Liver Disease

Among hospitalized patients with cirrhosis, a machine learning (ML) model enhanced mortality prediction compared with traditional methods and was consistent across country income levels in a large global study.

“This highly inclusive, representative, and globally derived model has been externally validated,” Jasmohan Bajaj, MD, AGAF, professor of medicine at Virginia Commonwealth University in Richmond, Virginia, told GI & Hepatology News. “This gives us a crystal ball. It helps hospital teams, transplant centers, gastroenterology and intensive care unit services triage and prioritize patients more effectively.”

The study supporting the model, which Bajaj said “could be used at this stage,” was published online in Gastroenterology. The model is available for downloading at https://silveys.shinyapps.io/app_cleared/.

 

CLEARED Cohort Analyzed

Wide variations across the world regarding available resources, outpatient services, reasons for admission, and etiologies of cirrhosis can influence patient outcomes, according to Bajaj and colleagues. Therefore, they sought to use ML approaches to improve prognostication for all countries.

They analyzed admission-day data from the prospective Chronic Liver Disease Evolution And Registry for Events and Decompensation (CLEARED) consortium, which includes inpatients with cirrhosis enrolled from six continents. The analysis compared ML approaches with logistical regression to predict inpatient mortality.

The researchers performed internal validation (75/25 split) and subdivision using World-Bank income status: low/low-middle (L-LMIC), upper middle (UMIC), and high (HIC). They determined that the ML model with the best area-under-the-curve (AUC) would be externally validated in a US-Veteran cirrhosis inpatient population.

The CLEARED cohort included 7239 cirrhosis inpatients (mean age, 56 years; 64% men; median MELD-Na, 25) from 115 centers globally; 22.5% of centers belonged to LMICs, 41% to UMICs, and 34% to HICs.

A total of 808 patients (11.1%) died in the hospital.

Random-Forest analysis showed the best AUC (0.815) with high calibration. This was significantly better than parametric logistic regression (AUC, 0.774) and LASSO (AUC, 0.787) models.

Random-Forest also was better than logistic regression regardless of country income-level: HIC (AUC,0.806), UMIC (AUC, 0.867), and L-LMICs (AUC, 0.768).

Of the top 15 important variables selected from Random-Forest, admission for acute kidney injury, hepatic encephalopathy, high MELD-Na/white blood count, and not being in high income country were variables most predictive of mortality.

In contrast, higher albumin, hemoglobin, diuretic use on admission, viral etiology, and being in a high-income country were most protective.

The Random-Forest model was validated in 28,670 veterans (mean age, 67 years; 96% men; median MELD-Na,15), with an inpatient mortality of 4% (1158 patients).

The final Random-Forest model, using 48 of the 67 original covariates, attained a strong AUC of 0.859. A refit version using only the top 15 variables achieved a comparable AUC of 0.851.

 

Clinical Relevance

“Cirrhosis and resultant organ failures remain a dynamic and multidisciplinary problem,” Bajaj noted. “Machine learning techniques are one part of multi-faceted management strategy that is required in this population.”

If patients fall into the high-risk category, he said, “careful consultation with patients, families, and clinical teams is needed before providing information, including where this model was derived from. The results of these discussions could be instructive regarding decisions for transfer, more aggressive monitoring/ICU transfer, palliative care or transplant assessments.”

Meena B. Bansal, MD, system chief, Division of Liver Diseases, Mount Sinai Health System in New York City, called the tool “very promising.” However, she told GI & Hepatology News, “it was validated on a VA [Veterans Affairs] cohort, which is a bit different than the cohort of patients seen at Mount Sinai. Therefore, validation in more academic tertiary care medical centers with high volume liver transplant would be helpful.”

 

Furthermore, said Bansal, who was not involved in the study, “they excluded those that receiving a liver transplant, and while only a small number, this is an important limitation.”

Nevertheless, she added, “Artificial intelligence has great potential in predictive risk models and will likely be a tool that assists for risk stratification, clinical management, and hopefully improved clinical outcomes.”

This study was partly supported by a VA Merit review to Bajaj and the National Center for Advancing Translational Sciences, National Institutes of Health. No conflicts of interest were reported by any author.

A version of this article appeared on Medscape.com.

Among hospitalized patients with cirrhosis, a machine learning (ML) model enhanced mortality prediction compared with traditional methods and was consistent across country income levels in a large global study.

“This highly inclusive, representative, and globally derived model has been externally validated,” Jasmohan Bajaj, MD, AGAF, professor of medicine at Virginia Commonwealth University in Richmond, Virginia, told GI & Hepatology News. “This gives us a crystal ball. It helps hospital teams, transplant centers, gastroenterology and intensive care unit services triage and prioritize patients more effectively.”

The study supporting the model, which Bajaj said “could be used at this stage,” was published online in Gastroenterology. The model is available for downloading at https://silveys.shinyapps.io/app_cleared/.

 

CLEARED Cohort Analyzed

Wide variations across the world regarding available resources, outpatient services, reasons for admission, and etiologies of cirrhosis can influence patient outcomes, according to Bajaj and colleagues. Therefore, they sought to use ML approaches to improve prognostication for all countries.

They analyzed admission-day data from the prospective Chronic Liver Disease Evolution And Registry for Events and Decompensation (CLEARED) consortium, which includes inpatients with cirrhosis enrolled from six continents. The analysis compared ML approaches with logistical regression to predict inpatient mortality.

The researchers performed internal validation (75/25 split) and subdivision using World-Bank income status: low/low-middle (L-LMIC), upper middle (UMIC), and high (HIC). They determined that the ML model with the best area-under-the-curve (AUC) would be externally validated in a US-Veteran cirrhosis inpatient population.

The CLEARED cohort included 7239 cirrhosis inpatients (mean age, 56 years; 64% men; median MELD-Na, 25) from 115 centers globally; 22.5% of centers belonged to LMICs, 41% to UMICs, and 34% to HICs.

A total of 808 patients (11.1%) died in the hospital.

Random-Forest analysis showed the best AUC (0.815) with high calibration. This was significantly better than parametric logistic regression (AUC, 0.774) and LASSO (AUC, 0.787) models.

Random-Forest also was better than logistic regression regardless of country income-level: HIC (AUC,0.806), UMIC (AUC, 0.867), and L-LMICs (AUC, 0.768).

Of the top 15 important variables selected from Random-Forest, admission for acute kidney injury, hepatic encephalopathy, high MELD-Na/white blood count, and not being in high income country were variables most predictive of mortality.

In contrast, higher albumin, hemoglobin, diuretic use on admission, viral etiology, and being in a high-income country were most protective.

The Random-Forest model was validated in 28,670 veterans (mean age, 67 years; 96% men; median MELD-Na,15), with an inpatient mortality of 4% (1158 patients).

The final Random-Forest model, using 48 of the 67 original covariates, attained a strong AUC of 0.859. A refit version using only the top 15 variables achieved a comparable AUC of 0.851.

 

Clinical Relevance

“Cirrhosis and resultant organ failures remain a dynamic and multidisciplinary problem,” Bajaj noted. “Machine learning techniques are one part of multi-faceted management strategy that is required in this population.”

If patients fall into the high-risk category, he said, “careful consultation with patients, families, and clinical teams is needed before providing information, including where this model was derived from. The results of these discussions could be instructive regarding decisions for transfer, more aggressive monitoring/ICU transfer, palliative care or transplant assessments.”

Meena B. Bansal, MD, system chief, Division of Liver Diseases, Mount Sinai Health System in New York City, called the tool “very promising.” However, she told GI & Hepatology News, “it was validated on a VA [Veterans Affairs] cohort, which is a bit different than the cohort of patients seen at Mount Sinai. Therefore, validation in more academic tertiary care medical centers with high volume liver transplant would be helpful.”

 

Furthermore, said Bansal, who was not involved in the study, “they excluded those that receiving a liver transplant, and while only a small number, this is an important limitation.”

Nevertheless, she added, “Artificial intelligence has great potential in predictive risk models and will likely be a tool that assists for risk stratification, clinical management, and hopefully improved clinical outcomes.”

This study was partly supported by a VA Merit review to Bajaj and the National Center for Advancing Translational Sciences, National Institutes of Health. No conflicts of interest were reported by any author.

A version of this article appeared on Medscape.com.

Among hospitalized patients with cirrhosis, a machine learning (ML) model enhanced mortality prediction compared with traditional methods and was consistent across country income levels in a large global study.

“This highly inclusive, representative, and globally derived model has been externally validated,” Jasmohan Bajaj, MD, AGAF, professor of medicine at Virginia Commonwealth University in Richmond, Virginia, told GI & Hepatology News. “This gives us a crystal ball. It helps hospital teams, transplant centers, gastroenterology and intensive care unit services triage and prioritize patients more effectively.”

The study supporting the model, which Bajaj said “could be used at this stage,” was published online in Gastroenterology. The model is available for downloading at https://silveys.shinyapps.io/app_cleared/.

