults with chronic liver disease and diabetes also rose sharply during the pandemic – from 0.4% in the first quarter of 2020 to 12.9% in the last quarter of 2020 – with no considerable difference between men and women.
 

Blame it on lockdowns?

Dr. Kim and colleagues say research is needed to better understand the direct and indirect influence of COVID-19 on coexisting chronic liver disease and diabetes.

“It is plausible that psychosocial stress and a higher predisposition to psychiatric disorders during the COVID-19 pandemic can increase the risk of alcohol use disorder and ALD,” they write.

“Furthermore, it is prudent to suspect that COVID-19–related lockdowns may increase the risk of obesity, leading to a higher risk of insulin resistance and metabolic complications, including diabetes and NAFLD. Future studies are needed to improve our understanding of these possible pathogenetic links. More importantly, emergency preparedness or contingency plans must be in place to continue and provide uninterrupted care for chronic ailments during times of disaster,” they add.

The study had no specific funding. The authors report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The COVID-19 pandemic fueled a sharp uptick in deaths related to chronic liver disease and cirrhosis among people with diabetes, largely owing to nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), new data show.

“Our observations confirm that COVID-19 had a higher likelihood of impacting vulnerable populations with pre-existing chronic liver diseases and diabetes, with a death rate as high as 10% in individuals with co-existing chronic liver disease and diabetes,” write the authors.

“The inability to attend regular outpatient clinics for close monitoring and treatment accompanied by diversion of health care resources to COVID-19 care may have resulted in the suboptimal or delayed clinical care of individuals with diabetes and chronic liver disease during the COVID-19 pandemic,” they add.

Donghee Kim, MD, PhD, with the Division of Gastroenterology and Hepatology, Stanford (Calif.) University School of Medicine, and colleagues report their findings in the journal Digestive and Liver Disease.
 

Vulnerable group

The researchers used U.S. national mortality data (2017-2020) to estimate chronic liver disease–related mortality trends among individuals with diabetes before and during the COVID-19 pandemic.

Before the pandemic, the quarterly mortality for chronic liver disease remained stable (quarterly percentage change, 0.6%) but then sharply increased during the pandemic (QPC, 8.6%).

A similar trend was seen with cirrhosis-related mortality (QPC, 0.3% before the pandemic vs. 8.4% during the pandemic).

NAFLD and ALD mortality among individuals with diabetes was steadily increasing before the pandemic (QPC, 4.2% and 3.5%, respectively) but showed a more rapid increase during the pandemic (QPC, 9.6% and 7.7%, respectively).

ALD-related mortality in men was more than threefold higher than in women, while NAFLD-related mortality in women was more than twofold higher than in men.

Mortality for hepatitis C virus infection declined before the pandemic (QPC, −3.3%) and remained stable during the pandemic.

COVID-19–related mortality among adults with chronic liver disease and diabetes also rose sharply during the pandemic – from 0.4% in the first quarter of 2020 to 12.9% in the last quarter of 2020 – with no considerable difference between men and women.
 

Blame it on lockdowns?

Dr. Kim and colleagues say research is needed to better understand the direct and indirect influence of COVID-19 on coexisting chronic liver disease and diabetes.

“It is plausible that psychosocial stress and a higher predisposition to psychiatric disorders during the COVID-19 pandemic can increase the risk of alcohol use disorder and ALD,” they write.

“Furthermore, it is prudent to suspect that COVID-19–related lockdowns may increase the risk of obesity, leading to a higher risk of insulin resistance and metabolic complications, including diabetes and NAFLD. Future studies are needed to improve our understanding of these possible pathogenetic links. More importantly, emergency preparedness or contingency plans must be in place to continue and provide uninterrupted care for chronic ailments during times of disaster,” they add.

The study had no specific funding. The authors report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The COVID-19 pandemic fueled a sharp uptick in deaths related to chronic liver disease and cirrhosis among people with diabetes, largely owing to nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), new data show.

“Our observations confirm that COVID-19 had a higher likelihood of impacting vulnerable populations with pre-existing chronic liver diseases and diabetes, with a death rate as high as 10% in individuals with co-existing chronic liver disease and diabetes,” write the authors.

“The inability to attend regular outpatient clinics for close monitoring and treatment accompanied by diversion of health care resources to COVID-19 care may have resulted in the suboptimal or delayed clinical care of individuals with diabetes and chronic liver disease during the COVID-19 pandemic,” they add.

Donghee Kim, MD, PhD, with the Division of Gastroenterology and Hepatology, Stanford (Calif.) University School of Medicine, and colleagues report their findings in the journal Digestive and Liver Disease.
 