 

CLEARED Cohort Analyzed

Wide variations across the world regarding available resources, outpatient services, reasons for admission, and etiologies of cirrhosis can influence patient outcomes, according to Bajaj and colleagues. Therefore, they sought to use ML approaches to improve prognostication for all countries.

They analyzed admission-day data from the prospective Chronic Liver Disease Evolution And Registry for Events and Decompensation (CLEARED) consortium, which includes inpatients with cirrhosis enrolled from six continents. The analysis compared ML approaches with logistical regression to predict inpatient mortality.

The researchers performed internal validation (75/25 split) and subdivision using World-Bank income status: low/low-middle (L-LMIC), upper middle (UMIC), and high (HIC). They determined that the ML model with the best area-under-the-curve (AUC) would be externally validated in a US-Veteran cirrhosis inpatient population.

The CLEARED cohort included 7239 cirrhosis inpatients (mean age, 56 years; 64% men; median MELD-Na, 25) from 115 centers globally; 22.5% of centers belonged to LMICs, 41% to UMICs, and 34% to HICs.

A total of 808 patients (11.1%) died in the hospital.

Random-Forest analysis showed the best AUC (0.815) with high calibration. This was significantly better than parametric logistic regression (AUC, 0.774) and LASSO (AUC, 0.787) models.

Random-Forest also was better than logistic regression regardless of country income-level: HIC (AUC,0.806), UMIC (AUC, 0.867), and L-LMICs (AUC, 0.768).

Of the top 15 important variables selected from Random-Forest, admission for acute kidney injury, hepatic encephalopathy, high MELD-Na/white blood count, and not being in high income country were variables most predictive of mortality.

In contrast, higher albumin, hemoglobin, diuretic use on admission, viral etiology, and being in a high-income country were most protective.

The Random-Forest model was validated in 28,670 veterans (mean age, 67 years; 96% men; median MELD-Na,15), with an inpatient mortality of 4% (1158 patients).

The final Random-Forest model, using 48 of the 67 original covariates, attained a strong AUC of 0.859. A refit version using only the top 15 variables achieved a comparable AUC of 0.851.

 

Clinical Relevance

“Cirrhosis and resultant organ failures remain a dynamic and multidisciplinary problem,” Bajaj noted. “Machine learning techniques are one part of multi-faceted management strategy that is required in this population.”

If patients fall into the high-risk category, he said, “careful consultation with patients, families, and clinical teams is needed before providing information, including where this model was derived from. The results of these discussions could be instructive regarding decisions for transfer, more aggressive monitoring/ICU transfer, palliative care or transplant assessments.”

Meena B. Bansal, MD, system chief, Division of Liver Diseases, Mount Sinai Health System in New York City, called the tool “very promising.” However, she told GI & Hepatology News, “it was validated on a VA [Veterans Affairs] cohort, which is a bit different than the cohort of patients seen at Mount Sinai. Therefore, validation in more academic tertiary care medical centers with high volume liver transplant would be helpful.”

 

Furthermore, said Bansal, who was not involved in the study, “they excluded those that receiving a liver transplant, and while only a small number, this is an important limitation.”

Nevertheless, she added, “Artificial intelligence has great potential in predictive risk models and will likely be a tool that assists for risk stratification, clinical management, and hopefully improved clinical outcomes.”

This study was partly supported by a VA Merit review to Bajaj and the National Center for Advancing Translational Sciences, National Institutes of Health. No conflicts of interest were reported by any author.

A version of this article appeared on Medscape.com.

Neighborhood-level social determinants of health (SDOH) are associated with the burden, comorbidities, and mortality of metabolic dysfunction-associated steatotic disease (MASLD). These health mediators should be considered along with individual SDOH in clinical care and healthcare quality and equity improvement, a large retrospective study of adults with MASLD at a multi-state healthcare institution concluded.

Across quartiles, patients in the most disadvantaged neighborhoods (according to home addresses) vs the least disadvantaged had worse outcomes and were also disproportionately Hispanic, Black, and Native American/Alaska Native, more often Spanish-speaking in primary language, and more often uninsured or on Medicaid, according to Karn Wijarnpreecha, MD, MPH, of the Division of Gastroenterology and Hepatology at University of Arizona College of Medicine–Phoenix, and colleagues writing in Clinical Gastroenterology and Hepatology.

Even after adjustment for measures in the Social Deprivation Index (SDI), the incidence of death, cirrhosis, diabetes mellitus (DM), and major adverse cardiovascular events (MACE) was higher in Native American/Alaska Native patients compared with their non-Hispanic White counterparts. The SDI is a composite measure of seven demographic characteristics from the American Community Survey, with scores ranging from 1 to 100 and weighted based on characteristics from national percentile rankings.

Aligning with the growing prevalence of obesity and DM, MASLD has increased substantially over the past three decades, and is now the leading cause of chronic liver disease in this country and the world. 

This rise in prevalence has underscored health disparities in MASLD and prompted research into linkd between liver disease and SDOH, defined as the conditions under which people are born, grow, live, work, and age. These are fundamental drivers of health disparities, including those in MASLD.
 

Study Details

Primary outcomes were MASLD burden, mortality, and comorbidities by neighborhood SDOH, assessed using the SDI in cross-sectional and longitudinal analyses.

A total of 69,191 adult patients (more than 50% female) diagnosed with MASLD were included, 45,003 of whom had at least 365 days of follow-up. They were treated from July 2012 to June 2023 in Banner Health Systems, a network that includes primary-, secondary-, and tertiary-care centers in Arizona, Colorado, Wyoming, Nevada, Nebraska, and California.

The median follow-up time was 48 months. Among patients across SDI quartiles (age range 49 to 62 years), 1390 patients (3.1%) died, 902 (2.0%) developed cirrhosis, 1087 (2.4%) developed LRE, 6537 (14.5%) developed DM, 2057 (4.6%) developed cancer, and 5409 (12.0%) developed MACE.

Those living in the most disadvantaged quartile of neighborhoods compared with the least had the following higher odds:

• cirrhosis, adjusted odds ratio [aOR], 1.42 (P < .001)
• any cardiovascular (CVD) disease, aOR, 1.20 (P < .001),
• coronary artery disease, aOR, 1.17 (P < .001)
• congestive heart failure, aOR, 1.43 (P < .001)
• cerebrovascular accident, aOR, 1.19 (P = .001)
• DM, aOR, 1.57 (P < .001)
• hypertension, aOR, 1.38 (P < .001).

They also had increased incidence of death (adjusted hazard ratio [aHR], 1.47; P < .001), LRE (aHR, 1.31; P = .012), DM (aHR, 1.47; P < .001), and MACE (aHR, 1.24; P < .001). 

The study expands upon previous SDOH-related research in liver disease and is the largest analysis of neighborhood-level SDOH in patients with MASLD to date. “Our findings are consistent with a recent study by Chen et al of over 15,900 patients with MASLD in Michigan that found neighborhood-level social disadvantage was associated with increased mortality and incident LREs and CVD,” Wijarnpreecha and colleagues wrote. 

“Beyond screening patients for individual-level SDOH, neighborhood-level determinants of health should also be considered, as they are important mediators between the environment and the individual,” they added, calling for studies to better understand the specific neighborhood SDOH that drive the disparate outcomes. In practice, integration of these measures into medical records might inform clinicians which patients would benefit from social services or help guide quality improvement projects and community partnerships.

Wijarnpreecha had no conflicts of interest to disclose. Several coauthors reported research support, consulting/advisory work, or stock ownership for various private-sector companies.
 

Neighborhood-level social determinants of health (SDOH) are associated with the burden, comorbidities, and mortality of metabolic dysfunction-associated steatotic disease (MASLD). These health mediators should be considered along with individual SDOH in clinical care and healthcare quality and equity improvement, a large retrospective study of adults with MASLD at a multi-state healthcare institution concluded.

Across quartiles, patients in the most disadvantaged neighborhoods (according to home addresses) vs the least disadvantaged had worse outcomes and were also disproportionately Hispanic, Black, and Native American/Alaska Native, more often Spanish-speaking in primary language, and more often uninsured or on Medicaid, according to Karn Wijarnpreecha, MD, MPH, of the Division of Gastroenterology and Hepatology at University of Arizona College of Medicine–Phoenix, and colleagues writing in Clinical Gastroenterology and Hepatology.

Even after adjustment for measures in the Social Deprivation Index (SDI), the incidence of death, cirrhosis, diabetes mellitus (DM), and major adverse cardiovascular events (MACE) was higher in Native American/Alaska Native patients compared with their non-Hispanic White counterparts. The SDI is a composite measure of seven demographic characteristics from the American Community Survey, with scores ranging from 1 to 100 and weighted based on characteristics from national percentile rankings.

Aligning with the growing prevalence of obesity and DM, MASLD has increased substantially over the past three decades, and is now the leading cause of chronic liver disease in this country and the world. 

This rise in prevalence has underscored health disparities in MASLD and prompted research into linkd between liver disease and SDOH, defined as the conditions under which people are born, grow, live, work, and age. These are fundamental drivers of health disparities, including those in MASLD.
 

Study Details

Primary outcomes were MASLD burden, mortality, and comorbidities by neighborhood SDOH, assessed using the SDI in cross-sectional and longitudinal analyses.

A total of 69,191 adult patients (more than 50% female) diagnosed with MASLD were included, 45,003 of whom had at least 365 days of follow-up. They were treated from July 2012 to June 2023 in Banner Health Systems, a network that includes primary-, secondary-, and tertiary-care centers in Arizona, Colorado, Wyoming, Nevada, Nebraska, and California.

The median follow-up time was 48 months. Among patients across SDI quartiles (age range 49 to 62 years), 1390 patients (3.1%) died, 902 (2.0%) developed cirrhosis, 1087 (2.4%) developed LRE, 6537 (14.5%) developed DM, 2057 (4.6%) developed cancer, and 5409 (12.0%) developed MACE.

Those living in the most disadvantaged quartile of neighborhoods compared with the least had the following higher odds:

• cirrhosis, adjusted odds ratio [aOR], 1.42 (P < .001)
• any cardiovascular (CVD) disease, aOR, 1.20 (P < .001),
• coronary artery disease, aOR, 1.17 (P < .001)
• congestive heart failure, aOR, 1.43 (P < .001)
• cerebrovascular accident, aOR, 1.19 (P = .001)
• DM, aOR, 1.57 (P < .001)
• hypertension, aOR, 1.38 (P < .001).

They also had increased incidence of death (adjusted hazard ratio [aHR], 1.47; P < .001), LRE (aHR, 1.31; P = .012), DM (aHR, 1.47; P < .001), and MACE (aHR, 1.24; P < .001). 

The study expands upon previous SDOH-related research in liver disease and is the largest analysis of neighborhood-level SDOH in patients with MASLD to date. “Our findings are consistent with a recent study by Chen et al of over 15,900 patients with MASLD in Michigan that found neighborhood-level social disadvantage was associated with increased mortality and incident LREs and CVD,” Wijarnpreecha and colleagues wrote. 

“Beyond screening patients for individual-level SDOH, neighborhood-level determinants of health should also be considered, as they are important mediators between the environment and the individual,” they added, calling for studies to better understand the specific neighborhood SDOH that drive the disparate outcomes. In practice, integration of these measures into medical records might inform clinicians which patients would benefit from social services or help guide quality improvement projects and community partnerships.

Wijarnpreecha had no conflicts of interest to disclose. Several coauthors reported research support, consulting/advisory work, or stock ownership for various private-sector companies.
 

Neighborhood-level social determinants of health (SDOH) are associated with the burden, comorbidities, and mortality of metabolic dysfunction-associated steatotic disease (MASLD). These health mediators should be considered along with individual SDOH in clinical care and healthcare quality and equity improvement, a large retrospective study of adults with MASLD at a multi-state healthcare institution concluded.

Across quartiles, patients in the most disadvantaged neighborhoods (according to home addresses) vs the least disadvantaged had worse outcomes and were also disproportionately Hispanic, Black, and Native American/Alaska Native, more often Spanish-speaking in primary language, and more often uninsured or on Medicaid, according to Karn Wijarnpreecha, MD, MPH, of the Division of Gastroenterology and Hepatology at University of Arizona College of Medicine–Phoenix, and colleagues writing in Clinical Gastroenterology and Hepatology.

Even after adjustment for measures in the Social Deprivation Index (SDI), the incidence of death, cirrhosis, diabetes mellitus (DM), and major adverse cardiovascular events (MACE) was higher in Native American/Alaska Native patients compared with their non-Hispanic White counterparts. The SDI is a composite measure of seven demographic characteristics from the American Community Survey, with scores ranging from 1 to 100 and weighted based on characteristics from national percentile rankings.

Aligning with the growing prevalence of obesity and DM, MASLD has increased substantially over the past three decades, and is now the leading cause of chronic liver disease in this country and the world. 

This rise in prevalence has underscored health disparities in MASLD and prompted research into linkd between liver disease and SDOH, defined as the conditions under which people are born, grow, live, work, and age. These are fundamental drivers of health disparities, including those in MASLD.
 

Study Details

Primary outcomes were MASLD burden, mortality, and comorbidities by neighborhood SDOH, assessed using the SDI in cross-sectional and longitudinal analyses.

A total of 69,191 adult patients (more than 50% female) diagnosed with MASLD were included, 45,003 of whom had at least 365 days of follow-up. They were treated from July 2012 to June 2023 in Banner Health Systems, a network that includes primary-, secondary-, and tertiary-care centers in Arizona, Colorado, Wyoming, Nevada, Nebraska, and California.

The median follow-up time was 48 months. Among patients across SDI quartiles (age range 49 to 62 years), 1390 patients (3.1%) died, 902 (2.0%) developed cirrhosis, 1087 (2.4%) developed LRE, 6537 (14.5%) developed DM, 2057 (4.6%) developed cancer, and 5409 (12.0%) developed MACE.

Those living in the most disadvantaged quartile of neighborhoods compared with the least had the following higher odds:

• cirrhosis, adjusted odds ratio [aOR], 1.42 (P < .001)
• any cardiovascular (CVD) disease, aOR, 1.20 (P < .001),
• coronary artery disease, aOR, 1.17 (P < .001)
• congestive heart failure, aOR, 1.43 (P < .001)
• cerebrovascular accident, aOR, 1.19 (P = .001)
• DM, aOR, 1.57 (P < .001)
• hypertension, aOR, 1.38 (P < .001).

They also had increased incidence of death (adjusted hazard ratio [aHR], 1.47; P < .001), LRE (aHR, 1.31; P = .012), DM (aHR, 1.47; P < .001), and MACE (aHR, 1.24; P < .001). 

The study expands upon previous SDOH-related research in liver disease and is the largest analysis of neighborhood-level SDOH in patients with MASLD to date. “Our findings are consistent with a recent study by Chen et al of over 15,900 patients with MASLD in Michigan that found neighborhood-level social disadvantage was associated with increased mortality and incident LREs and CVD,” Wijarnpreecha and colleagues wrote. 

“Beyond screening patients for individual-level SDOH, neighborhood-level determinants of health should also be considered, as they are important mediators between the environment and the individual,” they added, calling for studies to better understand the specific neighborhood SDOH that drive the disparate outcomes. In practice, integration of these measures into medical records might inform clinicians which patients would benefit from social services or help guide quality improvement projects and community partnerships.

Wijarnpreecha had no conflicts of interest to disclose. Several coauthors reported research support, consulting/advisory work, or stock ownership for various private-sector companies.
 

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), the leading causes of liver disease, are now emerging as the main risk factors globally for primary liver cancer (PLC). Although the incidence of PLC from most etiologies is declining, MASH and alcohol-related liver disease (ALD) are exceptions.

A recent analysis in Clinical Gastroenterology and Hepatology found a near doubling of cases in from 2000 to 2021 in data from the 2024 Global Burden of Disease study.

The analysis assessed age-standardized incidence, mortality, and disability-adjusted life years (DALYs) from MASH-associated PLC, stratified by geographical region, sociodemographic index, age, and sex.

The burden of MASH-associated primary liver cancer (PLC) is rising rapidly while, thanks to effective suppressive treatments, the incidence of PLC from viral hepatitis is declining.

“Given the shifting epidemiology and limited global data, this analysis was timely to provide updated, comprehensive estimates using the GBD 2021 database,” lead authors Ju Dong Yang, MD, MS, and Karn Wijarnpreecha, MD, MPH, told GI & Hepatology News in a joint email. Yang is an associate professor and medical director of the Liver Cancer Program at Cedars-Sinai Medical Center in Los Angeles, and Wijarnpreecha is a transplant hepatologist in the of Division of Gastroenterology at University of Arizona College of Medicine in Phoenix. “Our study helps identify regions, populations, and sex-specific trends that are most affected and informs global policy response.”

Interestingly,the United States ranks among the top three countries worldwide in terms of MASH-associated PLC burden, with nearly 3,400 newly diagnosed cases reported in 2021 alone. The Americas in general experienced the highest percentage increase in age-standardized incidence rate (APC, 2.09%, 95% CI, 2.02–2.16), age-standardized death rate (APC, 1.96%; 95% CI, 1.69–2.23), and age-standardized DALYs (APC, 1.96%; 95% CI, 1.63–2.30) from MASH-associated PLC.

Globally, there were 42,290 incident cases, 40,920 deaths, and 995,470 DALYs from PLC. Global incidence (+98%), death (+93%), and DALYs (+76%) from MASH-associated PLC increased steeply over the study period.

Among different etiologies, the global study found that only MASH-associated PLC had increased mortality rates, for an annual percent change of +0.46 (95% confidence interval [CI], .33%–.59%). Africa and low-sociodemographic index countries exhibited the highest age-standardized incidence, death, and DALYs from MASH-associated PLC.