Vulnerable group

The researchers used U.S. national mortality data (2017-2020) to estimate chronic liver disease–related mortality trends among individuals with diabetes before and during the COVID-19 pandemic.

Before the pandemic, the quarterly mortality for chronic liver disease remained stable (quarterly percentage change, 0.6%) but then sharply increased during the pandemic (QPC, 8.6%).

A similar trend was seen with cirrhosis-related mortality (QPC, 0.3% before the pandemic vs. 8.4% during the pandemic).

NAFLD and ALD mortality among individuals with diabetes was steadily increasing before the pandemic (QPC, 4.2% and 3.5%, respectively) but showed a more rapid increase during the pandemic (QPC, 9.6% and 7.7%, respectively).

ALD-related mortality in men was more than threefold higher than in women, while NAFLD-related mortality in women was more than twofold higher than in men.

Mortality for hepatitis C virus infection declined before the pandemic (QPC, −3.3%) and remained stable during the pandemic.

COVID-19–related mortality among adults with chronic liver disease and diabetes also rose sharply during the pandemic – from 0.4% in the first quarter of 2020 to 12.9% in the last quarter of 2020 – with no considerable difference between men and women.
 

Blame it on lockdowns?

Dr. Kim and colleagues say research is needed to better understand the direct and indirect influence of COVID-19 on coexisting chronic liver disease and diabetes.

“It is plausible that psychosocial stress and a higher predisposition to psychiatric disorders during the COVID-19 pandemic can increase the risk of alcohol use disorder and ALD,” they write.

“Furthermore, it is prudent to suspect that COVID-19–related lockdowns may increase the risk of obesity, leading to a higher risk of insulin resistance and metabolic complications, including diabetes and NAFLD. Future studies are needed to improve our understanding of these possible pathogenetic links. More importantly, emergency preparedness or contingency plans must be in place to continue and provide uninterrupted care for chronic ailments during times of disaster,” they add.

The study had no specific funding. The authors report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Acute kidney injury (AKI) in patients with cirrhosis is potentially preventable, and there are clear steps that can be taken to manage and reverse the condition, concludes a clinical practice update from the American Gastroenterological Association.

AKI occurs in 47% of patients hospitalized with complications of cirrhosis and in approximately 30% of outpatients with cirrhosis, resulting in a total cost in the United States of $4 billion, explained Patrick S. Kamath, MD, division of gastroenterology and hepatology, Mayo Medical School, Rochester, Minn., one of the authors of this update.

Moreover, Dr. Kamath told this news organization, among patients with cirrhosis and AKI, morbidity and mortality is sevenfold higher in comparison to those without cirrhosis, and repeated episodes of AKI increase the risk of progression to chronic kidney disease.

To provide practical advice for the clinical management of patients with cirrhosis and AKI, the authors conducted an expert review of the best available published evidence and gathered expert opinion.

The update was published online in Clinical Gastroenterology and Hepatology.
 

Some key takeaways

Among its 14 best practice statements, it describes three situations indicative of AKI:

• A serum creatinine increase of 0.3 mg/dL or more within 48 hours, or
• A serum creatinine increase of 50% or more from baseline, which is a stable serum creatinine in the past 3 months.
• Reduction in urine output of up to 0.5 mL/kg per hour for more than 6 hours.

The update also emphasizes the importance of an accurate diagnosis, inasmuch as not all cases of AKI are due to hepatorenal syndrome (HRS), for example. It goes on to advise that the specific type of AKI be identified through medical history and physical examination, as well as with blood biochemistry, urine microscopic examination, urine chemistry, selected urinary biomarkers, and renal ultrasound.

Additionally, it underscores the need to identify and treat infections and to closely monitor fluid status.

Nancy S. Reau, MD, Rush Medical College, Chicago, who was not involved in the update, commented to this news organization that fluid status is important when giving albumin replacement therapy because of the increased risk for pulmonary edema.

She also highlighted that this update advises against transjugular intrahepatic portosystemic shunts (TIPSs) as a specific treatment for HRS-AKI, noting that, although the 2022 North American Practice-Based Recommendations for Transjugular Intrahepatic Portosystemic Shunts in Portal Hypertension do not advocate for TIPS for this indication, they also indicated that there was enough evidence to advise against it.

In other key best practice advice statements, the update advises clinicians to hold diuretics and nonselective beta blockers and to discontinue nonsteroidal anti-inflammatory drugs (NSAIDs).
 

‘Timely’ update

Overall, Dr. Reau believes that the update is “timely, especially in light of the recent [U.S.] approval of terlipressin, which will change our treatment options.”