MASH promotes PLC through chronic liver inflammation, oxidative stress, lipotoxicity, and fibrosis, which together create a procarcinogenic environment even in the absence of cirrhosis. “This distinct pathway makes MASH-associated PLC harder to detect early, especially when cirrhosis is not yet evident,” Yang and Wijarnpreecha said.

By gender, DALYs increased in females (APC, .24%, 95% CI, .06–.42) but remained stable in males. “Males have higher absolute rates of MASH-associated PLC in terms of incidence and DALYs. However, our study found that the rate of increase in MASH-associated PLC-related disability is steeper in females. This suggests a growing burden among women, possibly related to aging, hormonal changes, and cumulative metabolic risk,” the authors said. In terms of age, “while our study did not assess age at onset, separate analyses have shown that both MASH-associated and alcohol-associated liver cancer are rising among younger individuals.”

Yang and Wijarnpreecha emphasized the need for a multi-pronged remedial strategy, including broad public health policies targeting obesity and metabolic syndrome and better risk stratification tools such as no-invasive biomarkers and genetic profiling. They called for investment in liver cancer surveillance, especially in populations at risk, and special attention to sex disparities and health equity across regions.

“We’re entering a new era of liver cancer epidemiology, where MASLD is taking center stage. Clinicians must recognize that MASH can progress to liver cancer even without cirrhosis,” they said. “Early diagnosis and metabolic intervention may be the best tools to curb this trend, and sex-based approaches to risk stratification and treatment may be essential moving forward.”

Yang’s research is supported by the National Institutes of Health. He consults for AstraZeneca, Eisai, Exact Sciences, and FujiFilm Medical Sciences.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), the leading causes of liver disease, are now emerging as the main risk factors globally for primary liver cancer (PLC). Although the incidence of PLC from most etiologies is declining, MASH and alcohol-related liver disease (ALD) are exceptions.

A recent analysis in Clinical Gastroenterology and Hepatology found a near doubling of cases in from 2000 to 2021 in data from the 2024 Global Burden of Disease study.

The analysis assessed age-standardized incidence, mortality, and disability-adjusted life years (DALYs) from MASH-associated PLC, stratified by geographical region, sociodemographic index, age, and sex.

The burden of MASH-associated primary liver cancer (PLC) is rising rapidly while, thanks to effective suppressive treatments, the incidence of PLC from viral hepatitis is declining.

“Given the shifting epidemiology and limited global data, this analysis was timely to provide updated, comprehensive estimates using the GBD 2021 database,” lead authors Ju Dong Yang, MD, MS, and Karn Wijarnpreecha, MD, MPH, told GI & Hepatology News in a joint email. Yang is an associate professor and medical director of the Liver Cancer Program at Cedars-Sinai Medical Center in Los Angeles, and Wijarnpreecha is a transplant hepatologist in the of Division of Gastroenterology at University of Arizona College of Medicine in Phoenix. “Our study helps identify regions, populations, and sex-specific trends that are most affected and informs global policy response.”

Interestingly,the United States ranks among the top three countries worldwide in terms of MASH-associated PLC burden, with nearly 3,400 newly diagnosed cases reported in 2021 alone. The Americas in general experienced the highest percentage increase in age-standardized incidence rate (APC, 2.09%, 95% CI, 2.02–2.16), age-standardized death rate (APC, 1.96%; 95% CI, 1.69–2.23), and age-standardized DALYs (APC, 1.96%; 95% CI, 1.63–2.30) from MASH-associated PLC.

Globally, there were 42,290 incident cases, 40,920 deaths, and 995,470 DALYs from PLC. Global incidence (+98%), death (+93%), and DALYs (+76%) from MASH-associated PLC increased steeply over the study period.

Among different etiologies, the global study found that only MASH-associated PLC had increased mortality rates, for an annual percent change of +0.46 (95% confidence interval [CI], .33%–.59%). Africa and low-sociodemographic index countries exhibited the highest age-standardized incidence, death, and DALYs from MASH-associated PLC.

MASH promotes PLC through chronic liver inflammation, oxidative stress, lipotoxicity, and fibrosis, which together create a procarcinogenic environment even in the absence of cirrhosis. “This distinct pathway makes MASH-associated PLC harder to detect early, especially when cirrhosis is not yet evident,” Yang and Wijarnpreecha said.

By gender, DALYs increased in females (APC, .24%, 95% CI, .06–.42) but remained stable in males. “Males have higher absolute rates of MASH-associated PLC in terms of incidence and DALYs. However, our study found that the rate of increase in MASH-associated PLC-related disability is steeper in females. This suggests a growing burden among women, possibly related to aging, hormonal changes, and cumulative metabolic risk,” the authors said. In terms of age, “while our study did not assess age at onset, separate analyses have shown that both MASH-associated and alcohol-associated liver cancer are rising among younger individuals.”

Yang and Wijarnpreecha emphasized the need for a multi-pronged remedial strategy, including broad public health policies targeting obesity and metabolic syndrome and better risk stratification tools such as no-invasive biomarkers and genetic profiling. They called for investment in liver cancer surveillance, especially in populations at risk, and special attention to sex disparities and health equity across regions.

“We’re entering a new era of liver cancer epidemiology, where MASLD is taking center stage. Clinicians must recognize that MASH can progress to liver cancer even without cirrhosis,” they said. “Early diagnosis and metabolic intervention may be the best tools to curb this trend, and sex-based approaches to risk stratification and treatment may be essential moving forward.”

Yang’s research is supported by the National Institutes of Health. He consults for AstraZeneca, Eisai, Exact Sciences, and FujiFilm Medical Sciences.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), the leading causes of liver disease, are now emerging as the main risk factors globally for primary liver cancer (PLC). Although the incidence of PLC from most etiologies is declining, MASH and alcohol-related liver disease (ALD) are exceptions.

A recent analysis in Clinical Gastroenterology and Hepatology found a near doubling of cases in from 2000 to 2021 in data from the 2024 Global Burden of Disease study.

The analysis assessed age-standardized incidence, mortality, and disability-adjusted life years (DALYs) from MASH-associated PLC, stratified by geographical region, sociodemographic index, age, and sex.

The burden of MASH-associated primary liver cancer (PLC) is rising rapidly while, thanks to effective suppressive treatments, the incidence of PLC from viral hepatitis is declining.

“Given the shifting epidemiology and limited global data, this analysis was timely to provide updated, comprehensive estimates using the GBD 2021 database,” lead authors Ju Dong Yang, MD, MS, and Karn Wijarnpreecha, MD, MPH, told GI & Hepatology News in a joint email. Yang is an associate professor and medical director of the Liver Cancer Program at Cedars-Sinai Medical Center in Los Angeles, and Wijarnpreecha is a transplant hepatologist in the of Division of Gastroenterology at University of Arizona College of Medicine in Phoenix. “Our study helps identify regions, populations, and sex-specific trends that are most affected and informs global policy response.”

Interestingly,the United States ranks among the top three countries worldwide in terms of MASH-associated PLC burden, with nearly 3,400 newly diagnosed cases reported in 2021 alone. The Americas in general experienced the highest percentage increase in age-standardized incidence rate (APC, 2.09%, 95% CI, 2.02–2.16), age-standardized death rate (APC, 1.96%; 95% CI, 1.69–2.23), and age-standardized DALYs (APC, 1.96%; 95% CI, 1.63–2.30) from MASH-associated PLC.

Globally, there were 42,290 incident cases, 40,920 deaths, and 995,470 DALYs from PLC. Global incidence (+98%), death (+93%), and DALYs (+76%) from MASH-associated PLC increased steeply over the study period.

Among different etiologies, the global study found that only MASH-associated PLC had increased mortality rates, for an annual percent change of +0.46 (95% confidence interval [CI], .33%–.59%). Africa and low-sociodemographic index countries exhibited the highest age-standardized incidence, death, and DALYs from MASH-associated PLC.

MASH promotes PLC through chronic liver inflammation, oxidative stress, lipotoxicity, and fibrosis, which together create a procarcinogenic environment even in the absence of cirrhosis. “This distinct pathway makes MASH-associated PLC harder to detect early, especially when cirrhosis is not yet evident,” Yang and Wijarnpreecha said.

By gender, DALYs increased in females (APC, .24%, 95% CI, .06–.42) but remained stable in males. “Males have higher absolute rates of MASH-associated PLC in terms of incidence and DALYs. However, our study found that the rate of increase in MASH-associated PLC-related disability is steeper in females. This suggests a growing burden among women, possibly related to aging, hormonal changes, and cumulative metabolic risk,” the authors said. In terms of age, “while our study did not assess age at onset, separate analyses have shown that both MASH-associated and alcohol-associated liver cancer are rising among younger individuals.”

Yang and Wijarnpreecha emphasized the need for a multi-pronged remedial strategy, including broad public health policies targeting obesity and metabolic syndrome and better risk stratification tools such as no-invasive biomarkers and genetic profiling. They called for investment in liver cancer surveillance, especially in populations at risk, and special attention to sex disparities and health equity across regions.

“We’re entering a new era of liver cancer epidemiology, where MASLD is taking center stage. Clinicians must recognize that MASH can progress to liver cancer even without cirrhosis,” they said. “Early diagnosis and metabolic intervention may be the best tools to curb this trend, and sex-based approaches to risk stratification and treatment may be essential moving forward.”

Yang’s research is supported by the National Institutes of Health. He consults for AstraZeneca, Eisai, Exact Sciences, and FujiFilm Medical Sciences.

SAN DIEGO — Boston Pharmaceuticals’ once-monthly efimosfermin alfa (formerly BOS-580) prescribed for metabolic dysfunction–associated steatohepatitis (MASH) with F2 and F3 fibrosis significantly improved MASH resolution and fibrosis after 24 weeks, according to results of a phase 2 trial presented at Digestive Disease Week (DDW) 2025.

An analogue of the fibroblast growth factor 21 (FGF21) protein, the agent regulates metabolic processes to reduce liver fat. It has a half-life of about 21 days, said study presenter Margaret J. Koziel, MD, chief medical officer at Boston Pharmaceuticals.

MASH is marked by inflammation and fibrosis and can progress to cirrhosis and liver failure. About 2%-5% of US adults have MASH, according to the American College of Gastroenterology. Up to 20% of adults who are obese may have the condition.

The researchers randomly assigned 84 participants with biopsy-confirmed F2/F3 MASH to receive once-monthly injections of 300 mg efimosfermin alpha (43 patients) or placebo (41 patients) for 24 weeks.

The mean body mass index (BMI) of participants in both groups was about 37. Most study sites were in the southern United States, so that BMI “reflects the demographics,” Koziel said. Mean age was 55 years in the placebo group and 53 years in the treatment group, and about half of patients in both groups were women. Eighteen patients in each group had a fibrosis stage of F3.

Primary endpoints were safety and tolerability.

Exploratory objectives included the proportion of patients achieving fibrosis improvement of one or more stages without MASH worsening, MASH resolution without worsening of fibrosis, or both fibrosis improvement and MASH resolution.

Sixty-seven patients completed the treatment, and 65 post-baseline biopsies were collected — 34 in the placebo group and 31 in the treatment group.

 

Positive Results

“We saw statistically significant changes in fibrosis improvement,” Koziel said. “This has been the hardest barrier to hit.”

After 24 weeks, 45% of patients in the treatment group and 21% in the placebo group showed fibrosis improvement of one or more stages without worsening of MASH (P = .038), and 68% of those in the treatment group and 29% in the placebo group had MASH resolution without fibrosis worsening (P = .002).

The between-group difference in fibrosis improvement and MASH resolution did not reach statistical significance, with 39% of patients in the treatment group and 18% in the placebo group achieving the combined endpoint (P = .066). “It just missed statistical significance,” Koziel said, but she viewed the outcome as meaningful.

Additionally, “a third of the group taking efimosfermin normalized their liver fat, and all but one normalized their liver enzymes,” she said.

Adverse events — most often nausea, vomiting and diarrhea — were mild to moderate in both groups, Koziel said. In the treatment group, one patient withdrew from the study due to a grade 3 serious adverse event, and two others did so due to low-grade adverse events.

“These data support further development of once-monthly efimosfermin for the treatment of MASH-related fibrosis,” the research team concluded.

 

Hopeful Development

“Finally, there’s hope,” said DDW attendee Na Li, MD, associate clinical professor of internal medicine at Ohio State University Wexner Medical Center, Columbus, Ohio, whose clinical focus is on metabolic-associated steatotic liver disease.

The new hope, she said, refers not only to the phase 2 study results but to the Food and Drug Administration approval of resmetirom (Rezdiffra) last year, which reduces liver fat by stimulating thyroid hormone receptor beta. “That was the first medication that got approved with a specific indication to treat MASH,” she said. Before that, lifestyle measures aimed at weight loss were the only approach.

Lifestyle measures are still important, Li said, but it’s helpful to have additional options. “There are quite a few agents in the pipeline now,” she said. One example is another FGF21 analogue efruxifermin, which is in phase 3 trials.

Li had no disclosures. Koziel declared being an employee of Boston Pharmaceuticals.

A version of this article appeared on Medscape.com.

SAN DIEGO — Boston Pharmaceuticals’ once-monthly efimosfermin alfa (formerly BOS-580) prescribed for metabolic dysfunction–associated steatohepatitis (MASH) with F2 and F3 fibrosis significantly improved MASH resolution and fibrosis after 24 weeks, according to results of a phase 2 trial presented at Digestive Disease Week (DDW) 2025.

An analogue of the fibroblast growth factor 21 (FGF21) protein, the agent regulates metabolic processes to reduce liver fat. It has a half-life of about 21 days, said study presenter Margaret J. Koziel, MD, chief medical officer at Boston Pharmaceuticals.

MASH is marked by inflammation and fibrosis and can progress to cirrhosis and liver failure. About 2%-5% of US adults have MASH, according to the American College of Gastroenterology. Up to 20% of adults who are obese may have the condition.

The researchers randomly assigned 84 participants with biopsy-confirmed F2/F3 MASH to receive once-monthly injections of 300 mg efimosfermin alpha (43 patients) or placebo (41 patients) for 24 weeks.

The mean body mass index (BMI) of participants in both groups was about 37. Most study sites were in the southern United States, so that BMI “reflects the demographics,” Koziel said. Mean age was 55 years in the placebo group and 53 years in the treatment group, and about half of patients in both groups were women. Eighteen patients in each group had a fibrosis stage of F3.

Primary endpoints were safety and tolerability.

Exploratory objectives included the proportion of patients achieving fibrosis improvement of one or more stages without MASH worsening, MASH resolution without worsening of fibrosis, or both fibrosis improvement and MASH resolution.

Sixty-seven patients completed the treatment, and 65 post-baseline biopsies were collected — 34 in the placebo group and 31 in the treatment group.

 

Positive Results

“We saw statistically significant changes in fibrosis improvement,” Koziel said. “This has been the hardest barrier to hit.”

After 24 weeks, 45% of patients in the treatment group and 21% in the placebo group showed fibrosis improvement of one or more stages without worsening of MASH (P = .038), and 68% of those in the treatment group and 29% in the placebo group had MASH resolution without fibrosis worsening (P = .002).

The between-group difference in fibrosis improvement and MASH resolution did not reach statistical significance, with 39% of patients in the treatment group and 18% in the placebo group achieving the combined endpoint (P = .066). “It just missed statistical significance,” Koziel said, but she viewed the outcome as meaningful.

Additionally, “a third of the group taking efimosfermin normalized their liver fat, and all but one normalized their liver enzymes,” she said.

Adverse events — most often nausea, vomiting and diarrhea — were mild to moderate in both groups, Koziel said. In the treatment group, one patient withdrew from the study due to a grade 3 serious adverse event, and two others did so due to low-grade adverse events.

“These data support further development of once-monthly efimosfermin for the treatment of MASH-related fibrosis,” the research team concluded.

 

Hopeful Development

“Finally, there’s hope,” said DDW attendee Na Li, MD, associate clinical professor of internal medicine at Ohio State University Wexner Medical Center, Columbus, Ohio, whose clinical focus is on metabolic-associated steatotic liver disease.

The new hope, she said, refers not only to the phase 2 study results but to the Food and Drug Administration approval of resmetirom (Rezdiffra) last year, which reduces liver fat by stimulating thyroid hormone receptor beta. “That was the first medication that got approved with a specific indication to treat MASH,” she said. Before that, lifestyle measures aimed at weight loss were the only approach.

Lifestyle measures are still important, Li said, but it’s helpful to have additional options. “There are quite a few agents in the pipeline now,” she said. One example is another FGF21 analogue efruxifermin, which is in phase 3 trials.

Li had no disclosures. Koziel declared being an employee of Boston Pharmaceuticals.

A version of this article appeared on Medscape.com.

SAN DIEGO — Boston Pharmaceuticals’ once-monthly efimosfermin alfa (formerly BOS-580) prescribed for metabolic dysfunction–associated steatohepatitis (MASH) with F2 and F3 fibrosis significantly improved MASH resolution and fibrosis after 24 weeks, according to results of a phase 2 trial presented at Digestive Disease Week (DDW) 2025.

An analogue of the fibroblast growth factor 21 (FGF21) protein, the agent regulates metabolic processes to reduce liver fat. It has a half-life of about 21 days, said study presenter Margaret J. Koziel, MD, chief medical officer at Boston Pharmaceuticals.

MASH is marked by inflammation and fibrosis and can progress to cirrhosis and liver failure. About 2%-5% of US adults have MASH, according to the American College of Gastroenterology. Up to 20% of adults who are obese may have the condition.

The researchers randomly assigned 84 participants with biopsy-confirmed F2/F3 MASH to receive once-monthly injections of 300 mg efimosfermin alpha (43 patients) or placebo (41 patients) for 24 weeks.