This update also supports the American Association for the Study of Liver Diseases (AASLD) 2021 Practice Guidance guidelines on HRS, she added.

Zobair Younossi, MD, MPH, professor of medicine, Virginia Commonwealth University, Inova Campus, Falls Church, Va., who was not involved in writing the update, told this news organization that the document is important because of the huge increase in mortality among patients with cirrhosis and AKI.

He commented that there has been much advancement in understanding the condition, with updated nomenclature and novel medical treatments, and that this makes the update timely.

Moreover, the update will help clinicians who are involved in the care of patients with cirrhosis, he added.

Dr. Younossi said the update offers a very clearly stated algorithm for how to identify patients whose condition is easily reversible with volume repletion, in comparison with those patients who require medical treatment or even liver transplantation.

“Those things are important because that pathway gives clinicians an idea of how to do this properly,” he said.

“The key for clinicians is to make sure they understand, in the context of cirrhosis, some of the easy things that they can do to prevent AKI,” he continued. He added that the use of NSAIDs in these patients is “going to be problematic.”

Dr. Kamath has a relationship with Sequana Medical. Other authors’ relevant financial relationships are listed in the original article. Dr. Reau has relationships with Salix and Intercept. Dr. Younossi has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

This article was updated 12/12/2022.

Acute kidney injury (AKI) in patients with cirrhosis is potentially preventable, and there are clear steps that can be taken to manage and reverse the condition, concludes a clinical practice update from the American Gastroenterological Association.

AKI occurs in 47% of patients hospitalized with complications of cirrhosis and in approximately 30% of outpatients with cirrhosis, resulting in a total cost in the United States of $4 billion, explained Patrick S. Kamath, MD, division of gastroenterology and hepatology, Mayo Medical School, Rochester, Minn., one of the authors of this update.

Moreover, Dr. Kamath told this news organization, among patients with cirrhosis and AKI, morbidity and mortality is sevenfold higher in comparison to those without cirrhosis, and repeated episodes of AKI increase the risk of progression to chronic kidney disease.

To provide practical advice for the clinical management of patients with cirrhosis and AKI, the authors conducted an expert review of the best available published evidence and gathered expert opinion.

The update was published online in Clinical Gastroenterology and Hepatology.
 

Some key takeaways

Among its 14 best practice statements, it describes three situations indicative of AKI:

• A serum creatinine increase of 0.3 mg/dL or more within 48 hours, or
• A serum creatinine increase of 50% or more from baseline, which is a stable serum creatinine in the past 3 months.
• Reduction in urine output of up to 0.5 mL/kg per hour for more than 6 hours.

The update also emphasizes the importance of an accurate diagnosis, inasmuch as not all cases of AKI are due to hepatorenal syndrome (HRS), for example. It goes on to advise that the specific type of AKI be identified through medical history and physical examination, as well as with blood biochemistry, urine microscopic examination, urine chemistry, selected urinary biomarkers, and renal ultrasound.

Additionally, it underscores the need to identify and treat infections and to closely monitor fluid status.

Nancy S. Reau, MD, Rush Medical College, Chicago, who was not involved in the update, commented to this news organization that fluid status is important when giving albumin replacement therapy because of the increased risk for pulmonary edema.

She also highlighted that this update advises against transjugular intrahepatic portosystemic shunts (TIPSs) as a specific treatment for HRS-AKI, noting that, although the 2022 North American Practice-Based Recommendations for Transjugular Intrahepatic Portosystemic Shunts in Portal Hypertension do not advocate for TIPS for this indication, they also indicated that there was enough evidence to advise against it.

In other key best practice advice statements, the update advises clinicians to hold diuretics and nonselective beta blockers and to discontinue nonsteroidal anti-inflammatory drugs (NSAIDs).
 

‘Timely’ update

Overall, Dr. Reau believes that the update is “timely, especially in light of the recent [U.S.] approval of terlipressin, which will change our treatment options.”

This update also supports the American Association for the Study of Liver Diseases (AASLD) 2021 Practice Guidance guidelines on HRS, she added.

Zobair Younossi, MD, MPH, professor of medicine, Virginia Commonwealth University, Inova Campus, Falls Church, Va., who was not involved in writing the update, told this news organization that the document is important because of the huge increase in mortality among patients with cirrhosis and AKI.

He commented that there has been much advancement in understanding the condition, with updated nomenclature and novel medical treatments, and that this makes the update timely.

Moreover, the update will help clinicians who are involved in the care of patients with cirrhosis, he added.