The mean body mass index (BMI) of participants in both groups was about 37. Most study sites were in the southern United States, so that BMI “reflects the demographics,” Koziel said. Mean age was 55 years in the placebo group and 53 years in the treatment group, and about half of patients in both groups were women. Eighteen patients in each group had a fibrosis stage of F3.

Primary endpoints were safety and tolerability.

Exploratory objectives included the proportion of patients achieving fibrosis improvement of one or more stages without MASH worsening, MASH resolution without worsening of fibrosis, or both fibrosis improvement and MASH resolution.

Sixty-seven patients completed the treatment, and 65 post-baseline biopsies were collected — 34 in the placebo group and 31 in the treatment group.

 

Positive Results

“We saw statistically significant changes in fibrosis improvement,” Koziel said. “This has been the hardest barrier to hit.”

After 24 weeks, 45% of patients in the treatment group and 21% in the placebo group showed fibrosis improvement of one or more stages without worsening of MASH (P = .038), and 68% of those in the treatment group and 29% in the placebo group had MASH resolution without fibrosis worsening (P = .002).

The between-group difference in fibrosis improvement and MASH resolution did not reach statistical significance, with 39% of patients in the treatment group and 18% in the placebo group achieving the combined endpoint (P = .066). “It just missed statistical significance,” Koziel said, but she viewed the outcome as meaningful.

Additionally, “a third of the group taking efimosfermin normalized their liver fat, and all but one normalized their liver enzymes,” she said.

Adverse events — most often nausea, vomiting and diarrhea — were mild to moderate in both groups, Koziel said. In the treatment group, one patient withdrew from the study due to a grade 3 serious adverse event, and two others did so due to low-grade adverse events.

“These data support further development of once-monthly efimosfermin for the treatment of MASH-related fibrosis,” the research team concluded.

 

Hopeful Development

“Finally, there’s hope,” said DDW attendee Na Li, MD, associate clinical professor of internal medicine at Ohio State University Wexner Medical Center, Columbus, Ohio, whose clinical focus is on metabolic-associated steatotic liver disease.

The new hope, she said, refers not only to the phase 2 study results but to the Food and Drug Administration approval of resmetirom (Rezdiffra) last year, which reduces liver fat by stimulating thyroid hormone receptor beta. “That was the first medication that got approved with a specific indication to treat MASH,” she said. Before that, lifestyle measures aimed at weight loss were the only approach.

Lifestyle measures are still important, Li said, but it’s helpful to have additional options. “There are quite a few agents in the pipeline now,” she said. One example is another FGF21 analogue efruxifermin, which is in phase 3 trials.

Li had no disclosures. Koziel declared being an employee of Boston Pharmaceuticals.

A version of this article appeared on Medscape.com.

Adult patients with metabolic dysfunction–associated steatohepatitis (MASH) and moderate or advanced liver fibrosis showed improved liver histology with a once-weekly dose of semaglutide (Wegovy), an ongoing randomized placebo-controlled trial reported.

The glucagon-like peptide 1 receptor agonist (GLP-1 RA) is currently a candidate for treating MASH.

Preliminary results of the two-part phase 3, double-blind ESSENCE trial, conducted in at 253 clinical sites in 37 countries, were published in The New England Journal of Medicine.

 

A previous phase 2 study by Loomba et al suggested semaglutide was effective in reducing liver injury. “That study, however, did not show improvement in liver fibrosis, which this study has done,” study co-lead Philip Newsome, PhD, professor in the department of immunology and immunotherapy and Honorary Professor of Experimental Hepatology at the University of Birmingham in England, said in an interview.

“The results aligned with expectations in that the impact on liver fibrosis was anticipated — but with some uncertainty, so this study is important in that regard.” 

 

Study Details

From May 2020 to April 2023, researchers led by Newsome and Arun J. Sanyal, MBBS, MD, of Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University School of Medicine, Richmond, randomized 1197 patients with a mean age of 56 years. Of these, 57% were women and 67.5% were White individuals. Mean body mass index was 34.6, and 55.9% had type 2 diabetes.

All had biopsy-defined MASH and fibrosis stage 2 or 3 according to the Nonalcoholic Steatohepatitis Clinical Research Network classification and a Nonalcoholic Fatty Liver Disease Activity Score ≥ 4.

Rates of fibrosis were 31.3% for stage 2 fibrosis and 68.8% for stage 3. Diverse geographic site locations included Asia (25.1%), Europe (25.3%), North America (35.0%), and South America (7.9%), and others (6.8%).

In a 2:1 ratio, they were assigned to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. A planned interim analysis of the first 800 patients was done at week 72, with primary endpoints being resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis.

Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% CI, 21.1-36.2, P < .001).

A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of semaglutide recipients and 22.4% of placebo recipients (estimated difference, 14.4 percentage points; 95% CI, 7.5-21.3, P < .001). 

In secondary findings, the combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% in the semaglutide group vs 16.1% in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2-22.8; P < .001). 

The mean change in body weight was –10.5% with semaglutide and –2.0% with placebo (estimated difference, –8.5 percentage points; 95% CI, –9.6 to –7.4, P < .001). Mean changes in bodily pain scores did not differ significantly between arms. 

The histologic benefits of semaglutide also emerged in improvements on all prespecified noninvasive tests — including aspartate transaminase and alanine transaminase levels and liver stiffness. Emerging evidence has suggested an association between reductions in liver stiffness and clinical benefit. 

Gastrointestinal adverse events were more common in the semaglutide group.

 

Commenting on the study from a nonparticipant’s perspective, Naga P. Chalasani, MD, AGAF, professor of gastroenterology and hepatology at Indiana University School of Medicine, Indianapolis, said results from the ESSENCE trial were “long awaited and they certainly advance the field of MASH clinical trials substantially.”

Furthermore, he added, the results are well aligned with those of a phase 2b trial of semaglutide by Newsome and colleagues for what was then termed nonalcoholic steatohepatitis, and “they also align with what is known about the positive role of incretins, digestive hormones imitated by GLP-1s to improve liver health in patients with MASLD and MASH.” 

“The results from this study certainly make a case for semaglutide to be the backbone therapy for diabetic or obese patients with MASH and fibrosis,” Chalasani said. “More than 80% of patients with MASH and fibrosis have either diabetes and/or obesity.” 

He added that a better understanding is needed of how semaglutide works in patients with MASH cirrhosis since the previous small study was unsuccessful. “But this may need to be repeated as the published study was underpowered. Outcomes in the ESSENCE trial will help to clarify whether semaglutide will improve clinical outcomes beyond improving liver histology.”

According to Newsome, GLP-1s will become the backbone of therapy in MASH given their range of metabolic and liver benefit. But questions remain, he said. “Will there be further improvements with longer treatment with semaglutide? What noninvasive tests should we use to determine treatment success? Which patients will benefit from combination treatment?”

This study was supported by Novo Nordisk, the manufacturer of Wegovy. Sanyal reported having various financial relationships with multiple private-sector companies, including Novo Nordisk. Newsome reported consulting for Novo Nordisk and Boehringer Ingelheim. Several study coauthors reported having similar relationships with pharmaceutical companies or employment with Novo Nordisk. Chalasani declared being involved in several MASH clinical trials conducted by other pharmaceutical companies.

A version of this article appeared on Medscape.com.

Adult patients with metabolic dysfunction–associated steatohepatitis (MASH) and moderate or advanced liver fibrosis showed improved liver histology with a once-weekly dose of semaglutide (Wegovy), an ongoing randomized placebo-controlled trial reported.

The glucagon-like peptide 1 receptor agonist (GLP-1 RA) is currently a candidate for treating MASH.

Preliminary results of the two-part phase 3, double-blind ESSENCE trial, conducted in at 253 clinical sites in 37 countries, were published in The New England Journal of Medicine.

 

A previous phase 2 study by Loomba et al suggested semaglutide was effective in reducing liver injury. “That study, however, did not show improvement in liver fibrosis, which this study has done,” study co-lead Philip Newsome, PhD, professor in the department of immunology and immunotherapy and Honorary Professor of Experimental Hepatology at the University of Birmingham in England, said in an interview.

“The results aligned with expectations in that the impact on liver fibrosis was anticipated — but with some uncertainty, so this study is important in that regard.” 

 

Study Details

From May 2020 to April 2023, researchers led by Newsome and Arun J. Sanyal, MBBS, MD, of Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University School of Medicine, Richmond, randomized 1197 patients with a mean age of 56 years. Of these, 57% were women and 67.5% were White individuals. Mean body mass index was 34.6, and 55.9% had type 2 diabetes.

All had biopsy-defined MASH and fibrosis stage 2 or 3 according to the Nonalcoholic Steatohepatitis Clinical Research Network classification and a Nonalcoholic Fatty Liver Disease Activity Score ≥ 4.

Rates of fibrosis were 31.3% for stage 2 fibrosis and 68.8% for stage 3. Diverse geographic site locations included Asia (25.1%), Europe (25.3%), North America (35.0%), and South America (7.9%), and others (6.8%).

In a 2:1 ratio, they were assigned to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. A planned interim analysis of the first 800 patients was done at week 72, with primary endpoints being resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis.

Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% CI, 21.1-36.2, P < .001).

A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of semaglutide recipients and 22.4% of placebo recipients (estimated difference, 14.4 percentage points; 95% CI, 7.5-21.3, P < .001). 

In secondary findings, the combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% in the semaglutide group vs 16.1% in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2-22.8; P < .001). 

The mean change in body weight was –10.5% with semaglutide and –2.0% with placebo (estimated difference, –8.5 percentage points; 95% CI, –9.6 to –7.4, P < .001). Mean changes in bodily pain scores did not differ significantly between arms. 

The histologic benefits of semaglutide also emerged in improvements on all prespecified noninvasive tests — including aspartate transaminase and alanine transaminase levels and liver stiffness. Emerging evidence has suggested an association between reductions in liver stiffness and clinical benefit. 

Gastrointestinal adverse events were more common in the semaglutide group.

 

Commenting on the study from a nonparticipant’s perspective, Naga P. Chalasani, MD, AGAF, professor of gastroenterology and hepatology at Indiana University School of Medicine, Indianapolis, said results from the ESSENCE trial were “long awaited and they certainly advance the field of MASH clinical trials substantially.”

Furthermore, he added, the results are well aligned with those of a phase 2b trial of semaglutide by Newsome and colleagues for what was then termed nonalcoholic steatohepatitis, and “they also align with what is known about the positive role of incretins, digestive hormones imitated by GLP-1s to improve liver health in patients with MASLD and MASH.” 

“The results from this study certainly make a case for semaglutide to be the backbone therapy for diabetic or obese patients with MASH and fibrosis,” Chalasani said. “More than 80% of patients with MASH and fibrosis have either diabetes and/or obesity.” 

He added that a better understanding is needed of how semaglutide works in patients with MASH cirrhosis since the previous small study was unsuccessful. “But this may need to be repeated as the published study was underpowered. Outcomes in the ESSENCE trial will help to clarify whether semaglutide will improve clinical outcomes beyond improving liver histology.”

According to Newsome, GLP-1s will become the backbone of therapy in MASH given their range of metabolic and liver benefit. But questions remain, he said. “Will there be further improvements with longer treatment with semaglutide? What noninvasive tests should we use to determine treatment success? Which patients will benefit from combination treatment?”

This study was supported by Novo Nordisk, the manufacturer of Wegovy. Sanyal reported having various financial relationships with multiple private-sector companies, including Novo Nordisk. Newsome reported consulting for Novo Nordisk and Boehringer Ingelheim. Several study coauthors reported having similar relationships with pharmaceutical companies or employment with Novo Nordisk. Chalasani declared being involved in several MASH clinical trials conducted by other pharmaceutical companies.

A version of this article appeared on Medscape.com.

Adult patients with metabolic dysfunction–associated steatohepatitis (MASH) and moderate or advanced liver fibrosis showed improved liver histology with a once-weekly dose of semaglutide (Wegovy), an ongoing randomized placebo-controlled trial reported.

The glucagon-like peptide 1 receptor agonist (GLP-1 RA) is currently a candidate for treating MASH.

Preliminary results of the two-part phase 3, double-blind ESSENCE trial, conducted in at 253 clinical sites in 37 countries, were published in The New England Journal of Medicine.

 

A previous phase 2 study by Loomba et al suggested semaglutide was effective in reducing liver injury. “That study, however, did not show improvement in liver fibrosis, which this study has done,” study co-lead Philip Newsome, PhD, professor in the department of immunology and immunotherapy and Honorary Professor of Experimental Hepatology at the University of Birmingham in England, said in an interview.

“The results aligned with expectations in that the impact on liver fibrosis was anticipated — but with some uncertainty, so this study is important in that regard.” 

 

Study Details

From May 2020 to April 2023, researchers led by Newsome and Arun J. Sanyal, MBBS, MD, of Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University School of Medicine, Richmond, randomized 1197 patients with a mean age of 56 years. Of these, 57% were women and 67.5% were White individuals. Mean body mass index was 34.6, and 55.9% had type 2 diabetes.

All had biopsy-defined MASH and fibrosis stage 2 or 3 according to the Nonalcoholic Steatohepatitis Clinical Research Network classification and a Nonalcoholic Fatty Liver Disease Activity Score ≥ 4.

Rates of fibrosis were 31.3% for stage 2 fibrosis and 68.8% for stage 3. Diverse geographic site locations included Asia (25.1%), Europe (25.3%), North America (35.0%), and South America (7.9%), and others (6.8%).

In a 2:1 ratio, they were assigned to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. A planned interim analysis of the first 800 patients was done at week 72, with primary endpoints being resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis.

Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% CI, 21.1-36.2, P < .001).

A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of semaglutide recipients and 22.4% of placebo recipients (estimated difference, 14.4 percentage points; 95% CI, 7.5-21.3, P < .001). 

In secondary findings, the combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% in the semaglutide group vs 16.1% in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2-22.8; P < .001). 

The mean change in body weight was –10.5% with semaglutide and –2.0% with placebo (estimated difference, –8.5 percentage points; 95% CI, –9.6 to –7.4, P < .001). Mean changes in bodily pain scores did not differ significantly between arms. 

The histologic benefits of semaglutide also emerged in improvements on all prespecified noninvasive tests — including aspartate transaminase and alanine transaminase levels and liver stiffness. Emerging evidence has suggested an association between reductions in liver stiffness and clinical benefit. 

Gastrointestinal adverse events were more common in the semaglutide group.

 

Commenting on the study from a nonparticipant’s perspective, Naga P. Chalasani, MD, AGAF, professor of gastroenterology and hepatology at Indiana University School of Medicine, Indianapolis, said results from the ESSENCE trial were “long awaited and they certainly advance the field of MASH clinical trials substantially.”

Furthermore, he added, the results are well aligned with those of a phase 2b trial of semaglutide by Newsome and colleagues for what was then termed nonalcoholic steatohepatitis, and “they also align with what is known about the positive role of incretins, digestive hormones imitated by GLP-1s to improve liver health in patients with MASLD and MASH.” 

“The results from this study certainly make a case for semaglutide to be the backbone therapy for diabetic or obese patients with MASH and fibrosis,” Chalasani said. “More than 80% of patients with MASH and fibrosis have either diabetes and/or obesity.” 

He added that a better understanding is needed of how semaglutide works in patients with MASH cirrhosis since the previous small study was unsuccessful. “But this may need to be repeated as the published study was underpowered. Outcomes in the ESSENCE trial will help to clarify whether semaglutide will improve clinical outcomes beyond improving liver histology.”

According to Newsome, GLP-1s will become the backbone of therapy in MASH given their range of metabolic and liver benefit. But questions remain, he said. “Will there be further improvements with longer treatment with semaglutide? What noninvasive tests should we use to determine treatment success? Which patients will benefit from combination treatment?”

This study was supported by Novo Nordisk, the manufacturer of Wegovy. Sanyal reported having various financial relationships with multiple private-sector companies, including Novo Nordisk. Newsome reported consulting for Novo Nordisk and Boehringer Ingelheim. Several study coauthors reported having similar relationships with pharmaceutical companies or employment with Novo Nordisk. Chalasani declared being involved in several MASH clinical trials conducted by other pharmaceutical companies.

A version of this article appeared on Medscape.com.

An experimental study in zebrafish has suggested the decades-old, first-generation antihistamine chlorcyclizine and/or other antihistamines may be a strategy for treating erythropoietic protoporphyria (EPP)-associated liver disease by decreasing hepatic protoporphorin IX (PP-IX) accumulation.

Currently, liver transplantation is the primary treatment for this rare, painful, and life-threatening genetic disease, which is caused by excessive PP-IX accumulation and affects about 4000 people in the United States.

The findings could eventually lead to a simpler treatment that prevent shepatic damage at a much earlier stage, according to researchers led by M. Bishr Omary, MD, PhD, a professor in the Center for Advanced Biotechnology and Medicine and Robert Wood Johnson Medical School at Rutgers University in Piscataway, New Jersey.

Reporting in Cellular and Molecular Gastroenterology and Hepatology, the investigators found that chlorcyclizine reduced PP-IX levels. EPP is caused by mutations leading to deficiency of the enzyme ferrochelatase, which inserts iron into PP-IX to generate heme. The resulting condition is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. “Despite available drugs that address photosensitivity, the treatment of EPP-related liver disease remains an unmet need,” Omary and colleagues wrote.

 

The Study

In order to trigger PP-IX overproduction and accumulation, the investigators administered delta-aminolevulinic acid and deferoxamine to zebrafish. These freshwater tropical fish share many physiological characteristics with humans and have been used to model human disease and develop drugs. Furthermore, these fish are transparent at the larval stage, allowing quantification and visualization of porphyrin, which is fluorescent.