Dr. Younossi said the update offers a very clearly stated algorithm for how to identify patients whose condition is easily reversible with volume repletion, in comparison with those patients who require medical treatment or even liver transplantation.

“Those things are important because that pathway gives clinicians an idea of how to do this properly,” he said.

“The key for clinicians is to make sure they understand, in the context of cirrhosis, some of the easy things that they can do to prevent AKI,” he continued. He added that the use of NSAIDs in these patients is “going to be problematic.”

Dr. Kamath has a relationship with Sequana Medical. Other authors’ relevant financial relationships are listed in the original article. Dr. Reau has relationships with Salix and Intercept. Dr. Younossi has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

This article was updated 12/12/2022.

Acute kidney injury (AKI) in patients with cirrhosis is potentially preventable, and there are clear steps that can be taken to manage and reverse the condition, concludes a clinical practice update from the American Gastroenterological Association.

AKI occurs in 47% of patients hospitalized with complications of cirrhosis and in approximately 30% of outpatients with cirrhosis, resulting in a total cost in the United States of $4 billion, explained Patrick S. Kamath, MD, division of gastroenterology and hepatology, Mayo Medical School, Rochester, Minn., one of the authors of this update.

Moreover, Dr. Kamath told this news organization, among patients with cirrhosis and AKI, morbidity and mortality is sevenfold higher in comparison to those without cirrhosis, and repeated episodes of AKI increase the risk of progression to chronic kidney disease.

To provide practical advice for the clinical management of patients with cirrhosis and AKI, the authors conducted an expert review of the best available published evidence and gathered expert opinion.

The update was published online in Clinical Gastroenterology and Hepatology.
 

Some key takeaways

Among its 14 best practice statements, it describes three situations indicative of AKI:

• A serum creatinine increase of 0.3 mg/dL or more within 48 hours, or
• A serum creatinine increase of 50% or more from baseline, which is a stable serum creatinine in the past 3 months.
• Reduction in urine output of up to 0.5 mL/kg per hour for more than 6 hours.

The update also emphasizes the importance of an accurate diagnosis, inasmuch as not all cases of AKI are due to hepatorenal syndrome (HRS), for example. It goes on to advise that the specific type of AKI be identified through medical history and physical examination, as well as with blood biochemistry, urine microscopic examination, urine chemistry, selected urinary biomarkers, and renal ultrasound.

Additionally, it underscores the need to identify and treat infections and to closely monitor fluid status.

Nancy S. Reau, MD, Rush Medical College, Chicago, who was not involved in the update, commented to this news organization that fluid status is important when giving albumin replacement therapy because of the increased risk for pulmonary edema.

She also highlighted that this update advises against transjugular intrahepatic portosystemic shunts (TIPSs) as a specific treatment for HRS-AKI, noting that, although the 2022 North American Practice-Based Recommendations for Transjugular Intrahepatic Portosystemic Shunts in Portal Hypertension do not advocate for TIPS for this indication, they also indicated that there was enough evidence to advise against it.

In other key best practice advice statements, the update advises clinicians to hold diuretics and nonselective beta blockers and to discontinue nonsteroidal anti-inflammatory drugs (NSAIDs).
 

‘Timely’ update

Overall, Dr. Reau believes that the update is “timely, especially in light of the recent [U.S.] approval of terlipressin, which will change our treatment options.”

This update also supports the American Association for the Study of Liver Diseases (AASLD) 2021 Practice Guidance guidelines on HRS, she added.

Zobair Younossi, MD, MPH, professor of medicine, Virginia Commonwealth University, Inova Campus, Falls Church, Va., who was not involved in writing the update, told this news organization that the document is important because of the huge increase in mortality among patients with cirrhosis and AKI.

He commented that there has been much advancement in understanding the condition, with updated nomenclature and novel medical treatments, and that this makes the update timely.

Moreover, the update will help clinicians who are involved in the care of patients with cirrhosis, he added.

Dr. Younossi said the update offers a very clearly stated algorithm for how to identify patients whose condition is easily reversible with volume repletion, in comparison with those patients who require medical treatment or even liver transplantation.

“Those things are important because that pathway gives clinicians an idea of how to do this properly,” he said.

“The key for clinicians is to make sure they understand, in the context of cirrhosis, some of the easy things that they can do to prevent AKI,” he continued. He added that the use of NSAIDs in these patients is “going to be problematic.”

Dr. Kamath has a relationship with Sequana Medical. Other authors’ relevant financial relationships are listed in the original article. Dr. Reau has relationships with Salix and Intercept. Dr. Younossi has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

This article was updated 12/12/2022.