The researchers had screened some 2500 approved and bioactive compounds and identified chlorcyclizine as a potent PP-IX–lowering agent.

High-throughput compound screening of ALA + DFO-treated zebrafish found that the HH-1 blocker reduced zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes, transgenic mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine. 

Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and quantitative polymerase chain reaction.

Chlorcyclizine-treated zebrafish larvae as well as the two types of mice all showed reduced hepatic PP-IX levels compared with controls. While the neurotransmitter played an important role in PP-IX accumulation in porphyrin-stressed hepatocytes, blockading notably decreased PP-IX levels. 

Detailed analysis showed that chlorcyclizine appeared to work through multiple mechanisms, helping the liver clear toxic porphyrin buildup and reducing inflammation. It also decreased the presence of histamine-producing mast cells. The result was less liver injury, decreased porphyrin-triggered protein aggregation and oxidation, and increased clearance of s PP-I in stool.

Interestingly, in both mouse models, chlorcyclizine lowered PP-IX levels in female but not male mice in liver, erythrocytes, and bone marrow. This sex-specific effect appeared to be related to the greater speed at which male murines metabolize the drug, the authors explained in a news release. In rats, for example, the metabolism of chlorcyclizine is 8 times higher in male than in female livers. 

The investigators plan to launch a clinical trial in EPP patients to evaluate the effectiveness of chlorcyclizine for both liver and skin involvement. And a phase 2 trial is already underway testing the antacid cimetidine for treating EPP skin manifestations. It is possible that the different antihistamines may act additively or synergistically.

This work was supported by National Institutes of Health (NIH) grants and the Henry and Mala Dorfman Family Professorship of Pediatric Hematology/Oncology.

Omary is a member of the NIH/National Institute of Diabetes and Digestive and Kidney Diseases Data and Safety Monitoring Board of the Porphyrias Consortium.

A provisional patent application has been submitted for the use of H1-receptor blockers with or without receptor blockers to treat protoporphyrias associated with PP-IX accumulation.
 

An experimental study in zebrafish has suggested the decades-old, first-generation antihistamine chlorcyclizine and/or other antihistamines may be a strategy for treating erythropoietic protoporphyria (EPP)-associated liver disease by decreasing hepatic protoporphorin IX (PP-IX) accumulation.

Currently, liver transplantation is the primary treatment for this rare, painful, and life-threatening genetic disease, which is caused by excessive PP-IX accumulation and affects about 4000 people in the United States.

The findings could eventually lead to a simpler treatment that prevent shepatic damage at a much earlier stage, according to researchers led by M. Bishr Omary, MD, PhD, a professor in the Center for Advanced Biotechnology and Medicine and Robert Wood Johnson Medical School at Rutgers University in Piscataway, New Jersey.

Reporting in Cellular and Molecular Gastroenterology and Hepatology, the investigators found that chlorcyclizine reduced PP-IX levels. EPP is caused by mutations leading to deficiency of the enzyme ferrochelatase, which inserts iron into PP-IX to generate heme. The resulting condition is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. “Despite available drugs that address photosensitivity, the treatment of EPP-related liver disease remains an unmet need,” Omary and colleagues wrote.

 

The Study

In order to trigger PP-IX overproduction and accumulation, the investigators administered delta-aminolevulinic acid and deferoxamine to zebrafish. These freshwater tropical fish share many physiological characteristics with humans and have been used to model human disease and develop drugs. Furthermore, these fish are transparent at the larval stage, allowing quantification and visualization of porphyrin, which is fluorescent.

The researchers had screened some 2500 approved and bioactive compounds and identified chlorcyclizine as a potent PP-IX–lowering agent.

High-throughput compound screening of ALA + DFO-treated zebrafish found that the HH-1 blocker reduced zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes, transgenic mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine. 

Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and quantitative polymerase chain reaction.

Chlorcyclizine-treated zebrafish larvae as well as the two types of mice all showed reduced hepatic PP-IX levels compared with controls. While the neurotransmitter played an important role in PP-IX accumulation in porphyrin-stressed hepatocytes, blockading notably decreased PP-IX levels. 

Detailed analysis showed that chlorcyclizine appeared to work through multiple mechanisms, helping the liver clear toxic porphyrin buildup and reducing inflammation. It also decreased the presence of histamine-producing mast cells. The result was less liver injury, decreased porphyrin-triggered protein aggregation and oxidation, and increased clearance of s PP-I in stool.

Interestingly, in both mouse models, chlorcyclizine lowered PP-IX levels in female but not male mice in liver, erythrocytes, and bone marrow. This sex-specific effect appeared to be related to the greater speed at which male murines metabolize the drug, the authors explained in a news release. In rats, for example, the metabolism of chlorcyclizine is 8 times higher in male than in female livers. 

The investigators plan to launch a clinical trial in EPP patients to evaluate the effectiveness of chlorcyclizine for both liver and skin involvement. And a phase 2 trial is already underway testing the antacid cimetidine for treating EPP skin manifestations. It is possible that the different antihistamines may act additively or synergistically.

This work was supported by National Institutes of Health (NIH) grants and the Henry and Mala Dorfman Family Professorship of Pediatric Hematology/Oncology.

Omary is a member of the NIH/National Institute of Diabetes and Digestive and Kidney Diseases Data and Safety Monitoring Board of the Porphyrias Consortium.

A provisional patent application has been submitted for the use of H1-receptor blockers with or without receptor blockers to treat protoporphyrias associated with PP-IX accumulation.
 

An experimental study in zebrafish has suggested the decades-old, first-generation antihistamine chlorcyclizine and/or other antihistamines may be a strategy for treating erythropoietic protoporphyria (EPP)-associated liver disease by decreasing hepatic protoporphorin IX (PP-IX) accumulation.

Currently, liver transplantation is the primary treatment for this rare, painful, and life-threatening genetic disease, which is caused by excessive PP-IX accumulation and affects about 4000 people in the United States.

The findings could eventually lead to a simpler treatment that prevent shepatic damage at a much earlier stage, according to researchers led by M. Bishr Omary, MD, PhD, a professor in the Center for Advanced Biotechnology and Medicine and Robert Wood Johnson Medical School at Rutgers University in Piscataway, New Jersey.

Reporting in Cellular and Molecular Gastroenterology and Hepatology, the investigators found that chlorcyclizine reduced PP-IX levels. EPP is caused by mutations leading to deficiency of the enzyme ferrochelatase, which inserts iron into PP-IX to generate heme. The resulting condition is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. “Despite available drugs that address photosensitivity, the treatment of EPP-related liver disease remains an unmet need,” Omary and colleagues wrote.

 

The Study

In order to trigger PP-IX overproduction and accumulation, the investigators administered delta-aminolevulinic acid and deferoxamine to zebrafish. These freshwater tropical fish share many physiological characteristics with humans and have been used to model human disease and develop drugs. Furthermore, these fish are transparent at the larval stage, allowing quantification and visualization of porphyrin, which is fluorescent.

The researchers had screened some 2500 approved and bioactive compounds and identified chlorcyclizine as a potent PP-IX–lowering agent.

High-throughput compound screening of ALA + DFO-treated zebrafish found that the HH-1 blocker reduced zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes, transgenic mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine. 

Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and quantitative polymerase chain reaction.

Chlorcyclizine-treated zebrafish larvae as well as the two types of mice all showed reduced hepatic PP-IX levels compared with controls. While the neurotransmitter played an important role in PP-IX accumulation in porphyrin-stressed hepatocytes, blockading notably decreased PP-IX levels. 

Detailed analysis showed that chlorcyclizine appeared to work through multiple mechanisms, helping the liver clear toxic porphyrin buildup and reducing inflammation. It also decreased the presence of histamine-producing mast cells. The result was less liver injury, decreased porphyrin-triggered protein aggregation and oxidation, and increased clearance of s PP-I in stool.

Interestingly, in both mouse models, chlorcyclizine lowered PP-IX levels in female but not male mice in liver, erythrocytes, and bone marrow. This sex-specific effect appeared to be related to the greater speed at which male murines metabolize the drug, the authors explained in a news release. In rats, for example, the metabolism of chlorcyclizine is 8 times higher in male than in female livers. 

The investigators plan to launch a clinical trial in EPP patients to evaluate the effectiveness of chlorcyclizine for both liver and skin involvement. And a phase 2 trial is already underway testing the antacid cimetidine for treating EPP skin manifestations. It is possible that the different antihistamines may act additively or synergistically.

This work was supported by National Institutes of Health (NIH) grants and the Henry and Mala Dorfman Family Professorship of Pediatric Hematology/Oncology.

Omary is a member of the NIH/National Institute of Diabetes and Digestive and Kidney Diseases Data and Safety Monitoring Board of the Porphyrias Consortium.

A provisional patent application has been submitted for the use of H1-receptor blockers with or without receptor blockers to treat protoporphyrias associated with PP-IX accumulation.